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Neuropsychology
Neuropsychology
A Review of Science and Practice, III
Edited by
Sandra Koffler
Independent Practice
Philadelphia, Pennsylvania
E. Mark Mahone
Kennedy Krieger Institute
Johns Hopkins University School of Medicine
Baltimore, Maryland
Bernice A. Marcopulos
James Madison University
Harrisonburg, Virginia
University of Virginia
Charlottesville, Virginia
Douglas Johnson-Greene
Miller School of Medicine
University of Miami
Miami, Florida
Glenn Smith
Clinical and Health Psychology
University of Florida
Gainesville, Florida
1
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Names: Koffler, Sandra, editor. | Mahone, E. (E. Mark), editor. | Marcopulos, Bernice A., editor. |
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Title: Neuropsychology : a review of science and practice, volume III / edited by Sandra Koffler, E. Mark
Mahone, Bernice A. Marcopulos, Douglas Johnson-Greene, Glenn Smith.
Description: New York, NY : Oxford University Press, [2019] | Includes bibliographic references.
Identifiers: LCCN 2018035009 | ISBN 9780190652555
Subjects: LCSH: Clinical neuropsychology. | Neuropsychiatry.
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Contents
Preface to Volume III vii

Contributors ix
1. Studies in Cannabis Use: Year in Review 1

Ileana Pacheco-Colón, Jacqueline C. Duperrouzel, and Raul Gonzalez
2. Hypertension and Cognitive Impairment in Older Adults: Review and

Update 22
Richard F. Kaplan and Lauren Strainge
3. Technologically Enhanced Neuropsychological Assessments:

Review and Update 59
Thomas D. Parsons and Robert Kane
4. Cross-Cultural Tests in Neuropsychology: A Review of Recent Studies and

a Modest Proposal 93
Alberto Luis Fernández and Bernice A. Marcopulos
5. Interventions for Functional Impairments 129

Alyssa Weakley and Maureen Schmitter-Edgecombe
6. Recent Research Trends in the Neuropsychology of HIV Disease 171

David P. Sheppard, Savanna T. Tierney, Kelli L. Sullivan, Victoria M. Kordovski,
Gunes Avci, and Steven Paul Woods
7. Parkinson’s Disease: Recent Strides 211

Alexander I. Tröster
8. Pediatric Epilepsy Update 243

Madison M. Berl
Index 277
v
PREFACE TO VOLUME III
This, the third volume of the series Neuropsychology: A Review of Science and Practice,
will provide the reader with timely and comprehensive reviews of the literature rel-
evant to clinical neuropsychology and related professions. Unique to this series, the
practitioner, investigator, and student will find that the chapters in Volume III con-
tribute to practice in its most broad definition: in the office, the laboratory, and the
classroom. The reviews in this volume provide resources for furthering ongoing re-
search, providing incentives for new studies and enhancing our value and service to
patients. Following is a brief summary of the chapters.
In Chapter 1, on cannabis and neurocognition, Pacheco-Colón, Duperrouzel, and
Gonzalez report their review of 30 neurobehavioral and neuroimaging studies. They
found that the non-acute effects of cannabis use are heterogeneous, but earlier onset
and heavier use are associated with memory and executive functioning deficits in
adults. The effects on adolescents are mixed. The authors conclude that in order to
further understand the long-term effects of cannabis use, confounding variables such
as cannabis composition and potency must be considered.
In Chapter 2, literature on arteriosclerosis, the small vessel disease of the brain,
is reviewed by Kaplan and Strainge for its association with age-related cognitive de-
cline, dementia, and possible late-life depression. The association of hypertension and
aging as risk factors for small vessel disease is reviewed, as well as the significant di-
agnostic studies that identify the associated brain lesions. Studies on the moderating
factor of cognitive reserve and the implications for clinical practice are presented.
Drs. Parsons and Kane, in Chapter 3, provide a state-of-t he-art technology review
of technology-enhanced assessment for the field of neuropsychology. The authors
consider advances in technology-enhanced assessment of specific conditions such
as attention deficit disorder, concussion, and cognitive aging. They discuss the dif-
ferent platforms (e.g., web-based vs. tablet-based) for administering more classic as-
sessment paradigms. Parsons and Kane explore how neuropsychology practitioners
may engage in telemedicine to expand access to clinical services. They further ex-
plore how technology can be deployed to enhance ecologically valid assessments.
This chapter is a primer on how ubiquitous technology is changing the status quo.
Chapter 4, on cross-cultural tests, reviews recent literature on cross-cultural neu-
ropsychological assessment with a focus on adults. Three methods for addressing this
issue are evaluated by Fernández and Marcopulos: (1) adapting existing tests through
language translation and norm development; (2) developing new tests specific to the
culture of interest; and (3) developing universal tests that can be adapted and used
with any language and culture.
vii
viii preface to volume iii
In Chapter 5, on interventions for functional impairments, Weakley and Schmitter-

Edgecombe observe that many neurological conditions result in functional deficits
with an inability to perform occupational tasks and activities of daily living that are
necessary for a person to remain living independently. Neuropsychological tests en-
able us to understand the relationship between cognitive and functional impairments
and provide evidenced-based interventions. This chapter highlights cognitive inter-
vention approaches, compensatory strategies, and assistive technology, such as vir-
tual reality, aimed at improving and promoting functional independence and quality
of life for persons with functional impairments.
Chapter 6, on the neuropsychological effects of HIV, summarizes an extensive
literature pertaining to cognition and HIV, including the latest findings on HIV-
associated neurocognitive disorders (HAND) and the influence of clinical, demo-
graphic, and other moderating factors. Sheppard, Tierney, Sullivan, Kordovski, Avci,
and Woods review the latest data on prevalence and screening and the impact of
HAND on functioning, as well as its treatment with pharmacological interventions
and cognitive rehabilitation.
The cognitive findings in patients with Parkinson’s disease are reviewed by Tröster
in Chapter 7, with emphasis on the role of clinical neuropsychology in documenting
the changes that may take place. Included are studies evaluating individuals at risk
for Parkinson’s disease, the Parkinson’s associated risk Syndrome (PARS), and per-
sons who are genetically at risk. Mild cognitive impairment is reviewed with respect
to different presentations (subtypes) and their implication for further cognitive de-
cline. The validity of differences in screening instruments is discussed.
Epilepsy is a common neurological disorder among children but is not unitary;
rather, epilepsy is a complex set of disorders that often co-occur with several other
neurodevelopmental disorders. In Chapter 8, on pediatric epilepsy, Berl provides an
opportunity for neuropsychologists to update their practice and contributes to our
understanding of the field, reporting advances in neurosurgery, genetics, pharmaco-
logical treatment, neuroimaging, and big data analysis.
CONTRIBUTORS
Gunes Avci Victoria M. Kordovski

Department of Psychology Department of Psychology
University of Houston University of Houston
Houston, Texas Houston, Texas
Madison M. Berl Bernice A. Marcopulos

Division of Neuropsychology Department of Graduate Psychology
Children’s National Health System James Madison University
Washington, DC Harrisonburg, Virginia
Department of Psychiatry and
Jacqueline C. Duperrouzel
Neurobehavioral Sciences
Center for Children and Families
University of Virginia
Department of Psychology
Charlottesville, Virginia
Florida International University
Miami, Florida Ileana Pacheco-Colón
Alberto Luis Fernández
Universidad Católica de Córdoba
Miami, Florida
Universidad Nacional Córdoba
Cordoba, Argentina Thomas D. Parsons
Computational Neuropsychology and
Raul Gonzalez
Simulation Laboratory
NetDragon Digital Research Center
Department of Learning Technologies
University of North Texas
Miami, Florida
Denton, Texas
Robert Kane
Maureen Schmitter-Edgecombe
Cognitive Consults and
Technology, LLC
Washington State University
Washington, DC
Pullman, Washington
Richard F. Kaplan
David P. Sheppard
Departments of Psychiatry and
Neurology
University of Houston
University of Connecticut Health
Houston, Texas
Farmington, Connecticut
ix
x contributors
Lauren Strainge Alexander I. Tröster

Department of Psychological Sciences Department of Clinical
University of Connecticut Neuropsychology and Center for
Stores, Connecticut Neuromodulation
Barrow Neurological Institute
Kelli L. Sullivan
Phoenix, Arizona
University of Houston Alyssa Weakley
Houston, Texas Department of Psychology
Washington State University
Savanna T. Tierney
Pullman, Washington
University of Houston Steven Paul Woods
Houston, Texas Department of Psychology
University of Houston
Houston, Texas
1
Studies in Cannabis Use
Year in Review
Ileana Pacheco-Colón, Jacqueline C. Duperrouzel,

and Raul Gonzalez
INTRODUCTION
Many patients presenting for neuropsychological assessments, in either the clinic or
the laboratory, have used cannabis at some point in their lives. During 2015, 44%
of Americans over 12 years of age reported ever having used the drug and 8.3%
endorsed past-month use (Center for Behavioral Health Statistics and Quality, 2016).
Among 12th graders, 45% have used cannabis and 23% have used in the past month
(Johnston, Miech, O’Malley, Bachman, & Schulenberg, 2016). Annual prevalence of
use rose from 24% during 1991 to 36% during 2016 among 12th graders. Concurrently,
public opinion toward legalization of cannabis has become more permissive. When
the Pew Research Center began surveying, in 1969, public opinion toward cannabis
legalization, 12% supported legalization, whereas 84% did not (Pew Research Center,
2016). A reversal occurred more recently, with 57% of Americans supporting and
37% opposing cannabis legalization during 2016. Consistent with these trends, 28
U.S. states have passed medical marijuana laws and 8 have legalized recreational use
for adults over the age of 21. These trends can also be observed around the world. For
instance, Uruguay legalized recreational use, while other countries such as Germany,
Canada, Argentina, Czech Republic, Italy, and Mexico have passed medical mari-
juana legislation. Also, in countries like the Netherlands and Spain, cannabis use is
decriminalized and largely tolerated.
Cannabis and its constituents are also the subject of research efforts focused on
medical applications. Results from studies examining the effectiveness of cannabis
as medicine suggest that it may be effective for treating nausea among patients with
cancer, anorexia among those with cancer or HIV, pain among patients with HIV or
multiple sclerosis (MS), and urinary dysfunction in those with MS (Borgelt, Franson,
Nussbaum, & Wang, 2013; Koppel et al., 2014). A recent meta-analysis examined
79 clinical trials and concluded that cannabinoids may be beneficial for nausea and
vomiting, pain reduction, and reduced spasticity (Whiting et al., 2015). If the trend for
medical cannabis continues to grow, one can expect additional patients presenting for
1
2 neuropsychology: a review of science and pr actice, iii
neuropsychological assessment with cannabis included in their list of medications,

particularly considering that many of the medical applications to date have focused
on disorders that affect the central nervous system (e.g., MS, epilepsy, HIV). Thus, it
could be argued that it is now more important than ever for neuropsychologists to be
aware of the effects of cannabis on neurobehavioral functioning in order to consider
its impact on observed test results and inform diagnostic decision-making.
The effects of cannabis on the central nervous system occur primarily through ac-
tivity at cannabinoid receptor type 1 (CB1) (Pertwee, 2006, 2008). CB1 receptors are
located throughout the cortex and densely concentrated in numerous brain regions
important for cognition and psychomotor functioning (Glass, Faull, & Dragunow,
1997). Thus, it is not surprising that cannabis use (particularly when use is regular)
has an impact on neurobehavioral functioning. Two meta-analyses synthesized
results from studies examining associations between cannabis use and neuropsy-
chological functioning. Both focused on non-acute effects (i.e., when participants
were not acutely intoxicated) and included only studies that attempted to control
for critical confounds that would otherwise hamper interpretation of findings. The
meta-analysis by Grant, Gonzalez, Carey, Natarajan, and Wolfson (2003) included
15 studies, resulting in data from 704 cannabis users and 484 non-using controls.
Levels of cannabis use varied widely across and within study samples, ranging from
one to seven times per week to at least 22 days out of the previous 30 days. Overall,
evidence emerged for a “residual cannabis effect” that was statistically significant
but small in magnitude (effect size [ES] = −.15, 99% confidence interval [CI] [−.29,
−.02]), suggesting that cannabis users’ neuropsychological performance was about
one-sixth of a standard deviation (SD) worse than that of controls. For individual
neuropsychological domains, the only statistically significant effects were observed
for learning (ES = −.21, 99% CI [−.39, −.02]) and forgetting (ES = −.27, 99% CI [−.49,
−.04]). A more recent meta-analysis by Schreiner and Dunn (2012) used guidelines
for study inclusion and grouping of neurocognitive domains that were similar to
those used by Grant et al. (2003) but included only studies published since 2000,
to minimize overlap. Their analyses included 33 studies, yielding 1,010 cannabis
users and 839 controls. An overall negative association between cannabis use and
neuropsychological functioning was also observed (ES = −.29, 95% CI [−.46, −.12]).
Significant detrimental effects of cannabis use were observed for learning (ES = −.35,
CI 95% [−.55, −.15]) and forgetting/retrieval (ES = −.25, CI 95% [−.47, −.02]), abstrac-
tion/executive functions (ES = −.21, CI 95% [−.38, −.05]), attention (ES = −.36, CI 95%
[ES = −.56, −.16]), motor skills (ES = −.34, CI 95% [−.57, −.11]), and verbal/language
(ES = −.23, CI 95% [−.47, −.001]). Thus, both meta-analyses suggest that cannabis
use is associated with poorer neuropsychological functioning, with the magnitude of
these effects hovering around one-t hird of a standard deviation.
This chapter reviews key studies published mainly in 2016 focusing on can-
nabis and neurobehavioral functioning, as well as those focusing on neuroimaging
outcomes. With the exception of a few studies, we focused on studies examining
effects of cannabis when individuals were not acutely intoxicated (as would be the
usual case in the clinic or laboratory). Our review is organized such that new review
3 Studies in Cannabis Use: Year in Review
articles and meta- analyses are discussed first, followed by new cross- sectional
studies, and finally a review of new longitudinal studies. Cross-sectional studies con-
tinue to yield valuable insights into the effects of cannabis and have been valuable
in advancing research in this area. Yet, they have an important limitation: they pre-
clude making strong causal inferences between use of cannabis and declines in neu-
ropsychological functioning. They do not answer the question, “Does cannabis use
cause declines in neuropsychological functioning?” Studies that assess how changes
in cannabis use prospectively influence changes in neuropsychological functioning,
compare neuropsychological performance before and after onset of cannabis use, or
make use of co-t win designs are more apt for inferring causation. Thus, we review
these studies separately. Although such studies have been rare in the past, they are
now rapidly emerging. Each section is further subdivided into neurobehavioral and
neuroimaging studies. Finally, we briefly summarize some notable studies that do
not fall neatly into the aforementioned categories but that we thought would still be
of interest to readers. We then offer a summary and conclusion.
REVIEWS AND META-A NALYSES

Neurobehavioral Studies
Several reviews examining the links between cannabis use and neurocognition were
published in 2016. Ganzer, Bröning, Kraft, Sack, and Thomasius (2016) conducted
a systematic review of 38 studies between 2004 and 2015 examining the residual
neurocognitive effects of cannabis use in adolescents and adults after a prolonged
period of abstinence. Overall, the findings regarding neurocognition were hetero-
geneous. Most studies reported some deficits in attention or concentration in absti-
nent cannabis users, as well as in different aspects of memory. There were, however,
mixed findings in the domains of inhibition, impulsivity, visuospatial functioning,
and decision-making. Although not many studies examined motor function, most of
those that did reported worse performance in abstinent users relative to non-using
controls even after prolonged abstinence. Furthermore, results suggested that neu-
ropsychological functioning in individuals who initiated cannabis use at an earlier
age was not significantly different from that of individuals with a later age of onset
(Ganzer et al., 2016).
On the other hand, a review by Curran et al. (2016) identified episodic memory
impairments as the most consistently reported long-term effects of cannabis use, while
findings for working memory, attention, and impulsivity were mixed. Somewhat
similarly, Broyd, van Hell, Beale, Yücel, and Solowij (2016) identified verbal learning
and memory as the neurocognitive domain most consistently impaired by acute and
long-term cannabis use. This review suggested that impairments in working memory,
attention, and psychomotor performance are observed with acute cannabis intoxica-
tion, and may persist with chronic cannabis exposure, but are often resolved with
long periods of abstinence (Broyd et al., 2016). Different subdomains of executive
functioning also appear to be differentially affected by acute and chronic cannabis
exposure. Specifically, there are clear acute impairments in inhibition, but the effects
on planning, problem solving, reasoning, and interference control are mixed (Broyd
et al., 2016).
Overall, findings on the effects of cannabis use on neurocognition appear heter-
ogeneous. As a possible explanation for this heterogeneity, Volkow et al. (2016) pos-
ited that the magnitude of neurocognitive impairment and the persistence of this
impairment after abstinence may depend on factors such as frequency and duration
of cannabis use, age of onset, and the length of the abstinence period. Furthermore,
the aforementioned reviews identify gaps in our knowledge and suggest areas for
future investigation, such as the neurocognitive effects of varying levels of cannabis
use at different stages of neural development (such as during adolescence), as well as
elucidating the effects of different types of cannabis (high vs. low potency; different
ratios of tetrahydrocannabinol [THC] to cannabidiol [CBD]) on neurocognition
(Broyd et al., 2016; Curran et al., 2016; Ganzer et al., 2016; Volkow et al., 2016).
Finally, Schoeler, Kambeitz, Behlke, Murray, and Bhattacharyya (2016) conducted
a meta-analysis investigating the effects of cannabis on memory performance in
healthy individuals and patients with psychosis. Across 88 studies comprising 7,697
healthy participants and 3,261 patients with psychosis, results revealed moderate ef-
fect sizes suggesting that cannabis use in healthy individuals was associated with sig-
nificantly impaired prospective memory, and small effect sizes for impaired global,
verbal immediate and delayed recall, and visual recognition. In those with psychosis,
however, there were small to moderate effect sizes suggesting that cannabis use was
associated with better global memory, visual immediate recall, and recognition rel-
ative to healthy cannabis users. Healthy cannabis users had higher depression scores
than age-matched non-users, and cannabis-using patients had lower depression levels
and were of a younger age than non-using patients. Thus, while cannabis appears to
have differential effects on memory for users with and without psychotic disorders,
these differences may have been due to the confounding influences of variables like
depression and age. Specifically, the lower level of depression and younger age of the
cannabis-using patients with psychosis may have attenuated the adverse effects of
cannabis on memory. Furthermore, longer duration of abstinence reduced cannabis
effects on memory across groups.
Neuroimaging Studies
Lorenzetti et al. (2016) conducted a review of 13 functional magnetic resonance im-
aging (fMRI) studies that involved tasks assessing working memory (e.g., N-back),
inhibition (e.g., go/no-go), and reward processing (e.g., monetary incentive delay
[MID]) in adolescents. All studies reviewed cross-sectionally compared healthy non-
using controls to cannabis user groups, with most samples smoking a mean of 400
lifetime occasions. Results suggested altered brain function in the frontal-parietal
network, a network thought to mediate cognitive control, particularly among heavier
users. Abnormalities reported across studies were heterogeneous across tasks, yet
hyperactivity in the posterior parietal region and medial prefrontal cortices was
consistently cited relative to non-cannabis-using controls. Hyper-and hypoactivity of

anterior cingulate cortex, superior frontal regions, and cerebellum were also reported
in abstinent users compared to controls. However, despite observed differences in
brain activation, there were no significant differences in behavioral task performance
between adolescent cannabis users and controls. The study samples reviewed were
relatively small (n = 7–28) and consisted of mostly male participants with an average
age of 18, which may limit the generalizability of these findings to other adolescent
cannabis users. Furthermore, few of these studies controlled for the influence of po-
tential confounds, such as other substance use and mental health problems.
Another review of 31 structural neuroimaging studies examined associations be-
tween levels of cannabis use and neuroanatomical alterations among adolescents
and adults (Lorenzetti, Solowij, & Yücel, 2016). Brain regions most consistently re-
ported as altered relative to non-using controls were the hippocampus (reductions in
volume and shape), amygdala, striatum, cerebellum, and orbitofrontal, parietal, and
insular cortices. Unsurprisingly, these regions, which are dense in CB1 receptors,
are thought to be most vulnerable to the neurotoxic properties of high levels and
exposure to THC during adolescence. The authors noted that CBD, a potentially
therapeutic compound found in cannabis, may provide neuroprotection to these re-
gions. Of note, recent changes in cannabis composition and potency may contribute
to these neural alterations, as low levels of CBD and high levels of THC are common
in recreational cannabis. Despite these findings, the wide array of measurements of
cannabis use and cannabinoid levels (i.e., dose, frequency, duration, age of onset) re-
ported across studies continues to be a limitation.
Similarly, a review by Weinstein, Livny, and Weizman (2016) of 103 structural and
functional studies suggested differences in gray matter and white matter volumes,
blood oxygenation level–dependent (BOLD) response, and neurotransmitter re-
lease between cannabis users (i.e., regular and recreational users) and non-users.
Definitions of regular cannabis use varied across studies. The authors concluded
that regular cannabis use was associated with no global structural changes, although
alterations were consistently reported in the hippocampus and parahippocampus,
as well as frontal and cerebellar regions. Additionally, alterations in BOLD re-
sponse in structures implicated in executive functioning, decision-making, atten-
tion, memory, inhibitory control, and emotional processing were identified among
users when compared to non-users during functional and resting-state neuroim-
aging. Structures with such alterations included the anterior cingulate, dorsolateral
prefrontal cortex, orbitofrontal cortex, amygdala, ventral tegmental area, thalamus,
and striatum. Reduced BOLD activity in limbic regions (i.e., amygdala and anterior
cingulate) was also consistently reported in cannabis users across multiple studies,
suggesting a disruption in emotional processing. Consistent findings of increased
striatal dopamine release (i.e., via [11C]-racloprid binding measurement in positron
emission tomography [PET] imaging) in cannabis users and healthy volunteers
under acute THC administration were also reviewed, highlighting cannabis effects
on dopamine transmission and its influence as a possible rewarding and motivating
mechanism for continued use. Furthermore, the pharmacological studies examined
suggested opposing effects of CBD and THC, with THC often inducing psychotic
symptoms and CBD acting as an antipsychotic and anxiolytic agent.
CROSS- S ECTIONAL STUDIES

Several cross-sectional studies published in 2016 examined the impact of age of
onset of cannabis use on adult neurocognitive performance. For instance, Schuster,
Hoeppner, Evins, and Gilman (2016) examined the association between age of
onset and learning impairments in a sample of 48 young adults who reported using
cannabis at least once a week, as compared to 48 age-and sex-matched non-users.
Users were classified according to age of first use, with early use defined as use at
or before age 16, and late use defined as use after age 16. Cannabis users with early
onset showed lower overall learning and worse delayed recall performance on the
California Verbal Learning Test–II (CVLT-II) than late-onset users and controls.
However, once delayed recall was adjusted based on the learning phase of the CVLT-
II, there were no significant between-group differences in delayed recall. Early-onset
users also evidenced significantly less semantic clustering than controls, though this
difference in learning strategy use did not mediate the association between onset of
cannabis use and delayed recall. Thus, these results suggest that the poor memory
performance typically associated with cannabis use may be explained by factors such
as age of onset and learning inefficiencies.
Similarly, Dahlgren, Sagar, Racine, Dreman, and Gruber (2016) assessed the im-
pact of different patterns of cannabis use on executive functioning, as measured by
the Stroop Color and Word Test and the Wisconsin Card Sorting Task (WCST).
Participants were 44 adult chronic, heavy cannabis users (used at least five times per
week) and 32 non-users. Users were subdivided into early onset (regular use before
age 16) and late onset (regular use at or after age 16), with “regular use” broadly de-
fined as cannabis use on a routine, expected, and consistent basis. Cannabis users
showed poorer performance on both the Stroop and WCST relative to non-users.
These differences, however, were driven by the performance of the early-onset can-
nabis users; late-onset users’ performance was similar to that of non-users. The as-
sociation between early onset and poorer performance on WCST was still present
after accounting for frequency and amount of weekly cannabis use, suggesting that
age of onset of regular cannabis use uniquely contributed to executive functioning
impairments. Though these findings are compelling, they are based on a sample
of heavy cannabis users and thus may not be generalizable to more occasional
cannabis users.
Taken together, these cross-sectional studies suggest that poor neurocognitive
performance by cannabis users may be explained, at least in part, by age of onset.
However, different definitions of “age of onset” make these findings harder to
interpret. While Schuster et al. (2016) classified users based on age of first use,
Dahlgren et al. (2016) classified them based on age of onset of “regular” cannabis
use (i.e., age at which they began using cannabis on a routine and consistent basis).
Even though both studies found that age of onset was important, future research
should examine whether age of first use or age of onset of regular use has a greater
impact on later outcomes and should be consistent in defining “regular” use in
order to facilitate better interpretation of findings (Crane, Schuster, Mermelstein,
& Gonzalez, 2015). Furthermore, although both studies used age 16 years as a
cutoff point between early and late onset, one classified age 16 onset as early and
the other as late onset.
Another set of cross-sectional studies from 2016 examined the effects of can-
nabis on various domains of neurocognition. For instance, Hirst, Young, Sodos,
Wickham, and Earleywine (2017) sought to explore whether the commonly reported
neurocognitive impairments in cannabis users could be due to a lack of effort put
forth during testing. They examined effort as a potential mediator of the association
between cannabis use and learning/memory performance in a sample of 62 young-
adult chronic cannabis users, defined as those using at least 4 days a week over the
past year. Participants completed a neurocognitive battery, which included tests
such as the CVLT-II and the Rey Complex Figure Test, as well as the Word Memory
Test, which assesses effort. Hirst et al. (2017) found that frequent cannabis users had
higher scores on the CVLT-II, thus failing to replicate previous research. However,
frequent cannabis use was associated with decreased effort, underscoring the impor-
tance of assessing effort with this population.
In order to examine the combined effects of cannabis and tobacco use on
neurocognition, Schuster, Mermelstein, and Hedeker (2016) employed an ecolog-
ical momentary assessment protocol in a sample of 287 community young adults.
The protocol involved a 7-d ay data-monitoring period in which participants used
handheld computers to complete assessments in real time. The devices provided
random prompts to the participants multiple times a day. Participants were also
instructed to initiate assessments immediately after smoking tobacco. During
both random and participant-initiated prompts, participants indicated whether
they had used cannabis or alcohol in the past hour. During these prompts,
participants also completed a brief spatial working memory task. Using a within-
subjects design, results indicated that working memory was poorer with cannabis
use (as well as alcohol use), but better with tobacco use. There was no interaction
between cannabis and tobacco use. Thus, tobacco use may compensate for the
adverse effects on working memory among young-adult cannabis users, as previ-
ously suggested in the context of episodic memory (Schuster, Crane, Mermelstein,
& Gonzalez, 2015).
Jakabek, Yücel, Lorenzetti, and Solowij (2016) conducted a cross-sectional study
using diffusion tensor imaging (DTI) examining differences in white matter
structure in a sample of 56 regular cannabis users compared to 20 non-u sers.
White matter integrity was assessed by deriving fractional anisotropy (FA),
axial diffusivity, and radial diffusivity maps from diffusion-weighted images.

Correlational analyses examined associations between the diffusion measures and
factors such as age of onset, as well as duration, frequency, and dose of current
cannabis use. Results revealed lower FA for cannabis users in the forceps minor
tract. Younger users also showed predominantly reduced axial diffusivity, while
older users showed higher radial diffusivity in widespread tracts. Duration of can-
nabis use was also associated with higher axial diffusivity in the cingulum angular
bundle. These findings suggest that cannabis use may alter normal brain matura-
tion, and this effect may be age related.
A cross-sectional study conducted by Orr, Paschall, and Banich (2016) used DTI,
voxel-based morphometry, and shape analyses to examine the white matter integ-
rity and subcortical morphometry in a subset of adult recreational cannabis users
(n = 466) from the Human Connectome Project (HCP) consortium, a large data-
base of neuroimaging data from a community sample. Participants completed the
Semi-Structured Assessment for the Genetics of Alcoholism, a self-report measure
used to quantify the number of times used and age of first use of cannabis on a 5-
point ordinal scale. Similar to Jakabek et al.’s (2016) study, white matter integrity
was measured by deriving FA, axial diffusivity, radial diffusivity, and mean diffu-
sivity maps from diffusion-weighted images. Also, analyses of voxelwise gray matter
morphometry were conducted to examine the effects of cannabis on cortical and
subcortical volumes, as well as cortical thickness across several regions of interest
(ROIs). Finally, shape analyses of subcortical ROIs (hippocampus, amygdala, nucleus
accumbens) were conducted. All analyses included age, sex, years of education, and
use of alcohol and tobacco as covariates. Results revealed that earlier age of onset
of cannabis use was associated with lower white matter coherence, as evidenced by
lower FA and higher radial diffusivity in long-range tracts, suggesting that adoles-
cent cannabis use may impact the development of white matter tracts. Although
there were no associations between cannabis use and cortical volume, earlier age of
onset was associated with abnormalities in nucleus accumbens shape, while number
of lifetime uses was linked to differences in the shape of the amygdala and hippo-
campus. Thus, these findings suggest that earlier onset of cannabis use is associated
with subtle structural changes in subcortical regions that are consistently implicated
in the process of addiction.
Additionally, Rigucci et al. (2016) used DTI to examine the effects of cannabis
potency on the microstructure of the corpus callosum in a sample of 56 first-episode
psychosis patients (37 of whom were cannabis users) and 43 healthy adults (22 of
whom were cannabis users), using similar metrics to those in the studies discussed
earlier. Frequent users of high-potency (i.e., high levels of THC and low levels of CBD;
“skunk-like”) cannabis had higher mean and axial diffusivity in the corpus callosum
than users of low-potency cannabis (i.e., hash-like) and non-users, with no effect in
the psychosis group, suggesting that corpus callosum integrity may be highly sensi-
tive to high levels of THC. These findings highlight the importance of examining the
effects of varying potencies, especially as use of high-potency cannabis is becoming
increasingly prevalent.
LONGITUDINAL STUDIES
In a prospective cohort study, Mokrysz et al. (2016) examined the association be-
tween adolescent cannabis use and IQ and educational outcomes in a sample of
2,235 adolescents from the Avon Longitudinal Study of Parents and Children. IQ
was assessed at ages 8 and 15, and educational performance data were collected at
ages 10–11 and 16. Users were categorized into five levels based on their cumulative
cannabis use frequency. Results indicated that cannabis users who had used can-
nabis at least 50 times by age 15 had lower IQ and poorer educational performance
at age 15 than those who had never used cannabis. However, after accounting for a
variety of potentially confounding variables, including pre-exposure IQ and educa-
tional performance, maternal and early life factors, childhood behavioral problems,
mental health, and adolescent use of other drugs, these associations were no longer
significant. Of these factors, cigarette use was the most influential in predicting edu-
cational outcome. These findings highlight the importance of accounting for poten-
tially confounding factors when examining the associations between cannabis use
and various outcomes. Of note, because the levels of cannabis use reported in this
sample were modest, it is possible that associations between cannabis use and IQ and
educational outcomes may manifest at higher levels of use.
Another longitudinal study, by Fishbein et al. (2016), examined the neurocognitive
characteristics associated with early onset of cannabis use. They followed a sample of
465 substance-naïve adolescents from a high-risk community from ages 10–12 at base-
line to ages 12–15. Participants underwent testing spanning multiple neurocognitive
domains, including IQ, memory, attention, decision-making, emotional perception,
and other executive functions. Results from a stepwise regression model revealed
significant associations between initiation of cannabis use and baseline performance
on neurocognitive tests, particularly on an Emotional Stroop Task, a task in which
children are asked to state the color that an emotional word (positive or negative)
is written in while disregarding the content of the word and which assesses cog-
nitive processing interference generated by emotional stimuli, as well as the Facial
Recognition Task (FACES). Specifically, misattribution of sad faces on the FACES
task and greater interference for positive than for neutral words on the Emotional
Stroop Task best predicted initiation of cannabis use. However, after controlling for
age, sex, and caregiver education, misattribution of sad faces on the FACES task was
the only significant predictor of initiation. The authors concluded that deficits in per-
ception of emotions may be a risk factor associated with early-onset cannabis use. It
is important to note, however, that this study focused on initiation of cannabis use;
more research is needed to understand the neurocognitive effects associated with
escalation in cannabis use.
Notably, Jackson et al. (2016) employed a co-t win design examining associations
between cannabis use and neurocognition using a sample of 3,066 twins from two
longitudinal cohorts. Twins from the Risk Factors for Antisocial Behavior (RFAB)
study underwent IQ testing at ages 9–10 and then again at 19–20, while those from
the Minnesota Twin Family Study (MTFS) underwent IQ testing at ages 11–12 and
17–19. Participants were classified as cannabis users or non-users, with users further
classified on the basis of whether they had used 30 or more times, as well as whether
they had been daily users for a period lasting 6–12 months. Across both cohorts,
results from mixed-effects linear regression revealed significant decreases over time
in Vocabulary and Information subtest performance in users relative to non-users.
After controlling for the confounding effects of age, sex, race, zygosity, and socioec-
onomic status, these differences persisted in the RFAB cohort but not in the MTFS
cohort. There were no differences in performance over time when participants were
classified on the basis of their patterns of use. Most importantly, results from the
co-t win control analyses revealed that changes in IQ did not differ for twin pairs dis-
cordant for cannabis use. In other words, there were no differences in neurocognitive
performance over time between cannabis-using twins and their abstinent siblings,
regardless of zygosity or frequency of use. Thus, these results suggest that observed
differences in IQ between users and non-users may not be a direct result of cannabis
use but rather of confounding familial factors that influence both initiation of sub-
stance use and IQ.
Additionally, a small, preliminary longitudinal analysis by Gruber et al. (2016)
examined the impact of medical marijuana on executive functioning in a sample of
11 adults. To be included in the study, participants had to be either cannabis-naïve
or abstinent for at least 10 years prior to study entry. All participants had a valid cer-
tification for medical marijuana as prescribed for a variety of conditions, including
anxiety, depression, sleep problems, and chronic pain. Participants completed exec-
utive functioning assessments at baseline and 3-month follow-up. Results indicated
that, in general, patients experienced significant improvement in measures of exec-
utive functioning at the follow-up visit, namely the Stroop Color and Word Test and
the Trail Making Test, such that they were faster but equally accurate. Furthermore,
although there were no significant improvements in the WCST or the letter-number
sequencing task, there were trends suggesting slight improvements. Although the
influence of practice effects could not be ruled out, the authors noted that practice
effects are typically observed for these tasks only with more frequent administration
and that they used alternate versions of each of these tasks at follow-up. Gruber et al.
(2016) proposed that the observed improvements may have been due to participants
experiencing amelioration of their clinical symptoms or to differences in the active
ingredients in medical (e.g., high CBD, low THC) versus recreational marijuana (e.g.,
high THC, low CBD). However, these findings are preliminary in nature and must
be further explored in a larger sample in order to elucidate the effects of medical
marijuana on cognition. Also, it should be noted that the conditions for which med-
ical marijuana was prescribed in this sample were very heterogeneous and carried
their own cognitive risks. Future research should examine the interactions between
neurocognition, medical marijuana, and the specific conditions for which medical
marijuana is prescribed.
Two large-scale longitudinal studies examining the long-term effects of can-
nabis use on middle-aged adult neurocognition were published in 2016. McKetin,
Parasu, Cherbuin, Eramudugolla, and Anstey (2016) examined cannabis use as a

