CORRELATES OF PSYCHIATRIC DISORDERS
NEUROCOGNITIVE AND NEUROPHYSIOLOGICAL
CORRELATES OF PSYCHIATRIC DISORDERS
By JENNA E. BOYD, B.Sc.
A Thesis Submitted to the School of Graduate Studies in Partial Fulfillment of the Requirements
for the Degree Master of Science
McMaster University © Copyright by Jenna Boyd, August 2014
McMaster University MASTER OF SCIENCE (2014) Hamilton, Ontario (Neuroscience)
TITLE: Neurocognitive and Neurophysiological Correlates of Psychiatric Disorders AUTHOR:
Jenna E. Boyd, B.Sc. (University of Guelph) SUPERVISOR: Dr. Margaret C. McKinnon, Ph.D.,
C.Psych NUMBER OF PAGES: x, 96
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Abstract
This thesis presents research aimed at elucidating neurophysiological and neuropsychological
correlates of two psychiatric disorders, schizophrenia and PTSD. Although psychiatric disorders
are not traditionally known for featuring cognitive deficits, research over the past three decades
has revealed that deficits in many aspects of cognitive functioning are present across a wide
range of disorders. Here, we aim to further our understanding of these deficits and provide
evidence of the clinical utility of neurophysiological correlates of cognitive dysfunction. The
cause and course of cognitive deficits in PTSD is poorly understood, and an investigation of one
potential explanatory mechanism, dissociative symptomatology, is presented in the first part of
this thesis. Our results suggest that dissociative symptomatology plays a role in cognitive
dysfunction in PTSD, as among the clinical variables tested (including PTSD symptomatology,
dissociative symptoms, depressive symptoms, and anxiety symptoms) dissociative symptoms
were the only significantly correlated variables to cognitive dysfunction in a sample of combattrauma exposed veterans with and without PTSD. In the second part of this thesis, we investigate
the potential clinical utility of a neurophysiological biomarker for semantic processing deficits,
the N400, in schizophrenia. Our results indicate that N400 measures are stable over a one week
period and therefore may be clinically useful as a neurophysiological biomarker for semantic
processing abnormalities in schizophrenia. Overall, these two studies contribute to our
knowledge of cognitive deficits in psychiatric disorders and demonstrate their complexity as well
as their potential to provide clinically useful tools to aid in the identification of novel treatments
targeted at ameliorating cognitive deficits in schizophrenia and PTSD.
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Acknowledgements
First and foremost, I would like to thank my supervisor, Dr. