Handbook of Clinical Neurology, Vol.

163 (3rd series)

The Frontal Lobes
M. D’Esposito and J.H. Grafman, Editors
https://doi.org/10.1016/B978-0-12-804281-6.00008-2
Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 8

Frontal lobe syndromes

JUSTIN REBER1,3 AND DANIEL TRANEL2*
1
Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA, United States
2
Department of Neurology, University of Iowa College of Medicine, Iowa City, IA, United States
3
Department of Psychiatry, University of Iowa College of Medicine, Iowa City, IA, United States

Abstract
The frontal lobes contain a complex set of diverse anatomic regions that form multiple distinct, complex
networks with cortical and subcortical regions. Damage to these cortical–subcortical networks can
have dramatic behavioral consequences, ranging from apathy to impairments in executive functioning.
This chapter provides a brief overview of the common syndromes caused by damage to the mediodorsal
and dorsolateral prefrontal circuits, followed by a more detailed review of the syndrome—sometimes
referred to as pseudopsychopathy or acquired sociopathy—associated with damage to the ventromedial
prefrontal circuit.

INTRODUCTION the central role of the frontal lobes in higher cognitive

The frontal lobes make up over one-third of the human
cerebral cortex and comprise several diverse anatomic
units with distinct and highly complex connections
(unidirectional and bidirectional) to other cortical and
subcortical regions and to each other. Despite major
progress over the past couple of decades in cognitive
neuroscience and neuropsychology, clinicians (espe-
cially clinical neuropsychologists, behavioral neuro-
logists, neuropsychiatrists, and neurosurgeons) who
evaluate and treat frontal lobe dysfunction still face many
of the challenges and limitations encountered by prior
generations. Acquired damage can disrupt in myriad
ways the varied and complex neuroanatomic and func-
tional systems in the frontal lobes, systems which for
the most part remain incompletely understood. Chal-
lenges presented by the anatomic complexity of the fron-
tal lobes are paralleled by the equally daunting array
of signs and symptoms of frontal lobe damage, and in
particular by the fact that such signs and symptoms do
not lend themselves easily to quantitative analysis in
a laboratory setting (including clinical neuropsycho-
logic evaluation, e.g., Lezak et al., 2012). Thus, although
functions is not in question, and there is similarly little
question that frontal dysfunction contributes to many
prominent psychiatric disorders, the precise character-
ization and measurement of cognitive and behavioral
manifestations of frontal lobe dysfunction remain elu-
sive. In this chapter, we review salient cognitive and
behavioral changes that result from focal damage to
the frontal lobes. To keep the scope of our review trac-
table, we focus on the prefrontal cortex and on cognitive
and behavioral manifestations that are most commonly
encountered in clinical practice with patients who have
focal, acquired damage to the prefrontal cortex (readers
are referred to other chapters in this volume for other
perspectives).
PREFRONTAL SYNDROMES
Damage to the prefrontal lobes can have widely varying
behavioral consequences, depending upon the location,
extent, and etiology of the lesion or degeneration. Fur-
thermore, damage to the prefrontal lobes is rarely limited
to a single region, but often affects multiple areas
and disrupts their connections with other cortical and

*Correspondence to: Daniel Tranel, Ph.D., Neuroscience PhD Program Director, Associate Dean of Graduate and Postdoctoral
Studies, Department of Neurology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 2155 RCP, Iowa City, IA
52242, United States. Tel: +1-319-384-6050, Fax: +1-319-356-4505, E-mail: daniel-tranel@uiowa.edu
148 J. REBER AND D. TRANEL
Fig. 8.1. Stylized three-dimensional renderings of the brain depicting the major cortical areas involved in the medial frontal,
dorsolateral, and ventromedial circuits.
subcortical structures (Cummings, 1993). Damage to
white matter tracts can also disrupt these circuits, causing
far more severe impairments than would be expected
from the extent of cortical damage. It is important, there-
fore, to consider lesions in the prefrontal lobes not as iso-
lated neurologic injuries, but as disruptions in complex
anatomic and functional networks.
Despite the complexity of prefrontal networks, the
majority of symptoms resulting from prefrontal dysfun-
ction can be sorted into three broad categories, each
closely linked with one of three parallel yet relatively
segregated frontal–subcortical circuits. The first category
generally involves disruptions in motivation and willful
behavior, including the striking manifestations of apathy,
abulia, and akinetic mutism. Such manifestations typ-
ically occur with lesions to the medial frontal circuit
and the anterior cingulate gyrus and underlying white
matter (Fig. 8.1). The second category, hallmarked by
impairments in executive functioning, is associated with
damage to the dorsolateral prefrontal circuit. The final
category of symptoms, often labeled pseudopsychopathy
or acquired sociopathy, involves disturbances in perso-
nality, affect, social conduct, and behavioral regulation,
and typically follows lesions to the orbitofrontal circuit
and the associated ventromedial cortex and white matter.
This chapter will provide a brief overview of the first
two categories, followed by a more detailed review of
the last category.
DIMINISHED MOTIVATION: MEDIAL
FRONTAL AND ANTERIOR CINGULATE
LESIONS
Disruption and damage to the anterior cingulate or
the medial frontal circuit can cause a spectrum of impa-
irments in motivation and willful behavior. The mildest
form, apathy, derived from the Greek root pathos, is
marked behaviorally by limited spontaneous activity,
such as speech, movement, and gesture, with unaffected
consciousness, attention, and mood (Marin, 1990; Marin
and Wilkosz, 2005; Filley, 2011). Patients with apathy
are capable of planning and initiating behavior, but
they do so less frequently than normal individuals. In
striking contrast to their impoverished outward behav-
ioral expressions, the patients tend to have normal emo-
tional experiences. Abulia is often used to describe a
more severe version of apathy, accompanied by psycho-
motor slowing, long latency to speech, and a further
dampening of initiative, cognition, and emotion. Neither
apathy nor abulia entail a complete lack of affect—in
fact, apathetic and abulic patients may experience intense
bouts of irrational anger or euphoria, but these emotional
experiences are rare. Furthermore, apathy and abulia
resulting from damage to the medial frontal circuit is
distinguished from major depressive disorder by the
lack of distress and negative cognitions predominant
in the latter.
 FRONTAL LOBE SYNDROMES
In the most severe cases, both unilateral and bila-
teral lesions to the anterior cingulate or the dorsomedial
prefrontal circuit can cause akinetic mutism, a condition
wherein patients display a complete loss of sponta-
neous speech and motor behavior. While they retain
consciousness and continue to track their environ-
ment, patients with akinetic mutism lack any other overt
behaviors, a condition described by Cairns et al. (1941)
as “motionless, mindless wakefulness” (Marin and
Wilkosz, 2005). These patients will not groom them-
selves, eat and drink only when fed, and often lack
bowel and bladder control. Although the conditions
can have similar behavioral profiles, akinetic mutism
may be differentiated from locked-in syndrome by
the fact that the lack of movement in akinetic mutism
is not due to paralysis, but rather due to lack of voli-
tion. Unlike patients with locked-in syndrome, patients
with akinetic mutism can make significant recove-
ries, regaining their mobility, speech, and goal-directed
behavior once their motivation returns (Yang et al.,
2007). Although akinetic mutism is rare and often
transient, varying degrees of apathy and abulia are
among the most common symptoms of traumatic brain
injury, with studies recording incidence of apathy
between 41% and 71% in patients (Craig et al., 1996;
Kant et al., 1998; Ciurli et al., 2011). Notably, Parvizi
et al. (2013) observed that direct electrical stimulation
of the dorsomedial circuit by way of the anterior cin-
gulate can produce a sort of reverse apathy, a sense of
increased motivation that they dubbed “the will to
persevere.”
Anatomy and common etiologies
The medial frontal circuit includes the cingulate gyrus
and the dorsomedial surface of the prefrontal cortex,
including the supplementary motor area, and the
white matter subjacent to these regions. These areas
can be damaged by vascular events involving the anterior
cerebral artery, closed-head trauma, normal-pressure
hydrocephalus, or neoplasms such as cysts or menin-
giomas arising from the falx cerebri. Similar symptoms
can accompany damage to the diencephalon and/or the
midbrain. Focal damage to this circuit, however, is rela-
tively uncommon. Typically, apathy or abulia may arise
from unilateral or bilateral damage to the dorsal prefro-
ntal structures; akinetic mutism more often results from
bilateral mediodorsal lesions, although some unilateral
cases have been reported (Saint-Cyr et al., 2002).
Illustrative case
At age 53, VY500 (a fully right-handed woman with
12 years of formal education) suffered rupture of an
anterior communicating artery aneurysm, and she was
149
treated emergently with a surgical intervention to clip
the aneurysm. She sustained bilateral lesions to the
medial prefrontal region, including the anterior cingulate
gyrus (Fig. 8.2). In the acute epoch, immediately follo-
wing surgery, she was awake and alert, but had profound
akinesia and mutism, displaying no spontaneous speech
or motion. She improved substantially during the first
several weeks following surgery, and she was speak-
ing normally and showing normal motor behavior by
one month postonset. However, she remained severely
“flat” in her behavioral presentation, appearing devoid
of normal emotional animation (in both verbal and
motor outputs). Her caregivers described her as having
“no emotion.” She also evidenced severe anterograde
amnesia and impaired insight (anosognosia). Her
deficits in emotional expressivity, anterograde memory,
and awareness of her condition persisted into the
chronic epoch.
IMPAIRMENTS IN EXECUTIVE
FUNCTIONING: DORSOLATERAL
LESIONS
Executive functioning is a complex term that has
been defined and redefined so many times in the past
decades that it has grown to encompass a wide range
of loosely related higher-order cognitive functions,
including planning, goal-directed behavior, and attention
(Stuss and Benson, 1986; Tranel et al., 1994; Elliott,
2003; Cummings and Miller, 2007). As a higher-order
cognitive construct, executive functioning is multi-
faceted and reliant upon many other “basic” cognitive
domains, such as language, attention, perception, and
memory, but it does not fall into any of these categories
itself. The ability to anticipate future outcomes, to select
a goal, to plan actions to achieve that goal, to monitor
one’s progress toward that goal, and to flexibly adapt
one’s behaviors based upon feedback all fall under
the wide umbrella of executive functioning. Therefore,
dysexecutive symptoms resulting from damage to the
dorsolateral prefrontal circuit typically disrupt patients’
abilities to efficiently and adaptively plan and pursue
goals. Unlike patients with disorders of motivation as
elaborated earlier (e.g., apathy, abulia, akinetic mutism),
who lack the will to form goals in the first place, patients
with dorsolateral lesions often put forth great amounts of
inefficient effort pursuing goals, to the point of persever-
ative behaviors and patterns of misplaced behaviors.
A large part of the difficulty in rigorously defining
executive functioning is its close relationship with the
role of the prefrontal cortex. “Frontal lobe functioning”
is often used interchangeably with executive function-
ing, but this conflation of terms leads to both a muddying
of definitions and furthers the misconception that the
150 J. REBER AND D. TRANEL
Fig. 8.2. Horizontal slices from CT scan of patient VY500, with bilateral lesions to the anterior cingulate and medial frontal circuit.
frontal lobe is an independent, uniform functional
unit with a single set of functions. Not only does this
hamper attempts to understand the functional fraction-
ation of the prefrontal cortex, but it also stifles investiga-
tion of the role of other neurologic structures, such as
the cerebellum, in executive functioning (Schmahmann
and Sherman, 1998; Winn, 1998). Stuss and Alexander
(2007) have argued that even the term “dysexecutive
syndrome” is overly broad and misleading, and that
further fractionation of executive functioning and its neu-
rologic correlates is necessary for a fuller understanding
of prefrontal function. Investigations of neuropsycho-
logic batteries designed to measure impairments in exe-
cutive functioning, for instance, have found that the
deficits in the cognitive aspects of executive function-
ing correspond with damage to the dorsolateral circuit,
while social/emotional executive dysfunction map onto
ventromedial circuit dysfunction (Robinson et al., 2014).
Because executive functioning covers such a broad
spectrum of cognitive functions, dysexecutive symptoms
arising from damage to the dorsolateral prefrontal circuit
can manifest in a wide variety of forms. Patients with
lesions to this circuit often display deficits in general aca-
demic and intellectual functioning, especially on tasks
that test “fluid” intelligence or “high g” tasks that require
complex problem-solving (Waltz et al., 1999; Glascher
et al., 2010; Lezak et al., 2012). There is evidence that
the types of intellectual functions supported by the dor-
solateral circuit are lateralized—unilateral damage to the
left dorsolateral prefrontal cortex impairs verbal perfor-
mance, such as letter and semantic fluency tasks
(Benton, 1968; Stuss et al., 1998). In these tasks, partic-
ipants are asked to list as many distinct words as they can
in a short time period that either begin with a given letter
or fall within a semantic category (e.g., animals or fruits).
Patients with bilateral lesions or unilateral damage to the
left, but not the right, dorsolateral prefrontal region pro-
duce far fewer words during both tasks and make propor-
tionally more errors while doing so. Right-sided lesions
to the circuit, on the other hand, impair performance
upon nonverbal “design fluency” tasks (Fig. 8.3;
Jones-Gotman and Milner, 1977).
Lesions to either side of the dorsolateral circuit also
often cause perseveration, the inappropriate or inflexible
continuation or repetition of actions in light of changing
contexts (Sandson and Albert, 1984). When asked to
draw a clock, a patient with dysexecutive symptoms
might keep numbering the clock after she reaches 12,
 FRONTAL LOBE SYNDROMES 151

Fig. 8.3. Design fluency task performance. Modified from Tranel D, Anderson S, Benton A (1994). Development of the concept of
“executive function” and its relationship to the frontal lobes. In: Boller F, Grafman J (eds.), Handbook of neuropsychology.
Amsterdam: Elsevier. Image from Elsevier publication.

either repeating the numbers or continuing the sequence

(Fig. 8.4), or they may simply continue drawing clocks
after completing the first drawing. The two main neu-
ropsychological tasks used to assess behavioral flexibi-
lity and perseveration are the Wisconsin Card Sorting
Test (WCST) and the Trail Making Test, Part B. In
the WCST, patients must sort cards according to a sor-
ting criterion (color, shape, or number) that they must
determine through trial and error. Once a criterion is
adequately learned, it changes, and patients must then
shift to the new criterion by a new trial and error pro-
cess. Patients with perseveration following dorsolateral
lesions have little difficulty learning the initial criterion,
but often fail to shift their behavior once the sorting
criterion changes. In the Trail Making Test, Part B,
patients are asked to connect circles containing numbers
and letters, alternating between the two (1 to A, A to 2, 2
to B, etc.). Patients with impaired executive functioning
often perseverate and frequently commit errors, failing
to shift between numbers and letters appropriately
(Stuss et al., 2001).
One component of executive functioning that has
been studied primarily through functional neuroimaging
Fig. 8.4. Examples of clocks drawn by patients with impaired
is working memory (cf. Baddeley, 2012). Conceptually
executive functioning and perseveration. Modified from Libon
similar to short-term memory in that it is limited in both DJ, Malamut BL, Swenson R, et al. (1996). Further analyses of
capacity and duration, working memory also integrates clock drawings among demented and nondemented older sub-
attentional processes into its conceptualization. Defined jects. Arch Clin Neuropsychol 11: 193–205, with permission
as the ability to temporarily maintain and manipulate from Oxford University Press and Tranel D, Anderson S, Benton
information of different modalities, the operation of A (1994). Development of the concept of “executive function”
working memory has been closely correlated with and its relationship to the frontal lobes. In: Boller F, Grafman
increased BOLD signal in the dorsolateral prefrontal J (eds.), Handbook of neuropsychology. Amsterdam: Elsevier.
region by a multitude of fMRI studies (cf. D’Esposito,
2001). In contrast to the rich neuroimaging literature memory (Damasio et al., 2013). However, recent
linking the dorsolateral circuit with working memory, research by Barbey et al. (2013) found that patients with
there has been a notable dearth of human lesion cases lesions to the left and right dorsolateral prefrontal cortex
that show clinically significant impairments in working performed significantly worse than comparisons on
152 J. REBER AND D. TRANEL
Fig. 8.5. Perseverative errors made by a patient following completion of a line cancellation test. Red circles indicate perseverative
errors made upon the subsequent trailmaking tasks. Modified from Sandson J, Albert ML (1984). Varieties of perseveration.
Neuropsychologia 22: 715–732. Image from Elsevier publication.
classic working memory tasks such as the N-back test, in
which participants must identify whether each given
stimulus in a sequence is a repeat of the one presented
n items back.
Anatomy and common etiologies
The dorsolateral prefrontal circuit includes a wide swath
of the prefrontal lobes, including the middle frontal gyrus
extending caudally to the premotor cortex. This area
encompasses several Brodmann areas, occupying BA
9, 46, 8, and 10 (Lezak et al., 2012). Association areas
of the temporal and parietal lobes also contribute to
the circuit (Saint-Cyr et al., 2002). The regions compris-
ing the dorsolateral circuit are primarily supplied by the
middle cerebral artery, and vascular damage to this region
often arises from embolic stroke and thrombosis of this
artery. Closed head trauma can also affect the region, as
well as compression and ischemic damage from neo-
plasms. Focal lesions to the dorsolateral circuit, therefore,
are almost exclusively unilateral, and bilateral damage to
this region is mostly due to neurodegenerative diseases,
such as frontotemporal dementia, or extensive vascular
events that affect regions beyond the frontal lobes.
Illustrative case
Sandson and Albert (1984) related the case of J.K., a
62-year-old right-handed man who was admitted to
the hospital for a dementia evaluation. He struggled
primarily with verbal tasks, performing poorly on nam-
ing, verbal fluency, and reading/writing tasks. Additio-
nally, he showed impairment on tests of mathematical
ability as well as verbal memory tests, although his per-
formance on nonverbal memory tests was largely
normal. Notably, however, he demonstrated severe per-
severative behaviors throughout testing. For instance,
once he completed a line cancellation test in which he
was asked to draw lines through every existing line on
a page, he continued to cancel out lines during the unre-
lated Trail Making Test. As shown in Fig. 8.5, he dili-
gently continued to bisect every line on the page of the
Trail Making Test, during which he was simply supposed
to connect the numbers on the page with lines. When
asked to repeat sets of numbers backwards during the
Digit Span Backwards test, he continued to repeat them
in the order in which they had been presented, as he had
been instructed to do during the preceding task.
PERSONALITY CHANGE, SOCIAL AND
EMOTIONAL DYSFUNCTION, AND
DECISION-MAKING IMPAIRMENTS:
VENTROMEDIAL LESIONS
Although damage to the prefrontal cortex can cause
many types of impairments ranging from abulia to mem-
ory deficits, one cluster of symptoms has been the sub-
ject of particular scientific fascination for decades.
Partially because of their relative frequency compared
to other rarer prefrontal syndromes such as akinetic
mutism, and partially because their effects upon human
behavior are simultaneously subtle and disastrous,
impairments of inhibition, emotion, and social comport-
ment are the best-known result of damage to the prefro-
ntal cortex. It is nearly impossible to find an introductory
psychology textbook that does not feature a section ded-
icated to Phineas Gage and the consequences of prefro-
ntal brain damage. Yet despite the widespread scientific
and nonscientific fascination with this particular prefro-
ntal syndrome, our understanding of it is far from com-
plete. Due to the variable and largely qualitative nature
of their presentation and the compromised insight of
many who experience them, the behavioral effects of
damage to the ventromedial prefrontal cortex remain
somewhat mysterious and often misunderstood by
scientists, clinicians, and the general public alike.
 FRONTAL LOBE SYNDROMES
Although it has long been well-established that dam-
age to the ventromedial prefrontal circuit causes changes
in personality and social comportment (Blumer and
Benson, 1975; Macmillan, 2000), it was only somewhat
recently that neuropsychologists discovered that these
severe behavioral impairments were not accompanied
by impairments in memory or abstract social cognition
(Saver and Damasio, 1991). Unlike lesions to the dor-
solateral circuit, which frequently produce noticeable
impairments on laboratory measures of intellect and
executive functioning, ventromedial damage often
spares those abilities, making the symptoms particularly
difficult to quantify and detect using standard neuropsy-
chologic tests. Nevertheless, decades of neuropsycho-
logic research have led to the identification of several
common behavioral consequences of lesions to the ven-
tromedial prefrontal lobes, the majority of which fall
under the umbrella term of acquired sociopathy.
Pseudopsychopathy and acquired
sociopathy
Many cases of individuals exhibiting personality
changes and uncharacteristic antisocial behavior follo-
wing damage to the ventromedial prefrontal circuit have
been documented throughout history under varying
descriptors such as pseudopsychopathy (Blumer and
Benson, 1975) and acquired sociopathy (Eslinger and
Damasio, 1985). Phineas Gage is certainly the best-
known case of dramatic personality changes following
damage to the ventromedial circuit, but the sparse
accounts of both his lesion and behavior by Harlow
(1848, 1868) have led to assertions that the behavioral
153
effects of his brain damage have been exaggerated
by modern scholars (Macmillan, 2002). The past century
of neuropsychologic research, however, has provided
ample clinical evidence of this phenomenon, in much
greater depth than Harlow’s accounts (cf. Brickner,
1934, 1936; Hebb and Penfield, 1940; Ackerly and
Benton, 1947; Eslinger and Damasio, 1985; Damasio
et al., 1990).
In 1975, Blumer and Benson coined the label
“pseudopsychopathy” to capture the personality traits
that developed in the wake of damage to the ventro-
medial circuit, describing the condition as “best char-
acterized by the lack of adult tact and restraints.” They
differentiated these traits from those of
“developmental” psychopathy by denoting that they
must result from “injury to the orbital frontal lobe or
pathways traversing this region,” but did not propose
any formal definition of the condition (Blumer and
Benson, 1975). Furthermore, they offered little specula-
tion on the degree of overlap between the traits displayed
by neurologic patients and those displayed by more con-
ventional criminal psychopaths.
Modern interest in ventromedial prefrontal dysfun-
ction as a cause of antisocial or psychopathic behavior
was largely renewed by Eslinger and Damasio’s (1985)
case study of patient EVR. A college-educated accoun-
tant, church elder, and father of two, EVR was a model
of respectability until his family and colleagues began
to notice changes in his personality in 1973. Both his
marriage and his career suffered. In 1975, EVR under-
went a surgical resection of a meningioma from his bilat-
eral ventromedial prefrontal cortex (Fig. 8.6). Although
he showed no noticeable disturbances in his memory, IQ,