moderator of the association between age and cognitive functioning in a sample of
1,897 adults ages 40–46 years at baseline. Participants underwent neuropsycholog-
ical testing at three different waves, four years apart. Tests administered included
subtests of the CVLT, the Wechsler Memory Scale, and the Symbol-Digit Modalities
Test. Participants were classified categorically, based on their cannabis use over the
past 12 months, into three groups: no use, less than weekly use, or weekly or greater
use. Results revealed between-group effects, such that the heavier cannabis users had
significantly poorer immediate and delayed recall performance than did non-users,
although these associations were attenuated when factors such as age, sex, education,
other substance use, and mental health were controlled. Furthermore, there was no
within-person effect of cannabis, suggesting no significant changes in performance
during waves when users were using cannabis relative to waves when they were not.
These findings suggest that the poorer recall observed in the heavier cannabis use
group may not be related to the current levels of cannabis use but more likely reflect
a residual effect of cannabis use or a possible weakness in verbal recall that predates
cannabis use.
On the other hand, Auer et al. (2016) studied the association between cannabis use
and cognitive function in a sample of 5,115 adults aged 18 to 30 at baseline (part of
the Coronary Artery Risk Development in Young Adults [CARDIA] study) followed
over a period of 25 years. Participants underwent neurocognitive testing at the year
25 visit, which included the Rey Auditory Verbal Learning Test (RAVLT), the Stroop
test, and the Digit Symbol Substitution Test. In the unadjusted analyses, past-year
cannabis use frequency was associated with reductions in RAVLT and Digit Symbol
Substitution performance, while lifetime cannabis use was associated with poorer
performance across all three measures. However, after controlling for potentially
confounding variables, including sex, race, education, other substance use, and
mental health, results revealed a dose-dependent association between lifetime can-
nabis use frequency and worsening verbal memory in middle age. Specifically, for each
additional 5 years of cannabis exposure, verbal memory decreased by 0.13 standard
units relative to non-users on the RAVLT. There were, however, no associations be-
tween lifetime cannabis use frequency and executive function or processing speed.
Taken together, these studies suggest a link between cannabis use and verbal
memory deficits in middle age and stress the importance of controlling for the
effects of potential confounds, such as age, sex, education, other substance use,
and mental health factors. However, while McKetin et al. (2016) suggested that
these verbal memory deficits may predate cannabis use, Auer et al. (2016) found
that cannabis use frequency led to decreased verbal memory performance in a
dose-dependent fashion. The discrepancies between these results may be explained
by several factors. First, Auer et al. (2016) examined cannabis use continuously,
whereas McKetin et al. (2016) used a categorical variable, the levels of which were
not necessarily homogeneous (e.g., a daily cannabis user might have greater im-
pairment than one who uses once a week). Therefore, this study may have failed
to detect more nuanced dose-dependent associations between cannabis use, age,
and neurocognitive performance. Second, McKetin et al. (2016) focused on past

12-month use, whereas Auer et al. (2016) examined both 12-month and life-
time use, but found significant effects only for lifetime use after controlling for
confounds. Third, while participants in the study by Auer et al. (2016) under-
went neurocognitive testing only at the year 25 visit, participants in the study
by McKetin et al. (2016) underwent neurocognitive testing at all three meas-
urement waves. The latter was therefore better able to examine fluctuations in
neurocognition as they related to changes in levels of cannabis use. Nevertheless,
both studies made important contributions to the literature of cannabis and
neurocognition, particularly with regard to middle-a ged adults.
Camchong, Lim, and Kumra (2017) conducted a longitudinal study examining
changes in resting state functional connectivity in a sample of 22 abstinent users
with a diagnosis of cannabis use disorder who were recruited from treatment settings
(with an average of 7 days of having completed treatment at baseline) compared to 43
non-users over a period of 18 months. Results revealed increased functional connec-
tivity from baseline visit to 10-month follow-up between caudal anterior cingulate
cortex and superior frontal gyrus in non-users but not in users. Also, functional con-
nectivity between caudal anterior cingulate cortex and dorsolateral and orbitofrontal
cortices declined over time in abstinent users with a formal diagnosis of cannabis
use disorder when compared to non-users, for whom connectivity remained stable.
However, these differences were only observed among users who relapsed (n = 15)
during the interval period prior to follow-up scan. These results provide evidence
of observable functional differences in cannabis users after exposure during ado-
lescence and represent a potential biomarker for risk of relapse. Importantly, the
structures identified as having reduced connectivity are often implicated in tasks of
decision-making, inhibitory control, attention, working memory, reward, and moti-
vation and may contribute to poorer executive functioning, thus influencing rate of
relapse. Although these results support the theory of neural network imbalance of
addiction (Volkow, Wang, Tomasi, & Baler, 2013), this study lacked sufficient power
to conduct categorical comparisons between users who remained abstinent and
those who relapsed.
To explore whether gray matter volumes are affected by greater cannabis exposure,
Koenders et al. (2016) conducted a longitudinal study using a sample of 20 heavy can-
nabis users and 22 non-users. Findings revealed that continued cannabis use was
not significantly associated with changes in gray matter volumes between baseline
and three-year follow up. However, cross-sectional analyses at baseline and follow-
up revealed significant associations between amount of cannabis use (in grams) and
cannabis-related problems (score on Cannabis Use Disorder Identification Test) and
reduced gray matter volume of the left hippocampus, amygdala, and superior tem-
poral gyrus. These results suggest that chronic cannabis use (>5 years) in late adoles-
cence and early adulthood may not affect changes in gray matter morphology over
time, rather, the associations between cannabis use and gray matter volumes may
have been present prior to the study.
OTHER NOTABLE STUDIES

Several studies published over 2016 examined the acute effects of cannabis use in
different populations. In the first study to administer cannabis to users under the
age of 18, Mokrysz, Freeman, Korkki, Griffiths, and Curran (2016) conducted a
double-blind, placebo-controlled study to compare the acute effects of cannabis
use in adolescent and adult males. Groups were matched on baseline measures in-
cluding premorbid IQ, anxiety, depression, impulsivity, and schizotypy. After re-
ceiving either active or placebo cannabis, participants completed a prose recall task
and spatial N-back task assessing episodic and working memory, as well as a stop
signal task assessing response inhibition. When intoxicated with cannabis, adults
showed greater impairment in delayed recall of prose and had longer reaction times
on the spatial N-back task than did adolescents. Also, cannabis administration
led to impaired response inhibition accuracy in adolescents but not in adults. Of
note, although all participants in this study were considered regular cannabis users,
adolescents reported greater frequency of use per month than the adults. Thus, the
reduced impairment seen in adolescents relative to adults may reflect tolerance effects,
though evidence of tolerance to cannabis effects on memory has been inconsistent
(Broyd et al., 2016; Ramaekers, van Wel, Spronk, Toennes, et al., 2016). Alternatively,
adolescents have a higher basal metabolism and a lower percentage body fat than
adults, which could lead to adolescents metabolizing THC more quickly, potentially
resulting in reduced memory effects. Finally, adolescents reported more frequent
and heavier use of cigarettes than did adults, which may offset cannabis effects on
working memory (Schuster et al., 2015; Schuster, Mermelstein, et al., 2016), as well as
less frequent alcohol use. Therefore, it is possible that age group differences in use of
other substances may have influenced these findings.
Ramaekers, van Wel, Spronk, Toennes, et al. (2016) assessed neurocognitive
performance in a sample of 132 adult users of cannabis and cocaine. Participants
entered a double-blind, placebo-controlled study in which they received a dose of
cannabis, cocaine, or placebo. Cannabis use frequency in this sample ranged from
infrequent to daily. Participants completed a neurocognitive battery assessing execu-
tive functioning (Tower of London task), impulse control (stop signal task), attention
(divided attention task), and psychomotor performance (critical tracking task). This
study found a main effect of cannabis intoxication across all measures, such that the
cannabis group showed worse performance relative to those who received placebo.
Although there was no main effect of cannabis use history, there was an interaction
between cannabis use history and psychomotor performance, such that cannabis-
induced impairment decreased with increasing frequency of use, which would sug-
gest tolerance effects. However, these effects on psychomotor performance may have
been driven by worsening psychomotor performance over time in the placebo group,
rather than in any of the drug conditions, for which psychomotor performance
remained stable. These results suggest that acute cannabis-induced neurocognitive

impairment does not depend on cannabis use history, and that tolerance to these
acute effects is generally absent in regular users.
To examine the moderating influences of genetics, Spronk, Van der Schaaf, et al.
(2016) examined the acute effects of cannabis and cocaine on reversal learning as a
function of DRD2 Taq1A (A2/A2 and A1 carriers) and COMT Val108/158Met geno-
type by conducting a double-blind, placebo-controlled study in which 64 male sub-
stance users received either cannabis, cocaine, or placebo. Participants completed
a reward-based reversal learning task, an attention switch task, and the Tower of
London planning task. Results indicated that participants who received cannabis
were less accurate than those who received placebo across all tasks, thus replicating
the link between cannabis intoxication and poorer neuropsychological performance
(Crean, Crane, & Mason, 2011). Modulation of reversal learning performance by
DRD2 or COMT genotype was then assessed through a series of regressions. Results
revealed that the acute effects of cocaine on accuracy were moderated by genotype,
such that cocaine-induced improvement was greater in A1 than A2/A2 carriers.
However, there was no such moderation for the acute effects of cannabis. There was
no effect of COMT Val108/158Met genotype on performance in either drug condition.
Ramaekers, van Wel, Spronk, Franke, et al. (2016) also examined genetic expres-
sion, particularly with regard to the enzyme dopamine β-hydroxylase (DβH), which
transforms dopamine to noradrenaline, and tonic dopamine levels in 122 regular
users (i.e., used at least twice over 3 months) of cannabis and cocaine (i.e., used at
least five times in past year). Individuals were identified as having either low-activity
or high-activity DβH genotypes. All participants received acute doses of cannabis,
cocaine, or placebo and completed the Matching Familiar Figures Test to assess cog-
nitive impulse control. Additionally, resting state fMRI was used to examine func-
tional connectivity between the nucleus accumbens and subcortical areas after acute
administration of cannabis, cocaine, or placebo in a subset of 35 users. Users with the
low-activity, in contrast to the high-activity, DβH genotype under acute intoxication
of cannabis or cocaine showed reduced resting-state functional connectivity between
the nucleus accumbens and limbic lobe, prefrontal cortex, striatum, and thalamus,
in addition to increased cognitive impulsivity on the Matching Familiar Figures
Test. These results suggest that certain cannabis users who use cocaine may be at risk
for experiencing hyperdopaminergic cognitive states influencing substance-driven
behaviors, especially among users with high-risk DβH genotypes.
A neuroimaging study by Spronk, Verkes, et al. (2016) used event-related potentials
(ERP) derived from electroencephalography (EEG) to examine the electrophysio-
logical correlates of performance-monitoring processes and response inhibition in
adults under acute intoxication with cannabis and cocaine. To assess monitoring
during a Flanker task, error- related negativity, error positivity, and post- error
slowing amplitudes were recorded among 64 non-addicted polydrug users. Acutely
intoxicated adult cannabis users displayed diminished error-related negativity and
error-positivity amplitudes when compared to users acutely intoxicated with co-
caine and those receiving placebo. These results suggest that acute drug intoxication
affects the later, evaluative stages of response inhibition. Observed cannabis-induced

