Continuum Behavioral Neurology Volume 16 Number 4 August 201

L I F E L O N G L E A R N I N G I N N E U R O L O G Y®
BEHAVIORAL NEUROLOGY
Volume 16 Number 4 August 2010
Authors
MURRAY GROSSMAN, MD, FAAN, Guest Editor

Professor of Neurology and Psychiatry, University of Pennsylvania,
Philadelphia, Pennsylvania
*Dr Grossman has received personal compensation for consulting from Allon
Therapeutics Inc., Forest Laboratories, Inc., and Pfizer Inc, and for serving as editor
of Cognitive and Behavioral Neurology. Dr Grossman’s compensation and/or research
work has been funded entirely or in part by a grant to his university from a
governmental organization.
†Dr Grossman has nothing to disclose.
JASON J. S. BARTON, MD, PhD, FRCPC

Professor and Canada Research Chair, University of British Columbia, Vancouver, British
Columbia, Canada
*†Dr Barton has nothing to disclose.
ANDREW E. BUDSON, MD
Deputy Chief of Staff and Neurologist, Geriatric Research Education Clinical Center,
Boston VA Healthcare System, Boston, Massachusetts; Associate Director for Research,
Boston University Alzheimer’s Disease Center, Boston, Massachusetts; Professor of
Neurology, Boston University School of Medicine, Boston, Massachusetts
*Dr Budson has received personal compensation for speaking engagements from Eisai
Inc., Forest Laboratories, Inc., Johnson & Johnson Services, Inc., and Pfizer Inc.
Dr Budson’s compensation and/or research work has been funded entirely or in part
by a grant from a governmental organization to his university.
†Dr Budson has nothing to disclose.
ANJAN CHATTERJEE, MD, FAAN

Professor of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania
*Dr Chatterjee has received personal compensation for editorial work from Journal of
Cognitive Neuroscience.
†Dr Chatterjee discusses the experimental use of dopamine agonists for neglect.
*Relationship Disclosure
†Unlabeled Use of Products/Investigational Use Disclosure
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

H. BRANCH COSLETT, MD, FAAN
Professor of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania
*†Dr Coslett has nothing to disclose.
THOMAS J. GRABOWSKI, MD, FAAN

Professor of Radiology and Neurology; Director, Integrated Brain Imaging Center;
University of Washington, Seattle, Washington
*†Dr Grabowski has nothing to disclose.
RACHEL G. GROSS, MD
Fellow, Cognitive Neurology and Movement Disorders, University of Pennsylvania
School of Medicine, Philadelphia, Pennsylvania
*†Dr Gross has nothing to disclose.
KENNETH M. HEILMAN, MD, FAAN

The James E. Rooks Jr. Distinguished Professor of Neurology, College of Medicine,
University of Florida, Gainesville, Florida
*Dr Heilman has received personal compensation for review activities from
Journal Watch. Dr Heilman’s compensation and/or research work has been funded
entirely or in part by grants to his university from a governmental organization,
a nonprofit tax-exempt organization, Myriad Pharmaceuticals, Inc., Novartis
Pharmaceuticals Corporation, Esai Pharmaceuticals, and the Alzheimer’s Association.
†Dr Heilman has nothing to disclose.
ARGYE E. HILLIS, MD
Professor, Deputy Director of Neurology, Director, Neurology Residency Program,
Johns Hopkins University School of Medicine, Baltimore, Maryland
*Dr Hillis has received personal compensation for serving as the editor of Behavioural
Neurology. Dr Hillis’ personal compensation/and or research work has been funded
entirely or in part by governmental organization grants to her university.
†Dr Hillis has nothing to disclose.

WILLIAM T. HU, MD, PhD
Assistant Professor, Department of Neurology, Emory University School of Medicine,
Atlanta, Georgia
*Dr Hu has received research support from the Penn-Pfizer Alliance.
†Dr Hu discusses the unlabeled use of medications for frontotemporal degeneration,
including cholinesterase inhibitors and memantine.
ELIZABETH H. LACEY, PhD

Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC;
Cognitive Neuropsychology Laboratory, Department of Neurology, Georgetown
University Medical Center, Washington, DC
*†Dr Lacey has nothing to disclose.
DANIEL LARRIVIERE, MD, JD

Assistant Professor, University of Virginia School of Medicine, Department of Neurology,
Charlottesville, Virginia; Academic Instructor, University of Virginia School of Law,
Charlottesville, Virginia
*Dr Larriviere has received personal compensation for speaking engagements from
the American Association for the Advancement of Science and has received research
support in the form of an unrestricted educational grant from Allergan, Inc.
†Dr Larriviere has nothing to disclose.
M.-MARSEL MESULAM, MD, FAAN

Professor of Neurology, Psychiatry, and Psychology; Director, Cognitive Neurology and
Alzheimer’s Disease Center, Northwestern University, Chicago, Illinois
*†Dr Mesulam has nothing to disclose.
BRUCE L. MILLER, MD
A.W. and Mary Margaret Clausen Distinguished Professor, Departments of Neurology
and Psychiatry, University of California, San Francisco, San Francisco, California
*Dr Miller has received personal compensation for editorial activities from Neurocase.
†Dr Miller has nothing to disclose.

STEPHEN E. NADEAU, MD
Chief, Neurology Service, Malcom Randall VA Medical Center, Gainesville, Florida;
Professor of Neurology, University of Florida College of Medicine, Gainesville, Florida
*Dr Nadeau has received personal compensation for speaking engagements from the
Halifax Medical Society and the University of Florida College of Medicine, Department
of Medicine. Dr Nadeau has received personal compensation as an associate editor of
the Journal of the International Neuropsychology Society. Dr Nadeau’s compensation
and/or research work has been funded entirely or in part by a grant to his university
from a governmental organization.
†Dr Nadeau discusses the unlabeled use of acetylcholinesterase inhibitors to treat
psychotic manifestations, apathy, indifference, and anxiety in patients with dementia.
KATHERINE P. RANKIN, PhD

Associate Professor, Department of Neurology, University of California, San Francisco,
San Francisco, California
*†Dr Rankin has nothing to disclose.
DAVID P. ROELTGEN, MD, FAAN

Professor of Neurology, Georgetown University School of Medicine, Washington, DC
*†Dr Roeltgen has nothing to disclose.
HYUNGSUB SHIM, MD
Resident, Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City,
Iowa
*†Dr Shim has nothing to disclose.
MARC SOLLBERGER, MD
Senior Physician, Memory Clinic, Department of Geriatrics; Department of Neurology,
University of Basel, Basel, Switzerland
*†Dr Sollberger has nothing to disclose.

DAVID A. WOLK, MD
Assistant Professor, Department of Neurology, Assistant Director, Penn Memory Center,
University of Pennsylvania, Philadelphia, Pennsylvania
*Dr Wolk has received personal compensation for consulting activities with GE
Healthcare, Inc., and Avacat Consulting, LLC.
†Dr Wolk has nothing to disclose.
MULTIPLE-CHOICE QUESTION WRITERS
EDUARDO E. BENARROCH, MD, DSci, FAAN

Professor of Neurology, Mayo Clinic, Rochester, Minnesota
*Dr Benarroch has received personal compensation in an editorial capacity
from Neurology.
†Dr Benarroch has nothing to disclose.
D. JOANNE LYNN, MD, FAAN

Associate Professor, Department of Neurology, Ohio State University College of
Medicine, Columbus, Ohio; Associate Dean for Student Life, Ohio State University
College of Medicine, Columbus, Ohio
*Dr Lynn holds $10,000 worth of stock in Abbott Laboratories, Inc., Bristol-Myers
Squibb Company, Hospira, Inc., and Johnson & Johnson Services, Inc. Dr Lynn is the
principal or co-investigator for clinical trials supported by Accelerated Cure Project for
Multiple Sclerosis, Acorda Therapeutics, Inc., Allergan, Inc., Biogen Idec, BioMS Medical
Corporation, EMD Serono, Inc., Genentech, Inc., Genzyme Corporation, Immune
Tolerance Network, National Institutes of Health, National Multiple Sclerosis Society,
Novartis Pharmaceuticals, Inc., TEVA Neuroscience, UCB, and University of California,
San Francisco.
†Dr Lynn has nothing to disclose.

EDITOR FOUNDING PROGRAM DIRECTOR

Aaron E. Miller, MD, FAAN Theodore L. Munsat, MD
New York, New York
Relationship Disclosure: Dr Miller has received personal EDITORIAL BOARD
compensation for activities with Acorda Therapeutics, Inc.,
Biogen Idec, BioMarin Pharmaceutical Inc., Daiichi Sanyko
Viveca Bhat, MD, Baltimore, Maryland
Company, Ltd., EMD Serono, Inc., GlaxoSmithKline, Merck & Kersti Bruining, MD, FAAN, Traverse City, Michigan
Co., Inc., Novartis, Ono Pharmaceutical Co, Ltd., Pfizer Inc,
Sanofi-Aventis, and Teva Neuroscience as a consultant and
Cynthia L. Comella, MD, FAAN, Chicago, Illinois
speaker. Dr Miller has received personal compensation from Matthew E. Fink, MD, New York, New York
the AAN for serving as the editor of Continuum: Lifelong
Learning in Neurology and from Lippincott Williams &
Carlayne E. Jackson, MD, FAAN, San Antonio, Texas
Wilkins for serving as an editorial advisory board member for Steven L. Lewis, MD, FAAN, Chicago, Illinois
Real Living with Multiple Sclerosis. Dr Miller has received
research support from Acorda Therapeutics, Inc., Biogen
Laszlo Mechtler, MD, Amherst, New York
Idec, Genzyme Corporation, Immune Tolerance Network, Jonathan W. Mink, MD, PhD, FAAN, Rochester,
Sanofi-Aventis, and Teva Neuroscience.
New York
ASSOCIATE EDITOR Jennifer R. Molano, MD, Nashville, Tennessee
Steven L. Lewis, MD, FAAN Joel R. Saper, MD, FAAN, Ann Arbor, Michigan
Chicago, Illinois Mark J. Tullman, MD, New York, New York
Relationship Disclosure: Dr Lewis has received personal
compensation in an editorial capacity for Neurology. Charles Zollinger, MD, Canton, Ohio
ASSOCIATE EDITOR OF ETHICS AMERICAN ACADEMY OF NEUROLOGY

Saint Paul, Minnesota
Michael A.Williams, MD, FAAN
Baltimore, Maryland Robert C. Griggs, MD, FAAN, President
Relationship Disclosure: Dr Williams’ life partner holds stock Catherine M. Rydell, Executive Director/CEO
in Ecolab, General Electric Company, Life Technologies
Corporation, Medtronic Corporation, and Pfizer Inc. EDITORIAL STAFF
Saint Paul, Minnesota
ASSOCIATE EDITOR OF PRACTICE
Andrea J. Weiss, Executive Editor
Larry B. Goldstein, MD, FAAN
Durham, North Carolina Cecelia Adams, Production Editor
Relationship Disclosure: Dr Goldstein has received personal Amanda Doering Tourville, Editorial Administrator
compensation for serving on committees from Abbott
Laboratories, AGA Medical Corporation, and Pfizer Inc; for Sarah Glover, Registrar, CME
serving as a consultant from Allergan, Inc., and Boeringer
Ingelheim; and for speaking from Bayer. Dr Goldstein has PUBLISHER
received research support from AGA Medical Corporation. Lippincott Williams & Wilkins
FOUNDING EDITOR Two Commerce Square
Elliott L. Mancall, MD, FAAN 2001 Market Street
(1993–2002) Philadelphia, PA 19103

EDITOR’S LETTER
More than any other capacity that is perhaps
subspecialty area of neu- an absolutely unique
rology, behavioral neurol- aspect of the human
ogy addresses those brain condition. In this con-
functions that uniquely text extensive neural
define us as humans. Of- networks are implicated
ten these capacities are and the impact of so-
not easily explicable by called disconnection syn-
simple neuroanatomic dromes is recognized.
pathways, but rather in- First, Dr Argye Hillis dis-
volve complex neural cusses the expressive
networks. In this issue elements of language in
of , Dr her article, ‘‘Naming and
Murray Grossman has Language Production.’’
recruited some of the
More than any Drs HyungSub Shim
most renowned experts other subspecialty and Thomas Grabowski
in the field, as well as area of neurology, follow this with an anal-
some rising stars, to offer behavioral neurology ysis of the receptive com-
not only clear explanations ponents of language. Of
where they are known but
addresses those course, speech is not
current plausible theo- brain functions that the only form of com-
retical discussion where uniquely define munication; written lan-
information is less firmly us as humans. guage is also of major
established. I have no importance. While dis-
doubt that you will find orders of reading and
13
this issue fascinating and enlightening. writing frequently follow, pari passu,
Disorders of memory are perhaps the with those of spoken language, some-
most frequent behavioral disturbances times impairments in dealing with
encountered in neurologic practice. When written language occur independently.
severe, such impairment is among the Drs David Roeltgen and Elizabeth Lacey
most incapacitating neurologic condi- analyze alexias and agraphias in their
tions. But not all memory is the same. article, ‘‘Reading, Writing, and Their
In the first article of this issue, Drs David Disorders.’’
Wolk and Andrew Budson review am- Communication between people is
nestic impairments in the context of not confined to language. We not only
discussions of episodic, semantic, and express emotions but need to recognize
procedural memory. emotion and social signals from others.
The next three articles are devoted to Although this has been a much less well-
aspects of symbolic language function, a studied area of human behavior than
Copyright # 2010, American Academy of Neurology. All rights reserved.

" EDITOR’S LETTER
language, the concepts and the nature of ting. Dr M.-Marsel Mesulam, a foremost
the investigations are fascinating. Drs authority on the subject, presents the
Marc Sollberger, Katherine Rankin, and current state of knowledge in his article,
Bruce Miller bring you up to speed ‘‘Attentional and Confusional States.’’
on the current status of this aspect of The ability to plan, organize, and
human behavior in their article on social carry out complex tasks is another
cognition. critical aspect of human behavior,
As a student and resident in neu- known as executive function. A variety
rology, I was particularly intrigued by of disorders impair this neurobehavio-
the notion of apraxia, the inability to ral capacity, particularly degenerative
perform skilled motor acts despite the disorders including perhaps most no-
preservation of the sensorimotor ap- tably frontotemporal dementia. Dr
paratus to do so. I suspect that you are Rachel Gross, and Guest Editor Gross-
similarly fascinated. Dr Kenneth Heil- man discuss this important subject in
man, who has been one of the most their article, ‘‘Executive Resources.’’
thoughtful and productive investiga- In the Ethical Perspectives in Neu-
tors on this subject, illuminates the rology section of this issue, Dr Daniel
various forms of apraxia. Larriviere addresses the ‘‘stimulating’’
Vision is, of course, one of the most question of prescriptions for neuro-
critical tools with which humans ac- enhancement. Dr Stephen Nadeau
quire information about their envi- follows this with his practical advice
ronment. How the brain processes on optimizing cognitive function in
information gained through this spe- the cognitively fragile patient in the
cial sense is the subject of discussion section Practice Issues in Neurology.
in the next two articles of this issue. As usual, I exhort you to maximize
Drs Anjan Chatterjee and H. Branch your educational experience of this
Coslett first address disorders of vi- issue of by working
suospatial processing, including dis- through the Patient Management
cussion of the fairly common phenom- Problem contributed by Dr William
enon of neglect, as well as elements Hu, as well as the Multiple-Choice
that comprise Balint syndrome and Questions prepared by Drs Eduardo
visuospatial deficits that accompany Benarroch and Joanne Lynn. Remem-
dementia. Then Dr Jason Barton fo- ber that you can easily achieve CME
cuses specifically on disorders of color credits by submitting the answers to
and object recognition, which include the questions online.
14 the important subject of facial process- I am confident that you will share
ing and its disorder, prosopagnosia. my enthusiasm about the exhilarating
In order to set the stage for the full trip through the spectrum of human
panoply of human behavior, individu- behavior provided by this issue. We
als must be in a state of alertness and are grateful to Dr Grossman and his
able to attend properly to a variety of outstanding faculty for serving as our
stimuli. Disturbances of attention, as guides.
well as confusional states, are among
the most frequent reasons for neuro- —Aaron E. Miller, MD
logic consultation in the hospital set- Editor-in-Chief
Continuum Lifelong Learning Neurol 2010;16(4)

KEY POINT
MEMORY SYSTEMS A When medial

temporal lobe
David A. Wolk, Andrew E. Budson structures are
damaged and
episodic
memory is
ABSTRACT impaired,
Converging evidence from patient and neuroimaging studies suggests that memory is learning can
a collection of abilities that use different neuroanatomic systems. Neurologic injury still occur
may impair one or more of these memory systems. Episodic memory allows us to through other
mentally travel back in time and relive an episode of our life. Episodic memory memory
depends on the hippocampus, other medial temporal lobe structures, the limbic systems such as
system, and the frontal lobes, as well as several other brain regions. Semantic memory procedural
provides our general knowledge about the world and is unconnected to any specific memory.
episode of our life. Although semantic memory likely involves much of the neocortex,
the inferolateral temporal lobes (particularly the left) are most important. Procedural
memory enables us to learn cognitive and behavioral skills and algorithms that
operate at an automatic, unconscious level. Damage to the basal ganglia, cerebellum,
and supplementary motor area often impair procedural memory.
Continuum Lifelong Learning Neurol 2010;16(4):15–28.
INTRODUCTION assertions that human memory is sub-

The ability to remember one’s personal served by several different memory sys-
past is a fundamental feature that defines tems was by the 18th century French
the human conscious experience. Dis- philosopher Maine de Biran, the charac-
orders of memory can have devastating terization of the famous patient Henry
consequences for patients and families. Molaison (‘‘HM’’; 1926—2008) pro-
Although numerous medical conditions vided the experimental support to pop-
may precipitate memory loss, the aging ularize this conception. HM underwent
of our population, with its accordant bilateral medial temporal lobe (MTL)
increased prevalence of Alzheimer dis- resections for intractable epilepsy in
ease (AD) and other neurodegenerative 1953. Unfortunately, the procedure re-
conditions, has accentuated the need sulted in the unintended consequence
for the clinician to have a general un- of profound amnesia in which he was
derstanding of normal memory func- unable to acquire new memories of ex- 15
tioning and the differential diagnosis periences or events following the sur-
associated with its disruption. gery. The description of this outcome
Critical to any discussion of memory firmly established the MTL system as
is the concept of a memory system, essential to episodic memory and was
which can be loosely defined as a brain disseminated to the scientific commu-
system that supports the maintenance nity in the highly influential 1957 manu-
of information that impacts behavior script by Milner and Scoville entitled
after passage of time from initial ac- ‘‘Loss of Recent Memory after Bilateral
quisition.1 Although one of the earliest Hippocampal Lesions.’’2
Relationship Disclosure: Dr Wolk has received personal compensation for consulting activities with GE
Healthcare, Inc.; and Avacat Consulting, LLC. Dr Budson has received personal compensation for speaking
engagements with Eisai Inc., Forest Laboratories, Inc., Johnson & Johnson Services, Inc., and Pfizer Inc.
Dr Budson’s compensation and/or research work has been funded entirely or in part by a grant from a
governmental organization to his university.
Unlabeled Use of Products/Investigational Use Disclosure: Drs Wolk and Budson have nothing to disclose.

" MEMORY SYSTEMS
KEY POINT
It was the sparing of other aspects involve explicit access or conscious aware-
A Memory
of HM’s learning and memory, how- ness of information, whereas nondeclar-
impairment may
be seen even if
ever, that provided the foundation for ative memories cannot be verbalized and
the medial the notion of separable memory sys- are instead manifested by changes in
temporal lobes tems. For example, his ability to learn behavior. In the current review, we will
are spared. new motor skills, demonstrate the ef- discuss two forms of declarative memory—
Frontal lobes, fects of perceptual priming, and re- episodic and semantic—and one form
inferolateral trieve remote pieces of semantic mem- of nondeclarative memory—procedural.
temporal lobes, ory suggested that these processes Working memory, another form of de-
basal ganglia, were not entirely dependent on MTL clarative memory, is covered elsewhere
and cerebellum function. Additional dissociations rein this issue, although we have included
may all cause vealed in HM and other patients provide it in selected tables and figures for com-
certain kinds of
evidence that there are separable mem- parison (Table 1-1). As outlined below,
memory
impairment.
ory systems. one of the major values of considering
Although there is not complete agree- memory in this manner is that these
ment on the best way to categorize these systems rely on a dissociable neuroanat-
systems, almost all accounts involve sep- omy, which has variable sensitivity to
aration into declarative and nondeclar- different disease processes and, thus,
ative forms of memory. Declarative mem- has localizing and diagnostic implica-
ories can be put into words and generally tions in the context of impairment.
TABLE 1-1 Comparison of Clinically Relevant Memory Systems
Memory Length of Major Anatomic

System Examples Awareness Storage Structures
Episodic Remembering a short story, Explicit Minutes Medial temporal lobe,

memory what you had for dinner Declarative to years anterior thalamic nucleus,
last night, and what you mamillary body, fornix,
did on your last birthday prefrontal cortex
Semantic Knowing who was the Explicit Minutes to Inferior lateral temporal
memory first US president, the color Declarative years lobes
of a lion, and how a fork
16 and comb are different
Procedural Driving a standard Implicit Minutes to Basal ganglia, cerebellum,
memory transmission car and Nondeclarative years supplementary motor
learning the sequence of area
numbers on a touch-tone
phone without trying
Working Phonologic: keeping a phone Explicit Seconds to Phonologic: prefrontal
memory number ‘‘in your head’’ Declarative minutes; cortex, Broca area,
before dialing information Wernike area
actively
Spatial: Mentally following a Spatial: prefrontal cortex,
rehearsed or
route, or rotating an object in visual association areas
manipulated
your mind
Reprinted from Budson AE, Price BH. Memory dysfunction. N Engl J Med 2005;352(7):629–699. Copyright # 2005, with permission from
Massachusetts Medical Society. All rights reserved.

KEY POINTS
EPISODIC MEMORY own experience of an event. (2) Only
A Episodic memory
Definitions episodic memory is tightly linked to a impairments
sense of time. Indeed, time forms part are common
The patient in Case 1-1 had a rela-
of the context by which these events are and often
tively selective impairment of episodic
represented, allowing for differentiation disrupt the lives
memory.
of events in the recent past from more of patients and
Episodic memory is the memory their families.
remote events.
system that allows us to remember past
experiences and episodes in our life, or
Episodic memories may be fraction- A Episodic memory
ated in a number of different ways, is the type of
as Endel Tulving put it, the kind of mem- which often have implications for the memory we
ory that allows us to ‘‘mentally travel’’ nature of an impairment of memory usually mean
in time.3 Two features differentiate epi- and the underlying neural substrate when we talk
sodic memory from other memory sys- involved. One such division is the dif- about memory.
tems. (1) Episodic memory involves a ference between item and associative It is memory for
form of consciousness in which the self is memory. Whereas item memories are an episode of
central—autonoetic or self-knowing con- one’s life.
for individual items without context, as-
sciousness according to Tulving. In other sociative memories involve the linking
words, it involves remembering one’s of multiple aspects of an event. For
Case 1-1
A 75-year-old man had decline in his memory over about 1 year. Per his wife, this was manifested
by his repeating questions and forgetting their daily plans. She noted little change in his ability
to perform instrumental activities of daily living, such as driving or handling the finances, but
he did have greater difficulty with
remembering details of books or shows
that they had watched together. He
admitted that his memory was poorer
and felt a sense of foreboding about the
future. On examination, he showed very
poor verbal and visual memory, and
limited knowledge of current events
despite avidly watching the news.
Although he recalled 6/10 words on the
third immediate recall trial of a verbal
memory task, his delayed recall was 0/10, 17
and he only recognized 4/10 items and
made one false alarm. His retention of a
story based on initial encoding was very
poor. Nonetheless, he performed in
the normal range on almost all tests
of language, executive functioning,
attention, and visuospatial ability. He FIGURE 1-1 MRI coronal T1-weighted image. Note
the relatively disproportionate atrophy
was given a diagnosis of amnestic mild of the bilateral hippocampi consistent
with the temporolimbic memory impairment
cognitive impairment. Note the of this patient.
diminutive hippocampi on his MRI
(Figure 1-1).
Comment. This patient has an impairment of episodic memory. A relatively isolated
impairment of episodic memory is a common feature of early AD given the early neuropathology
in the MTLs with this condition. This patient has a high likelihood of progressing from amnestic
mild cognitive impairment to clinical AD.

" MEMORY SYSTEMS
KEY POINT
example, one may remember having ability to form new memories, whereas
A The hippocampus
seen a friend earlier in the day and also retrograde amnesia is the loss of pre-
and other
the color of the friend’s shirt and the viously acquired memories.
medial temporal
lobe structures
location of the meeting. A common
test of associative memory is to have Functional Neuroanatomy of
are critical for
normal episodic subjects study word pairs. At testing, Episodic Memory
memory function. the subject is shown one word in the The MTL—and particularly the
pair and is asked to recall the second, hippocampus—is traditionally thought
associated word. A related concept is to be the anatomic seat of episodic
source memory, which is the ability to memory, as exemplified by the severe
remember the specific context from amnesia of HM; however, a number
which a memory came. A common of other neural systems appear to be
memory error is related to this notion, involved. The processes that support
sometimes referred to as reality mon- episodic memory occur from the time
itoring. An example is when you are the to-be-remembered event is encoun-
unable to remember whether you tered (encoding) to the act of remem-
actually turned off the stove or just bering (retrieval). In between are pro-
thought about turning it off. Source cesses involved in the maintenance of
memory is frequently tested in the these memories. If the memory is to
laboratory by having subjects study two last for an extended period of time, an
lists. At testing, they need to decide not additional process known as consolida-
only whether a particular item was tion occurs. Given the disparate nature
studied, but remember from which list of these operations, it is perhaps not
it came. surprising that episodic memory re-
A related formulation to the item quires diverse neural systems for its
versus associative or source memory proper function and, thus, a variety of
distinctions is the difference between brain injuries can result in impaired
familiarity and recollection,4 a differ- memory. Historically, it has been diffi-
ence that may reflect dissociable under- cult to gain traction on the nature of
lying medial temporal and neocortical neural activity associated with these
structures. Familiarity is conceptualized different stages of memory. The advent
as an acontextual sense of prior en- of functional neuroimaging techniques
counter. An example of an experience of has allowed for assessment of neural
familiarity is when people see someone activity during memory encoding and
that they are sure they have previously retrieval, which has added greatly to
18 met but cannot recall how it is that they our understanding of these processes
know that person (‘‘That person is so (Figure 1-2). We will outline a num-
familiar to me! Where do I know him ber of critical brain regions associated
from?’’). In contrast, recollection is the with episodic memory function.
more detailed retrieval of information Medial temporal lobe. Much of
(‘‘Oh, that’s Bob. I met him at my sis- what we know about normal episodic
ter’s birthday party last week’’). Al- memory function comes from studying
though sometimes recollection occurs patients with amnesia resulting from
spontaneously, at other times addi- MTL lesions. The MTL is a complex struc-
tional conscious, effortful searching of ture frequently divided into hippocam-
one’s memory stores is needed. pal and extrahippocampal regions.5 The
A final important distinction is be- hippocampal structures include the den-
tween retrograde and anterograde am- tate gyrus, cornus ammonis subfields
nesia. Relative to the time of the brain (CA 1, CA2, and CA3), and the postsub-
injury, anterograde amnesia is the in- iculum. Extrahippocampal structures

KEY POINT
A An injury to
episodic
memory
typically causes
(1) anterograde
amnesia: an
inability to
form new
memories, and
(2) retrograde
amnesia: a loss
of previous
memories.
There are,
however,
always (3) some
preserved
remote
memories.
FIGURE 1-2 Episodic memory. The medial temporal lobes, including the hippocampus and
parahippocampus, form the core of the episodic memory system.
Adapted from Budson AE, Price BH. Memory dysfunction. N Engl J Med 2005;352(7):692–699.
Copyright # 2005, with permission from Massachusetts Medical Society. All rights reserved.
include the entorhinal, perirhinal, and hippocampus differentially encode ob-

parahippocampal cortices. ject and spatial elements of an episode,
Whereas isolated hippocampal le- respectively, which are then bound by
sions produce significant amnesia, inclu- the hippocampus (Figure 1-3).8
sion of surrounding extrahippocampal In addition to significant anterograde
MTL structures tends to produce even amnesia, patients with MTL injury fre-
more profound memory loss.6 Some quently experience retrograde amnesia.
work has suggested that there may be a Often times, the retrograde amnesia is
division of labor within the MTLs with greatest for events learned nearest the
regard to the nature of their memory time of MTL injury but is spared for
stores.6–8 Hippocampal lesions tend to more remote episodes. This somewhat 19
produce impairment on tasks of asso- paradoxical pattern of memory loss has
ciative memory, source memory, and re- been labeled as Ribot law9 and may
collection, with relative sparing of item reflect the changing representation of
memory and familiarity. However, the memories over time. One popular ac-
additional involvement of extrahippo- count to explain this phenomenon is
campal MTL regions impairs item mem- the ‘‘standard consolidation’’ model.10,11
ory as well. These and other findings sug- This model argues that when memories
gest that the hippocampus is involved are initially formed, the MTL—likely, the
in the binding of different elements of hippocampus—binds neocortically rep-
a prior study episode. By contrast, the resented features of an event. Partial
perirhinal cortex and parahippocampus cues that reactivate elements of the epi-
appear critical for the storage of these sode will also activate related features
individual elements. An influential model mediated by connections with the hip-
is that the perirhinal cortex and para- pocampus. However, over time, these

" MEMORY SYSTEMS
form the perforant pathway (the main

input to the hippocampus). Such pa-
thology appears to result in a cortico-
hippocampal disconnection,12 perhaps
preventing the binding of different neo-
cortical elements necessary for effec-
tive encoding. Thus, it is not surprising
that memory loss is an early feature of
this condition (Case 1-1). As AD prog-
resses, all regions of the MTL become
significantly involved, further devastat-
ing the episodic memory system. Other
factors that likely contribute to the mem-
ory loss include reduced cholinergic in-
put due to basal forebrain pathology and
involvement of frontal-subcortical net-
works. It has also recently become ap-
Functional organization of the medial
parent that -amyloid (A), the protein
FIGURE 1-3 fragment that forms the hallmark amy-
temporal lobe system. Neocortical input
regarding the object features (what) loid plaques of AD, in its soluble form
converges in the perirhinal cortex (PRC) and lateral entorhinal
area (LEA), whereas details about the location (where) of may inhibit long-term potentiation, a
objects converge in the parahippocampal cortex (PHC) and critical cellular mechanism for learning
medial entorhinal area (MEA). These streams converge in
the hippocampus, which represents items in the context in and memory.13
which they were experienced. Reverse projections follow Extended medial temporal mem-
the same pathways back to the parahippocampal and
neocortical regions. Back projections to the PHC-MEA may ory system. Several structures with sig-
support recall or context, whereas back projections to the nificant connectivity to the MTL proper
PRC-LEA may support recall of item associations. are critical to episodic memory, as evi-
Adapted with permission from Eichenbaum H, Yonelinas AP, Ranganath C. denced by the amnesia associated with
The medial temporal lobe and recognition memory. Annu Rev Neurosci
2007;30:123–152. their injury. Many of these regions were
previously described by Papez in the
circuit that bears his name.14 Lesions to
neocortical representations form their the mamillary bodies, bilateral fornices
own associations and the critical role (an efferent pathway from the hippo-
of the MTL in retrieval may become di- campus to the mamillary bodies), and
minished or absent, and, thus, an older the anterior thalamic nucleus (which
20 memory may not be affected by MTL receives inputs via the mamillothalamic
pathology. track from the mamillary bodies) all
A number of conditions produce produce episodic memory impairment
memory impairment through MTL in- that is difficult to distinguish from hippo-
jury. These conditions include AD, de- campally based amnesia (Figure 1-2).6
mentia with Lewy bodies, hippocampal Additionally, the posterior cingulate
sclerosis, posterior cerebral artery stroke, and retrosplenial cortex also have dense
hypoxic-ischemic injury, and viral and connections with the hippocampus and
limbic encephalitis. By far the most anterior thalamic nucleus, and amnesia
common cause of memory loss in associated with retrosplenial lesions
older adults is AD, which is associated have been described.15 Although iso-
with extensive neuropathology in the lated lesions in these related structures
MTL. In particular, early neurofibrillary are uncommon, Korsakoff syndrome rep-
tangle pathology is found in the ento- resents a classic form of amnesia associ-
rhinal cortex layer II neurons, which ated with pathology in the anterior

KEY POINTS
thalamic nucleus and the mamillary These patients may conflate details of
A Alzheimer
bodies.16 various events and are susceptible to
disease is by far
Frontal lobes. While their deficit is errors of reality monitoring reflective of the most
generally more subtle than that seen source memory confusions. In more ex- common cause
with medial temporal lesions, patients treme cases, patients may exhibit spon- of episodic
with frontal lobe damage frequently taneous and sometimes elaborative con- memory
exhibit episodic memory impairment. fabulations. Potential contributors to the impairment.
These patients tend to have relatively tendency to confabulate include com- A Memory
selective impairment on memory tasks bined MTL and frontal lobe dysfunction distortions,
that require the linking of different fea- (such as is seen in AD, frontotemporal false memories,
tures of a prior episode. As such, pa- degeneration, and Korsakoff amnesia), and confabulation
tients with frontal lobe damage tend poor selection or focus of the to-be- may occur with
to have difficulty on tests of associa- retrieved memories, impaired monitor- damage to
tive or source memory,17 memory for ing and editing of retrieved information, frontal cortex.
temporal order of presentation,18 and and impaired source monitoring and re- A Think of episodic
recollection.4 However, performance is trieval of temporal contextual details.22 memory as a
often normal on tests of item memory Differences in memory performance filing system:
or familiarity. Patients with frontal lobe between conditions that affect the MTL The frontal
damage also tend to have more dif- and those that affect the frontal lobes lobes are the
ficulty on memory tasks that require can be conceptualized by analogy. The filing clerk, the
medial temporal
spontaneously generated encoding or episodic memory system can be thought
lobes are the
retrieval strategies, but show improve- of as a filing system. The frontal lobes
recent memory
ment in the context of ‘‘environmental are analogous to the ‘‘file clerk’’ of the file cabinet, and
support.’’ For example, patients with episodic memory system, the MTL (and other cortical
frontal lobe lesions tend to perform Papez circuit) to the ‘‘recent memory file regions are the
more poorly on a memory test if told to cabinet,’’ and other cortical regions to older memory
simply study a list of words rather than the ‘‘remote memory file cabinet.’’ Thus, file cabinet.
when instructed to perform a specific if the frontal lobes are damaged, it is
encoding operation, such as to form a difficult—but not impossible—to get
mental image of each study item. This information in and out of storage. Ad-
notion also applies to different test for- ditionally, when the frontal lobes are
mats, as an unconstrained free recall task damaged, the information stored in
is much more difficult for patients with memory may be distorted due to ‘‘im-
frontal lobe lesions than cued recall or proper filing’’ that leads to an inaccurate
recognition memory.19 On these latter source, context, or sequence. If, on the
tasks, these patients may show little or other hand, the MTLs are impaired, it 21
no deficit at all. Thus, as a general prin- may be impossible for recent information
ciple, prefrontal regions appear to be to be stored. Older information that has
involved in different aspects of cognitive been consolidated over months to years
control mechanisms that enhance mem- is likely stored in other cortical regions
ory encoding and retrieval20 rather than and will therefore be available for retriev-
supporting the retention of information al even when the MTL or Papez circuit is
(likely a medial temporal function). damaged. See Table 1-2 for character-
In addition to failure to retrieve in- istics of memory impairment due to
formation from prior events, patients frontal versus medial temporal injuries.
with frontal lobe lesions are particularly A number of conditions produce
susceptible to memory distortions and memory impairment that is due, at
false memories. This is likely related to least in part, to frontal lobe dysfunc-
their poor memory for contextual or tion. In addition to frontal strokes
associative details of a prior episode.21 and mass lesions, other conditions

" MEMORY SYSTEMS
TABLE 1-2 Memory Deficits With Medial Temporal Lobe Versus

Frontal Lobe Lesions
Medial Temporal
Characteristic Lobe Lesion Frontal Lobe Lesion
Immediate memory Normal to mildly impaired Impaired

Free recall Impaired Impaired
Recognition memory Impaired Often normal
or cued recall
Source or associative Impaired Impaired
memory (ie, recollection)
Item memory Impaired Normal
(ie, familiarity)
Effects of environment Minimal enhancement of Significant enhancement
support memory performance of memory performance
Tendency for false Variable High
memory or confabulation
associated with a frontally based epi- Other regions. Several other re-
sodic memory impairment include gions appear to be important substrates
frontotemporal degeneration, vascular for episodic memory function. Lesions
dementia (particularly when associat- of the basal forebrain, often due to an-
ed with subcortical white matter dis- terior communicating artery aneurysm
ease), dementia with Lewy bodies, rupture, produce memory impairment.
multiple sclerosis, depression, and head This region is the main source of cho-
trauma. Distinguishing between memo- linergic input to the MTLs and neocor-
ry impairment due to medial temporal tex. Blockade of acetylcholine with the
injury and that associated with frontal muscarinic antagonist scopolamine pro-
lobe dysfunction has potential diagnos- duces amnesia in healthy individuals.25
tic value. For example, while measures The relative decline in acetylcholine as-
of free recall and associative memory do sociated with basal forebrain pathology
22 not differentiate patients with AD from in AD is the rationale for the use of cho-
those with subcortical vascular demen- linesterase inhibitors in this condition.
tia, measures of recognition memory Given a general decline in cholinergic
(with patients with AD performing function with aging, it is not surprising
more poorly) appear to have better that cholinergic blockers, such as sco-
specificity.23 Although generally more polamine, have greater effects on mem-
subtle, ‘‘healthy’’ age-associated memory and cognition in older than young
ory loss tends to be qualitatively similar adults, which is why anticholinergic
to memory loss due to frontal lobe medicines should be avoided in older
injury. This phenomenology is consis- individuals.
tent with data supporting the relative- Recent work, driven largely by the
ly selective vulnerability of frontal lobe functional imaging literature, has sug-
function in aging as a result of cortical gested that the parietal lobes also par-
volume loss, anterior white matter dis- ticipate in episodic memory retrieval.
ruption, and dopaminergic depletion.24 Studies have consistently revealed

KEY POINT
midline and lateral parietal activations ness.27,28 A number of potential hypoth-
A Semantic memory
associated with successful retrieval of eses have been postulated as to the
is memory for
memories.26 While midline structures, function of the parietal cortex in epi- knowledge of
including retrosplenial cortex, have been sodic memory and are just now begin- the world when
implicated in episodic memory, prior ning to be tested experimentally.26 it is unconnected
work had not suggested a role for the with a specific
lateral parietal cortex. A recent focus SEMANTIC MEMORY episode of
on episodic memory in patients with one’s life.
lateral parietal lesions has revealed, per- Definitions
haps, subtle deficits in this population. The patient in Case 1-2 had a rela-
While these patients appear to retrieve tively selective impairment of seman-
contextual details of prior episodes to a tic memory. Semantic memory defines
similar extent as controls, they seem to our knowledge of the world, including
have greater difficulty doing so spon- general information about objects, peo-
taneously and their memories may be ple, historical events, and word mean-
associated with less confidence or vivid- ing.3 Examples of semantic knowledge
Case 1-2
A 73-year-old man had several years of cognitive decline. Most salient to him was difficulty
naming and even recognizing a variety of items that used to be familiar to him. For example,
his wife bought a bag of microwave popcorn that he examined at great length, eventually asking
his wife what it was used for. On the way to one of his clinic visits he saw a cement truck and
commented that he had never seen such an unusual truck before. He described marked difficulty
in being able to name or even recognize close friends—they did not look familiar to him. Despite
these issues, he had minimal functional decline and scored 24/30 on the Mini-Mental State
Examination. His wife described his
day-to-day memory as essentially
unchanged. He spoke fluently on
examination and had reasonable
comprehension of simple words. He had
marked naming impairment on the
Boston Naming Test (14/30 correct), and
he could name only three vegetables in
1 minute. He performed average to above
average on tests of executive function,
attention, and visuospatial memory.
23
An MRI scan revealed severe bilateral
anterior and inferior-lateral temporal
lobe atrophy. This patient was
felt to have the early stages of semantic
variant of primary progressive aphasia.
Note the significant atrophy in the
anterior, inferior, and lateral temporal
lobe on an MRI scan (Figure 1-4).
Comment. This patient had a
relatively selective deficit of semantic
memory, but essentially spared episodic FIGURE 1-4 MRI sagittal T1-weighted image. Note the
severe temporal lobe atrophy, which
memory function. This case further includes anterior, inferior, and lateral
illustrates the dissociation of these two regions, relative to the rest of the brain.
memory systems.

" MEMORY SYSTEMS
KEY POINTS
are tigers have stripes and Philadelphia Semantic memory impairment is most
A Previously
frequently manifested by naming defi-
is the largest city in Pennsylvania. This
learned semantic
form of declarative memory can be dif- cits. This impaired naming is not miti-
information will
be intact when ferentiated from episodic memory be- gated by the use of phonemic cues, and
a patient cause its retrieval is not associated with often naming errors reflect semantically
experiences an a sense of self-experience or linked to a related word choices (eg, dog for lion).
isolated loss of particular spatial and temporal context. Different from a pure anomia, however,
episodic memory. For example, remembering watching these patients will also display evidence
A The inferolateral President Barack Obama’s inauguration of nonverbal impairment, such as match-
temporal lobes speech on television with one’s wife ing pictures of items into different seman-
(particularly the is an example of an episodic memory tic categories, and difficulty in providing
left) are critical while knowing that he is president is a definitions or descriptions of items when
for semantic semantic one. That episodic and seman- provided with their names. Category
memory. tic memory represent different mem- fluency, in which patients are asked to
ory systems is supported by the disso- name as many items as they can think
ciations in impairment associated with of in a particular semantic category (eg,
different brain lesions. For example, the animals), is another bedside test that is
patient HM, who had bilateral MTL re- often impaired in those with semantic
sections, displayed profound amnesia memory dysfunction.
with relative sparing of previously learned
semantic information. Functional Neuroanatomy of
Semantic Memory
While semantic memory is likely repres-
ented in a distributed fashion through-
out much of the neocortex, the infero-
lateral temporal lobes (particularly the
left) are the brain regions whose injury
is most associated with disruption of
semantic knowledge. Indeed, seman-
tic variant of primary progressive apha-
sia, the archetypal disease producing a
relative pure semantic knowledge im-
pairment, is associated with relatively
focal neurodegeneration in this region
(Figure 1-5).
24 Rare instances of category-specific
semantic deficits have provided addi-
tional insight into the neural organiza-
Semantic, procedural, and working memory. tion of semantic memory. The litera-
FIGURE 1-5
The anterior and inferolateral temporal ture describes a number of patients
lobes are important in the naming and
categorization tasks by which semantic memory is typically with relatively selective impairment of
assessed. However, in the broadest sense, semantic memory may knowledge of living things (eg, animals
reside in multiple and diverse cortical areas that are related to
various types of knowledge. The basal ganglia, cerebellum, and vegetables) but preserved knowl-
and supplementary motor area are critical for procedural edge of artifacts, such as tools.29 The
memory. The prefrontal cortex is active in virtually all working opposite dissociation has also been
memory tasks; other cortical and subcortical brain regions will
also be active, depending on the type and complexity of the described, strengthening the functional
working memory task. segregation of these forms of seman-
Adapted from Budson AE, Price BH. Memory dysfunction. N Engl J Med tic memory. Work has suggested that
2005;352(7):692–699. Copyright # 2005, with permission from Massachusetts
Medical Society. All rights reserved. these dissociated representations may
be a reflection of the nature by which

KEY POINTS
one experiences these different cate- tic memories overlap. These memories
A Because
gories.30 For example, our knowledge of our own personal experiences are
Alzheimer disease
of animals usually is largely related to generally conceived as a type of episodic affects the
the visual modality, while our experi- memory. More remote autobiographic inferolateral
ence with tools is more related to mo- memories, however, often become qual- temporal lobes,
tor representations. itatively more akin to semantic knowl- it is the most
Semantic memory deficits are most edge and are likely supported, in part, common cause of
commonly seen in patients with AD and by the semantic memory system. One semantic memory
are likely a reflection of the pathology simple test is that if, when recalling a impairment.
in inferolateral temporal neocortex. Of memory, you can see yourself in it, the Semantic variant
course, AD is also associated with sig- memory is likely semantic rather than of primary
progressive
nificant episodic memory impairment, episodic, since you would not ordinarily
aphasia,
which often dominates the initial clini- see yourself in a memory.
encephalitis,
cal picture. Other conditions associated trauma, and
with semantic memory impairment in- PROCEDURAL MEMORY stroke are other
clude semantic variant of primary pro- causes of semantic
gressive aphasia, herpes encephalitis, Definitions
memory
trauma, and occasionally stroke. Procedural memory is the nondeclar- impairment.
ative memory system that refers to the
Overlap Between Semantic and A Procedural
ability to learn cognitive and behavioral
memory is
Episodic Memory skills and algorithms that operate at an memory for
Despite being considered separate mem- automatic, unconscious level. Examples cognitive and
ory systems, semantic and episodic mem- include learning to ride a bicycle or play behavioral skills
ory interact in important ways. For the piano. Because procedural memory and algorithms
example, work from the cognitive psy- is spared in patients who have severe that are typically
chology and functional imaging litera- deficits of the episodic memory system operating
ture supports the benefit of semantic (such as those who have undergone unconsciously—
encoding on subsequent episodic mem- surgical removal of the MTLs), it is clear such as riding a
bicycle.
ory of studied items.31,32 Further, se- that the procedural memory system is
mantic deficits themselves sometimes separate and distinct from the episodic A Critical brain
correlate with performance on episodic memory system.35 regions for
memory tasks, presumably by reduc- procedural
Functional Neuroanatomy of memory are the
ing the effectiveness of the encoding
Procedural Memory basal ganglia,
process.33
cerebellum, and
The episodic memory system is also Patients with damage to the basal gan-
critical for the formation of new se- glia or cerebellum show impairment in
supplementary 25
motor area.
mantic memories, as evidenced by the learning procedural skills.36 Functional
profound impact of MTL lesions on such neuroimaging has found that these
new semantic memory formation. While regions—and the supplementary motor
factlike learning in patients with severe area—become active as a new proce-
bilateral medial temporal injury has been dural memory task is being learned37
reported, this appears largely relegated (Figure 1-5). Because the basal ganglia,
to fragmented information likely sup- cerebellum, and supplementary motor
ported by perceptual learning rather area are relatively spared in early AD,
than true pieces of new semantic infor- these patients show normal acquisition
mation.34 Even relatively limited hippo- and maintenance of their procedural
campal lesions can seriously degrade the memory skills, despite their episodic
acquisition of new semantic knowledge. and semantic memory deficits.38
Autobiographic memories are an- Patients in the early stages of Parkin-
other area in which episodic and seman- son disease show impaired procedural

" MEMORY SYSTEMS
KEY POINT
memory while performing nearly nor- explicit thinking becomes required for
A Parkinson disease
mally on episodic memory tests.38 Proce- their performance. As a result, patients
is the most
common dural memory is also disrupted by other with damage to the procedural memory
disorder causes of damage to the basal ganglia system lose the automatic effortlessness
disrupting or cerebellum, including Huntington of simple motor tasks that healthy in-
procedural disease, olivopontocerebellar degenera- dividuals take for granted. Lastly, it is
memory. tion, tumors, strokes, and hemorrhages. worth noting that patients whose epi-
Huntington Patients with major depression may sodic memory has been devastated by
disease, tumors, also show impairment in procedural a static disorder, such as encephalitis,
strokes, and memory tasks, perhaps because depres- have had successful rehabilitation by
hemorrhages sion involves dysfunction of the basal using procedural memory (and other
may also disrupt
ganglia.39 nondeclarative forms of memory) to
procedural
Disruption of procedural memory learn new skills.40
memory.
should be suspected when patients
show evidence of either the loss of
previously learned skills (compared CONCLUSIONS
with their baseline) or substantial dif- Evidence from patient studies and more
ficulties in learning new skills. For ex- recent neuroimaging research suggest
ample, patients may lose the ability to that memory is composed of separate
perform automatic, skilled movements, and distinct systems. An understanding
such as writing, playing a musical in- of these different memory systems will
strument, or swinging a tennis racket. aid the clinician in the diagnosis and
Although these patients may be able to treatment of the memory disorders of
relearn the fundamentals of these skills, their patients.
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NAMING AND
LANGUAGE PRODUCTION
Argye E. Hillis
ABSTRACT
Naming and sentence production are complex tasks, each requiring a number of
cognitive processes and representations, which can be selectively impaired by focal
brain damage, such as stroke, or by neurodegenerative disease. The types of errors
made by the patient and the pattern of performance across tasks can provide clues
regarding the location of the lesion and sometimes the most likely pathology.
Understanding the nature of the deficit can help the physician provide guidance
on how to facilitate communication.
INTRODUCTION other than the earliest levels of percep-

Impaired word retrieval or naming is tion and recognition (which will only
a ubiquitous problem in all neurologic be described for vision). Comparison of
diseases that affect language. It is also a naming performance across these mo-
cognitive function that declines with nor- dalities of input is often useful in iden-
mal aging. Word retrieval is only one tifying the patient’s impairment, as will
aspect of language production that can be illustrated in some of the cases. Evi-
be affected by age or neurologic disease, dence for proposing the role of each
however. Other aspects that will be of the cognitive processes underlying
considered in this article are grammati- naming comes from consideration of
cal sentence production and speech arti- the demands of the tasks and from
culation. Organization of discourse will neurologically impaired patients whose
be only briefly touched on, because the pattern of performance across language
complexity of this aspect of language tasks can be explained by assuming se-
would require greater space to be ade- lective damage to that cognitive func- 29
quately covered. tion. Then, the neurologic diseases and
First, the cognitive processes under- sites of lesions in the brain that lead
lying naming (including articulation of to impairments of each of these com-
the name) will be described. The focus ponents of naming will be discussed.
will be on naming visual stimuli, but one The section on sentence production
can also name objects from their sound will have a similar structure, moving
(eg, a flute or a dog), tactile exploration, from the cognitive processes underly-
smell, or a description. All of these tasks ing sentence production to associated
require the same cognitive processes, diseases. The article will end with
Relationship Disclosure: Dr Hillis has received personal compensation for serving as the editor of Behavioural
Neurology. Dr Hillis’ personal compensation and/or research work has been funded entirely or in part by
governmental organization grants to her university.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Hillis has nothing to disclose.

" NAMING AND LANGUAGE
KEY POINT
A The task of
producing the
name of a
pictured item
requires many
distinct
cognitive
processes and
recruits a
complex
network of
brain regions.
FIGURE 2-1 Schematic representation of the cognitive processes underlying naming.
practical recommendations for evalua- processes (schematically represented

tion and management of naming and in Figure 2-1) and recruits a complex
sentence production deficits. network of brain regions (as reflected
in functional imaging studies of nam-
COGNITIVE PROCESSES ing (Figure 2-2). The importance of
UNDERLYING NAMING each cognitive process will be intro-
The task of producing the name of a duced by describing patients who have
pictured item, such as a horse, would relatively selective impairment in the
seem to be very simple. However, this process or level of representation.
task requires many distinct cognitive
Impaired Visual Recognition
In order to name a pictured horse one
30 must first recognize the horse as a
familiar entity. This in itself requires com-
putation of several levels of visual rep-
resentation1 that culminate in a three-
dimensional image (independent of the
orientation, size, or location of the pic-
ture) that can be matched to stored
information about familiar items (some-
FIGURE 2-2 fMRI scan showing areas of the brain times called structural descriptions). Im-
activated during oral naming relative to rest pairments of this level of processing are
in 10 neurologically healthy control subjects.
Left: right hemisphere, Right: left hemisphere. known as apperceptive visual agnosia. A
Adapted from Prabhakaran V, Raman SP, Grunwald MR, et al. Neural patient with apperceptive visual agnosia
substrates of word generation during stroke recovery: the influence would be able to see the picture and
of cortical hypoperfusion. Behav Neurol 2007;18(1):45–52.
Copyright # 2007, with permission from IOS Press. trace it, but would not recognize it or
be able to match it to a picture of the

KEY POINTS
Case 2-1 A A patient with

A 70-year-old man first had trouble reading 3 years ago and had several apperceptive
car accidents before he was told by a neurologist not to drive. He initially had visual agnosia
right homonymous hemianopia, but had progressive difficulty with visual would be able
perception in both visual fields. He could not recognize faces of even familiar to see the
people but recognized them by voice. He could avoid bumping into things but picture of a
needed to touch or hear objects to recognize them. He could not name any horse and trace
pictures correctly but often named them as something visually similar (eg, he it but would
called a picture of a pear a light bulb). He began to develop mild verbal not recognize it
memory deficits. His spoken language was normal in conversation, but he or be able to
could not read. He orally spelled words well, but his writing was illegible. Serial match it to a
MRI scans showed progressive bilateral occipitotemporal atrophy. He was picture of the
diagnosed with the ventral form of posterior cortical atrophy, which is usually same horse
caused by Alzheimer disease pathology. (The dorsal form of posterior cortical from a different
atrophy is characterized by Balint syndrome, with impaired visually guided viewpoint.
reaching, simultagnosia, and optic apraxia, and can be due to either Alzheimer A Patients with
disease or corticobasal degeneration pathology with atrophy in the impaired
occipitoparietal cortex bilaterally.) conceptual
Comment. Like many patients with posterior cortical atrophy, his knowledge
initial symptoms were motor vehicle accidents and trouble reading. He often use
developed alexia without agraphia and optic aphasia (impaired access objects
to semantics from vision, as described later in this chapter) and inappropriately,
proposagnosia (impaired face recognition, all consequences of bilateral particularly less
temporooccipital damage or left temporooccipital damage combined familiar objects.
with damage to the white matter tracts that connect the hemispheres.
Eventually he developed apperceptive agnosia.
same horse from a different viewpoint more abstract features such as ‘‘can be
(Case 2-1). domesticated’’). Patients with impaired
conceptual knowledge, such as the woman
in Case 2-2, often use objects, particularly
Impaired Semantics
less familiar objects, inappropriately.2,3
(Conceptual Semantics and
Lexical Semantics)
Once an item, such as horse, is recog- Impaired Lexical Semantics and
nized as a familiar entity, it is essen- Impaired Access to Lexical 31
tial to access its meaning. Meaning or Semantics From Vision
semantics includes at least two levels Cases 2-3 and 2-4 describe individuals
of knowledge: (1) conceptual knowl- who are impaired in accessing only
edge or information shared by a culture the subset of semantic features known
about the use and associations of the as lexical semantics or lexical seman-
item (eg, that cowboys ride horses, that tic representations, which allow a per-
horses wear saddles, that they are not son to know what makes a horse a
typically eaten in the United States), and horse and what distinguishes it from
(2) lexical semantics—the defining fea- related items such as a deer or a cow.
tures of all things that share the name Patients with impaired lexical seman-
(eg, what makes a horse a horse and tics ( but intact conceptual knowledge)
what makes it distinct from related do not use items inappropriately, but
items like a cow or a deer, including incorrectly label them or match them
physical features such as a mane and to their names. For example, a patient

KEY POINT
A A patient with Case 2-2
impaired lexical A 66-year-old woman had progressive difficulty communicating for the
semantics (or past 2 years. She initially had impaired word retrieval only, but then had
impaired ability fluent, well-articulated, but meaningless, speech. She could not follow
to access lexical directions or point to named objects. When asked to point to the ceiling,
semantics from she said, ‘‘Ceiling? What is a ceiling?’’ She had been living independently
vision, a until her family became concerned when she served boiled pizza for
problem known dinner. She also had tried to eat soup with a knife. She could read out loud
as associative fairly well but made regularization errors in reading irregular words (eg,
visual agnosia read bear as ‘‘beer’’), and did not understand what she was reading (a
or optic pattern of reading known as surface dyslexia). Her MRI showed bilateral
aphasia) might anterior and inferior temporal atrophy, worse on the left. She was
point to a cow diagnosed with the semantic variant of primary progressive aphasia (PPA)
when asked to (also called semantic dementia).
point to a Comment. This woman shows typical defining features of the semantic
horse. The variant of PPA, including impaired word meaning in the face of spared
patient, speech fluency and grammar. It is typical for these patients to ask the
however, meaning of nouns such as ceiling. They often show the pattern of surface
would neither dyslexia and surface dysgraphia (reading and spelling by phonics). The
try to saddle a semantic variant of PPA is usually associated with atrophy of the anterior
cow nor and inferolateral temporal cortex, more marked on the left.
consider
milking a horse.
with impaired lexical semantics, like saddle a cow or consider milking a

the patient in Case 2-3 (or impaired horse. In each case, the person might
ability to access lexical semantics from access a subset of features (eg, hooved
vision; a problem known as associa- animal) that are equally compatible with
tive visual agnosia or optic aphasia, semantic-related words (horse, deer, cow),
as in Case 2-4), might point to a cow and so they make semantic paraphasias—
when asked to point to a horse. How- incorrect words that are semantically
ever, neither of them would try to related to the target.
32 Case 2-3
A 66-year-old accountant had sudden onset of jargon speech and could not
understand what was being said to him. He was found to have Wernicke
aphasia due to a large left temporoparietal stroke caused by new-onset
atrial fibrillation. After a few days, he began to say some intelligible words
but often made semantic paraphasias in naming pictures (eg, named a
bicycle as car). He made the same sorts of errors in conversation and
naming objects from tactile exploration. When asked to point to named
objects, he pointed to semantically related objects as often as to the correct
object. However, he was independent in activities of daily living and did
not use objects inappropriately. He called a knife a spoon but did not try to
eat soup with the knife. He also had surface dyslexia (Case 2-2).
Comment. This patient has impaired lexical semantics (so he misnames
items and points incorrectly to named items), but has spared conceptual
semantics (so he uses items appropriately). He does not understand printed
words, but can sound them out, resulting in surface dyslexia.

KEY POINTS
Case 2-4 A Anomia, or

A 72-year-old woman developed sudden inability to read or see things in impaired word
her right visual field 1 week ago. She had fluent, well-articulated, and retrieval, is
grammatical speech and did not make semantic paraphasias in conversation. well-known to
She followed directions well, except when asked to point to named pictures all of us when
or objects. In these tasks, she pointed to semantically related objects. She also we have a word
made semantic paraphasias in naming pictures or objects from vision but on the tip of
named the same objects correctly after exploring them with her hands. She the tongue.
named them accurately if they were described to her (eg, she named a This partial
pictured bird as ‘‘dog’’ but said ‘‘bird’’ when asked what animal can fly). She information
could not read accurately but tried to read by slowly reading letter by letter. often activates
However, she made some errors in identifying the letters. When words were phonologically
spelled aloud to her, she named them accurately. For example, she read chair similar words
as, ‘‘C-n-a-l-r. . . canaler?,’’ but when it was spelled to her, she said, ‘‘chair’’). for output,
She wrote accurately to dictation. She was diagnosed with optic aphasia and such that the
alexia without agraphia, secondary to a stroke in the left posterior cerebral person makes a
artery (PCA) distribution, with infarct involving the left occipital cortex phonemic
and splenium of the corpus callosum. paraphasia or
Comment. This patient has classic pure alexia or letter-by-letter reading activates
as well as optic aphasia. Since the 1880s these two clinical syndromes have semantically
been described as disconnection syndromes with the same basic account. In related words
most cases, typically a lesion in the left occipital cortex prevents visual for output, thus
information from reaching left hemisphere language cortex directly, and a making a
lesion in the splenium of the corpus callosum prevents visual information semantic
from the right occipital cortex from reaching the left hemisphere language paraphasia.
areas via the corpus callosum. Therefore, visual information cannot be A Some patients
named or read aloud. The patient, however, can name items from tactile can write
input or letters that are read aloud to her (and often resorts to tracing each names even
letter with her finger to read). Sometimes visual information can slowly when they
cross to the left hemisphere through nonsplenial white matter paths, but cannot retrieve
inefficiently and inaccurately, resulting in errors naming visual stimuli. the
pronunciation
of the names
Impaired Access to vates phonologically similar words for (despite intact
motor speech).
Modality-Independent Lexical output, such that the person makes
Other patients
Representations (Lemmas) a phonemic paraphasia (eg, calling a
The meaning of the item, or lexical horse a horn) or activates semantically
show the
opposite—the
33
semantic representation, is used to se- related words for output, such that the ability to say
lect a lexical representation or lemma patient makes a semantic paraphasia the name but
that is independent of output modality (eg, calling a horse a cow). Sometimes inability to
(oral versus written). Impairments at the partial phonologic information and retrieve the
this level of processing are manifest partial semantic information combine spelling of the
as anomia or impaired word retrieval. to result in mixed errors, such as calling same name.
This deficit is well-known to all of us a shirt a skirt (Case 2-5).
(increasingly with age) when we have a
word ‘‘on the tip of the tongue.’’ We can Impaired Access to
neither write the word nor say it, al- Modality-Specific Lexical
though we may retrieve some partial Representations
information, such as the first letter or The lemma is used to select a modality-
sound, the approximate length, and so specific lexical representation—the pho-
on. This partial information often acti- nologic representation (spoken word

Case 2-5
A 62-year-old woman developed sudden difficulty retrieving words in spontaneous speech. The
first day of her symptoms, she spoke fairly fluently, except for hesitations for word retrieval and
circumlocutions (eg, ‘‘It’s the thing you use to cut paper. . .knife. . . no, I can’t think of it’’). She
followed directions and repeated sentences well but was very poor in saying or writing the names
of objects on examination. MRI with dynamic contrast perfusion-weighted imaging showed
hypoperfusion in the left posterior middle/inferior temporal cortex, with minimal infarct. She had
severe stenosis of the inferior branch of the left middle cerebral artery (MCA). She also had low
blood pressure (mean arterial pressure of 80 mm Hg). She was given boluses of saline and
midodrine to increase her blood pressure to normal (mean arterial pressure of 100 mm Hg). A
repeat MRI showed reperfusion of the previously hypoperfused area, and repeat testing showed
resolution of her anomic aphasia (Figure 2-3).
Comment.
This patient has
pure anomic
aphasia
resulting from
acute ischemia
in an area of
cortex posterior
and inferior
to Wernicke
area. Stroke
limited to this
area or to the
left angular
gyrus or other
parts of the
parietal cortex
can cause pure
anomia. Anomic
aphasia can
also be the
residual deficit FIGURE 2-3 MRI (diffusion-weighted image showing area of acute infarct [left], dynamic
after recovery contrast perfusion weighted image showing area of hypoperfusion [right])
scans at day 1 (left) and day 2 after reperfusion therapy (right) in a patient who
from nearly had severe anomia at day 1 and recovered to normal naming at day 2 after reperfusion of
any aphasia the posterior, inferior temporal cortex.
34 subtype.
form or learned pronunciation of the ability to say the name but inability to
name) or the orthographic representa- retrieve the spelling of the same name.
tion (written word form or learned spell- Once a spoken word form or phono-
ing of the name). Patients with selective logic representation has been accessed,
impairment in accessing one or the other it is must be spoken aloud. There are
have been described (Case 2-6).4–8 Some two aspects to this process. One requires
patients can write names even when they maintaining the phonologic represen-
cannot retrieve the pronunciation of the tation (the correct sequence of speech
names (despite intact motor speech). sounds that comprise the pronunciation)
Other patients show the opposite—the while the sounds are produced, and the

KEY POINTS
Case 2-6 A Patients with

A 74-year-old woman had progressive difficulty speaking for 10 years. She apraxia of
was independent in activities of daily living, including driving. Her speech speech are
articulation was effortful, with distorted speech sounds, and limited to aware of their
nouns or short phrases with nouns. She rarely produced a complete errors and try
sentence. Her spoken output was generally intelligible. She made sound to correct
substitution errors in naming and spontaneous speech but self-corrected them, while
them. Her repetition was similar to her spontaneous speech. She followed those who
simple directions and had good single-word comprehension but had make
trouble understanding syntactically complex sentences (eg, passive voice). phonemic
In oral-naming tasks, she named nouns (objects) much more accurately paraphasias
than verbs (actions) but made some errors on both. However, she wrote are generally
the names of both nouns and verbs accurately. Her MRI showed atrophy in unaware of
the left posterior inferior frontal cortex and insula. She was diagnosed with their errors.
the agrammatic/nonfluent variant of PPA. She had impaired access to Apraxia of
phonologic or spoken word forms, in addition to some motor speech speech is
impairment (apraxia of speech). characterized
Comment. This patient had the main features of the nonfluent/ by various
agrammatic variant of PPA, including effortful, halting, distorted off-target
speech and agrammatic sentence production. She also had impaired productions
comprehension of syntactically complex sentences, which is common in this of the word,
variant. Additionally, she had impaired access to phonologic word forms, when
but spared access to written word forms, so writing was much more attempting to
accurate than speaking even for words that she could articulate well. say the same
word multiple
times, and is
more apparent
second is motor output—articulation. nemic paraphasias are generally unaware
in polysyllabic
Failure to activate or maintain activation of their errors. Apraxia of speech is often words.
of the complete phonologic representa- characterized by various off-target pro-
tion will result in phonemic paraphasias ductions of the word when attempting to A Dysarthria can be
such as substitution, insertion, and trans- distinguished
say the same word multiple times and is
from apraxia
positions of phonemes (speech sounds) more apparent in production of polysyl-
of speech by
resulting in a different word (eg, horn labic words, which require more com- its consistency
for horse) or nonwords (eg, porse for plex motor planning. Even when motor across words
horse). Articulation of the word requires planning is intact, the word might be and is
motor planning or programming of the articulated incorrectly because of dysar-
complex movements of the lips, tongue, thria, a motor speech impairment caused
associated with
weakness or
35
palate, vocal folds, and respiratory mus- by impaired strength, range, rate, or tim- reduced
cles, followed by implementation of ing of movements of the lips, tongue, range/rate of
these movements. Impairment of motor palate, or vocal folds. Dysarthria can be movement of
planning or programming of speech artic- distinguished from apraxia of speech by the muscles
ulation is sometimes known as apraxia its consistency across words (eg, the involved in
speech.
of speech and can also be manifest by same speech sound will typically be dis-
errors of insertion, deletion, transposi- torted in both short and long words
tion, substitution of speech sounds, or consistently across trials in dysarthria, but
distortions of speech sounds in the ab- is much more likely to be inconsistently
sence of impaired strength, range, or rate misarticulated in long words compared
of any of the speech muscles. Impor- to short words in apraxia of speech).
tantly, patients with apraxia of speech are Dysarthria is also associated with weak-
very aware of their errors and try to cor- ness or reduced range/rate of movement
rect them, while those who make pho- of the muscles involved in speech.

KEY POINTS
Diseases and Sites of Lesions lexical semantic representations might
A Impaired visual
Associated With Impairment be integrating in the anterior temporal
recognition, or
of Each Cognitive Process lobes bilaterally. Damage to only one
apperceptive
visual agnosia, Underlying Naming side does not disrupt the meaning of
is typically Impaired visual recognition, or apper- objects or their use, perhaps because
caused by ceptive visual agnosia, is typically caused this critical function is duplicated in the
bilateral by bilateral temporal or fusiform lesions. two hemispheres because of its evolu-
temporal or Such lesions can occur as result of head tionary importance. The most common
fusiform lesions. trauma, herpes encephalitis, top-of-the- disease affecting the bilateral anterior tem-
A Associative basilar stroke, or neurodegenerative poral lobes (usually left greater than right)
visual agnosia, disease (particularly a rare form of is the semantic variant of PPA (formerly
or optic Alzheimer disease that selectively in- called semantic dementia).17–19 Herpes
aphasia, with volves these areas known as the ventral encephalitis also can affect this area bi-
impaired access form of posterior cortical atrophy.9–12 laterally. Patients with the semantic vari-
to semantics Associative visual agnosia, or optic ant of PPA and herpes encephalitis show
from vision, is aphasia, with impaired access to seman- impaired use of objects, particularly less
typically caused familiar ones.
tics from vision, is typically caused by
by stroke in the
stroke in the distribution of the PCA. Lexical semantics refers to a subset of
distribution of
Both the left occipital lobe (including the semantic representation that de-
the posterior
striate cortex) and the splenium of the fines the word.20 Evidence from stroke
cerebral artery.
Both the right corpus callosum are damaged. Patients suggests that the posterior, superior
occipital lobe will have right homonymous hemiano- temporal gyrus or Wernicke area is es-
(including pia, such that all visual information is sential for accessing this subset of se-
striate cortex) initially processed in the right hemi- mantic information that represents the
and the sphere. However, the visual information meaning of the word.21–24 Acute infarcts
splenium cannot be transferred to the left hemi- or hypoperfusion in this area causes
of the corpus sphere language cortex to be named. impaired word comprehension, and
callosum are The patients’ visual information can only restoration of perfusion to Wernicke
damaged. access the limited conceptual informa- area can result in recovery of word
A Impaired access tion in the right hemisphere, which comprehension.20,25–27
to conceptual would allow them to produce gestures Impaired access to the lemma, or
semantics appropriate to the picture and match modality-independent lexical represen-
requires it to pictures of the same item from tation, is known as anomia. Anomia,
damage to both different views.8,13–15 manifest as inability to retrieve either
hemispheres, Impaired access to conceptual se- the spoken or the written name, can be
36 with the anterior mantics requires damage to both hemi- the residual deficit in individuals who
and inferior
spheres, with the anterior and inferior have recovered from any type of aphasia
temporal lobes
temporal lobes probably being the most caused by stroke (eg, Broca aphasia,
probably being
the most critical, critical, perhaps as an essential node caused by infarcts in the territory of the
perhaps as an or hub in a complex network that links superior division of the left MCA, or
essential node or different types of information about Wernicke aphasia, caused by infarcts in
hub in a complex items stored in separate parts of the the territory of the inferior division of
network that brain.16 Information about color, smell, the left MCA). Anomia can also result
links different and shape might be stored in parietal from isolated infarcts or hypoperfusion
types of lobes, while information about how it is in the left angular gyrus,28 left thala-
information manipulated or held is stored in the mus,29 or left posterior inferior/middle
about items frontal lobes, and how it moves is stored temporal gyrus.20,30 Restoring blood
stored in
in area MT (also called area V5), the flow to the last area can result in re-
separate parts
visual motion area of the temporal lobe. covery of oral and written naming.31
of the brain.
These aspects of the conceptual and Anomia is often the first sign of PPA, the

KEY POINTS
most disabling deficit in the logopenic result from any lesion to the subcortical
A Evidence from
variant of PPA,32 and a common deficit structures (eg, internal capsule, basal gan-
stroke suggests
in Alzheimer disease, where it likely glia), motor cortex, cerebellum, or brain- that the posterior,
results from dysfunction in the poste- stem. When it is caused by supratentorial superior temporal
rior temporal and or inferior parietal lesions, it is typically mild, unless bilateral gyrus, or
cortex. damage is present. Wernicke area is
Modality-specific naming deficits, caused an essential area
by impaired access to phonologic or for accessing the
orthographic lexical representations COGNITIVE PROCESSES subset of semantic
(ie, spoken or written word forms) are UNDERLYING SENTENCE information that
uncommon but can be observed in the PRODUCTION AND represents the
agrammatic/nonfluent variant of PPA,7 ASSOCIATED LESIONS meaning of the
word.
in which atrophy in the left poste- In a model of sentence production de-
rior inferior frontal cortex and insula scribed by Garrett (Figure 2-4), produc- A Anomia,
is present,19 or after stroke in the left tion of a sentence starts with a concept manifest as
posterior inferior frontal cortex.6,33 to be conveyed (the message level).36 inability to
Apraxia of speech occurs with damage Then, a particular syntactic structure retrieve either
the spoken or
in the same areas,34,35 caused by the and particular modality-independent con-
the written
same diseases. tent words ( lemmas) are selected at the
name, can be
Dysarthria, which is not a language functional level. Next, at the positional
the residual
deficit but rather a motor deficit, can level of representation, a sentence planning deficit in
individuals who
have recovered
from any type of
aphasia caused
by stroke.
A Dysarthria,
which is not a
language deficit
but rather a
motor deficit,
can result from
any lesion to the
subcortical
structures (eg,
internal capsule, 37
basal ganglia),
motor cortex,
cerebellum, or
brainstem.
When it is
caused by
supratentorial
lesions, it is
typically mild,
A schematic representation of the levels of representation underlying sentence unless bilateral
FIGURE 2-4
production. damage is
v = verb; n = noun; S = sentence; NP = noun phrase; VP = verb phrase. present.
Data from Mitchum CC, Berndt RS. Verb retrieval and sentence construction: effects of targeted intervention.
In: Humphreys GW, Riddoch JM, eds. Cognitive neuropsychology and cognitive rehabilitation. East Sussex,
UK: Lawrence Erlbaum Associates, 1994:317–348.

KEY POINTS
frame is created that specifies the word Impairment of the Functional
A Impairment at
the message
order, the grammatical morphemes (eg, Level of Sentence Production
level of sentence suffixes and prefixes, determiners like Impairment at the functional level re-
production is the, auxiliary verbs). Specific word forms sults in agrammatic speech with incor-
manifest by or phonologic lexical representations rect or missing verbs or other content
jargon speech, are then selected to fill the ‘‘slots’’ in the words (eg, ‘‘The girl hit the boy’’ might
which may be sentence planning frame. be produced as, ‘‘The boy was hit the
strings of words girl’’). It is often associated with anomia
that do not
Impairment at the Message and working memory deficits, as shown
make sense
Level of Sentence Production in Case 2-8. It can be caused by left
together, or
neologisms
frontal or left inferior temporoparietal
Impairment at the message level of
(nonsense lesions or atrophy (often involving
sentence production is manifest by jar-
wordlike supramarginal gyrus) as in severe log-
gon speech, which may be strings of
utterances) or a openic variant PPA and severe conduc-
words that do not make sense together,
combination tion aphasia (Table 2-1).
or neologisms (nonsense wordlike ut-
of both.
terances), or a combination of both
A Impairment at (Case 2-7). Disruption at this level is Impairment at the Positional
the functional often seen in the semantic variant of Level of Sentence Production
level results in PPA (affecting left greater than right Impairment of the positional level also
agrammatic results in agrammatic spoken output,
anterior and inferior temporal cortex
speech with
[Tables 2-1 and 2-2]), Wernicke apha- but the correct content words have been
incorrect or
sia (affecting the left superior temporal selected in this case. However, the word
missing verbs
or other gyrus [Tables 2-1 and 2-2]), and trans- order may be incorrect, or the sentence
content words. cortical sensory aphasia (affecting left may be missing determiners, auxiliary
posterior temporal/parietal or temporal/ verbs, or word endings (eg, ‘‘The boy
A Impairment of
occipital cortex). Although stroke is was kicked by the girl’’ may be produced
the positional
the most common cause of the latter as, ‘‘Girl boy kick.’’). Deficits at these two
level also results
two vascular syndromes, tumors, ab- levels often co-occur, as both are typi-
in agrammatic
spoken output, scesses, or other lesions in the same cally seen with damage to the left pos-
but the correct regions can result in the same clinical terior, inferior frontal cortex (including
content words syndromes. Broca area), as seen in the agrammatic/
have been
selected in this
38
case. However, Case 2-7
the word order
A 78-year-old woman awoke from bypass surgery with some deficits in
may be
understanding and producing language. A CT scan showed a posterior
incorrect, or
watershed stroke, an infarct in the area between the left MCA and left PCA
the sentence
in the posterior parietal and inferior temporal cortex. When she tried to
may be missing
describe her occupation as a nurse, she said, ‘‘I the things that you know
determiners,
we all wish we did with the other ones.’’ However, she added gesture and
auxiliary verbs,
intonation that convey some meaning. She made semantic errors in
or word
naming and word comprehension, but her sentence repetition was nearly
endings.
perfect. A speech-language pathologist told her family that she had
transcortical sensory aphasia.
Comment. Transcortical sensory aphasia is characterized by jargon
speech, impaired comprehension, but relatively spared sentence repetition.
It is typically a result of lesions surrounding Wernicke area, but often
posterior and inferior to Wernikce area. It can be seen in Alzheimer
disease and other dementias.

TABLE 2-1 Aphasia Syndromes and Associated Sites of Damage and Etiologies—
Vascular Syndromes
Site of
Aphasia Spontaneous Damage Most Common
Syndrome Speech Comprehension Repetition or Atrophy Etiology
Broca Nonfluent, Relatively intact Nonfluent, Left posterior, Stroke involving

aphasia agrammatic, except for agrammatic, inferior frontal left superior
articulatory syntactically articulatory cortex and division MCA
errors complex errors insula
sentences
Wernicke Fluent jargon Impaired for Fluent jargon Left posterior, Stroke involving
aphasia words and superior the left inferior
sentences temporal cortex division MCA
Global None, or Impaired for Profoundly Usually large Stroke involving

aphasia one or two words and impaired area involving the entire
perseverative sentences left frontal, left MCA
utterances temporal, distribution
(eg, no, no, no) and/or parietal
cortex
Conduction Fluent with Relatively intact Disproportionately Controversial; Stroke involving

aphasia some phonemic except for impaired usually left branch of the
paraphasias syntactically supramarginal left inferior
(eg, sleep! complex gyrus +/ division MCA
‘‘skeet, !skeep’’) sentences arcuate
fasciculus
Transcortical Nonfluent, Relatively intact Relatively spared Watershed area Left ICA stroke
motor agrammatic, except for (more accurate between left or left ACA
aphasia articulatory syntactically than spontaneous MCA and ACA stroke
errors complex speech) territories, or
sentences left medial
frontal cortex
Transcortical Fluent jargon Impaired for Relatively spared Watershed area Left ICA stroke
sensory words and (more accurate between left or stroke
aphasia sentences than spontaneous MCA and PCA involving branch 39
speech) territories or of left PCA to
left thalamus thalamus
Mixed None, or Impaired for Relatively spared Watershed area Left ICA stroke
transcortical one or two words and (more accurate between left or dementia
aphasia perseverative sentences than spontaneous MCA and ACA (eg, Alzheimer
utterances speech) and between disease)
(eg, no, no, no) left MCA and
PCA territories
Optic Normal, but Normal, but Normal Left occipital Left PCA stroke
aphasia makes errors makes errors cortex and
in naming in pointing splenium
visual stimuli to visual stimuli
MCA = middle cerebral artery, ACA = anterior cerebral artery, ICA = internal carotid artery, PCA = posterior cerebral artery.

TABLE 2-2 Primary Progressive Aphasia Syndromes and Associated Sites of Damage
and Etiologies
Primary
Progressive Site of
Aphasia Spontaneous Damage or Most Common
Syndromes Speech Comprehension Repetition Atrophy Etiology
Nonfluent/ Nonfluent, Relatively Nonfluent, Left posterior, Tauopathy

agrammatic agrammatic, intact, except agrammatic, inferior frontal (eg, corticobasal
variant PPA speech sound for syntactically speech sound cortex and degeneration,
errors complex errors insula frontotemporal
sentences lobar
degeneration)
Logopenic/ Fluent with Relatively Disproportionately Left inferior Alzheimer

phonologic some phonemic intact, except impaired parietal, disease
variant PPA paraphasias for syntactically superior
(eg, sleep! complex temporal
‘‘skeet, !skeep’’) sentences cortex
Semantic Fluent jargon Impaired for Fluent jargon Left anterior Ubiquitinopathy
variant PPA words and and inferior (eg, TDP-43)37
sentences temporal
cortex
PPA = primary progressive aphasia.
nonfluent form of PPA, and superior sentences in a way that makes the idea
division MCA strokes (Case 2-9). clear to the listener and augmenting
the words and sentences with prosody
Discourse (changes in vocal pitch, loudness, and
Normal communication requires con- duration, to add stress and intonation to
veying ideas through putting together convey emotion or meaning), gesture,
Case 2-8
A 68-year-old man had progressive impairment in speech production, characterized by marked
40 anomia, for the past 3 years. He had trouble naming pictures or sounds and thinking of words in
conversation. His speech production was slow and hesitant, with long pauses for word retrieval.
He understood conversation well. He had marked trouble repeating sentences or writing down
phone numbers that were spoken to him. In describing his work as a car mechanic he said, ‘‘I, well,
do the cars when they are . . .you know. When your car is. . .it won’t go. . . and I, you know, do it. . .and
then it can.’’ When asked to repeat the sentence, ‘‘The mechanic fixes foreign cars,’’ he said, ‘‘The
man, like me, does the cars. . .from other. . .other, you know, places. . .big places.’’ He was diagnosed
with logopenic/phonologic variant PPA.
Comment. This patient is more nonfluent than many patients with logopenic variant PPA
because he is so severely anomic. But he has islands of fluently articulated speech with no motor
speech problems in oral reading, making nonfluent/agrammatic variant PPA less likely. It is his
disproportionate impairment in repetition of sentences that is the key feature of logopenic
variant PPA in this case, along with spared motor speech and spared word comprehension.
Patients are sometimes described as having a primary progressive conduction aphasia, because of
their poor repetition and phonologic errors.

KEY POINTS
Case 2-9 A Patients

A 65-year-old man had sudden-onset difficulty with speech production, with right
with relatively good comprehension. An MRI showed a left posterior hemisphere
frontal stroke. He had mild dysarthria and mild apraxia of speech, but his middle cerebral
main problem was in formulating sentences. When asked to describe a artery territory
picture of a woman washing dishes with the sink flowing over and children stroke or other
behind her stealing cookies from a cookie jar, he said, ‘‘Woman wash disk, large lesions
no, dish. Water over to foor. . .floor. . .and oh no, two kid. . .cookie. . . of the right
steal. . .gonna fall, the stool. . .chaos!’’ When asked to repeat, ‘‘It’s a sunny hemisphere
day in Maine,’’ he said, ‘‘Maine. . .sunny day.’’ His Broca aphasia was may have
caused by occlusion of the superior branch of the left MCA. His oral trouble putting
reading of the same sentence was similar to his repetition. together a
Comment. The key feature of Broca aphasia in this case is that the concise and
patient was agrammatic in all sentence production tasks—spontaneous meaningful
speech, repetition, and oral reading. He had a motor speech impairment story, and
and relatively spared comprehension. often have
flat tone of
voice even
in trying to
and facial expression. These aspects of both hemispheres can cause similar convey
communication are more often disrup- problems. emotional
ted by right hemisphere lesions than information.
EVALUATION OF LANGUAGE
left hemisphere lesions. Patients with A The neurologist’s
right hemisphere MCA territory stroke PRODUCTION
bedside
or other large lesions of the right hemi- The neurologist’s bedside evaluation evaluation
sphere may have trouble putting to- should include short tests of oral and should include
gether a concise and meaningful story, written picture naming, naming from oral and written
and often have flat tone of voice even another modality (eg, from a verbal de- picture naming;
in trying to convey emotional infor- scription), and reading aloud. Repeat- naming from
mation (Case 2-10). Focal dementias ing words with increasing number of another
modality; and
involving the right hemisphere (eg, syllables (eg, but, butter, butterfly) is
reading aloud,
behavioral variant frontotemporal de- also important to distinguish between
repeating words
generation) or dementias that affect motor speech impairments. Sentence with increasing
number of
syllables to
Case 2-10 distinguish
41
A 72-year-old woman was found by her husband to have left-sided weakness between
and seemed confused. She was unaware of left-sided weakness initially motor speech
but later knew that she had left hemiplegia caused by a large right MCA impairments,
stroke. However, when asked why she was in the hospital she said, ‘‘I was sentence
watching baseball on TV. I like to watch baseball and my husband usually production,
watches it with me. It was a good game and the mayor was there. We like word
the mayor, we voted for him twice. He does a good job.’’ When redirected to comprehension,
explain why she was in the hospital, she continued, ‘‘Well, I was watching and
TV, and then I fell. I fell onto the carpet. It is a new carpet, with swirls in it, and comprehension
is 2 inches thick. It is a lovely color, and we got it on sale.’’ and repetition
Comment. This response illustrates the difficulty patients with right of sentences
hemisphere stroke have with getting to the point when speaking. They with various
often address the question without ever answering it. They have trouble grammatical
sorting out relevant from irrelevant information to integrate components complexities.
into a whole and meaningful picture.

KEY POINTS
production should be evaluated through Therapies that involve medications (stimu-
A Improvement of
description of complex pictures or re- lants, cholinesterase inhibitors, or do-
language
production is sponses to open-ended questions (eg, paminergic medications), transcranial
common after ‘‘Why are you in the hospital?’’). Oral magnetic stimulation, or other modal-
stroke and reading or even scrambled words (ana- ities to augment behavioral therapies
other focal, grams) to formulate into sentences (to are also under investigation.
stable lesions. tease apart agrammatism from severe
The mainstay of anomia as the cause of inability to for- SUMMARY
management is mulate complete sentences) can also be
speech and Naming and sentence production are
helpful. Assessment of word compre-
language therapy. complex tasks. Each requires a number of
hension and both comprehension and
relatively distinct cognitive processes or
A Naming and repetition of sentences with various
representations, which can be selectively
sentence grammatical complexities is essential
disrupted by focal brain damage, most
production are to distinguish among the various types
often caused by stroke or neurodegen-
complex tasks, of aphasia.
each requiring a erative disease (such as PPA). Careful
number of Treatment of Naming and analysis of the types of errors and patterns
relatively distinct Language Production of performance across tasks can provide
cognitive clues as to the localization and even the
Improvement of language production is
processes or most likely pathology in some cases. For
common after stroke and other focal,
representations, example, bilateral but asymmetric an-
which can be stable lesions. The mainstay of manage-
terior and inferior temporal damage is
selectively ment is speech and language therapy.
most likely caused by herpes enceph-
disrupted by The therapist will identify the patients’
alitis or the semantic variant of PPA,
focal brain priorities in communication and then
the latter usually associated with a
damage, most develop ways to facilitate communica-
ubiquitinopathy.38,39 These two disor-
often caused by tion to allow them to reach their goals.
stroke or
ders are easily distinguished by the
Often, therapy involves guided or cued
neurodegenerative time course (very rapid onset in the
practice in sentence production, nam-
disease (such case of herpes encephalitis, and more
ing, or other affected skills. Sometimes
as PPA). gradual, progressive course in PPA) and
the focus is on using intact modalities of
associated symptoms (eg, fever in en-
communication (gesture, drawing, etc)
cephalitis). Understanding the underly-
to compensate for speech and language
ing cognitive impairment is also useful
deficits. Sometimes anomic patients ben-
in facilitating communication with the
efit from creating a pocket-sized word
affected individual.
notebook, with pages or sections con-
42 taining names of family members, names
of friends, places they like to go, foods ACKNOWLEDGMENT
they like to eat, and so on. When they are Some of the research reported in this
unable to think of a word or name, they paper was supported by NIH (NIDCD)
can often find it in their notebook. through RO1 DC 05375.
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KEY POINTS
COMPREHENSION A Neural systems

for comprehension
HyungSub Shim, Thomas J. Grabowski are closely and
integrally related
to neural systems
supporting
ABSTRACT perception,
Comprehension is the aspect of cognition in which information is retrieved and memory, language,
consciously integrated. It occurs between the input of perception and memory, and executive
and the output of language and executive functioning. This article focuses on functioning; and
disorders of comprehension of linguistic information and semantic knowledge. disorders of
Comprehension of speech begins with the interpretation of acoustic-phonetic comprehension
input as word forms. These concepts to which the word forms are semantically are often
associated must then be retrieved, in parallel with interpretation of word order accompanied by
and grammatical marking, to achieve comprehension of discourse. Neural systems disorders in
for semantic memory are closely related to those for lexical processing. Disorders these other
of language comprehension and semantic knowledge for concrete entities give spheres.
insight into the relationship of these processes to neural systems. A Integration of
information
(cognition) is
supported in
the cerebral
INTRODUCTION hension are often accompanied by neocortex by
Comprehension is the retrieval and disorders in these other spheres. It is systems of
thus appropriate that impairments of distributed
integration of information about some-
comprehension are considered in a cortical regions.
thing of which one is aware and occurs
in concrete and abstract contexts. The number of articles in this issue.
richness and complexity of contexts that In this specific article we focus on
can be comprehended is one measure disorders of comprehension of linguis-
of intelligence. tic information, disorders of semantic
One’s own conscious processes are knowledge about concrete entities,
seamless and accessible, but the state and what is known about the relation-
of comprehension of another person ship of comprehension, in this re-
(or of a patient) must be inferred in- stricted scope, to neural systems.
directly from what is said or done.
LARGE-SCALE FUNCTIONAL
Language is particularly crucial for com-
ANATOMY
45
municating comprehension. This brief
introduction emphasizes that compre- It is generally accepted that integra-
hension in a clinical context is a ‘‘hidden tion of information (cognition) is sup-
layer’’ of cognition that must be consid- ported in the cerebral neocortex by
ered in regard to perception and mem- systems of distributed cortical regions
ory, on the input side, and to language and their supporting subcortical struc-
and executive functioning, on the out- tures. Such systems are permitted by
put side. Neural systems for compre- patterns of anatomic connectivity among
hension are in fact closely and integrally cortical ‘‘nodes,’’ which also enable
related to neural systems supporting per- nodes to be shared by more than
ception, memory, language, and exec- one system, just as many airlines can
utive functioning; disorders of compre- share one airport. The integration of
Relationship Disclosure: Drs Shim and Grabowski have nothing to disclose.

Unlabeled Use of Products/Investigational Use Disclosure: Drs Shim and Grabowski have nothing to disclose.

" COMPREHENSION
KEY POINTS
information across systems is sup- word selection, and discourse planning
A Posterior
ported by association regions, which and comprehension.
heteromodal
association act as ‘‘hub’’ nodes.
regions (parietal, Association regions are classified as COMPREHENSION OF
occipital, unimodal (related at a systems level to LANGUAGE
temporal) are the motor or to one sensory channel)
Language is the communication of in-
mainly concerned or heteromodal (related to more than
formation with a symbol system. Most
with perceiving one such sensorimotor channel and/or
and integrating natural languages use a sound symbol
paralimbic regions), depending on the
sensory system (phonology), although equally
pattern of connectivity and the pattern
information, rich and complete sign languages are
of deficit that ensues after damage.
ie, with constructed around a visuospatial sym-
For example, the unimodal areas sur-
comprehension bol system. This article will focus on
rounding the primary auditory cortex
of concrete understanding speech (see the article
entities and
in the superior temporal gyrus and
‘‘Reading, Writing, and Their Disorders’’
knowledge. posterior insula are concerned with
for consideration of reading and alexia).
higher aspects of audition and, when
A In the realm of
damaged, lead to deficits confined to
comprehension, Speech Perception
anterior systems
auditory tasks (see later discussion of
are relevant to pure word deafness). Progressively abstract levels of linguis-
phonetic Similarly, the association regions in- tic representation are extracted from
perception, terposed between visual and auditory speech, starting with the phonetic level.
syntax, word unimodal regions in the extrasylvian Phonetics links the concrete, surface
selection, and left temporal lobe are associated with features of an utterance to an abstract
discourse the integration of visual concepts and set of phonemes. Speech sounds differ
planning and auditory symbols; ie, they are the neu- from each other acoustically by the
comprehension. ral substrates for lexical-semantic inte- ratios between and the contours of
A Language is the gration (see later discussion of Wernicke their constituent formant frequencies.
communication aphasia). In general, there is a trend from These acoustic features last fractions of
of information primary cortex to unimodal to hetero- a second. This task is complicated by the
with a symbol modal association cortex for the func- facts that one phoneme many have
system. tional architecture to be characterized many phonetic forms and that same
A Phonetics links by wider receptive fields, less topo- acoustic information may be interpreted
the concrete, graphic mapping, more cross-modal differently in different contexts. Vision
surface features connectivity, and longer-range cortico- normally assists this process, as demon-
of an utterance cortical projections. As a result, heter- strated by McGurk and MacDonald, who
46 to an abstract
omodal regions span the largest di- showed that subjects interpreted ba ba
set of phonemes.
versity of subsystems. An overarching as ‘‘da da’’ when they simultaneously
A The whole-word principle that emerges from these re- saw a speaker mouth ‘‘ga ga’’ (ie, the
phonologic lationships is that the posterior heter- McGurk effect).1
form (lexeme)
omodal association regions (parietal, A higher level of abstraction is the
is the level
occipital, temporal) are mainly con- whole-word phonologic form (lexeme),
of form
representation
cerned with perceiving and integrating which is the level of form representation
associated with sensory information, ie, with com- associated with meaning. Phoneme and
meaning. prehension of concrete entities and lexeme processing are auditory associ-
knowledge, while anterior heteromodal ates that are processed in the surround
regions (frontal lobe) are mainly of the auditory cortex in the posterior
concerned with functions of an execu- superior temporal lobe.
tive character. In the realm of compre- Simultaneously, the order of and re-
hension, these anterior systems are lationships among the words are inter-
relevant to phonetic perception, syntax, preted in the process of syntax, so that

KEY POINTS
propositions may be understood. Fur- do not understand what they have
A The phonologic
thermore, the context of these propo- heard and uttered.
forms of words
sitions and their relation to each other are processed
and to the real world also affect their Pure Word Deafness using the
interpretation at the level of discourse. well-known
Pure word deafness is a deficit in the
perisylvian
ability to understand speech despite
language
Impairments of Phonetic and otherwise intact language abilities.6 The
system of
Phonologic Comprehension syndrome occurs with bilateral temporal the language-
damage or occasionally after left tem- dominant
It is well established that left perisyl-
poral damage in which a significant hemisphere,
vian strokes cause problems with pho-
disconnection between the Heschl gyrus encompassing
netic processing, identifying a critical
and the underlying structures occurs.7 the classic
role for the temporal or parietal sec-
Patients with pure word deafness are anterior (Broca
tors.2 Functional imaging studies also
acutely aware of their deficit and de- area) and posterior
demonstrate a role for the Broca area (Wernicke area)
scribe their native language as sounding
and surrounding areas in the frontal language zones.
foreign or noiselike. Although contextual
lobe. For instance, Poldrack and col-
clues and lipreading can help, they gen- A Pure word
leagues demonstrated that when the
erally are not sufficient to allow patients deafness is a
time course of recorded sentences was deficit in the
to compensate.
compressed, increased activation oc- ability to
Pure word deafness can be seen in
curred within both Wernicke and Broca understand
the absence of other auditory deficits,
areas to the point at which the speech speech despite
but this is rare. Generally, the syn-
was incomprehensible when the activ- otherwise
drome is seen in conjunction with
ity was observed to decrease.3 In fact, intact language
auditory agnosia, which is defined as
Broca aphasics have difficulty with the abilities.
the inability to identify sounds, which
perceptual distinction of similar pho-
may include environmental sounds, A Wernicke
nemes, such as b and p.4 Additionally, aphasia is
music (termed environmental sound
Broca aphasics tend to do worse on marked
agnosia), and the identity of familiar
phoneme identification tasks than those by severe
voices (phonagnosia). Unlike cortical impairment in
with Wernicke aphasia, despite having
deafness, in which loss of electrophys- comprehension
far better comprehension in general,
iologic response to sound in the bilat- of speech and
implicating the left frontal lobe, includ-
eral primary auditory cortices is present, written language.
ing the inferior frontal gyrus, in con-
in auditory agnosia the cortical re- Verbatim
scious recognition of phonemes.5
sponses are normal or only moderately repetition and
Thus the phonologic forms of words
are processed using the well-known peri-
diminished.6 naming are also 47
impaired, while
sylvian language system of the language- prosody,
dominant hemisphere, encompassing Wernicke Aphasia articulation,
the classic anterior (Broca area) and pos- Wernicke aphasia is marked by severe and fluency
terior (Wernicke area) language zones. impairment in comprehension of speech remain intact.
The sufficiency of this system for the and written language. Verbatim repeti-
comprehension and production of word tion and naming are also impaired,
forms is demonstrated most dramatical- while prosody, articulation, and fluency
ly by the rare condition of isolation of remain intact. In fact, speech may be
speech, in which the core of the middle hyperfluent but dominated by low-
cerebral artery territory that includes information content words, such as pro-
the classic language regions is flanked nouns, prepositions, and articles. This
by anterior and posterior border zone last feature points out that the prob-
infarction. Patients with this condition lem perceiving word forms is com-
are able to repeat speech verbatim but pounded by difficulty selecting them

" COMPREHENSION
KEY POINTS
for production. Invariably, paraphasic Wernicke aphasia is caused by dam-
A The relationship
age to the left posterior superior tem-
errors, both semantic and phonemic,
between verbal
symbols and occur. Patients with Wernicke aphasia poral gyrus (Wernicke area) and some-
the concepts may become frustrated when others times the surrounding areas (Case 3-1),
they convey cannot understand them; however, this typically by ischemia affecting the infe-
is termed element of anosognosia is not invariable. rior division of the middle cerebral artery.
semantics.
A The
neurophysiologic Case 3-1
basis of thinking A 45-year-old right-handed man with a long history of cigarette smoking
about words abruptly developed language and speech problems. On examination, he
must involve the had a right homonymous hemianopia. He answered and took turns in
coordination of conversation at the appropriate times, and his speech was well articulated,
activity in the fluent, and prosodic; but he made frequent phonemic and semantic
relatively distinct paraphasic errors with neologisms. He was unable to name objects and
systems initially could not follow any commands or repeat verbatim more than a
processing single syllable.
word forms and He was asked to match a printed word to one of several pictures but did
conceptual not understand the instructions and instead read the presented words. He
structure, ie, made frequent paralexic errors, such as reading recreation as ‘‘suggestion,
the perisylvian secrestidon, secreston, secreaston, the creation’’ and pouring as ‘‘pourling.’’
cortex for the His attempts at verbatim repetition mimicked the phrase length and
implementation prosody but not the content, eg, rendering the sentence, ‘‘He sold his
of word forms house, and they moved to the farm,’’ as ‘‘How hose shows does it look.
and the posterior How do they look.’’ On picture naming he could pantomime and
heteromodal sometimes describe the object’s use but could not name it. For instance,
regions for support when shown a picture of a saw, he said, ‘‘Know how to cut with this,’’
of concepts. and made a sawing motion with his hands. He was also able to
pantomime brushing his teeth when shown a toothbrush.
A In some patients,
A CT at presentation showed a left posterior perisylvian infarct, which
naming
was shown on subsequent MRI imaging (Figure 3-1) to involve the
impairment
posterior superior temporal gyrus, including the planum temporale
is the
and Heschl gyrus.
predominant or
Comment. This
only problem
patient has a
from the
classic profile of
outset. Most
Wernicke aphasia
48 such cases of
associated with
primary anomia
an infarct in the
are caused by
classic location.
damage to the
Note the two-way
extrasylvian
impairment of
cortex of the
mapping of
left temporal lobe.
phonemes to word
forms (lexemes), FIGURE 3-1 Axial and coronal T1-weighted images of
the patient described in Case 3-1. The
manifested in infarct involves the left superior temporal
defects in auditory gyrus, including Heschl gyrus, the mid and posterior superior
temporal gyrus, and planum temporale.
comprehension
and in accessing
phonologic forms for production. Semantic knowledge is probably more
or less intact, as suggested by the retained abilities to describe objects and
to pantomime.

Homonymous hemianopsia commonly
accompanies Wernicke aphasia because
of the collateral involvement of the
optic radiations, comprising an impor-
tant clinical syndrome. At times, this
presentation of stroke is misdiagnosed
because of the lack of sensory or motor
deficits.
SEMANTIC COMPREHENSION
Comprehension of Words
The relationship between verbal sym-
bols and the concepts they convey is
termed semantics. A link between a
specific phonologic form and a spe-
cific meaning is at the core of what is
FIGURE 3-2 The Wernicke-Lichtheim model, more than
meant by word. The neurophysiologic 100 years old, remains useful for representing
basis of thinking about words must functional relationships among
involve the coordination of activity in language-related regions in the brain. Wernicke proposed
an articulatory center (M, the inferior frontal gyrus, Broca
the relatively distinct systems process- area) distinct from an auditory image center (A, the posterior
ing word forms and conceptual struc- superior temporal gyrus, Wernicke area). Lichtheim proposed
the separability of B, the concept center(s) from them,
ture, ie, the perisylvian cortex for the explaining the possibility of transcortical aphasias. Disorders
implementation of word forms and discussed in this article include: transcortical sensory aphasia
(damage at point 6, disconnecting A and B); Wernicke
the posterior heteromodal regions for aphasia (damage at point 2, ie, directly to A); and pure word
support of concepts. deafness (damage at point 7, disconnecting the auditory
apparatus from A). The Wernicke-Lichtheim model does not
As we have seen, impairments of lexi- incorporate syntactic comprehension or a neural substrate for
cal selection are associated with damage concepts. As described in the text, the neural substrate of
to the phonologic regions in the poste- semantic knowledge is distributed in extrasylvian cortex. The
figure shows the lesion of a patient who survived herpes
rior superior temporal region (Wernicke simplex encephalitis and has impairments of lexical/semantic
area). When the damage is posterior knowledge, particularly for natural entities.
or inferior to the perisylvian region, Adapted from Caplan D. Neurolinguistics and linguistic aphasiology.
Cambridge, UK: Cambridge University Press, 1987:56. Reprinted with
selective impairment of access to word permission from Cambridge University Press.
meaning can occur, with sparing of the
perception and implementation of the
phonologic word form (Figure 3-2). typical of herpes simplex encephalitis or 49
Semantic anomia. In some patients, degenerative disease, a demonstrable two-
naming impairment is the predominant way breakdown of associations occurs
or only problem from the outset. Most between phonologic forms of words
such cases of primary anomia are caused and the lexical concepts they denote. In
by damage to the extrasylvian cortex of such cases of semantic anomia8 patients
the left temporal lobe, especially the left cannot name objects and cannot even
inferotemporal region, the left temporal point to them when their names are
pole, and the left temporoparietal junc- spoken. This deficit tends to occur in
tion. In many cases of primary anomia, the context of other impairments, nota-
the deficit is a one-way failure to activate bly transcortical sensory aphasia and/or
the phonologic word form for produc- visual object agnosia, and deficits of
tion, such as the familiar tip-of-the- conceptual knowledge may be present.
tongue state. However, with larger left Transcortical sensory aphasia.
or bilateral temporal lesions, eg, those Transcortical sensory aphasia is the

" COMPREHENSION
KEY POINTS
condition in which spoken and written bance of structures concerned with
A In cases of
language comprehension is impaired, maintaining representations in working
semantic
anomia, but word-form processing is spared, in memory and/or with syntactic process-
patients cannot contrast to Wernicke aphasia. Word ing per se.
name objects, forms cannot be connected to their Agrammatism in Broca aphasia.
and they referents. This leads to impairment in Agrammatism is characteristic of Broca
cannot even confrontational naming as well as com- aphasia, and we emphasize this fea-
point to them prehension. Yet verbatim repetition is ture here (Case 3-2). The production
when their spared. Other aspects of language, such is telegraphic and lacks normal word
names are as speech fluency and articulation, syn- order, grammatical markers, and func-
spoken. This tax, and prosody, are intact. tors (prepositions, auxiliary verbs, etc).
deficit tends to
Transcortical sensory aphasia is seen Nevertheless, the grammatical deficit is
occur in the
with damage that is inferior and poste- not confined to production. For in-
context of other
impairments,
rior to the Wernicke area, usually near stance, patients with Broca aphasia do
notably the temporoparietooccipital junction poorly at interpreting reversible passive
transcortical (Figure 3-2). This area is not commonly sentences, in which the subject and
sensory aphasia damaged in isolation, so transcortical object of the verb are not readily dis-
and/or visual sensory aphasia is uncommon. Patients cernable semantically (eg, ‘‘The man
object agnosia. with Wernicke aphasia occasionally im- was chased by the woman.’’). Perfor-
A Transcortical prove to fit the profile of transcortical mance on the token test, in which
sensory aphasia sensory aphasia over time but more subjects follow commands with a syn-
is the condition commonly tend toward a profile of con- tactic element, such as, ‘‘Touch the key
in which duction aphasia. and then a pen,’’ (see later discussion) is
spoken and usually impaired in Broca aphasia.
written language Comprehension of Syntax While Broca aphasia was traditionally
comprehension is Comprehension of language also de- linked to damage in the Broca area, ie,
impaired, but pends on syntax, the rules governing in the left inferior frontal gyrus, lesions
word-form
the relationship among linguistic sym- limited to this area generally cause a
processing is
bols. Although this article discusses milder deficit, and patients with Broca
spared, in
syntax and semantics separately, they aphasia usually have damage extending
contrast to
Wernicke aphasia. are processed simultaneously to form into the cortex of the surrounding
the meaning of a proposition. frontal lobe and insula, and deep to
A Patients with
It is well-known from lesion studies Broca area in the white matter.
Wernicke aphasia
that the inferior frontal gyrus plays an
occasionally
important role in syntax.4 Electrophys-
50 improve to fit
iologic and functional imaging studies Comprehension of Sentences
the profile of
also implicate left frontal regions. Syn- and Discourse
transcortical
sensory aphasia tactic anomalies evoke left frontal ac- Comprehension of discourse is a less
over time but tivity in EEG/event-related potential9 well-studied area, and no consensus
more commonly and fMRI10 paradigms; the former is exists on the neuroscience of discourse.
tend toward a absent in Broca aphasia. Other brain Factors thought to be important in dis-
profile of regions are also implicated. For instance, course comprehension include semantic
conduction aphasia. the implication of the left anterior su- coherence, working memory, compre-
A The implication perior temporal region in sentence com- hension of metaphor, and theory of mind.
of the left anterior prehension is particularly robust across For this reason, deficits in discourse com-
superior temporal fMRI studies.11 prehension co-occur with deficits in other
region in sentence A disturbance of sentence comprehen- spheres, especially executive and right
comprehension is sion is highly characteristic of Wernicke hemisphere functioning.
robust across
and transcortical sensory aphasia. This A robust relationship between ac-
fMRI studies.
impairment is possibly due to distur- tivity evoked in the temporal poles,

Case 3-2
A 65-year-old right-handed man with obstructive sleep apnea, hypertension, and dyslipidemia
was admitted for transient right upper extremity weakness and slurred speech. He underwent
angioplasty and stenting of a tightly stenotic left internal carotid artery. After the procedure, he
was mute and did not follow commands. He had a right gaze palsy, right hemiplegia, and right
hemihypoalgesia. A diffusion-weighted MRI scan (Figure 3-3) disclosed an infarct in the
distribution of the left middle cerebral artery, predominantly in the anterior division.
Overnight,
the weakness,
sensory loss,
and gaze
paresis resolved,
but dysarthria,
dysfluent
speech, and
word-finding
difficultypersisted.
He made
frequent
phonemic FIGURE 3-3 Diffusion-weighted MR images of the patient described in Case 3-2. They
demonstrate infarction in the territory of the superior division of the left middle
paraphasic errors. cerebral artery, mostly restricted to inferior frontal gyrus and anterior insula.
Object naming
was poor.
He could not repeat and comprehend phrases longer than four words. Otherwise the neurologic examination
was remarkable only for mild right facial weakness.
Neuropsychological evaluation confirmed a profile of Broca aphasia. A spontaneous writing
sample demonstrated agrammatism: ‘‘The red farm is going to painted.’’ He made errors on
the token test following commands involving more than one object. The 1-minute letter fluency
score was 3, and the 1-minute category fluency score was 20.
Comment. This patient demonstrates the key characteristics of Broca aphasia and illustrates
the characteristic agrammatism. Patients with Broca aphasia will routinely fail the token test of
speech comprehension because of syntactic deficits.
especially on the left, and compre- versus those with semantic or syntactic
hension of discourse has been con- violations.13
sistent across PET and fMRI studies. These findings suggest that the an-
For example, Xu and colleagues added terior temporal regions are integral to 51
levels of abstraction from the lexical integrating semantic and syntactic pro-
(word) level to the discourse (narra- cessing. On the other hand, lesion-
tive) level and found activation of the deficit studies do not strongly support
temporal poles only occurred at the the localization of discourse to the
level of the sentence or narrative and temporal pole. Cases of semantic vari-
was accompanied by increased activ- ant of primary progressive aphasia
ity in the precuneus, medial prefron- (PPA) tend to have relatively good sen-
tal, and temporoparietooccipital re- tence level comprehension, at least early
gions.12 Vandenberghe and colleagues on, and stroke cases with the greatest
also found that the left temporal pole deficits in discourse comprehension in-
and, to a lesser extent, the left anterior volve the posterior temporal lobe, such
superior temporal sulcus and left poste- as in Wernicke aphasia. Crinion and
rior middle temporal gyrus, were prefer- colleagues suggest the discrepancy is
entially activated with normal sentences an effect of functional disconnection.

" COMPREHENSION
KEY POINTS
They demonstrated reduced activation prefrontal cortex, angular gyrus, and
A A disturbance
of the structurally undamaged anterior supplementary motor area.19
of sentence
comprehension superior temporal sulcus of patients
is highly with Wernicke aphasia who were lis-
tening to narratives.14 Comprehension of
characteristic of
Wernicke and Beyond the level of the sentence, Semantic Knowledge
transcortical discourse comprehension relies on co- About Concrete Entities
sensory aphasia herence, the relationship among sen- The available evidence indicates that
caused by tences within the discourse and their conceptual information is supported
disturbance of relationship to the topic of discussion. by widely distributed neural systems
structures This process involves making inferen- and that these systems have a sub-
concerned with
ces based on both the information structure, with the precise systems
maintaining
in the sentences and on real world involved having something to do with
representations
in working
knowledge. In studies by St George the information content. One influential
memory and/or and colleagues and Martin-Loeches school of thought (sensorimotor the-
with syntactic and colleagues, subjects were pre- ory) posits that concepts are radically
processing per se. sented a passage whose topic would based on sensorimotor primitives. For
be difficult to ascertain without further example, comprehension of manipula-
A Agrammatism is
characteristic of
information, either with or without a tion depends on motor regions, and
Broca aphasia. title that gives the topic.15,16 These comprehension of visually based con-
fMRI studies found that greater activa- cepts depends on visual regions.
A Factors thought
tion occurred in the left parietal lobe This formulation was originally ad-
to be important
in discourse
when the passage was given with a vanced to explain category-related se-
comprehension title and was presumably better com- mantic impairments that occur in neu-
include semantic prehended. These results suggest a rologic disease (Case 3-3) but has found
coherence, working role for left parietal cortex in discourse considerable additional support in func-
memory, comprehension.17 tional imaging studies, which show, for
comprehension Evidence also suggests that the right example, a consistent activation of visual
of metaphor, hemisphere plays a role in discourse systems when semantic tasks are per-
and theory of comprehension. In the study of Xu and formed with animate entities, and con-
mind. colleagues discussed earlier, with in- sistent activation of premotor and pari-
A A robust creased complexity, an increase also etal regions and the temporal region
relationship occurred in the amount of right hemi- adjacent to visual motion area MT when
between sphere activity. Recent studies have tasks are transacted with manmade ma-
activity evoked shown right hemisphere greater than nipulable entities.20,21
52 in the temporal left hemisphere activity in higher-level The theory has gained additional
poles, especially language tasks, including comprehend- support based on topographic correla-
on the left, and
ing metaphors and jokes, drawing in- tions with specific actions. For instance,
comprehension
ferences, and sequencing events in a action words activate brain areas that
of discourse has
been consistent
narrative.18 In a study by Caplan and overlap or abut the motor strip that
across PET and Dapretto, judging the logic of a ques- would be used for those actions. For
fMRI studies. tion and a provided answer (checking instance, lick, pick, and kick activated
that answer against real-world knowl- areas that are activated by movement of
edge) activated classic language areas the tongue, fingers, and feet, respec-
(Brodmann areas 44/45,22), whereas tively.22 Sentences about actions involv-
judging a response to be off-topic (coming the hand as opposed to the arm
paring semantic information related cause a greater extent of activation in
to the question and the answer) also sensorimotor areas. Sentences about
activated those same areas in the right looking at objects activate an area in
hemisphere, as well as the right dorsal the secondary visual cortex.23

Case 3-3
A 73-year-old right-handed woman presented with trouble remembering names of people and
objects over the past 3 years. No other neurologic or psychiatric symptoms were reported. Her
mother had dementia.
On examination she was alert, vigorous, oriented to time and place, and accurately rendered
her own history. She could not name famous people, a pen, or a watch, or recall any of three
words after a delay. The Mini-Mental State Examination score was 22/30. Imaging studies
disclosed circumscribed left temporal atrophy and temporal hypometabolism (Figure 3-4).
One year
later, she
remained
competent in
daily activities,
living alone with
an organized
house and good
bookkeeping.
Her speech was
fluent but had
a paucity of
content and
included few
nouns. Speech
comprehension
was mildly
impaired.
Verbatim
repetition was
relatively
spared. Reading
was impaired,
although she
could read
single words. FIGURE 3-4 T1-weighted MRIs (left, center) and fludeoxyglucose PET images (right)
of a patient with semantic variant of primary progressive aphasia (Case 3-3).
She had marked The images show asymmetric (left greater than right) anterior temporal atrophy
and temporal hypometabolism.
up her phone
book extensively Reprinted from Grabowski TJ Jr, Anderson SW, Cooper GE. Cardinal symptoms of disordered cognition. Continuum
with notes
Lifelong Learning Neurol 2002;8(2):55. Copyright # 2002, with permission from American Academy of Neurology. 53
All rights reserved.
about friends
and
acquaintances. She often failed to recognize faces and voices of family members who dropped in
unexpectedly. She used the words ‘‘eat,’’ ‘‘drink,’’ and ‘‘get’’ interchangeably. She had difficulty
recognizing animals; eg, on one occasion she was puzzled by a firefly and on another did not
recognize an elephant at the circus. She did not benefit from written labels on food products. Her
personality had become rigid, and she insisted on doing things at certain times. At the same time, she
had become more adventurous and assertive.
Three years later, she continued to keep a neat house, kept her checkbook accurately, took
extensive notes, and made surprisingly effective use of memory-assistive strategies. She had
become more obsessive. She laboriously copied the names (which she could not read) of items
from the labels of empty boxes so that she could select replacements at the grocery store. Her
continued on page 54

" COMPREHENSION
Continued from page 53

speech was characterized by an earnest tone, elaborate circumlocution, abundant stock phrases,
and semantic paraphasias. She called her daughter her sister. She called a $20 bill 20 cents. In spite
of all this, she managed to continue to carry on written correspondence with her physician.
Comment. This is a typical case of semantic variant of PPA, a syndrome of fluent aphasia and
semantic amnesia that occurs in the setting of asymmetric (left greater than right) atrophy of
the anterior temporal lobes. The characteristic leading symptom is anomia, which is followed by
deficient aural comprehension, visual agnosia, and more pervasive semantic impairment. The
aphasia in this case could have been characterized as anomic aphasia in the early phase and as
transcortical sensory aphasia when more advanced. The semantic amnesia displayed category
selectivity, being worse for natural entities and persons, and better for manmade objects.
Sensorimotor theory has thus had dorsal temporooccipital junction; tools in

some success in explaining why seman- the left posterolateral temporal region
tics maps on to brain structure with and the temporoparietooccipital junc-
some macroscopic effects, but its ex- tion; persons in the left temporal pole).
planatory power is limited for many Lesions impairing recognition were in
categories of concrete nouns and ab- different locations from those causing
stract words, and no consensus exists corresponding naming impairments, of-
on the overarching principles of orga- ten in the right hemisphere (animals in
nization of semantic memory. Recent the mesial occipital and right ventral
work with pattern-recognition fMRI has temporal regions; tools in the left tem-
provided a powerful new tool in this poroparietooccipital junction; persons
area.24,25 in the right temporal pole).
Category-related semantic impair- The available evidence does not estab-
ments. A notable feature of semantic lish unequivocally whether category-
impairments arising from damage to the related functional segregation occurs
ventral temporal and occipital lobes is at both lexical and conceptual levels. A
that they may be category related.26 The prevalent view is that category-related
most common pattern of impairment is naming impairments are one aspect
for natural entities relative to manmade of a more general loss of semantic
objects, although the opposite pattern knowledge for the depicted entities.
has also been found.27 Such a double It may be the case that the arbitrary
54 dissociation is strong evidence that large- association between phonology and se-
scale systems for semantic knowledge mantic knowledge results in an infor-
in these two categories are somewhat mationally sparse association that is
distinct. A study by Damasio and col- more vulnerable than other aspects of
leagues in which recognition and naming semantic knowledge, explaining why
deficits were assessed for five categories small lesions and early degenerative
in subjects with unilateral stable lesions disease may present a ‘‘pure’’ anomia
found that only about 10% of subjects but larger lesions and later degenera-
with left hemisphere lesions and im- tive disease of the left temporal lobe
paired naming had impairments in all present semantic impairments.
categories.21 Most had impairment in Dementia. By far the most com-
only one or two categories.28 Lesions im- mon settings of semantic deficits in
pairing naming in each category clustered clinical practice are the degenerative
in different locations (animals in the left dementias, especially Alzheimer disease,
anterior inferotemporal region and the in which the impairments are almost

KEY POINTS
always concurrent with severe antero- is a visual modality-specific inability to
A Discourse
grade memory impairment and other retrieve the identity of a person from
comprehension
cognitive deficits. that person’s unique face. relies on
Semantic variant of primary Dynamics of neural systems. We coherence, the
progressive aphasia. A selective and have briefly reviewed what we know relationship
progressive semantic deficit occurs in about the neural basis of conceptual among sentences
semantic variant of PPA, a temporally and semantic processes from functional within the
focused frontotemporal lobar degen- imaging and lesion-deficit correlation discourse and
eration (Case 3-3). Semantic variant of studies. However, these sources pro- also their
PPA may begin as a more or less pure vide only slim clues about the dynamics relationship to
anomia, ie, a production problem but of these processes. For example, during the topic of
discussion.
is followed by a progressive two-way the recognition of a picture, processing
dissolution of the mapping of word proceeds from perception of the pic- A The available
forms and meaning; emptiness of speech ture to structural description to concept evidence
marked by use of nonspecific words, to lexical frame, but this description is indicates that
such as things; use of supraordinate cat- misleadingly serial. Although the archi- conceptual
information is
egories (eg, animal versus dog); dif- tecture of cortical connectivity is some-
supported by
ficulty with irregular word forms; and what hierarchical, information probably
widely distributed
impaired understanding of speech. Well- flows in both directions. The suggestion neural systems
designed studies suggest that nonver- has been made that an important role of and that these
bal conceptual knowledge is also im- such a pattern of reciprocal connectivity systems have a
paired. Patients do not have difficulty is to support synchronization of cortical substructure, with
with phonologic tasks, such as verbatim activity in distributed sites.31 In this the precise
repetition.29 view, the representation activated at systems involved
Atrophy is seen in the temporal each stage is not localized but rather a having something
lobes bilaterally, especially the tempo- system state resulting from interactive to do with the
ral pole and the medial and ventral processing in the convergent-divergent information
sectors. It is usually asymmetric.30 The connectional architecture of the poste- content.
associated deficits reflect tissue loss rior cortices. Thus higher processes can A A notable feature
throughout the ventral stream. Patients influence early stages of the processing of semantic
tend to have difficulty with semantic stream. In an important sense, compre- impairments
knowledge. Prosopagnosia, the inability hension is resolved at all stages of the arising from
damage to the
to recognize individuals by their faces, processing hierarchy, although some
ventral temporal
and other visual associative agnosias are nodes are critical and when damaged
and occipital
common in semantic variant of PPA, cannot be compensated sufficiently to
demonstrating an impairment of visual avoid overt failures of performance. By
lobes is that they 55
may be category
as well as lexical access to semantics. focusing on the deficits that result when related.
Disorders of conceptual knowl- neurologic disease intersects these crit-
A A selective and
edge. More or less pure impairments ical system points, this article sidesteps progressive
of conceptual knowledge can occur the interesting question of how the semantic deficit
early in right hemisphere-predominant brain really supports the integration occurs in semantic
semantic variant of PPA. The profile of of information. variant of primary
early impairment in such patients may progressive
include defective recognition and knowl- CLINICAL ISSUES aphasia, a
edge of specific persons. Patients with temporally
this syndrome of so-called progressive Evaluating Comprehension focused
prosopagnosia cannot recognize indi- Oftentimes, a comprehension deficit is frontotemporal
viduals by any modality of information apparent on interviewing the patient. lobar
degeneration.
(eg, gait, voice, or face), in distinction to Evaluating the existence and extent
classic associative prosopagnosia, which of such a deficit is crucial because

" COMPREHENSION
KEY POINTS
comprehension deficits affect the in- comb,’’ ‘‘Touch the key and then a
A More or less pure
terpretation of the rest of the cogni- pen.’’ The difficulty may be escalated
impairments of
conceptual tive evaluation. The first issue to settle by adding adjectives to distinguish
knowledge is whether the comprehension deficit pairs of items or adding grammatical
can occur occurs in the setting of a global at- complexity. ‘‘Touch the key with the
early in right tentional impairment and/or clouded black pen,’’ is an example of both.
hemisphere– sensorium. Assuming not, a basic eval- Keep in mind that performing multi-
predominant uation of language comprehension step commands is susceptible to being
semantic variant can be done at bedside or in the clinic confounded by apraxia.
of primary using the following approaches: (1) Lexical semantic processing is most
progressive yes/no questions, (2) verbal commands, conveniently assessed with picture
aphasia.
(3) picture naming, and (4) category naming (intact naming implying more
A In an important fluency. or less intact semantic knowledge)
sense, Yes/no questions require no ad- and category fluency tests in which
comprehension is vance preparation and are not con- patients are asked to generate exem-
resolved at all founded by apraxia. At least six direct, plars in a specific category (usually
stages of the
concrete questions should be asked, animals or supermarket items) in 1
processing
eg, ‘‘Am I wearing a tie?’’ or, ‘‘Is there a minute. Normal subjects can generally
hierarchy,
although some
dog in the room?’’ Normal subjects produce more than 16 items, but
nodes are critical never make errors on such questions performance is age-related such that
and when as long as they have normal auditory 14 items is normal at age 70 and 10
damaged cannot acuity. Answering two or more ques- items at age 80.
be compensated tions incorrectly is clearly abnormal.
sufficiently to Comprehension with verbal com- Neuropsychological
avoid overt mands can be tested in several ways. A Assessment
failures of simple way is to ask (verbally only) the Standardized neuropsychological as-
performance. patient to point to objects in the sessment affords important advantages
A Evaluating the room. A token test is a more sensitive over a typical mental status examina-
existence and method, particularly for detecting tion, including quantification, replicabil-
extent of a agrammatism. The informal version ity, sensitivity, and wider scope of
comprehension of this test is performed at bedside assessment. It can be invaluable in
deficit is crucial using an array of common objects, characterizing mild or early impair-
because
such as a comb, a key, two different ments, and in disorders affecting multi-
comprehension
pens, and two different coins. Simple ple spheres of cognition. It may not be
deficits affect
commands with no redundant content suitable for patients with severe impair-
56 the interpretation
or functors are given, eg, ‘‘Point to the ments of comprehension.
of the rest of
the cognitive
evaluation.
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2004;23(1):156–166.
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58

READING, WRITING,
AND THEIR DISORDERS
David P. Roeltgen, Elizabeth H. Lacey
ABSTRACT
Reading and writing are complex forms of communication. Disorders of these
abilities reflect this complexity. Although distinct syndromes do exist, it is more
common to see these disorders in the context of related dysfunction. For example,
alexia and agraphia commonly occur together. Not only do they occur together,
but frequently, although not exclusively, a patient with both has similar patterns of
performance in each modality. Reading, the transformation of written symbols
into spoken output, is intimately related to visual input and speech. Disorders of
these abilities are commonly reflected in alexia. Writing, the transformation of oral
input (writing to dictation) or conceptual thought into written symbols, is in-
terconnected with speech and motor function. Again, disorders of these abilities
are commonly reflected in agraphia. Understanding alexia and agraphia allows
insight into multiple realms of left hemispheric dysfunction and provides sig-
nificant clinical insight into patients with left hemispheric lesions.
INTRODUCTION tic impairments (dementia), and atten-

Written language is a late evolutionary tion impairments (confusional state and
arrival in human communication. As hemispatial neglect). Figure 4-1 is a
such, it is unlikely that adaptive pres- model of how the written language
sures led to its neurologic systems. systems interact with the sensory/motor
Instead, written language appears su- systems. When someone reads, the vi-
perimposed on neurologic mechanisms sual system perceives symbols (orthog-
that exist for other purposes. These raphy) that are associated with specific
neurologic mechanisms utilize symbols sounds (phonology) in order to access
and sounds to interact with meaning. meanings (semantics). When writing, 59
Understanding this basic concept allows the representation of sounds, mean-
us insight into common findings and the ings, or both is internally generated (or
clinical evaluation and research investi- generated from an auditory or visual
gation of alexia and agraphia. Disorders stimulus) and then transformed into
of written language are a common visual symbols using the motor system.
finding in lesions of the left hemisphere. The level of representation at which
They may occur with oral language these visual or written symbols are stored
deficits (aphasia), deficits of motor pro- is controversial. It could be at the whole-
cessing and output (pyramidal and extra- word level (also called the lexical level),
pyramidal impairments and apraxia), spa- the single-letter level, or in word frag-
tial deficits (constructional apraxia), visual ments. In discussing access to the
processing deficits (hemianopia), seman- written-word systems of the brain, or
Relationship Disclosure: Drs Roeltgen and Lacey have nothing to disclose.