Fig. 8.6. The brain lesion in patient EVR, projected onto a Montreal Neurological Institute (MNI) template brain. The lesion
(marked in red) encompasses most of the right and part of the left orbital cortices, both frontal poles, and the right mesial cortex
extending dorsally into part of the right dorsolateral prefrontal cortex.
154 J. REBER AND D. TRANEL
or on other standard neuropsychologic measures, he
exhibited even more dramatic changes in his personality
and real-world decision-making. He became irrespon-
sible, impulsive, and impaired in social relationships.
Following his surgery, EVR made a large investment
with an unreliable business partner. Consequently, he lost
his entire investment and was forced to declare bank-
ruptcy. He was fired from several different jobs, divorced
his wife, and eventually married a prostitute for a few
months. While he was able to provide rational, appro-
priate responses to questions about normative social
and moral behavior in a laboratory setting, his ability
to act in accordance with his abstract social knowledge
was catastrophically impaired in real life (Saver and
Damasio, 1991).
EVR’s sudden and dramatic personality shift after
his operation led Eslinger and Damasio to dub his condi-
tion “acquired sociopathy,” and his case sparked interest
in the ventromedial circuit’s role in personality and
sociomoral behavior. Further research on patients with
similar lesions began to paint a broader picture of the
impairments associated with ventromedial prefrontal
damage, and led to a resurgent interest in historical cases
such as Phineas Gage (Damasio et al., 1994). Research
on these lesion patients has also uncovered several nota-
ble similarities between the cognitive, behavioral, and
physiological symptoms of these patients and those of
individuals high in psychopathic traits.
Psychopathy
To better understand the behavioral and personality
implications of pseudopsychopathy and acquired
psychopathy, it is important to understand the traits of
developmental psychopathy. The modern conceptua-
lization of psychopathy dates back to Cleckley (1941),
whose 16-trait model of the condition set the stage
for future research. According to Cleckley, psychopathy
was marked by a series of interpersonal and behav-
ioral features such as superficial charm, lack of remor-
se, lack of insight, inadequately motivated antisocial
behavior, poor judgment, pathologic egocentricity, and
failure to follow any specific life plan. The patients
Cleckley chronicled were outwardly charming and
well-adjusted, yet were impulsive, irresponsible, and at
times unapologetically cruel and manipulative.
As Cleckley’s model of psychopathy gained popu-
larity, it soon became apparent that the lack of any
standardized measure of psychopathy was hindering
the advancement of empirical research on the subject
(Hare, 1998). To address this gap in the assessment
of psychopathy, Hare (1980, 1991) used Cleckley’s
model to develop the Psychopathy Checklist (PCL)
and later refined that into the 20-trait Psychopathy
Checklist-Revised (PCL-R), which has served as a stan-
dard in psychopathy assessment for many years
(Table 8.1). Merging Cleckley’s model with the objective
behavioral criteria for Antisocial Personality Disorder in
the DSM-III, the PCL-R placed heavier emphasis upon
developmental and criminal factors in the condition
while still retaining several of the personality features
that were central to the Cleckley model, such as grand-
iosity, superficial charm, and callousness. Items such
as “Fantastic and uninviting behavior with drink and
sometimes without” were dropped as criteria for the
disorder in favor of more concrete behavioral obser-
vations such as juvenile delinquency and history of
violations of conditional release. Even more recent
models of psychopathy, such as the Psychopathic
Personality Inventory-Revised (Lilienfeld et al., 2005),
have shifted toward personality models that emphasize
traits over behavioral history, and the centrality of
criminal behavior to the construct of psychopathy
has been hotly debated in recent years (Hare and
Neumann, 2010; Skeem and Cooke, 2010a,b).
Despite the PCL-R’s added focus upon antisocial
behavior and recent revisions to the criteria for antisocial
personality disorder (ASPD) in the DSM-5, psychopathy
and ASPD are still separate, albeit increasingly overlap-
ping, constructs (e.g., Hart and Hare, 1996; Poythress
et al., 2010; Ogloff et al., 2016). Psychopathic persona-
lity traits, although more important in the most recent
revision to the ASPD criteria, remain optional features
of the disorder rather than necessary for its diagnosis.
Although the majority of people with high PCL-R scores
meet criteria for an ASPD diagnosis, only a small per-
centage (5.5%, according to Ogloff et al., 2016) of
patients with ASPD are high in psychopathic traits.
Thus, a person with a consistent history of impulsive,
antisocial behavior would have a relatively high chance
of meeting criteria for a diagnosis of ASPD, but would
most likely fall short of a full psychopathy diagnosis
based upon a PCL-R score.
Patients with acquired sociopathy due to ventrome-
dial circuit damage, on the other hand, display many
of the affective and social personality traits of psychop-
athy, as well as many similar impairments in decision-
making, but most lack the history of violent or callous
behaviors that are a large part of both the PCL-R and
ASPD criteria. Still, because both pseudopsychopathy
and acquired sociopathy lack formal definitions beyond
descriptive rubrics, the extent of overlap between these
conditions, psychopathy, and antisocial personality dis-
order remains difficult to quantify. The usage of both
the terms “psychopathy” and “sociopathy” within the
literature to refer to the similar but distinct conditions
of conventional psychopathy and ASPD further mud-
dies the delineations between the three conditions.
Table 8.1
Features of ventromedial prefrontal damage, acquired sociopathy, and psychopathic personality.

Psychopathic Personality
Common changes after Inventory-Revised
ventromedial prefrontal damage Characteristics of syndrome of acquired Hare Psychopathy Checklist-Revised (Lilienfeld and Widows,
(Damasio et al., 2013) sociopathy (Tranel, 2002) (Hare, 1991) 2005)

● Inability to organize future activity ● General dampening of emotional Factor 1—Interpersonal/Affective Factor 1:
and hold gainful employment experience Facet 1—Interpersonal
● Tendency to present a favorable view ● Poorly modulated emotional reactions ● Social potency
of themselves ● Disturbances in decision-making ● Glibness/superficial charm ● Fearlessness
● Stereotyped but correct manners ● Disturbances in goal-directed ● Grandiose sense of self-worth ● Stress Immunity
● Diminished ability to respond to behavior ● Pathologic lying
● ●
Factor 2:
punishment and experience pleasure Disturbances in social behavior Conning and manipulative behavior
● Diminished sexual and exploratory ● Marked lack of insight into
Facet 2—Affective ● Machiavellian
drives acquired changes
●
Egocentricity
Lack of motor, sensory, or
● Lack of remorse/guilt ● Impulsive
communication defects
● Shallow affect Nonconformity
● Overall intelligence within
● Callous/lack of empathy ● Blame Externalization
expectations based on educational and
● Failure to accept responsibility ● Carefree
occupational background
●
Nonplanfulness
Lack of originality and creativity Factor 2—Social deviance
● Inability to focus attention Facet 3—Lifestyle Other
● Recent memory vulnerable to
interference ● Need for stimulation/proneness to boredom ● Coldheartedness
● A tendency to display inappropriate ● Impulsivity
emotional reactions ● Parasitic lifestyle
● Irresponsibility
● Lack of realistic, long-term goals
Facet 4—Antisocial

● Poor behavior controls

● Early behavioral problems
● Juvenile delinquency
● Revocation of conditional release
● Criminal versatility
Other