worsening of response inhibition performance suggests that acute cannabis intoxica-
tion might lead to risky and unsafe behaviors.
Focusing on residual effects, Thames, Mahmood, Burggren, Karimian, and Kuhn
(2016) examined the independent and combined effects of HIV and different levels of
cannabis use on neurocognition. HIV-positive and HIV-negative participants were
classified as non-users (never used cannabis), light users (used 2–14 times per week),
and moderate-to-heavy users (used 18–90 times per week), based on their weekly use.
Participants completed a brief neurocognitive battery, which was used to calculate
an index of global neuropsychological performance. Results indicated main effects
of cannabis use, such that moderate-to-heavy users performed worse than light users
and non-users on the domains of processing speed, learning and memory, and ex-
ecutive functioning. Furthermore, there was an interaction between cannabis group
and HIV status, such that HIV-positive moderate-to-heavy users had lower learning
and memory than light users and non-users. Surprisingly, HIV-positive light users
performed better in the domain of verbal fluency than HIV-negative light users.
These results underscore the complexity of the associations between cannabis use,
HIV, and neurocognition.
Finally, this past year saw the publication of an evidence-based consensus report
from the National Academy of Sciences, Engineering, and Medicine (2017) on the
health effects of cannabis. This undertaking brought together leading experts from
various fields to carry out the most comprehensive review to date on the on the health
effects of cannabis. The committee used standardized language and review criteria
to present clearly interpretable conclusions that weight the strength of available evi-
dence. One section of the report focused on psychosocial outcomes, which included
effects on cognition. The authors concluded that there is “moderate evidence” for a
statistical association between cannabis use and impairments in learning, memory,
and attention after acute cannabis use. With regard to statistical associations be-
tween cannabis and these neurobehavioral domains after sustained abstinence,
the committee concluded that there was moderate evidence for acute effects (i.e.,
under intoxication) of cannabis on cognitive abilities, but only limited evidence for
associations under abstinence.
CONCLUSIONS
This chapter reviewed findings from 30 studies published over 2016–17 that examined
associations between cannabis use, neurocognition, and brain structure and func-
tion in adolescents and adults. Overall, findings were heterogeneous and nuanced
yet continue to move forward our understanding of cannabis-associated effects on
neurocognition. Recent studies have seen a trend toward more work focused on ado-
lescence, novel imaging methods, and use of longitudinal designs. Furthermore, there
is growing recognition of the likelihood of neurocognitive deficits that may predate
and perhaps contribute to problematic cannabis use, the importance of careful control
of relevant confounds, and the need to consider cannabis potency and composition.
Finally, a shift to more longitudinal studies is enabling us to better understand causal

associations between cannabis use and neurocognition. With regard to implications
for neuropsychological clinical practice and research, it can be concluded that daily
or almost daily cannabis users are likely to exhibit lower neuropsychological perfor-
mance than non-users, particularly on measures of learning and memory. However,
after abstaining from use for over a month, these deficits are likely to remit. Those
that persist may represent preexisting individual differences. Furthermore, earlier
cannabis use onset seems to be associated with poorer outcomes. Whether these
results generalize to new cannabis users who are undergoing supervised use of can-
nabis for medical purposes is yet to be determined. However, the provocative results
from the preliminary study by Gruber et al. (2016) suggest that cannabis use may
even improve neurocognition under certain circumstances.
Across the reviewed studies, adolescent cannabis use was linked to lower per-
formance across a variety of domains, including attention, memory, IQ, and emo-
tional processing. However, some studies with strong experimental designs that
allow for more causal inferences suggest that these effects may not be a consequence
of cannabis exposure but that they predate cannabis use or may be accounted for
by confounding variables. For adults, cannabis use has been consistently linked to
acute and residual impairments in memory performance, as well as less consistently
linked to poorer executive functioning performance. Neuroimaging findings across
both adolescents and adults suggest that cannabis use is associated with a range of
alterations, including differences in white matter structure, gray matter volumes, and
brain activation. Results have been largely inconsistent regarding the pattern of these
differences (e.g., hypo-vs. hyperactivation), the specific areas affected, and whether
these alterations are accompanied by worse neurocognitive performance. In addition
to within-method heterogeneity, there is significant heterogeneity across methods.
For instance, functional imaging studies include PET, fMRI, and functional con-
nectivity studies, while structural imaging studies can examine regional or global
volumes, cortical thickness, shape differences, and white matter structure and integ-
rity. Furthermore, other methods such as ERP and EEG examine neurophysiological
correlates of cognitive processes. Although all of these techniques provide valuable
information, this heterogeneity can make integration and interpretation of findings
a daunting task.
Results from the studies reviewed in this chapter underscore the importance
of carefully assessing and controlling for variables that may confound results,
owing to their associations with cannabis and/or neurocognition. Controlling for
confounds could also allow for identification of variables that consistently drive these
associations, which could, in turn, inform clinical practice, as clinicians would know
specifically which other factors they should assess. For instance, initial analyses
by Mokrysz, Landy, et al. (2016) suggested an association between adolescent can-
nabis use and reduced IQ. However, after confounds such as IQ, mental health, and
use of other substances were considered, this association was no longer significant.
Interestingly, out of all the variables included in the analyses, cigarette use was most
strongly associated with IQ. Though smaller samples in neuroimaging studies may
cause them to be underpowered, it would be interesting to examine associations be-

tween cannabis use and brain structure and function after controlling for more com-
prehensive sets of confounds.
Importantly, the majority of the studies reviewed in this chapter conducted
analyses using categorized variables, such as use levels created using cutoffs,
which may result in inconsistency across studies, heterogeneity within levels, and
loss of nuanced data. For the cannabis use variables, the cutoffs used varied across
studies. For instance, McKetin et al. (2016) classified cannabis users as less than
weekly users and at least weekly users. In these analyses, daily users were classi-
fied in the same group as those who use once weekly, which increases the heter-
ogeneity within that category and may have caused neurocognitive differences
between those users to be obscured. On the other hand, Mokrysz et al. (2016) clas-
sified users on the basis of their cumulative instances of cannabis use; users with
49 uses were classified differently from those who had used 50 times. Furthermore,
there is a great deal of inconsistency across studies in the operationalization of
terms such as “regular” cannabis use, which ranged from daily to monthly use, as
well as in the quantification and assessment of prior cannabis use. For instance,
some studies measure use of cannabis in grams, while others measure number of
joints, and others use number of days or times used. Also, some rely on lifetime
use, while others focus on past-month or past-week use. Thus, this categorization
also creates cross-study inconsistencies, which may make reconciliation of results
more difficult across studies. Similar problems arise with other variables, such as
age of onset.
In conclusion, studies published in 2016 have made significant contributions
to the literature regarding the effects, both acute and residual, of cannabis use on
neurocognition. However, several questions remain unanswered, including those re-
garding the effects of lower levels of cannabis use that are more prevalent, as well
as the long-term effects of different types of cannabis (e.g., different CBD-to-THC
ratios, different potencies). Furthermore, although recent studies have certainly
made advances in this regard, more longitudinal research is needed to determine
whether impairments linked to cannabis use are a direct consequence of or a risk
factor for cannabis use. The effects of cannabis on neurocognition at different devel-
opmental stages are also of interest, especially given the increased vulnerability to
the neurotoxic effects of substance use in the adolescent brain (Witt, 2010). In order
to address some of these issues, several NIH Institutes launched the Adolescent Brain
and Cognitive Development (ABCD) study, which consists of 21 leading universities
working together on a 10-year prospective longitudinal study of brain development
with a nationally representative sample of 10,000 drug-naïve children ages 9–10 years.
The study will assess neurocognition, brain structure and function, substance use,
mental health, physical activity, family environment, culture, genetics, hormones,
and many other domains, throughout adolescence. The large sample size and longi-
tudinal design, which begins before youth start experimenting with substances, will
allow for making strong causal inferences between cannabis use and neurocognition,
as well as the many mediators and moderators that may influence this relationship.
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2
Hypertension and Cognitive
Impairment in Older Adults
Review and Update
Richard F. Kaplan and Lauren Strainge
INTRODUCTION
We live in an aging society. In 2000, one in eight Americans was aged 65 or older,
and by 2030 one in five Americans will be over the age of 65 (He, Sengupta, Velkoff,
& DeBarros, 2005). Diseases such as cardiovascular disease and dementia are often
associated with old age. Beyond aging, hypertension is the major cardiovascular
risk factor for small vessel brain disease among older adults (Abraham et al., 2016).
Moreover, studies have also shown hypertension to be a strong risk factor for age-
related cognitive decline (Verhaaren et al., 2013). Given that the current prevalence of
systolic hypertension in the U.S. population 60 years of age or older is 67% (Benjamin
et al., 2017), and given the relationship between hypertension, brain disease, and cog-
nitive decline, and the potential for treatment, hypertension is of major importance
to neuropsychological science and practice.
HISTORICAL BACKGROUND
Our understanding of cardiovascular disease begins with the seminal work of
William Harvey (1578–1657), an English physician, who, in 1628, proposed that the
heart propelled the blood through a closed vascular circuit (Fye, 2005). The knowl-
edge that vascular disease contributed to many of the brain syndromes we know today
can also be credited to Giovanni Battista Morgagni (1682–1771), founder of the study
of modern pathology. Morgagni emphasized the importance of clinical pathological
correlations and proposed the concept of “cerebral congestion” as a cause of apoplexy
(stroke) in 1761, work which had a profound influence in elucidating the mechanisms
of stroke and stroke treatment during the next 150 years (Ventura, 2000).
During the nineteenth century, investigations of cardiovascular pathology, brain,
and behavior became of great interest to neurologists. In 1838, Amedee Dechambre
(1812–1886), a French physician, used the term lacune to describe a small cavity
22
23 Hypertension and Cognitive Impairment in Older Adults
formed in the core of cerebral infarcts in the course of liquefaction and resorption
of the infarct (Roman, 2002). Lacune derives from the Latin lacuna and in French
refers to an “empty space.” In 1843, Maxime Durand-Fardel (1815–1899) refined
the term to mean a small cavity in the brain “without any change in consistency
or color.” Durand-Fardel believed that lacunae were healed infarcts, distinctly
separate from other vascular lesions. He used the term etat crible (translated as
“sieve-like state”) to describe sections of the subcortical white matter surrounded
by quite normal white matter (Libon, Price, Davis Garrett, & Giovannetti, 2004).
Pierre Marie (1853–1940) provided additional physiological descriptions of lacunae,
suggesting that they likely represented small infarcts or possibly microscopic
hemorrhages (Libon et al., 2004).
However, it was Otto von Binswanger (1852–1929) who, in 1894, distinguished
syphilitic dementia (the most common cause of dementia of that era) from dementia
caused by arteriosclerosis (Caplan, 1995). Binswanger introduced the term encephalitis
subcorticalis chronica progressiva to describe a disorder of the white matter related to in-
sufficient blood supply. Alois Alzheimer (1864–1915), who had studied with Binswanger,
provided pathological evidence to support Binswanger’s ideas and hypotheses, and
renamed this disease Binswanger’s disease. Alzheimer noted that, in Binswanger’s dis-
ease, the cortex was relatively well preserved, while white matter was narrowed, gray,
and studded with patches. Moreover, Alzheimer noted that arteriosclerotic dementia
resulted in a different clinical presentation, marked by deficits in retrieval rather than a
true memory loss, and slowed reaction time (Libon, Price, Swenson, Haake, & Pennisi,
2009). In this disorder the personality remained largely intact, and insight and judg-
ment appeared altered only during sudden episodes of exacerbation (Roman, 2002).
Binswanger’s disease was later described as involving loss of total white matter volume,
hydrocephalus, areas of diffuse and focal white matter myelin loss (especially in periven-
tricular, regions, the corona radiata, and the centrum semiovale), and lacunar infarcts in
the basal ganglia, thalamus, pons, and cerebral white matter, with sparing of subcortical
white matter and short association U fibers (Caplan, 1995).
Much of our current knowledge of white matter lesions related to vascular in-
sufficiency comes from C. Miller Fisher’s (1913–2012) detailed descriptions of post-
mortem dissections of stroke patients (Fisher, 1965). Fisher observed lacunae in
the deep brain structures after occlusion of 200–800 μm penetrating arteries and
connected them with lacunar stroke syndromes. Lacunar infarcts are located almost
exclusively in deep regions of the brain, with the majority occurring in the pons, the
basal ganglia, and/or the internal capsule (Mohr, 1982). Lacunae are caused by oc-
clusion of a single deep penetrating artery that arises directly from the constituents
of the circle of Willis, cerebellar arteries, and the basilar artery. The corresponding
lesions occur in the deep nuclei of the brain (37% putamen, 14% thalamus, and 10%
caudate), as well as in the pons (16%) or the posterior limb of the internal capsule
(10%). They occur less commonly in the deep cerebral white matter, the anterior limb
of the internal capsule, and the cerebellum.
Since Fisher’s early descriptions, the proliferation of neuroimaging, particularly
magnetic resonance imaging (MRI), has led to a dramatic shift in our thinking
regarding Binswanger’s disease. Early MRI studies showed some degree of peri-
ventricular white matter hyperintensity (WMH) in many patients who had no ev-
idence of vascular cognitive impairment (Zimmerman, Fleming, Lee, Saint-Louis,
& Deck, 1986). These findings brought into question the validity of Binswanger’s
disease (Hachinski, Potter, & Merskey, 1987). Authors argued that the concept of
Binswanger’s disease evolved from an inaccurate and overreaching description of
white matter abnormalities to describe not only the pathology relating to vascular
dementia but also more common and benign incidents of white matter changes that
did not produce dementia. As a result, the term leukoaraiosis (LA), meaning “rarified
white matter,” was introduced to reflect a more neutral characterization of white
matter abnormalities.
IMAGING WHITE MATTER DISEASE