Unlabeled Use of Products/Investigational Use Disclosure: Drs Roeltgen and. Lacey have nothing to disclose.

" READING, WRITING DISORDERS
signs, understanding medication in-

structions). Diagnosis and treatment of
acquired reading disorders are major
components of rehabilitation after ce-
rebral injury, although written language
disturbances receive much less atten-
tion than oral language disturbances.
Evidence-based behavioral therapies
show improved functional capabilities
for patients with alexia.3 These therapies
are based on understanding function
and dysfunction in alexic syndromes.
In contrast, evaluation for agraphia af-
fords diagnostic information but is less
important in therapeutics, although it
is addressed.4
FIGURE 4-1 The figure shows how written language is
decoded and produced using sensory/motor
systems. Disruption of peripheral versus
central levels of the reading and writing systems results in ASSESSMENT
different behavioral deficits.
Distinguishing types of alexia and
agraphia is accomplished through be-
havioral testing. Assessment involves non-
the orthographic lexicon, we often use language and language tests with the
the phrase ‘‘orthographic or lexical’’ latter including varying word types de-
to acknowledge that this debate is signed to display the patient’s strengths
ongoing. and weaknesses.5 Pseudowords, ortho-
Many models describe these func- graphic stimuli that follow the same
tions, their interactions, and the ana- rules as real words but are not associated
tomic regions associated with them with any meaning (eg, mub), are com-
(Figure 4-1 is a simplified model). monly used to assess phonologic ability.
Some of these models are information Words of varying classes (eg, concrete
processing or neuropsychological (box nouns dog versus function words but),
and arrow), and others are distributed varying imageability (eg, dog versus
network (connectionist) models.1,2 Most law), varying orthographic regularity
of these models include semantics, (eg, regular words animal versus irreg-
60 orthography, and phonology. Some of ular words yacht), and pseudowords
them emphasize similarities between are used to assess linguistic, language-
reading and writing, and others em- based, or central components (seman-
phasize differences. For the purpose of tics, orthography, and phonology) of
clinical understanding, we will empha- the alexias and agraphias. Additionally,
size the similarities. Alexia and agraphia as indicated in Figure 4-1, there are
may occur separately, without aphasia peripheral components. For reading,
(as in pure alexia and pure agraphia), or these components are primarily sensory
together, with or without aphasia. The and related to vision, visuospatial per-
clinical usefulness of examining for these ception, and attention. Peripheral defi-
disorders varies, depending on the cir- cits can be revealed by testing with
cumstances. For example, reading is an words of varying length (eg, law versus
essential skill and important for main- constitution). For writing, the periph-
taining independence in activities of eral components are primarily motor
daily living (eg, navigation using road related.

KEY POINTS
ALEXIAS visual-processing disorder that happens
A Written language
to be most apparent with the highly
Peripheral Alexias disorders may
complex visual stimuli involved in read- be viewed from
Pure alexia. Pure alexia, or alexia with- ing.7 One area of the left fusiform gyrus, multiple
out agraphia, is the best-known periph- referred to by some as the visual word perspectives.
eral alexia, likely because of its striking form area (VWFA) (Figure 4-2), is often One set of
clinical presentation: patients can some- involved in lesions causing pure alexia.10 differing
times write a word without difficulty The degree to which damage to this perspectives
but are unable to read what they have area contributes to pure alexic deficits concerns
written (Case 4-16).7 Some patients as well as the level of specificity with whether or not
(also called global alexics) cannot name which this area is involved in reading in the clinical
single letters.6,8 Others can identify sin- control subjects is the subject of great presentation of
alexia or agraphia
gle letters but cannot read words and controversy. In fMRI studies, the VWFA
is associated
resort to the strategy of letter-by-letter has been shown to respond preferen- with another
reading. This laborious process is ex- tially to word stimuli.10 Considering its neurologic
tremely inefficient for longer words, location at the junction of the left oc- dysfunction. A
often causing a linear increase in read- cipital and temporal lobes, it is reason- second is the
ing time with each additional letter.7 able to expect this area to be involved in degree to which
The syndrome is associated with lesions decoding visual symbols with linguistic alexia and
to left temporooccipital cortex, often significance. However, some fMRI stud- agraphia reflect
with additional damage to the splenium ies show that the VWFA is also active for the same or
of the corpus callosum or other white nonreading tasks,11 supporting the con- dissociable
matter pathways.8 Because of the lesion tention that it cannot be considered to cognitive systems.
location (Figure 4-2), most pure alexics be highly specific to word reading. A Alexia often
also have a right hemianopia and may Hemianopic alexia. Hemianopic accompanies
have visual-processing deficits unre- alexia is another peripheral alexia and oral
lated to linguistic stimuli.9 This find- is a milder disorder than pure alexia communication
ing indicates that pure alexia may be a (Case 4-2). Patients who recover from deficits.
Although
reading has
great functional
Case 4-1 significance to
A 67-year-old man presented to the emergency department with speech
patients, it
problems and confusion and was confirmed to have suffered a cerebral
usually receives
hemorrhage. A CT scan done 3 months later showed damage to left posterior
less focus in
temporal and lateral occipital lobes. Fourteen months postonset he continued
therapy.
to have some word-finding and comprehension difficulties as well as a 61
lower right homonymous quadrantopia. He demonstrated a marked length
effect in reading single words aloud. He could recognize words that were
spelled to him (31/32) but was severely impaired at reading those same words
aloud (8/32). He was also unable to read pseudowords and read nouns better
than function words, but he was able to identify all of these words with
equally high accuracy when they were orally spelled to him. He attempted to
read letter by letter but was unable to do so because his single-letter naming
abilities were impaired (10/26 to 15/26).
Comment. This patient is a severe pure alexic whose inability to identify
single letters prevents him from using a letter-by-letter compensatory
strategy to read whole words. He benefited from a therapy designed to
retrain letter naming by using the strategy of drawing the letters on his
hand, thus providing tactile-kinesthetic input.
Modified from Lott SN, Friedman RB. Rationale and efficacy of a tactile-kinaesthetic treatment for alexia. Aphasiology
1994;8(2):181–195.

posterior cerebral artery stroke and

from an acute pure alexia often have a
persistent right visual field cut. Resid-
ual reading deficits may be subtle, and
it is unclear whether they are caused
by the field cut alone or by the field
cut in addition to disturbance of the
visual word form system.12 These
patients are able to read but do so
with difficulty, reporting reduced read-
ing speed and ease.3 This complaint is
frequently underappreciated, yet it
may respond to rehabilitation.3,13
Linguistic Alexias
Phonologic alexia. Linguistic alexias are
commonly associated with aphasia. Pho-
nologic alexia is due to impairment of the
FIGURE 4-2 Areas associated with reading and writing
and the common lesion locations for their phonologic system or its connections to
major disorders. orthography and is thought to occur
SF = sylvian fissure; SMG = supramarginal gyrus; from perisylvian lesions (Figure 4-213).14
ANG = angular gyrus; STG = superior temporal gyrus; Patients with phonologic alexia have dif-
MTG = middle temporal gyrus; ITG = inferior temporal gyrus;
VWFA = visual word form area. ficulty reading words of low semantic
value, such as function words (eg, it, the)
Case 4-2
A 55-year-old man presented with sudden right lateral field vision loss
and was diagnosed with migraine and sent home. He returned 48 hours later
with persistent vision loss, headache, and nausea. He also had mild anomia,
reading difficulties, and some single-letter confusions in writing (eg, M for N).
An MRI revealed infarction of the left posterior parietal, occipital, and
temporal lobes, including the junction between inferior temporal and
fusiform gyri. One year postonset, the patient was back at work in a
high-profile media job, seemingly functioning well. He still had a right
62 superior quadrant visual loss, however, and was frustrated because of slow
reading. He felt that his work and personal life were greatly affected. His oral
reading was somewhat halting, with self-corrected errors on word endings
(eg, he initially read provide as ‘‘project’’) and greater difficulty with longer
words. However, no clear length effect at the single-word level was
measurable. He was at ceiling on all sections of standardized assessments of
memory, intelligence, and language, including naming, reading, auditory
comprehension, and writing. He participated in a rehabilitation study to
increase speed of text reading in which he showed improvement.
Comment. This case is an example of hemianopic alexia. These patients
experience residual deficits in reading that might prompt them to seek
evaluation, even when recovery appears nearly complete. Because of
their field cut, they often believe their problem is purely visual and see
an ophthalmologist.
Modified from Lacey EH, Lott SN, Snider SF, et al. Multiple oral re-reading treatment for alexia: the parts may be
greater than the whole. Neuropsychol Rehabil. 2010;20(4):601–623.

KEY POINTS
and words of no semantic value (pseudo- follow regular spelling to sound corre-
A Damage to left
words). Evidence suggests that this re- spondences and may even think they
posterior
flects patients’ reliance on the semantic are real words. For example, they might temporal/occipital
system because they commonly read report that the pseudoword sope is cortex can result
concrete words well.5 Lesions causing ‘‘what you use to wash your hands.’’ in deficits
phonologic alexia are usually in the dis- Although this type of alexia can be ob- ranging from a
tribution of the left middle cerebral ar- served after parietal or temporoparietal severe pure
tery (MCA), often involving the superior stroke, many of the patients reported in alexia in which
temporal lobe, angular gyrus, and supra- the literature suffer from the semantic patients are
marginal gyrus.15 Deep alexia is a similar variant of primary progressive aphasia.16 unable to
disorder, but patients also make seman- Tests of oral single-word reading as decode any
tic errors (eg, reading nail as hammer) described here do not measure silent words, to a right
visual field cut
(Case 4-3). These patients generally reading of text, which is the common
that may slow
have larger left hemisphere lesions that method of reading. Patients with alexia reading but does
impair semantic ability, leading to the often have impairments on tests of read- appear to
semantic errors.5,15 ing comprehension and report that they affect its
Surface alexia, another central alexia, cannot understand what they read si- linguistic aspects.
involves impaired ability to translate ir- lently. Testing oral single-word reading
A Central alexias
regular orthography to phonology and provides insight into the underlying de- include
an overreliance on regular phonology to ficits causing their text-reading diffi- phonologic
orthography correspondences. There- culties, and it is through these insights alexia, deep
fore, the hallmark error in this disorder that comprehension may eventually be alexia, and
is difficulty reading irregular words. For improved.3 surface alexia.
example, a patient using intact phono- Patients with
logic processing in an attempt to sound AGRAPHIAS phonologic and
out the written word sew might respond, Agraphia (acquired disorder of writ- deep alexia have
‘‘Sue—it’s what you do when you take ing) is common in brain dysfunction. disrupted
someone to court.’’ Conversely, these It occurs frequently from focal lesions phonology,
causing difficulty
patients can read pseudowords that of the left hemisphere. Many types
with pseudowords
like mub and
relative accuracy
Case 4-3 with real words
A 32-year-old woman suffered a left hemisphere cerebrovascular accident like tub. A
subsequent to being in a high-speed car accident. A CT confirmed a patient with
left MCA infarct with mass effect and mild midline shift. Five years after deep alexic
her injury, she continued to have significant difficulty with oral expression might read tub
63
(she was unable to provide her home address). Oral reading showed a as ‘‘washing.’’
part-of-speech effect consistent with phonologic alexia (14/41 concrete
nouns, 5/41 abstract nouns, 6/41 adjectives, 0/41 verbs, 0/41 functors). Her
errors were also consistent with deep alexia (eg, she read king as ‘‘prince,’’
and read hill as ‘‘mountains’’). She was unable to read pseudowords
and often made errors that seemed to be semantic errors for real words
similar to pseudowords (eg, she may have processed the pseudoword chun
as chin, leading to her response, ‘‘elbow’’). Despite her significant
deficits, she was able to drive and lived independently.
Comment. This patient demonstrates the complex errors that can be
encountered in patients with the more severe phonologic/deep alexia, but
also demonstrates that these patients can maintain a high quality of life
despite their deficits. This patient married, bought a house, and had a
child after her accident.

KEY POINTS
of agraphia and associated lesion lo- semantics), and, like alexia, a patient
A Patients with
cations have been identified. Writing with agraphia is assessed using pseudo-
surface alexia
have intact
requires multiple abilities, including words (eg, nud) and words of various
phonology and initiation of activity, use of semantics, linguistic types. Words with orthograph-
tend to rely grammar, correct spelling, production ically regular spellings (eg, animal) can
on regular of letter form, attention, motor coordi- be spelled using either a nonlexical
orthography to nation, praxis, and spatial ability. There- phonologic system (transforming indi-
phonology fore, unlike pure alexia, a term describ- vidual sounds to letters) or more ho-
correspondence ing a specific disorder, pure agraphia listically using a lexical or orthographic
to such a degree can describe many types of dysfunction system (transforming groups of sounds
that irregular from multiple lesion sites. Lesion stud- to groups of letters, according to a
words become ies of pure agraphia provide examples learned lexicon of spellings). In con-
difficult. They of the diversity of left cerebral regions trast, orthographically irregular words
might identify
employed in writing, including the su- (eg, yacht) can only be spelled using an
irregular words
perior parietal lobule, posterior infero- orthographic or lexical system.
like yacht as
pseudowords
temporal region, frontal premotor re- Phonologic agraphia. Impairment
and might read gion, parietooccipital junction, insular of the nonlexical or phonologic system
the pseudoword cortex, basal ganglia, and thalamus. is called phonologic agraphia.18 It is
dreem accurately Also, it is not surprising that agraphia characterized by impaired ability to spell
but identify it is the most common finding in acute pseudowords (usually tested by spelling
as the real confusional states.17 Studies have shown to dictation) with preserved ability to
word dream. that agraphia is common and diagnos- spell orthographically regular and or-
A Because writing tically helpful in determining delirium thographically irregular, familiar words
has multiple in postoperative geriatric patients and (Case 4-4). (Conventionally, writing and
cognitive in psychiatric patients. Common features oral spelling are termed spelling; for
constituents, in these patients’ writing reflect the com- the linguistic agraphias, the output,
agraphia is plex cognitive demands listed above and whether written or orally spelled, tends
a common include spatial disturbances, motor dis- to be similar.) Only rarely does impaired
clinical finding turbances, impairments of letter form, spelling of pseudowords occur as an
in acute medical and gross illegibility.
conditions,
isolated finding. Usually some impair-
The most common classification sys- ment of real words is also present. Spel-
including
tem for agraphia is based on analysis ling errors produced by patients with
confusional states,
postoperative
similar to that of alexia and typically phonologic agraphia are usually phono-
delirium, and divides the agraphias into two types: pe- logically incorrect (eg, horse for house).
psychiatric ripheral and linguistic. Unlike the sen- There may be a high degree of visual
64 delirium. sory and linguistic dissociation for alexia, similarity between the stimulus and
however, the dissociation for agraphia is the response, supporting the conclu-
primarily linguistic and motor or output. sion that ‘‘visual word images’’ may
Output systems must generate properly play a role in the functioning of the pre-
formed letters (graphemes). Allographic served orthographic or lexical system.19
information (knowledge of letter shape), Clinical-radiologic correlations demon-
praxis (knowledge of the kinesthetic se- strate that phonologic agraphia typically
quences necessary for the letter), spatial occurs from lesions of the left perisyl-
ability, and motor programming ability vian region (Figure 4-2).20 Similar to
are all required.2 phonologic alexia and deep alexia, pho-
nologic and deep agraphia are also as-
Linguistic Agraphias sociated. Patients with deep agraphia,
Similar to alexia, agraphia may reflect a in addition to trouble spelling pseudo-
disturbance of three linguistic compo- words, have relative difficulty spelling
nents (phonology, orthography, and words of low imageability (eg, law)

KEY POINT
Case 4-4 A Linguistic

A 71-year-old retired male university professor, who had above-average agraphias include
spelling and reading abilities premorbidly, was hospitalized because of a phonologic,
sudden but mild change in oral language skills. Seventeen days after lexical, and
the event, detailed written language testing showed mild anomia and semantic. These
normal reading. Testing also showed impairment of oral spelling of real disorders present
words and a somewhat more severe impairment of written spelling, with good letter
consistent with apraxic agraphia. The patient scored above 12th grade form and spelling
level on an achievement test for reading and oral spelling of single impairments
words. On additional reading and spelling tests, he scored within the that reflect the
normal range on reading and spelling real words. In contrast, he breakdown of
was impaired, compared to age-matched control subjects, on spelling the associated
two to seven phoneme pseudowords (60% correct). On CT imaging, he system, with
had a small intracerebral hemorrhage involving the posterior superior impairment of
temporal gyrus. pseudowords,
Comment. From the standpoint of written language, the results orthographically
demonstrate a relatively isolated phonologic agraphia from a posterior irregular words,
perisylvian lesion. On standard bedside neurologic testing, it is possible and homophones
that this man’s dysfunction could have gone unnoticed. respectively.
compared to words of high imageability est’’). Clinical-radiological correlations of

(eg, dog) and function words (eg, yet) semantic agraphia typically include ana-
compared to nouns. These patients also tomic regions associated with semantic
make semantic paragraphic errors (eg, processing.24
flight for propeller). Most models of spelling have a tran-
Lexical agraphia. Impairment of sition step from linguistic to motor pro-
the lexical or orthographic system is cesses, the graphemic buffer. This sys-
usually termed lexical agraphia.21 This tem is highly attention dependent and
disorder is characterized by impaired can be defined as a temporary store of
ability to spell orthographically irregu- abstract letter information prior to that
lar words compared to orthographically information being converted into spe-
regular words and pseudowords. Spelling cific written or oral letters. Similar to the
errors produced by patients with lexical findings in linguistic agraphia, disrup-
agraphia are commonly phonologically tion of the graphemic buffer shows sim-
correct (ie, yat for yacht) (Case 4-522). ilar errors in written and oral spelling. 65
Clinical-radiologic correlations of lexical The errors are more common among
agraphia typically include nonperisylvian the middle letters in the word.
lesions of the left hemisphere.2
A third linguistic agraphia, semantic Peripheral Agraphias
agraphia, reflects impaired semantics Apraxic agraphia. Apraxic agraphia
or a disconnection of semantics from may occur with or without limb apraxia
spelling.23 Patients with semantic agraphia and is characterized by impairment in
have impaired ability to incorporate the sequencing of the writing strokes.
meaning into their spelled or written Most cases of apraxic agraphia have
productions. This may present semantic been associated with lesions of the
jargon in sentences or inability to pro- dominant parietal lobe. Impairment of
duce semantically correct homophones. spatial ability is commonly associated
(eg, spelling dough when asked to spell with the neglect syndrome and is man-
‘‘doe, as in the doe ran through the for- ifested by lateralized impairment,

KEY POINT
A Peripheral Case 4-5
agraphias A 69-year-old man with mitral valve replacement and pacemaker
are typically presented with a chief concern of ‘‘I can’t read.’’ CT showed an acute
associated lesion of the superior parietal lobule, the angular gyrus, the lateral
with similar occipital gyrus, and the adjacent superior temporal gyrus. On oral
impairments language testing he had a moderate anomic aphasia. He could not read
in modalities any pseudowords and read nouns better than function words (72% versus
other than 47%). He read correctly 60% of 72 real words of one to three syllables with
writing and only a mild difference between matched regular and irregular words
present with (64% versus 56%), and he made phonologic errors. Written spelling
impairments of showed impairment of stroke sequences. Oral spelling was superior to
the letter form. writing (80% versus 10% correct on the same sample). Orally, he spelled
correctly 89% of pseudowords and, on the same 72 words that were
read, 67% of regular and 28% of irregular words. Many of his responses
were phonologically correct (ie, ‘‘epesile’’ for epistle).22
Comment. This case is an example of dissociations between reading and
spelling for phonologic processing, between oral and written language,
and between linguistic and motor processing in writing. All of the clinical
features can be explained by the lesion (parietal lobe lesion causing apraxic
agraphia and lexical agraphia, and the lateral occipital gyrus/posterior
temporal gyrus causing the phonologic alexia).
Modified from Roeltgen DP, Heilman KM. Lexical agraphia: further support for the two-system hypothesis of linguistic
agraphia. Brain 1984;107:811–827.
including writing on only one-half of the pyramidal, extrapyramidal, and ce-

the page and making errors on the ini- rebellar systems, is beyond the scope
tial letters of words.25 of this article.
Other Peripheral Agraphias CONCLUSION

After abstract letter information is stored It should be noted that for a clear
in the graphemic buffer, it is subsequently pattern of these syndromes to emerge,
converted to letters. Oral letters prob- it is often necessary to present pa-
ably require the speech systems. How- tients with long lists of words similar
ever, selective disruption of this ability to the examples given here. Variability
is very rare and has limited clinical util- is common, but careful assessments
66 ity. Disruption of the grapheme produc- have indicated that reading and writ-
tion is more common and may reflect ing are dissociable, as are the cognitive
any of the impairments described pre- components that allow us to perform
viously. Disruption of the allographic these tasks. Research into rehabilita-
store (a system that produces correct tion designed specifically for the dis-
case and font) is manifested by impaired rupted cognitive components can be
ability to accurately produce one or effective in retraining these skills, teach-
more specific fonts. Motor program- ing compensatory strategies, and im-
ming, including abilities subserved by proving quality of life.
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16. Wilson SM, Brambati SM, Henry RG, et al. The neural basis of surface dyslexia in
semantic dementia. Brain 2009;132(pt 1):71–86.
17. Chedru F, Geschwind N. Writing disturbances in acute confusional states.

18. Shallice T. Phonological agraphia and the lexical route in writing. Brain 1981;104:
413–429.
19. Roeltgen DP, Sevush S, Heilman K. Phonological agraphia, writing by the

lexical-semantic route. Neurology 1983;33(6):755–765.

20. Henry ML, Beeson PM, Stark AJ, Rapcsak SZ. The role of the left perisylvian cortical
regions in spelling. Brain Lang 2007;100(1):44–52.
21. Beauvois MF, Derouesne J. Lexical or orthographic agraphia. Brain 1981;104(pt 1):
21–49.
22. Roeltgen DP, Heilman KM. Lexical agraphia: further support for the two-system
hypothesis of linguistic agraphia. Brain 1984;107:811–827.
23. Roeltgen DP, Rothi L, Heilman K. Linguistic semantic agraphia: a dissociation of the
lexical spelling system from semantics. Brain Lang 1986;27(22):257–280.
24. Rapcsak SZ, Beeson PM. Neuroanatomic correlates of writing and spelling. In: Hillis
AE, ed. The handbook of adult language disorders. New York, NY: Psychology Press,
2002:71–99.
25. Croisile B, Hibert O. Spatial or afferent agraphia without left-sided neglect.

Aphasiology 1998;12(2):147–159.
68

KEY POINT
SOCIAL COGNITION A Social cognitive

neuroscience is
Marc Sollberger, Katherine P. Rankin, Bruce L. Miller a novel field of
interdisciplinary
research that
examines
ABSTRACT socio-emotional
Social cognitive neuroscience is a novel field of interdisciplinary research that cognition and
examines socio-emotional cognition and behavior by emphasizing the neural behavior by
substrates of these processes. Insights from this biological perspective have emphasizing
established that socio-emotional processing does not happen in a sequential order the neural
but in a recursive and interlinked fashion; that individual brain regions are not substrates of
associated with one, but multiple, distinct social functions; and that brain regions these
are organized into dynamically interacting networks. These factors explain why it is processes.
difficult to pinpoint the neural substrates of particular social deficits in patients
with brain diseases. With that said, there are specific brain regions that are highly
specialized for the perception, regulation, and modulation of emotion and behav-
ior. This article will review key aspects of social processing beginning with their
underlying neural substrates, including (1) perception of social signals, (2) social
and emotional evaluation, and (3) behavioral response generation and selection.
Case studies will be used to illustrate the real-life social deficits resulting from
distinct patterns of neuroanatomic damage, highlighting the brain regions most
critical for adequate social behavior.
INTRODUCTION factors explain why it is difficult to pin-

Social cognitive neuroscience is a novel point the neural substrates of particular
field of interdisciplinary research that social deficits in patients with brain dis-
examines the emotional and cognitive eases. While it is beyond the scope of this
processes necessary for navigating the chapter to give a comprehensive review
human social world by emphasizing the of the existing theories on the domains
neural substrates underlying these proof social cognition and their underlying
cesses.1 Multiple distinct theories about neural basis, we will provide a neuroanat-
the domains of social cognition exist, omically based overview of key social
reflecting its complexity and interdis- processes, including those implicated in 69
ciplinary character. the perception of socially relevant stimuli,
These diverse theories agree (1) that their evaluation, and the generation of
processes involved in social cognition behavioral responses. We will also em-
do not happen in a sequential order but phasize the critical roles emotional and
in a recursive and interlinked fashion; motivational functioning play in healthy
(2) that brain regions are not associated social behavior. The devastating impact
with only one, but likely multiple, social of dysfunctional emotional processing
functions; and (3) that brain regions are on social behavior, sometimes in the pres-
organized into networks, which inter- ence of quite intact cognitive functions,
act dynamically with each other. These will also be illustrated by case vignettes.
Relationship Disclosure: Drs Sollberger and Rankin have nothing to disclose. Dr Miller has received personal
compensation for editorial activities from Neurocase.
Unlabeled Use of Products/Investigational Use Disclosure: Drs Sollberger, Rankin, and Miller have nothing to
disclose.

" SOCIAL COGNITION
KEY POINTS
PERCEPTION OF SOCIAL goals of others, an effect seen in several
A Brain regions
SIGNALS fMRI studies in which superior temporal
in the
temporooccipital Perception of socially relevant signals is sulcus regions were activated together
neocortex central to successful navigation of the with other brain regions when healthy
involved in social world. Inputs relevant to social cog- individuals inferred the intentions of
encoding nition arrive via vision, audition, touch, another person.7
representations and smell. Of all the sensory systems In addition, anterior superior tempo-
of socially involved in perception of social signals, ral sulcus regions, which some label the
relevant visual we may understand vision the best. human selective voice area, play an im-
and auditory portant role in voice perception, which is
Social visual signals include infor-
signals likely also of fundamental importance in social
mation about the face, such as emo-
also play a role interactions.8 fMRI studies show that
in processing
tional expression and direction of gaze,
as well as the body, in the form of predominantly right-sided anterior su-
the emotional
socially communicative postures, ges- perior temporal sulcus regions respond
content of
these signals tures, and movements.2 Electrophysi- more to vocal than nonvocal sounds,
in concert with ologic and neuroimaging studies in more to human than animal vocaliza-
other brain animals and humans converge to indi- tions, and are involved in discriminating
regions. cate that three major visual-association voices from different persons.8
areas in the ventral occipitotemporal All these reported brain regions in the
A Posterior lesions
temporooccipital neocortex involved
causing
cortex and around the superior tempo-
ral sulcus are involved in the perceptual in encoding representations of socially
impaired
perception of representation of these socially relevant relevant visual and auditory signals likely
biological and visual signals.3–5 (1) A region composed play a role in processing the emotional
nonbiological of the fusiform gyrus and its adjacent content of these signals in concert with
signals do not inferior temporal and occipital gyri with other brain regions.9,10 We will discuss
necessarily right hemispheric dominance has been these processes in more detail in the
cause labeled as the fusiform face area, since next section.
inappropriate it is preferentially activated by static fa- Although few would argue that these
social behaviors. cial features in functional neuroimaging regions are not fundamental to social
A Upon perception studies.4 Its critical role in face recog- perception, it is important to note that
of a social nition is supported by evidence that posterior brain lesions causing impaired
stimulus damage to this area and brain regions perception of biological and nonbiolog-
from the adjacent to it is associated with pro- ical signals do not necessarily cause inap-
environment, sopagnosia, the inability to identify fa- propriate social behaviors. In fact, indi-
the organism miliar faces.6 (2) An area of the right viduals with these posterior lesions may
70 needs to lateral occipitotemporal cortex, termed become even more sympathetic and
automatically the extrastriate body area, responds friendly in social interactions (Case 5-1).
and rapidly
preferentially to pictures of the human
recognize
body, suggesting a specialized system EVALUATION OF SOCIAL
whether the
stimulus has
for processing the visual appearance SIGNALS
any personal of the human body.5 (3) More anterior
and dorsal regions of the temporal lobe, Recognizing the Salience of
relevance.
situated in and near the superior tem- Environmental Stimuli
poral sulcus, are preferentially involved Upon perception of a social stimulus
in the perception of biological motion, from the environment, the organism
such as gaze direction, as well as move- needs to automatically and rapidly rec-
ments of the face (eg, lips and mouth), ognize whether the stimulus has any
head, hands, and body.3 These signals personal relevance, essentially separat-
provide information about the actions ing signal from noise. This initial step
and, by extension, the predicted action is necessary in order to focus cognitive

Case 5-1
A 56-year-old nurse practitioner noticed that it was taking her progressively longer to read
and that her spelling was worsening. Her writing skills deteriorated also, although to a lesser
degree. In addition, she became more hesitant in unfamiliar places and had difficulties finding
routine landmarks, such as restrooms. One to 2 years later she also started having difficulty
reading the time on both digital and analog timepieces and noted word-finding and multitasking
problems. In the behavioral domain, the patient became more relaxed relative to the onset of
the disease, showing less mental rigidity, although she became anxious when she experienced
visual trouble. Her family history was significant for a father with onset of a dementia of
unknown origin at the age of 82.
Examination revealed a pleasant, fully oriented woman showing visual agnosia,
simultanagnosia, severe acalculia and visuospatial deficits, and mild anomia and agraphia.
Mild executive dysfunction was present, whereas her memory appeared totally spared. Tasks
assessing her ability to identify another person’s thoughts and feelings were normal. Caregiver
reports revealed no disease-associated changes in social graces, and the patient maintained
an active social life with an extensive network of friends. MRI showed left greater than right
atrophy of the temporooccipital and parietooccipital cortices (Figure 5-1), and amyloid PET with
Pittsburgh compound B (PiB) scan revealed amyloid deposits in the parietal and occipital lobes
with relative sparing of the frontal lobe. Symptoms progressed within the next 2 years; in
particular,
declines in
visuospatial
and executive
functions,
calculating,
confrontation
naming, and
visual episodic
memory were
observed.
Comment.
This patient’s
symptoms
and findings
are most FIGURE 5-1 Regions of patient’s gray matter loss relative to age-matched female healthy
subjects using voxel-based morphometry. Voxel based morphometry reveals
consistent atrophy of the left occipitotemporal cortex, predominantly involving the inferior and
with a medial occipital gyri. Regions of gray matter loss are superimposed on rendered and sliced images of a
diagnosis of
standard brain from a single normal subject. The sliced image is displayed in radiologic convention (left 71
is right); the rendered image with posterior view is displayed in neurologic convention (left is left).
posterior
ax = axial.
cortical
atrophy.
Based on the positive amyloid PET scan, Alzheimer disease is the most likely underlying
neuropathology. The case highlights that affliction of brain regions involved in perception
of social signals does not necessarily result in socially dysfunctional behavior. In some cases,
and to some degree in the present case, patients with posterior brain lesions become even
more sympathetic and friendly in social interactions, especially when the right hemisphere is
less affected.
resources on performing additional, this low-level salience detection pro-

more in-depth processing only on the cess, all of which have been implicated
stimuli deemed important. A number in functional and lesion studies of so-
of structures play an essential role in cial cognition.11,12

" SOCIAL COGNITION
KEY POINT
The amygdala is involved in at least that appear in an unpredictable fash-
A The amygdala is
three aspects of this salience-detection ion.19,20 Herry and colleagues demon-
involved in
recognizing process relevant to social cognition. strated in mice and humans that the
and assigning a (1) The amygdala is known to auto- amygdala was more responsive to se-
valence to matically unconsciously assign a va- quences with unpredictable tones than
sensory stimuli lence (ie, emotional and motivational to sequences with predictable tones.19
that are value associated with a stimulus) to Amygdala responses are also height-
potentially biological stimuli,13 probably facilitat- ened in response to potentially threat-
salient. ing rapid processing of their potential ening images, such as knives or guns.21
reward or punishment value. For ex- These findings suggest that the amyg-
ample, an fMRI study showed that the dala is involved in recognizing and as-
right amygdala is selectively sensitive signing a valence to sensory stimuli that
to faces that had been associated with are potentially salient.20
emotional descriptions compared to Another critical brain structure for
faces that had been associated with identifying the social salience of stim-
neutral descriptions, even when sub- uli is the insula, which represents the
jects were not consciously aware of physiologic state of the body (intero-
the relationship between faces and de- ceptive information) and brings it into
scription.14 Another study supported awareness.22 Interoceptive information
and extended these findings by show- is mapped onto the posterior dorsal in-
ing that healthy people unconsciously sula by way of the ventromedial thal-
preferred abstract images with high amic nucleus. Cortical representations
probability of food reward, whereas pa- of the interoceptive information are
tients with anterior temporal lobe re- then re-represented in the insula in a
sections that included the amygdala posterior-to-anterior fashion. As this gra-
were not influenced by these stimulus- dient moves to the right anterior insula,
valence associations.15 (2) It is well estab- higher-level information from the frontal
lished that amygdala activity influences lobes and anterior temporal structures
how more posterior occipitotemporal interacts with these representations
structures process emotional faces and to bring the physiologic condition of
bodies, in particular those faces with neg- the body into awareness (interocep-
ative valence (eg, fear).16 fMRI studies tive awareness), likely subserving sub-
show that activations of face-selective jective experience of emotions (emo-
brain regions, such as the fusiform face tional awareness).22,23 These functions
area, are enhanced in response to emo- allow the insula to rapidly evaluate in-
72 tional faces compared to emotionally coming stimuli for personal and social
neutral faces,9 an effect likely due to salience and to bring relevant stimuli
modulatory feedback from the amyg- to greater awareness.
dala.13 Lesion studies support these Often, the insula is coactivated with
findings showing decreased fusiform the anterior cingulate cortex (ACC)
cortex activations in response to fear- during autonomic arousal in response
ful faces in individuals with amygdala to salient biological stimuli. Whereas
lesions.17 Similarly, the strength of amyg- the insula has been termed limbic sen-
dala response to emotional body pos- sory cortex based on its function in rep-
tures correlates with the intensity of resenting the physiologic state of the
activations of body-selective brain re- body, the ACC has been termed lim-
gions, such as the extrastriate body bic motor cortex because of its role
area.18 (3) The amygdala seems not only in autonomic control, aspects of per-
to be implicated in salience processing formance monitoring such as error pro-
of biological stimuli, but also of stimuli cessing in effortful cognitive processes,

KEY POINTS
and behavioral drive.12,22 Integrated brain regions involved in autonomic
A The insula has
with the insula, the ACC assigns a mo- arousal such as the hypothalamus, amyg-
been termed
tivational valence to stimuli, partly by dala, insula, and OFC, as well as higher- limbic sensory
modulating first-order autonomic cen- order sensory regions in more posterior cortex based on
ters such as the hypothalamus and mo- portions of the temporal lobes. 30 Sim- its function in
tor centers such as the periaquaductal ilarly to the amygdala, the temporal poles representing the
gray region in the brainstem.24 are responsive to emotional faces.31 In physiologic
The orbitofrontal cortex (OFC), es- addition, humans who either have un- state of the
pecially its lateral part, is involved in dergone surgical resection of the right body; the
evaluating biological and, by extension, anterior temporal lobe, or have sustained anterior
social stimuli for their potential for pun- tissue loss in this area in the course of cingulate cortex
ishment. Functional neuroimaging stud- semantic variant of primary progres- has been
termed limbic
ies in humans indicate that the lateral sive aphasia (PPA), sometimes fail to rec-
motor cortex
OFC is involved in evaluating the pun- ognize personally familiar faces and/or because of
ishment value of stimuli (eg, painful voices,32,33 suggesting that the right its role in
touch, angry facial expression), likely temporal pole is implicated in coupling autonomic
facilitating a change in behavior.25 The person-specific knowledge with polymo- control, aspects
lateral OFC is also involved in the sup- dal perceptual representations.29 In con- of performance
pression and habituation to aversive trast, prosopagnosic patients with more monitoring, and
stimuli, such as a loud burst of noise.26 posterior temporal damage are solely behavioral drive.
When these functions are disrupted by impaired in recognizing familiar faces, A The lateral
lateral OFC damage, as observed in pa- but not voices, and can still identify orbitofrontal
tients with behavioral variant fronto- emotional facial expressions.6 Decoupl- cortex is
temporal degeneration (bvFTD) and pa- ing of polymodal perceptual representa- involved in
tients with OFC lesions, patients can tions from their emotional and social con- evaluating the
overreact to unpredicted stimuli or, contents might explain why lesion studies in punishment
versely, might be impaired in allocating animals and humans often associate value of stimuli
attention to novel environmental stim- right-sided or bilateral lesions of the an- likely facilitating
a change in
uli, eventually resulting in impaired goal- terior temporal lobes with abnormal so-
behavior.
directed behavior.27 Lastly, the lateral cial behavior. For example, female mon-
OFC inhibits activation of the amygdala keys with lesions of the temporal poles, A The temporal pole
during the recognition of socially salient excluding the amygdala, lose their emo- plays a role in
stimuli such as emotional faces.28 This tional attachment to peer monkeys and linking sensory
inhibitory function of the OFC probably even to their own infants.34 Similarly, emo- representations
with emotion
resets the amygdala to ‘‘baseline’’ functional detachment from close others has
tion, allowing the amygdala to resume been observed in patients suffering from
and social 73
memory.
its surveillance function for novel envi- bilateral medial and anterior temporal
ronmental signals. lobe lesions due to herpes encephalitis,35
The temporal pole, particularly on the and in patients with semantic variant of
right side, is not directly involved in au- PPA showing predominantly atrophy of
tonomic arousal in response to salient right anterior temporal regions.36
stimuli but does play a role in linking sen- In semantic variant of PPA, neuro-
sory representations with emotion and degeneration primarily affects right or
social memory, providing higher-level in- left anterior temporal regions, consis-
put into the decision about whether a tently including the temporal poles, and
stimulus is emotionally and socially sa- subsequently involves contralateral tem-
lient.29 The functional role of the temporal regions and also insular and
poral pole is reflected by its structural orbitofrontal regions37; thus this condi-
connectivity. In monkeys, the temporal tion provides important information
poles are highly interconnected with about the role of the right temporal pole

" SOCIAL COGNITION
KEY POINTS
in human social behavior. Patients with work of these brain regions. This ‘‘sa-
A Patients with
semantic variant of PPA with right-sided lience network,’’ which likely serves as a
semantic variant
of primary involvement typically show abnormal so- gateway to emotional states and emo-
progressive cial behavior, including social withdrawal tional awareness, has further been shown
aphasia with associated with emotional distance, bi- to share structural covariance in normal
right-sided zarre facial expressions, irritability, im- brains and to be preferentially damaged
involvement pulsiveness, mental rigidity (including in bvFTD.41
typically show both obsessions and compulsions), and
abnormal social disruption of physiologic drives (eg, ap- Emotion Recognition/
behavior, petite, sleep) (Case 5-2).36,38 Interest- Subjective Experience of
including social ingly, some of these patients exhibit Emotion
withdrawal fixed facial expressions, although they Once a stimulus is identified as per-
associated with
report that they feel happy, and have sonally relevant, it immediately takes
emotional
distance, mental
difficulties in posing different facial ex- on an emotional and motivational va-
rigidity pressions. Another common feature of lence. Because of this, the cortical and
(including both these patients is the dissociation be- subcortical brain regions implicated in
obsessions and tween ‘‘cold’’ and ‘‘hot’’ reasoning about identifying the salience of environmen-
compulsions), social situations. The cognitive func- tal stimuli are also key regions in emo-
and disruption tions required for evaluating and react- tion recognition and the subjective
of physiologic ing to complex situations in life (eg, experience of emotion. These overlap-
drives. knowing what measures to take in a ping functions have been highlighted
A The salience medical emergency and acting accord- by Seeley and colleagues, who showed
network, which ingly) might be still quite intact, but that subjects’ self-ratings of anxiety cor-
likely serves as a their awareness of another person’s feel- relate with the level of functional connec-
gateway to ings (empathy) is often decimated.36 tivity of the dorsal ACC of the resting-
emotional states This dissociation may explain why these state salience network.40 The role of this
and emotional patients are often perceived as cold and intrinsic connectivity network in emo-
awareness, has arrogant in social interactions.39 tion recognition and emotional states
been shown to Viewed individually, it is clear from is corroborated by other studies show-
be preferentially the established functions of these key ing functional or structural involvement
damaged in
cortical and subcortical brain regions of these structures in social and emo-
behavioral
variant
that they are implicated in recognizing tional cognition. In individuals experi-
frontotemporal the salience of environmental stimuli encing both autonomic and emotional
degeneration. and have relevance to social and emo- arousal in response to various socially
tional functioning. Furthermore, recent salient stimuli, such as viewing faces
74 A Cortical and
evidence unequivocally supporting the of loved ones42 or social rejection,43
subcortical
tight functional integration of these the ACC and anterior insula are often
brain regions
implicated in
structures comes from functional con- coactivated. Internally inducing states
identifying the nectivity analyses of healthy human of emotion by recalling personally rele-
salience of brains.40 In a task-free state, Seeley and vant emotional events also coactivates
environmental colleagues showed that blood oxygen- the ACC and insula.44
stimuli are also ation level-dependent (BOLD) signal This link between the perception and
key regions in fluctuations of the amygdala, anterior experience of emotions is one mecha-
emotion insula, dorsal ACC, and portions of the nism by which observing another’s emo-
recognition and right temporal pole, together with brain tional state can automatically induce the
the subjective regions mostly implicated in homeo- same emotion internally. Electrophys-
experience of static regulation and emotion such as iologic and functional neuroimaging
emotion.
brainstem regions or the ventral stria- studies in animals and humans con-
tum, covary across time, indicating an verge to indicate that regions that are
intrinsically connected functional net- activated by observing another person

Case 5-2
A 55-year-old accountant noted increasing difficulty recalling names of persons and objects. He also
slowed down in reading and became impaired in comprehending and spelling common words. In
addition, he had increasing difficulty recognizing familiar faces, up to the point that he was unable to
differentiate between his two daughters. Around the same time, behavioral changes appeared,
the first signs of which were a series of major life events within a short time period, including the loss
of his job, likely because of interpersonal conflicts, and the divorce from his wife. At this time he
was severely depressed and had suicidal ideas. Based on his brother’s report he started to show little
respect for personal boundaries, especially with women, and developed rigid, obsessive eating
behaviors based on books he read. Likely due to his diet regimen, he lost 7 kg (15 lbs) to 9 kg (20 lbs)
within 2 years. The patient also seemed impaired in perceiving other persons’ social signals; eg, he
would keep on talking even when the other person clearly appeared uncomfortable. He evidenced
deficits in emotional control, in particular for positive emotions; eg, when talking to a family member
on the phone he sometimes became euphoric and occasionally burst into tears. Family history was
notable for a dementia syndrome in the Parkinson spectrum in his father and early-onset Alzheimer
disease in his paternal grandmother.
On examination, he showed little eye contact and his affect was exceptionally flat. On a couple
of occasions, though, for example when being asked to smile, the patient’s eyes became tearful,
occasionally followed by laughing. He stated that he had a water problem in his head, which
explained why he would cry too much when he was happy. During conversation he made several
semantic
paraphasic
errors and
frequently
used
nonspecific
words such as
‘‘stuff’’ and
‘‘thing.’’ He
was severely
impaired in
naming and
drawing
objects; ie, his
drawing of a
snake included
two feet.
He hardly
75
recognized
any famous
faces and had
almost no
knowledge
about famous
people. He FIGURE 5-2 Regions of patient’s gray matter loss relative to age-matched male healthy
subjects using voxel-based morphometry (VBM). VBM reveals predominantly
evidenced right-sided anterior temporal lobe atrophy, including the temporal pole,
amygdala, anterior fusiform and parahippocampal cortices, and the inferior temporal gyrus and
some mild predominantly right-sided insular atrophy. Regions of gray matter loss are superimposed on
executive rendered and sliced images of a standard brain from a single normal subject. Images are displayed
dysfunction, in radiologic convention (left is right).
whereas cor = coronal; ax = axial.
verbal and

" SOCIAL COGNITION

nonverbal episodic memory and visuospatial functions were preserved. He was severely impaired at
labeling the emotions he saw in brief videos and was unable to recognize when someone spoke
sarcastically, although he had good comprehension of sincere social exchanges. Caregiver reports
on his interpersonal behavior revealed decreased extraversion and assertiveness, and greater
coldness relative to his premorbid personality. MRI showed moderate right greater than left
atrophy of the anterior temporal lobes, the insula, and the anterior cingulate cortex, and mild
right-sided orbitofrontal and caudate atrophy (Figure 5-2). Amyloid PET-PiB scan was negative,
and fluorodeoxyglucose (FDG)-PET showed predominantly right-sided anterior temporal
hypometabolism. Within the next 2 years symptoms further increased, with further losses of
caregiver-rated empathy. In addition, his hygiene deteriorated and he became impaired in activities
of daily living; ie, his brother started managing his finances.
Comment. This patient’s syndrome is most consistent with a diagnosis of semantic variant of PPA,
the temporal variant of frontotemporal degeneration, with features of temporal lobe involvement
on the right (emotional blunting, impaired perception of social cues, and prosopagnosia) and left side
(anomia and semantic loss). In this case, symptoms related to right temporal involvement started
somewhat earlier than left temporal symptoms, and this dissociation is reflected by the right
predominance of his temporal atrophy. Typically, patients with predominantly left-sided semantic
variant of PPA, who are more often reported in the literature than patients with right-sided semantic
variant of PPA,38 initially have near-normal social behavior, while their behavior becomes increasingly
disordered with the advent of right-sided involvement.
experiencing pain, emotion, or action emotional functioning, studies have

largely overlap with regions that are not established whether these regions
activated by experiencing those phe- are critical for understanding another
nomena, an occurrence sometimes re- person’s intentions or emotional ex-
ferred to as shared representations.45 periences, or merely play a supportive
For example, parts of the cortical net- role. In addition, as we will discuss later,
work (ie, inferior parietal, inferior frontal this automatic overlapping of actions
pars opercularis, and premotor regions) and emotions belonging to the self and
activated when an individual is observ- other is not sufficient to fully infer the
ing another person performing a mo- other’s mental state, which requires
tor action are also activated while that additional processes, such as correct
individual is performing that action.46 attribution of agency and effortful, high-
This ‘‘mirror’’ neuron system allows us level executive operations.
76 to automatically and covertly simulate Human lesion studies also support the
another person’s actions and may pro- interconnection of salience, arousal, and
vide a basis for understanding another emotion. Insula lesions interfere with
person’s intentions, since this system the ability to process aversive sensory
seems to encode the goal of an ob- stimuli, in particular facial and vocal
served action. A similar role for mirror expressions of disgust,48 and ACC le-
neurons in emotion sharing has been sions (including medial prefrontal re-
suggested, because similar brain regions Brodmann area 9) alter patients’
gions, including the anterior insula and capacity for both identifying and ex-
ACC, are activated when observing periencing emotions.49 Furthermore,
another person experiencing pain or decreased gray matter volume of the sub-
expressing an emotion as also when genual ACC is observed in patients with
experiencing one’s own pain or emo- emotion regulation disorders, such as
tion.47 While shared representations major depression and bipolar disorder.50
may be important for optimal socio- Importantly, rostro-ventral portions of

the ACC and the right greater than left in personality toward introversion and
anterior insula are among the earliest passivity, impaired insight into behav-
and most consistently affected brain re- ioral changes, and poor judgment.52
gions in patients with bvFTD.51 bvFTD
is characterized by early, striking social
behavior changes, which typically pre- Self-Other Distinction/
cede major cognitive deficits (Case 5-3). Attribution of Agency
Early behavioral symptoms include apa- In the previous section, we described
thy, loss of social inhibitions, changes the neural mechanisms underlying
Case 5-3
A 62-year-old physician became progressively more aloof, exhibiting increased insensitivity to
others. On one occasion he abandoned his two 3-year-old grandchildren at night a block from
their house, believing they could return home on their own. One to 2 years later, he started to
behave in a sexually inappropriate manner toward different women, to eat voraciously (subsisting
on junk food, pizza, and ice cream), to drink wine heavily, and to misuse medications such as
diazepam (up to 30 mg a day). On several occasions, even after being explicitly told not to do so,
he entered his neighbor’s garage and stole liquor. The patient lacked any insight into the
inappropriateness of his actions. Family members reported that he also showed impaired decision
making and
problem
solving in daily
life situations,
eg, shuffling
boxes around
without
purpose
during a
family move.
Family history
revealed no
neurologic or
psychiatric
disorders
apart from
myasthenia
gravis of
77
the patient’s
father.
The
neurologic
examination
was normal FIGURE 5-3 Regions of patient’s gray matter loss relative to age-matched male healthy
subjects using voxel-based morphometry (VBM). VBM reveals predominantly
apart from a right-sided atrophy of the frontal lobe, including the orbitofrontal cortex and the
proximal medial prefrontal and dorsolateral prefrontal cortices. In addition, there is atrophy of the right
symmetric anterior caudate nucleus, right anterior insula, and the right anterior temporal lobe, in particular
the temporal pole. Regions of gray matter loss are superimposed on rendered and sliced
weakness of images of a standard brain from a single normal subject. Images are displayed in radiologic
the upper convention (left is right).
and lower cor = coronal; ax = axial; sag = sagittal.
extremities.

" SOCIAL COGNITION

Standard neuropsychological test scores were within the average range apart from mild
impairments in verbal generation and a complex executive task requiring a combination of
set-shifting and verbal response inhibition. Despite his quite preserved cognitive skills, his
emotion recognition for faces and voices was impaired, as was his ability to detect sarcasm and
deception and to adopt another person’s perspective. Based on caregiver reports, his empathic
concern for others was abnormally low and had decreased substantially since disease onset. MRI
revealed right greater than left medial prefrontal, orbitofrontal, insular, and anterior temporal
atrophy (Figure 5-3).
The patient died 12 months after the first evaluation as a result of sepsis, probably caused by
an invasive chondrosarcoma. The neuropathologic pattern was consistent with Pick disease, showing
tau-positive neurons especially within the hippocampus and the temporal lobe, ballooned
achromatic neurons in the cingulate gyrus, and scattered tau-positive astrocytes within the
cerebral cortex and subcortical white matter.53
Comment. This patient suffered from Pick disease, and his clinical presentation met diagnostic
criteria for bvFTD. Despite quite intact executive functioning, he was impaired in high-level
socio-cognitive tasks involving his ability to adopt another person’s thoughts and feelings. This
discrepancy has been observed frequently in other patients with bvFTD, suggesting that while
impairment in executive functions as measured by standard neuropsychological tests is not necessary
for failure of these high-level socio-cognitive tasks, the ability to concurrently recognize and
experience emotions plays an essential role.
shared representations and suggested studies indicate that the right temporo-
that others’ fundamental emotional and parietal junction is critical for attributing
motivational states can be automatically a sense of agency, ie, comparing self-
mirrored in one’s own internal state. generated and other-generated actions.56
While this is an important initial step Transcranial magnetic stimulation ap-
toward understanding others, additional plied over the right inferior parietal
cognitive processes are required to cortex to generate transient functional
recognize where the self ends and the lesions causes impaired discrimination
other begins. Without self-other dis- between one’s own face and other famil-
tinction, our interpretation of others’ iar faces.57 Similarly, electrical stimula-
behavior remains egocentric and inaccu- tion of this region causes out-of-body
rate.54 Self-other distinctions set the experiences (ie, the experience that
stage for perspective taking and allow an one’s body is no longer one’s own),58
78 internal emotional state generated by and damage to this region is associated
perceiving another’s emotion to tran- with unawareness of paresis and mis-
scend the level of primitive emotional identification of one’s own limbs. The
contagion and lead to a mature empathic temporoparietal junction is an essen-
response (eg, ‘‘It makes me sad that her tial part of the right-lateralized ventral
dog died, but it was her dog, not mine, attention network, which reorients at-
so I should be comforting her’’). tention to salient, novel stimuli in both
Neuroanatomically, the right inferior visual and auditory modalities.59 In a
parietal cortex at the junction of the pos- social context, it seems to function in
terior temporal cortex (the temporo- part as an ‘‘other detector,’’ interrupt-
parietal junction), plays an important ing ongoing cognitive processes to alert
role in identifying who initiated an emo- one to the presence of an agency that is
tion or action intention and provides a not one’s own, and diverting attentional
basis for distinguishing the self from resources toward this potentially impor-
the other.55 Functional neuroimaging tant stimulus. While many studies have

KEY POINTS
shown activations of the temporoparietal cessful social interactions require one
A Automatic
junction in the context of social per- to make an effort to identify where the
overlapping of
spective taking, they suggest that it co- other’s perspective differs from self- actions and
activates with medial frontal structures. perspective.45 Even one’s own self- emotions
While the right temporoparietal junc- perspective differs across time, such belonging to
tion is involved in more low-level aspects that one’s current desires and drive the self and
of making self-other distinctions, right states can influence what one believes other is not
dorsomedial prefrontal regions perform one might have thought or done in sufficient to fully
the more abstract functions involved in the past or would think or do in the infer the other’s
mental state attribution.55 future.54 Thus, the ability to accurately mental state.
estimate even one’s own perspective, A Behavioral
HIGH-LEVEL SOCIAL-COGNITIVE much less another’s perspective, can variant
PROCESSING AND BEHAVIORAL require elements of mental time travel frontotemporal
RESPONSE SELECTION as well as self-regulation. (1) The ability degeneration is
The socio-emotional functions described to project oneself into the past or the characterized
in the previous two sections are com- future is partly mediated by a network by early,
paratively primitive and are hard-wired of structures often called the memory striking social
behavior
into the human brain, meaning that network or the default mode network,
changes, which
they are fairly robust, show little vari- which includes medial frontal as well
typically
ability across individuals, and do not as parietal and hippocampal regions.60 precede major
require much education, effort, or gen- Notably, patients with autistic disorder, cognitive
eral intelligence. Clearly, however, many who are impaired in adopting another’s deficits.
aspects of social cognition are suscepti- mental or emotional perspective, show A Without
ble to environmental factors, such as de- decreased activity in this time travel net- self-other
velopmental milieu and cultural training, work when simply lying in the scanner distinction, our
as well as intrinsic factors, such as gen- without performing any task, ie, in the interpretation
eral fluid intelligence and temperament. resting state.60 (2) Effortful self-regulation of others’
Individual differences in capacity for is also required for accurate high-level behavior
remains
these higher-level social functions ac- perspective taking, because the ability
egocentric and
count for the tremendous variability in to set aside one’s own current perspec-
inaccurate.
social skills and personality across nor- tive requires both mental flexibility and
A The
mal persons, and only part of this can active inhibitory processes,45 abilities that temporoparietal
be explained by neural factors. How- to some degree overlap with traditional junction plays
ever, some higher-order components executive functions and may be median important
of social functioning, such as the abil- ated by frontopolar, dorsolateral frontal, role in
ity to perform complex reasoning about and parietal structures. identifying
79
another’s perspective, do rely on spe- Functional neuroimaging studies who initiated
cific neural networks. of self-perspective taking and other- an emotion
perspective taking reveal a variety of ac- or action
Adopting Another’s tivations, usually including dorsal and intention and
Perspective rostral medial prefrontal cortex and ad- provides a
basis for
One’s ability to create shared representa- jacent paracingulate cortex, the right
distinguishing
tions and simulate others’ emotions pro- posterior superior temporal sulcus, the the self from
vides a basis for understanding others; right temporoparietal junction, and the other.
however, one’s representations of the the temporal poles.61 Of these regions,
other are rooted in one’s personal the medial prefrontal cortex and adja-
knowledge, attitudes, and beliefs de- cent paracingulate gyrus are the most
rived from life experiences. This means consistently activated regions when
that one’s own perspective is the default adapting another person’s perspective.
mode of the human mind; thus, suc- Results from lesion studies, however,

" SOCIAL COGNITION
KEY POINTS
are less consistent. While Shamay-Tsoory cits abound. For example, both patients
A Successful social
and colleagues found that right medial with bvFTD and with Alzheimer disease
interactions
require one to prefrontal lesions were the region most are impaired on inferring mental states,66
make an effort likely to be affected in frontal lesion although in patients with Alzheimer dis-
to identify patients with abnormal perspective tak- ease impaired cognitive perspective-
where the ing,62 other studies have pointed out taking ability is likely primarily the result
other’s that focal lesions of the dorsomedial of cognitive deficits such as impaired
perspective prefrontal cortex and/or ACC do not working memory and set-shifting. In con-
differs from necessarily result in impaired perspec- trast, patients with bvFTD and patients
self-perspective. tive taking of mental states such as with OFC lesions, but not patients with
A The medial thoughts and intentions.63,64 These find- Alzheimer disease, are impaired in infer-
prefrontal ings suggest that perspective taking, or ring emotional experience.67
cortex and more broadly, the ability to correctly While the ability to imagine what
adjacent infer others’ thoughts and intentions, another person thinks is important,
paracingulate does not rely solely on dorsomedial pre- it should not be considered a marker
gyrus are the frontal structures, but probably also on for healthy social skills. Cognitive per-
most the other brain regions of the network, spective taking can remain intact in
consistently
ie, right posterior superior temporal patients with dysfunctional social be-
activated
sulcus, right temporoparietal junction, havior,68 suggesting that the ability to
regions when
adapting
and the temporal poles. While these understand another person’s inten-
another other regions seem not uniquely as- tions is not adequate to prevent social
person’s sociated with mental state inference, deficits. In contrast, loss of emotional
perspective. they provide supportive information perspective taking or lack of empathy
by recognizing goal-directed behavior is consistently associated with dysfunc-
A The medial
orbitofrontal
(posterior superior temporal sulcus), tional social behavior, highlighting the
cortex is far distinguishing between one’s own and crucial role of intact emotion process-
more recruited others’ agency and intentions (right tem- ing on social behavior.
in emotional poroparietal junction), and retrieving
than in cognitive semantic and autobiographical knowl- Behavioral Regulation
perspective edge (temporal poles). Having understood the other person’s
taking. While both cognitive and emotional thoughts and feelings, one must reg-
A Loss of emotional perspective taking can share these time ulate one’s behavioral response in a
perspective travel and executive functioning ele- manner appropriate to the context. Be-
taking is ments, cognitive perspective taking (the havioral regulation involves top-down
consistently capacity to attribute mental states such control processes, including both emo-
80 associated with as thoughts and intentions, or cognitive tion regulation and integration of atti-
dysfunctional theory of mind) can be distinguished tudes with external social context. These
social behavior. from emotional perspective taking (the processes are primarily mediated by a dor-
capacity to attribute emotional experi- solateral and ventrolateral prefrontal net-
ences, emotional theory of mind, or em- work, but also by dorsomedial prefrontal
pathy). Emotional perspective taking is regions, including the dorsal ACC.27
based on the more fundamental capac- The capacity for emotion regulation
ity to automatically and covertly simulate has a particularly critical influence on
another’s emotions, utilizing the ventro- maintaining adequate social behavior.
medial frontal circuits described earlier. One important strategy for emotion
A recent fMRI study revealed that the me- regulation is known as cognitive reap-
dial OFC is far more recruited in emotional praisal and involves the conscious rein-
than in cognitive perspective taking.65 terpretation of the meaning of an emo-
Clinical dissociations between cognitive tional experience in order to change the
and emotional perspective-taking defi- emotional response. Effective reappraisal

KEY POINTS
is associated with better interpersonal functions from vision and sensorimo-
A Primarily
functioning and psychological and tor processing to attentional control and
neocortical,
physical well-being.69 Interestingly, ac- memory. These functional networks dorsal
tivations of brain regions involved in closely match structural networks in hu- prefrontal
emotion reappraisal modulate the ac- mans, as revealed by diffusion-tensor regions exert
tivity of emotion-processing regions, imaging tractography71 and structural control over
such as the amygdala, subgenual ACC, covariance studies.41 Identification of limbic/paralimbic,
ventromedial prefrontal cortex, and in- how these intrinsically connected net- ventral
sula.70 These relationships imply that works work together to support dif- prefrontal, and
primarily neocortical, dorsal prefron- ferent aspects of social cognition may anterior
tal regions exert control over limbic/ provide a new level of explanation to temporal
paralimbic, ventral prefrontal, and ante- existing theories about brain-behavior regions to
modulate
rior temporal regions to modulate emo- relationships.
emotional
tional experience and autonomic arousal. While extraordinary advances have experience and
Brain regions involved in cognitive con- been made in social cognitive neurosci- autonomic
trol of emotion are important for attenu- ence because of task-based functional arousal.
ating emotional distress, thus facilitating imaging studies, studies of humans with
goal-oriented interpersonal behavior, but brain lesions are still required to demon- A A greater
emphasis is
they seem not as critical for adequate strate causality in neuroanatomic mod-
placed on
emotional and social behavior as the phy- els of emotion and social cognition. One
identifying the
logenetically older emotion-processing alternative to patient-based research, interactive
regions situated in the ventromedial pre- which by necessity has relied on obser- neural networks
frontal and anterior temporal cortices. vational rather than experimental re- that underpin
search designs, might be the application social and
FUTURE DIRECTIONS of the noninvasive transcranial magnetic emotional
The trend is moving away from re- stimulation to healthy humans. Trans- functioning.
ducing social and emotional cognition cranial magnetic stimulation, which in- A Human lesion
down to the functions of single brain duces transient changes in brain activity studies are still
regions, and a greater emphasis is be- by rapidly changing magnetic fields, has required to
ing placed on identifying the interac- already been used to isolate neuroana- demonstrate
tive neural networks that underpin so- tomic structures underlying higher so- causality in
cial and emotional functioning. One cial cognitive processes such as decision neuroanatomic
recent technical development in fMRI making72 and perspective taking.73 In models of
has made it possible to identify these net- combination with observational studies emotion and
works by showing which brain regions of brain-damaged patients showing aber- social
functionally covary in task-free resting- rant social behavior, such as patients with cognition. 81
states. This approach, applied to healthy bvFTD, the temporary lesions created by
individuals, has revealed a number of this experimental intervention can more
highly reproducible intrinsically con- precisely characterize the neural basis of
nected networks that are involved in social and emotional processes.
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KEY POINT
A Apraxia is
defined as an
APRAXIA
inability to Kenneth M. Heilman
correctly carry
out purposeful
skilled
movements ABSTRACT
when this Humans need to perform skilled movements to successfully interact with their envi-
deficit is not ronment as well as take care of themselves and others. These important skilled
caused by purposeful actions are primarily performed by the forelimb, and the loss of these
elemental motor skills is called apraxia. This review describes the means of testing, the patho-
or sensory deficits, physiology, and the clinical characteristics that define five different general forms
abnormal of forelimb apraxia including: (1) ideational apraxia, an inability to correctly se-
involuntary quence a series of acts leading to a goal; (2) conceptual apraxia, a loss of me-
movements, chanical tool knowledge; (3) ideomotor apraxia, a loss of the knowledge of how
or cognitive when making transitive and intransitive movements to correctly posture and move
disorders. the forelimb in space; (4) dissociation apraxia, a modality-specific deficit in elicit-
ing learned skilled acts; and (5) limb-kinetic apraxia, a loss of hand-finger deftness.
INTRODUCTION apraxic agraphia). Because of space lim-

The two major goals of humans’ brains itations these task-specific disorders
are to maintain body homeostasis and will not be discussed in this article. In
to allow us to successfully interact with this article, however, we will discuss
the environment. It is the upper limbs the forms of forelimb apraxia that are
or forelimbs that perform most of the general and can impair almost all pur-
interactions with objects in the environ- poseful movements made by the fore-
ment, as well as a person’s own body. limb. Many disorders might impair a
The joints and muscles of humans’ up- person’s ability to perform purposeful
per limb, including the arm, forearm, skilled movements, and the diagnosis
hand, and fingers allow us to perform of apraxia is in part one of exclusion.
almost any type of movement. To suc- If a person cannot make purposeful
cessfully interact with the environment, movements because of deficits such
the goal-oriented movements made by as weakness, abnormal movements (eg,
86 the forelimb have to be guided by in- tremor, chorea, ballismus, myoclonus),
structions or programs from the brain. severe sensory-perceptual deficits, or
Apraxia is a term first used by Steinthal cognitive impairments, such as an im-
to describe impairments of humans’ paired comprehension or attention, then
ability to correctly carry out purpose- this disorder is not considered a form
ful skilled movements.1 There are two of apraxia. The forelimb apraxias that
major forms of forelimb apraxia: task spe- we will discuss can be induced by a va-
cific and general. Task-specific apraxias riety of diseases. We will not be able to
are disorders that are limited primar- discuss all these diseases in detail; how-
ily to one form of activity (eg, dress- ever, any neurologic disease that impairs
ing apraxia, constructional apraxia, and the neuronal networks responsible for
Relationship Disclosure: Dr Heilman has received personal compensation for review activities from Journal Watch.
Dr Heilman’s compensation and/or research work has been funded entirely or in part by a grant to his university
from a governmental organization, a nonprofit tax-exempt organization, Myriad Pharmaceuticals, Inc., Novartis
Pharmaceuticals Corporation, Esai Pharmaceuticals, and the Alzheimer’s Association.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Heilman has nothing to disclose.

KEY POINTS
A The term
ideational
apraxia has
been suggested
for the disorder
in which
patients have
an inability to
correctly
sequence a
series of acts
that lead to
Cartoon of system mediating purposeful movements. Ovals with letters are a goal.
FIGURE 6-1
different lesion sites.
A Conceptual
SMA = supplementary motor area; a = dissociation apraxia, b = conceptual apraxia,
c = ideomotor apraxia; d = limb-kinetic apraxia. apraxia is
the loss of
mechanical
knowledge.
programming these movements can in- the disorder in which patients have an Subtypes of
duce apraxia. For example, apraxia is of- inability to correctly sequence a series conceptual
ten observed with hemispheric strokes, of acts that lead to a goal (Case 6-1).6 apraxia include
especially those that injure the left he- problem
misphere; degenerative diseases such Tests unawareness,
as Alzheimer disease; and corticobasal tool-selection
To test for ideational apraxia, all the
deficit,
degeneration. At least five types of gen- material to complete a goal, such as tool-action–
eral forelimb apraxia have been iden- making a ham and cheese sandwich, association
tified, and the diagnosis of the specific should be placed before the subject. deficit, and
type of apraxia is dependent on the The subject should be asked to make a impaired
means by which errors are elicited and ham and cheese sandwich. knowledge
the types of errors made by the patient of mechanical
(Figure 6-1). In the next sections the Pathophysiology advantage.
clinical aspects, means of testing, and Most often the patients with ideational
pathophysiology of each of these five apraxia have some form of degenera-
disorders will be briefly described. tive dementia. This disorder has, how-
ever, not been systematically studied
IDEATIONAL APRAXIA in the various forms of degenerative 87
Clinical Description dementia. Liepmann thought that the
Unfortunately, the term ideational lesion that induced this disorder was
apraxia has been used to label many located in the left occipital parietal re-
different disorders, including dissocia- gion.6 However, the support for his hy-
tion apraxia2 and conceptual apraxia.3 pothesis is not strong, and injury to the
DeRenzi and Lucchelli used this term prefrontal regions, especially in the left
for patients with ideomotor apraxia hemisphere, is frequently associated with
who are impaired when they use ac- sequencing deficits.
tual tools and implements.4 However, CONCEPTUAL APRAXIA
Poizner and colleagues demonstrated
that patients with ideomotor apraxia Clinical Description
can often be impaired when using ac- Although making changes in the envi-
tual tools.5 Liepmann suggested that ronment can be performed by just us-
the term ideational apraxia be used for ing one’s hands and fingers, many tasks

" APRAXIA
Case 6-1
A 69-year-old woman had been an excellent cook her entire life. In the past few months, her
husband noticed that she appeared to have some problems controlling her temper and was not
keeping the house as clean as she used to keep it, but thought these changes were just part of
aging. One morning, wanting to make a cheese omelet for her husband, she took out the liquid
eggs, slices of American cheese, and butter. After putting the frying pan on the gas range, she
turned on the range and waited until the pan got hot. She then dropped the cheese onto the hot
pan and after a few minutes poured the eggs on top of the cheese. The cheese melted and
after the eggs hardened, she tried to slide the cheese omelet onto the plate but found it was
stuck to the frying pan. By the time she got the eggs and cheese out of the pan she had made
scrambled cheese eggs. This action alarmed her husband, who made an appointment for her to be
seen in a memory disorder clinic.
Comment. The patient’s inability to correctly order her acts to make a final product is
characteristic of the disorder called ideational apraxia.
cannot be accomplished by just the of mechanical knowledge is knowing

forelimbs in the absence of tools. Tools the characteristics of a tool that allow
provide the user with mechanical ad- it to perform a given action. For ex-
vantages. Several steps are necessary in ample, when attempting to drive a nail
correctly using a tool or implement to into a piece of wood and no hammer
alter the environment or one’s own self. is available in the tool chest, the pa-
The first step is the recognition that tient with impaired mechanical advan-
something needs to be altered. Some tage knowledge might select a screw-
patients cannot identify that an alter- driver rather than a wrench from this
ation action is required.7 This subtype chest.9 Mechanical knowledge is also
of conceptual apraxia is called prob- important for tool development, and
lem unawareness. Also, some patients patients with conceptual apraxia are of-
cannot recognize the tool that is needed ten unable to correctly develop tools.9
to perform or complete the required Conceptual apraxia is the loss of me-
action or the tool that works on specific chanical knowledge. There are several
objects (eg, hammers are used with subtypes of conceptual apraxia: problem
nails) (Case 6-2). This impairment is unawareness, tool-selection deficit, tool-
called a tool-selection deficit. In addi- action–association deficit, and impaired
tion, some patients might not recall the mechanical advantage knowledge.
88 type of actions associated with specific
tools and implements, a tool-action– Tests
association deficit (eg, hammers are (1) Problem awareness: Schwartz and
used to pound).3,8 A more complex form colleagues developed a test in which
Case 6-2
A 76-year-old retired carpenter was working on building a house for Habitat for Humanity. He
had retired because he was having some memory problems. While hammering a nail into a board,
the nail bent. He wanted to take this nail out, but his hammer did not have a claw. In his tool
chest he found a knife, and with the knife he tried to cut the wood around the nail so he could
remove it from the board but found this was not working. His friend seeing him do this said, ‘‘Use
the pliers!’’ This man was later diagnosed as having Alzheimer disease.
Comment. The loss of mechanical knowledge exhibited by this man is called conceptual
apraxia.

KEY POINT
patients are shown a series of pictures controlled by their disconnected right
A Patients with
of items that need work and then are hemisphere.10 In addition, Heilman and
ideomotor
asked to show the action that would colleagues studied right-handed pa- apraxia make
be required to complete this job.7 For tients who had either right or left hemi- three types of
example, a picture might show a piece sphere cerebral infarctions and found spatial errors:
of wood on two carpenter horses that that conceptual apraxia was more com- (1) postural
is only partially sawed in half, and the monly associated with left than right he- errors or internal
patient would need to show a saw- misphere injury.11 Although Liepmann configuration
ing motion. (2) Tool selection: Patients thought that conceptual mechanical errors; (2)
are shown the picture of an incom- knowledge is stored in the caudal pa- egocentric
plete task, such as a nail that is only rietal lobe,6 DeRenzi and Luccelli lo- movement errors
(use of incorrect
partially driven into the wood. They cated these representations in the
joints or incorrect
are shown an array of five different temporoparietal junction.4 Heilman and
coordination
tools, such as a handsaw, wrench, ham- colleagues, however, could find no spe- between
mer, screwdriver, and knife, and are cific anatomic region that appeared to be joints); and
asked to select the tool to be used critical for inducing conceptual apraxia. (3) allocentric
to complete this task. (3) Mechanical This result might have been related to movement errors
advantage—alternative tools: Patients having an inadequate number of sub- in which their
are shown a series of pictures that are jects, or that each subtype of conceptual actions are
the same as above, but in this test apraxia might have a different locali- not correctly
the tool that usually performs this ac- zation, or that in right-handed people targeted to the
tion is not present and the patient mechanical knowledge may be widely real or imaginary
must find an alternative tool to com- distributed in the left hemisphere. As object upon
which the
plete the task. For example, after being mentioned, conceptual apraxia can be
tool works.
shown a partially driven-in nail, the pa- associated with diseases that cause fo-
tient is shown five tools (eg, handsaw, cal brain damage, such as stroke, but it
wrench, screwdriver, knife, and wire is also commonly seen in patients suf-
cutter and is asked to point to the tool fering with degenerative dementia, such
he or she would use to complete the as Alzheimer disease.9
task. (4) Mechanical advantage—tool
fabrication: Ochipa and colleagues de- IDEOMOTOR APRAXIA
veloped a test in which subjects would
have to make a tool to solve a mechan- Clinical Description
ical problem.9 For example, they had to Patients with ideomotor apraxia (IMA)
retrieve a block with an eye hook on top make three types of spatial errors: (1)
that was in the bottom of a Plexiglas postural errors or internal configura- 89
cylinder and were provided with a tion errors; (2) egocentric movement
straight wire. To correctly solve this errors (use of incorrect joints or in-
problem, they had to bend the wire to correct coordination between joints);
make a hook that they could place in and (3) allocentric movement errors in
the eye and use this wire with hook to which their actions are not correctly
retrieve the wooden block. targeted to the real or imaginary ob-
ject upon which the tool works.
Pathophysiology When pantomiming a transitive act,
In right-handed people these mechan- patients with IMA will often fail to place
ical knowledge representations are their hand, forearm, and arm in the
stored in the left hemisphere. For exam- position that would enable them to
ple, patients with a callosal disconnec- correctly hold a tool or implement
tion demonstrate conceptual apraxia of (Case 6-3). Goodglass and Kaplan no-
the nonpreferred (left) hand, which is ticed that when patients are asked to

" APRAXIA
Case 6-3
A 55-year-old dentist returned to work after a 3-month world cruise. His
first patient had a cavity that was not deep. His assistant inserted a drill
bit into the drill and handed him the drill so that he could clean out the
decay. He asked the patient to open her mouth and pressed on the
pedal that made the drill rotate when he realized that he was not sure how
to correctly move the drill in the patient’s mouth. He told the patient
he could not work on her teeth and apologized. When examined in the
clinic and asked to pantomime transitive movements, he made postural
and movement errors, could not imitate transitive movements, and even
had trouble using actual tools. His deficit was much worse in his right
than left hand. In subsequent visits, he developed some plastic rigidity in
that arm and myoclonus.
Comment. This man’s spatial errors were typical of IMA. The presence
of unilateral IMA, asymmetric rigidity, and myoclonus suggest that this
man had corticobasal degeneration.
pantomime the use of a tool or imple- Tests

ment, they will often use their hand and The most sensitive test for assessing IMA is
fingers as the tool, a practice called body asking patients to gesture (pantomime)
part as tool errors (BPTEs).12 When asked transitive movement (such as using a tool)
to pantomime the use of a tool, even to verbal command. Although patients
healthy people will often make BPTEs, with IMA typically improve when imitating
but when asked to not use the hand and the examiner’s pantomimes of transitive
fingers as if they were tools and instead to
acts, the performance of patients with IMA
show the examiner how they would use
often remains impaired. In addition, when
the actual tool, healthy people usually
using actual tools or implements, their
stop making BPTEs. Many patients with
performance might improve even further.
IMA, however, unlike healthy people, will
This improvement might occur because
continue to make BPTEs even when they
they are provided with visual and tactile
are repeatedly corrected.13 In addition to
cues. Skilled movements also have char-
forming the correct posture to hold the
tool or implement, when properly using a acteristic temporal patterns. For example,
tool, people have to move the forelimb when using a hammer, the upswing is
90 joints in the proper fashion in order to usually slower that the downswing. Pa-
allow the tool to perform the desired tients with IMA often also move at in-
function. If people either move the incorrect speeds.5 Since some diseases,
correct joint or joints or do not properly such as corticobasal degeneration and
coordinate multiple joint movements, infarctions of the corpus callosum, can
they will move their hand and arm cause apraxia of one forelimb, both
incorrectly through space.5,14 To use a forelimbs should be tested. If one fore-
tool properly they must target the tool limb has an elemental sensory or motor
to the object upon which the tool disorder, such as weakness, that would
works (Case 6-3). In addition to mak- prevent testing, the opposite ipsilesional
ing egocentric postural and egocentric limb can still be tested. In addition to
movement errors, patients with IMA testing gesture to command, imitation of
also fail to properly direct their action both meaningful and meaningless move-
at the real or pretended target of the ments and with using actual objects, pa-
action, an allocentric error. tients should be tested to learn if they

KEY POINT
can discriminate between correct and mime or imitate transitive acts and not
A Ideomotor
incorrect pantomimes. correctly use tools with their left hand
apraxia is
but could correctly do so with their right associated with
Pathophysiology hand. These patients’ pattern of deficits injury to several
IMA is associated with injury to several appears to support Liepmann’s postulate structures,
structures, including the inferior pari- that the left hemisphere of right-handed including the
etal lobe, the premotor cortex (sup- people contains spatial-temporal move- inferior parietal
plementary motor area [SMA] and ment representations (movement for- lobe, the
convexity premotor cortex), and the cor- mula), and an injury of the corpus premotor cortex
pus callosum. Subcortical lesions that callosum disconnected these move- (supplementary
involve the basal ganglia, the thalamus, ment representations from the right motor area
and convexity
and the white matter connecting these hemisphere’s motor areas, inducing a
premotor
areas with the cortex can also be unilateral (left) IMA.
cortex), and the
associated with IMA. The means by Left hemisphere injury. Liepmann corpus callosum.
which injury in each of these areas studied a population of right-handed
causes IMA will be discussed later. patients who had damage confined to
Callosal disconnection. Liepmann either their left or right hemisphere and
and Maas reported Ochs, a right-handed found that none of the patients with
patient with a prior right hemiparesis right hemisphere injury had IMA, but
from an infarction in the pons, who also 50% of patients with left hemisphere
had a new lesion of his corpus callo- injury had IMA.15 These injuries oc-
sum.15 When tested, this patient was curred in several areas.
unable to correctly pantomime to com- Parietal lobe. Liepmann noted that
mands with his left arm, which could when a person with a left hemisphere
have been attributed to disconnection injury demonstrated signs of IMA, it
between a left hemisphere–mediated was highly likely that the person had
language network and the right hemi- an injury to the inferior parietal lobe.6
sphere’s motor areas, a language-motor Geschwind posited that inferior parie-
disconnection. Liepmann and Maas, how- tal lesions cause IMA because they in-
ever, also noted that this patient was duce a disconnection by damaging a
impaired imitating and using actual subcortical white matter pathway.19 Ac-
objects with his left forelimb. Since a cording to Geschwind, when a patient
person does not need language to imi- is given a command to perform a ges-
tate or use actual objects, this pa- ture, the incoming verbal message is
tient’s errors could not be explained decoded in the Wernicke area, but this
by a language disconnection. Liepmann message must then be transmitted to 91
and Maas suggested that the left hemi- the left premotor convexity cortex area
sphere of right-handed people con- for the command to be implemented
tains memories of the spatial-temporal by the left primary motor cortex. The
patterns required to make purpose- left hemisphere’s premotor cortex con-
ful skilled movements, and injury of nects with the primary motor cortex of
the corpus callosum disconnects these the left hemisphere as well as the pre-
‘‘movement formulas’’ from the right he- motor cortex of the right hemisphere.
misphere’s motor areas.15 Subsequent Thus, when attempting to carry out ver-
reports of patients with callosal le- bal commands, a disconnection of the
sions16,17 could not replicate the ob- Wernicke area from premotor cortex
servations of Liepmann and Maas, but would prevent the premotor cortex in
later Watson and Heilman,10 as well as both hemispheres from getting instruc-
Graff-Radford and colleagues,18 reported tions about the movement that was
patients who could not correctly panto- requested.

" APRAXIA
In addition to being impaired at pan- who have IMA but have an intact left
tomiming to verbal commands, patients inferior parietal lobe, with intact prax-
who have IMA from left inferior parietal icons, should be able to discriminate
lesions are also impaired when attempt- between incorrect and correct panto-
ing to imitate. Geschwind thought that a mimes performed by the examiner.
left hemisphere white matter pathway Heilman and colleagues20 and Rothi
that connects the visual association area and colleagues21 tested patients with
in the left hemisphere with the premo- anterior and posterior left hemisphere
tor area in this hemisphere is important cerebral lesions by assessing for the
for mediating manual imitation. How- presence of IMA as well as attempting
ever, to imitate gestures, a person does to learn if they had a disorder of pan-
not need speech-language, and thus tomime discrimination. These investi-
there should be no reason why the gators found that some patients with
undamaged right hemisphere could anterior lesions and some with poste-
not transmit visual information from rior lesions had the production deficits
the visual association areas to the pre- typical of IMA, but only the patients with
motor areas. In addition, many patients posterior damage had discrimination
with apraxia from left hemisphere injury disturbances. These results provided
are also impaired at correctly using ac- evidence against the parietal discon-
tual tools and implements. Geschwind’s nection hypothesis of IMA and sup-
disconnection hypothesis cannot fully port the postulate that injury of the
account for these patients’ inability to inferior parietal lobe induces IMA be-
correctly imitate gestures or use ac- cause this injury degrades the praxi-
tual tools.19 cons stored in this area. Halsband and
An alternative movement repres- colleagues22 replicated the results of
entation hypothesis was advanced by Heilman and colleagues20 and Rothi
Heilman and colleagues20 and Rothi and colleagues.21 Convergent evidence
and colleagues.21 These investigators for the postulate that the left inferior
suggested that in right-handed people parietal lobe stores movement repre-
the movement formula or movement sentations also comes from functional
representations (praxicons) that con- imaging studies performed with normal
tain the spatial and temporal parame- right-handed subjects.23
ters of purposeful actions are stored in In addition to strokes that damage
the left parietal lobe in the region of the inferior parietal lobe, patients with
the supramarginal and angular gyri. If Alzheimer disease often demonstrate IMA.
92 these praxicons become injured, de- Since these patients with Alzheimer
graded, or destroyed, the patient should disease have trouble recognizing cor-
not only demonstrate deficits of pan- rect from incorrect postures, their IMA
tomiming to command, imitating, and is probably related to degeneration
using actual objects, but because these of the inferior parietal lobe, which is
representations are degraded, these known to be affected by the patho-
patients should be unable to discrimi- logic changes associated with Alzheimer
nate between correctly and incorrectly disease.
performed transitive pantomimes per- Supplementary motor area. The
formed by the examiner. If these pra- movement representations or praxi-
xicons are intact, but they are unable cons that are stored in the left inferior
to access the premotor areas or the parietal lobe are probably stored in a
premotor areas are injured, these pa- three-dimensional supramodal (visuo-
tients would also be expected to dem- kinesthetic-spatial) code. The SMA re-
onstrate IMA. However, these patients ceives projections from parietal neurons

and projects directly to the convexity kinetic apraxia rather than IMA.29 This
premotor cortex as well as to the primary form of apraxia will be discussed later.
motor cortex. Physiologic studies have Basal ganglia and thalamus. Re-
demonstrated that the neurons in the ports have demonstrated that IMA can
supplementary motor cortex discharge be caused by subcortical lesions.30,31
before neurons in the primary motor Portions of the basal ganglia, such as
cortex. Complex movements, such as the putamen, have strong connections
those used in tasks that require transi- with areas of the cortex, such as the
tive movements, increase blood flow premotor areas, that when injured in-
in the SMA as well as in primary motor duce IMA. In addition, portions of the
cortex. When subjects do not move but thalamus also connect with areas of the
plan on making complex learned skilled cortex that when injured induce IMA.
movements, the blood flow (indicating For example, the pulvinar has strong
synaptic activity) to the SMA increases. connections with the inferior parietal
Watson and colleagues reported several lobes. Pramstaller and Marsden per-
patients who sustained left-sided medial formed an analysis of 82 cases of apraxia
frontal lesions that included the SMA, that appeared to be caused by subcor-
and these patients demonstrated IMA.24 tical lesions and reported that lesions
These patients with SMA lesions were confined to the basal ganglia, includ-
different than patients with left inferior ing the putamen, caudate nucleus, and
parietal lesions because the patients globus pallidus, rarely, if ever, cause
with the SMA lesions could discrimi- IMA.32 Unfortunately, in many of the
nate between correctly and incorrectly reports reviewed by Pramstaller and
performed pantomimes. It was thought Marsden, the subjects were tested with
that they could discriminate because imitation and not pantomime to com-
the praxicons were intact. mand. In addition these patients’ per-
Convexity premotor cortex. formance was scored as either correct
Geschwind also thought that the con- versus incorrect, and this scoring sys-
vexity premotor cortex, which connects tem might have been insensitive. Hanna-
with the motor cortex in the same he- Pladdy and colleagues studied and
misphere and the premotor cortex of compared patients with cortical and
the opposite hemisphere, was part of subcortical strokes.33 Although the
the pathway by which a person nor- participants with subcortical strokes
mally performs gestures to command.19 had involvement of the subcortical
Unfortunately, few studies have at- white matter, much of this white mat-
tempted to learn whether lesions of ter carries fibers from the cortex to 93
the left convexity premotor cortex in- basal ganglia and from the thalamus
duce IMA. Faglioni and Basso mention back to the cortex. These investigators
that they had difficulty finding any well- found that both the cortical and the
documented cases in which patients subcortical lesion groups made apraxic
had IMA as a result of injury to convexity errors, but the patients with cortical
premotor region.25 However, Kolb and lesions were more impaired. Hanna-
Milner,26 Barrett and colleagues,27 and Pladdy and colleagues found that the
Haaland and colleagues28 did report subcortical group made more postural
patients with frontal convexity premo- errors than did the cortical group, but
tor injury who appeared to have an the patients with cortical lesions made
IMA. Freund and Hummelsheim, how- more sequencing and content errors
ever, studied a population of patients (which are associated with conceptual
with convexity premotor lesions and apraxia).33 In regard to the thalamus,
also found that these patients had limb- there have been several case reports

" APRAXIA
KEY POINTS
of patients who developed IMA from also been called visuo-imitative apraxia
A The inability
lesions of the left thalamus in the and conduction apraxia.38
to correctly
pantomine region of the pulvinar nucleus,34 and,
as mentioned, this nucleus is con- Testing
when the
command is nected with the inferior parietal lobes. The methods used to test for the dif-
presented in ferent forms of dissociation apraxia are
one modality DISSOCIATION AND the same as those used to test for IMA.
but is correctly
CONDUCTION APRAXIA Pathophysiology
performed in
another modality Clinical The patients reported by Heilman2
is called Patients who have intact praxicons but and DeRenzi and colleagues35 who had
dissociation are impaired at accessing-activating dissociation apraxia of both hands prob-
apraxia.
these movement representations from ably had a left hemisphere injury that
A The loss of stimuli in one modality have dissocia- either induced a hemispheric language-
deftness, tion apraxia (Case 6-4). This term is movement formula disconnection or
including used because their movement repre- a vision-movement formula disconnec-
the ability to sentations have been dissociated from tion. Thus, depending on the location of
make precise
certain types of sensory input. Heilman2 the lesion, stimuli from one of these
independent but
first described three patients with verbal modalities (eg, speech-language) was
coordinated finger
dissociation apraxia. DeRenzi and col- not capable of activating the movement
movements, is
called limb-kinetic leagues35 reported patients who were representations, but stimuli in other
apraxia. similar to those reported by Heilman36 modalities (eg, vision) were able to ac-
but in addition reported patients who tivate these representations. Unfortu-
did not have a visual agnosia and could nately, the anatomic loci of the lesions
name tools presented to them, but could that cause many of these intrahemi-
not perform correctly when seeing spheric disassociation apraxias remain
tools. Unlike the patients reported by unknown.
Heilman,36 however, these patients per-
formed normally to verbal command. LIMB-KINETIC APRAXIA
Merians and colleagues37 described a
patient who had a left ventral temporal- Clinical Description
occipital lesion and was impaired at imi- Many acts performed by people when
tating the examiner’s pantomimes but either using their hand-fingers directly,
performed normally to verbal command. such as buttoning a shirt, or the use of
This disorder appears to be another tools, such as a pair of scissors, require
94 form of dissociation apraxia, which has deft movements. Patients with a loss
Case 6-4
A 43-year-old school teacher developed an anomic aphasia. When she was
tested for IMA, she was asked to show how she would put a key into a door
lock and open the door lock. After hearing the command, she looked
at her open hand with all her fingers fully extended and repeatedly
said, ‘‘Unlock the door.’’ Although it appeared that she might have a
speech comprehension disorder, her comprehension remained intact.
When, however, the examiner took out a key and she saw the key, she
immediately performed the pantomime correctly.
Comment. The inability to correctly pantomime when the command is
presented in one modality but is correctly performed in another modality is
called dissociation apraxia.

Case 6-5
A 78-year-old man with a history of hypertension had the sudden onset of a right hemiparesis and
trouble speaking (a nonfluent aphasia with intact comprehension and impaired repetition and
naming). Over a period of several days the weakness in his arm and hand abated, and when
examined 1 month after this stroke, the strength in his right forelimb, including his fingers was
normal. He noticed, however, that he had trouble buttoning his shirt and performing other
activities that required fine precise movements (deftness or dexterity). His brain imaging revealed
that he had a stroke that injured his motor cortex and par triangularis and opercularis (Broca area)
of his left hemisphere.
Comment. The loss of deftness, including the ability to make precise independent but
coordinated finger movements, is called limb-kinetic apraxia.
of deftness might be unable to perform limb-kinetic apraxia.6 Lawrence and

these motor acts. This loss of deftness or Kuypers demonstrated a loss of preci-
dexterity is called limb-kinetic apraxia sion grasp in monkeys with lesions of
(melokinetic apraxia, innervatory apraxia) the pyramid that interrupted the cor-
by Liepmann (Case 6-5).6 ticospinal tract.41 However, Freund and
Hummelsheim reported that damage
Tests to the premotor cortex is also asso-
ciated with limb-kinetic apraxia.29 Con-
Many tests of deftness or dexterity are
verging evidence of the role of pre-
available, but the coin-rotation task is
motor cortex in programming deft
one of the simplest and sensitive bed-
finger movements comes from the work
side tests. In this test, patients are given
of Nirkko and colleagues, who, using
an American nickel in their palm and are
fMRI, demonstrated that discrete uni-
asked to rotate the nickel between their
lateral distal finger movements were
thumb, index, and middle fingers as
associated with activation of the con-
rapidly as possible for 20 revolutions.39
vexity premotor cortex.42
Another test, often used by neuropsy-
In people who are right handed, left
chologists, is the pegboard test. In this
hemisphere injury can induce ipsilateral
test, patients repeatedly lift one peg at a
(as well as contralesional) limb-kinetic
time, carry the peg to the hole, and then
apraxia.39,40 In contrast, in right-handed
place the peg in the hole. Lifting one
patients with right hemisphere dysfunc-
peg at a time and placing the peg ac-
tion who have limb-kinetic apraxia, this
curately in the hole requires deftness.
disorder is usually limited to the con- 95
Both hands of patients should be tested.
tralesional left hand. This asymmetry
Typically,patientswithhemisphericdam-
suggests that right-handed people have
age have a contralesional loss of deft-
asymmetric control of their hands such
ness. Heilman and colleagues40 as well
that their left hemisphere has stronger
as Hanna-Pladdy and colleagues39 have,
ipsilateral control of spinal motor neu-
however, found that people with right
rons than does the right hemisphere.
hand preference are more likely to have
Physiologic studies in normal subjects
an additional ipsilateral loss of deftness
appear to support this hypothesis,43 but
(limb-kinetic apraxia) with left than
it remains unclear whether this ipsilat-
with right hemispheric dysfunction.
eral (left hemisphere–left hand) control
is mediated by an ipsilateral cortico-
Pathophysiology spinal pathway or by influencing the op-
Liepmann thought that a lesion of the posite hemisphere by way of the corpus
primary sensorimotor cortex caused callosum or both.

" APRAXIA
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Verlagsbuchhandlung, 1871.
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3. Ochipa C, Rothi LJG, Heilman KM. Ideational apraxia: a deficit in tool selection and
use. Ann Neurol 1989;25(2):190–193.
4. DeRenzi E, Lucchelli F. Ideational apraxia. Brain 1968;113(5):1173–1188.
5. Poizner H, Mack L, Verfaellie M, et al. Three dimensional computer graphic analysis

of apraxia. Brain 1990;113(pt 1):85–101.
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" APRAXIA
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98

KEY POINT
DISORDERS OF A Neglect can

be a deficit of
VISUOSPATIAL lateralized
spatial attention,
PROCESSING intention, or
representation.
Anjan Chatterjee, H. Branch Coslett
ABSTRACT
Disorders of visuospatial function are common but poorly understood. In this
article we review the clinical symptoms, assessment, and processing impairments
underlying a number of clinical disorders in which visuospatial processing is the
primary manifestation. We start with a consideration of the neglect syndrome, a
disorder in which subjects exhibit deficits in attending to or representing in-
formation from the contralesional side of space. We also discuss the syndrome of
simultanagnosia, a disorder characterized by an inability to see more than one
object at a time. Although often unrecognized, misreaching to visualized targets,
or optic ataxia, is not uncommon; we review the manner in which this potentially
disabling disorder can be identified. Finally, we review the disorders of visuospatial
processing that are associated with degenerative diseases of the brain. These
disorders may be the initial and, for a number of years, the only manifestation of
Alzheimer disease and other disorders.
INTRODUCTION and attention (‘‘Attention and Confu-

Disorders of visuospatial processing are sional States’’).
a common and often disabling con-
sequence of brain dysfunction. Many of NEGLECT
these disorders are among the most The neglect syndrome is an appropri-
striking disturbances observed in the ate starting point for this topic be-
clinic. In most instances, the conditions cause this disorder, with its protean
result from dysfunction of the parietal manifestations, is among the most com- 99
lobe, whether induced by focal lesions mon and disabling disorders observed
or degenerative conditions. In this arti- in patients with brain dysfunction. In
cle we review the major disorders of the neglect syndrome, patients are un-
visuospatial processing, including the aware of entire sectors of space on the
neglect syndrome, simultanagnosia, op- side opposite to their lesion. Addition-
tic ataxia, and visuospatial deficits asso- ally, these patients may be inattentive
ciated with dementia. The interested or even deny the existence of parts of
reader is referred to other articles in this their own body, parts of their environ-
issue for a discussion of related top- ment, and even parts of scenes in their
ics, such as agnosia (‘‘Comprehension’’) imagination.
Relationship Disclosure: Dr Chatterjee has received personal compensation for editorial work from Journal
of Cognitive Neuroscience. Dr Coslett has nothing to disclose.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Chatterjee discusses the experimental use of
dopamine agonists for neglect. Dr Coslett has nothing to disclose.

" VISUOSPATIAL PROCESSING
KEY POINT
Theories of Neglect arousal and cognitive capacity, which
A Neglect is worse
No theory regarding neglect has been combines with hemispheric biases in di-
after right than
left hemisphere universally accepted, perhaps because recting attention to produce the mani-
damage. the disorder may be caused by a wide festations of left neglect.5 The right
range of processing deficits. In this sec- hemisphere is capable of directing at-
tion, we review some of the leading tention into both hemispaces, while
theories of neglect. the left hemisphere directs attention
Spatial attention. Attention is the only into contralateral space. Thus, af-
process by which some stimuli are se- ter right brain damage, the left hemi-
lected for processing, presumably be- sphere is ill equipped to direct attention
cause the nervous system has a limited into left hemispace. However, after left
capacity and cannot process all things at brain damage, the right is capable of di-
all times. Neglect is most often viewed recting attention to both directions and
as a disorder of spatial attention. In ne- neglect does not occur with the same se-
verity as after right brain damage.
glect, spatial attention is biased so that
Spatial intention. Spatial inten-
patients preferentially process stimuli in
tion refers to the cognitive processes
ipsilesional space over those in contra-
by which one selects spatial locations
lesional space.
for actions. The selection of locations for
Neglect is more common and se-
action contrasts with the selection for
vere with right than with left brain
perception,6 a distinction that underlies
damage. Kinsbourne postulated that
the idea of intentional and attentional
each hemisphere generates a vector of
neglect. Watson and colleagues ad-
spatial attention toward contralateral
vanced the idea that neglect patients
space, and these attentional vectors may have an intentional deficit, a dis-
are inhibited by the opposite hemi- inclination to initiate movements to-
sphere.1 On this account, the left hemi- ward or into contralesional hemispace.7
sphere’s vector of spatial attention is Rizzolatti and colleagues have extended
more strongly biased than that of the this idea even further by arguing that
right hemisphere. After right brain dam- preparations for actions might be criti-
age, the left hemisphere’s unfettered vec- cal to perception.8
tor of attention is powerfully oriented Spatial representation. Represen-
to the right. Since the right hemisphere’s tational theories of neglect propose that
intrinsic vector of attention is only weakly the inability to form adequate contra-
directed, left brain damage does not lateral mental representations of space
100 produce a similar orientation bias to underlies the clinical phenomena.9 In a
the left. Thus, neglect of the left side is classic observation, Bisiach and Luzzatti
more common and severe than neglect asked two patients to imagine the Piazza
of the right side. del Duomo in Milan, Italy, from two
Heilman and colleagues2 and Mesulam,3 perspectives: looking across the square
in contrast to Kinsbourne, proposed toward the cathedral, and looking from
that the right hemisphere is dominant the cathedral across the square.10 In
for arousal and spatial attention. Right each condition, the patients reported
brain damage produces greater elec- only landmarks to the right of their
troencephalographic slowing than left imagined position in the piazza. In ad-
brain damage. These patients also have dition to their difficulties with evoking
decreased galvanic skin responses com- contralateral representations from mem-
pared to healthy patients or patients ory, patients with neglect may also have
with left hemisphere damage.4 Thus, difficulties with forming new contralat-
right hemisphere damage diminishes eral representations.11 Neglect for images

KEY POINT
evoked from memory may dissociate mark to the right of the true midposi-
A Neglect is
from neglect of stimuli in extrapersonal tion, demonstrating a rightward orien-
assessed at the
space.12,13 Thus, the processes by which tation bias. Patients make larger errors bedside easily
spatial representations are formed by with longer lines.15 On cancellation with line
memory and those that are derived tasks, patients demonstrate reluctance bisection,
online from perception may be dam- to explore contralesional peripersonal cancellation, or
aged selectively. space. When asked to ‘‘cancel’’ targets drawing tasks.
presented in an array, patients neglect
Assessment left-sided targets and typically start at
Observing patients provides a rough the top right of the display and often
indication of personal neglect. Patients search in a vertical pattern. On drawing
with this disorder ignore the left side tasks, patients copy or draw objects and
of their body and might not use a comb scenes from memory. When asked to
on that side or use makeup or shave copy drawings with multiple objects, or
the left side of their face. Patients with complex objects with multiple parts,
personal neglect often deny owner- patients may omit left-sided objects in
ship of their left arm even after this the array and/or omit the left side of
limb is brought into their view (Case 7-1). individual objects.
They may fail to explore the left side
of their body. Patients may be aware Spatial Reference Frames
of their contralesional limb but not Space is mentally represented along
that it is paralyzed.9 This phenome- different reference frames. These ref-
non, called anosognosia for hemiple- erence frames may be centered on the
gia, is not all or none; some patients viewer, the object, or the environment.
have partial awareness of their contra- For example, we can locate a chair in a
lesional weakness.14 room in each of these frames. A viewer-
Commonly used tests for neglect are centered frame would locate the chair
line bisection, cancellation, and drawing to the left or right of the viewer. An
tasks. On line bisection tasks, patients object-centered frame refers to the in-
with left neglect typically place their trinsic spatial coordinates of the object
Case 7-1
A 68-year-old man was brought to the hospital with a left hemiparesis. He
appeared drowsy, and his eyes and head were deviated to the right. He
responded to questions by turning even further to the right, even when
101
the examiner approached him from the left. He said that he was not well,
but was not specific about his concern. When asked if he was weak, he
stated, ‘‘yes generally,’’ but denied that he was weak in one or the other
limb. When shown his own left hand, he insisted that it belonged to
the examiner. After a few days in the hospital, he recognized his hand and
acknowledged that it was weak, but did not think that this weakness
might affect his plans for a previously planned hiking trip in 2 weeks.
Comment. This patient presented with decreased arousal, a common
phenomenon following right hemisphere damage. He oriented
preferentially to the right, demonstrating left neglect. He also had
personal neglect initially, denying ownership of his own limb. As he
recovered, he continued to have a partial anosognosia, or unawareness,
of his deficit. He could state that he was weak but did not appreciate
the practical consequences of his weakness.

KEY POINT
itself, its top or bottom or right and space. Cross-modal links between in-
A Spatial
left. The object-centered reference frame teroceptive sensations (vestibular and
representations
are formed by is not altered by changes in the position proprioceptive) with exteroceptive sen-
integrating of the viewer. The top of the chair sations(vision,audition,andtouch)mod-
different remains its top regardless of where the ulate neglect. Rubens demonstrated that
sensory input, viewer is located. An environment- left-sided vestibular input with cold wa-
including centered reference frame refers to the ter caloric stimulation improves left ne-
vision, audition, location of the object in relation to its glect.19 Such vestibular stimulation can
touch, and surround, also independent of the lo- also improve contralesional somato-
proprioceptive cation of the viewer. The chair would be sensory awareness.20 The deployment
and vestibular coded with respect to other objects in of spatial attention may also be influ-
sensations,
the room and its relation to gravitational enced by changes in posture, which are
with motor
coordinates. presumably mediated by otolith ves-
output systems.
Viewer-centered reference frames can tibular inputs.18 Proprioceptive input
be divided further into retinal, head- from neck muscles can also modify ne-
centered, or body-centered coordinates. glect. Visual input close to the location
For example, Nadeau and Heilman de- of tactile stimulation may improve con-
scribed a patient with a ‘‘gaze depen- tralesional tactile awareness.
dent hemianopia.’’16 This patient seemed Movement may also modulate sen-
to have a left visual field defect when sory awareness of these patients. Patients
his eyes gazed straight ahead, but not with tactile extinction are more likely
when he gazed 308 to his right. His to be aware of contralesional tactile
neglect of left-sided stimuli was deter- stimuli when they actively move their
mined by ‘‘left’’ with respect to his limbs than when they apprehend these
head or trunk and not his eyes. Others stimuli passively.21 The fact that patients
have described dissociations of neglect with neglect can have personal neglect
within different viewer-centered refer- and deficits of contralesional body rep-
ence frames.17 In object-centered neglect, resentations raises the question of how
patients are unaware of parts of objects personal space is integrated with extra-
in ways that cannot be explained by personal space.22 Tactile sensations are
viewer-centered reference frames. Forms experienced as being produced by ob-
of object-centered neglect have been jects on the body, the surface of personal
demonstrated when patients draw pic- space. Visual sensations are experienced
tures, take photographs, perceive ro- as being produced by objects at a distance
tated objects, and read single words. from the body, in extrapersonal space.
102 Environment-centered coordinates may The integration of these two sources of
also influence neglect. Gravitational in- information may contribute to bringing
fluences and the vestibular system help personal and peripersonal space into
anchor this reference frame.18 Some register.23
patients’ performances on search tasks
and line bisection tasks are influenced Prognosis
by changes in the patients’ body posi- Neglect occurs in about half of all pa-
tion, which alter vestibular input and tients with right hemisphere lesions.24
can disentangle the environmental axis The severity of neglect and pattern of
from viewer and object axes.18 recovery are highly variable. Hier and
colleagues found that after right hemi-
Cross-Modal and Sensorimotor sphere stroke, visual inattention and
Interactions neglect recovered much more quickly
Different sensory and motor systems (median 8 to 9 weeks) than hemianopia
interact to give rise to our sense of (median 32 weeks) or hemiparesis

KEY POINT
(median 64 weeks).25 More subtle symp- ralysis of gaze.’’ As the first two disor-
A Neglect is
toms associated with neglect, such as ders are common, either in isolation or
associated with
extinction (median 19 weeks) and motor as part of a Balint syndrome, they are poor outcome;
impersistence (median 26 weeks), lasted discussed below. treatments
longer. Recovery was related to size of have been
lesion, and hemorrhagic strokes recov- Optic Ataxia disappointing
ered more quickly than ischemic strokes. Optic ataxia is a disorder characterized to date.
Levine and colleagues reported that ne- by misreaching to visual targets that
glect severity and rate of recovery were cannot be explained on the basis of
adversely affected by premorbid cortical weakness, clumsiness, or incoordina-
atrophy, suggesting that the integrity tion. In its most obvious form, patients
of undamaged structures plays a role with this disorder can describe an object
in the recovery from neglect.26 The pres- within arm’s reach but when attempting
ence of neglect acutely is associated to pick up the object, miss the target
with longer hospitalizations and poor and are reduced to groping randomly
recovery to functional independence in for an item that they clearly see. In many
stroke patients.24 instances, the disorder is restricted to
the visual modality; thus, patients may
Management be unable to reach to a set of visualized
Although no treatment protocols have keys but, with their eyes closed, they
been demonstrated to be unequivocally may reach accurately to the keys if they
efficacious in neglect, a number of prom- are rattled.
ising rehabilitation approaches are emerg- Misreaching to visualized targets when
ing. These include behavioral as well as looking directly at the target—a phe-
pharmacologic interventions. Several nomenon Jax and colleagues termed
reviews of potential treatments for ne- foveal optic ataxia—is relatively un-
glect have recently been published.27 common; more subtle forms of optic
Although some of the treatments ap- ataxia, however, are not infrequent but
pear promising, it is clear that much typically unrecognized.29 In ‘‘nonfoveal’’
work remains to be done before an optic ataxia, the disorder is apparent
effective therapy is developed. only when the locations to which pa-
tients direct their gaze and the location
BALINT SYNDROME to which they reach are dissociated.
In 1909, a Hungarian physician, Reszo This is easily assessed by asking a patient
Balint, described the striking behavior of to look at the examiner’s nose while at-
a middle-aged engineer who reported tempting to reach to the examiner’s fin- 103
difficulties using his hands and finding ger that is held peripherally. Whereas
his way.28 Despite his disabling deficits, normal subjects reach quickly and ac-
the patient performed well in a variety curately to a target even without fixat-
of domains. His language was normal ing the target, subjects with optic ataxia
and visual fields were full; ocular move- miss the target. Errors can be consistent
ments were conjugate with full excur- or random. In the former case, patients
sion. He was not weak and was able to may, for example, err to the right consis-
walk. Despite these preserved faculties, tently across trials.
Balint’s patient was effectively blind and The hand used to reach and the
was utterly unable to function in the hemispace in which the target is pre-
world without assistance. Balint identi- sented are additional important deter-
fied three core deficits that have come minants of performance in optic ataxia.
to define this order: (1) optic ataxia, (2) As noted by DeRenzi, many subjects
simultanagnosia, and (3) ‘‘psychic pa- misreach only with one hand; other

KEY POINT
patients misreach with both hands but intraparietal sulcus. The association of
A Optic ataxia
only in one hemispace (that is, side of typical nonfoveal optic ataxia with a
is relatively
common but the environment).30 Still other patients small, well-defined surgical lesion sug-
often missed misreach only with one hand in one gests that this region is crucial for the
because hemispace. Thus, in this instance, a coordinate transformations described
reaching and patient may miss a nonfoveated target in above.
direction of the left hemispace but only when
gaze are not reaching with the left hand. Finally, on Assessment of Optic Ataxia
dissociated. occasion one encounters patients who In order to diagnose optic ataxia, one
misreach with both hands in both must first confirm that any deficits one
hemispaces. observes are not attributable to an im-
paired motor system. The finger-nose-
Accounts of Optic Ataxia finger test is particularly useful in this
A number of different explanations have regard. Deficits attributable to weak-
been proposed for optic ataxia. Reflect- ness, clumsiness, or incoordination should
ing the prevailing explanatory frame- be apparent when reaching to the finger
work of his time, Balint attributed the as well as the patient’s nose. Patients
disorder to a disconnection between with optic ataxia, however, are likely to
intact sensory and motor systems. err when reaching to the examiner’s
Holmes argued that the disorder re- finger only as the patient’s nose is not
flected a failure of the visual system.31 defined by vision. For reasons described
While both accounts explain some of above, assessment of optic ataxia should
the features of the disorder, they fail also include reaching to foveated and
to explain important features of the nonfoveated targets. Both hands should
syndrome. For example, neither theory be tested in both hemispaces.
is clear on why optic ataxia would be
expected to exhibit substantial differ- SIMULTANAGNOSIA
ences for foveated and nonfoveated Simultanagnosia is a disorder in which
targets. We have argued that the im- patients see only one object or com-
pairment reflects a failure to transform ponent of an object at a time. For ex-
locations mapped in retinal coordinates ample, when shown a picture of a
into spatial coordinates that are appro- kitchen, the subject may report seeing
priate for the motor system.32 On this only the refrigerator or when shown
account, the parietal lobe is crucial for the number 1089 may report seeing
translating between frames of reference only the 8. Although patients may re-
104 based on retinal coordinates, eye posi- port only one part of a single object, the
tion, head position, and, finally, the po- deficit is particularly pronounced when
sition of the reaching extremity.29 the patient is confronted with complex
arrays involving multiple items. We have
Anatomic Basis of Optic Ataxia reported a patient who, when shown a
Optic ataxia is typically associated with table set for a group and covered with
dysfunction of the posterior parietal food, reported seeing only a spoon.33
lobe; the precise localization remains Despite being given unlimited time to
controversial, however, as relatively few inspect the scene and being told that
patients have been carefully assessed there were multiple other items on the
and the lesions tend to be extensive. We table, she was utterly unable to report
have recently evaluated a patient who anything else until the spoon was
developed prominent optic ataxia after removed, at which point she reported
surgical resection of a small low-grade seeing only a knife. In milder forms,
glioma at the posterior portion of the patients may be able to eventually

discern the contents of an array, but this which there is no stored knowledge to
is achieved in a slow and laborious pro- assist identification. When shown non-
cess by which individual items are words, simultanagnostics tend to report
identified serially. As a consequence of a single letter.34,35 For example, we have
this debilitating condition, subjects are reported patients who reported seeing
often effectively blind despite the fact an e when shown the letter string
that, like Balint’s patient, they may have kammer.36 Finally, striking evidence
full visual fields and normal visual acuity for top-down or semantic effects in per-
(Case 7-2). ception comes from the fact that iden-
Substantial evidence suggests that tification of items in an array is strongly
top-down effects, such as the mean- influenced by the relationship between
ingfulness of a stimulus, influence per- the objects in simultanagnosia; eg,
ception. In most instances, patients when shown two-item arrays, patients
report the largest meaningful ‘‘object’’ are more likely to report both words or
in an array; eg, when shown a picture of pictures when the objects are from the
a hand, they are likely to report seeing a same semantic category. That is, if shown
hand rather than a finger or knuckle. two line drawings in an array, patients are
The same principle applies for letter more likely to identify both stimuli if
strings. When shown the letter string they are both animals (eg, tiger and lion)
hammer, subjects are likely to report as compared to one animal and one
this correctly; responses such as ‘‘ham,’’ vegetable (eg, dog and asparagus).34,33
in which a component of the stimulus is
reported, are quite rare. The effect of Mechanisms Underlying
meaningfulness or familiarity is evident Simultanagnosia
in patients’ performance with non- Several explanations for simultanagnosia
words, or unfamiliar letter strings for have been proposed. Some investigators
Case 7-2
A 63-year-old man with a history of an old left parietal stroke from
which he appeared to recover fully was seen in consultation after
inadvertently starting a fire by putting out his cigarette on a newspaper.
When queried, he indicated that he was looking directly at the ashtray
but missed. He also noted that for the past few days he had experienced
difficulty finding his way in his apartment, often falling over large
objects, such as his sofa, because he failed to see them. Examination
105
demonstrated that when attempting to touch the examiner’s hand at
which he was gazing directly, he missed the target by several inches. He
reached less accurately with his left hand and was worse with both hands
in the left side of space. When asked to read a page from a magazine,
he reported a disjointed series of words making no sense. Finally, although
smooth pursuit was normal in all directions, he was unable to volitionally
direct his gaze to a verbally specified target, such as the ceiling or door.
Comment. The patient exhibits the three classic features of Balint
syndrome: (1) optic ataxia, (2) simultanagnosia, and (3) psychic paralysis
of gaze. As would be expected given this clinical setting, the MRI scan
demonstrated a subacute stroke of the right posterior parietal cortex
as well as an old left parietal stroke. Although his inability to control
the location to which he gazes persisted for only 1 week, optic ataxia and
simultanagnosia persisted for years.

KEY POINTS
have suggested that simultanagno- appear constricted, whereas if they are
A Simultanagnosia
sia is caused by ‘‘sticky’’ visual atten- instructed to gaze to a fixed location
is best assessed
by presenting tion; that is, when confronted with an but not focus location on a target,
complex array, patients identify the first item visual fields may be full. Assessment
visual arrays to which their attention is drawn but should include complex scenes that
and stimuli. are unable to disengage their attention include multiple items. Additionally,
A Visuospatial
from the objects and remain stuck on text reading is often informative.
disorders the object.37 Other investigators have
may be the proposed that the disorder reflects a
presenting and failure to bind information regarding VISUOSPATIAL DEFICITS
predominant object location computed in the dorsal IN DEMENTIA
impairment in visual stream and object identity com- Disorders of visuospatial processing are
many patients puted in the ventral or what stream.34 common in a number of primary de-
with Alzheimer It appears likely that no single account generative dementias, such as Alzheimer
disease, explains all cases of simultanagnosia; disease (AD), corticobasal degenera-
corticobasal rather the disorder may reflect a va- tion, and dementia with Lewy bodies.
degeneration,
riety of higher-level visual processing The syndrome characterized by pro-
and dementia
deficits, the specifics of which depend found visuospatial deficits in the con-
with Lewy
bodies.
on the location, nature, and extent of text of relatively preserved memory
the pathology. and cognition more generally was de-
signated posterior cortical atrophy by
Benson and colleagues.40 For those
Anatomic Basis of patients with presumed AD, the disor-
Simultanagnosia der is often referred to as visual variant
Balint’s patient with simultanagnosia of AD.
suffered bilateral posterior parietal strokes Several recent studies suggest that
with limited occipital lobe involvement. AD is the most common cause of pos-
Most subsequently reported patients, terior cortical atrophy. Renner and col-
including the beautifully studied pa- leagues reported that 16 of 21 patients
tients of Holmes, have also had bilat- with the disorder had AD pathology
eral posterior lesions.31 Simultanagno- (five with associated Lewy bodies), two
sia has also been reported, however, had corticobasal degeneration, two had
in patients with unilateral left occipi- prion disease, and one had subcortical
tal lesions.38 In these patients, the dis- gliosis.41 Similarly, Tang-Wai and col-
order is often less severe. We have leagues reported that seven of nine
106 argued elsewhere for a distinction be- pathologically confirmed cases had
tween simultanagnosia caused by bi- AD whereas two had corticobasal
lateral posterior lesions and left occipi- degeneration.42,43
tal lesions.39 Patients with posterior cortical at-
rophy often present between the ages
of 55 and 65 with symptoms of visual
Assessment of impairment in complex tasks such as
Simultanagnosia reading text, driving, completing jigsaw
Visual fields and acuity should be puzzles, etc. Most patients come to
carefully assessed. It should be noted neurologic attention only after having
that the outcome of the visual fields purchased several pairs of new eyeglasses
evaluation may crucially depend on and having seen multiple ophthalmolo-
the manner in which the testing is gists. General cognitive functions, includ-
performed. If patients are required to ing memory, are often preserved for
focus on a small stimulus, fields may years into the course of the illness.

One of the characteristic impairments Assessment of Posterior
in patients with the visual variant of AD Cortical Atrophy
is a gradual restriction in the ‘‘spotlight A number of simple bedside tests are
of attention.’’44 Although an imperfect useful in eliciting signs of posterior
analogy, psychologists have for decades cortical atrophy. One useful measure
likened visual attention to a spotlight is the dot counting task in which sub-
because the focus of attention can ex- jects are asked to simply count eight
pand to cover a large area with low re- to 10 dots arrayed randomly on a sheet
solution or constrict to cover a small area of paper; because of disordered visual
with high resolution. In visual variant search, subjects often fail to count some
AD, patients behave as if the power of dots and/or count the same dot multi-
the spotlight is diminished with the con- ple times. Another useful task requires
sequence that the area from which vi- patients to identify overlapping or super-
sual information can be integrated is imposed stimuli such as letters. Finally,
decreased and the size of the objects hierarchical stimuli such as a T com-
that can be identified is diminished. posed of 15 m’s represent a problem
Consistent with this, we have reported for patients with posterior cortical atro-
patients who could read the word cat phy; in this case, patients will often iden-
printed in 2.5-cm-high letters but when tify the small, constituent letter but fail
shown the same stimulus 1 year later to identify the large letter.
reported seeing only a t; at that time,
however, the patients could read the
word cat when printed in 1-cm letters. CONCLUSION
It should be noted that this pattern of We have reviewed a number of clinical
deficit has much in common with simul- disorders in which visuospatial process-
tanagnosia from focal biparietal lesions ing may be seriously compromised.
except that in the former condition the Careful assessment of these disorders
size of the object or array makes little represents a crucial first step in under-
difference, whereas in this condition, standing the clinical consequences of
size of objects and the spatial extent of these disorders and the development of
the array are important determinants programs to compensate for their often
of performance. devastating consequences.
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110

DISORDERS OF
COLOR AND OBJECT
RECOGNITION
Jason J. S. Barton
ABSTRACT
Although lesions of the striate cortex are associated with hemifield defects, lesions of
the inferior and medial occipitotemporal cortex often are associated with disorders
of more high-level and complex visual processing. These disorders of the ventral
processing stream can be considered as impairing the perception of color and rec-
ognition of objects, in contrast to the problems with motion and spatial localization
seen with lesions of the dorsal occipitoparietal stream. Dysfunction in the ventral
stream leads to the prototypic syndromes of achromatopsia, general visual agnosia,
prosopagnosia, alexia without agraphia, and some forms of topographagnosia.
Most of these are not single entities but families of disorders in which dysfunc-
tion in different cognitive and perceptual processes can lead to the same symptom.
Although striate cortex springs to visual signals. It has proved useful to

mind first when one thinks of the ce- conceive of these regions and their func-
rebral contribution to vision, this area tions as belonging to at least two main
is really only the beginning of a com- processing streams.1 (1) A ventral medial
plex network of cortical regions and occipitotemporal stream has functions crit-
processes involved in the formation of ical for the processing of form and color
our visual percept of the world. Un- for object recognition—the what path-
derstanding how this percept is con- way. Lesions in this stream tend to cause
structed from the activity of so many problems such as achromatopsia, general
different regions is the focus of much visual agnosia, alexia, prosopagnosia, and
research. The nature of visual dysfunc- some varieties of topographagnosia. (Al- 111
tion in neurologic patients has made a though most neurologists think of alexia
significant contribution to this under- without agraphia as a disconnection syn-
standing, complementing neurophysi- drome, some cases may represent a type
ologic experiments and more recent of visual word-form agnosia and hence be
functional neuroimaging studies. the paradigmatic example of left occipito-
A taxonomy of higher-order visual dys- temporal contributions to visual object
function can be built from neurophysio- processing; however, this topic will be
logic concepts of specialized modules covered elsewhere in this issue.) (2) A
and processing streams. Numerous re- dorsal lateral occipitoparietal stream is in-
gions of the brain are involved in vi- volved in motion and spatial processing,
sual processing, and these regions have including attention and localization—
highly differentiated roles in decoding the where pathway. Lesions in this stream
Relationship Disclosure: Dr Barton has nothing to disclose.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Barton has nothing to disclose.