● Promiscuous sexual behavior

● Many short-term marital relationships
156 J. REBER AND D. TRANEL
We will therefore use the terms pseudopsychopathy and
acquired sociopathy interchangeably to refer to the
neurologic syndrome resulting from damage to the ven-
tromedial prefrontal circuit, and we will use the term
psychopathy or psychopathic traits to refer to the per-
sonality traits delineated within the PCL-R and PPI-R
conceptualizations of psychopathy.
Characteristics of acquired sociopathy and
psychopathy
PERSONALITY
The most rigorous assessments of the personality
changes resulting from ventromedial prefrontal circuit
lesions to this date were conducted by Barrash et al.
(1997, 2000, 2011), who tested multiple patients with
acquired sociopathy on a battery of several established
and novel personality assessments. They found that
many standard personality measures, including the Min-
nesota Multiphasic Personality Inventory-2 (MMPI-2;
Butcher et al., 1989), the structured interview for
DSM-III-R Personality Disorders (Pfohl et al., 1989),
and the PCL-R, did not appear to capture the social
dysfunction and personality disturbances that were evi-
dent from the patients’ established behavioral histories
and collateral reports (Barrash et al., 1994). This discon-
nect between the assessment results and clinical observa-
tions can be explained as a combination of a few key
factors: first, the majority of standard personality assess-
ments rely to some degree upon accurate self-report, and
patients with ventromedial prefrontal damage display a
prominent lack of insight (anosognosia) into their own
acquired impairments (Barrash et al., 2000; Tranel,
2002). Second, patients with acquired sociopathy have
normal premorbid functioning, personalities, and social
knowledge, and remain capable of normal sociomoral
reasoning on abstract measures even after their lesions
(Saver and Damasio, 1991). Finally, standard personality
assessments measure current functioning, rather than
change in functioning, which is the key feature of
acquired sociopathy (Koenigs and Tranel, 2006).
To address this, Barrash et al. (1997) developed the
Iowa Rating Scales of Personality Change, later revised
to the Iowa Scales of Personality Change. Rather than
relying upon self-report assessments to measure person-
ality changes in patients with poor insight into their
own impairments, the Iowa Scales of Personality Change
reflect collateral ratings of changes in 30 different per-
sonality characteristics. In comparison with patients
with lesions outside of the ventromedial prefrontal
circuit, individuals with focal, bilateral damage to the
ventromedial circuit were rated by their spouses or
family members as displaying significantly dampened
emotional experience, poorly modulated emotional
reactions, decision-making impairments, impairments
in goal-directed behavior, and lack of insight after their
lesions. Importantly, these changes were not only com-
mon to patients with bilateral damage to the ventromedial
circuit, but also specific to those patients. Individuals
with brain damage occurring outside of the circuit dis-
played few, if any, of the personality disturbances noted
in the patients with ventromedial damage. These findings
served to empirically corroborate the profile of acquired
sociopathy that had previously been based exclusively
upon clinical observations of patients, such as Phineas
Gage and EVR, who had suffered damage to the ven-
tromedial prefrontal circuit. Even beyond the common
personality features such as irresponsibility, impulsivity,
difficulty with planning, there is significant overlap
between psychopathy and the symptoms of damage
to the ventromedial prefrontal circuit. Key aspects of
both conditions—e.g., poor planning and decision-
making, lack of empathy and social impairment, and
low frustration tolerance—have been observed not only
qualitatively but also in behavioral and psychophysi-
ological assessments of both psychopathic individuals
and patients with ventromedial prefrontal lesions.
DECISION-MAKING
Not only do patients with ventromedial circuit damage
and individuals high in psychopathic traits display
poor decision-making in their daily lives, they also per-
form poorly on laboratory tests of decision-making.
Although Saver and Damasio (1991) had previously
observed that individuals with ventromedial circuit
lesions performed normally on Kohlbergian moral rea-
soning tasks, Koenigs et al. (2007) found that there were
subtle but consistent alterations in the moral judgments
of individuals after ventromedial prefrontal damage.
When presented with difficult moral dilemmas that
offered a forced choice between directly causing harm
to an individual and indirectly causing harm to several
people, both patients with acquired sociopathy and peo-
ple high in psychopathic traits agreed to sacrifice others
for the greater good at an abnormally high rate (Bartels
and Pizarro, 2011). For instance, when presented with
an abstract moral dilemma asking whether they would
smother a crying infant in order to prevent a group
of people from being discovered and killed by enemy
soldiers, both groups answered in the affirmative
significantly more often.
Unlike individuals with executive functioning imp-
airments stemming from lesions to the dorsolateral pre-
frontal circuit, patients with ventromedial prefrontal
circuit lesions display little to no impairment on the
Wisconsin Card Sort Task or the N-back task. However,
both ventromedial prefrontal circuit lesions and high
 FRONTAL LOBE SYNDROMES
levels of psychopathic personality traits have been asso-
ciated with poor performance on the Iowa Gambling
Task (IGT), a computerized card-choice task designed
to simulate the complexity and uncertainty found in
real-world decision-making (Bechara et al., 1994). The
IGT was initially created specifically as an alternative
to established neuropsychologic tests to assess the
decision-making deficits of patients with ventromedial
prefrontal lesions whose deficits do not appear on other
intelligence, memory, or executive functioning tests
(Bechara et al., 1994, 1996, 2000). During the task, par-
ticipants are instructed to win as much virtual money as
possible by choosing repeatedly between four decks of
cards over a series of trials. Two decks are advantageous,
offering moderate rewards interspersed with occasional
penalties, and two are disadvantageous, providing larger
rewards with severe penalties that lead to net losses.
Although neurologically healthy participants typically
learn to draw almost exclusively from the advantageous
decks, patients with acquired sociopathy consistently do
poorly on the task, drawing heavily from the disadvanta-
geous decks even after they can explicitly describe the
contingencies of each deck (Fig. 8.7). Administration
of the IGT to both juveniles and adults with high levels
of psychopathic traits has revealed similar patterns
of deficits on the task (Blair, 2001; Mitchell et al.,
2002; van Honk et al., 2002).
Additional research upon the task by Bechara et al.
revealed that, relatively early in the task, neurologically
healthy participants would begin to generate an increased
anticipatory skin conductance response (SCR) when they
were choosing from disadvantageous decks. A further
study showed that this anticipatory SCR occurred
even before participants could identify the contingencies
of the decks (Bechara et al., 1997). Patients with ventro-
medial prefrontal lesions who performed poorly on
the IGT, on the other hand, showed reduced anticipa-
tory autonomic arousal when choosing from the
disadvantageous decks for the entire duration of the
task, despite the fact that several of them could explain
which decks were advantageous and disadvantageous
at the end (Bechara et al., 1996, 1997). This led some
of the authors to theorize that the loss of psychophy-
siological, “somatic” responses in anticipation of poten-
tially negative experiences was one of the fundamental
deficits underlying the decision-making impairments
of patients with damage to the ventromedial prefrontal
circuit (Damasio, 1994, 1996, 1999). Importantly, this
key characteristic of acquired sociopathy mirrored
Lykken’s (1957) observation that psychopathic indi-
viduals displayed less autonomic arousal in anticipa-
tion of electric shocks, which correlated with reduced
avoidance of punished responses on an avoidance-
learning task.
157
This type of hypoactive psychophysiological res-
ponse to socially and emotionally salient stimuli is a
key behavioral correlate of psychopathy and a common
result of damage to the ventromedial prefrontal circuit,
one that has been hypothesized to underlie the social
impairments and lack of empathy associated with
both conditions (Damasio, 1996). Classic findings in
psychopathy research, for example, have shown that
people scoring higher on measures of psychopathy
tend to exhibit lower physiological arousal to seeing
other people in pain (House and Milligan, 1976;
Aniskiewicz, 1979) and seeing fearful people (Blair
et al., 1997). Likewise, damage to the ventromedial pre-
frontal circuit has been associated with reduced auto-
nomic arousal in reaction to social stimuli, including
photos of nude people and injuries (Damasio et al.,
1990). Furthermore, both psychopathy and acquired
sociopathy have been associated with impairments in
identifying emotions, especially fear and disgust, based
on facial expressions (Hornak et al., 1996; Blair et al.,
1997; Kosson et al., 2002).
Although the decision-making impairments that
occur after damage to the ventromedial frontal circuit
have been primarily observed in sociomoral and affec-
tive domains, there is evidence that ventromedial les-
ions impair general neurocognitive mechanisms of
goal-directed behaviors. Wheeler and Fellows (2008),
for instance, found that patients who had suffered
ventromedial prefrontal lesions performed poorly on
a probabilistic reinforcement learning task. They further
elucidated that this deficit was not due to difficulty
learning to discriminate between the stimulus contingen-
cies, nor was it due to a lack of responses to a stimulus
paired with reward. Patients with ventromedial lesions,
however, were much less likely to avoid a stimulus
that had previously been paired with punishment. This
selective insensitivity to negative feedback and hyper-
sensitivity to reward mirrors classic research in psycho-
pathy, showing that individuals high in psychopathic
traits are relatively insensitive to punishment, especi-
ally when presented with competing reward cues
(e.g., Newman and Kosson, 1986; Blair et al., 2004).
This change in reward processing appears to extend
beyond conscious cognition—a study by Manohar and
Husain (2016) of patients with acquired sociopathy
found that they were hypersensitive to reward cues on
a task measuring the effect of reward cues upon eye
saccade velocity. This basic impairment in the processing
of reward values may lead to some of the more unusual
behavioral consequences of ventromedial prefrontal
circuit damage. Anderson et al. (2005), for instance,
reported several cases of patients with ventromedial
lesions who had amassed enormous collections of use-
less objects, such as old newspapers, broken appliances,
158 J. REBER AND D. TRANEL