LA differentiates white matter lesions that are caused by cerebral small vessel dis-
ease (SVD), as opposed to lesions caused by demyelinating, infectious, toxic, or
metabolic processes. When these white matter changes are seen on MRI, they are
usually referred to as WMHs or white matter lesions. WMHs are typically defined
as regions that appear hyperintense on proton- density, fluid-
attenuated inver-
sion recovery (FLAIR), and T2-weighted images (Figure 2.1), without prominent
hypointensity on T1-weighted scans. WMHs can be focal or multifocal and, as they
become more extensive, they become confluent and may involve large areas of the
white matter. WMHs are not randomly distributed and appear to form distinct
patterns (Artero et al., 2004). These abnormalities develop progressively, extend
outward from the anterior and posterior aspects of the lateral ventricles, and are
associated with vascular disease risk factors like hypertension, and increasing age
(Wakefield et al., 2010).
Brain imaging using diffusion tensor imaging (DTI) is a noninvasive method
of assessing the anatomical integrity of white matter microstructure and has been
shown to detect white matter abnormalities not visible on MRI (Gallo et al., 2005;
Werring, Clark, Barker, Thompson, & Miller, 1999). DTI is particularly useful in
white matter disease (WMD), as it takes advantage of the tendency of water to dif-
fuse linearly along intact myelin, as compared to increased radial diffusion when
myelin is degraded. DTI findings suggest that WMHs only represent the extreme
end of a continuous spectrum of white matter injury (Sullivan et al., 2001). This
may explain the very modest correlations between WMHs and behavioral findings
in normal elderly persons without cognitive impairment (Kaplan et al., 2009;
Wakefield et al., 2010).
SMALL VESSEL DISEASE AND WHITE MATTER

HYPERINTENSITIES
Neuropathological studies provide strong evidence that WMHs are the consequence
of SVD. Although there is clear overlap, the risk factors for SVD differ from those
Figure 2.1. Examples of minimal, mild, and moderate white matter hyperintensities (WMHs)
in elderly individuals as T2 hyperintensity in axial FLAIR images. The degree of global WMH
burden can be appreciated visually, particularly in the peritrigonal, periventricular, and centrum
semiovale regions.
for large vessel disease, with hypertension as the primary risk factor for SVD (Khan,
Porteous, Hassan, & Markus, 2007). SVD causes narrowing of the smaller blood
vessels that provide the blood flow to brain white matter. In regions of leukoaraiosis,
alterations in the structure of these damaged vessels are characterized by hyaline
thickening and arteriosclerosis (O’Sullivan, 2008) (Figure 2.2). This combination of
arteriolosclerosis and hyaline wall thickening of the long penetrating arterioles can
contribute to hypoxia and ischemia in white matter.
Postmortem studies show that WMHs are heterogeneous in terms of histo-
pathology. Longitudinal observations from the multicenter Leukoaraiosis and
Disability (LADIS) study suggest that WMHs are likely the result of stenosis of mul-
tiple small vessels, and vary from subtle diffuse ischemia to incomplete infarction.
Tissue damage ranges from slight disentanglement of the matrix to varying degrees
of myelin and axonal loss. In contrast, lacunae result from the complete occlusion of
a single deep arteriole. However, lacunae often develop in areas of WMHs because
perfusion to these regions is already compromised (Gouw et al., 2008).
Figure 2.2. Pathology of leukoaraiosis. Two small vessels (arrows) are shown with concentric
hyaline thickening, loss of smooth muscle cells, and luminal narrowing. The perivascular space is
widened, and the surrounding white matter appears gliotic.
Adapted from O’Sullivan (2008).
AGING AND THE BRAIN

Aging is also a well-documented risk factor for WMHs. Age-related shrinkage in
brain volume has been well described, although traditionally this has focused on
changes occurring in gray matter (Abe et al., 2008). In white matter, the severity of
subcortical and periventricular white matter lesions are dependent on age and sex.
A large population study of older adults, aged 60–90, showed that most individuals
had measurable WMHs, with only 8% showing lesion-free subcortical white matter,
and 20% showing lesion-free periventricular white matter (de Leeuw et al., 2001).
Mean volumes of both subcortical white matter lesions and periventricular white
mater lesions increased significantly in subjects between 80 and 90 years of age
compared to subjects aged between 60 and 70 years. Women tended to have more
white matter lesions of both kinds, especially in the frontal region. The reason for this
is unclear, but it may be due to reductions in estrogen after menopause. Subcortical
white matter lesion volume was highest in the frontal and parietal lobes, 20 and 100
times higher than in the occipital and temporal lobes, respectively (de Leeuw et al.,
2001). Additionally, it has been estimated that about 10% of people aged 50–75 without
cognitive complaints show regions of WMH on MRI (O’Sullivan, 2008), and longi-
tudinal analysis of non-demented older adults in the Baltimore Longitudinal Study
of Aging revealed widespread white matter changes, with an average of 3.1 cm3 of
white matter lost annually (Resnick, Pham, Kraut, Zonderman, & Davatzikos, 2003).
A recent longitudinal study of 99 well-educated normal elderly persons showed an

unanticipated increase in the mean WMH volume by 76%, with WMHs at baseline
predicting WMHs at 4 years (Wolfson et al., 2013) (Figure 2.3). These findings sug-
gest a continuously progressive process.
DTI studies reveal additional age-related declines in white matter tract integrity
in healthy adults whose white matter volume declines were otherwise undetect-
able by standard MRI (O’Sullivan, 2008). DTI evidence suggests that aging leads to
declines in fractional anisotropy (FA), a nonspecific metric of white matter tract in-
tegrity (Ardekani, Kumar, Bartzokis, & Sinha, 2007; Benedetti et al., 2006; Charlton
et al., 2006). Moreover, age-related regional differences show greater FA decline in
frontal brain networks, suggesting an anterior-to-posterior gradient of decline and
diffusivity (Sullivan & Pfefferbaum, 2006). Microstructural damage in fiber tracts
mediating the default mode network, a set of interacting brain regions active during
wakeful rest, has also been observed (Papma et al., 2014). Together, these findings
Figure 2.3. Location and frequency of white matter hyperintensities (WMHs) in subjects with
magnetic resonance images from three time points: baseline (left column), 2 years (center column),
and 4 years (right column). WMHs (color) are overlaid on the grayscale slice (0.87-mm thickness)
of the common anatomical brain (International Consortium on Brain Mapping). Columns: Two
slices separated by 12.2 mm are shown. The vertical color bar represents the frequency (%) of
WMHs, for example, color corresponding to 70% indicates that 70% percent of subjects had WMHs
in that brain area. The lettering below the color bar indicates right (R), left (L), anterior (A), and
posterior (P) brain aspects.
Adapted from Wolfson et al. (2013).
suggest that disconnection among distributed neural systems may be a fundamental

mechanism of age-related variability in cognitive performance (Madden, Bennett, &
Song, 2009).
WHITE MATTER HYPERINTENSITIES AND AGE-