" COLOR AND OBJECT RECOGNITION
KEY POINT
cause akinetopsia, hemineglect, astere- ing the color to pop out when the object
A Achromatopsia
opsis, and Balint syndrome. Spatial pro- moves from the defective to the normal
is best
diagnosed by a cessing is also discussed in ‘‘Disorders field.
test requiring of Visuospatial Processing.’’ The cur-
rent article focuses on the disorders of More Complex Color
subjects to sort
chips by hues, the ventral stream that impair color Phenomena
such as the and object recognition. Achromatopsia may also affect color
Farnsworth- constancy. The wavelengths reaching
Munsell 100 or our eyes from an object depend also on
DISORDERS OF COLOR
D-15 color test. the lighting, but despite this we per-
PROCESSING—CEREBRAL
ACHROMATOPSIA ceive object color as a stable property.
Color constancy, also referred to as dis-
Symptoms and Signs counting the illuminant, requires cor-
Cerebral achromatopsia is the loss of tical computations that average over
color vision acquired after a cerebral large regions of the background to
lesion: if partial, the term dyschroma- infer the illumination, which is then
topsia is sometimes preferred. Subjects taken into account when judging object
with achromatopsia report that every- color.6 Failure of these computations will
thing appears in shades of gray.2 Less result in color percepts that vary with
frequently vision is tinted, as if peering changes in lighting. Poor color con-
through a colored filter. Impaired color stancy has been shown in patients with
discrimination can affect activities such partial dyschromatopsia.7
as distinguishing money, stamps, and Not all color function is lost in ach-
traffic lights. Hemiachromatopsia is loss romatopsia. Significant color effects re-
of color limited to the contralateral he- main from the function of the cones and
mifield, typically asymptomatic and as- retinal ganglion cells of the eye. Behav-
sociated with a homonymous superior ioral and evoked potential measures con-
quadrantanopia (Case 8-1).3 tinue to show trichromatic patterns of
When tested, many achromatopsics sensitivity (eg, evidence for the function
cannot name colors; however, those of short, medium, and long wave cones)
with a partial defect may be able to and color opponency, which originates
name broad categories such as red in the retinal ganglion cells.4,8 Achroma-
and blue. Clinical pseudoisochromatic topsics can use these color-opponent
plates may be a bit better test than signals to detect the boundaries between
naming, but some achromatopsics can differently colored regions, even though
112 see the color boundaries between the they cannot identify the colors.7 This
digits and the background if the plates ability to see color boundaries can sup-
are held far away, and therefore answer port form and movement perception for
correctly.4,5 The best tests for achroma- stimuli that contain only differences in
topsia require the patient to sort colors, color and not luminance.
as with the Farnsworth-Munsell 100
color test or the D-15 test, both of which Anatomy
test hue perception. Achromatopsic sub- Bilateral lesions of the lingual and fu-
jects generally have abnormal discrimi- siform gyri cause achromatopsia, and
nation of hue and saturation but normal unilateral lesions cause hemiachro-
perception of brightness.2,4 Hemiachro- matopsia (Figure 8-1). Lesions of the
matopsics can use their normal hemi- middle third of the lingual gyrus or
field to pass these tests: their defect the white matter behind the poste-
is best shown by moving a colored ob- rior tip of the lateral ventricle are crit-
ject across the vertical meridian, allow- ical.2,9 Some suggest that this region

KEY POINT
Case 8-1 A Central

A 74-year-old woman was at the circus with her granddaughter when she achromatopsia
suddenly noted a visual disturbance. By the time she reached the requires
emergency department she had determined that the right side of her bilateral lesions
vision was impaired. Visual acuity was 20/25 in both eyes with correction, of the lingual
and she read 13 of 14 pseudoisochromatic (Ishihara) plates. Confrontation and fusiform
testing showed a congruent right superior quadrantanopia. In addition, gyri; unilateral
although she could see and identify objects in her right lower quadrant, lesions limit the
she could not discriminate red from green colors there until the targets problem to the
crossed over the vertical contralateral
meridian into her left lower hemifield.
quadrant. She could identify
faces and objects but read
slowly. The rest of her
neurologic examination was
normal. Paroxysmal atrial
fibrillation was discovered,
and she was anticoagulated.
MRI showed a stroke
involving the left fusiform
and lingual gyri, sparing the
occipital pole (Figure 8-1).
Comment. In addition to
her superior quadrantanopia,
she has a contralateral
hemiachromatopsia,
consistent with damage to
the lingual and fusiform gyri.
As with most patients with
hemiachromatopsia, she was
not aware of the defect until
it was shown to her. This FIGURE 8-1 Hemiachromatopsia. Axial
magnetic resonance image
unawareness and the failure of a woman with stroke
of clinicians to test for affecting the lingual gyrus (arrow) in the left
posterior cerebral arterial territory, causing right
hemiachromatopsia probably upper quadrantanopia with hemiachromatopsia
mean that this condition is apparent in the right lower quadrant.
underrecognized.
113
contains a human homolog of area Associated Signs

V4, the first monkey region found to Achromatopsia can be accompanied
have color-selective responses, but by prosopagnosia, topographagnosia,
lesions limited to V4 do not impair and superior homonymous field de-
hue perception in monkeys.10 Rather, fects, and less frequently by general
human functional neuroimaging reveals visual agnosia, alexia when a right hem-
several color-processing regions, includ- ianopia is present, and amnesia when
ing V4, a second area named V4a or V8 damage extends to the anterior tem-
in the fusiform gyrus, and more distant poral lobe. It is most often caused by
regions.11 Severe achromatopsia may strokes, such as bilateral sequential or
require disabling of several components simultaneous infarctions from poste-
of this color network.12 rior cerebral arterial occlusions or a

KEY POINT
coagulopathy. It may be the initial sual agnosia have trouble recogniz-
A General visual
symptom or final outcome from a re- ing or learning to recognize objects by
object agnosia
can be broadly solving cortical blindness. sight, even though they can identify
divided into them through other modalities such
Other Disorders Involving Color as touch or sound.17,18 In some cases
apperceptive
and associative Achromatopsia needs to be differenti- this appears to be a perceptual dys-
forms, each ated from a few other color-related dis- function, while in others it seems to
with further orders, most of which are even rarer. be a problem associating what is seen
subtypes. Subjects with these other disorders see with what is known from the past. This
colors and sort them normally but can- apperceptive/associative dichotomy is
not name them for a variety of reasons. rarely encountered in a pure form,
Color anomia may occur as part of an though, as Lissauer recognized more
anomic aphasia or as a specific entity than 100 years ago. The distinction
with left occipital lesions that cause between apperceptive and associative
alexia and right homonymous hemiano- agnosia traditionally has relied on two
pia. It is attributed to a callosal discon- criteria: (1) whether patients can copy
nection that prevents color information drawings, and (2) whether they can
in the intact right hemisphere from ac- match simple shapes. Failure on
cessing language processors in the left either of these tasks would point to
angular gyrus.13 Color dysphasia carries an apperceptive defect. Many other
an additional problem in that patients reasons beside poor perception may
also cannot state the colors that are ap- cause poor drawing, however, whereas,
propriate to familiar objects,14 which on the other hand, agnosics who can
indicates loss of an internal lexicon for match and draw tolerably well often
colors. Most have lesions of the left do so in a very slow and laborious man-
angular gyrus, with alexia with agraphia, ner, suggesting that there is neverthe-
Gerstmann syndrome, and right hom- less something anomalous about their
onymous hemifield defects. Color ag- perception.19
nosia goes one step further, in that More recent work has fractionated
patients also cannot color line draw- these two broad categories further.19
ings appropriately or state whether Object perception involves many pro-
drawings have been colored by others cesses, such as shape coding, figure-
correctly.15 Therefore, this is not just a ground segmentation, grouping and
lexicon problem but lack of knowl- integration of features into wholes, and
edge about the color properties of the so on, all of which are at least theoret-
114 world. Most of these subjects have left ically dissociable from each other. One
occipitotemporal lesions, some with a influential taxonomy thus includes sev-
right hemianopia. A rare developmen- eral varieties of apperceptive general
tal form may be inherited in an auto-
visual agnosia.20,21
somal dominant fashion.16
Apperceptive Visual Agnosia
DISORDERS OF BASIC OBJECT In shape agnosia or visual form ag-
RECOGNITION—GENERAL nosia, patients have trouble seeing
VISUAL AGNOSIA shapes because of a defect in repre-
General visual agnosia is the inability to senting basic properties such as cur-
recognize or identify objects visually, vature, surface, and volume.20,22 They
despite intact low-level visual function, perform the standard tests of shape
the latter usually inferred from pre- matching and of copying of drawings
served sensitivity to light and contrast very poorly. Shape misperception falls
(Case 8-2). Subjects with general vi- along a continuum, with some patients

Case 8-2
A 62-year-old woman had persistent visual difficulties after cataract surgery 3 years earlier. An
ophthalmologist had noted a right hemifield defect. Over the prior year, however, she had noticed
more trouble reading words, even though she could read individual letters and numbers. She had
trouble searching for items, and she stumbled on objects when walking. Over the prior 6 months, she
had found it difficult to identify money and could not recognize faces in her photo albums. It was
hard for her to find the numbers when dialing on her phone. Her acuity was 20/40 right eye and 20/20
left eye. She could not read pseudoisochromatic plates. Confrontation testing and Goldmann
perimetry showed a partial right hemianopia. With line drawings she mistook a glove for a snake, a
chair for a cookie, and a hammock for grass with a baby bird. She mistook a quarter for a penny,
correcting the error when the coin was placed in her hand. When the cookie theft picture was
produced, she stated she had been tested with it before, named several of the items in it, but could
not give a coherent description of the whole picture and had to search to find items that she
remembered being present in it, such as the stool. She read single letters rapidly but hesitated with
words, making more errors with low-frequency or long words.
MRI scan (axial fluid-attenuated inversion recovery and sagittal T1-weighted images) revealed
bilateral cortical atrophy of the occipital lobes, as well as some white matter hyperintensities
(Figure 8-2).
Comment. This woman has visual agnosia. Note that the identities of objects that elude her
visually become immediately obvious when she can feel them. The nature of the disorder is
pervasive,
affecting her
reading, face
recognition,
and even
identification of
simple objects,
despite the fact
that she has
good visual
acuity and at
least one
apparently
normal hemifield.
These contrast
with her excellent
attention and
memory. Her
115
slowly progressive
course and the
MRI changes are
consistent with a
posterior cortical
atrophy, a focal
degenerative
process that
often turns out to
be a variant
of Alzheimer FIGURE 8-2 Apperceptive general visual agnosia. Magnetic resonance images of a woman with
posterior cortical atrophy showing reduction in occipital gyri. She presented with
disease. 1 year of trouble reading, searching for items, identifying money and faces, and
reading the numbers on the phone dial.

perceiving simple shapes well but not Associative Visual Agnosia

more complex ones.23 When trying to Associative general visual agnosia can
recognize objects, they seize on frag- also be fractionated in a number of
ments of the picture and often try to ways. One division is between semantic
make inferences from texture and color. access agnosia, the inability to access
They may benefit from the movement intact memories or stored representa-
of objects or depth cues to object structions of objects, and semantic agnosia,
ture, information that may be processed in which those memory representations
in the dorsal stream. Likewise, intact have been destroyed.20 The distinction
dorsal stream function may allow them can be made through tests of visual im-
to orient their grasp intuitively to the agery that probe verbally what a patient
shape of an object or to recognize ges- remembers about objects. It is debated
tures and actions better than objects. whether a visually selective semantic ag-
The fundamental problem in visual nosia actually exists, or if semantic agno-
form agnosia is debated. One thought sia is always multimodal and therefore
is that diffuse occipital damage may pep- not really a visual agnosia.21
per thousands of tiny scotomata across A second division reflects the separa-
their vision.24 Based partly on simulation of object knowledge into two broad
tions in controls, however, others pro- types: (1) stored structural descriptions,
pose the problem more likely reflects about object appearance, and (2) stored
difficulty using grouping cues that help semantic knowledge, about object func-
determine what features belong to an tion, habitat, history, etc.27 Thus, in re-
object and thus define its shape.25 Visual gard to the latter, some patients with
form agnosia is associated with wide- visual agnosia can describe what objects
spread and diffuse occipital lesions, look like but cannot name or pantomime
most typically carbon monoxide poi- their use. They cannot categorize visual
soning,24 otherwise bilateral hypoxic- objects by semantic similarity (eg, ‘‘Is a
ischemic occipital injury or posterior baseball more similar to a bat or to a to-
cortical atrophy. mato?’’), although they can when given
In integrative general visual agno- the names of objects.
sia, patients can perceive elementary Potentially related is a distinction be-
shapes but do not integrate the parts tween living and nonliving things.28 Most
into a perceptual whole.26 They match frequently reported is a more severe im-
simple shapes slowly and produce la- pairment for recognition of living than
borious and slavishly correct copies of nonliving things. Some argue that such
116 drawings in a part-by-part fashion but a dissociation implies separate represen-
fail to appreciate how the parts go to- tations for animate and inanimate ob-
gether. Because of this they do not see jects.29 Living things may be distinguished
the errors in impossible objects like primarily by their structure and shape,
some Escher drawings and may not whereas nonliving things are coded pri-
appreciate the falsity of objects cob- marily by semantic properties such as
bled together from a collage of dis- their functions.30 Furthermore, others
parate object parts, such as an animal suggest that, because functionality often
with bunny ears and a horse’s rear end. involves manipulation and use, nonliv-
They also have trouble teasing apart the ing objects may access sensorimotor
objects represented in drawings where representations not available for living
the figures overlap each other. Cases things.31 Other reasons why the recogni-
with integrative agnosia have had bilat- tion of living things may be more vulner-
eral peristriate occipital infarcts or pos- able to damage include greater reliance
terior cortical atrophy. of the recognition of animate objects on

KEY POINTS
global processing32 and greater similarity shown that the patient can recognize
A Patients with
in structure between different living people through other means, such as
associative
things than between different nonliving hearing their voice, but auditory tests agnosia can
things, making discriminations harder are hard to find. Also, the patient should differ in the kind
for the former.33 be able to provide biographical data of knowledge
Associative agnosia and semantic ac- when given the names of people instead impairment they
cess deficits may be more prominent of their faces, to exclude a more gen- have, as with
with left occipital damage that involves eral semantic problem with knowledge contrasts
the parahippocampal, fusiform, and lin- about people. The cultural background between
gual gyri,34 although some believe in needs to be considered in interpreting knowing what
the necessity of bilateral lesions. In these tests. Tests of short-term recogni- objects look like
Alzheimer disease, neurofibrillary tan- and what they
tion of anonymous faces, such as the
are used for, or
gles in Brodmann areas 18, 19, and 37 Warrington Recognition Memory Test38
between living
are correlated with associative deficits and the Cambridge face memory test,39 and nonliving
in object recognition but not with ap- can be useful complements. things.
perceptive deficits.35
Other Related Visual Abilities A Prosopagnosia is
best diagnosed
DISORDERS OF FACE Patients with prosopagnosia can vary con-
by tests that
PROCESSING—PROSOPAGNOSIA siderably in their ability to process other
probe the ability
types of facial information, such as emo-
Symptoms and Signs of patients to
tional expression, age, gaze direction, and tell familiar
Prosopagnosia is the impaired ability gender. Preservation of expression pro- faces from
to recognize familiar faces and to learn cessing may reflect the fact that this uses anonymous
new faces (Case 8-3).36 Rarely patients anatomic regions and networks (eg, the ones, or faces
may have an anterograde form, in that superior temporal sulcus and amygda- that they have
the problem only affects faces seen la) that differ from the regions that recently seen
after the onset of their lesion. Proso- process identity (eg, the fusiform face from those they
pagnosics have trouble telling which area and anterior temporal cortex).40 have not.
faces they have seen before and are bi- Whether prosopagnosia affects the
ased to say that most faces are un- processing of faces alone is highly con-
familiar. To compensate, they identify troversial, with reported patients seem-
people by voices or other visual cues, ing to vary in whether or not they also
such as gait or mannerisms, or distinct have mild object recognition defects that
facial features like hairstyles or scars affect their ability to tell apart different
that circumvent the need to scrutinize types of birds, cars, coins, flowers, foods,
the whole face. The context of an en- and so on. To a degree, this reflects an 117
counter sometimes facilitates recogni- ongoing debate about whether face rec-
tion, so that they recognize a colleague ognition is accomplished by a network that
at work but not on the street. Most proso- is dedicated solely to face processing,41 or
pagnosics are aware of their problem if it is performed by an expertise network
and its social difficulties, and a few are that can be recruited for subtle distinctions
severely dysphoric as a result. between exemplars of any object category
To diagnose prosopagnosia the pa- with which the observer is expert.42 How-
tient is shown photographs of family ever, given the size of naturally occurring
members or public persons, as in the lesions, it is difficult to know in proso-
famous faces test, preferably mixed pagnosics whether recognition problems
with some anonymous faces so that with other objects are part and parcel of
one can determine whether the pa- the face recognition defect or if they
tient can distinguish known from un- merely reflect collateral damage to struc-
known faces.37 Ideally, it should be tures adjacent to face-processing regions.

Case 8-3
A 41-year-old man 21 years earlier had been the driver of a car that overturned. He suffered
a right subdural hematoma, which was treated surgically. He was blind for about 2 weeks but
this gradually improved until he was left with a permanent right hemianopia. Ever since that time,
he had noted that colors were ‘‘off,’’ although he was able to recognize their approximate
categories. Reading was a bit slow but acceptable to him. He occasionally became lost walking
his dog or driving around his hometown. Most notably, he was unable to recognize people by
their faces. He relied on cues, such as the blonde hair of his wife or moustaches on men, and
often waited until people talked before he tried to identify them. His acuity was 20/20 in each
eye. Although he read 13 of 14 pseudoisochromatic plates, detailed experimental testing
showed marked elevation of his threshold for color saturation. He had a complete right
hemianopia. He identified most line drawings of objects, only mistaking a feather for a flower.
He read letters and sentences well, making one mistake for the end of one long word. His verbal
and nonverbal memory was excellent, and his drawings of objects were good. On a famous
faces test, he showed no recognition ability, identifying only two of 20 faces as famous and
mistakenly asserting that three of 20 anonymous faces were familiar.
MRI scan (coronal T1) showed bilateral ventral occipitotemporal lesions (Figure 8-3).
Comment.
This patient has
prosopagnosia.
Elements of his
history also
suggest a
topographagnosia,
and detailed
testing
confirmed
a partial
dyschromatopsia.
In contrast to
his severe
problems
recognizing
faces, his
recognition of
objects at a
more general
118 level is normal,
and his
reading is quite FIGURE 8-3 Apperceptive prosopagnosia. Coronal magnetic resonance images in a man
showing bilateral inferior occipital lesions from head trauma 21 years
good, despite earlier, affecting the region of the right and left fusiform face areas. He has
the right prosopagnosia, dyschromatopsia, and right hemianopia.
hemianopia.
Some patients with prosopagnosia differentiation between familiar and un-

also show evidence of some residual familiar faces, or even recognition of
unconscious or ’’covert’’ face recogni- correct matches between names and
tion.43 When variables such as reaction faces. This unconscious processing may
times, forced-choice guesses, or lie- reflect either the residual function of a
detector measures of skin conductance partially damaged face-processing net-
are measured, these patients show some work44 or, particularly in the case of

KEY POINT
residual autonomic indices, a parallel age to the lingual and fusiform gyri.
A Prosopagnosia
pathway involving the superior tem- A second group has unilateral right oc-
is a family of
poral sulcus and amygdala.45 cipitotemporal lesions, most of which disorders, with
also involve the right fusiform gyrus.47 occipitotemporal
Pathophysiology Rarely, there are cases with unilateral left lesions causing
Prosopagnosia is a syndrome, a family occipitotemporal lesions, most often in problems with
of functional disorders rather than just subjects who are left-handed.50 A third accurately
one dysfunction. Cognitive models de- type of prosopagnosia is associated with perceiving faces
compose face recognition into a series bilateral or right anterior temporal lesions. and anterior
of stages46: visual processing creates a Medial occipitotemporal lesions likely affect temporal lesions
facial percept, which is then matched a number of face-selective regions found impairing access
to a store of memories of previously with functional neuroimaging (Figure 8-4), to facial
memories.
seen faces, from which a successful including the fusiform face area and the
match leads to person-identity nodes occipital face area,40 damage to which
that access biographical and semantic most likely leads to an apperceptive form
data about people. In theory, proso- of prosospagnosia.49 Anterior temporal
pagnosia can arise from dysfunction at lesions tend to affect facial imagery
any stage. In practice, the large and more than face perception and hence
often multiple lesions in prosopagno- may be linked more to associative proso-
sic patients may mean that one stage pagnosia (Figure 8-5).
is predominantly affected with other
stages mildly impaired. As with general Associated Signs
visual agnosia, classic accounts divide Prosopagnosia with fusiform lesions is
prosopagnosia into two broad classes. often although not invariably accompa-
In apperceptive prosopagnosia, the pa- nied by three other findings: (1) a visual
tient’s visual system cannot accurately field defect that is usually a left or
encode the percept of a face. This is bilateral superior quadrantanopia, or a
marked by defects in processing quan- left hemianopia, (2) achromatopsia or
titative aspects of facial structure47and hemi-achromatopsia, and (3) topogra-
holistic forms of processing.48 In some phagnosia. Mild amnestic deficits may
subjects, there is particularly poor en- accompany prosopagnosia following an-
coding of the eye region, normally the terior temporal lesions. The most com-
most informative facial area for identify- mon causes of prosopagnosia are pos-
ing people.48,49 In associative prosopag- terior cerebral artery infarctions, head
nosia, the percept is good but fails to trauma, and viral encephalitis, all lesions
access facial memory stores. In some that have a propensity for bilateral dam- 119
cases, this may be because of a discon- age. Tumors, hematomas, abscesses, and
nection between percepts and memory surgical resections are also common
stores; in others, the facial memories among cases with unilateral lesions.
may be lost. One means of probing the Progressive forms occur with focal tem-
status of facial memories is imagery.44 poral atrophy. Interest in a develop-
Loss of imagery for famous faces is pro- mental form of prosopagnosia is also
nounced in prosopagnosia following an- growing.51 At present no proven treat-
terior temporal lesions.49 ment exists for prosopagnosia, which
is usually permanent.
Anatomy
Prosopagnosia is caused by a variety Related Disorders of Face
of lesions, which can be grouped into Processing
three main categories.49 The first group A few disorders should be kept dis-
has the classic lesions of bilateral dam- tinct from prosopagnosia. (1) Some

FIGURE 8-4 The core face-processing network. Functional magnetic resonance images
in a healthy subject showing coronal (COR, left column), axial (TRA, middle),
and sagittal (SAG, right column) images. The red regions indicate significantly
greater blood oxygenation level-dependent signal when viewing faces than when viewing
objects. The top row shows the occipital face area, the middle row the fusiform face area,
and the bottom row the superior temporal sulcus. R = right; L = left, A = anterior;
P = posterior.
Figure courtesy of Chris J. Fox, PhD, Vancouver General Hospital, Vancouver, Canada.
120
individuals with lesions of the right or temporal sulcus.53 (3) While most
temporal pole have a people-specific patients with prosopagnosia claim that
amnesia.52 This is a multimodal prob- no one looks familiar anymore, some
lem in which no visual, auditory, or patients with large middle cerebral
semantic cues are able to prompt artery strokes may have false recogni-
memories about people; hence it is tion of faces.54 It is surmised that right
not just about faces. (2) As predicted by prefrontal damage in these individ-
evidence from functional neuroimaging uals may impair decision monitoring,
that identity and expression may have leading to a failure to reject erroneous
distinct neural substrates, evidence judgments of facial similarity based
suggests that face expression deficits on fragmentary data. However, some
without prosopagnosia can occur in cases may occur following left occipital
individuals with damage to the superi- lesions also.

KEY POINT
A Topographagnosia
is a term that
encompasses
a variety of
disorders,
including
agnosia for
landmarks,
trouble with
cognitive map
formation, and
egocentric
disorientation,
among others.
FIGURE 8-5 MRI showing bilateral anterior temporal lesions in a patient who developed
prosopagnosia after herpes encephalitis. His core face-processing network was
intact on fMRI, and his perceptual matching skills for faces were preserved.
SAG = sagittal; COR = coronal; TRA = axial; A = anterior; P = posterior;
R = right; L = left.
121
DISORDERS OF different patients, leading to a taxonomy
ENVIRONMENTAL for this family of disorders.55
RECOGNITION— One form that is particularly associ-
TOPOGRAPHAGNOSIA ated with prosopagnosia and achroma-
Topographagnosia (or topographic dis- topsia as a type of object recognition
orientation), the loss of the ability to deficit is landmark agnosia, the inability
represent the layout of the environment to identify familiar landmarks and build-
correctly, usually manifests as problems ings.56 This follows right ventral tempor-
with navigation. Thus patients with this ooccipital lesions.57 The debate about
disorder get lost in familiar surround- the pathophysiology of landmark ag-
ings. With a complex task, such as route nosia revolves around whether it re-
finding, a number of cognitive strategies flects a selective multimodal memory
can be used to navigate. Topographag- disturbance rather than a strictly vi-
nosia can arise for different reasons in sual problem.58 However, functional

imaging has revealed a parahippocam- blocks, turn left, travel another block,
pal place area, a region adjacent to the then turn right). A deficit in this strategy
fusiform face area that is activated by is referred to as egocentric disorienta-
seeing buildings and places.59 It seems tion, since subjects cannot represent the
highly likely that a lesion of the para- sequence of the route with respect to
hippocampal place area could create their location as they move through the
an agnosia for landmarks and explain environment.55
the frequent association with proso- A heading disorientation is failure
pagnosia, but further research is nec- to represent direction with respect to
essary to make this link. cues in the external environment, rather
Studies (Figure 8-6) also show that than in relation to the subject. This has
when subjects form and use a mental been associated with posterior cingu-
map of their environment, the hip- late lesions.62 This may have also been
pocampi and retrosplenial cortex are the case in a subject with a left para-
recruited.60 This cognitive map forma- hippocampal and retrosplenial lesion
tion (sometimes referred to in the past who had defective route finding as-
as allocentric navigation) is one of the sociated with alexia and other severe
most efficient and flexible ways to orient visual amnestic deficits.63
within a world in which our current Parahippocampal lesions have also
location is constantly varying. Recent been implicated in an anterograde to-
work has shown that congenital top- pographagnosia, in which new routes
ographagnosic disorientation can be as- cannot be learned, although old routes
sociated with impaired cognitive map are still known.64
formation and failure to activate the hip- Establishing which of these strategies
pocampi and retrosplenial cortex dur- is impaired in a patient with topograph-
ing navigation (Case 8-4).61 agnosia is a challenge and requires care-
Right parietotemporal lesions may ful attention to the description by the
impair the spatial processing needed to patient of the problems, with confirma-
describe, follow, or memorize routes.57 tion through a battery of tests of these
This type of strategy is similar to fol- different functions, such as can be found
lowing gas station directions (eg, go two at the website www.gettinglost.ca.
122
FIGURE 8-6 Functional MRI of subjects as they make use of

a cognitive map (ie, a mental representation of
the environment) while orienting in a virtual
reality environment. The blue in the figure shows increased
neural activity within the hippocampal complex (coronal image,
left) and retrosplenial cortex (sagittal image, right). y and x refer
to Tailarach coordinates.
Figure courtesy of Giuseppe Iaria, PhD, Hotchkiss Brain Institute.

Case 8-4
This 43-year-old left-handed woman had never been able to find her way
around any environment as long as she could remember, despite normal
motor, language, and cognitive development. She had never left home
alone because she got lost each time she tried. Her sisters or parents
brought her to and from school every day, and in her teenaged years her
friends always accompanied her when she left her house. No other family
members had a similar problem.
As an adult she lived with her father and worked in a downtown office. To
get there she took a bus and recognized a distinctive square where she must
exit and from which she can see the office building 30 m (98 ft) away. If she
deviated from this straight path to the office, she became hopelessly lost. To
return home was more difficult as she could not see her house from the bus
stop. Not infrequently, she became lost on her way through her neighborhood
and had to phone her father from an intersection, give him the names of the
streets at the intersection, and ask him to come and get her. Although she
could recognize many familiar buildings, she had trouble finding her way to
stores and theaters. She sought help when her office decided to relocate.
Her neuropsychological assessment showed normal attention, memory,
and perception. Her drawings of the plan of her house and the route to work
were highly inaccurate in their scaling and spatial dimensions; for less familiar
items, such as her neighborhood or city, she could not draw any maps at
all. When tested with a virtual reality simulation, she was extremely slow in
her ability to form a cognitive map of the simple test environment, requiring
30 minutes to do what others did in 10 minutes. When asked to use her
cognitive map to find landmarks in this virtual environment, she made many
mistakes and took 5 times as long as controls to reach her destinations.
Although clinical MRI scans did not show any obvious anomaly, an fMRI
performed while she attempted to form cognitive maps showed that she
lacked the normal hippocampal and retrosplenial activation seen in controls.
Comment. This patient has a developmental topographic disorientation,
which in her case appears to be caused by inability to form and use
cognitive maps—mental representations of the layout of the environment.
123
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127

KEY POINT
A The overall
attentional
ATTENTIONAL AND
matrix
represents the CONFUSIONAL STATES
collective
manifestation M.-Marsel Mesulam
of all
attentional
modulations. ABSTRACT
The term attention refers to the preferential allocation of cognitive and neural
resources to events that have become behaviorally relevant. Attention is modulated
by the bottom-up influence of the ascending reticular activating system and the top-
down influence of association and limbic cortices. Focal lesions that interfere with the
bottom-up or top-down regulation of attention, or multifocal partial lesions that
interrupt multiple domain-specific processing pathways, can disrupt the attentional
matrix and give rise to the acute confusional state syndrome.
INTRODUCTION independent modulations are exerted

Attention can be defined as the prefer- predominantly through the bottom-up
ential allocation of neuronal resources to influence of the ascending reticular acti-
events that have temporarily become vating system (ARAS) and the top-down
relevant. Attention can be distributed influence of the cerebral cortex, especially
globally or focally; it can act on stimuli in the frontal lobes (Figure 9-1). Through
parallel or serially; and it can be attracted these two channels, attentional modula-
exogenously by external events or di- tions become responsive not only to the
rected endogenously to mental phe- physical properties of the stimulus but
nomena. Concentration and vigilance also to arousal levels, motivational va-
are positive aspects of attention, whereas lence, cognitive state, and volition. The
distractibility, impersistence, and confu- ARAS tends to play a greater role in
sion reflect attentional deficits. Although attentional modulations related to stimu-
some might consider arousal and atten- lus features and arousal, whereas the
tion virtually synonymous, this can be cerebral cortex is more closely involved in
128 debated since attentional deficits can modulations related to cognitive state,
occur in perfectly awake individuals and past experience, and expectation.
since extreme levels of arousal—as in The overall attentional matrix (as re-
pain or terror—may impair the flexibility flected by phenomena such as detection
of attention. efficiency, focusing power, concentra-
Attentional modulations can be do- tion span, vigilance level, novelty-seeking
main specific or domain independent tendencies, resistance to interference,
(global). Visual neurons mediate domain- and online processing capacity) repre-
specific attentional responses to visual sents the collective manifestation of all
stimuli, face neurons to faces, posterior attentional modulations. The syndrome
parietal neurons to spatial targets, lan- of acute confusional state reflects an
guage areas to words, and so on. Domain- impairment of the attentional matrix as a
Relationship Disclosure: Dr Mesulam has nothing to disclose.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Mesulam has nothing to disclose.

whole, whereas the syndrome of spatial
neglect reflects a domain-specific impair-
ment in distributing attention across the
extrapersonal space. This article will con-
fineitselfto theattentionalmatrixandcon-
fusional states. Spatial attention will be
reviewed in another article in this issue.
CONFUSIONAL STATES AS
DISORDERS OF THE
ATTENTIONAL MATRIX
The acute confusional state is arguably
the single most common neurocognitive
disturbance that most physicians will
see. An acute confusional state is also
known as delirium, organic psychosis, or
acute organic brain syndrome. It can be
defined as a change of mental state in
which the most salient deficits involve
FIGURE 9-1 A schematic representation of the three
the overall attentional tone. The atten- compartments that regulate the
tional deficits do not necessarily emerge attentional matrix.
in isolation. Indeed, patients in acute ARAS = Ascending reticular activating system.
confusional states commonly have addi-
tional cognitive and behavioral distur-
bances, such as memory loss, agitation, tion of a coarse tremor, myoclonus, or
and hallucinations. It is also important to asterixis. Attentional deficits arise at
realize that not all patients with atten- several levels of behavior. Vigilance is
tional disturbances can automatically be defective. Attention either wanders aim-
described as being in a confusional state. lessly or is suddenly focused with in-
For example, patients with the typical appropriate intensity on an irrelevant
form of Alzheimer disease commonly stimulus that becomes the source of
also have attentional difficulties. How- distractibility. Thought and skilled move-
ever, they cannot be said to exhibit a ment become vulnerable to interference,
confusional state since the salient feature impersistence, and perseveration. The
is typically amnesia rather than inatten- stream of thought loses its coherence
tion. Many patients in confusional states because of the frequent intrusions by 129
are also disoriented. This is not a nec- competing thoughts and sensations. Se-
essary feature of the condition, however, quences associated with skilled move-
and it is possible to see patients in con- ment, even those as automatic as dialing
fusional states who maintain orientation. the telephone or using eating utensils,
It is the salience of the attentional deficit lose their coherence and show signs of
rather than the presence of disorienta- disintegration, perseveration, and imper-
tion that is the sine qua non for the sistence. Tests that assess the various
diagnosis of a confusional state. components of sustained attention, di-
vided attention, selective attention, inhi-
Clinical Picture bition of inappropriate responses, and
Toxic-metabolic encephalopathies are resistance to distractibility reveal consid-
the most common causes of confusional erable impairment. Thus performance in
states. Usually no focal neurologic signs attentional tasks, such as the Digit Span
are present with the possible excep- Test, is impaired. When asked to recite

" ATTENTIONAL AND CONFUSIONAL STATES
KEY POINTS
the months of the year in reverse or- other characteristics of confusional states
A The most
der, the patient may say, ‘‘December, No- are the rapid fluctuation of mental state
characteristic
feature of a vember, October, September...October, that may occur from hour to hour and
confusional November, December, January,’’ show- the rather typical nocturnal exacerbation
state is an ing the inability to withhold the more (sundowning).
impairment customary response tendencies in this Great individual variations occur in the
of attention test of working memory. This clinical de- susceptibility to confusional states in-
rather than scription highlights the three cardinal duced by toxic-metabolic encephalopa-
disorientation. features of confusional states: (1) distur- thy. In general, the older adults and those
A In general, bance of vigilance, heightened distracti- with preexisting brain disease—especially
older adults bility, and impaired working memory, (2) dementia—seem more vulnerable to
and patients inability to maintain a coherent stream of developing acute confusional states in
with preexisting thought, and (3) inability to carry out a response to even mild metabolic stresses.
brain disease— sequence of goal-directed movements. In the young, only severe toxic-metabolic
especially Difficulties in additional aspects of insults can induce a confusional state,
dementia— mental function are also common in con- and the removal of the underlying cause
seem more fusional states. Perceptual distortions results in rapid and dramatic improve-
vulnerable to
may lead to illusions. Hallucinations, ment. Elderly patients, however, are much
developing
ideas of reference, misidentifications of more vulnerable to milder forms of toxic-
acute
place and people, and agitation may metabolic perturbations. In some, im-
confusional
states in arise. The patient is often, but not always, provement may not start for days after
response to disoriented and shows evidence of faulty the correction of the underlying condi-
even mild memory. Mild anomia, dysgraphia, dys- tion and may last for months (Case 9-1,
metabolic calculia, and constructional deficits are Figure 9-2). Furthermore, some of these
stresses. common. Judgment may be faulty; in- patients may never regain a fully normal
sight appears blunted; and affect is quite mental state despite considerable im-
labile with a curious tendency for face- provement. It is not clear why recovery
tious witticism. Some of these deficits are can take so long after the presumptive
probably secondary to attentional diffi- offending agent has been removed or why
culties. For example, if the patient is it is sometimes incomplete. Perhaps this
allowed sufficient drilling during the ac- reflects the state of diminished neural
quisition stage of a learning task, memory reserve characteristic of the aging brain and
improves. Calculations that appear dev- also the fact that some toxic-metabolic
astated when tested mentally may prove encephalopathies lead to at least some
to be quite accurate when the patient is irreversible neural damage.
130 allowed the use of a pencil and paper. It is also conceivable that individ-
Some confusional states are char- uals who show this pattern of extreme
acterized by apathy; others, especially vulnerability and indolent recovery may
when related to alcohol, barbiturate, or have a preexisting degenerative brain
opiate withdrawal, lead to extreme agi- disease, most probably of the Alzheimer
tation. In their more severe forms, con- type, that has not yet reached its full
fusional states may lead to stupor and clinical manifestations. In fact, the most
coma. This gives rise to the widely held florid confusional states take the form
opinion that confusional states are merely of a ‘‘beclouded dementia’’ in patients
disorders of wakefulness and arousal. already afflicted with degenerative CNS
However, in the early stages of most diseases of the Alzheimer type. Even an
confusional states attention is impaired occult urinary tract infection may be suf-
out of proportion to the drowsiness, ficient to induce a severe exacerbation of
suggesting that the mechanisms of atten- mental state impairment in this group
tion are impaired independently. Two of patients. Although the presence of a

Case 9-1
An 83-year-old man with congestive heart failure developed a confusional
state, which interfered with daily living activities. His clock drawing on
the day of presentation showed poor planning and marked perseveration.
The tracings above the clock show his performance in the alternating
sequences task. The very top tracing is the examiner’s model. The patient
was asked to copy it and then to continue with the same pattern until he
reached the end of the page. The patient performed reasonably well
during the copying phase. However, he subsequently could not resist the
perseverative tendency to repeat the segment just drawn (Figure 9-2, left).
The congestive
heart failure
responded to
treatment and
disappeared in a
matter of a few
days. However,
the improvement
of the confusional
state was gradual
and took
approximately
6 months to reach
a plateau. By that
time, he was
driving and
successfully
performing FIGURE 9-2 Temporal evolution of a confusional state
customary daily
living activities. His
performance 7 months later in the alternating sequences and in drawing a
clock was much improved. He could even copy a cube reasonably well, a
task he had found impossible during the acute episode (Figure 9-2, right).
Comment. The evolution of the confusional state in this man shows that
recovery may take a long time and that the physician should avoid
reaching hasty conclusions on prognosis.
131
preexisting dementia precludes a return such as hemianopia or aphasia, the par-
to complete normalcy, the treatment of tial dysfunction of multiple cortical sys-
the toxic-metabolic encephalopathy can tems can trigger processing perturba-
be very beneficial because it leads to an tions that collectively lead to a confusional
improvement of the superimposed con- state.
fusional state.
In contrast to cerebrovascular lesions, BIOLOGY OF THE
which tend to cause a relatively complete ATTENTIONAL MATRIX
but focal destruction of the afflicted Neurons of sensory and association areas
area, toxic-metabolic encephalopathies display attentional modulations that re-
induce partial dysfunction in many parts flect the intrinsic properties of the stimu-
of the cerebral cortex, including all lus, the bottom-up influence of the ARAS,
components of the attentional matrix. and the top-down influence of hetero-
While insufficient to cause focal deficits modal and limbic cortices.

Domain-Specific Attentional receptive fields, indicating that this part

Modulation in the of visual association cortex may play
Cerebral Cortex a role in filtering out irrelevant infor-
Attentional modulations are present in mation.5 In fact, monkeys with infero-
primary sensory and modality-selective temporal lesions show learning deficits
cortex, although they are relatively mod- caused by an inability to ignore irrele-
est when compared to those seen at vant visual information, and a similar
the more downstream and heteromodal condition may exist in the human as
synaptic relays of sensory pathways. Neu- illustrated by a patient who displayed
rons in early visual association areas, excessive visual distractibility following
such as V5, give distinctly enhanced re- an infarct of the visual association areas
sponses to dots moving in their pre- in the right temporal lobe.6
ferred direction if the animal is engaged Domain-specific attentional effects can
in a task that requires attentiveness to also be identified in cortical areas special-
the moving stimuli. When attention is ized for more complex functions, such as
shifted outside the receptive field of such face and object recognition, spatial atten-
a neuron, the specificity of its direction- tion, and language. When compared to a
dependent responses to movement is re- passive viewing condition, for example,
duced.1 Furthermore, visual-association the attentive examination of faces (but
neurons in V4 and inferotemporal cor- not of houses) increased the activation
tex display larger and more selective re- of the fusiform face area.7 Furthermore,
sponses to attended visual stimuli, and words at an attended location elicit
such response enhancements are associ- greater P300 responses in the posterior
ated with improved performance in the parts of the left hemisphere, suggest-
behavioral task.2,3 ing that language cortex gives enhanced
Domain-specific modulations have neural responses to attended words.8
also been observed in tasks of selective In the inferior parietal lobule and
attention in which optimal performance frontal eye fields, two critical nodes of
necessitates the suppression of the un- a distributed network that controls spa-
attended input channels. When subjects tial attention, neurons give enhanced
who were exposed to concurrent visual, responses to behaviorally relevant ex-
auditory, and somatosensory stimula- trapersonal targets that are likely to at-
tion were asked to ignore two of the tract visual and manual grasp but not
modalities while making a difficult dis- to neutral stimuli at identical spatial
crimination in the third, the sensory locations. Damage to the spatial atten-
132 association area in the attended modal- tion network leads to contralesional
ity displayed the most activation.4 How- unilateral neglect, a domain-specific im-
ever, the association cortices in the two pairment of attention directed to extra-
deliberately ignored modalities contin- personal spatial targets.
ued to display some activation as well, Modality-specific and domain-specific
showing that attentional filtering is un- attentional modulations are also seen
likely to follow a strict ‘‘early selection’’ in conjunction with working memory
pattern and that it occurs on a represen- and novelty-seeking behaviors. Working
tation that has already been subjected memory is a special type of attentional
to considerable cortical processing. In process that enables the online hold-
the monkey, neurons in V4 and infer- ing and manipulation of information
otemporal visual association cortex (but for short intervals. In a typical experi-
not in primary visual area V1), show a ment, a monkey is first briefly shown a
dramatic reduction of responses to sample cue (a color, pattern, or loca-
unattended visual stimuli within their tion), exposed to a variable delay, and

KEY POINT
rewarded for responding to a subse- lations in the modalities and domains
A Working
quent test stimulus only if it matches the for which it is specialized. Attention to
memory is
sample. The crucial component of work- a given event is not encoded by a special a special type
ing memory is the delay period, no group of dedicated neurons, but by of attentional
longer than a few minutes in length, modulations in the activity of neurons process that
during which the animal has to maintain normally involved in the processing of enables the
an online mental representation of a cue the relevant category or modality. Such online
that is no longer visible. Each part of modulations are much more prominent holding and
the modality-selective association cortex in more downstream parts of association manipulation of
seems to participate in the maintenance cortex where they help to construct information for
of working memory in its own area of a personally edited representation of short intervals.
specialization. For example, neurons with the world based on significance rather
increased activity during delay periods than appearance. The following two
are seen in inferotemporal cortex in ex- sections will show how the intensity of
periments in which the stimuli are this attentional modulation in each mo-
colors or visual patterns, and in posterior dality is influenced by ascending and
parietal cortex when the stimuli are spa- descending domain-independent con-
tial locations.9,10 Furthermore, working trol mechanisms located in the ARAS
memory performance in visual and au- and high-order (transmodal) association
ditory tasks is severely impaired after cortices.
damage to visual and auditory association
cortices, even when the lesions leave
elementary sensory abilities in the rele- Ascending Reticular Activating
vant modality relatively intact.11,12 As will System Bottom-Up Modulation
be discussed later in this article, prefron- of Attentional Tone
tal cortex has a pivotal role in supporting The ARAS contains two major axes: (1) a
all neural processes related to working reticulo-thalamocortical pathway, the
memory. activation of which promotes cortical
Preferential attention to novel events arousal by facilitating the transthalamic
is one of the most characteristic features passage of sensory information toward
of the primate brain. Nearly all cortical the cerebral cortex; and (2) transmitter-
areas respond preferentially to novel specific transthalamic pathways, which
stimuli in their specific domains of spe- originate in the brainstem and basal
cialization. In the monkey, inferotem- forebrain and send direct projections to
poral neurons give greater responses the cerebral cortex.
to the sight of unfamiliar objects and The ARAS exerts a domain-independent 133
show decremental responses to repeated global influence on attentional modula-
presentations of geometric shapes.13,14 tion. Its relevance to human attention
Furthermore, face-responsive inferotem- was shown in a functional imaging ex-
poral cells alter their firing to a face as it periment in which the transition from
becomes more familiar.15 In the human relaxed wakefulness to intense attentive-
brain, enhanced responses to novel vi- ness was associated with the activation
sual events are quite conspicuous in V4 of the midbrain reticular formation and
and the visual-association cortices of the the intralaminar thalamic nuclei.18 The
fusiform gyrus.16 As in the case of work- ARAS was one of the first neural systems
ing memory, prefrontal cortex plays a to be investigated systematically from
particularly prominent role in novelty- the vantage point of behavioral phy-
seeking behaviors.17 siology. Soon after the introduction of
This brief survey shows that each cor- EEG recording, spontaneous electrical
tical area can display attentional modu- rhythms were found to be very sensitive

KEY POINT
to levels of consciousness and attention- linergic and originates from the pedun-
A The ascending
al states. High-voltage slow waves, for culopontine and laterodorsal tegmental
reticular
activating example, are associated with drowsiness nuclei of the brainstem reticular forma-
system and certain sleep states, whereas de- tion.19 This cholinergic projection tends
influences the synchronized fast activity is associated to promote the transfer of information
cerebral cortex with arousal, excitement, attentiveness, toward the cerebral cortex. Innervation
both directly and REM sleep. The pacemakers for these from the reticular formation reaches all
through EEG rhythms are located in components thalamic nuclei but is particularly intense
transthalamic of the ARAS, such as the brainstem re- within the intralaminar, reticular, and
pathways and ticular formation, the thalamus, and the limbic nuclei.20,21 The pathways ema-
thalamic relays. nucleus basalis. nating from the intralaminar nuclei are
Neurons in the midbrain reticular widely distributed within the cerebral
core and in the intralaminar thalamic cortex (as opposed to the much more
nuclei tend to have higher firing rates focal projections of sensory relay nuclei),
during states of EEG desynchronization tend to favor layer I, can have a wide-
(waking and REM sleep) than during spread and bilateral influence on corti-
slow-wave sleep. Increased activity in cal activity, and may modulate signal-to-
midbrain reticular neurons is correlated noise ratios during attentional focusing
with a facilitation of the transthalamic and sensory discrimination.21
transmission of sensory information to- The reticular nucleus of the thalamus
ward the cerebral cortex and with an receives projections from the brainstem
increased depolarization of cortical out- and cerebral cortex but does not project
put neurons. The activity of these brain- back to the cerebral cortex.22 Through
stem pacemakers and the concurrent -aminobutyric acid (GABA)-ergic pro-
desynchronization of the EEG thus cor- jections it inhibits the activity of the
respond to states in which sensory other thalamic nuclei.23 Cholinergic in-
events can have a greater impact on nervation has an excitatory influence
cortical circuitry and also where the cor- on all thalamic nuclei except for the
tex has an enhanced readiness for ef- reticular nucleus where it exerts an in-
ferent responses. Damage to these hibitory effect. Stimulation of the cho-
brainstem neurons leads to permanent linergic projection from the brainstem
states of stupor and coma. Neuronal to the thalamus thus releases the spe-
activity in the midbrain reticular core cific thalamic nuclei from the inhibi-
is high not only during wakefulness tion of the reticular nucleus at the same
but also during REM sleep. Activation of time that it activates them directly. The
134 the midbrain reticular core is there- descending projections from the cere-
fore necessary but not sufficient for bral cortex to the reticular nucleus are
wakefulness and attentiveness to exter- excitatory and therefore suppress tha-
nal events. lamocortical transmission. These char-
The brainstem reticular core receives acteristics suggest that the reticular nu-
collaterals from a large number of as- cleus may act as an attentional valve
cending and descending pathways in a for regulating thalamocortical transmis-
way that would enable it to integrate sion according to the integrated influ-
a wide spectrum of neural information ence of the cortex and the brainstem
related to the extrapersonal world and reticular core.
the internal milieu. The ARAS influences The ARAS also contains transmitter-
the cerebral cortex both directly through specific pathways, which innervate the
transthalamic pathways and also through cerebral cortex without a thalamic relay.
thalamic relays. The projection from the These pathways include noradrenergic
brainstem to the thalamus is mostly cho- projections from the nucleus locus

KEY POINTS
coeruleus, serotonergic projections from specialization. Prefrontal and posterior pa-
A Many
the raphe nuclei, dopaminergic connec- rietal cortices, however, influence work-
neurotransmitters
tions from the substantia nigra-ventral ing memory in all domains. Thus, in can influence
tegmental area, cholinergic and GABA- delayed-matching-to-sample tasks, pre- attention.
ergic projections from the nucleus basalis frontal neurons display delayed firing
of Meynert, and histaminergic projec- for faces, inanimate objects, and spatial A Observations
suggest that
tions from the hypothalamus. These path- locations. One of the most remarkable
prefrontal and
ways exert partially overlapping effects properties of these prefrontal neurons is
posterior
upon the surface EEG and attentional a resistance to interference. Prefrontal parietal
modulations. neurons may therefore play a critical role cortices exert
in protecting the contents of work- a top-down
ing memory from distraction. Lesions of influence on
Frontal Lobes and the Top-Down prefrontal cortex in the monkey impair domain-specific
Modulation of Attention performance in all types of working attentional
Prefrontal, parietal, and limbic cortices memory tasks and also decrease the modulations
mediate the top-down modulation of selectivity of delay activity in other parts in all other
attentional responses in ways that are of the cerebral cortex, suggesting that cortical areas
in a manner
sensitive to context, motivation, acquired domain-specific working memory activi-
that may
significance, and intent. The metabolic ties in all cortical areas are subject to top-
mediate the
activation of prefrontal and posterior pa- down modulations emanating from pre-
volitional
rietal cortex is a common correlate of frontal cortex. regulation of
almost all attentional tasks, regardless of The importance of the human pre- the attentional
modality or domain. In one experiment, frontal cortex to working memory had focus.
for example, a task of sustained attention been inferred from cases of brain dam-
(vigilance) led to the activation of the age and was confirmed in the 1970s
superior parietal lobule and of prefrontal by a functional imaging experiment
cortex in Brodmann areas (BA) 8, 9, 44, that found that reverse digit-span tasks
46, regardless of the sensory modality resulted in hemodynamic activations
that was used for stimulation.24 In an- that were maximal over the frontal
other experiment, a task of sustained lobes.26 Since then, numerous studies
attention led to inferior parietal lobule have confirmed the presence of domain-
(BA40) activation, whereas divided at- independent frontal lobe activations dur-
tention was associated with prefrontal ing working memory tasks based on
(BA46) activation.25 In a selective atten- verbal, perceptual, or spatial stimuli. Work-
tion task in which one of three modalities ing memory is usually divided into two
had to be attended and the other two groups of processes: (1) the online main- 135
ignored, prefrontal activation occurred tenance of information and (2) its active
regardless of the modalities that were manipulation. The latter aspect is at-
ignored or attended, indicating that it tributed to the function of a ‘‘central
may play a supramodal role in selective executive’’ agency. In human subjects,
attention.4 These observations suggest tasks that emphasize the executive as-
that prefrontal and posterior parietal pects of working memory elicit the
cortices exert a top-down influence on activation of prefrontal dorsolateral cor-
domain-specific attentional modulations tex, whereas tasks based on the online
in all other cortical areas in a manner that maintenance of information elicit the
may mediate the volitional regulation of activation of both prefrontal cortex and
the attentional focus. posterior parietal cortex.27–29
As noted earlier, many cortical areas As noted earlier, many areas of the
display modulations related to working brain give preferential responses to
memory in their specific domain of novel or unexpected events within their

KEY POINT
specific domain of specialization. The explain why focal lesions in prefrontal
A Mood and
frontal lobe plays a particularly critical cortex, posterior parietal cortex, and
motivation
strongly role in this realm of function and in- medial temporal cortex cause acute
influence the fluences novelty-related activity in all confusional states.34–36
allocation of realms of processing. Damage to frontal The top-down control of the atten-
attentional cortex, for example, induces a placid tional matrix by prefrontal and parie-
resources. disinterest in the environment.17 In tal cortices displays a pattern of relative
neurologically intact subjects, the P300 right hemisphere specialization. Thus, sus-
response elicited by novel or deviant tained and divided attention tasks in any
stimuli is critically dependent on the sensory modality elicit greater activa-
integrity of prefrontal cortex. Further- tion in the right posterior parietal and
more, an N2-P3 response that is maxi- prefrontal cortices.24,25 Furthermore, the
mal over prefrontal cortex appears to posterior parietal or prefrontal lesions
determine the attentional resources that that give rise to confusional states
will be allocated to novel events, and the are usually located in the right hemi-
region of the frontal eye fields belongs sphere.36–39 The strongest evidence for
to a distributed network for explor- right hemisphere specialization comes
ing the extrapersonal space and seeking from observations on contralesional
motivationally relevant targets. Prefron- hemispatial neglect. This syndrome is
tal cortex thus seems to play a global more severe and frequent after right
role in promoting orientation toward than left hemisphere lesions. The asym-
novel events and may be the source of metry is consistent with a neural model
top-down projections that enhance the according to which the right hemi-
responsivity of other cortical areas to sphere directs attention to both sides
novel events. of space, whereas the left hemisphere
Mood and motivation strongly in- directs attention only contralaterally to
fluence the allocation of attentional the right hemispace.40
resources. The degree of hunger, for
example, enhances the response of the
orbitofrontal taste area to food items OVERVIEW AND CONCLUSIONS
and of parietal neurons to pictures of Attention permeates all aspects of behav-
edible objects.30,31 Many of these mood- ior. A flexible interplay between concen-
and motivation-related modulations are tration and distractibility is an essential
mediated through top-down projections ingredient of advanced mental activity.
emanating from limbic structures, espe- Excess in either direction can lead to
136 cially the amygdala. For example, amyg- psychopathology. The judicious deploy-
daloid activity modulates the response of ment of attentional resources is a difficult
extrastriate visual cortex to faces display- skill to master, and the directive to ‘‘pay
ing certain types of emotional expres- attention’’ is ubiquitous in the education
sion.32 Limbic structures can thus induce of children. In fact, attentional deficits
widespread attentional modulations that probably constitute the single most com-
modify the impact of sensory inputs mon type of developmental learning
according to the emotional and motiva- disability of childhood.
tional relevance of the event.31,33 Although no neuron is exclusively
Limbic, parietal, and prefrontal cor- devoted to attention, all areas of the
tices can collectively exert a global top- cerebral cortex display attentional mod-
down influence on attentional modu- ulations. These modulations are under
lations in all modalities and domains. the bottom-up influence of the ARAS
Damage to these parts of the brain may and the top-down influence of trans-
induce multiple attentional deficits and modal cortices. Through these complex

attentional calibrations, the mental rep- ACKNOWLEDGMENT
resentation of experience transcends This work is supported in part by a grant
surface appearances and becomes sen- AG13854 from the National Institute
sitive to behavioral relevance. on Aging.
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139

KEY POINT
A Executive
resources allow
EXECUTIVE RESOURCES
for flexible, Rachel G. Gross, Murray Grossman
adaptive,
goal-directed
behavioral
responses to ABSTRACT
environmental Executive resources allow for flexible, adaptive, goal-directed responses to envi-
circumstances. ronmental circumstances in essentially all facets of daily living. Executive function
is composed of related, but separable, components. This article will highlight three
essential aspects of executive function: (1) working memory, (2) planning and or-
ganizing, and (3) inhibitory control. Working memory is the system by which in-
formation is maintained in an active mental state so that it can be used for other
purposes. Planning and organizing of behavior involves the way in which in-
dividuals optimize the execution of multistep tasks to achieve a goal. Inhibitory
control allows an individual to inhibit inappropriate responses and to shift re-
sponses when necessary. These aspects of executive function appear to depend in
part on large-scale neural networks that are centered in distinct areas of prefrontal
cortex, working in concert with other brain regions, such as parietal cortex and the
basal ganglia. Executive function is a fundamental aspect of human cognition that
is compromised in patients with a wide range of medical conditions.
INTRODUCTION resources allow for flexible, adaptive,

Executive resources are defined as higher- goal-directed behavioral responses to
order processes involved in the con- environmental circumstances. Indeed,
trol of cognition and goal-directed executive resources are fundamental
behavior. Intact executive functioning to success in the wide range of cog-
supports a multitude of behaviors, un- nition domains covered in this issue of
derscoring the ubiquitous involvement .
of executive resources in human be- Individuals with executive dysfunc-
havior and cognition. Examples of ex- tion can exhibit a broad range of mani-
ecutive functions include initiation of festations in their daily lives.2 Patients
goal-directed behavior, planning and may have difficulty grocery shopping
140 sequencing of complex tasks, perform- or preparing a meal. They may have
ing more than one task simultaneously trouble keeping up with demands at
(multitasking), shifting attention to sa- work. They may become distressed
lient items or events, strategic decision when the day’s plan changes and exhibit
making, extracting the gist of a scenario, difficulty switching situations, behav-
sustaining behavior despite distraction iors, or thoughts. Because the ability
or interference, overriding automatic to appreciate the larger picture, man-
responses with more appropriate be- age multiple options, and assess con-
haviors, and terminating behavior at an sequences may be compromised, pa-
opportune time.1 In short, executive tients show impaired judgment in daily
Relationship Disclosure: Dr Gross has nothing to disclose. Dr Grossman has received personal compensation for
consulting from Allon Therapeutics Inc., Forest Laboratories, Inc., and Pfizer Inc, and for serving as editor of
Cognitive and Behavioral Neurology. Dr Grossman’s compensation and or research work has been funded
entirely or in part by a grant to his university from a governmental organization.
Unlabeled Use of Products/Investigational Use Disclosure: Drs Gross and Grossman have nothing to disclose.