Fig. 8.7. Iowa Gambling Task. Individuals with lesions to the vmPFC typically choose cards from the disadvantageous decks
throughout the task, leading to a net loss. Neurologically healthy individuals typically learn to avoid the disadvantageous decks
early on, and eventually draw almost exclusively from the advantageous decks. Reproduced with permission from Reber J, Tranel
D (2017). Sex differences in the functional lateralization of emotion and decision making in the human brain. J Neurosci Res 95:
270–278. Adapted from Bechara A, Damasio H, Damasio AR (2000). Emotion, decision making and the orbitofrontal cortex.
Cereb Cortex 10: 295–307.

and rotting food. Some patients had such large coll-
ections that it was nearly impossible to navigate their
living spaces. Further research has found that patients
with ventromedial prefrontal lesions exhibited impair-
ments on a classic reinforcer devaluation task, continuing
to expend abnormal amounts of effort to win food
rewards that they had already eaten to satiation (Reber
et al., 2017). Even after they reported being too full to
eat any more of a given food, the patients would not alter
their behaviors in order to win different rewards.
The low tolerance for frustration and reactive anger
that have been documented in both psychopathic indi-
viduals and patients with ventromedial circuit lesions
also have loosely corresponding laboratory findings.
Koenigs et al. (2007, 2010), for instance, have reported
similarities in the behavioral patterns of psychopaths and
ventromedial lesion patients on economic tasks. In con-
trast with healthy comparison participants, both indi-
viduals high in psychopathic traits and patients with
acquired sociopathy showed relatively low acceptance
 FRONTAL LOBE SYNDROMES 159
rates for unfair offers on the Ultimatum game, a neuro-
economic task in which participants were offered a share
of a set monetary amount (e.g., they were offered $2
out of a $10 pot, with the individual making the offer
receiving the remaining $8) and had to choose whether
to accept or refuse the offer, in which case both the
participant and the individual allocating the money
received nothing. Nevertheless, both groups made far
more unfair offers than nonpsychopathic and nonbrain-
damaged comparison groups in the Dictator game, in
which the participants simply made the allocations
themselves with no chance of offers being rejected.
The authors of these studies theorized that both groups
rejected unfair offers at a higher rate due to a low thres-
hold for anger. Moreover, when Krajbich et al. (2009)
tested several patients with ventromedial prefrontal
circuit lesions on a similar battery of economic games,
they found that the abnormal offers made by the patients
in the Ultimatum and Dictator games appeared to be Fig. 8.8. Coronal MRI images and a surface rendering of
driven by those patients’ insensitivity to guilt, another B.W.’s brain; the site of the lesion is marked by arrows and
highlighted in the image. Modified from Boes AD, Grafft
key trait in psychopathy. These similarities in the beha-
AH, Joshi C, et al. (2011). Behavioral effects of congenital
vioral correlates of both conditions, along with the ventromedial prefrontal cortex malformation. BMC Neurol
original qualitative observations of abnormal social 11: 151, under Creative Commons License BY 2.0.
behaviors in early case studies of individuals like Gage
and EVR, add to a growing literature implying that
psychopathy and acquired sociopathy have a great
Illustrative case
deal in common.
One notable developmental case, reported by Boes et al.
(2011), demonstrated multiple psychopathic personality
Early-onset lesions
traits that patients with adult-onset ventromedial circuit
To add further complexity, there is a growing literature lesions rarely display, such as a penchant for manipula-
on patients with “developmental” lesions to the ven- tive deception and domineering, violent behaviors. The
tromedial circuit acquired at an early age and individuals patient, known as B.W., was originally admitted to the
with congenital malformations of the ventromedial pre- hospital at the age of 4 years after experiencing seizures,
frontal cortex. Not only do they display the typical aff- and was diagnosed with a lesion to the ventromedial pre-
ective and social abnormalities found in the adult-onset frontal circuit thought to be caused by Taylor type focal
ventromedial prefrontal lesion patients, but the early- cortical dysplasia along the gyrus rectus (Fig. 8.8). As the
onset ventromedial lesion patients have behavioral patient grew older, his seizures were managed with
histories that are starkly similar to high-scoring psycho- medications with limited success, but his behaviors grew
paths, including risky sexual behaviors, pathologic dis- increasingly antisocial and out of control. In contrast
honesty, significant criminal records, and a marked with his five well-behaved biological siblings, he was
lack of guilt or remorse (Anderson et al., 1999, 2000, aggressive and disobedient, prone to stealing and lying.
2006; Eslinger et al., 2004; Boes et al., 2011). In assess- He was intelligent but manipulative, often convincing his
ments of explicit moral judgment, they differ signifi- friends to steal from their parents, and even going so far
cantly from adult-onset ventromedial circuit lesion as to feign depression and suicidal ideation in an attempt
patients, rating actions that harm others for self-serving to acquire a cell phone. He was seemingly indifferent to
purposes as morally appropriate at a much higher punishment, repeatedly engaging in behaviors that had
rate than both adult-onset patients and neurologically recently been punished. By the age of 14, he had pur-
healthy comparisons (Taber-Thomas et al., 2014). posely started fires at his home and church, attempted
Unlike the adult-onset patients, who give normative to break into a house with a box cutter and a hammer,
answers to dilemmas that pit self-interest against moral assaulted his school principal, threatened his mother
norms, such as “Would you lie on your taxes to save with a knife, and attacked his father with a crescent
money?,” the developmental-onset patients endorsed wrench. Despite all of his behavioral problems, B.W.
these self-serving actions at a much higher rate. was otherwise developmentally normal.
160 J. REBER AND D. TRANEL
Evidence from the developmental-onset patients such
as B.W. suggests a closer and perhaps even causal relation-
ship between ventromedial prefrontal circuit damage and
psychopathic traits, the severity of which may be moder-
ated by the age of lesion onset (earlier lesions causing
more severe disturbances). However, the actual pres-
ence and severity of specific psychopathic traits in both
adult-onset and developmental-onset ventromedial les-
ion patients have never been formally assessed, leaving
researchers with an incomplete picture of acquired socio-
pathy and the extent of the ventromedial prefrontal circuit’s
role in psychopathy and moral development in general.
Additionally, the resurgence of interest in moral
psychology and the neurologic basis of moral behavior
and cognition has led to an unfortunate conflation of
psychopathy and acquired sociopathy, leading to a wide-
spread belief that damage to the ventromedial prefrontal
circuit turns individuals into remorseless psychopaths.