RELATED COGNITIVE IMPAIRMENT AND DEMENTIA
Age-related changes in cognition involve multiple cognitive domains and have been
linked to changes in gray matter, particularly the hippocampus (Tisserand et al.,
2004). White matter abnormalities, including WMHs, and decreases in hippocampal
and amygdala volume predict neuropsychological test performance in normal eld-
erly persons and are predictors of cognitive decline. Hippocampal atrophy seems
most directly related to learning and memory loss (Hackert et al., 2002; Ystad et al.,
2009), whereas WMHs appear to be linked more closely to processing speed and
executive functioning (Papp et al., 2014). Decreases in hippocampal volume with
age are well documented (Bartzokis et al., 2001; Chen, Chuah, Sim, & Chee, 2010;
Jernigan et al., 1991; Pruessner, Collins, Pruessner, & Evans, 2001; Ystad et al., 2009),
with increasing declines after age 70 (Scahill et al., 2003). Mungas and colleagues
(2005) observed an annual 1.1% rate of decline in hippocampal volume over an av-
erage of 3.4 years in their study of non-demented adults aged 58–87.
Similarly, numerous studies have demonstrated a relationship between WMD
and poorer cognition, particularly slower processing speed, and executive dysfunc-
tion (Gunning-Dixon & Raz, 2000; Raz, Rodrigue, Kennedy, & Acker, 2007; van den
Heuvel et al., 2006). In their review of the literature, Gunning-Dixon and Raz (2000)
found that increased WMH volume in healthy elderly persons was most consistently
related to declines in processing speed, executive functioning, and memory, but not
to crystallized or fluid intelligence and fine motor skills. In a study from our group
(Wakefield et al., 2010), an increase of 1% of total WMH volume resulted in a 1.5-to
2.4-fold increase in the likelihood of slowed performances on the Stroop Color and
Word Test, the Trail Making Test B, and a continuous performance measure.
Attempts to more precisely define the relationship between white matter integrity
and cognition by analyzing regional differences in WMHs have shown mixed results.
Declines in processing speed in non-demented elderly have been linked to the integ-
rity of white matter in the corpus callosum (Bucur et al., 2008; Jokinen et al., 2006),
pericallosal frontal region (Bucur et al., 2008), anterior brain areas (Kennedy & Raz,
2009), and periventricular white matter (van den Heuvel et al., 2006). However,
others have argued that individual tracts show no association with processing speed
beyond what can be explained by overall tract integrity (Penke et al., 2010).
Although there is a strong relationship between regional and total WMHs
(Wakefield et al., 2010), it appears that frontal, but not posterior, WMHs most af-
fect processing speed and executive functioning, independent of age (Kaplan et al.,
2009). WMHs in the splenium of the corpus callosum have also been associated with
decreased reaction time, whereas other white matter tracts in the corpus callosum
have not (Papp et al., 2014), further suggesting some regional specificity.
It is important to note that few processing speed and executive functioning tests
involve a single cognitive domain. Any individual processing speed task demands
a mix of cognitive skills and abilities in addition to speed. When hippocampal and
WMH volumes were examined together in a series of processing speed measures,
age-related cognitive decline was significantly correlated with both increased WMHs
and decreased hippocampal volume, which, while associated with age, varied inde-
pendently (Papp et al., 2014).
Vascular cognitive impairment (VCI) has been viewed as a risk factor for vas-
cular dementia similar to the way in which amnestic mild cognitive impairment
(MCI) is a risk factor for Alzheimer’s disease. However, the natural history linking
VCI and vascular dementia is different and less well defined than that for MCI and
Alzheimer’s disease (Libon et al., 2009). In a Canadian study, half the community-
dwelling residents over age 65 with VCI without dementia developed dementia in
5 years (Wentzel et al., 2001). Another large, population-based study showed asymp-
tomatic (silent) brain infarcts on MRI were associated with greater neuropsycholog-
ical impairment and double the risk for dementia, with thalamic infarcts associated
with declines in memory performance, and non-t halamic infarcts with a decline in
psychomotor speed (Vermeer et al., 2003).
HYPERTENSION, WHITE MATTER DISEASE, AND

VASCULAR COGNITIVE IMPAIRMENT
Blood pressure (BP) is determined both by the amount of blood the heart pumps
and the amount of resistance to blood flow in the arteries. The more blood the heart
pumps and the narrower the arteries, the higher one’s BP. High BP, called hyper-
tension, is a common condition in which the long-term force of the blood against
artery walls is high and, left uncontrolled, eventually causes changes to the vascular
system. The modern concept of hypertension began in the late nineteenth century
with Frederick Akbar Mahomed’s (1849–1884) description of what later came to
be known as “essential hypertension,” separating it from similar vascular changes
seen in chronic glomerulonephritis such as Bright’s disease (Saklayen & Deshpande,
2016). Mahomed further demonstrated that hypertension could exist in apparently
healthy individuals and was more likely to occur in older populations. Moreover, he
wrote that other organs, such as the heart, kidneys, and brain, could be affected by
high arterial tension. With the introduction of the mercury sphygmomanometer in
1905, and the defining metric of systolic and diastolic BP, the modern concept of hy-
pertension became established (Roman, 2002).
Currently, hypertension is defined as a systolic pressure greater than 140 mmHg
and diastolic pressure greater than 90 mmHg (Benjamin et al., 2017). Hypertension is
the most prevalent of all non-communicable chronic diseases, with most recent statis-
tics in the United States reporting a prevalence of 34% for adults over age 20 and 67%
for adults over 60 (Benjamin et al., 2017). Although rates for identifying hypertension
have reached a laudatory goal of 83%, the control rate is still only 50% (49% for men
and 55% for women). Hypertension may be primary, which may develop as a result
of environmental or genetic causes, or secondary to multiple etiologies, including

renal, vascular, and endocrine causes. Primary or essential hypertension accounts
for 90–95% of adult cases, and secondary hypertension accounts for 2–10% of cases
(Benjamin et al., 2017). Left uncontrolled, eventually hypertension causes changes to
the vascular system, leading to diseases of the heart and brain. Cardiovascular dis-
ease, including stroke, heart attack, and heart failure, is the leading cause of death
and disability worldwide; elevated BP accounts for 62% of stroke and 49% of coro-
nary heart disease cases (Benjamin et al., 2017).
Hypertension also threatens cerebral white matter. A longitudinal population
study of 665 individuals aged 55 and older showed people with treated but uncon-
trolled hypertension to have significantly more WMD progression than people with
treated controlled hypertension (Verhaaren et al., 2013). The integrity of white matter
tracts depends on intact vasculature to provide a continuous supply of oxygen and
nutrients to myelinated fibers throughout the brain. In hypertension, physical and
functional changes can cause the vasculature to become compromised, resulting
in damage and dysfunction. The vessels feeding the white matter are typically very
small, measuring between 20 and 50 mm in length with an average diameter of 100 to
200 µm (Moody, Bell, & Challa, 1990). Blood supply of periventricular white matter
originates in pial vessels at the brain surface, then flows through long, penetrating
arteries to periventricular regions, forming a distal irrigation field at risk for ischemia
(Pantoni & Garcia, 1997). While the association between white matter lesions and
vascular risk factors may be mediated through several different pathways, hyperten-
sion is consistently reported as a major risk factor for the development of white matter
lesions (de Leeuw et al., 2001). White matter lesions may additionally be caused by
mechanisms such as arteriosclerosis directly occluding small arteries nourishing the
white matter, as well as subclinical ischemia in the form of repeated transient events
characterized by moderate drops in blood flow (Pantoni & Garcia, 1997).
Hypertension is associated with decreases in cerebral blood flow (CBF), known as
hypoperfusion, in prefrontal, anterior cingulate, and occipital areas (Beason-Held,
Moghekar, Zonderman, Kraut, & Resnick, 2007). Using a continuous spin-labeled
MRI technique, Dai et al. (2008) reported significant diffuse clusters of hypoperfusion
in hypertensive compared with normotensive elderly subjects. These clusters in-
cluded the right and left anterior cingulate gyrus with extension to the subcallosal
region; left posterior cingulate gyrus and medial precuneus; left lateral inferior and
superior frontal, inferior parietal, left orbitofrontal, and left superior and middle tem-
poral cortices; left hippocampus; bilateral putamen; and globus pallidus. In addition,
hypertension may also lead to alterations in the blood–brain barrier (BBB) that are
thought to cause white matter lesions via cerebral edema, activation of astrocytes,
or destructive enzymes and other matter which pass through damaged vessel walls
(Girouard & Iadecola, 2006).
Studies have also shown that BP, like many physiological systems, has a circadian
pattern (Smolensky, 1996). The characteristic pattern of periods of relatively higher
BP while awake and lower BP while asleep may be altered in hypertensive patients,
such that some individuals experience minimal change in BP during sleep, and some
individuals experience excessive declines in BP during sleep (Shimada et al., 1990;

Smolensky, 1996). Both patterns can negatively impact small arteries supplying white
matter. Older hypertensive patients with these abnormal circadian patterns are at
high risk for cerebrovascular disease and are more likely show basal ganglia lacunar
infarction and white matter signal abnormalities than individuals with more typical
circadian BP changes (Kario, Matsuo, & Shimada, 1996; Shimada et al., 1990). Studies
also have shown abnormalities in the circadian rhythm to be associated with poorer
cognition, as measured by the Mini Mental Status Exam, in a small sample of older
adults with hypertension (Bellelli et al., 2004) and in a group of elderly individuals
residing in nursing homes and geriatric hospitals (Ohya et al., 2001). To our knowl-
edge, more detailed studies of the effects of circadian BP variability on cognition
have not yet been done.
RECENT ADVANCES IN THE STUDY OF HYPERTENSION

AND WHITE MATTER DISEASE
Two lines of research have helped clarify the mechanisms by which hypertension
contributes to cerebral vascular dysfunction and WMD, changes in CBF, and en-
dothelial dysfunction (De Silva & Faraci, 2016; Hughes & Sink, 2016; Meissner,
2016). Under normal circumstances, CBF is regulated through a number of complex
processes that allow for adaptation to changing perfusion pressures (autoregulation)
and metabolic needs that fluctuate with neural activity (neurovascular coupling).
Under conditions of chronic hypertension, these processes are disrupted by a number
of structural and functional changes.
Autoregulation
Autoregulatory processes enable the brain to maintain a relatively constant CBF
across a substantial range of perfusion pressures, both through changes in resting
tone and in response to changing pressure. In hypertension, a number of structural
changes, including vessel hypertrophy, inward remodeling, increased arterial stiff-
ness, damage to vessel walls, and rarefaction, increase cerebrovascular resistance and
reduce the brain’s ability to maintain adequate blood flow (Abraham et al., 2016; De
Silva & Faraci, 2016; Hu, De Silva, Chen, & Faraci, 2017; Meissner, 2016). Hypertrophy,
or a thickening of vessel walls, can narrow the vessel lumen and restrict vasodilation,
leading to increased vascular resistance to CBF (Harvey, Montezano, Lopes, Rios, &
Touyz, 2016; Harvey, Montezano, & Touyz, 2015; Meissner, 2016). Inward remodeling
constitutes rearrangement of the vessel wall, also reducing lumen, and may have an
even greater impact on resistance and vasodilator reserve than hypertrophy (De
Silva & Miller, 2016; Harvey et al., 2015; Iddings, Kim, Zhou, Higashimori, & Filosa,
2015) These changes within the cerebral vasculature reduce the extent to which
vessels can dilate in response to changing blood flow needs (Hu et al., 2017; Meissner,
2016), which can compromise blood flow to cerebral white matter, causing WMD and
cognitive decline (van Sloten et al., 2015).
Several vasoactive factors derived from the endothelium, including nitric oxide
(NO), are also involved in coordinating local responses to changes in cerebral BP
(Karlsson, Sørensen, & Kruuse, 2017; Meissner, 2016). Chronic elevated BP can
damage the vessel endothelium, disrupting the normal function of these factors and
their important roles in regulating blood flow through the cerebral microvasculature
(Fan et al., 2015; Iddings et al., 2015; Moore, Zhang, Maeda, Doerschuk, & Faber,
2015; Pires, Jackson, & Dorrance, 2015). Accumulation of plaque in the blood vessels
(atherosclerosis) is highly comorbid with hypertension and acts to further increase
vascular resistance by narrowing lumen diameter (Hong, Wang, & Liao, 2013; Hu
et al., 2017; Rahimic-Catic, Vegar-Zubovic, Delilovic-Vranic, & Lozo, 2013; Su et al.,
2001), exacerbating the effects of hypertrophy and inward remodeling.
Hypertension is also associated with the loss of blood vessels, known as rarefac-
tion. Recent evidence from mouse models supports the occurrence of rarefaction
in the cerebral microvasculature in hypertension, notably in pial collateral vessels
(Moore et al., 2015; Tarantini et al., 2016b). Collateral vessels naturally connect
arteries and arterioles, providing an additional mechanism for maintaining CBF in
the presence of ischemia or hypoperfusion (Shuaib, Butcher, Mohammad, Saqqur,
& Liebeskind, 2011). Collateral rarefaction thus undermines an important protec-
tive factor within the cerebral vasculature and may contribute directly to reduced
CBF (de la Torre, 2012). Rarefaction seems to be related to deficits in endothelium-
mediated NO signaling and is exacerbated by deficiencies in insulin-like growth
factor-1 (IGF-1) (Faber et al., 2011; Moore et al., 2015; Tarantini et al., 2016a, 2016b),
although the precise mechanisms of these processes remain unclear.
Hypertrophy, remodeling, arterial stiffness, endothelial dysfunction, athero-
sclerosis, and rarefaction interact to increase cerebrovascular resistance and im-
pair the brain’s ability to accommodate to transient changes in BP. As a result of
these combined factors, cerebral autoregulation shifts, such that higher perfusion
pressures are required to maintain the same level of CBF (De Silva & Faraci, 2016; Hu
et al., 2017; Pesek et al., 2016; Pires, Dams Ramos, Matin, & Dorrance, 2013). Changes
in autoregulation therefore increase the risk for hypoperfusion at lower perfusion
pressures that could be accommodated in the absence of hypertension (Malenfant
et al., 2016). Subsequent hypoperfusion may contribute to a state of chronic hypoxia
and predispose the brain to ischemic injury.
Neurovascular Coupling
Under normal conditions, increased neuronal activity activates a cellular and molec-
ular signaling cascade that results in localized vascular changes and increased CBF
(Hillman, 2014). This coupling facilitates increased neuronal activity by ensuring
adequate supplies of oxygen and glucose and metabolic waste removal (De Silva &
Faraci, 2016). In models of hypertension, this coupling can be impaired, suggesting
that hypertension in general and angiotensin II in particular may interfere with suc-
cessful vascular adaptation to changing energy demands (Bloch, Obari, & Girouard,
2015; Calcinaghi et al., 2013; Dunn & Nelson, 2014; Pires, Jackson, & Dorrance,
2014). However, neurovascular coupling mechanisms in parenchymal arterioles