KEY POINTS
decision making and problem solving. deed, studies demonstrating relatively
A Executive
Their stories and conversations may low correlation in performance across
functions are
be poorly organized and difficult to fol- various executive tasks suggest that ex- attributed to
low. They may not grasp jokes or puns ecutive function is composed of related, the frontal lobes,
because of limited capacity for abstract but separable, components.14 This dis- but growing
thinking. Many report memory loss, as sociability of executive functions un- evidence
forgetfulness can result from inatten- derscores the need to test a range of demonstrates
tion, perseveration, and poorly planned executive skills at the bedside or in the that frontal
information retrieval. Thus it is evident clinic.15 Although executive function- structures are
that, for patients and their loved ones, ing can be partitioned in many differ- part of larger
the functional consequences of execu- ent ways, we will discuss three essential cortical-cortical
and cortical-
tive dysfunction are far-reaching and aspects of executive resources in this
subcortical
devastating. article: (1) working memory, (2) plan-
networks that
In general, executive functions are at- ning and organizing, and (3) inhibitory subserve executive
tributed to the frontal lobes, in particu- control. functioning.
lar to the prefrontal cortex. In fact, this
association is so strong that the litera- A Various facets
WORKING MEMORY of executive
ture commonly conflates the terms ex-
Definition function can
ecutive function and frontal function.
be affected
Growing evidence, however, demon- Working memory is the system by which independently
strates that frontal structures are part information is maintained in an active in patients
of larger cortical-cortical and cortical- mental state during the course of pro- with diseases
subcortical networks that subserve execu- cessing so that it can be used for other affecting
tive functioning. For instance, functional purposes. It is this system that allows different brain
neuroimaging studies have implicated us, for instance, to understand a lengthy regions,
frontoparietal networks in various ex- sentence or to retain a phone number suggesting that
ecutive functions, including working long enough to run to the telephone executive
memory, set shifting, and inhibition.3,4 and dial it. The working memory system functioning is
not a unitary
In addition, functional neuroimaging is intimately related to various aspects
phenomenon.
provides evidence for basal ganglia in- of executive function: information must
This dissociability
volvement in executive tasks such as remain in an active state so that it is ac-
of executive
planning.5 Disruption of frontal-striatal cessible for use in higher-order behav- functions
circuitry or the basal ganglia is thought iors, such as planning and organizing, underscores
to underlie executive difficulties in pa- decision making, and problem solving. the need to
tients with movement disorders, such Working memory dysfunction in the pa- test a range of
as Parkinson disease,6 Huntington dis- tient described in Case 10-1 did indeed executive skills
141
ease,7 and progressive supranuclear interfere with many facets of her daily at the bedside
palsy.8 functioning, such as shopping and man- or in the clinic.
Some authors have argued for a com- aging the household finances. A Working memory
mon mechanism underlying the various Baddeley and Hitch proposed an is the system
aspects of executive function. Candidate early and influential model of working by which
mechanisms include general intelli- memory stipulating two distinct limited- information is
gence,9 working memory,10 processing capacity buffers for temporarily storing maintained in
speed,11 and behavioral inhibition.12 different types of information and a an active mental
However, the observation that various third component to coordinate the buff- state during
the course of
facets of executive function can be af- ers.16 The first buffer, the phonologic
processing so
fected independently in patients with loop, involves temporary storage of
that it can be
diseases involving different brain re- sound-related information (eg, words,
used for other
gions suggests that executive function digits, and musical elements) and a purposes.
is not a unitary phenomenon.13 In- rehearsal mechanism that maintains

" EXECUTIVE RESOURCES
Case 10-1
A 75-year-old right-handed woman presented in the outpatient neurology clinic with confusion
and forgetfulness. About 4 years earlier, the patient’s husband had noted that she was
increasingly frustrated. At first he attributed her mood swings to depression and his daily
presence at home since his retirement, but she denied these concerns. Over time, she had
progressive difficulty managing daily household activities, such as shopping and paying the bills.
Her husband took over the household finances after several checks bounced. More recently,
she seemed confused when grocery shopping, walking up and down the same aisle, putting items
in the cart, and then removing them when she realized she had already obtained a similar item.
In conversation, she had intermittent word-finding difficulty and at times lost track of what she
had intended to say.
On examination, she was alert and fully oriented. She was mildly distractible but could be easily
redirected. On a six-item word-learning task, she had difficulty registering the words, and she recalled
only one word after a delay. Her digit span was six forward and two in reverse. When asked to list
words beginning with F in 1 minute, she named five unique words with multiple repetitions.
Language and visuoperceptual/visuospatial functioning were within normal limits for age. The
neurologic examination otherwise revealed mildly masked facies and stooped posture.
Over the next year, the patient’s husband assumed increasing responsibility for the household.
Her inattentiveness worsened, her gait became increasingly characterized as shuffling, and
she had several falls. Recently, she admitted to seeing her grandchildren (who live in another city)
and small animals in her house, particularly at night.
Comment. This patient has dementia with Lewy bodies. In this condition, patients present with
cognitive difficulty preceding or within 1 year of the onset of parkinsonian features. Executive
limitations, such as poor working memory and inattention, are common early manifestations
of cognitive impairment in dementia with Lewy bodies. Other features of this condition, such
as worsening gait dysfunction and well-formed hallucinations, typically emerge over the course of
the disease.
information in an active state so it can sketch pad is housed in the right hemi-
be used. The second buffer, termed the sphere, including inferior parietal and
visuospatial sketch pad, is responsible prefrontal structures. As described for
for storage and rehearsal of nonverbal the phonologic loop, it is thought that
information. The third component of the anterior-posterior distinctions between
model is the central executive, thought storage and rehearsal processes exist
to orchestrate higher-order operations, within the nonverbal working memory
142 such as shifts of attention between the system as well.4 The central executive is
two buffer systems and strategic retrieval thought to be contained within prefron-
of information for appropriate use. tal cortex.17,18 According to an influential
hierarchical two-stage model, ventrolat-
Anatomy of Working Memory eral regions of prefrontal cortex are in-
The Baddeley and Hitch working mem- volved with retrieval and online mainte-
ory system depends on a network of nance of information stored in more
structures with specialized functions. posterior cortical areas, while dorsolat-
The phonologic loop has been local- eral prefrontal structures are involved in
ized to left perisylvian structures, in- more active monitoring and manipula-
cluding the left inferior parietal area tion of those representations.19
for storage of verbal information and
the dorsal portion of Broca area for Assessment of Working Memory
rehearsal of material to be maintained Testing working memory involves tasks
in an active state.4 The visuospatial that require information to be held in an

KEY POINT
active state so that it can be manipulated justing the plan in real time, and com-
A Planning is
or used in some way. In the digit span pleting the series of actions.22 Studies
the ability to
task, the patient repeats progressively of patients with executive dysfunction identify and
longer number sequences in the for- resulting from Alzheimer disease and organize the
ward or the reverse direction. Although frontotemporal degeneration (FTD) have many elements
digit span is affected by both age and shown difficulty understanding the or- required to
education, typical adult performance is ganization of steps in familiar activities, achieve a goal.
about seven digits forward with a re- such as making coffee.23 In daily life, im- Planning is
verse span that does not differ by more pairment of planning and organizing often needed
than two digits.20 Visuospatial working can compromise the ability to multitask, to help
memory can be tested with an analo- resulting in difficulties at home and at optimize the
gous pointing span task (an examiner work. Difficulty organizing complex ac- execution of
complex tasks.
points to a series of circles of increasing tivities also can interfere with social in-
number; the patient is asked to point teractions that require the appreciation
to the items in the same or the reverse of subtle cues in a continually changing
order). Typically, pointing span is one and highly interactive environment. With
to two items shorter than digit span.20 more severe deficits, everyday behavior
Other working memory tasks involve breaks down with devastating conse-
spelling world forward and backward, quences for the ability to live indepen-
reciting the days of the week or the dently. Even the simplest of routine
months of the year in reverse order, or actions, such as brushing one’s teeth or
subtracting a specified number (usually making a sandwich, can be impossible
3 or 7) serially from 100 (eg, 100, 93, 86, without prompting from others.
and so on). Patients referred for formal Like other daily activities, aspects of
neuropsychological testing may be giv- language can be conceptualized as com-
en the Paced Auditory Serial Addition plex multistep tasks that require plan-
Test.21 In this task, single digits are pres- ning and organizing. Words and phrases
ented at regular intervals and patients must be organized into sentences and
are asked to add each digit to the one story events into coherent narratives.22
preceding it and state the sum before Nonaphasic patients with executive dys-
hearing the next number. function related to Parkinson disease
and FTD show impaired production
PLANNING AND ORGANIZING and comprehension of grammatically
complex sentences.24,25 Moreover, non-
Definition aphasic patients with FTD and traumatic
In this section, we discuss the ability to brain injury have difficulty with narra- 143
plan and organize complex behavior— tive functions, such as telling an orga-
that is, how individuals carry out multi- nized, coherent tale or comprehending
step tasks, such as making coffee or go- the gist of a story, related to their exec-
ing grocery shopping. Planning is the utive limitations.26,27 The manifestation
ability to identify and organize the of executive dysfunction in language in-
many elements required to achieve a terferes with patients’ ability to interact
goal. Planning is often needed to help with others, compromising indepen-
optimize the execution of complex tasks. dence and quality of life.
Patients with impaired planning may ex- Planning and organizing also play a
hibit difficulty developing a flexible plan crucial role in social interactions. The
appropriate to the circumstances, initi- ability to perceive subtle, nuanced be-
ating the plan, carrying out a series of havior in a social interaction and modify
steps in the correct order, maximizing one’s behavior accordingly is termed
efficiency and time management, ad- theory of mind.28 Theory of mind

involves the ability to switch perspec- adaptability; that is, subroutines within
tives to optimize participation in a multistep task can be managed in a
social exchanges. The ability to en- flexible manner in response to external
gage in theory of mind is extraordi- circumstances while the overall goal is
narily demanding, yet we take it for maintained.
granted. Theory of mind is frequently
compromised in diseases affecting Anatomy of Planning and
the frontal lobes, such as FTD29 and Organizing
traumatic brain injury.30 As suggested by Case 10-2, substan-
Models of planning and organizing tial evidence associates the dorsolat-
generally fall into two categories. Some eral region of the frontal lobes with
authors argue that complex, multi- planning and organizing of complex
step actions are processed in a linear- actions needed to complete a task.
sequential manner. In this case, events Patients with frontal lobe injury ob-
within a script are accessed sequen- served during everyday activities, such
tially, according to established knowl- as shopping, have shown impaired plan
edge of the order in which they oc- execution and goal achievement.34 Le-
cur.31 An alternate model stipulates sion studies also have demonstrated
that complex actions consist of clusters an association between particular as-
of associated events that are arranged pects of multitasking, such as task
hierarchically in order to achieve an switching and planning, and damage
outcome or goal.32,33 For instance, in a to prefrontal cortex, including the left
multistep activity such as fishing, groups polar and right dorsolateral regions.35,36
of highly associated actions (eg, open Patients with focal neurodegenerative
can of worms and place worm on hook) syndromes, such as behavioral variant
are combined with other event groups FTD, show impaired performance on
(eg, raise the pole and reel in the line) measures of executive control that re-
to accomplish the task. The advantage quire planning and organization.37 More-
of clustered hierarchical models is over, prefrontal atrophy as measured
Case 10-2
A 45-year-old right-handed lawyer was noted by his colleagues to have worsening performance
at work. His long-time administrative assistant had assumed increasing responsibility for
144 managing his office. The patient knew he had to call clients and gather information from others
for active cases but seemed unable to complete the necessary steps. His assistant made phone
calls on his behalf to obtain the information and increasingly assembled case materials for
him. Once an avid tennis player, he was less apt to organize matches with his colleagues. Others
were concerned that he was ‘‘burnt out’’ or depressed because of his many obligations and
responsibilities, but he denied these. Instead, he described enjoying his legal practice but feeling
overwhelmed by its rapid pace. Several months later, he had a generalized tonic-clonic seizure
at work and was taken by ambulance to the hospital. Head CT in the emergency department
revealed a space-occupying mass in the right dorsolateral frontal lobe. Subsequent evaluation was
consistent with metastatic melanoma.
Comment. In this case, a tumor in the dorsolateral prefrontal cortex resulted in impaired ability
to initiate goal-directed behavior and to plan and organize daily activities. Patients with this type
of executive disorder often report feeling overwhelmed at work, as any given task requires
substantially more time to complete. Their job performance suffers because of difficulty initiating,
organizing, and completing tasks as they arise.

KEY POINT
by structural MRI has been related to ble. The frequent observation that pa-
A Inhibitory control
difficulty producing coherent narra- tients exhibit difficulty in everyday
involves the
tives and comprehending the organi- functioning out of proportion to their crucial ability
zation of task events in patients with performance on common executive as- to inhibit
FTD23,27 and focal prefrontal injury.38 sessments in the office has inspired ef- inappropriate
Functional neuroimaging studies in forts to utilize more realistic tasks.15 responses
healthy individuals also implicate the The Naturalistic Action Task evaluates and to shift
prefrontal cortex in executive tasks re- patients’ ability to carry out daily activ- responses when
quiring planning.39 Prefrontal cortex ities (eg, making coffee) using a struc- necessary.
activation also has been demonstrated tured assessment of their actual per-
in healthy subjects asked to process formance of the task.45
the order of events in multistep tasks,
such as eating at a restaurant.40 More- INHIBITORY CONTROL AND
over, transcranial direct cortical stimu- COGNITIVE FLEXIBILITY
lation to the left dorsolateral prefrontal
cortex has been shown to improve Definition
planning ability, implicating this re- Here we discuss the crucial ability to in-
gion in this aspect of executive func- hibit inappropriate responses and to
tion.41 fMRI also has suggested that shift responses when necessary. This
regions of the frontal lobe, arrayed anato- type of cognitive flexibility prevents one
mically in a caudal-rostral fashion, pro- from replaying a certain behavior re-
cess increasingly complex materials in- peatedly. Failure to inhibit can lead to
volving decisions based on higher levels perseverative and stimulus-bound be-
of abstraction.42 havior. As illustrated in Case 10-3, pa-
tients may involuntarily repeat what
another person says (echolalia) or imi-
Assessment of Planning and tate another person’s actions (echopra-
Organizing xia). Patients may fixate on objects in the
In the clinic, planning and organizing environment despite attempts to redi-
can be evaluated as patients carry out rect their attention. They may feel com-
a number of tasks. Verbal fluency tasks pelled to pick up and use an object even
require patients to list exemplars of a if it is unnecessary or redundant (utili-
designated category in a fixed period zation behavior). It is not uncommon
of time (eg, animals or words begin- for a patient with utilization behavior
ning with the letter F in 60 seconds). to pick up a pen on the desk and start
During this task, one can assess the pa- writing or take the eyeglasses out of the 145
tient’s ability to search the mental lexi- examiner’s pocket and put them on.
con for information in an organized and Friedman and Miyake propose three
efficient manner. Impairment in plan- aspects of inhibition: (1) suppression of
ning and organizing can manifest itself automatic responses, (2) resistance to
in a disorganized approach to copying irrelevant information that can distract
a complex design, such as the Rey- from the task at hand, and (3) pre-
Osterrieth figure.43 The Tower of London vention of the intrusion of previously
task is a classic test of planning and or- relevant information into ongoing be-
ganizing administered during formal havior.46 These aspects of inhibition
neuropsychological evaluations and com- can be applied to control of behavioral
monly used in research.44 In this task, responses in both the motor and cog-
subjects are asked to move colored nitive domains.47
pieces to achieve an illustrated ar- Logan and colleagues propose a ‘‘race
rangement in as few moves as possi- model,’’ whereby the behavior observed

Case 10-3
An 85-year-old right-handed woman was brought to the outpatient
neurology clinic by her daughter because of increasing forgetfulness
and difficulty with daily activities. Although her home had always been
scrupulously clean, unwashed dishes were now piled in the kitchen
sink and on the countertops. This change occurred in the context of a
3-year history of increasing memory problems, particularly for recent
events. Her daughter said that when she asked the patient a question,
she would often repeat the question without answering it.
On examination, the patient echoed the examiner’s questions. She
demonstrated profound episodic memory difficulty. When asked to name
pictures of objects, she got stuck on the name of the first object and
repeated it for all subsequent items. When asked to list words beginning
with F, she provided two words and then repeated the third word over
and over. When asked to copy a geometric design, she could not prevent
herself from tracing the model. During the motor examination, she
seemed to mirror the activities of the examiner.
Comment. The tendency to get stuck on a particular behavior is called
perseveration. Perseveration can occur in multiple domains, including
repetition of speech (echolalia) and mimicking the gestures of others
(echopraxia). Perseverative behavior may be seen with focal disease in
ventrolateral prefrontal or orbitofrontal regions, as in traumatic brain
injury. Perseverative behavior also occurs in various neurodegenerative
conditions as disease affects frontal structures and other areas of the
cerebrum. This patient’s prominent memory impairment and gradual
decline suggest a diagnosis of Alzheimer disease.
is the response—go or no-go—that severation by biasing the competition

reaches a certain threshold first.48 Con- between automatic behaviors and stra-
sider the antisaccade test. In this task, tegic, adaptive responses via shifts of
the contest takes place between looking attention, incorporation of feedback,
at the target (the more automatic re- and maintenance of the goal in working
sponse) and looking away from the memory.47,49
target (the less automatic, volitional re-
sponse). Correctly performed antisac- Anatomy of Inhibitory Control
146 cades result when the volitional re- Motor response inhibition is thought
sponse ‘‘wins’’ and is able to inhibit the to be mediated by areas of prefrontal
more reflexive action.47 Moreover, con- cortex functioning in concert with more
trol of behavior involves the ability to posterior cortical and basal ganglia re-
‘‘shift set’’ in response to changing cir- gions.47 fMRI studies have further shown
cumstances. In a given task, a cognitive activation in a distributed frontopari-
set is established when an individual’s etal network during motor response in-
behavior is rewarded for being correct, hibition tasks.3,50 In a study by Ford and
and it ultimately becomes relatively au- colleagues, subjects were instructed
tomatic. When circumstances change, whether to produce an antisaccade in
an individual must switch set by inhib- anticipation of stimulus presentation.50
iting the previously appropriate, more The authors noted increased dorsolat-
automatic behavior and adopting a new eral prefrontal cortex activation during
response.47 An important role of execu- this preparatory period for planning
tive control mechanisms is to avoid per- trials with correct antisaccades relative

to those with errors, consistent with The Stroop task is used frequently
the notion of a frontally generated in research and in neuropsychologi-
inhibitory signal that biases the system cal evaluations to assess response in-
toward the desired response.49,50 When hibition.59 In the interference part of
motor response inhibition tasks focus this task, subjects see color words writ-
on the period of response execution ten in a discordant color (eg, the word
(rather than the preparatory phase), blue written in red ink). They are asked
however, studies emphasize the role of to report the color of the font and in-
right ventrolateral prefrontal cortex in hibit the more automatic response of
the act of inhibition per se.51,52 Connec- reading the word itself. The Wisconsin
tions between prefrontal areas and basal Card Sorting Task is employed in sim-
ganglia structures, such as the striatum ilar settings to assess cognitive flex-
and the subthalamic nucleus, also have ibility, use of feedback, and response
been implicated in performance on mo- inhibition.60 Individuals are asked to
tor response inhibition tasks.53,54 Like sort cards according to various param-
motor response inhibition, cognitive set eters (color, form, or number). They
shifting is subserved by a network of must deduce the sorting rule based on
frontal, parietal, and basal ganglia struc- simple feedback they receive (ie, cor-
tures.3,47 Studies intended to isolate rect or incorrect). Throughout the task,
the process of response inhibition dur- the sorting rule changes without warn-
ing set-shifting tasks have implicated ing after a sorting principle has been
the ventrolateral prefrontal and orbito- deduced, and subjects must inhibit
frontal cortex.51,55 the old sorting rule and ascertain the
new rule.
Assessment of Inhibition,
Set-Shifting, and Cognitive
Flexibility CONDITIONS INTERFERING
A commonly used test of response in- WITH EXECUTIVE FUNCTION
hibition is the go-no-go paradigm.56 In As described above, working memory
this task, the examiner instructs the pa- and other executive resources are in-
tient to lift a finger when the examiner volved in an enormous range of cog-
taps once, but not to respond when nitive processes and behaviors. Given
the examiner taps twice, assessing the the ubiquitous nature of executive re-
ability to inhibit response to a no-go sources, impairment of this kind can
stimulus. The antisaccade test is similar be disabling to a wide range of patients
in principle. Trail-making tasks evaluate encountered by the medical profession. 147
set-shifting and response inhibition.57 Executive function is particularly sus-
Patients are asked to alternate between ceptible to conditions marked by frontal
letters and numbers in a sequential man- lobe injury or dysfunction in frontal-
ner (eg, 1-A-2-B-3-C. . .), which can be parietal and frontal-striatal networks.
performed orally or by asking the pa- Perhaps the most common neurologic
tient to draw a line connecting letters disorders associated with executive dys-
and numbers in the appropriate order. function are traumatic brain injury; neu-
In the Luria alternating hand sequence rodegenerative conditions such as Al-
task, patients are shown a sequence of zheimer disease, dementia with Lewy
three hand movements and are asked to bodies, and progressive supranuclear
repeat the sequence multiple times.58 A palsy; and conditions that cause hy-
similar task involves drawing an alter- drocephalus. Table 10-1 summarizes
nating sequence of square and trian- conditions commonly associated with
gular shapes. executive dysfunction.

TABLE 10-1 Conditions TABLE 10-1 Continued

Associated With
Executive
Dysfunction " Infectious
Viral encephalitis (including
" Structural herpes simplex virus encephalitis)
Stroke/vascular dementia Delirium secondary to systemic
infection (eg, urinary tract
Intracranial hemorrhage infection)
(eg, intraparenchymal
hemorrhage, subdural " Toxic-Metabolic
hematoma) Hyperglycemia/hypoglycemia
Tumor Hypercalcemia/hypocalcemia
Normal pressure Hypernatremia/hyponatremia
hydrocephalus
Hypercapnia
Traumatic brain injury
Hypoxemia
Multiple sclerosis
Uremia
Leukodystrophies
(eg, adrenoleukodystrophy, Hyperammonemia/hepatic
metachromatic encephalopathy
leukodystrophy, Hyperthyroidism/hypothyroidism
Alexander disease)
B12 deficiency
Other autoimmune
conditions (eg, lupus, Wilson disease
CNS vasculitis) Lead poisoning
Radiation vasculopathy Medications
" Neurodegenerative Alcohol
Frontotemporal degeneration Illicit/recreational drugs
Alzheimer disease (eg, marijuana, 3,4-methylene-
dioxymethamphetamine
Huntington disease [ecstasy], phencyclidine,
Parkinson disease opiates, chronic cocaine and
methamphetamine use)
Dementia with Lewy bodies
Withdrawal/delirium tremens
148 Progressive supranuclear palsy
" Developmental
Corticobasal degeneration
Autism/Asperger syndrome
Multiple system atrophy
Attention deficit
Motor neuron disease hyperactivity disorder
(eg, ALS)
Mental retardation/
Creutzfeldt-Jakob disease developmental delay
" Infectious " Psychiatric
HIV/AIDS dementia complex Depression
Neurosyphilis Anxiety and panic disorders
Lyme disease Schizophrenia
Meningitis Bipolar disorder

CONCLUSION dence and quality of life. The need
We discussed three crucial aspects of remains for pharmacologic treatments
executive function: (1) working mem- and behavioral strategies for patients
ory, (2) planning and organizing, and with executive dysfunction. Greater un-
(3) inhibitory control. Although all are derstanding of component executive
clearly associated with prefrontal cor- functions and their neural substrates
tex, components of executive function can help guide development of ther-
involve partially overlapping networks apeutic interventions.
of prefrontal, parietal, and basal ganglia
structures. Intact executive resources ACKNOWLEDGMENT
allow us to formulate goals, plan our This work was supported in part by the
behavior, and respond in flexible, adap- National Institutes of Health (AG17586,
tive ways to contingencies as they arise. AG15116, NS44266, and NS53488) and
As such, executive impairment can have a fellowship grant from the American
enormous impact on patient indepen- Academy of Neurology.
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PATIENT MANAGEMENT PROBLEM

William T. Hu
The following patient management problem was chosen to reinforce the subject matter
presented in this issue. It emphasizes decisions facing the practicing physician. At each
decision point determine how you, as the neurologist, would respond. Then answer the
questions provided. The weight or “value” indicates the relative strength or weakness
of the response as determined by the faculty. Use these values, as well as the critical
comments, to assess your own understanding and handling of the problem. A review of
all responses, not merely the ones you select, is recommended.
Learning Objective
The goal of this patient management problem is to reinforce understanding of the clinical
evaluation of patients with cognitive concerns and the utilization of appropriate diagnostic
tools, using this clinical syndrome as an example.
Case History
A 59-year-old right-handed woman, accompanied by her daughter, presents with a
chief concern of cognitive symptoms. She says, “I have a lot of memory problems.” She
first noticed trouble remembering what she wanted to say about 2 years ago and now
also has a hard time remembering things her daughter and husband tell her. She
retired from teaching a few years ago and continues to be active as an artist in her
local community. She can carry out familiar tasks, such as cooking and grocery
shopping. She denies any alcohol or tobacco use.
Decision Point A. Which of the following symptoms are important to ask about when 153
trying to determine whether someone may have an amnestic disorder, such as
Alzheimer disease?
A1. Recall of recent events
A2. Recall of remote events
A3. Repetition of questions or stories
A4. Word-finding difficulties
A5. Misplacement of familiar items, such as keys and wallet
A6. Depression
A7. Poor decision making/judgment
Upon further questioning, the patient has an extremely difficult time describing the
nature of her memory problems. Instead, she demonstrates significant circumlocution
Relationship Disclosure: Dr Hu has received research support from the Penn-Pfizer Alliance.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Hu discusses the unlabeled use of medications for frontotemporal degeneration,
including cholinesterase inhibitors and memantine.
Copyright © 2010, American Academy of Neurology. All rights reserved.

in her conversational speech and poverty of content without significant word-finding

pauses, alteration in speech rate (in terms of words per minute), or any sign of
dysarthria. In the absence of informative history from the patient herself, the neurologist
obtains collateral history from her daughter. The patient’s daughter has noted that her
mother has minimal difficulties with recall of recent events, such as when the patient
went to the zoo with her family, and remote events regarding family members.
However, the patient sometimes answers, “I don’t know,” or “I don’t understand” to
questions regarding details of recent and remote events. She has not been repeating
questions except, “What do you mean?,” and she has not been repeating stories. She
often struggles with expressing her thoughts and spends a lot of time trying to explain
to others what she wants. She has not misplaced any of her own belongings, but she
sometimes cannot find her husband’s car key or wallet when he asks her for them.
This can occur even when the items are in their usual locations. She appears slightly
more irritable than she used to be, but she has not had any emotional outburst or
drastic change in behavior. She remains pleasant during family gatherings, but she has
a hard time following conversations. Her mood is normal, and she has not demonstrated
any change in judgment or decision-making abilities. She continues to drive to the
grocery store, although her family is concerned about her driving. Laboratory studies
performed by her primary care physician include the following:
Thyrotropin, 3.2 mIU/L (normal 0.5 mIU/L to 4.5 mIU/L)
Vitamin B12 level, 412 pg/mL (normal 200 pg/mL to 800 pg/mL)
Sedimentation rate, 18 mm/h (normal up to 30 mm/h)
Antinuclear antibody, negative (normal negative)
Rapid plasma reagin, negative (normal negative)
Lyme serology, negative (normal negative)
Decision Point B. Difficulties in which of the following cognitive functions may offer
additional clues to specific brain regions affected in this patient?
B1. Participation in conversations
B2. Following new recipes
B3. Understanding single words
154 B4. Identifying familiar objects
B5. Use of grammatical structures
B6. Naming of familiar items from line drawing
Her daughter, who is also a teacher, reports that the patient seems to have more
trouble with use of language than memory and has been quieter during social
gatherings. For example, when she was asked to take part in a video at a recent family
event, she responded with, “I can’t remember what videotaping means.” When they
cook together, she has difficulty picking out the appropriate utensils when asked. On
examination, her spontaneous speech is fluent without agrammatism or dysarthria,
although there is a paucity of content and significant circumlocution. She is unable to
name a number of familiar objects, such as a corkscrew or the picture of a camel, and
she has trouble sight-reading words such as pint or yacht. When asked what a
flamingo looks like, she answers, “I don’t remember.” She is mildly disinhibited, and
her daughter corroborates that this is not her usual personality. The neurologist

decides that she most likely has a primary progressive aphasia (PPA), with the
semantic variant, also known as semantic dementia (SD), representing the most
probable PPA subtype.
Decision Point C. Which studies would be most helpful in diagnosis?

C1. EEG
C2. MRI
C3. Lumbar puncture
C4. Fluorodeoxyglucose-PET
C5. Neuropsychological testing
C6. Genetic testing for mutations leading to early-onset Alzheimer disease
Her MRI shows moderate atrophy in the left temporal pole and possibly some mild
atrophy in the right temporal pole and the bifrontal regions (Figure 1). There is
otherwise no structural lesion or evidence of small vessel ischemic disease.
Neuropsychological testing shows significant difficulties in attention, confrontation
naming, letter-guided fluency, category fluency, and executive functions. Her delayed
recall is less affected, and visuospatial abilities are relatively preserved.
Decision Point D. What can the neurologist tell the patient at this time regarding the
cause of her symptoms?
D1. They result from an age-related change
D2. They result from repeated vascular insult not seen on MRI
D3. They result from nonamnestic mild cognitive impairment
D4. They result from frontotemporal lobar degeneration, although atypical or unusual
presentation of Alzheimer disease is also a possibility
D5. It is not Alzheimer disease
The neurologist shares the diagnostic impression with the patient and her daughter.
The patient responds, “I don’t quite understand what you just told me, but is there a
pill that will make me better?” Her daughter adds that she is concerned about medication
side effects, as her mother has been very sensitive to medications in the past.
155
FIGURE 1 MRI of the brain shows significant

left temporal atrophy with relative
preservation of left hippocampus in an axial T1 image
(A) and a coronal T2-weighted image (B).

Decision Point E. What medications should be considered for the patient?

E1. Cholinesterase inhibitor therapy
E2. NMDA antagonist therapy
E3. Antidepressant
E4. Atypical antipsychotic
E5. Antiepileptic
The patient and her daughter remember that one of their family friends was diagnosed
with Alzheimer disease, and donepezil was prescribed. He had diarrhea that was very
challenging to manage, and they are afraid that the patient would have the same
experience. They defer donepezil at this time, although they are interested in
considering memantine after discussing it with the patient’s husband. The patient’s
daughter has heard about commercial APOE testing for Alzheimer disease and would
like to know if that would be helpful.
Decision Point F. What other advice about this disease should be given to the patient
and her family?
F1. She should stop driving
F2. This is a potentially inheritable disease
F3. She should have frequent EMGs, as she may develop ALS
E4. She should undergo genotyping for APOE
F5. She should start speech therapy right away
F6. She should complete advance directives and health care power of attorney if none exist
WEIGHTS AND COMMENTS

EXPLANATION OF WEIGHTS:
+5 Unequivocally required for diagnosis or effective treatments, without which management
would be negligent
156 +3 Important for diagnosis and treatment but not immediately necessary
+1 Potentially useful for diagnosis and treatment (routine studies fall into this category)
0 Neutral impact; neither clearly helpful nor harmful under given circumstances
–1 Not harmful; but nonproductive, time-consuming, and not cost-effective
–3 Nonproductive and potentially harmful
–5 Totally inappropriate and definitely harmful; may threaten life
A1. Recall of recent events +5

Patients often report “memory problems” when they present for cognitive
difficulties, so it is useful to clarify in more detail the specific nature of the memory
problem. One can often be misled in the differential diagnosis of a subjective

memory concern if the exact nature of cognitive difficulties is not qualified. Patients
with aphasia can report “loss of memory for words,” for example, even though
episodic memory for everyday events may be relatively preserved.1 Preserved
memory for recent events in aphasic patients can be difficult to demonstrate at the
bedside because of the underlying comprehension and word-finding difficulties,2
and collateral history by observant family members of relatively preserved recent
memory despite moderate language difficulties can be extremely helpful. At the
same time, impairment in recent memory can be seen in patients with pathologically
confirmed frontotemporal lobar degeneration,3 and the presence of mild memory
impairment should not be used as a litmus test if there is strong clinical suspicion
for the presence of aphasia to account for the patient’s clinical deficits. In the setting of
aphasia, it is also possible to assess episodic memory using the acquisition and
recall of visual material, such as a geometric design.
A2. Recall of remote events +5

A pattern of temporally graded memory loss (with recent memory most severely affected)
is common in clinically diagnosed cases of Alzheimer disease.4 In fact, recall of recent
events may be more preserved than more remote memory in some patients with semantic
variant of PPA or SD.5,6
A3. Repetition of questions or stories +3

Repetition of questions and/stories is another common feature in clinically probable
Alzheimer disease. However, some patients with comprehension difficulties may also
repeatedly ask family members similar questions secondary to their language deficits,
and this distinction may not be apparent to the collateral historians.
A4. Word-finding difficulties +1

Word-finding difficulties can be the predominant symptom in certain subtypes of PPA
and can also accompany memory difficulties in Alzheimer disease.
A5. Misplacement of familiar items, such as keys and wallet +5

Other clues to memory difficulties, such as misplacing familiar objects, could be useful
in clinically diagnosing Alzheimer disease, although patients with semantic variant PPA
157
or SD could also demonstrate similar symptoms not associated with episodic recall.7
A6. Depression +1
Considering the contribution of a mood disorder in cognitive impairment is important
from diagnostic and treatment perspectives, although the common co-occurrence of
depressive symptoms and Alzheimer disease makes depressive symptoms a relatively
weak classifier compared to other cognitive symptoms.
A7. Poor decision making /judgment +1

Symptoms associated with the behavioral variant of frontotemporal dementia can also
be helpful in the differential diagnosis, although executive dysfunction is common in
Alzheimer disease and the executive dysfunction insufficiently discriminates between
Alzheimer disease and other dementing syndromes.

B1. Participation in conversations 0
Patients with different subtypes of PPA have relatively unique clinical characteristics
that can help the observant clinician determine the basis of the deficit.8 Difficulties in
comprehension, grammar, speech production, and word finding, along with behavioral
apathy without significant language abnormalities, all impair the patient’s ability to
participate in conversations.
B2. Following new recipes 0
Inability to follow a new recipe is a nonspecific concern and offers no additional diagnostic
value in determining the PPA subtype or predicting the underlying pathology responsible
for the clinical syndrome.
B3. Understanding single words +5

Patients with semantic variant of PPA or SD often have loss of single word and object knowledge.
Clinically, they demonstrate difficulties with meaning of single words and meaning/use of
objects, especially words and objects that are infrequently encountered in daily activities.
They also often demonstrate surface dyslexia,9 in which patients demonstrate deficits in
reading exception words (eg, low-frequency words with atypical spelling-to-sound
correspondence such as yacht and pint).
B4. Identifying familiar objects +3

The identification of more frequently encountered objects may be preserved early in
the disease course of semantic variant of PPA or SD, and speech can be relatively
fluent if it is not punctuated by word-finding pauses.
B5. Use of grammatical structures +5

Patients with progressive nonfluent aphasia (PNFA) demonstrate slowed, effortful speech
with rate of word production at about one-third that of cognitively healthy subjects.10
Grammatical omissions in spontaneous speech are often observed in PNFA and can be quite
characteristic for the syndrome.
B6. Naming of familiar items from line drawing +1

158 Naming is impaired in logopenic progressive aphasia, a PPA subtype more commonly
associated with underlying pathology of Alzheimer disease and characterized by frequent
word-finding pauses and auditory-verbal short-term memory impairment.8,11,12 At the same
time, naming is also impaired in SD; thus naming deficit alone is insufficient for distinguishing
between SD and logopenic progressive aphasia.
C1. EEG –1
EEG in SD can be normal, abnormal and lateralizing to the left, or abnormal but
nonlateralizing.13 Importantly, routine clinical EEG provides little additional value in the
syndromic diagnosis or pathologic prediction in PPA,13 and its use should be limited in
the evaluation of PPA unless suspicion for an epileptic phenomenon is present.
C2. MRI +5
At this point of the evaluation, structural imaging is the most important diagnostic test in a
patient suspected of a progressive aphasic syndrome. Focal lesions, such as a meningioma
associated with local mass effect, can create a clinical picture fulfilling syndromic criteria for

SD (William T. Hu, MD PhD; Murray Grossman MD, FAAN; personal observation), and the
possibility of a nondegenerative cause of PPA should not be ignored even when symptoms
are considered pathognomonic. Degenerative causes of semantic variant of PPA are associated
with left anterior temporal atrophy, and atrophy in the right anterior temporal lobe can
become evident with disease progression.8 Sufficient coverage of the anterior temporal
regions is necessary for the complete evaluation of this region-specific atrophy, and subtle
atrophy can be missed when thick imaging slices are used.
C3. Lumbar puncture +1

Measurements of tau, p-tau181, and -amyloid 42-peptide levels in the patient’s CSF can
help identify the probable underlying pathologic substrate responsible for the clinical
syndrome.11,14 This can be useful as a complementary test, although it is likely not the
first test to order.
C4. Fluorodeoxyglucose-PET +1
Fluorodeoxyglucose (FDG)-PET imaging can show hypometabolism in the left temporal
region or bitemporal regions,15,16 although this is usually paralleled by the degree of
structural change on MRI. Thus, while FDG-PET can potentially confirm the syndromic
diagnosis based on clinical evaluation and structural imaging, its utility in providing further
information (eg, pathologic substrate, prognosis) likely does not warrant routine clinical
use unless no clear pattern of structural change is seen on MRI.
C5. Neuropsychological testing +3

Detailed neuropsychological analysis can confirm the clinical syndromic diagnosis of SD,
although deficits in multiple domains need to be considered in the context of significant
language abnormalities.2 Relative patterns in certain neuropsychological subtests could potentially
predict the underlying pathology as Alzheimer disease or non-Alzheimer disease.17
C6. Genetic testing for mutations leading to early-onset Alzheimer disease –3

Without evidence strongly supportive of a familial early-onset Alzheimer disease related to
one of the known mutations, genetic testing at this stage is likely premature.
D1. They result from an age-related change –1

The history, clinical evaluation, and MRI pattern of asymmetric lobar atrophy are not 159
consistent with normal aging.
D2. They result from repeated vascular insult not seen on MRI –3
Vascular insults insufficiently detected by routine imaging modalities can potentially contribute
to or even create a clinical picture of progressive aphasia, but the significant anterior temporal
atrophy without evidence of mild to moderate small vessel disease should warrant consideration
for a primary degenerative diagnosis.
D3. They result from nonamnestic mild cognitive impairment –3

While a language-predominant syndrome can be considered a nonamnestic syndrome, the
clinical history and findings are more consistent with a diagnosis of PPA.
D4. They result from frontotemporal lobar degeneration, although atypical or

unusual presentation of Alzheimer disease is also a possibility +5
A syndromic diagnosis of semantic variant of PPA or SD is helpful in the characterization
of the brain-behavioral relationship and can be clinically helpful in the rational application

of substrate-specific therapy in the future (eg, -secretase inhibitor) if a strong correlation

exists between the clinical syndrome and underlying pathology. Patients with frontotemporal
lobar degeneration (FTLD) spectrum disorders often ask, “Is this Alzheimer disease?” The
distinction between the clinical syndrome (dementia of the Alzheimer type or clinically probable
Alzheimer disease) and pathologic change of Alzheimer disease is not always apparent even
to the most informed patients and caregivers. Given the clinicopathologic heterogeneity in
PPA, FTLD remains the most likely substrate for PPA, although Alzheimer disease can account
for up to 33% of clinically diagnosed PPA cases.8
D5. It is not Alzheimer disease 0

A statement such as “It is not Alzheimer disease” can lead to significant confusion if the
patient is found to have Alzheimer disease pathology on autopsy, and an explanation of the
dominant etiologies that can lead to the same clinical/syndromic picture is often constructive
in counseling patients.
E1. Cholinesterase inhibitor therapy +1

Currently, no medication for clinical syndromes related to FTLD has been approved by the
US Food and Drug Administration, although off-label use of medications approved for Alzheimer
disease is common in the community and academic centers.18 In one study, patients with
frontotemporal dementia or PPA treated with galantamine in the open-label phase did not
demonstrate any significant improvement in behavior or language, although a treatment effect
may have occurred in the PPA group during the placebo-controlled withdrawal phase of the
study.19 At the same time, behavioral symptoms in FTLD could worsen with donepezil,20 and
behavioral symptoms should be closely monitored in patients with SD on cholinesterase
inhibitor therapy.
E2. NMDA antagonist therapy +3

Memantine appeared to be well tolerated by patients with FTLD spectrum disorders in an
open-label study21 and may have been associated with better neuropsychiatric outcome in
patients with SD in another open-label study.22 A multicenter trial is underway to determine
the effect of memantine on SD and other FTLD subtypes.
160 E3. Antidepressant –3

Among other medications considered in FTLD, trazodone was shown to improve the
neuropsychiatric symptoms in patients with behavioral disturbances without improving
performance on cognitive testing 23 but is likely not necessary in a patient without significant
neuropsychiatric symptoms.
E4. Atypical antipsychotics –3

Prophylactic initiation of atypical antipsychotic medications is not warranted, as these
medications target specific symptoms without any known disease-modifying effects.
E5. Antiepileptics –3
Prophylactic initiation of antiepileptic medications is not warranted. Future therapies
targeting the underlying pathology of PPA24 should complement symptomatic treatment
with neurotransmitter-based strategies.

F1. She should stop driving –1
Assessing whether a cognitively impaired patient can safely operate a vehicle has
significant impact on the safety and mobility of the patient, safety of others, and
mobility of the patient. In 2010, the American Medical Association and the National
Highway Traffic and Safety Administration put out a second edition of the
“Physician’s Guide to Assessing and Counseling Older Drivers” to guide physicians
through this often contentious process.25 This guide includes the most up-to-date
state-specific licensing and reporting requirements and, importantly, whether the
reporting physician is granted reporting immunity. Most of the existing literature on
driving safety in dementia focuses on elderly patients with Alzheimer disease, and
it is unclear whether the same standards should be applied to patients with FTLD
spectrum disorders. For example, while patients with SD may have more preserved
visuospatial abilities than patients with Alzheimer disease or corticobasal syndrome,
their inability to interpret road signs and traffic signals may jeopardize their and
others’ safety. Whether a patient in the mild stage of FTLD poses the same safety risk
as a driver with mild Alzheimer disease likely depends on the FTLD phenotype26,27
and may be better addressed by a structured road test than bedside clinical
assessment alone.28
F2. This is a potentially inheritable disease +1

In counseling patients with an FTLD-related disorder, the issue of heritability sometimes
creates confusion. While patients with FTLD-related disorders have a higher likelihood of
having a family history of neurodegenerative disorders than patients with Alzheimer disease,
this probability varies across the clinical phenotypes. Specifically, SD is much less likely to
have an autosomal dominant pattern of inheritance than behavioral variant of frontotemporal
dementia,29,30 although SD can be the presenting syndrome for common mutations associated
with FTLD.31
F3. She should have frequent EMGs, as she may develop ALS –3
Patients with SD infrequently develop motor neuron disease,32 and longtitudinal clinical
follow-up is likely preferred over frequent EMG evaluations.
161
F4. She should undergo genotyping for APOE –3
The APOE ε4 allele has been associated with the development of Alzheimer disease,
but its role in the development and prognosis of FTLD-related disorders remains
controversial.33 APOE genotyping should thus not be routinely recommended
in the clinical care of patients with FTLD, as disclosure of this information mixed
with increased inheritability of FTLD may be misinterpreted by patients and
their adult children.
F5. She should start speech therapy right away +1

As expected, language impairment is the most disabling symptom in semantic variant of
PPA or SD. Certain therapies, such as errorless learning, may transiently improve the
naming deficits,34 although the significant individualization necessary for success may
make this impractical.

F6. She should complete advance directives and health care power of attorney
if none exist +3
The younger average age of onset in SD may mean lower rates of advance care
planning,35 a process that becomes progressively more challenging with degradation of
word and object knowledge. Repetition and paraphrasing by family members while
establishing advance care plans should improve the patient’s ability to participate in
such processes, and a simplified format with graphic aids could potentially improve
comprehension.36 Frontotemporal dementia and PPA are conditions included in the Social
Security Administration’s Compassionate Allowance program, which should facilitate the
processing of disability claims in younger patients.
REFERENCES
1. Pijnenburg YA, Gillissen F, Jonker C, Scheltens P. Initial complaints in frontotemporal lobar

degeneration. Dement Geriatr Cogn Disord 2004;17(4):302–306.
2. Libon DJ, Massimo L, Moore P, et al. Screening for frontotemporal dementias and Alzheimer’s
disease with the Philadelphia Brief Assessment of Cognition: a preliminary analysis. Dement Geriatr
Cogn Disord 2007;24(6):441–447.
3. Hodges JR, Davies RR, Xuereb JH, et al. Clinicopathological correlates in frontotemporal dementia.
Ann Neurol 2004;56(3):399–406.
4. Cullen B, Coen RF, Lynch CA, et al. Repetitive behaviour in Alzheimer’s disease: description,
correlates and functions. Int J Geriatr Psychiatry 2005;20(7):686–693.
5. Hodges JR, Graham KS. Episodic memory: insights from semantic dementia. Philos Trans R Soc Lond
B Biol Sci 2001;356(1413):1423–1434.
6. Piolino P, Desgranges B, Belliard S, et al. Autobiographical memory and autonoetic consciousness:

triple dissociation in neurodegenerative diseases. Brain 2003;126(pt 10):2203–2219.
7. Lee AC, Rahman S, Hodges JR, et al. Associative and recognition memory for novel objects in
162 dementia: implications for diagnosis. Eur J Neurosci 2003;18(6):1660–1670.
8. Grossman M. Primary progressive aphasia: clinicopathological correlations. Nat Rev Neurol

2010;6(2):88–97.
9. Woollams AM, Ralph MA, Plaut DC, Patterson K. SD-squared: on the association between semantic
dementia and surface dyslexia. Psychol Rev 2007;114(2):316–339.
10. Ash S, Moore P, Vesely L, et al. Non-fluent speech in frontotemporal lobar degeneration.
J Neurolinguistics 2009;22(4):370–383.
11. Hu WT, McMillan C, Libon DJ, et al. Multi-modal predictors for Alzheimer’s disease in non-fluent
primary progressive aphasia. Neurology 2010. In press.
12. Gorno-Tempini ML, Brambati SM, Ginex V, et al. The logopenic/phonological variant of primary
progressive aphasia. Neurology 2008;71(16):1227–1234.
13. Chan D, Walters RJ, Sampson EL, et al. EEG abnormalities in frontotemporal lobar degeneration.
Neurology 2004;62(9):1628–1630.

14. Shaw LM, Vanderstichele H, Knapik-Czajka M, et al. Cerebrospinal fluid biomarker signature in
Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol 2009;65(4):403–413.
15. Tyrrell PJ, Warrington EK, Frackowiak RS, Rossor MN. Heterogeneity in progressive aphasia due to
focal cortical atrophy: a clinical and PET study. Brain 1990;113(pt 5):1321–1336.
16. Desgranges B, Matuszewski V, Piolino P, et al. Anatomical and functional alterations in semantic
dementia: a voxel-based MRI and PET study. Neurobiol Aging 2007;28(12):1904–1913.
17. Grossman M, Xie SX, Libon DJ, et al. Longitudinal decline in autopsy-defined frontotemporal lobar
degeneration. Neurology 2008;70(22):2036–2045.
18. Bei Hu, Ross L, Neuhaus J, et al. Off-label medication use in frontotemporal dementia.
Am J Alzheimers Dis Other Demen 2010;25(2):128–133.
19. Kertesz A, Morlog D, Light M, et al. Galantamine in frontotemporal dementia and primary
progressive aphasia. Dement Geriatr Cogn Disord 2008;25(2):178–185.
20. Mendez MF, Shapira JS, McMurtray A, Licht E. Preliminary findings: behavioral worsening on
donepezil in patients with frontotemporal dementia. Am J Geriatr Psychiatry 2007;15(1):84–87.
21. Boxer AL, Lipton AM, Womack K, et al. An open-label study of memantine treatment in 3 subtypes
of frontotemporal lobar degeneration. Alzheimer Dis Assoc Disord 2009;23(3):211–217.
22. Diehl-Schmid J, Forstl H, Perneczky R, et al. A 6-month, open-label study of memantine in patients
with frontotemporal dementia. Int J Geriatr Psychiatry 2008;23(7):754–759.
23. Lebert F, Stekke W, Hasenbroekx C, Pasquier F. Frontotemporal dementia: a randomised, controlled

trial with trazodone. Dement Geriatr Cogn Disord 2004;17(4):355–359.
24. Trojanowski JQ, Duff K, Fillit H, et al. New directions for frontotemporal dementia drug discovery.
Alzheimers Dement 2008;4(2):89–93.
25. AMA. Physician’s guide to assessing and counseling older drivers, 2nd edition. Available at:
www.ama-assn.org/ama1/pub/upload/mm/433/older-drivers-guide.pdf. Accessed March 22, 2010.
26. de Simone V, Kaplan L, Patronas N, et al. Driving abilities in frontotemporal dementia patients.
Dement Geriatr Cogn Disord 2007;23(1):1–7.
27. Ernst J, Krapp S, Schuster T, et al. [Car driving ability of patients with frontotemporal lobar
degeneration and Alzheimer’s disease]. Nervenarzt 2010;81(1):79–85.
28. Ott BR, Anthony D, Papandonatos GD, et al. Clinician assessment of the driving competence of
163
patients with dementia. J Am Geriatr Soc 2005;53(5):829–833.
29. Goldman JS, Farmer JM, Wood EM, et al. Comparison of family histories in FTLD subtypes and
related tauopathies. Neurology 2005;65(11):1817–1819.
30. Rohrer JD, Guerreiro R, Vandrovcova J, et al. The heritability and genetics of frontotemporal lobar
degeneration. Neurology 2009;73(18):1451–1456.
31. Finch N, Baker M, Crook R, et al. Plasma progranulin levels predict progranulin mutation status in
frontotemporal dementia patients and asymptomatic family members. Brain 2009;132(pt 3):583–591.
32. Hu WT, Seelaar H, Josephs KA, et al. Survival profiles of patients with frontotemporal dementia
and motor neuron disease. Arch Neurol 2009;66(11):1359–1364.
33. Borroni B, Grassi M, Agosti C, et al. Establishing short-term prognosis in frontotemporal lobar
degeneration spectrum: role of genetic background and clinical phenotype. Neurobiol Aging
2010;31(2):270–279.

34. Henry ML, Beeson PM, Rapcsak SZ. Treatment for anomia in semantic dementia. Semin Speech
Lang 2008;29(1):60–70.
35. Lingler JH, Hirschman KB, Garand L, et al. Frequency and correlates of advance planning among
cognitively impaired older adults. Am J Geriatr Psychiatry 2008;16(8):643–649.
36. Sudore RL, Landefeld CS, Barnes DE, et al. An advance directive redesigned to meet the literacy
level of most adults: a randomized trial. Patient Educ Couns 2007;69(1–3):165–195.
164

ETHICAL PERSPECTIVES IN
NEUROLOGY: PRESCRIPTIONS TO
HELP HEALTHY PATIENTS FOCUS
Daniel Larriviere
The practice of neurology presents a series of ethical challenges for the clinician. These
rarely have simple or straightforward solutions, but require careful consideration by the
neurologist. This section of , written by colleagues with particular interest in
the area of bioethics, provides a case vignette that raises one or more ethical questions
related to the subject area of this issue. The discussion that follows should help the reader
understand and resolve the ethical dilemma.
Learning Objective
To identify the ethical principles raised by a request from an adult patient for
neuroenhancement therapy.
NOTE: This is a hypothetical case.

A 45-year-old lawyer who felt as though he was slowing down because he was not able to
bill as many hours as he used to asked his neurologist to prescribe a medication to help
him “focus.” He was afraid that if he could not keep up at work, his position would be in
jeopardy. He had heard that certain prescription drugs will make people smarter and that
college students use them all the time. Based on his discussions with junior colleagues
who had used these medications and his perusal of various Internet sites, he said he
would like a prescription for “whatever medication you think works the best.” He had
already tried gingko biloba and did not think it helped. He had no other medical history.
COMMENT
165
Recently, persons without a diagnosed medical or mental health condition have been
increasingly using prescription medications to enhance their memory or cognitive skills.
This practice is known as neuroenhancement (NE).1
Although no one knows precisely how common the practice is, some data suggest that
it is widespread. Surveys of college students in the United States have found that between
4% and 34% of the respondents had used NE illegally, over half of them for the first time
while in college.2,3 In one survey of 1733 students, 89% of the respondents obtained the
medications from friends (87%) or significant others (4%). The vast majority of respondents
used NE to “stay awake to study” or to “concentrate on my work.”3
In 2008, Nature conducted a poll to determine the prevalence of NE among its readers.
Of the 1400 people who responded, one in five admitted to using NEs. The most common
Relationship Disclosure: Dr Larriviere has received personal compensation for speaking engagements from the American Association for the
Advancement of Science and has received research support in the form of an unrestricted educational grant from Allergan, Inc.
Unlabeled Use of Products / Investigational Use Disclosure: Dr Larriviere has nothing to disclose.
Continuum Lifelong Learning Neurol 2010;16(4):165–169. Copyright © 2010, American Academy of Neurology. All rights reserved.
ETHICAL PERSPECTIVES IN NEUROLOGY
reason for taking NEs was to improve concentration or focus for a specific task. Eighty
percent of the respondents (all respondents, not just those taking NEs) thought that healthy
adults should be able to take NEs if they want to do so. Over half of those taking NEs
obtained them using a prescription from a physician.4
Based on their growing popularity among adults young and old, neurologists should be
prepared to receive a request for NE from their patients—probably sooner than expected.
Does the Lawyer’s Request for Neuroenhancement Make Him the

Neurologist’s Patient?
The establishment of the physician-patient relationship is voluntary, and its formation
requires the intent of both parties. Physicians (with some exceptions, such as
emergencies) may generally decide which patients they will accept5 and may refuse
to see someone as long as the reasons for refusal do not violate legal principles
of discrimination.5
In the present case, the physician agreed to see the patient and scheduled him for
an office visit. The lawyer accepted the appointment and arrived at the appropriate
time. A physician-patient relationship was thereby formed. The purpose of the
appointment—to request an NE—does not negate the existence of the relationship.
Does the Neurologist Have to Take Such a Request Seriously?

The neurologist has a duty to take the patient’s request seriously. However, the
neurologist also has a duty to minimize harm (nonmaleficence) and maximize good
(beneficence) for the patient. In the present case, the neurologist may wish to interpret
the patient’s request as a request to investigate a decline in cognitive functioning.
When viewed in this way, a request for NE becomes a chief concern. As with any
chief concern, the neurologist is under an ethical duty to perform an appropriate
history and physical examination to determine the current level of cognitive function
and whether this represents a significant difference from a prior level of function.
The neurologist will determine whether further tests, if any, are necessary to arrive
at a diagnosis.
166 If, after the history, physical examination, and an appropriate workup, the patient
does not have sufficient signs, symptoms, or abnormalities of test results to satisfy
criteria for a medical or mental health condition, nor accepted criteria to be considered
at risk for a medical or mental health condition that can be prevented with appropriate
measures, then the patient could be considered “normal” and the prescription of
medication to improve cognitive function would be considered NE.
Is It Ethical for the Neurologist to Prescribe Neuroenhancement?

The practice of medicine can be divided into three areas: (1) a core domain of
traditional practices (eg, prevent and diagnose disease or injury, cure or treat disease
or injury, reduce suffering), (2) a domain of generally accepted practices (eg, aesthetic
surgical procedures, prescription of “lifestyle” medications [eg, sildenafil]), and (3) a
domain of prohibited practices (eg, physician participation in torture or interrogation
of prisoners, physician participation in capital punishment).

Like aesthetic forms of cosmetic surgery, NE represents the use of medical knowledge
to enhance the well-being of normal persons. As such, it is ethically permissible to
prescribe NE.
Does the Neurologist Have to Prescribe Neuroenhancement?

A neurologist does not have to prescribe NE. Once it has been established that the
patient has no disease or disorder, the neurologist may refuse to prescribe NE. There
are many reasons to refuse. The risks of NE are difficult to define with precision
because few studies of these medications in normal populations are available. The
studies that have been done suggest the medications currently used for NE (eg,
modafinil, methylphenidate, donepezil) do not appear to act uniformly to improve
executive function or memory across age groups, populations, or tasks6 and in some
cases may make cognitive function worse. No studies are currently evaluating the
long-term effects on cognitive function in normal patients. Many neurologists will ethically
refuse to prescribe NE because the benefits are not clear and the risk of harm
(long-term and short-term) is unknown.
Refusing to treat someone who is normal does not cause harm. The patient will not
be harmed by refusal to prescribe NE. The neurologist should explain the reasons to
the patient in terms he can understand, however.
Can Neurologists Legally Prescribe Neuroenhancement?

Neurologists can, however, legally prescribe NE. Prescribing NE is off-label use of a
medication and is legal in the United States.7 To avoid constraining physicians’ ability
to treat patients, the US Food and Drug Administration’s (FDA) position is that lack of
approval of a drug for a particular use (eg, NE) does not imply that such off-label use
is either disapproved or improper. This prerogative includes: (1) prescribing drugs for
conditions other than those for which they were approved; (2) prescribing drugs for
patient groups other than those for which they were originally approved; and (3) varying
from the approved dosage or method of administering drugs.
167
If Neuroenhancement Causes Side Effects or Harm to the Patient, Can the
Neurologist Be Sued for Prescribing Neuroenhancement?
Patients who have been injured by NE may sue their physicians. It is currently
unknown how a court would view such a claim. Would a judge treat it like a traditional
malpractice claim because it involves harms caused by prescription medications? Or
would the judge view it like an ordinary negligence case because it does not involve
the treatment of a disease or disorder?
Because of its similarity to cosmetic surgery, there is good reason to believe that
courts will treat an injury claim arising from the prescription of NE like a traditional
medical negligence case. However, case law exists that reduces the plaintiff’s burden
of proof in informed consent for cosmetic surgery cases by not requiring the testimony
of an expert medical witness.8 A court may choose to adopt this approach in a case
in which a patient claims that the physician failed to provide sufficient information
about potential harms when prescribing NE.

ETHICAL PERSPECTIVES IN NEUROLOGY
If the Neurologist Decides to Prescribe Neuroenhancement for the Patient,

What Should Be Kept in Mind?
Beneficence and nonmaleficence. Physicians who wish to prescribe NE to healthy
patients have several ethical principles to consider. Physicians have an obligation to
maximize benefits and minimize harm when treating patients.9 In traditional medical
practice, this involves weighing harms caused by illness or injury against the risks and
probable benefits of proposed therapy. With NE, however, the risks of the medication
must be weighed against the putative benefit a patient hopes to gain by the intervention.
Putative benefits are difficult to assess in a risk-benefit calculation, so helping the
patient to identify and clearly define the purpose of using NE will make it easier for
the neurologist and the patient to make an accurate assessment of the risks and benefits.
Clearly articulating the goals of NE therapy has additional benefits: (1) The
neurologist and the patient will share an understanding of their common goals and
when those goals are met; and (2) it will allow the neurologist to identify and respond
to any unrealistic expectations the patient may have regarding what NE can achieve.
Respect for autonomy. If the neurologist decides to prescribe NE, respect for
autonomy requires the physician to carefully and fully inform patients about the
medication. This includes but is not limited to the following information: (1) no FDA
approval of this medication for NE; (2) known side effects and potential risks to cognitive
function; (3) potential short-term and long-term risks of medication (with an explanation
of how much is not yet known); (4) alternatives to taking NE to achieve the same ends
(eg, community involvement, exercise, diet, weight loss, proper sleep).
Distributive justice. NE therapies are likely to be seen as lifestyle drugs and
therefore are unlikely to be covered by third-party payers. Their use might thus be
limited to a relatively small segment of the population who can afford them and
exacerbate existing inequalities in the distribution of opportunity and wealth.
Furthermore, as use of NE becomes more widespread, people may feel pressured to
take NEs in order to “keep up” with fellow students or coworkers. Neurologists may
wish to consider the effects that prescribing NE may have on society before providing
them to their patients.
168 CONCLUSION
Prescribing or refusing to prescribe NE takes place within the physician-patient
relationship. As a result, neurologists have ethical and legal obligations to the patient,
even if NE is the sole or primary purpose of the appointment. Although many patients
may seek NEs, neurologists have no obligation to prescribe them and may ethically
refuse to do so. However, neurologists may ethically prescribe NE by adhering to
bioethical principles of respect for autonomy, beneficence, nonmaleficence, and
distributive justice.
REFERENCES
1. Larriviere D, Williams MA, Rizzo M, Bonnie RJ; AAN Ethics, Law and Humanities Committee.
Responding to requests from adult patients for neuroenhancements: guidance of the Ethics, Law
and Humanities Committee. Neurology 2009;73(17):1406 –1412.