As more researchers seek to cross-fertilize and recon-
cile the established findings from the lesion studies on
acquired sociopathy with the growing neuroimaging
literature on psychopathy, many researchers appear to
assume that the conditions produce exactly the same
patterns of behavior. Furthermore, increasing efforts in
recent years to identify biologic and neurologic cor-
relates of psychopathy have led to further misidentifica-
tion of psychopathy as a brain disorder synonymous with
damage to the ventromedial prefrontal circuit. Although
various forms of neuroimaging have correlated levels
of psychopathic traits with lower activation in the ventro-
medial prefrontal cortex during tasks such as emotional
word viewing and aversive conditioning, the same tasks
have also identified several other brain regions correlated
with psychopathy, such as the superior temporal sulcus
and the dorsal anterior cingulate cortex (Blair, 2007;
Yang et al., 2008). While the converging behavioral
and neuroimaging evidence suggests that dysfunction
in the ventromedial circuit plays a significant role in
psychopathy, it is unclear which elements of psychopa-
thy, if any, are the direct results of abnormal ventromedial
prefrontal activity (Kiehl, 2008).
Laterality
Although the majority of instances of acquired sociopa-
thy arise from bilateral lesions to the ventromedial cir-
cuit, there is evidence that unilateral damage to the
circuit can be sufficient to cause significant changes in
personality (Meyers et al., 1992). Even a recent recon-
struction of Phineas Gage’s brain by Ratiu et al. (2004)
has posited that the damage in that landmark case was
unilateral and limited to the left frontal lobe, challenging
previous findings by Damasio et al. (1994) that the lesion
causing Gage’s severe personality changes was bilateral.
Furthermore, there is evidence that the functions under-
lying the ventromedial prefrontal circuit are often latera-
lized. Tranel et al. (2002) documented multiple cases of
personality changes, social impairments, and decision-
making deficits in individuals with unilateral lesions
to the ventromedial circuit, with patients who had lesions
in their right hemispheres showing considerably more
severe deficits in all three categories. However, this
right-side hemispheric dominance only appeared to hold
true for the male participants in the study; the single
female participant with a right hemisphere lesion showed
only mild symptoms. Following up on this result, Tranel
et al. (2005) found that sex modulated the functional lat-
eralization of the ventromedial circuit. Right-side lesions
caused acquired sociopathy and severe decision-making
impairments in men, but not women, and left-side lesions
had far direr consequences for women than for men.
Further research has found evidence that sex modulates
the functional lateralization of nonprefrontal structures
that are part of the ventromedial circuit, such as the
amygdala (Cahill, 2006; Sutterer et al., 2015; Reber
and Tranel, 2017).
Anatomy and common etiologies
The ventromedial prefrontal circuit includes the ventral
portions of the medial prefrontal cortex as well as
the medial surface of the orbital surface of the frontal
lobes, directly superior to the orbital plate of the frontal
bone. The cortical areas contained within the ventrome-
dial prefrontal circuit are heterogeneous and are linked
more by their susceptibility to lesions than by their
cytoarchitectonic similarity. This large region of the pre-
frontal cortex is especially vulnerable to damage from
multiple sources. Besides being affected by several neu-
rodegenerative diseases, its location atop the orbital bone
places it at a high risk of damage due to rapid acceleration
or deceleration, and closed-head trauma often affects
the region. Traumatic injuries to this region, however,
are seldom limited to the orbitofrontal area, and often
cause diffuse damage to white matter tracts as well as
other prefrontal circuits, such as the medial frontal circuit
(leading to a high incidence of apathy in cases of trau-
matic brain injury). Olfactory groove meningiomas aris-
ing from the cribriform plate and frontal sphenoidal
suture are the most common neoplasms in this region,
and due to the subtle effects and slow growth of orbito-
frontal meningiomas, they are often only detected once
they have grown to substantial size, causing significant
neurologic damage (Anderson et al., 1990; Adappa
et al., 2011). Furthermore, the anterior communicating
artery, which rests directly below the orbitofrontal cor-
tex, is particularly susceptible to aneurysm formation,
accounting, by some reports, for nearly a full quarter
 FRONTAL LOBE SYNDROMES
of cerebral aneurysms (Castro et al., 2009). Cons-
equently, there is a high incidence of hemorrhagic
lesions to the region. This vulnerability has led to a
high rate of damage to the orbitofrontal cortex rela-
tive to the mediodorsal and dorsolateral regions of
the prefrontal cortex.
CONCLUSIONS AND FUTURE
DIRECTIONS
The prefrontal cortex remains one of the most intriguing
and enigmatic cortical brain regions, and while many
important discoveries have been reported in the past
several decades, there is clearly much to be learned
about how varied complex human functions are sub-
served by prefrontal areas and circuits. One direction
that appears especially promising is the potential of
combining traditional neuropsychologic approaches
(e.g., lesion-deficit studies) with functional imaging
approaches, especially functional connectivity and brain
network information. For example, such an approach
was used recently to illustrate why lesions in apparently
remote brain regions could be systematically related to
poor performance on a quintessential “frontal lobe
task,” namely, the Iowa Gambling Task (Sutterer et al.,
2016). Although research using the lesion method is
naturally predisposed toward a localization model of
brain function—observing which functions are specifi-
cally impaired by damage to specific regions—the mod-
ern surge in functional imaging research means that
it is now more possible for lesion researchers to inves-
tigate which circuits and functional networks are
damaged by focal lesions (Boes et al., 2015).
One way to approach this question is by using fMRI
approaches in patients with focal lesions, to study plas-
ticity and recovery of function. For example, in some
patients with vmPFC lesions, we have found that there
is remarkable preservation of many activation patterns
during social decision-making tasks, provided the neural
sites are relatively distal to the lesion site and provided
there is no concomitant behavioral impairment: thus
there is clearly compensatory function. However, there
are certain regions that fail to be activated in specific
tasks, demonstrating a breakdown in the network
(presumably caused by the lesion) that prevents the
behavioral deficit from being successfully compensated.
Other nonlesion or virtual-lesion approaches that sys-
tematically manipulate neural activity using invasive
and noninvasive techniques can also yield valuable
data with more neurologic specificity than most naturally
occurring lesions. These types of approaches will
be important methods for furthering our understanding
of the complexities of the human prefrontal cortex.
161
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