are not impaired under conditions of enhanced tone in the presence of astrocyte
signaling (Iddings et al., 2015). This finding suggests possible protective mechanisms
and highlights the need to further elucidate how coupling mechanisms become im-
paired in hypertension (Bloch et al., 2015; Phillips, Chan, Zheng, Krassioukov, &
Ainslie, 2016).
Endothelial Dysfunction
In addition to local regulation of vasomotor tone, the endothelium is also impor-
tant for its role in maintaining the BBB and various trophic functions supporting
non-vascular cells. Endothelium-mediated trophic factors include various biologi-
cally active proteins and peptides that support the growth, survival, and function
of adjacent cells, including neurons and glial cells. Damage to the endothelium due
to chronically elevated BP can therefore lead to disruption of BBB function, loss of
trophic support, and increased inflammation.
Blood–Brain Barrier Integrity

Hypertension-induced endothelial dysfunction can result in changes to the perme-
ability and function of the BBB. BBB changes are common in hypertension but are
not well understood (Bean et al., 2016; De Silva, Silva, & Faraci, 2016; Etherton et al.,
2016; Maali et al., 2016; Srinivasan, Braidy, Chan, Xu, & Chan, 2016; Wei, Xu, Jin,
Feng, & Dong, 2017). Because of their important role in restricting the flow of ions
and molecules into neuronal space, tight junction proteins have been targets of recent
investigation (Fan et al., 2015a, 2015b; Srinivasan et al., 2016). Tight junction proteins
anchor cell membranes together, limiting the flow of molecules through intercellular
space and constituting of a vital component of the BBB. Preliminary findings suggest
that levels of tight junction proteins may decrease gradually with chronic hyperten-
sion, leading to sustained increases in BBB permeability (Fan et al., 2015a, 2015b;
Yang et al., 2016).
Trophic Functions
Cerebral endothelium also serves a number of supportive functions for non-vascular
cells. These trophic functions include promotion of white matter and oligodendro-
cyte function, support for neuronal signaling and synaptic plasticity, promotion of
neural progenitor cell function, and neurogenesis (Faraci, 2011; Katusic & Austin,
2014, 2016; Miyamoto, Pham, Seo, Kim, Lo, & Ariai, 2014). Endothelial cells also
seem to play an important role in processing amyloid precursor protein (APP) and
inhibiting activation of inflammatory immune cells, such as microglia (Katusic &
Austin, 2014, 2016). The loss of these crucial functions due to hypertension-related
damage to cerebral endothelium likely contributes to further disruptions in neuronal
and white matter function (De Silva & Faraci, 2016).
The interaction of hypertension-mediated cerebrovascular dysfunction with am-

yloid and APP is of particular note. Amyloid-β results from successive cleavages of
APP and is a central feature of Alzheimer’s disease neuropathology. Accumulation
of amyloid-β within the cerebrovasculature (i.e., cerebral amyloid angiopathy, or
CAA) is common in hypertension and is positively associated with BP (Hughes et al.,
2013; Hughes & Sink, 2016; Langbaum et al., 2012; Rodrigue et al., 2013). While
current evidence supports a causal role for hypertension in amyloid accumulation
and CAA, this may be a bidirectional relationship (Scott et al., 2015; Snyder et al.,
2015). Hypertension-mediated cerebrovascular disease seems to impair the brain’s
ability to catabolize and clear APP and amyloid-β, notably from the frontal cortex
(Ashby, Miners, Kehoe, & Love, 2016; Katusic & Austin, 2014, 2016; Kruyer, Soplop,
Strickland, & Norris, 2015). At the same time, CAA may interfere with CBF and ex-
acerbate cerebrovascular injury processes (Scott et al., 2015; Snyder et al., 2015), al-
though evidence for this relationship has been somewhat mixed (Cheema et al., 2015;
H. Li et al., 2014; Switzer et al., 2016; van Opstal et al., 2017).
Inflammation and Immune Activation

Hypertension-induced damage can also prompt endothelial activation, which is asso-
ciated with inflammation, brain imaging abnormalities, and increased risk of throm-
bosis (Hainsworth, Oommen, & Bridges, 2015; Shoamanesh et al., 2015; Uiterwijk
et al., 2016; Van Hooren et al., 2014). The inflammatory processes caused by damage
to endothelial cells can further exacerbate structural changes in a cycle of increasing
hypertension-mediated damage and dysfunction (De Silva & Miller, 2016; Meissner,
2016; Toth et al., 2015; Toth, Tarantini, Csiszar, & Ungvari, 2016).
The role of hypertension-related inflammation and immune activation in the
central nervous system remains an area of active research. A genetic model of hy-
pertension demonstrated microglial activation and accumulation in both cortex
and white matter, and infiltration of certain immune cells has been implicated in
increased BBB permeability (Bean et al., 2016; Nakagawa et al., 2013). Mounting evi-
dence suggests a prominent role for immune function and activation in hypertension
(McMaster, Kirabo, Madhur, & Harrison, 2015; Nicolls & Voelkel, 2016; Rabinovitch,
Guignabert, Humbert, & Nicolls, 2014), although the impact of these processes on
CBF, BBB integrity, and microvascular disease remains unclear.
IMPACT ON WHITE MATTER

The structural and functional changes that underlie hypertension-mediated cere-
brovascular dysfunction negatively impact the integrity and function of cerebral
white matter and contribute to WMD (Abraham et al., 2016; De Silva & Faraci,
2016; Meissner, 2016; Nation et al., 2015; Scott et al., 2015). As noted earlier, al-
tered autoregulation, the brain’s ability to adapt to changing perfusion pressures,
increases the risk for hypoperfusion, which may contribute to a state of chronic
hypoxia. Reduced CBF to white matter regions is observable in the early stages of
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Neuropsychology Science and Practice 3Rd Edition Sandra Koffler Editor Full Chapter

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Preface to Volume III vii

1. Studies in Cannabis Use: Year in Review 1

2. Hypertension and Cognitive Impairment in Older Adults: Review and

3. Technologically Enhanced Neuropsychological Assessments:

4. Cross-​Cultural Tests in Neuropsychology: A Review of Recent Studies and

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In Chapter 5, on interventions for functional impairments, Weakley and Schmitter-​

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Madison M. Berl Bernice A. Marcopulos

Lauren Strainge Alexander I. Tröster

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neuropsychological assessment with cannabis included in their list of medications,

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consistently cited relative to non-​cannabis-​using controls. Hyper-​and hypoactivity of

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axial diffusivity, and radial diffusivity maps from diffusion-​weighted images.

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and neurocognitive performance. Second, McKetin et al. (2016) focused on past

OTHER NOTABLE STUDIES

remained stable. These results suggest that acute cannabis-​induced neurocognitive

affects the later, evaluative stages of response inhibition. Observed cannabis-​induced

Finally, a shift to more longitudinal studies is enabling us to better understand causal

cause them to be underpowered, it would be interesting to examine associations be-

on executive function. Frontiers in Pharmacology, 7, 355. https://​doi.org/​10.3389/​

Richard F. Kaplan and Lauren Strainge

IMAGING WHITE MATTER DISEASE

SMALL VESSEL DISEASE AND WHITE MATTER

AGING AND THE BRAIN

A recent longitudinal study of 99 well-​educated normal elderly persons showed an

suggest that disconnection among distributed neural systems may be a fundamental

WHITE MATTER HYPERINTENSITIES AND AGE-​

HYPERTENSION, WHITE MATTER DISEASE, AND

of environmental or genetic causes, or secondary to multiple etiologies, including

individuals experience excessive declines in BP during sleep (Shimada et al., 1990;

RECENT ADVANCES IN THE STUDY OF HYPERTENSION

2014). However, neurovascular coupling mechanisms in parenchymal arterioles

Blood–​Brain Barrier Integrity

The interaction of hypertension-​mediated cerebrovascular dysfunction with am-

Inflammation and Immune Activation

IMPACT ON WHITE MATTER

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4. Cross-Cultural Tests in Neuropsychology: A Review of Recent Studies and

In Chapter 5, on interventions for functional impairments, Weakley and Schmitter-

Ileana Pacheco-Colón, Jacqueline C. Duperrouzel,

REVIEWS AND META-A NALYSES

consistently cited relative to non-cannabis-using controls. Hyper-and hypoactivity of

CROSS- S ECTIONAL STUDIES

axial diffusivity, and radial diffusivity maps from diffusion-weighted images.

remained stable. These results suggest that acute cannabis-induced neurocognitive

affects the later, evaluative stages of response inhibition. Observed cannabis-induced

on executive function. Frontiers in Pharmacology, 7, 355. https://doi.org/10.3389/

A recent longitudinal study of 99 well-educated normal elderly persons showed an

WHITE MATTER HYPERINTENSITIES AND AGE-

Blood–Brain Barrier Integrity

The interaction of hypertension-mediated cerebrovascular dysfunction with am-