2. McCabe SE, Knight JR, Teter CJ, Wechsler H. Non-medical use of prescription stimulants among US
college students: prevalence and correlates from a national survey. Addiction 2005;99(1):96 –106.
3. DeSantis AD, Webb EM, Noar SM. Illicit use of prescription ADHD medications on a college campus:
a multimethodological approach. J Am Coll Health 2008;57(3):315 – 323.
4. Maher B. Poll results: look who’s doping. Nature 2008;452(7188):674 – 675.
5. American Academy of Neurology: Code of professional conduct. St. Paul: American Academy of
Neurology; 2008. Available at www.aan.com/globals/axon/assets/3968.pdf. Accessed March 19, 2010.
6. deJongh R, Bolt I, Schermer M, Olivier B. Botox for the brain: enhancement of cognition,
mood and pro-social behavior and blunting of unwanted memories. Neurosci Biobehav Rev
2008;32(4):760 – 776.
7. Richardson v Miller, 44 SW3d 1 (Tenn Ct App 2000).
8. Zalazar v Vercimack, 633 NE2d 1223 (Ill App 3rd Dist 1993).
9. Beauchamp TL, Childress JF. Principles of biomedical ethics. 6th ed. New York: Oxford University
Press, 2009.
SUGGESTED ADDITIONAL READING
Kass L; The President’s Council on Bioethics. Beyond therapy: biotechnology and the pursuit of happiness.
Washington, DC: The President’s Council on Bioethics, 2003.
Greely H, Sahakian B, Harris J, et al. Towards responsible use of cognitive-enhancing drugs by the
healthy. Nature 2008;456(7223):702 –705.
Bernat, JL. Ethical issues in neurology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2008.
169

PRACTICE ISSUES IN NEUROLOGY:
OPTIMIZING COGNITIVE
FUNCTION IN THE COGNITIVELY
FRAGILE PATIENT
Stephen E. Nadeau
In addition to the lifelong learning of new clinical and scientific knowledge, neurologists
must understand the constantly evolving environment in which they practice. Changes
occur rapidly in reimbursement and regulatory areas, in the integration of evidence-based
medicine, and in the implementation of patient safety measures into clinical practice.
This section of presents a case-based example of these issues as they
relate to the clinical topic. These vignettes are written by neurologists with particular
experience in systems-based practice and practice-based learning and improvement.
Learning Objective
To discuss the challenges and opportunities that exist for optimizing cognitive function
in the cognitively fragile patient and in communicating related issues to the patient
and caregivers.
INTRODUCTION
Until primary treatments are developed for dementia, the role of the neurologist will lie
substantially in management. Optimizing cognitive function in frail elderly persons (who
may have reduced cognitive reserve) or in persons with dementia (who have exhausted
cognitive reserve) can improve quality of life for the patient, ease caregiver burden, and
delay institutionalization. Opportunities for mitigating cognitive dysfunction, as well as
long-term management strategies, should be discussed with the patient and the caregiver
170 at the time of initial diagnosis and reinforced during follow-up visits, and they should be
regularly conveyed to the patient’s primary care physician. The profoundly disheartening
prospect of progressive dementia can be rendered far more tolerable by emphasizing
strategic approaches to optimizing cognitive function. Both the patient and caregiver can
usually be included in such discussions, but the caregiver must be given the opportunity to
speak with the neurologist in private or by telephone as there may be issues that he
or she is not willing to bring up before the patient. The quality of life of the patient and
caregiver, and the caregiver’s ability to keep the patient at home, are critically dependent
on the skills and endurance of the caregiver. Thus, caregiver support is essential to any
management strategy. Social services and support groups can play instrumental roles in
caregiver support.
Relationship Disclosure: Dr. Nadeau has received personal compensation for speaking engagements from the Halifax Medical Society and the
Department of Medicine at the University of Florida College of Medicine. Dr Nadeau has received personal compensation as an associate editor
of Journal of the International Neuropsychology Society. Dr Nadeau’s compensation and/or research work has been funded, entirely or in part,
by a grant to his university from a governmental organization.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Nadeau discusses the unlabeled use of acetylcholinesterase inhibitors to treat psychotic
manifestations, apathy, indifference, and anxiety in patients with dementia.
Copyright © 2010, American Academy of Neurology. All rights reserved. Continuum Lifelong Learning Neurol 2010;16(4):170 –174
Case
A 75-year-old retired attorney with midstage Alzheimer disease lived at home with his wife
of 50 years and enjoyed what he and his wife felt was a reasonable quality of life. His
recent memory was very poor, his communication was relatively devoid of content, and he
had moderate ideomotor apraxia. Despite these impairments, he was largely independent
in activities of daily living with modest supervision by his wife. One evening, while they
were taking a walk, she failed to notice that he was not right beside her when they were
crossing a street. She spotted him on the other side of the road, and he began to cross,
only to be struck by an automobile. Emergency evaluation revealed that he had an
undisplaced humeral fracture that was treated by immobilization but no head or spine
injuries. He was admitted to the hospital for observation. He became extremely confused
and combative over the course of the evening, with active hallucinations, and had to be
put in four-point restraints. He was incontinent of both urine and stools. He was nearly
stuporous the following day. This cycle repeated for several days, despite the administration
of several psychoactive medications, whereupon the decision was made to place a feeding
gastrostomy and transfer him to a nursing home. There his cognitive function remained
substantially the same. Over the course of the next 3 months, he was admitted to an acute
care hospital 3 times for urosepsis or aspiration pneumonia. He died during the third
hospitalization. His spouse felt helpless during his entire downward course.
DISCUSSION
Almost certainly this tragic scenario could have been avoided and the patient might have
spent 1 or more additional years of fair quality life at home. He might eventually have died
with dignity, perhaps with the aid of hospice, and at a vastly lower health care cost. This
case vignette amply demonstrates the hazards of hospitalization of the cognitively fragile
patient. In addition, several strategies can be pursued to optimize the cognitive function of
this type of patient.
Treat Underlying Causes of Cognitive Impairment

Patients with dementia are susceptible to intercurrent illness or may receive treatment 171
that worsens cognitive deficits. Reversible conditions include nearly any infection,
metabolic disorders (most often dehydration, prerenal azotemia, and hyponatremia),
and structural processes, such as subdural hematomas. In addition, patients may be
given medications that can have a detrimental effect on cognition. The most characteristic
marker of an intercurrent process is a disorder of arousal (pathologic sleepiness) or a
disorder of attention (inability to sustain focus of sensory resources on the examiner),
features not characteristic of Alzheimer disease, frontotemporal degeneration, Parkinson
disease, vascular dementia, or other common neurodegenerative disorders. Acute or
subacute decline in cognitive function in and of itself commonly reflects a potentially
treatable etiology. Patients and families should be made aware of this at the time that
diagnosis is initially discussed. The process of informing patients and families of the
particular significance of acute or subacute declines in function also provides a logical
segue to discussion of advance directives. Most people understand advance directives only
as protecting the right of the patient or surrogate medical decision maker to demand
surcease from cardiopulmonary resuscitation and respirator support. They need to

PRACTICE ISSUES IN NEUROLOGY
understand that they legally and ethically have complete control over medical care,
and that this includes the right to refuse any and all medical interventions, including
antibiotic treatment of infections. People of any degree of sophistication can readily
understand Osler’s characterization of pneumonia as a friend of the aged, even as
religious beliefs may influence their decision making in these matters.
Avoidance of Drugs That Potentially Increase Cognitive Impairment

Drugs that may worsen an underlying cognitive impairment include clonidine, nearly
all typical and atypical neuroleptics, benzodiazepines, anticholinergics (eg, benztropine,
trihexyphenidyl, tricyclic antidepressants, and over-the-counter hypnotics, which
usually contain diphenhydramine), antihistamines, certain anticonvulsants (particularly
phenobarbital, primidone, and topiramate), and opiates. Certain classes of drugs (eg,
tricyclic antidepressants and opiates) have a highly variable dose responsiveness and
susceptibility to toxic effects. It may not be possible to entirely avoid drugs in these
broad classes, but treatment can be facilitated by explicit recognition of a potential
trade-off of cognitive compromise for improvement of debilitating symptoms or relief
of suffering. These decisions should be made with discussions of the benefits and risks
of alternative treatment strategies with the patient’s family and caregivers.
Avoidance of Drugs That Potentially Impede Neuroplasticity

A growing body of evidence suggests that the dementia phenotype at any given time
reflects the net result of the neurodegenerative process and cerebral neuroplastic
mechanisms that serve to palliate that process. This evidence provides a rationale for
avoiding drugs that potentially impair neuroplasticity.1 For some drugs (eg, anticholinergics),
evidence from human studies clearly demonstrates that drug treatment impairs learning,
hence neuroplasticity. Data for certain other drugs are based primarily on the results
of animal studies. These experiments confirm the potent antineuroplastic effects of
anticholinergics and implicate neuroleptics, anticonvulsants, benzodiazepines,
α1-noradrenergic blockers, and α2-noradrenergic agonists in the inhibition
172 of neuroplasticity.
Treatment of Disorders That May Worsen Cognitive Impairment

Depression may worsen cognitive function and, in some cases, may mimic the clinical
presentation of dementia. Sleep disorders, which are ubiquitous but infrequently
addressed by generalist physicians, can have a dramatic and pervasive detrimental
effect on cognitive function in patients with an underlying dementia. Families and
caregivers may provide considerable insights into the patient’s mood and changes in
sleep patterns. Remarkably, despite the substantial literature on invidious effects of
sleep deprivation on cognition in healthy individuals,2,3 almost no research is available
on the impact of sleep disorders on cognitive function in patients with cognitive
impairment. Persons without dementia who have a sleep disorder can develop clinically
apparent disorders of concentration (sustained attention), often misconstrued as
memory impairment. Characteristic symptoms include a tendency to mislay items, to go

somewhere to do something only to forget what it is by the time of arrival, to lose
track of thoughts in midsentence, to have to re-read material, to miss turns while
driving, and even to display disturbances of motor attention, such as dropping objects.
Patients with dementia may develop a florid late-day cognitive decline (commonly
referred to as sundowning) caused by the combined effects of sleep disorders and
abnormalities in diurnal rhythms. They may develop day-night reversal, exacerbated by
the perverse consequences of sensory deprivation as they lie awake much of the night.
They may develop signs of psychosis, including hallucinations, but more commonly
delusions, which may cause agitation or lead to a behavioral response. Delusions and
agitation are often associated with belligerence. Patients with Parkinson disease and, to
an even greater extent, those with Lewy body disease are particularly susceptible to
psychotic-type symptoms. In these patients, psychotic manifestations may be potentiated
by any dopaminergic agonist drug.
Sleep may be quantitatively reduced (insomnia), and sleep architecture may be
disrupted by periodic limb movements of sleep (PLMS) and obstructive sleep apnea
(OSA). Common causes of insomnia include poor sleep hygiene, restless legs syndrome
(RLS), pain, and nocturia, but in most cases, insomnia is idiopathic. A history of RLS
may be difficult to elicit in a patient with dementia. A sense on the part of caregivers
that the patient is restless or exhibits movements suggestive of PLMS, which usually
accompany RLS, may provide a crucial clue. RLS is sufficiently common to prompt an
empiric trial of a titrated dopaminergic agent (carbidopa/levodopa [Sinemet CR] 25/100
one to four tablets, pramipexole 0.25 mg to 0.75 mg, ropinirole 0.5 mg to 2.0 mg) at
bedtime. Pain causing insomnia may occasionally require treatment with an opiate
analgesic, but usually an adequate hypnotic regimen will suffice. Severe nocturia (more
than three episodes per night) that does not respond to an α1-noradrenergic blocker with
maximum specificity for urethral receptors (eg, tamsulosin or uroxatral) may benefit from
provision of a hospital bed with the head raised 20°. This unloads the left atrium and
reduces nocturnal secretion of natriuretic peptides, thereby reducing nocturnal diuresis.
Idiopathic insomnia can usually be treated with a titrated bedtime dose of trazodone.
Occasionally a titrated dose of a benzodiazepine (eg, lorazepam or temazepam) or
related drug (eg, zolpidem) may be helpful in patients with refractory initial insomnia.
Sleep disorders, including PLMS and OSA, can seriously impair sleep quality, even
though the patient may appear to be sleeping too much. PLMS responds as well as RLS
to dopaminergic treatment. OSA may be more difficult to treat, particularly in the
173
patient with dementia, because of poor tolerance for continuous positive airway
pressure (CPAP) ventilation. This can be addressed by a very gradual increase in the
amount of time CPAP is used and by judicious use of sedative hypnotic drugs
(eg, trazodone, sometimes a benzodiazepine).
It is common to use neuroleptics to treat psychotic manifestations of dementia.
Both typical and atypical neuroleptics, however, have a poor record of success in this
population or are fraught with serious side effects.4 The US Food and Drug Administration
has issued a black box warning related to the significant increase in mortality rate associated
with these drugs. Because few studies have been done on the impact of sleep management
on cognitive function in patients with dementia, the use of sleep management interventions
is based primarily on clinical experience. This experience suggests that in most cases
appropriate management of sleep disorders can be highly effective in mitigating
psychotic manifestations and optimizing cognitive function in the setting of dementia
and that neuroleptics rarely, if ever, need to be employed.

PRACTICE ISSUES IN NEUROLOGY
Palliative/Symptomatic Treatment of Dementia

Review of the neuroscience of cholinergic pharmacology suggests that the principal
effect of centrally acting acetylcholinesterase inhibitors is palliative—that is, they serve
to potentiate the formation of new or modified synapses (learning) even as these
synapses are being lost because of the disease process.5 It appears likely that
memantine also exerts a palliative effect, although its mechanisms of action are less
well understood. Phase 3 clinical trials show that acetylcholinesterase inhibitors exert
beneficial effects on psychotic symptoms, apathy, indifference, and anxiety in subjects
with Lewy body disease.6 These results have been replicated in studies of patients with
Parkinson disease, and it seems reasonable to extrapolate them to patients with
Alzheimer disease. The results of this trial argue strongly against the use of anticholinergic
drugs to treat Parkinson disease.
CONCLUSION
Although the cognitive and behavioral decline of dementia eventually challenges nearly all
management approaches, the strategies discussed here provide opportunities for improving
cognitive function and quality of life, even as they may contribute to a reduction in
medical costs by delaying nursing home placement.7,8 Patients and families should be
introduced to the list of treatment opportunities discussed here early on in their interaction
with the neurologist, and the message should be reinforced verbally and through actions
taken by the neurologist or physician extender during each follow-up visit. Family and
caregivers are important sources of information related to a patient’s mood, sleep patterns,
and behavior. The benefits and risks of changes in treatment strategy should be discussed.
Often, a follow-up visit devoted strictly to discussion of these issues is warranted shortly
after the diagnostic visit.
REFERENCES
1. Goldstein LB. Potential impact of drugs on poststroke motor recovery. In: Goldstein LB, ed.
Restorative neurology: advances in pharmacotherapy for recovery after stroke. Armonk, NY:
Future Publishing Co, 1998:241– 256.
174
2. Goel N, Rao H, Durmer JS, Dinges DF. Neurocognitive consequences of sleep deprivation. Semin
Neurol 2009;29(4):320 – 339.
3. Harrison Y, Horne JA. The impact of sleep deprivation on decision making: a review. J Exp Psychol
Appl 2000;6(3):236 – 249.
4. Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs in
patients with Alzheimer’s disease. N Engl J Med 2006;355(15):1525 –1538.
5. Gonzalez Rothi LJ, Fuller R, Leon SA, et al. Errorless practice as a possible adjuvant to donepezil in
Alzheimer’s disease. J Int Neuropsychol Soc 2009;15(2):311– 321.
6. McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies:
a randomised, double-blind, placebo-controlled international study. Lancet 2000;356(9247):2031– 2036.
7. Beusterien KM, Thomas SK, Gause D, et al. Impact of rivastigmine use on the risk of nursing home
placement in a US sample. CNS Drugs 2004;18(15):1143 –1148.
8. Feldman H, Gauthier S, Hecker J, et al. Economic evaluation of donepezil in moderate to severe

Alzheimer disease. Neurology 2004;63(4):644 – 650.

CODING TABLE
John Hart Jr, MD
Accurate coding is an important function of neurologic practice. This section of

, contributed by members of the AAN Medical Economics and
Management Committee, includes a table of helpful coding information related
to the issue topic. The table may include diagnosis coding, Evaluation and Man-
agement (E/M) coding, procedure coding, or a combination, depending on
which is most useful for the subject area of the issue.
Below are lists of diagnosis codes commonly used for encounters with patients with
behavioral neurology disorders. This list is not all-inclusive, and reference to a full
volume of the International Classification of Diseases, Ninth Revision, Clinical
Modification (ICD-9-CM) is recommended for helpful subterms, instructions, and
coding of other conditions that may be causative or affecting the presenting illness.
For a full set of rules regarding diagnosis coding, see the Official ICD-9-CM
Guidelines for Coding and Reporting, which may be found at: www.cdc.gov/nchs/
data/icd9/icdguide.pdf.
ICD-9 Codes Utilized for Procedures Commonly Used in the

Diagnosis and Treatment of Behavioral Neurology Disorders
The following two codes are second-listed codes for a visit or procedure
and must be preceded by a code for the associated neurologic condition:
294.10 Dementia in conditions classified elsewhere without

behavioral disturbance
294.11 Dementia in conditions classified elsewhere with behavioral

disturbance
042 [294.10] HIV without behavioral disturbance
046.19 Other and unspecified Creutzfeldt-Jakob disease
094.9 [294.11] Neurosyphilis with behavioral disturbance

175
275.1 [294.11] Wilson disease with behavioral disturbance
290.12 Binswanger’s disease
290.40 Vascular dementia

Multi-infarct (cerebrovascular) dementia
291.1 Alcohol-induced persisting amnestic disorder
continued on next page
Relationship Disclosure: Dr Hart has received personal compensation for serving on the Speakers Bureau for
Forrest Pharmaceuticals.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Hart has nothing to disclose.
Continuum Lifelong Learning Neurol 2010;16(4):175–177 Copyright # 2010, American Academy of Neurology. All rights reserved.

" CODING TABLE
Continued
293.0 Delirium due to conditions classified elsewhere
294.0 Korsakoff (Wernicke) disease, psychosis or syndrome

(nonalcoholic)
294.0 Amnestic (confabulatory) syndrome
294.8 Dementia
298.9 Confusion, confused (mental) (state) (see also State,

confusional)
310.2 Postconcussion syndrome
315.01 Alexia (congenital) (developmental)
322.0 Parkinsonism (arteriosclerotic) (idiopathic) (primary)
331.0 Alzheimer’s disease
331.11 [294.11] Pick’s disease with behavioral disturbance
331.19 [294.11] Other frontotemporal dementia with behavioral disturbance

Frontal dementia
331.5 Idiopathic normal pressure hydrocephalus
331.82 [294.11] Dementia with Lewy bodies with behavioral disturbances
331.83 Mild cognitive impairment
333.0 Shy-Drager syndrome (orthostatic hypotension with

multisystem degeneration)
333.0 Steele-Richardson (Olszewski) syndrome
333.4 Huntington’s chorea
176 348.30 Encephalopathy (acute)
368.16 Agnosia (visual)
436 Deficit due to cerebrovascular lesion
437.7 Transient global amnesia
768.70 Hypoxic-ischemic encephalopathy (HIE)
780.09 Delirium, delirious
780.93 Amnesia (retrograde)
781.8 Hemispatial neglect
continued on next page

Continued
784.3 Aphasia
784.51 Dysarthria
784.61 Alexia secondary to organic lesion
784.61 Agraphia with alexia
784.69 Agnosia
784.69 Agraphia (absolute)
784.69 Anomia
784.69 Apraxia (classic) (ideational) (ideokinetic) (ideomotor) (motor)
850.0 Concussion without loss of consciousness
850.5 Concussion with loss of consciousness
850.9 Concussion, unspecified
854.0 Traumatic brain injury (TBI) (see also Injury, intracranial)
E/M CODING
If doing a neurobehavioral examination the same day/same visit with a patient, then
take the E/M code and add a –25 (eg, 99204-25). Then you can also bill 96119 for a
neurobehavioral examination for more involved neurobehavioral testing that you
are doing as part of your evaluation. This is a time code that can include time of face-
to-face testing of the patient, data analysis, and report generation. It is best to submit
a separate report detailing the testing, scores, interpretation, and the time engaged.
If a physician extender (eg, testing technician) performs the neurobehavioral
testing, then add a –YR to the neurobehavioral examination code (eg, 96119-YR).
177

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180
TYPE A QUESTIONS (ONE BEST ANSWER)
1. A 74-year-old woman is brought for evaluation by her daughter, who is
quite concerned about her mother’s tendency to repeat herself constantly.
Old friends no longer wish to visit with her, and her housekeeping skills and
personal hygiene have declined. During the interview, she repeats the
physician’s questions several times. When asked to repeat the names of three
objects, she becomes focused on the name of the first object and repeats it,
seemingly unaware that three words were to be remembered. Injury to which
of the following areas may be associated with this tendency to repeat a given
behavior inappropriately?
A. corpus callosum
B. dorsolateral prefrontal cortex
C. orbitofrontal regions
D. subthalamic nucleus
E. temporoparietal cortex

2. A 67-year-old man is brought by his wife for evaluation because he
cannot recognize famous or even familiar people by their faces. She first
noticed this when they were going through a family album of photographs.
He can recognize familiar people through other clues, such as their voices.
Brain MRI shows a small infarct. Injury to which of the following areas is
most likely to produce such a deficit?
A. amygdala
B. anterior superior temporal sulcus
C. fusiform gyrus
D. insula
E. ventral prefrontal cortex
3. A 65-year-old man develops sudden onset of language problems. His
speech is fluent, prosodic, and well articulated, but he makes frequent
phonemic and semantic paraphasic errors. He cannot name objects or
repeat well. Comprehension is severely impaired. Brain MRI shows an
infarct in the left posterior perisylvian area. Which of the following additional
deficits would be most likely to occur?
A. agrammatism
B. hemiparesis
C. hemisensory deficit
D. homonymous hemianopsia
E. visual agnosia
4. A 73-year-old man presents for evaluation because of 6 months of
progressive difficulty using his right arm. He states that woodworking has been
a hobby his entire life. However, during the past several months, he has been
increasingly unable to use the tools in his garage workroom. When asked to
pantomime the use of a table saw, it is clear that he moves his arm and hand
incorrectly through space. In addition, he fails to properly direct his movements
at the pretended piece of wood. The neurologist also notes mild rigidity and
myoclonus of the right arm. Which of the following causes of ideomotor
apraxia are suggested by these findings?
A. Alzheimer disease
B. astrocytoma of corpus callosum 181
C. corticobasal degeneration
D. infarction of left parietal lobe
E. parietal lobe tumor
5. A 73-year-old right-handed retired businessman is evaluated for a 4-year-history
of cognitive decline. In particular, he has difficulty naming and even recognizing
persons or objects that used to be familiar to him. On examination, he has normal
attention, executive function, and visuospatial memory. He can name only 15/30
objects in the Boston Naming Test and can generate a list of only three animals in
1 minute. He cannot define an island or a newspaper and claims that he has
never heard these words before. Which is the most likely diagnosis?
B. corticobasal degeneration
C. dementia with Lewy bodies
D. primary nonfluent aphasia
E. semantic variant of primary progressive aphasia

6. A 66-year-old right-handed patient developed acute hemiplegia 6 hours ago. On

examination, he is somnolent and has profound left-sided hemineglect. He does
not respond to threatening visual stimuli when they are presented on his left
extrapersonal hemispace but does so when they are presented on the right. An
MRI reveals an area of restricted diffusion in the right parietal lobe. Which of the
following structures is part of the spatial attention network affected by this lesion?
A. frontal eye fields
B. fusiform gyrus
C. hippocampus
D. inferior colliculus
E. ventral lateral nucleus of the thalamus
7. A 77-year-old right-handed retired teacher awoke from surgery for an
abdominal aortic aneurysm with speech difficulties. She is fluent but makes
semantic errors. She has difficulty with comprehension, but her sentence
repetition is normal. The MRI shows an area of restricted diffusion in the left
hemisphere. Which of the following is the most likely location of the lesion?
A. inferior frontal gyrus
B. insula
C. supramarginal gyrus
D. watershed area between the middle and the anterior cerebral artery
E. watershed area between the middle and the posterior cerebral artery
8. A 69-year-old man has been the treasurer for his church for 35 years and
has always performed his duties very well until the past year. He has had
progressive difficulties doing the accounting, paying bills, and making budgets.
The office administrative assistant reports that he occasionally loses track of
what he meant to say and seems to have had a significant decline in his
memory. Which of the following tests would be most helpful in isolating a
deficit in working memory?
A. Paced Auditory Serial Addition Test
B. Stroop task
C. trail making tests
D. verbal fluency tasks
182 E. Wisconsin Card Sorting Task
9. A 72-year-old right-handed housewife is evaluated for progressive visual
difficulties over the past year. She has had trouble searching for items in the
grocery store and identifying money to pay for them. On examination, she
cannot identify a dog, horse, chair, or hammer in a line drawing but can name
these items after being given their verbal description. When she is shown a
paperclip, she mistakes it for a key, but she spontaneously corrects the error
when the paperclip is placed in her hand. Although she cannot name a house
shown in a line drawing, she is able to copy it and match it with the drawing
of an identical house. What is the most likely location of the lesion responsible
for her difficulties?
A. bilateral fusiform gyri
B. bilateral superior temporal sulcus
C. left supramarginal gyrus
D. right retrosplenial cortex
E. right temporal pole

10. A 69-year-old man develops sudden onset of left hemiparesis. His MRI
shows a moderately sized right hemispheric infarct that includes the parietal
lobe. A mild hemiparesis, as well as hemianopia and neglect, is present..
Over 3 months, these signs resolve. Which of the following symptoms
typically would be expected to last longer?
A. left homonymous hemianopia
B. optic ataxia
C. simultanagnosia
D. urinary incontinence
E. visual extinction
11. A 79-year-old man with a past medical history of hepatitis C infection

and diabetes mellitus undergoes right total hip replacement surgery. He
reports visual hallucinations after administration of narcotic analgesics. He is
confused for several days, prompting a neurologic consultation. Which of
the following disturbances of language function would likely be detected on
cognitive testing of this man with delirium?
A. agraphia
B. anomia
C. deep alexia
D. hemianopic alexia
E. pure alexia
12. A 55-year-old right-handed salesman is evaluated for progressive

behavioral changes over the past 6 months, leading to interpersonal conflicts
and loss of his job. According to his wife, he started to show little respect
for personal boundaries and seemed unable to perceive social signals. For
example, on several occasions he made inappropriate sexual comments to
his secretary and seemed unable to perceive the expression of discomfort
and embarrassment in her face. He became socially withdrawn and irritable
and unaware of the feelings of others, including his wife and children. What
is the primary location of the lesion producing these behavioral changes?
A. left medial temporal lobe
B. left posterior cingulate cortex
C. left posterior parietal cortex
183
D. right anterior temporal lobe
E. right inferior parietal lobule
13. A 45-year-old right-handed man is brought to the emergency department

because of abrupt onset of speech difficulties 4 hours earlier. According to his
wife, he started talking nonsense and appeared not to understand what she was
telling him. On examination, he has a well-articulated, fluent, and prosodic
speech but makes frequent phonemic and semantic paraphasic errors with
neologisms. He is unable to name objects, but he can pantomime their use.
The findings are consistent with a lesion in which of the following areas?
A. angular gyrus
B. entorhinal cortex
C. fusiform gyrus
D. perirhinal cortex
E. superior posterior temporal gyrus

14. A 65-year-old cellist reports the relatively sudden onset of difficulties with
performing previously learned pieces. She also finds it more challenging to learn
new musical pieces. Her neurologic examination reveals no obvious motor
deficits. Tests of episodic and semantic memory appear intact, and she appears
to have memory impairment that is relatively isolated to procedural memory.
Which of the following neuroanatomic areas is most likely to be involved?
A. anterior thalamic nucleus
B. hippocampus
C. inferior lateral temporal lobes
D. primary motor cortex
E. supplementary motor area
15. A 62-year-old right-handed electrician is evaluated for progressive difficulties

with his job because of impaired ability to use the screwdriver, pliers, and
other tools. Examination reveals normal attention, language, and visuospatial
abilities. Motor strength, coordination, and sensation are normal. He has severe
difficulties when asked to pantomime the use of a screwdriver or a hammer.
He is unable to imitate the pantomime when performed by the examiner and
even has trouble using the actual tool. He cannot discriminate whether the
examiner performs the correct pantomime. His deficit is much worse in his
right than left hand. Where is the most likely location of the lesion?
A. left inferior parietal cortex
B. left orbitofrontal cortex
C. right premotor cortex
D. right superior parietal cortex
E. right supplementary motor area
16. A 70-year-old right-handed woman with a 2-year history of mild but

slowly progressive memory difficulties is admitted for acute confusional state
in the setting of a urinary tract infection. Her attention improves significantly
following resolution of the infection with antibiotic therapy. Which of the
following is a physiologic correlate of improved attention in this patient?
A. decreased activity of intralaminar nuclei of the thalamus
B. decreased cholinergic influence on the reticular nucleus of the thalamus
184 C. decreased interference with multisynaptic corticocortical pathways
D. increased reticular thalamic input to the dorsolateral prefrontal cortex
E. increased slow, rhythmic activity in the dorsolateral prefrontal cortex
17. A 77-year-old woman presents with difficulty finding items in space. Her
visual acuity and visual fields are normal. Eye movements are conjugate and
full. Strength and coordination are normal. However, she cannot reach out
and touch objects in space except by groping around as if blind. Her
examination shows optic ataxia and psychic paralysis of gaze. In order to
meet criteria for diagnosis of Balint syndrome, what other abnormality must
be present on examination?
A. clumsiness of the left hand
B. inaccurate bisection of a line
C. intentional deficit
D. motor impersistence
E. simultanagnosia

18. A 55-year-old right-handed postal worker is evaluated for abrupt onset of
word-finding and reading difficulties. On examination, he has difficulties reading
single words aloud, although he can recognize them if they are spelled to him.
He has the same degree of difficulty reading nouns (eg, house), function words
(eg, when), or pseudowords (eg, frod). He is also unable to read letter by letter
or name single letters. He has no difficulty writing words on dictation but is
unable to read them. What is the most likely location of the lesion?
A. left angular gyrus
B. left anterolateral temporal cortex
C. left occipital cortex and splenium
D. left supramarginal gyrus and arcuate fasciculus
E. right occipital cortex and splenium
19. A 45-year-old right-handed physician was noted by his colleagues to have

worsening performance at work. He seems to lose track of the patients during
hospital rounds and takes an excessive amount of time making a decision about
the next step of the patient’s evaluation. He has been an enthusiastic teacher
and productive researcher but now has recently had difficulty organizing his
lectures and has not yet finished writing a research paper that he started
3 months ago. Involvement of which of the following structures can result in
these symptoms?
A. caudate nucleus
B. posterior cingulate cortex
C. pulvinar
D. supramarginal gyrus
E. tuberomammillary nucleus
20. A 45-year-old patient comes for follow-up 4 months after an ischemic stroke.
He reports that after the stroke he lost the pleasurable feeling of body relaxation
that he had previously experienced after smoking a cigarette, taking a hot shower,
or receiving a massage. Which of the following areas is most likely to be affected?
A. left lateral temporal cortex
B. left occipitotemporal cortex
C. right anterior insula
D. right posterior cingulate cortex
185
E. right supramarginal gyrus
21. A 65-year-old right-handed woman who had a left hemispheric stroke 3 months
ago is evaluated for persistent lack of finger dexterity. She has difficulty buttoning
her shirt, using a pair of scissors, and playing the piano despite having recovered
the strength in her hand and fingers. On examination, strength, muscle tone,
coordination, and sensation are normal in all limbs. However, she has difficulty
rotating a nickel between her thumb, index, and middle fingers as rapidly as
possible with either hand, although this is worse with the right hand. Where is
the most likely location of the lesion?
A. anterior cingulate motor area
B. left lateral premotor cortex
C. medial prefrontal cortex
D. postcentral gyrus
E. posterior parietal cortex

22. A 74-year-old man is brought by his wife to the office for neurologic
evaluation because of problems with naming objects. At first his wife thought
that he had problems with deteriorating vision because he reported progressive
difficulty with reading. She noted that he could not recognize faces of friends
but would remember their names when he heard their voices. However, over
the past year, he has shown more evidence of memory deficits and needs to
physically manipulate or hear objects in order to recognize them. His MRI shows
bilateral occipitotemporal atrophy. Which of the following diagnoses best describes
his complete clinical syndrome?
A. alexia without agraphia
B. Balint syndrome
C. optic aphasia
D. posterior cortical atrophy
23. A 66-year-old woman is evaluated for progressive visual difficulties over the
past 2 years. She has had increasing difficulty finding her way in her apartment
as she bumps into furniture because she fails to see it. She has become unable
to go shopping as she fails to see more than one item at a time on the shelf. She
incorrectly reaches for utensils on the dinner table despite being able to see them.
Examination shows normal attention span, learning, and recall. Motor strength
and eye movements are full. She performs normally in the finger-to-nose testing.
However, when she attempts to reach the examiner’s hand, she misses it by several
inches. She is unable to volitionally direct her gaze to a verbally specified target,
such as the door or the examining table. When shown the picture of a kitchen,
she reports only seeing the sink or the refrigerator, but not both. These manifestations
reflect bilateral involvement of which of the following cortical regions?
A. parietooccipital cortex
B. perirhinal cortex
C. supplementary eye fields
E. temporooccipital cortex
186 24. A 66-year-old right-handed painter is evaluated for sudden onset of visual
disturbance. While he was watching a color movie on TV, he noticed that all
the images turned into shades of gray. On examination, his visual acuity is
20/20 in both eyes with correction. He can read 12 of 14 pseudoisochromatic
(Ishihara) plates held at a distance, but he is unable to discriminate red from
green. The rest of his neurologic examination is normal. This disorder is a
manifestation of involvement of which the following cortical regions?
A. bilateral lingual gyri
B. bilateral superior temporal gyrus
C. left angular gyrus
D. left supramarginal gyrus
E. right precuneus

25. A 68-year-old cardiothoracic surgeon is brought to the emergency department
because of speech abnormalities. He understands questions well. His speech is
fluent, but he makes some phonemic paraphasias. When asked to describe what
he does for a living, he says “I, you know, take hearts when they are weak and,
you know, broken—the pipes are blocked and I, well, work it and make them
go.” Repetition is severely impaired. His brain MRI is most likely to show an
acute infarct in which of the following areas?
A. left frontal cortex and genu of the corpus callosum
B. left occipital cortex and splenium of the corpus callosum
C. left parietal cortex and underlying white matter
D. left temporal cortex and Meyer loop
E. left thalamus
26. A 74-year-old man with hypertension, hyperlipidemia, and hypothyroidism

presents with new-onset difficulty with reading. He has become aware of this
because he is no longer able to read stories to his 6-year-old granddaughter without
errors. He makes substitution errors on certain words, which make it confusing
to follow the story. For example, he sometimes reads it as and or that as other.
He rarely makes semantic errors when reading. On examination, he is unable
to read pseudowords. Which of the following is the most likely site of the lesion
that would cause this problem?
A. left and right thalami
B. left frontal premotor region
C. left parietooccipital junction
D. left perisylvian region
E. right insular cortex
27. A 40-year-old right-handed businessman is evaluated for abrupt onset of

inability to recognize people by their faces. Although he can recognize faces as
such, he relies on clues, such as the voices or mannerisms of his wife, children, 187
or coworkers, to identify the person. He cannot identify his parents in family
pictures and identifies only 3 of 20 famous faces despite his ability to tell why
they are famous after being given their names. Strikingly, he hesitates to answer
and becomes sweaty and tachycardic while watching the facial expression of
fear in a picture of his 3-year-old daughter. Preservation of what brain region
may explain his emotional reaction to facial expression?
A. angular gyrus
B. intraparietal sulcus
C. orbitofrontal cortex
E. superior temporal sulcus

28. A 73-year-old, right-handed, retired clerk is evaluated for confusion that

developed over the past 2 days. He has a history of high cholesterol and is on
rosuvastatin and tolterodine. He has a history of depression, and spastic bladder
for which amitriptyline was begun 3 days ago. On examination, he is inattentive,
incoherent, and unable to write to dictation or draw a clock. His pupils are dilated
and poorly reactive to light, and his heart rate is 110 beats/min. Which of the
following is the most likely cause of confusional state in this patient?
A. blockade of inputs from the laterodorsal tegmental nucleus to the thalamus
B. blockade of ventral tegmental inputs to the cerebral cortex
C. excessive influence of the dorsal raphe nucleus on the thalamus
D. excessive influence of the locus ceruleus on the cerebral cortex
E. excessive influence of the tuberomammillary nucleus on the thalamus
29. A 72-year-old man presents with a report of difficulties understanding

the speech of others. He says that even the speech of his wife of 40 years
sounds like an unfamiliar foreign language. He used to be able to identify
60 different bird calls, but now they all sound the same to him. He has no
other deficits. Where is the most likely localization of this problem?
A. bilateral temporal lobes
B. Broca area
C. left dorsal temporooccipital junction
D. right mesial occipitotemporal region
E. right temporal lobe
30. A 68-year-old man with history of hypertension and diabetes mellitus is

evaluated for progressive memory decline over the past 16 months. He tends
to repeat the same questions and forgets his medications. His wife is concerned
because once he was unable to recognize a new neighbor who had visited
them the day before and on another occasion could not recognize a new
necktie that had been given to him as a birthday present the same morning.
On examination, he recalls 7/10 words on the third immediate recall
188 trial of a verbal memory task, but his delayed recall is 0/10. He recognizes
4/10 items on a list. He performs in the normal range on tests of attention,
executive function, language, and visuospatial ability. Involvement of which of
the following areas of the cortex that has been implicated in recognition memory
is most likely to be affected by the degenerative process in this patient?
A. anterior cingulate involvement
B. medial temporal involvement
C. orbitofrontal involvement
D. posterior insular involvement
E. superior parietal involvement

31. An 84-year-old woman presents with bilateral strokes involving the lateral
temporoparietal regions. Which of the following neurologic deficits could be
associated with such a stroke?
A. achromatopsia
B. akinetopsia
C. alexia without agraphia
D. prosopagnosia
E. visual agnosia
32. A 70-year-old man is a subject in a neuropsychological study that involves

vigilance and attention to multimodal sensory stimuli. Pathways from the reticular
formation of the brainstem influence the transmission and integration of the
neural information by projection to all of the nuclei of the thalamus. Which
thalamic nucleus does not project to the cerebral cortex and inhibits the other
thalamic nuclei through γ-aminobutyric acid–ergic projections?
A. anterodorsal
B. interlaminar
C. medial dorsal
D. pulvinar
E. reticular
33. A 75-year-old, right-handed, retired accountant is evaluated for progressive

forgetfulness. Two years ago, his wife took over the household finances after he
had often forgotten to pay the bills and had bounced several checks. More recently,
he seems to lose track of what he intends to say during conversations with his
family and friends. His wife has noticed that he is unable to retain phone numbers
that he has just read in the phone book in order to make a call. Despite his
difficulties, he remains a pleasant, responsible, caring member of his family. On
examination, he is alert and fully oriented. His digit span is five forward and two 189
in reverse. He is unable to spell world backwards or recite the months of the year
in reverse order. When asked to list items starting with F in 1 minute, he is able
to produce only six, with multiple repetitions. Which is the most likely location
of the lesion?
A. anterior cingulate cortex
B. lateral prefrontal cortex
C. lateral temporal cortex
D. orbitomedial prefrontal cortex
E. parahippocampal cortex

34. A 45-year-old, right-handed, now disabled journalist is evaluated for persistent

difficulties reading following a left hemisphere stroke. She has a mild residual
fluent aphasia with difficulty naming and with comprehending and repeating.
She has no major difficulty reading real words (eg, tub) or pseudowords (eg,
mub). However, she has severe difficulty reading irregular words. For example,
she reports the word choir as chore and reads and interprets the pseudoword
fraim as the real word frame. Which of the following is the term used to
describe this disorder?
A. apperceptive alexia
B. deep alexia
C. peripheral alexia
D. phonologic alexia
E. surface alexia
35. A 68-year-old, right-handed, retired administrator is evaluated for increasing

difficulties remembering names of people and objects over the past 2 years. She
has also experienced difficulty communicating clearly with her family and friends
and finding items in the grocery store despite using a shopping list. On examination,
she is alert and oriented. Her speech is fluent but characterized by circumlocution
and paucity of content, particularly nouns. She is unable to name famous people,
animals, or objects, even after cueing by their description. Multiple choice does
not help naming. She is unable to name a coin placed on her hand or pantomime
the use of objects. Speech comprehension is mildly impaired, and repetition is
spared. Impairment of which of the following processes is the most likely
mechanism of anomia in this patient?
A. difficulty selecting word forms
B. impaired recognition memory
C. impaired retrieval strategies
D. impaired visual recognition
E. loss of semantic knowledge
36. A 54-year-old man with diabetes and hypertension is examined after presenting
with mild aphasia. When asked to demonstrate how he would use a pen to write,
he appears puzzled and is unable to complete the task. When he is shown a pen,
190 however, he can correctly perform a pantomime of writing. Which of the following
is the correct term for this type of apraxia?
A. dissociation
B. ideational
C. ideomotor
D. limb-kinetic
E. tool selection deficit
37. One of the memory systems allows us to remember past experiences and
specific events in our lives. This type of memory involves self-knowing consciousness
and an integrated recollection of the individual’s own experience of an event
and is tightly linked to a sense of time. Which of the following is the correct
term for this type of memory?
A. associative
B. episodic
C. procedural

D. semantic
E. working
38. A 45-year-old woman has survived a severe case of herpes encephalitis. After
months of rehabilitation, her cognition is still severely impaired. She is emotionally
detached from her family and friends and sometimes fails to recognize their faces
or voices. She does not seem to be able to read the mood of her family or caretakers.
Injury to which of the following structures is most closely implicated as the cause
of this type of socioemotional deficit?
A. caudate nucleus
B. fusiform gyrus
C. hippocampus
D. insula
E. temporal poles
39. A 60-year-old right-handed woman is evaluated for a 1-year history of progressive

visual difficulties. She first noticed difficulties completing jigsaw puzzles as she
was unable to see all the pieces on the table. More recently she has noticed
difficulties reading words, even though she is able to read individual letters and
numbers. Over the past 6 months she has found it hard to recognize faces in
her family photo album. Examination shows normal digit span, language, and
memory functions. Her visual acuity and visual fields on confrontation testing
are normal. She can read single letters rapidly but hesitates with words. She is
unable to produce volitional saccadic eye movements toward a verbally specified
target in the examining room. She also has difficulty recognizing faces of famous
people. When presented with a complex picture that she had seen before, she
can name several of the items in it but not give a coherent description of the
whole. The MRI of the head shows bilateral posterior cortical atrophy. Which
of the following is the most likely underlying cause?
B. amyotrophic lateral sclerosis
C. Creutzfeldt-Jakob disease
D. Lewy body disease
E. progressive supranuclear palsy
191
40. A 74-year-old right-handed woman is evaluated for slowly progressive
speech difficulty over the past 6 years. On examination, her speech
articulation is effortful, with distorted speech sounds, and is limited to
nouns or short phrases. She makes sound substitution errors in spontaneous
speech, naming, and repetition, feels frustrated, and self-corrects them. She
has good comprehension of single words but has trouble understanding
syntactically complex sentences. The rest of the neurologic examination,
including mental status examination, is normal. Which of the following is
A. left insula and posterior inferior frontal cortex
B. left medial frontal cortex
D. right anterior temporal cortex
E. right superior temporal cortex

PREFERRED RESPONSES
Following are the preferred responses and critiques for the multiple-choice
items in this issue. The questions and answer selections are
repeated, and the preferred response appears in bold print. In most cases,
this is followed by an explanation and a reference with which you may seek
more specific information. No score will be assigned to the answer form you
complete, since the emphasis of this program is on self-assessment. You are
encouraged to review the responses and explanations carefully to evaluate
your general understanding of the course material.
TYPE A QUESTIONS (ONE BEST ANSWER)

1. A 74-year-old woman is brought for evaluation by her daughter, who is
quite concerned about her mother’s tendency to repeat herself constantly.
Old friends no longer wish to visit with her, and her housekeeping skills
and personal hygiene have declined. During the interview, she repeats the
physician’s questions several times. When asked to repeat the names of
three objects, she becomes focused on the name of the first object and
repeats it, seemingly unaware that three words were to be remembered.
Injury to which of the following areas may be associated with this tendency
to repeat a given behavior inappropriately?
A. corpus callosum
B. dorsolateral prefrontal cortex
C. orbitofrontal regions
192 D. subthalamic nucleus
E. temporoparietal cortex
The correct answer is C. This woman displays perseveration, the tendency

to persist in a particular repetitive behavior. Perseverative behavior may
be seen with focal injury in the ventrolateral prefrontal or orbitofrontal
regions. This is often caused by traumatic brain injury or various
neurodegenerative conditions. For more information, refer to the article
“Executive Resources.”
2. A 67-year-old man is brought by his wife for evaluation because he

cannot recognize famous or even familiar people by their faces. She first
noticed this when they were going through a family album of photographs.
He can recognize familiar people through other clues, such as their voices.

Brain MRI shows a small infarct. Injury to which of the following areas is
most likely to produce such a deficit?
A. amygdala
B. anterior superior temporal sulcus
C. fusiform gyrus
D. insula
E. ventral prefrontal cortex
The correct answer is C. The fusiform gyrus of the ventral surface of the
temporal lobe and the adjacent inferior temporal and occipital gyri with
right hemispheric dominance have been labeled as the fusiform face area.
This area is preferentially activated by visual perception of static facial
features, and damage to this area and brain regions adjacent to it is
associated with prosopagnosia. For more information, refer to the article
“Social Cognition.”
3. A 65-year-old man develops sudden onset of language problems. His

speech is fluent, prosodic, and well articulated, but he makes frequent
phonemic and semantic paraphasic errors. He cannot name objects
or repeat well. Comprehension is severely impaired. Brain MRI shows an
infarct in the left posterior perisylvian area. Which of the following
additional deficits would be most likely to occur?
A. agrammatism
B. hemiparesis
C. hemisensory deficit
D. homonymous hemianopsia
E. visual agnosia
The correct answer is D. The patient described has Wernicke aphasia.

Homonymous hemianopsia often accompanies Wernicke aphasia because
of concomitant involvement of the optic radiations. Reading is relatively
preserved in patients with Wernicke aphasia. Agrammatism is characteristic
of Broca, not Wernicke, aphasia. Hemisensory or motor deficits are often
lacking in Wernicke aphasia, which can lead to a misdiagnosis of stroke. 193
For more information, refer to the article “Comprehension.”
4. A 73-year-old man presents for evaluation because of 6 months of

progressive difficulty using his right arm. He states that woodworking has
been a hobby his entire life. However, during the past several months, he
has been increasingly unable to use the tools in his garage workroom.
When asked to pantomime the use of a table saw, it is clear that he moves
his arm and hand incorrectly through space. In addition, he fails to properly
direct his movements at the pretended piece of wood. The neurologist also
notes mild rigidity and myoclonus of the right arm. Which of the following
causes of ideomotor apraxia are suggested by these findings?
B. astrocytoma of corpus callosum

PREFERRED RESPONSES
C. corticobasal degeneration
D. infarction of left parietal lobe
E. parietal lobe tumor
The correct answer is C. The diagnosis of corticobasal degeneration is

suggested by the presence of asymmetric rigidity and myoclonus in the right
arm in association with the findings of ideomotor apraxia. All of these
conditions, however, could be associated with ideomotor apraxia. For more
information, refer to the article “Apraxia.”
5. A 73-year-old right-handed retired businessman is evaluated for a

4-year-history of cognitive decline. In particular, he has difficulty naming
and even recognizing persons or objects that used to be familiar to him. On
examination, he has normal attention, executive function, and visuospatial
memory. He can name only 15/30 objects in the Boston Naming Test and
can generate a list of only three animals in 1 minute. He cannot define an
island or a newspaper and claims that he has never heard these words
before. Which is the most likely diagnosis?
B. corticobasal degeneration
C. dementia with Lewy bodies
D. primary nonfluent aphasia
The correct answer is E. The clinical features are those of semantic

variant of primary progressive aphasia, which is associated with atrophy in
the anterior, inferior, and lateral temporal lobes, particularly on the left side.
For more information, refer to the article “Memory Systems.”
6. A 66-year-old right-handed patient developed acute hemiplegia 6 hours

ago. On examination, he is somnolent and has profound left-sided
194 hemineglect. He does not respond to threatening visual stimuli when they
are presented on his left extrapersonal hemispace but does so when they
are presented on the right. An MRI reveals an area of restricted diffusion in
the right parietal lobe. Which of the following structures is part of the
spatial attention network affected by this lesion?
A. frontal eye fields
B. fusiform gyrus
C. hippocampus
D. inferior colliculus
E. ventral lateral nucleus of the thalamus
The answer is A. The frontal eye fields, together with the inferior parietal
lobule, are critical nodes of the right hemisphere– dominant spatial
attention network. Other components include the superior colliculus and
the pulvinar. For more information, refer to the article “Attentional and
Confusional States.”

7. A 77-year-old right-handed retired teacher awoke from surgery for an
abdominal aortic aneurysm with speech difficulties. She is fluent but makes
semantic errors. She has difficulty with comprehension, but her sentence
repetition is normal. The MRI shows an area of restricted diffusion in the
left hemisphere. Which of the following is the most likely location of the
lesion?
A. inferior frontal gyrus
B. insula
C. supramarginal gyrus
D. watershed area between the middle and the anterior cerebral artery
E. watershed area between the middle and the posterior cerebral artery
The correct answer is E. The findings are those of transcortical sensory

aphasia. This is typically associated with lesions in the watershed area
between the left middle cerebral artery and the posterior cerebral artery
territories or left thalamus due to left internal carotid artery stroke or stroke
involving a branch of the left posterior cerebral artery to the thalamus. For
more information, refer to the article “Naming and Language Production.”
8. A 69-year-old man has been the treasurer for his church for 35 years and
has always performed his duties very well until the past year. He has had
progressive difficulties doing the accounting, paying bills, and making
budgets. The office administrative assistant reports that he occasionally loses
track of what he meant to say and seems to have had a significant decline
in his memory. Which of the following tests would be most helpful in
isolating a deficit in working memory?
A. Paced Auditory Serial Addition Test
B. Stroop task
C. trail making tests
D. verbal fluency tasks
E. Wisconsin Card Sorting Task
The correct answer is A. The Paced Auditory Serial Addition Test assesses
working memory. Single digits are presented in a serial fashion at regular
intervals and must be held in working memory for serial addition tasks. 195
For more information, refer to the article “Executive Resources.”
9. A 72-year-old right-handed housewife is evaluated for progressive visual

difficulties over the past year. She has had trouble searching for items in the
grocery store and identifying money to pay for them. On examination, she
cannot identify a dog, horse, chair, or hammer in a line drawing but can
name these items after being given their verbal description. When she is
shown a paperclip, she mistakes it for a key, but she spontaneously corrects
the error when the paperclip is placed in her hand. Although she cannot
name a house shown in a line drawing, she is able to copy it and match it
with the drawing of an identical house. What is the most likely location of
the lesion responsible for her difficulties?
A. bilateral fusiform gyri
B. bilateral superior temporal sulcus

PREFERRED RESPONSES
D. right retrosplenial cortex

E. right temporal pole
The correct answer is A. The patient has general visual agnosia. This reflects
involvement of the ventral (occipitotemporal) visual pathway, frequently at
the level of the fusiform gyri, and usually bilateral. For more information,
refer to the article “Disorders of Color and Object Recognition.”
10. A 69-year-old man develops sudden onset of left hemiparesis. His MRI
shows a moderately sized right hemispheric infarct that includes the parietal
lobe. A mild hemiparesis, as well as hemianopia and neglect, is present.
Over 3 months, these signs resolve. Which of the following symptoms
typically would be expected to last longer?
A. left homonymous hemianopia
B. optic ataxia
C. simultanagnosia
D. urinary incontinence
E. visual extinction
The correct answer is E. Subtle symptoms associated with neglect caused by

right hemispheric strokes, such as extinction and motor impersistence, tend
to last longer than visual inattention, hemianopia, and hemiparesis, which
recover more quickly. For more information, refer to the article “Disorders
of Visuospatial Processing.”
11. A 79-year-old man with a past medical history of hepatitis C infection

and diabetes mellitus undergoes right total hip replacement surgery. He
reports visual hallucinations after administration of narcotic analgesics. He is
confused for several days, prompting a neurologic consultation. Which of
the following disturbances of language function would likely be detected on
cognitive testing of this man with delirium?
A. agraphia
B. anomia
196 C. deep alexia
D. hemianopic alexia
E. pure alexia
The correct answer is A. Agraphia is the most common finding in acute

confusional states, including delirium in postoperative geriatric patients. The
term agraphia refers to many types of dysfunction originating from multiple
different left cerebral sites, including spatial disturbances, motor disturbances,
impairments of letter form, spelling, and gross illegibility. For more
information, refer to the article “Reading, Writing, and Their Disorders.”
12. A 55-year-old right-handed salesman is evaluated for progressive

behavioral changes over the past 6 months, leading to interpersonal conflicts
and loss of his job. According to his wife, he started to show little respect
for personal boundaries and seemed unable to perceive social signals.
For example, on several occasions he made inappropriate sexual comments

to his secretary and seemed unable to perceive the expression of discomfort
and embarrassment in her face. He became socially withdrawn and irritable
and unaware of the feelings of others, including his wife and children. What
is the primary location of the lesion producing these behavioral changes?
A. left medial temporal lobe
B. left posterior cingulate cortex
C. left posterior parietal cortex
D. right anterior temporal lobe
E. right inferior parietal lobule
The correct answer is D. The patient’s inability to recognize emotional

expression is consistent with right temporal lobe involvement, as occurs
with the temporal variant of frontotemporal degeneration. This results
in impaired access of social visual signals, such as information about the
emotional expression of faces conveyed from the fusiform gyrus to the
amygdala and orbitofrontal cortex. For more information, refer to the article
“Social Cognition.”
13. A 45-year-old right-handed man is brought to the emergency department

because of abrupt onset of speech difficulties 4 hours earlier. According to
his wife, he started talking nonsense and appeared not to understand what
she was telling him. On examination, he has a well-articulated, fluent, and
prosodic speech but makes frequent phonemic and semantic paraphasic
errors with neologisms. He is unable to name objects, but he can pantomime
their use. The findings are consistent with a lesion in which of the
following areas?
A. angular gyrus
B. entorhinal cortex
C. fusiform gyrus
E. superior posterior temporal gyrus
The correct answer is E. The findings are typical of Wernicke aphasia,

which is associated with infarct involving the posterior portion of the 197
left superior temporal gyrus, which is supplied by the inferior division of
the left middle cerebral artery. For more information, refer to the
article “Comprehension.”
14. A 65-year-old cellist reports the relatively sudden onset of difficulties

with performing previously learned pieces. She also finds it more challenging
to learn new musical pieces. Her neurologic examination reveals no obvious
motor deficits. Tests of episodic and semantic memory appear intact, and
she appears to have memory impairment that is relatively isolated to
procedural memory. Which of the following neuroanatomic areas is most
likely to be involved?
A. anterior thalamic nucleus
B. hippocampus
C. inferior lateral temporal lobes

PREFERRED RESPONSES
D. primary motor cortex

E. supplementary motor area
The correct answer is E. This patient has specific impairment of her

procedural memory system. The major anatomic structures of this memory
system include the supplementary motor area, the cerebellum, and the basal
ganglia. Patients with focal lesions in these areas as well as patients with
degenerative diseases involving these structures, such as Parkinson disease,
spinocerebellar atrophy, and Huntington disease, may show problems
with procedural memory. Procedural memory may be preserved in early
Alzheimer disease despite significant episodic and semantic memory deficits.
15. A 62-year-old right-handed electrician is evaluated for progressive

difficulties with his job because of impaired ability to use the screwdriver,
pliers, and other tools. Examination reveals normal attention, language, and
visuospatial abilities. Motor strength, coordination, and sensation are normal.
He has severe difficulties when asked to pantomime the use of a screwdriver
or a hammer. He is unable to imitate the pantomime when performed by
the examiner and even has trouble using the actual tool. He cannot
discriminate whether the examiner performs the correct pantomime. His
deficit is much worse in his right than left hand. Where is the most likely
location of the lesion?
A. left inferior parietal cortex
B. left orbitofrontal cortex
C. right premotor cortex
D. right superior parietal cortex
E. right supplementary motor area
The correct answer is A. The patient has ideomotor apraxia. This is associated
with lesions involving the left inferior parietal cortex or supplementary
motor area. Inability to discriminate correct from incorrect postures is
consistent with involvement of the left inferior parietal lobule. For more
198
16. A 70-year-old right-handed woman with a 2-year history of mild but
slowly progressive memory difficulties is admitted for acute confusional
state in the setting of a urinary tract infection. Her attention improves
significantly following resolution of the infection with antibiotic therapy.
Which of the following is a physiologic correlate of improved attention in
this patient?
A. decreased activity of intralaminar nuclei of the thalamus
B. decreased cholinergic influence on the reticular nucleus of the thalamus
C. decreased interference with multisynaptic corticocortical pathways
D. increased reticular thalamic input to the dorsolateral prefrontal cortex
E. increased slow, rhythmic activity in the dorsolateral prefrontal cortex
The correct answer is C. The dorsolateral prefrontal cortex is interconnected

with the parietal cortex. They collectively exert a top-down control of the
attentional matrix. The metabolic abnormality of an infection disrupts these

synaptic networks. The resulting confusional state is particularly severe if
the patient also has a degenerative disease causing dementia. For more
information, refer to the article “Attentional and Confusional States.”
17. A 77-year-old woman presents with difficulty finding items in space. Her
visual acuity and visual fields are normal. Eye movements are conjugate and
full. Strength and coordination are normal. However, she cannot reach out
and touch objects in space except by groping around as if blind. Her
examination shows optic ataxia and psychic paralysis of gaze. In order to
meet criteria for diagnosis of Balint syndrome, what other abnormality must
be present on examination?
A. clumsiness of the left hand
B. inaccurate bisection of a line
C. intentional deficit
D. motor impersistence
E. simultanagnosia
The correct answer is E. Simultanagnosia, a disorder in which patients see

only one object or component of an object at a time is one of the cardinal
features of Balint syndrome. It is generally caused by bilateral posterior
cerebral lesions. For more information, refer to the article “Disorders
of Visuospatial Processing.”
18. A 55-year-old right-handed postal worker is evaluated for abrupt onset

of word-finding and reading difficulties. On examination, he has difficulties
reading single words aloud, although he can recognize them if they are
spelled to him. He has the same degree of difficulty reading nouns
(eg, house), function words (eg, when), or pseudowords (eg, frod ). He
is also unable to read letter by letter or name single letters. He has no
difficulty writing words on dictation but is unable to read them. What is the
most likely location of the lesion?
A. left angular gyrus
B. left anterolateral temporal cortex 199
C. left occipital cortex and splenium
D. left supramarginal gyrus and arcuate fasciculus
E. right occipital cortex and splenium
The correct answer is C. The patient has pure alexia, a form of peripheral
alexia associated with lesions in the left temporooccipital cortex, often with
additional damage of the splenium of the corpus callosum. For more
19. A 45-year-old right-handed physician was noted by his colleagues to

have worsening performance at work. He seems to lose track of the patients
during hospital rounds and takes an excessive amount of time making
a decision about the next step of the patient’s evaluation. He has been an
enthusiastic teacher and productive researcher but now has recently had
difficulty organizing his lectures and has not yet finished writing a research

PREFERRED RESPONSES
paper that he started 3 months ago. Involvement of which of the following

structures can result in these symptoms?
A. caudate nucleus
B. posterior cingulate cortex
C. pulvinar
E. tuberomammillary nucleus
The correct answer is A. Lesions affecting the dorsolateral prefrontal circuit

of the basal ganglia, which includes the head of the caudate nucleus, result
in dysexecutive syndrome, characterized by impairment of planning and
organization of complex behavior. For more information, refer to the article
“Executive Resources.”
20. A 45-year-old patient comes for follow-up 4 months after an ischemic

stroke. He reports that after the stroke he lost the pleasurable feeling of
body relaxation that he had previously experienced after smoking a
cigarette, taking a hot shower, or receiving a massage. Which of
the following areas is most likely to be affected?
A. left lateral temporal cortex
B. left occipitotemporal cortex
C. right anterior insula
D. right posterior cingulate cortex
E. right supramarginal gyrus
The correct answer is C. The insula brings interoceptive information into

awareness. Interoceptive information reaches the posterior insula and is
then re-represented in a posterior to anterior fashion to reach the right
anterior insula. Information from frontal and anterior temporal structures
interact with these representations to bring the physiologic condition of the
body into awareness, also likely subserving emotional awareness. For more
information, refer to the article “Social Cognition.”
21. A 65-year-old right-handed woman who had a left hemispheric stroke

200 3 months ago is evaluated for persistent lack of finger dexterity. She has 200
difficulty buttoning her shirt, using a pair of scissors, and playing the
piano despite having recovered the strength in her hand and fingers. On
examination, strength, muscle tone, coordination, and sensation are normal
in all limbs. However, she has difficulty rotating a nickel between her
thumb, index, and middle fingers as rapidly as possible with either hand,
although this is worse with the right hand. Where is the most likely location
of the lesion?
A. anterior cingulate motor area
B. left lateral premotor cortex
C. medial prefrontal cortex
D. postcentral gyrus
E. posterior parietal cortex
The correct answer is B. The patient has limb kinetic apraxia, which is the
loss of dexterity, including the inability to make precise but independent

coordinated movements of the fingers. This reflects damage to the ventral
lateral premotor cortex, which is involved in programming deft finger
movements. In people who are right-handed, left hemisphere injury can
induce ipsilateral as well as contralateral limb kinetic apraxia. For more
22. A 74-year-old man is brought by his wife to the office for neurologic
evaluation because of problems with naming objects. At first his wife
thought that he had problems with deteriorating vision because he reported
progressive difficulty with reading. She noted that he could not recognize
faces of friends but would remember their names when he heard their
voices. However, over the past year, he has shown more evidence of memory
deficits and needs to physically manipulate or hear objects in order to
recognize them. His MRI shows bilateral occipitotemporal atrophy. Which
of the following diagnoses best describes his complete clinical syndrome?
A. alexia without agraphia
B. Balint syndrome
C. optic aphasia
D. posterior cortical atrophy
The correct answer is D. This patient has impaired visual recognition caused
by the ventral form of posterior cortical atrophy. Balint syndrome is associated
with the dorsal form of posterior cortical atrophy. Semantic variant of primary
progressive aphasia is characterized by loss of conceptual knowledge about
items and progressive loss of meaning of speech. Optic aphasia and alexia
without agraphia are characterized by impaired ability to access lexical
semantics from vision. They describe components of his clinical syndrome
but not the entire clinical syndrome. For more information, refer to the
article “Naming and Language Production.”
23. A 66-year-old woman is evaluated for progressive visual difficulties over

the past 2 years. She has had increasing difficulty finding her way in her 201
apartment as she bumps into furniture because she fails to see it. She has
become unable to go shopping as she fails to see more than one item at a
time on the shelf. She incorrectly reaches for utensils on the dinner table
despite being able to see them. Examination shows normal attention span,
learning, and recall. Motor strength and eye movements are full. She
performs normally in the finger-to-nose testing. However, when she
attempts to reach the examiner’s hand, she misses it by several inches. She
is unable to volitionally direct her gaze to a verbally specified target, such as
the door or the examining table. When shown the picture of a kitchen,
she reports only seeing the sink or the refrigerator, but not both. These
manifestations reflect bilateral involvement of which of the following
cortical regions?
A. parietooccipital cortex
B. perirhinal cortex
C. supplementary eye fields

PREFERRED RESPONSES
E. temporooccipital cortex
The correct answer is A. The patient has Balint syndrome, which is typically
associated with bilateral involvement of the parietooccipital cortex. These
lesions interrupt the dorsal visual pathway by which visual information
reaches areas of the superior parietal lobule and intraparietal sulcus,
which are involved in visually guiding reach and saccadic eye movements.
This dorsal attention network also includes the frontal eye fields. The
supplementary eye fields are involved in programming complex saccades. For
more information, refer to the article “Disorders of Visuospatial Processing.”
24. A 66-year-old right-handed painter is evaluated for sudden onset of

visual disturbance. While he was watching a color movie on TV, he noticed
that all the images turned into shades of gray. On examination, his visual
acuity is 20/20 in both eyes with correction. He can read 12 of 14
pseudoisochromatic (Ishihara) plates held at a distance, but he is unable
to discriminate red from green. The rest of his neurologic examination is
normal. This disorder is a manifestation of involvement of which the
following cortical regions?
A. bilateral lingual gyri
B. bilateral superior temporal gyrus
C. left angular gyrus
D. left supramarginal gyrus
E. right precuneus
The correct answer is A. The patient has cerebral achromatopsia. This

is manifestation of bilateral lesions involving the lingual and fusiform gyri;
lesions in the middle third of the lingual gyrus appear to be critical to
produce the syndrome. For more information, refer to the article
“Disorders of Color and Object Recognition.”
25. A 68-year-old cardiothoracic surgeon is brought to the emergency

department because of speech abnormalities. He understands questions
202 well. His speech is fluent, but he makes some phonemic paraphasias. When
asked to describe what he does for a living, he says “I, you know, take
hearts when they are weak and, you know, broken—the pipes are blocked
and I, well, work it and make them go.” Repetition is severely impaired. His
brain MRI is most likely to show an acute infarct in which
of the following areas?
A. left frontal cortex and genu of the corpus callosum
B. left occipital cortex and splenium of the corpus callosum
C. left parietal cortex and underlying white matter
D. left temporal cortex and Meyer loop
E. left thalamus
The correct answer is C. This patient’s speech has features of conduction

aphasia with fluent speech with some phonemic paraphasias, relatively
intact comprehension, and disproportionately impaired repetition ability.

The site of damage usually involves the left supramarginal gyrus (within the
inferior parietal cortex) with or without the arcuate fasciculus. For more
information, refer to the article “Naming and Language Production.”
26. A 74-year-old man with hypertension, hyperlipidemia, and

hypothyroidism presents with new-onset difficulty with reading. He has
become aware of this because he is no longer able to read stories to his
6-year-old granddaughter without errors. He makes substitution errors
on certain words, which make it confusing to follow the story. For
example, he sometimes reads it as and or that as other. He rarely makes
semantic errors when reading. On examination, he is unable to read
pseudowords. Which of the following is the most likely site of the lesion
that would cause this problem?
A. left and right thalami
B. left frontal premotor region
C. left parietooccipital junction
D. left perisylvian region
E. right insular cortex
The correct answer is D. This patient has phonologic alexia, which is

characterized by difficulty reading words of low semantic value, such as
function words and pseudowords. These patients read concrete words
well and tend not to make semantic errors. Phonologic alexia is often
associated with perisylvian regions of the left hemisphere. For more
27. A 40-year-old right-handed businessman is evaluated for abrupt onset of

inability to recognize people by their faces. Although he can recognize faces
as such, he relies on clues, such as the voices or mannerisms of his wife,
children, or coworkers, to identify the person. He cannot identify his parents
in family pictures and identifies only 3 of 20 famous faces despite his ability
to tell why they are famous after being given their names. Strikingly, he
hesitates to answer and becomes sweaty and tachycardic while watching the 203
facial expression of fear in a picture of his 3-year-old daughter. Preservation
of what brain region may explain his emotional reaction to facial expression?
A. angular gyrus
B. intraparietal sulcus
C. orbitofrontal cortex
E. superior temporal sulcus
The correct answer is E. The patient has prosopagnosia, which is commonly

associated with bilateral lesions affecting the fusiform gyrus and/or the
anterior temporal lobe. Processing of facial expressions may involve
different brain networks than the processing of identity; most likely the
superior temporal sulcus and amygdala are involved. For more information,
refer to the article “Disorders of Color and Object Recognition.”

PREFERRED RESPONSES
28. A 73-year-old, right-handed, retired clerk is evaluated for confusion that

developed over the past 2 days. He has a history of high cholesterol and is
on rosuvastatin and tolterodine. He has a history of depression, and spastic
bladder for which amitriptyline was begun 3 days ago. On examination, he
is inattentive, incoherent, and unable to write to dictation or draw a clock.
His pupils are dilated and poorly reactive to light, and his heart rate is
110 beats/min. Which of the following is the most likely cause of confusional
state in this patient?
A. blockade of inputs from the laterodorsal tegmental nucleus to
the thalamus
B. blockade of ventral tegmental inputs to the cerebral cortex
C. excessive influence of the dorsal raphe nucleus on the thalamus
D. excessive influence of the locus ceruleus on the cerebral cortex
E. excessive influence of the tuberomammillary nucleus on the thalamus
The correct answer is A. The patient’s acute confusional state results from
blockade of cholinergic receptors by amitriptyline and tolterodine. These
receptors mediate the excitatory effects of cholinergic inputs from the
laterodorsal and pedunculopontine tegmental nucleus on thalamocortical
neurons, which are critical for attention as they promote transfer of
information from the thalamus to the cerebral cortex. For more information,
refer to the article “Attentional and Confusional States.”
29. A 72-year-old man presents with a report of difficulties understanding

the speech of others. He says that even the speech of his wife of 40 years
sounds like an unfamiliar foreign language. He used to be able to identify
60 different bird calls, but now they all sound the same to him. He has no
other deficits. Where is the most likely localization of this problem?
A. bilateral temporal lobes
B. Broca area
C. left dorsal temporooccipital junction
D. right mesial occipitotemporal region
E. right temporal lobe
204 The correct answer is A. This patient has pure word deafness, which is 204
characterized by a deficit in the ability to understand speech despite
otherwise intact language abilities. This syndrome occurs with bilateral
temporal damage or occasionally after left temporal damage in which
a significant disconnection occurs between Heschl gyrus and the underlying
structures. For more information, refer to the article “Comprehension.”
30. A 68-year-old man with history of hypertension and diabetes mellitus is

evaluated for progressive memory decline over the past 16 months. He
tends to repeat the same questions and forgets his medications. His wife is
concerned because once he was unable to recognize a new neighbor who
had visited them the day before and on another occasion could not
recognize a new necktie that had been given to him as a birthday present
the same morning. On examination, he recalls 7/10 words on the third
immediate recall trial of a verbal memory task, but his delayed recall is

0/10. He recognizes 4/10 items on a list. He performs in the normal range
on tests of attention, executive function, language, and visuospatial ability.
Involvement of which of the following areas of the cortex that has been
implicated in recognition memory is most likely to be affected by the
degenerative process in this patient?
A. anterior cingulate involvement
B. medial temporal involvement
C. orbitofrontal involvement
D. posterior insular involvement
E. superior parietal involvement
The correct answer is B. This patient has impairment of the medial temporal
memory system, as occurs with amnestic mild cognitive impairment. The
impaired recognition memory indicates involvement of the perirhinal cortex.
31. An 84-year-old woman presents with bilateral strokes involving the

lateral temporoparietal regions. Which of the following neurologic deficits
could be associated with such a stroke?
A. achromatopsia
B. akinetopsia
C. alexia without agraphia
D. prosopagnosia
E. visual agnosia
The correct answer is B. Akinetopsia may be seen with lesions involving the
occipitoparietal cortex and the dorsal occipitoparietal processing stream.
All of the other options are deficits that are caused by lesions involving the
ventral processing stream via the inferior and medial occipitotemporal
cortex. For more information, refer to the article “Disorders of Color and
Object Recognition.”
32. A 70-year-old man is a subject in a neuropsychological study that

involves vigilance and attention to multimodal sensory stimuli. Pathways
from the reticular formation of the brainstem influence the transmission and 205
integration of the neural information by projection to all of the nuclei of
the thalamus. Which thalamic nucleus does not project to the cerebral
cortex and inhibits the other thalamic nuclei through γ-aminobutyric
acid–ergic projections?
A. anterodorsal
B. interlaminar
C. medial dorsal
D. pulvinar
E. reticular
The correct answer is E. The reticular nucleus of the thalamus receives

projections from the brainstem and the cerebral cortex but does not project
back to the cerebral cortex. It inhibits the activity of other thalamic nuclei
through γ-aminobutyric acid– ergic projections. Cholinergic innervation from

PREFERRED RESPONSES
the brainstem has an excitatory influence on all of the thalamic nuclei

except for the reticular nucleus, which is inhibited. Therefore, activation of
these cholinergic projections releases specific thalamic nuclei from the
inhibition of the reticular nucleus, facilitating thalamocortical transmission.
The reticular nucleus appears to act as an attentional valve to regulate
thalamocortical transmission. For more information, refer to the article
“Attentional and Confusional States.”
33. A 75-year-old, right-handed, retired accountant is evaluated for

progressive forgetfulness. Two years ago, his wife took over the household
finances after he had often forgotten to pay the bills and had bounced
several checks. More recently, he seems to lose track of what he intends to
say during conversations with his family and friends. His wife has noticed
that he is unable to retain phone numbers that he has just read in the
phone book in order to make a call. Despite his difficulties, he remains a
pleasant, responsible, caring member of his family. On examination, he is alert
and fully oriented. His digit span is five forward and two in reverse. He is
unable to spell world backwards or recite the months of the year in reverse
order. When asked to list items starting with F in 1 minute, he is able to
produce only six, with multiple repetitions. Which is the most likely location
of the lesion?
A. anterior cingulate cortex
B. lateral prefrontal cortex
C. lateral temporal cortex
D. orbitomedial prefrontal cortex
E. parahippocampal cortex
The correct answer is B. The patient has difficulties with working memory,
both in terms of online maintenance of information (involving primarily the
ventrolateral prefrontal cortex) and monitoring and manipulation of this
information (involving the dorsolateral prefrontal cortex). For more
information, refer to the article “Executive Resources.”
34. A 45-year-old, right-handed, now disabled journalist is evaluated for

206 persistent difficulties reading following a left hemisphere stroke. She has a 206
mild residual fluent aphasia with difficulty naming and with comprehending
and repeating. She has no major difficulty reading real words (eg, tub) or
pseudowords (eg, mub). However, she has severe difficulty reading
irregular words. For example, she reports the word choir as chore and
reads and interprets the pseudoword fraim as the real word frame. Which
of the following is the term used to describe this disorder?
A. apperceptive alexia
B. deep alexia
C. peripheral alexia
D. phonologic alexia
E. surface alexia
The correct answer is E. The patient has surface alexia, one form of central
or linguistic alexia. The hallmark error in surface alexia is the difficulty
reading irregular words because of impaired ability to translate irregular
orthography to phonology. Phonologic alexia is characterized by difficulty

reading words of low semantic value, such as function words and words of
no semantic value (pseudowords), with preserved ability to read concrete
words. Deep alexia is a similar disorder, but patients also make semantic
errors. For more information, refer to the article “Reading, Writing, and
Their Disorders.”
35. A 68-year-old, right-handed, retired administrator is evaluated for

increasing difficulties remembering names of people and objects over the
past 2 years. She has also experienced difficulty communicating clearly with
her family and friends and finding items in the grocery store despite using a
shopping list. On examination, she is alert and oriented. Her speech is
fluent but characterized by circumlocution and paucity of content, particularly
nouns. She is unable to name famous people, animals, or objects, even after
cueing by their description. Multiple choice does not help naming. She is
unable to name a coin placed on her hand or pantomime the use of
objects. Speech comprehension is mildly impaired, and repetition is spared.
Impairment of which of the following processes is the most likely
mechanism of anomia in this patient?
A. difficulty selecting word forms
B. impaired recognition memory
C. impaired retrieval strategies
D. impaired visual recognition
E. loss of semantic knowledge
The correct answer is E. The clinical features are those of semantic

variant of primary progressive aphasia. For more information, refer to
the article “Comprehension.”
36. A 54-year-old man with diabetes and hypertension is examined after

presenting with mild aphasia. When asked to demonstrate how he would
use a pen to write, he appears puzzled and is unable to complete the task.
When he is shown a pen, however, he can correctly perform a pantomime
of writing. Which of the following is the correct term for this type of apraxia?
A. dissociation
B. ideational 207
C. ideomotor
D. limb-kinetic
E. tool selection deficit
The correct answer is A. This patient displays dissociation apraxia, in which

he is unable to pantomime the use of a pen with a verbal command prompt
but can perform the act when presented with the visual input of a pen. For
more information, refer to the article “Apraxia.”
37. One of the memory systems allows us to remember past experiences

and specific events in our lives. This type of memory involves self-knowing
consciousness and an integrated recollection of the individual’s own
experience of an event and is tightly linked to a sense of time. Which of
the following is the correct term for this type of memory?
A. associative
B. episodic

PREFERRED RESPONSES
C. procedural
D. semantic
E. working
The correct answer is B. Episodic memory is one type of declarative memory

that involves conscious awareness of specific past experiences in an
individual’s life. Episodic memory is declarative and explicit and may be
stored from minutes to years. It is subserved by anatomic structures that
include the medial temporal lobes, anterior thalamic nucleus, mammillary
bodies, fornix, and prefrontal cortex. For more information, refer to the
article “Memory Systems.”
38. A 45-year-old woman has survived a severe case of herpes encephalitis.

After months of rehabilitation, her cognition is still severely impaired. She is
emotionally detached from her family and friends and sometimes fails to
recognize their faces or voices. She does not seem to be able to read the
mood of her family or caretakers. Injury to which of the following structures
is most closely implicated as the cause of this type of socioemotional deficit?
A. caudate nucleus
B. fusiform gyrus
C. hippocampus
D. insula
E. temporal poles
The correct answer is E. The temporal poles, the most anterior parts of the
temporal lobes, seem to link polymodal perceptual representations with
person-specific knowledge. People who have undergone surgical resection
of the right anterior temporal lobe or have injury to this area sometimes
fail to recognize both familiar faces and voices and may lose emotional
attachments of family and friends. For more information, refer to the
article “Social Cognition.”
39. A 60-year-old right-handed woman is evaluated for a 1-year history of

progressive visual difficulties. She first noticed difficulties completing jigsaw
208 puzzles as she was unable to see all the pieces on the table. More recently
she has noticed difficulties reading words, even though she is able to read
individual letters and numbers. Over the past 6 months she has found it
hard to recognize faces in her family photo album. Examination shows
normal digit span, language, and memory functions. Her visual acuity and
visual fields on confrontation testing are normal. She can read single letters
rapidly but hesitates with words. She is unable to produce volitional
saccadic eye movements toward a verbally specified target in the examining
room. She also has difficulty recognizing faces of famous people. When
presented with a complex picture that she had seen before, she can name
several of the items in it but not give a coherent description of the whole.
The MRI of the head shows bilateral posterior cortical atrophy. Which of the
following is the most likely underlying cause?
B. amyotrophic lateral sclerosis
C. Creutzfeldt-Jakob disease

D. Lewy body disease
E. progressive supranuclear palsy
The correct answer is A. The involvement of both the occipitotemporal

(ventral) visual stream (prosopagnosia and alexia) and occipitoparietal
(dorsal) visual stream (simultanagnosia) is typical of posterior cortical
atrophy, as documented on MRI. Although several degenerative dementias
can produce this syndrome, several studies suggest that Alzheimer disease
is the most common cause. For more information, refer to the article
“Disorders of Visuospatial Processing.”
40. A 74-year-old right-handed woman is evaluated for slowly progressive

speech difficulty over the past 6 years. On examination, her speech
articulation is effortful, with distorted speech sounds, and is limited to
nouns or short phrases. She makes sound substitution errors in spontaneous
speech, naming, and repetition, feels frustrated, and self-corrects them. She
has good comprehension of single words but has trouble understanding
syntactically complex sentences. The rest of the neurologic examination,
including mental status examination, is normal. Which of the following is
A. left insula and posterior inferior frontal cortex
B. left medial frontal cortex
D. right anterior temporal cortex
E. right superior temporal cortex
The correct answer is A. The patient has apraxia of speech and agrammatic/
nonfluent variant of primary progressive aphasia. The cause is atrophy in
the left posterior inferior frontal cortex and insula, which, in general, is
associated with tau deposition. For more information, refer to the article
“Naming and Language Production.”
209

INDEX
central, 60f
classification of, 64
deep, 64– 65
delirium and, 64
Page numbers in boldface type indicate major
discussions. Letters after page numbers refer to the diagnosis and treatment of, 60
following: c = case study; f = figure; r = reference; linguistic, 64 – 65
t = table. lexical agraphia, 65, 66c
phonologic agraphia, 64 – 65, 65c
semantic agraphia, 65
peripheral, 60, 60f, 64, 65 – 66
apraxic agraphia, 65 – 66, 66c, 86
other types of, 66
A pure, 60
ACC. See Anterior cingulate cortex sensory/motor systems and, 59–60, 60f
Acetylcholine deficits, memory impairment due to, 22, 27r Akinetopsia, 112
Acetylcholinesterase inhibitors, 156, 160, 174, 174r Alexia(s), 59 – 63, 66r– 67r
Achromatopsia, cerebral, 111, 112–114, 113c, 123r–124r achromatopsia and, 113
anatomic basis of, 112 – 113 agraphia and, 59
color function remaining in, 112 aphasia and, 59, 60
definitions related to, 112 assessment for, 60
effect on color constancy, 112 brain regions involved in, 61, 62f
other signs associated with, 113 –114 central, 60f
prosopagnosia and, 119 deep, 63
symptoms and signs of, 112 diagnosis and treatment of, 60
tests for, 112 global, 61
Acute confusional state, 128 – 131 impaired reading comprehension and, 63
cognitive and behavioral disturbances associated with, linguistic, 62 – 63
129, 130 phonologic alexia, 62 – 63, 63c, 66c
core features of, 130 peripheral, 60, 60f, 61–62
dementia and, 130–131 hemianopic alexia, 61–62, 62c
as disorder of attentional matrix, 128, 129 – 131 pure alexia, 60, 61, 61c
due to toxic-metabolic encephalopathies, 129 –131 sensory/motor systems and, 59– 60, 60f
in elderly persons, 130, 131c surface, 63
recovery from, 130, 131c without agraphia, 111
AD. See Alzheimer disease Allocentric movement errors, 89, 90
Adopting another’s perspective, 79 – 80, 84r Allocentric navigation, 122
Advance directives, 162, 164r Allographic store, disruption of, 66
Affective lability, in acute confusional states, 130 Alzheimer disease (AD)
Agitation, in acute confusional states, 129, 130 acetylcholine deficit in, 22
Agnosia acute confusional state and, 130
color, 114 APOE genotyping for, 156, 161
landmark, 121–122 attentional deficits in, 129
210 phonagnosia, 47 conceptual apraxia in, 96r
prosopagnosia, 111 executive dysfunction in, 143, 146c, 147
in semantic variant of primary progressive aphasia, ideomotor apraxia in, 92
56, 73 memory impairment in, 15, 17c, 20, 22, 25, 27r –28r
simultanagnosia, 99, 104 – 106, 105c neuropathology of, 20, 22
topographagnosia, 111, 121 – 122, 123c frontal lobe dysfunction and, 21
visual, 124r – 125r medial temporal lobe pathology, 20, 43r
apperceptive, 30–31, 31c, 36, 114 –116, 115c semantic deficits in, 54–55
associative, 32, 36, 114, 116 –117 social cognition and, 71c
general, 111, 114 –117 transcortical sensory aphasia in, 38c
integrative, 116 visual variant of, 99, 106 –107, 110r
semantic, 116 Amygdala
semantic access, 116 in emotion reappraisal, 81
visual word-form, 111 in emotional face processing, 82r
Agrammatism, in Broca aphasia, 50, 51c in recognizing social salience of environmental stimuli,
Agraphia(s), 59, 63 – 66, 67r– 68r 72, 73, 82r
alexia and, 59 β-Amyloid protein, 20, 27r
aphasia and, 59, 60 Anomia, 33, 34c, 44r, 57r
assessment for, 60 in acute confusional states, 130
brain regions involved in, 63 – 64 color, 114, 124r

diseases and sites of lesions associated with, 36 – 37 general, 86
semantic, 49 ideational, 86, 87, 88c
Anosognosia clinical description of, 87
for hemiplegia, 101, 108r pathophysiology of, 87
in Wernicke aphasia, 48 tests for, 87
Anterior cingulate cortex (ACC), 82r ideomotor, 86, 87, 89– 94, 90c
in emotion reappraisal, 81 clinical description of, 89– 90, 90r
in emotion recognition and subjective experience of pathophysiology of, 91– 94
emotion, 74, 76 –77 tests for, 90–91
in recognizing social salience of environmental stimuli, innervatory, 95
72 –73 lesion sites and diseases associated with, 86 – 87,
social and emotional deficits due to lesions of, 85r 87f
Anterior thalamic nucleus lesions, memory impairment limb-kinetic, 86, 94 – 95, 95c
due to, 20– 21 clinical description of, 94– 95
Anterograde amnesia, 18, 19 pathophysiology of, 95
Antidepressants, 160 tests for, 95
Antiepileptics, 160 myelokinetic, 95
Antipsychotics, 160, 173, 174r of speech, 35, 37
Antisaccade test, 146 –147, 152r task-specific, 86
Anxiety, neural basis of self-ratings of, 74 visuo-imitative, 94
Apathy, in acute confusional states, 130 Apraxic agraphia, 65–66, 66c, 86
Aphasia, 42r – 44r, 57r–58r ARAS. See Ascending reticular activating system
alexia and, 59, 60, 62 Arousal
anomic, 33, 34f, 36 – 37 attention and, 128, 130
Broca, 36, 39t, 41c, 47, 50, 51c autonomic, 72 –73
conduction, 39t Ascending reticular activating system (ARAS)
global, 39t in modulation of attention, 128, 129f, 131, 133 –135
mixed transcortical, 39t reticulo-thalamocortical pathway of, 133 –134
optic, 31c, 32, 33c, 36, 39t, 43r, 125r transmitter-specific transthalamic pathways of, 133,
primary progressive, 42r – 44r, 58r 134 –135
logopenic/phonologic variant of, 38, 40c, 40t Association regions, unimodal and heteromodal, 47
nonfluent/agrammatic variant of, 35c, 37, 40t Associative prosopagnosia, 119
semantic variant of, 23c, 25, 32c, 36, 38, 40t, 51, Associative visual agnosia, 32, 114, 116 –117
53c –54c, 55, 73 –74, 75c–76c, 153 –162, 162r–164r diseases and sites of lesions associated with, 36
sites of damage and etiologies of, 40t Astereopsis, 112
sites of damage and etiologies of, 39t Attention, 128 –137, 137r–139r
transcortical motor, 39t arousal and, 128, 130
transcortical sensory, 38, 38c, 39t, 49 – 50, 49f deficits of, 128, 129
Wernicke, 32c, 36, 38, 39t, 43r, 46, 47– 49, 48c, 49f, in Alzheimer disease, 129
50, 51–52 in toxic-metabolic encephalopathies, 129 –131
Apolipoprotein E 4 genotyping, 156, 161 definition of, 128
Apperceptive prosopagnosia, 119 modulation of, 128, 129f
Apperceptive visual agnosia, 30–31, 31c, 114 –116, domain-independent, 128, 133 –135 211
115c domain-specific, 128, 132 –133
diseases and sites of lesions associated with, 36 spatial, 100, 129
Apraxia, 86 –95, 95r – 98r tests of, 129 –130
causes of, 86 – 87 Attentional matrix, 128–129
conceptual, 86, 87– 89, 88c acute confusional state as disorder of, 128, 129 –131
clinical description of, 87– 88 biology of, 131–136
mechanical advantage knowledge deficit, 88, 89 ascending reticular activating system, 128, 129f,
pathophysiology of, 89 131, 133 –135
problem unawareness, 88 – 89 domain-specific attentional modulation in cerebral
tests for, 88 – 89 cortex, 128, 132 –133
tool-selection deficit, 88, 89 frontal lobes, 135 –136
conduction, 94 Attribution of agency, 77–79, 84r
constructional, 86 Auditory agnosia, 47
definition of, 86 Auditory association regions, 46
dissociation, 94c, 86, 87, 94 Autobiographic memory, 25
clinical description of, 94 Autonomic arousal
pathophysiology of, 94 anterior cingulate cortex in, 72 –73
tests for, 94 temporal poles in, 73
dressing, 86 Autonomy of patient, 168

B nonfluent/agrammatic variant, 35c

semantic variant, 23c, 32c, 53c–54c, 75c–76c
Balint syndrome, 31, 103, 105c, 109r, 112 prosopagnosia, 31c, 118c
optic ataxia, 99, 103 – 104 pure alexia, 61c
simultanagnosia, 99, 104 – 106 topographagnosia, 123c
Basal forebrain, in episodic memory, 22 transcortical sensory aphasia, 38c
Basal ganglia Wernicke aphasia, 48c
in executive functioning, 141 Category fluency deficits, 23c, 24
ideomotor apraxia due to lesions of, 93 Cerebellum, in procedural memory, 15, 16t, 25–26
in procedural memory, 15, 16t, 25 –26, 28r Cerebral achromatopsia, 111, 112 –114, 113c, 123r–124r
Behavioral regulation, 80 – 81, 85r anatomic basis of, 112–113
Behavioral variant of frontotemporal dementia (bvFTD), color function remaining in, 112
73, 74, 77, 77c –78c, 83r, 84r, 144, 157 definitions related to, 112
Beneficence, 168 effect on color constancy, 112
Body language and perception of social signals, 70 other signs associated with, 113–114
Body part as tool errors (BPTEs), 90, 96r prosopagnosia and, 119
Boston Naming Test, 23c symptoms and signs of, 112
BPTEs (body part as tool errors), 90, 96r tests for, 112
Broca aphasia, 36, 39t, 41c, 47, 50, 51c, 57r Cholinesterase inhibitors, 156, 160, 174, 174r
Broca area, 47, 49f, 50 Cingulate gyrus lesions, memory impairment due to, 20
bvFTD (behavioral variant of frontotemporal Clock-drawing test, 131c, 131f
degeneration), 73, 74, 77, 77c –78c, 83r, 84r, 144, 157 Coding tables, 175–177
Cognitive and emotional perspective taking, 80, 84r
Cognitive flexibility, 145 –147
C assessment of, 147, 152r
Callosum disconnection, ideomotor apraxia and, 91, 96r set-shifting, 146
Cambridge face memory test, 117 Cognitive function, optimization of, 170 –174, 174r
Cancellation tasks, 101 cholinesterase inhibitors, 174
Carbidopa/levodopa, for restless legs syndrome, 173 drugs to avoid, 172
Case studies palliative/symptomatic treatment, 174
acute confusional state, 131c treating disorders that may worsen impairment, 172–173
alexia and optic aphasia, 33c treating underlying causes, 171–172
Alzheimer disease and social cognition, 71c Cognitive map formation, 122, 122f
anomic aphasia, 34c Cognitive processes underlying naming, 29, 30 – 37,
apperceptive visual agnosia, 31c, 115c 30f
apraxia Cognitive theory of mind, 80, 143–144, 151r
conceptual, 89c Coin-rotation task, 95
dissociation, 94c Color perception, 111–114, 123r–124r
ideational, 88c cerebral achromatopsia, 112 – 114, 113c
ideomotor, 90c color agnosia, 114
limb-kinetic, 95c color anomia, 114
Balint syndrome, 105c color constancy, 112
212 behavioral variant of frontotemporal degeneration, color dysphasia, 114
77c–78c Comprehension, 45 – 56, 56r–58r
Broca aphasia, 41c, 51c definition of, 45
discourse after middle cerebral artery stroke, 41c evaluation of, 55–56
episodic memory impairment, 17c functional neuroanatomy of, 45–46
executive dysfunction of language, 46 – 49
inhibitory control, 146c impairments of phonetic and phonologic
planning and organizing, 144c comprehension, 47
working memory, 142c pure word deafness, 47
hemiachromatopsia, 113c speech perception, 46– 47
hemianopic alexia, 62c Wernicke aphasia, 47– 49, 48c
impaired lexical semantics, 32c neuropsychological assessment of, 56
lexical agraphia, 66c reading, 63
neglect syndrome, 101c semantic, 49 –55
optimizing cognitive function in cognitively fragile comprehension of semantic knowledge about
patient, 171c concrete entities, 52–55, 53c–54c
phonologic agraphia, 65c comprehension of sentences and discourse, 50–52,
phonologic alexia, 63c, 66c 51c
primary progressive aphasia comprehension of syntax, 50
logopenic/phonologic variant, 40c comprehension of words, 49–50, 49f

Computed tomography (CT), in disorders of written Disorientation
language, 65c, 66c in acute confusional states, 129, 130
Concentration, 128 topographic, 121–122, 123c, 126r–127r
Conceptual apraxia, 86, 87– 89, 88c, 96r egocentric, 122
clinical description of, 87– 88 heading, 122
mechanical advantage knowledge deficit, 88, 89 Dissociation apraxia, 86, 87, 94, 94c, 97r
pathophysiology of, 89 clinical description of, 94
problem unawareness, 88 – 89 pathophysiology of, 94
tests for, 88 – 89 tests for, 94
tool-selection deficit, 88, 89 verbal, 94
Conceptual knowledge disorders, 55 Distractibility, 128, 130
Conduction aphasia, 39t Distributive justice, 168
Conduction apraxia, 94 Donepezil, 156, 160, 174r
Confabulation, 21 Dot-counting task, 107
Confusion. See Acute confusional state Drawing tasks, for neglect, 101
Constructional apraxia, 86 Dressing apraxia, 86
Continuous positive airway pressure (CPAP), 173 Driving, 161
Convexity premotor cortex lesions, ideomotor apraxia Dysarthria
due to, 93 sites of lesions associated with, 37
Cortical deafness, 47 vs apraxia of speech, 35
Corticobasal degeneration, visuospatial processing Dyscalculia, 130
disorders in, 106 Dyschromatopsia, 112, 124r
CPAP (continuous positive airway pressure), 173 prosopagnosia and, 118c
CT (computed tomography), in disorders of written Dysgraphia, 130. See also Agraphia(s)
language, 65c, 66c Dyslexia. See Alexia(s)
D E
D-15 test, 112 Echolalia, 145, 146c
Deafness Echopraxia, 145, 146c
cortical, 47 Egocentric disorientation, 122
pure word, 47 Egocentric movement errors, 89
Declarative (explicit) memory, 16, 16t Elderly persons, acute confusional state in, 130, 131c
Delirium, 129. See also Acute confusional state Emotional functioning
agraphia and, 64 cognitive and emotional perspective taking, 80, 84r
Dementia. See also Alzheimer disease emotion reappraisal and behavioral regulation,
acute confusional states and, 130 –131 80–81, 85r
depression and, 172 emotion recognition and subjective experience of
executive dysfunction in, 143, 146c, 147, 148t emotion, 74 –77
ideomotor apraxia in, 92 mirror neurons in emotion sharing, 76 213
optimizing cognitive function in, 170 – 174, 174r in semantic variant of primary progressive aphasia, 74
cholinesterase inhibitors, 174 social cognition and, 69, 70
drugs to avoid, 172 temporal poles in, 73
palliative/symptomatic treatment, 174 Environmental sound agnosia, 47
treating disorders that may worsen impairment, Environmental stimuli, recognizing salience of, 70 –74
172 –173 Episodic memory, 15, 16, 16t, 17–23, 26r–28r
treating underlying causes, 171–172 associative memory, 17–18
semantic (See Semantic variant of primary progressive source memory and, 18
aphasia) testing of, 18
sleep disorders and, 172–173 autobiographic memory, 25
theory of mind and, 144 consolidation of, 18
visuospatial processing disorders in, 99, 106 –107 definition of, 17
Depression, 172 encoding of, 18
Digit Span Test, 129, 143 familiarity vs recollection, 18, 26r
Discounting the illuminant, 112 functional neuroanatomy of, 15, 18 –23, 19f
Discourse, 29, 40 – 41 extended medial temporal memory system, 20–21
comprehension of, 50– 52 frontal lobes, 21–22, 22t
coherence, 52 medial temporal lobe, 18–20, 20f, 22t
middle cerebral artery stroke and, 41, 41c other regions, 22–23

impairment of, 17c

Henry Molaison (HM) case of, 15–16, 18, 24
G
item memory, 17 Galantamine, 160
overlap between semantic memory and, 25 Gaze-dependent hemianopia, 102, 108r
retrieval of, 18 Gerstmann syndrome, 114
Ethical issues: neuroenhancement therapy, 165 –168, Global aphasia, 39t
168r–169r Go-no-go task, 147, 152r
Executive dysfunction Grapheme production, disruption of, 66
conditions associated with, 141, 147, 148t
language and, 143
manifestations of, 140 –141
Executive function, 140 –149, 149r–152r
H
behaviors supported by, 140 Hallucinations, in acute confusional states, 129, 130
comprehension and, 45 Heading disorientation, 122
definition of, 140 Health care power of attorney, 162
essential aspects of, 140, 141, 149 Hemiachromatopsia, 112, 113c, 123r
inhibitory control and cognitive flexibility, 145–147 prosopagnosia and, 119
planning and organizing of behavior, 143–145 Hemianopia
working memory, 141–143 gaze-dependent, 102, 108r
neural basis of, 140, 141 homonymous, 48c, 49
testing of, 141 color anomia and, 114
underlying mechanisms of, 141 Hemianopic alexia, 61–62, 62c
Extrastriate body area, in perception of social signals, 70 Hemiplegia, anosognosia for, 101, 108r
Heteromodal association regions, 47
Hippocampus
in Alzheimer disease, 27r
F in episodic memory, 15, 17c, 18
Face processing, 70, 82r, 83r memory impairment due to lesions of, 17c, 18, 20, 26r
disorders of, 117– 120, 125r–126r new semantic memory formation, 25
face expression deficits without prosopagnosia, 120 in topographagnosia, 122, 122f
false recognition of faces, 120 Homonymous hemianopsia, 48c, 49
people-specific amnesia, 120 color anomia and, 114
prosopagnosia, 31c, 111, 117–120, 118c, 120f, 121f Hue perception tests, 112
neural basis of, 72–73 Human selective voice area, 70
Farnsworth-Munsell 100 color test, 112 Huntington disease, 141, 149r
fMRI. See Magnetic resonance imaging, functional
Forelimb apraxia. See Apraxia
Fornices, memory impairment due to lesions of, 20
Frontal lobes. See also Prefrontal cortex
I
in comprehension of syntax, 50 ICD-9-CM (International Classification of Diseases) codes,
in episodic memory, 21–22, 27r 175 –177
vs medial temporal lobe dysfunction, 22, 22t Ideational apraxia, 86, 87, 88c, 96r
214 in executive function, 140, 141, 149r–152r clinical description of, 87
inhibitory control, 146 –147 pathophysiology of, 87
planning and organizing, 144 –145 tests for, 87
working memory, 135, 142 Ideomotor apraxia (IMA), 86, 87, 89–94, 90c, 96r–97r
in modulation of attention, 135–136 clinical description of, 89–90, 90r
in phonetic and phonologic comprehension, 47 allocentric movement errors, 89, 90
Frontotemporal degeneration (FTD), 83r, 84r body part as tool errors, 90
behavioral variant of (bvFTD), 73, 74, 77, 77c–78c, egocentric movement errors, 89
144, 157 internal configuration errors, 89
difficulty with planning and organizing in, 143, 144 –145 pathophysiology of, 91–94
discourse impairment in, 150r basal ganglia and thalamus, 93–94
heritability of, 161, 163r callosal disconnection, 91
patient management problem on, 153–162, 162r–164r convexity premotor cortex, 93
theory of mind and, 144, 151r left hemisphere injury, 91–92
Functional magnetic resonance imaging. See Magnetic supplementary motor area, 92–93
resonance imaging, functional tests for, 90–91
Fusiform face area, 70, 72, 82r, 119, 120f, 126r Illusions, in acute confusional states, 130
Fusiform gyrus lesions IMA. See Ideomotor apraxia
achromatopsia and, 112 – 113 Impersistence, 128
prosopagnosia and, 119 Infectious disease, executive dysfunction due to, 148t

Inferolateral temporal lobes ideomotor apraxia and, 91– 92
naming deficits due to lesions of, 32c limb-kinetic apraxia and, 95
in semantic memory, 15, 24, 24f neglect syndrome and, 101
Inhibitory control, 140, 141, 145 – 147, 152r Lemmas, impaired access to
anatomy of, 146 –147 diseases and sites of lesions associated with, 36–37
aspects of, 145 modality-independent, 33, 34c
assessment of, 147 modality-specific, 33–35, 35c
definition of, 145 Lewy body dementia, 106, 147
race model of, 145 –146 Lexeme processing, 46
set shifting and, 146 Lexical agraphia, 65, 66c, 68r
Innervatory apraxia, 95 Lexical representation
Insomnia, dementia and, 173 orthographic, 34
Insula, 82r phonologic, 33–34
in emotion reappraisal, 81 semantic, 33
in emotion recognition and subjective experience of Lexical semantic processing
emotion, 74, 76 –77 assessment of, 56
in recognizing social salience of environmental stimuli, impairment of, 31–32, 32c, 33c
72–73 diseases and sites of lesions associated with, 36
Integrative visual agnosia, 116, 125r Limb-kinetic apraxia, 86, 94 –95, 95c, 97r– 98r
Internal configuration errors, 89 clinical description of, 94–95
International Classification of Diseases (ICD-9-CM) codes, pathophysiology of, 95
175–177 tests for, 95
Interoceptive information, 72, 83r Limbic motor cortex, 72
Isolation of speech, 47 Limbic sensory cortex, 72
Limbic system
in memory, 15
in modulation of attention, 136
J Line bisection tasks, 101
Lingual gyrus lesions
Jargon speech, 38, 38c achromatopsia and, 112–113
Judgment impairment prosopagnosia and, 119
acute confusional state with, 130 Linguistic agraphias, 64 – 65
executive dysfunction with, 140 –141 lexical agraphia, 65, 66c
phonologic agraphia, 64–65, 65c
semantic agraphia, 65, 68r
Linguistic alexias, 62– 63
K Luria alternating hand sequence task, 147
Kluver-Bucy syndrome, 83
Korsakoff syndrome, 20, 21, 27r
M
Magnetic resonance imaging (MRI), 56r 215
L in amnestic mild cognitive impairment, 17f
Landmark agnosia, 121–122 in anomic aphasia, 34f
Language comprehension, 45, 46 – 49, 56r–58r in apperceptive visual agnosia, 115, 115f
impairments of phonetic and phonologic in behavioral variant of frontotemporal degeneration,
comprehension, 47 77f, 78
in pure word deafness, 47 in Broca aphasia, 41c, 51f
speech perception, 46 – 47 in hemiachromatopsia, 113, 113f
in Wernicke aphasia, 47– 49, 48c of posterior cortical atrophy, 71c, 71f
Language production, 29– 42, 42r – 44r in prosopagnosia, 118, 118f, 121f
evaluation of, 41– 42 in semantic memory impairment, 23c, 23f, 32c
executive dysfunction and, 143, 150r –151r in semantic variant of primary progressive aphasia,
management of deficits in, 42 53f, 75f, 76, 155, 155f, 158 –159
naming, 29– 37 in Wernicke aphasia, 48f
sentence production, 29, 37– 41 Magnetic resonance imaging, functional (fMRI), 56r
Left hemisphere lesions of brain networks involved in social cognition, 70, 72,
conceptual apraxia and, 89 80, 81
disorders of written language and, 59, 63 – 64 of brain regions activated during naming, 30f
dissociation apraxia and, 94 of cognitive map formation, 122f, 123c
ideational apraxia and, 87 of comprehension of discourse, 51, 52

of comprehension of syntax, 50 MTL. See Medial temporal lobe

of executive tasks requiring planning, 145 Myelokinetic apraxia, 95
of face-processing network, 120f
during motor response inhibition tasks, 146
of orbitofrontal cortex in cognitive and emotional
perspective taking, 80
in prosopagnosia, 126r
N
in pure alexia, 61 Naming, 29–37
of social exclusion, 84r assessment of, 56
of voice perception, 70 brain regions involved in, 30, 30f
Mamillary body lesions, episodic memory impairment cognitive processes underlying, 29, 30–37, 30f, 43r
due to, 20– 21 diseases and sites of lesions associated with
McGurk effect, 46 impairment of, 36 –37
Mechanical advantage knowledge deficit, 88, 89 impaired access to modality-independent lexical
Medial temporal lobe (MTL), 26r representations, 33, 34c
Alzheimer disease pathology in, 20 impaired access to modality-specific lexical
in episodic memory, 15–16, 18–21, 19f representations, 33 –35, 35v
functional organization of, 19, 20f impaired lexical semantics and impaired access to
hippocampal and extrahippocampal structures of, 18 –19 lexical semantics from vision, 31–32, 32c, 33c
memory impairment due to lesions of, 15, 18–19, impaired semantics, 23c, 24, 31, 32c
26r–28r impaired visual recognition, 30 –31, 31c
in Alzheimer disease, 17c, 20 deficit in Wernicke aphasia, 47
disorders associated with, 20 management of deficits in, 42
new semantic memory formation, 25 NE (neuroenhancement), ethics of, 165 –168,
Ribot law of, 19 168r–169r
standard consolidation model of, 19–20 Neglect syndrome, 99–103, 101c, 107r –109r, 112
vs frontal lobe lesions, 22, 22t anosognosia for hemiplegia and, 101
Medications to avoid in dementia patients, 172 assessment of, 101
Memantine, 156, 160, 174 cross-modal and sensorimotor interactions and, 102
Memory, 15 –26, 26r–28r environment-centered, 102
autobiographic, 25 management of, 103
comprehension and, 45 object-centered, 101–102
consolidation of, 18 prognosis for, 102–103
declarative (explicit), 16, 16t proprioceptive input and, 102
definition of memory systems, 15 spatial reference frames and, 101–102
encoding of, 18 tests for, 101
episodic, 15, 16, 16t, 17–23, 17f, 19f theories of, 100 –101
neuroanatomical correlates of, 15 –16, 16t spatial attention, 100, 129
nondeclarative (implicit), 16, 16t spatial intention, 100
procedural, 15, 16, 16t, 25–26 spatial representation, 100 –101
retrieval of, 18 viewer-centered, 102
semantic, 15, 16, 16t, 23 – 25, 23c, 24f Neocortex, in semantic memory, 15, 24–25
216 working, 16, 16t, 140, 141–143 Neologisms, 38
Memory impairment, 15 Neuroanatomical correlates
achromatopsia and, 113 of achromatopsia, 112 –113
acute confusional state and, 129 of apraxia
anterograde vs retrograde, 18 conceptual, 89
of episodic memory, 15 –18, 17c dissociation, 94
executive dysfunction and, 141 ideational, 87
people-specific amnesia, 120 ideomotor, 91–94
of procedural memory, 25 – 26 limb-kinetic, 95
prosopagnosia and, 119 of attention, 131–136, 137r–139r
of semantic memory, 24, 25, 31 of comprehension, 45– 46
Mild cognitive impairment, amnestic, 17c language comprehension, 47 – 48
Mini-Mental State Examination, 23c semantic comprehension, 49–55, 49f
Mirror neurons, in emotion sharing, 76 of executive function, 140, 141
Misidentifications, in acute confusional states, 130 inhibitory control, 146–147
Mixed transcortical aphasia, 39t planning and organizing, 144–145
Motivational functioning, social cognition and, 69 working memory, 24f, 135, 142
MRI. See Magnetic resonance imaging of love, 84r

of memory, 15 –16, 16t Nocturia, 173
episodic memory, 18–23, 19f Nondeclarative (implicit) memory, 16, 16t
procedural memory, 24f, 25–26 Nonmaleficence, 168
semantic memory, 24–25, 24f
of naming, 30, 30f
of neglect syndrome, 100 O
of optic ataxia, 104
Object recognition disorders, 111, 114 –123, 125r –127r
of prosopagnosia, 119, 120f, 121f
general visual agnosia, 114 –117, 115c
of self and other perspective taking, 79 – 80, 84r
prosopagnosia, 117–120, 118c
of self-other distinction, 78
topographagnosia, 121–122, 123c
of simultanagnosia, 106
Obstructive sleep apnea (OSA), 173
of social cognition, 69, 70–79
Occipitotemporal cortex
of topographagnosia, 122
in color and object recognition, 111
of visual agnosia, 116, 117
prosopagnosia, 119, 120f
of written language disorders, 61, 62f, 63 – 64
in perception of social signals, 70
Neuroenhancement (NE), ethics of, 165 –168, 168r –169r
OFC. See Orbitofrontal cortex
Neurofibrillary tangles, 20
Optic aphasia, 31c, 32, 33c, 39t, 43r, 125r
Neuroimaging. See also specific imaging modalities
diseases and sites of lesions associated with, 36
in amnestic mild cognitive impairment, 17f
Optic ataxia, 99, 103–104, 105c, 109r
in anomic aphasia, 34f
accounts of, 104
in apperceptive visual agnosia, 115, 115f
anatomic basis of, 104
in behavioral variant of frontotemporal degeneration,
assessment of, 104
77f, 78
foveal vs nonfoveal, 103
in Broca aphasia, 41c, 51f
Orbitofrontal cortex (OFC), 83r, 84r
in disorders of written language, 65c, 66c
in cognitive and emotional perspective taking, 80
in hemiachromatopsia, 113, 113f
in evaluating punishment value of stimuli, 73
in prosopagnosia, 118, 118f
Organic brain syndrome, 129
in semantic memory impairment, 23c, 23f, 32c
Orthographics, 34, 59–60, 64
in semantic variant of primary progressive aphasia,
OSA (obstructive sleep apnea), 173
53f, 75f, 76, 155, 155f, 158 –159
in Wernicke aphasia, 48f
Neuroimaging, functional
of areas associated with impairment of phonetic and P
phonologic processing, 47 Paced Auditory Serial Addition Test, 143
of brain regions activated by emotion recognition and Palliative treatment of dementia, 174
perception, 74 –76 Pantomiming transitive movement to verbal command,
of brain regions activated during naming, 30f 90–91, 96r
of brain regions activated during social processing, Papez circuit, 20, 21
70, 71c, 72 Parahippocampal lesions, topographagnosia and, 122
of color-processing regions, 113 Paraphasias
of comprehension of discourse, 51, 52 phonemic, 33, 35
of comprehension of syntax, 50 semantic, 32, 32c, 33c
of executive tasks requiring planning, 145 in Wernicke aphasia, 48, 48c 217
in landmark agnosia, 122 Parietal lobes
during motor response inhibition tasks, 146 in comprehension of discourse, 52
of networks involved in executive functioning, 141 in episodic memory, 22–23, 27r–28r
of orbitofrontal cortex in cognitive and emotional ideomotor apraxia and, 91–92
perspective taking, 80 in modulation of attention, 135–136
of orbitofrontal cortex in evaluating punishment value optic ataxia and, 104
of stimuli, 73 visuospatial processing disorders and, 99
of self and other perspective taking, 79 Parkinson disease, 25, 141, 143
of self-other distinction, 78 Patient autonomy, 168
of social exclusion, 84r Patient management problem: frontotemporal
of visual word form area, 61 degeneration, 153 –162, 162r–164r
of voice perception, 70 Pegboard test, 95
Neuropathology People-specific amnesia, 120
of Alzheimer disease, 20 Perceptual disturbances, in acute confusional states,
of Pick disease, 78c 129, 130
Neuroplasticity, avoiding drugs that may impede, 172 Periodic limb movements of sleep (PLMS), 173
Neuropsychological assessment, 56 Perseveration, 145, 146, 146c

PET. See Positron emission tomography achromatopsia and, 113

Phonemic paraphasias, 33, 35 anatomical basis of, 119, 120f, 121f
in Wernicke aphasia, 48, 48c anterograde, 117
Phonetic processing, 46 apperceptive, 119
impairments of, 47 associative, 119
Phonetics, 46 causes of, 119
Phonagnosia, 47 definition of, 117
Phonologic agraphia, 64 – 65, 65c, 67r distinction from other disorders of face processing,
Phonologic alexia, 62 – 63, 63c, 66c 119–120
Phonologic comprehension, 46 face expression deficits without, 120
impairments of, 47 other related visual abilities and, 117–119
Phonology, 33 –34, 59– 60, 64 pathophysiology of, 119
Pick disease, 77c –78c. See also Frontotemporal progressive forms of, 119
degeneration in semantic variant of primary progressive aphasia,
Planning and organizing, 140, 143 – 145, 151r 55, 73
anatomy of, 144 –145, 144c signs associated with, 119
assessment of, 145 tests for, 117
definition of, 143 Pseudoisochromatic plates, 112, 118c
models of, 144 Pseudowords, 60, 64, 65
narrative function and, 143 Pure alexia, 60, 61, 61c, 67r
theory of mind and, 143 – 144 Pure word deafness, 47
PLMS (periodic limb movements of sleep), 173
Positron emission tomography (PET)
of comprehension of discourse, 51
of posterior cortical atrophy, 71c Q
in semantic variant of primary progressive aphasia, Quadrantanopia
53f, 76, 159 hemiachromatopsia and, 112, 113c
Posterior cortical atrophy, 71c, 71f, 109r –110r prosopagnosia and, 119
assessment of, 107
visual agnosia and, 115c, 116
visuospatial processing disorders and, 106 –107
Power of attorney for health care, 162
PPA. See Primary progressive aphasia
R
Practice issues: optimizing cognitive function, Reading disorders. See Alexia(s)
170 –174, 174r Restless legs syndrome (RLS), 173
Pramipexole, for restless legs syndrome, 173 Retrograde amnesia, 18, 19, 27r
Praxicons, 92 Retrosplenial cortex lesions
Prefrontal cortex episodic memory impairment and, 20, 23
dorsomedial, in self and other perspective taking, 79 – 80 topographagnosia and, 122, 122f
in emotion reappraisal, 81 Ribot law, 19
empathy deficits due to lesions of, 85r Right hemisphere
in executive function, 140, 141, 149r in discourse comprehension, 52
218 inhibitory control, 146 –147 lesions of
planning and organizing, 144 –145, 144c conceptual apraxia and, 89
working memory, 135, 142 limb-kinetic apraxia and, 95
Prefrontal lobes, in ideational apraxia, 87 neglect syndrome and, 101, 136
Primary progressive aphasia (PPA), 42r – 44r, 58r in spatial attention, 100
anomia in, 36 –37 in working memory, 142
logopenic/phonologic variant of, 38, 40c, 40t Rivastigmine, 174r
nonfluent/agrammatic variant of, 35c, 37, 40t RLS (restless legs syndrome), 173
semantic variant of, 23c, 25, 32c, 36, 38, 40t, 51, Ropinirole, for restless legs syndrome, 173
53c–54c, 55, 73 –74, 75c – 76c
patient management problem on, 153 –162, 162r–164r
sites of damage and etiologies of, 40t
Problem unawareness, 88 – 89 S
Procedural memory, 15, 16, 16t, 25 – 26, 28r Scopolamine-induced amnesia, 22
definition of, 25 SD (semantic dementia). See Semantic variant of primary
functional neuroanatomy of, 15, 24f, 25 – 26 progressive aphasia
impairment of, 26 Self-other distinction, 77–79, 84r
disorders associated with, 25 – 26 Semantic access agnosia, 116
Progressive supranuclear palsy, 141, 147, 149r Semantic agnosia, 116
Prosopagnosia, 31c, 111, 117– 120, 118c, 125r –126r Semantic agraphia, 65, 68r

Semantic anomia, 49 in behavioral variant of frontotemporal degeneration,
Semantic comprehension, 49–55, 57r–58r 73, 74, 77, 77c–78c
comprehension of semantic knowledge about concrete evaluation of social signals, 69, 70 – 79
entities, 52–55 emotion recognition/subjective experience of
category-related semantic impairments, 24, 28r, 54 emotion, 74 – 77
dementia, 54 –55 recognizing salience of environmental stimuli, 70 – 74
disorders of conceptual knowledge, 55 self-other distinction/attribution of agency, 77– 79
dynamics of neural systems, 55 future directions in studies of, 81
semantic variant of primary progressive aphasia, 23c, high-level processing and behavioral response
25, 32c, 36, 38, 40t, 42r, 43r, 51, 53c–54c, 55, 73 –74, selection, 79 – 81
75c–76c adopting another's perspective, 79– 80
comprehension of sentences and discourse, 50 –52, 51c behavioral regulation, 80 – 81
comprehension of syntax, 50 neural basis of, 69, 70, 71c
agrammatism in Broca aphasia, 50, 51c perception of social signals, 69, 70
comprehension of words, 49 –50, 49f role of planning and organizing in, 143–144
semantic anomia, 49 in semantic variant of primary progressive aphasia,
transcortical sensory aphasia, 49 –50, 49f 73 –74, 75c –76c
Semantic dementia (SD). See Semantic variant of primary theories about domains of, 69
progressive aphasia transcranial magnetic stimulation to isolate structures
Semantic memory, 15, 16, 16t, 23 –25, 27r involved in, 78, 81
definition of, 23 Source memory, 18
functional neuroanatomy of, 15, 24 –25, 24f Spatial attention, 100, 129
impairment of, 24 Spatial intention, 100
category fluency deficits and, 24, 28r, 54 Spatial reference frames, 101–102
conditions associated with, 25 Spatial representation, 100 –101
naming deficits due to, 23c, 24, 31, 32c Speech. See also Aphasia
overlap between episodic memory and, 25 articulation of, 29, 44r
retrieval of, 24 isolation of, 47
Semantic paraphasias, 32, 32c, 33c perception of, 46 – 47
in Wernicke aphasia, 48, 48c in Wernicke aphasia, 47
Semantic variant of primary progressive aphasia, 23c, 25, Speech and language therapy, 42, 161
32c, 36, 38, 40t, 42r, 43r, 51, 53c –54c, 55 Speech sounds, 46
patient management problem on, 153 –162, 162r –164r Spelling, 64 – 65, 68r
social cognition in, 73 –74, 75c–76c Stimulus-bound behavior, 145
Semantics, 49, 59 – 60, 64 Striate cortex lesions, 111
Sentence comprehension, 50 – 52 Stroop test, 147
Sentence production, 29, 37– 41 Supplementary motor area (SMA)
cognitive processes underlying, 37– 41 ideomotor apraxia due to lesions of, 92 – 93, 96r
impairment at functional level, 38, 40c in procedural memory, 15, 16t, 25
impairment at message level, 38, 38c, 39t, 40t Surface dyslexia, 32c
impairment at positional level, 38, 40, 41c Syntax, 46 – 47
model of, 37–38, 37f comprehension of, 50
discourse, 29, 40 – 41, 41c agrammatism in Broca aphasia, 50, 51c 219
management of deficits in, 42 neural systems involved in, 50
in nonaphasic patients with executive dysfunction,
143, 150r
Set-shifting, 146
assessment of, 147
Shape agnosia, 114 –116 T
Simultanagnosia, 99, 104 –106, 105c, 109r Tamsulosin, for nocturia, 173
anatomic basis of, 106 Temporal lobe(s)
assessment of, 106 in associative prosopagnosia, 119, 121f
clinical description of, 104 –105 in comprehension of discourse, 50 –52
definition of, 104 in comprehension of syntax, 50
mechanisms underlying, 105 –106 in language comprehension, 46, 47
Sinemet. See Carbidopa/levodopa pure word deafness and, 47
Sleep disorders, 172 –173, 174r medial (See Medial temporal lobe)
SMA (supplementary motor area) in perception of social signals, 70, 73
ideomotor apraxia due to lesions of, 92 – 93, 96r in semantic variant of primary progressive aphasia,
in procedural memory, 15, 16t, 25 55, 73 –74, 75f, 76
Social cognition, 69 – 81, 81r – 85r in social and emotional processing, 73 –74, 82r, 83r
in Alzheimer disease, 71c in word comprehension, 49

Temporoparietal junction, in self-other distinction, Visual dysfunction, 111–123, 123r –127r

78 –79, 84r Visual form agnosia, 114 –116
Thalamic lesions, ideomotor apraxia and, 93 – 94 Visual object agnosia, 49
Theory of mind, 80, 143 –144, 151r Visual recognition deficits, naming and, 30– 31, 31c
Tool-selection deficit, 88, 89 Visual word-form agnosia, 111
Topographagnosia, 111, 121–122, 122f, 123c, 126r–127r Visual word form area (VWFA), 61, 62f, 67r
achromatopsia and, 113 Visuo-imitative apraxia, 94, 97r
anterograde, 122 Visuospatial processing disorders, 99–107, 107r –110r
definition of, 121 Balint syndrome, 103, 105c
landmark agnosia, 121–122 optic ataxia, 99, 103–104
prosopagnosia and, 118c, 119 simultanagnosia, 99, 104 –106
tests for, 122 in dementia, 99, 106 –107
Toxic-metabolic encephalopathies neglect syndrome, 99–103, 101c
acute confusional states due to, 129 –131 Voice perception, 70
executive dysfunction due to, 148t Voice recognition, 73
Trail-making tests, 147, 152r VWFA (visual word form area), 61, 62f, 67r
Transcortical motor aphasia, 39t
Transcortical sensory aphasia, 38, 38c, 39t, 49 – 50, 49f
Transcranial magnetic stimulation, to isolate structures
involved in social processing, 78, 81, 85r W
Traumatic brain injury, 147 Warrington Recognition Memory Test, 117
Trazodone, 160 Wernicke aphasia, 32c, 36, 38, 39t, 43r, 46, 47– 49, 48c,
49f, 50, 51–52, 57r
Wernicke area, 47, 48, 49–50, 49f, 91
Wernicke-Lichtheim model of language regions of
U brain, 49f
Unimodal association regions, 47 Wisconsin Card Sorting Test, 147
Uroxatral, for nocturia, 173 Word comprehension, 49 –50, 49f
Utilization behavior, 145 semantic anomia, 49
transcortical sensory aphasia, 49 –50, 49f
Working memory, 16, 16t, 140, 141–143, 149r–150r
anatomy of, 24f, 135, 142
V assessment of, 142–143
Verbal dissociation apraxia, 94 definition of, 140, 141
Vigilance, 128 dysfunction of, 142c
disturbance in acute confusional states, 130 executive function and, 140, 141
Visual agnosia, 114 – 117, 124r–125r impairment in acute confusional states, 130
achromatopsia and, 113 model of, 141–142
apperceptive, 30 – 31, 31c, 36, 114 –116, 115c central executive, 142
associative, 32, 36, 114, 116 –117 phonological loop, 141–142
definition of, 114 visuospatial sketch pad, 142
general, 111, 114 –117 Written language disorders, 59–66, 66r–68r
220 integrative, 116 aphasia and, 59, 60
semantic, 116 left hemisphere lesions and, 59
semantic access, 116 other disorders associated with, 59
Visual-association areas, 70 sensory/motor systems and, 59– 60, 60f


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L I F E L O N G L E A R N I N G I N N E U R O L O G Y®

MURRAY GROSSMAN, MD, FAAN, Guest Editor

JASON J. S. BARTON, MD, PhD, FRCPC

ANJAN CHATTERJEE, MD, FAAN

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KATHERINE P. RANKIN, PhD

DAVID P. ROELTGEN, MD, FAAN

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MULTIPLE-CHOICE QUESTION WRITERS

EDUARDO E. BENARROCH, MD, DSci, FAAN

D. JOANNE LYNN, MD, FAAN

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EDITOR FOUNDING PROGRAM DIRECTOR

ASSOCIATE EDITOR OF ETHICS AMERICAN ACADEMY OF NEUROLOGY

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MEMORY SYSTEMS A When medial

INTRODUCTION assertions that human memory is sub-

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TABLE 1-1 Comparison of Clinically Relevant Memory Systems

Memory Length of Major Anatomic

Episodic Remembering a short story, Explicit Minutes Medial temporal lobe,

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include the entorhinal, perirhinal, and hippocampus differentially encode ob-

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form the perforant pathway (the main

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TABLE 1-2 Memory Deficits With Medial Temporal Lobe Versus

Immediate memory Normal to mildly impaired Impaired

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1. Budson AE, Price BH. Memory dysfunction. N Engl J Med 2005;352(7):692–699.

3. Tulving E. Memory and consciousness. Can Psychol 1985;26:1–12.

4. Yonelinas A. The nature of recollection and familiarity: a review of 30 years of

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10. Squire LR, Alvarez P. Retrograde amnesia and memory consolidation: a

11. Moscovitch M, Nadel L, Winocur G, et al. The cognitive neuroscience of remote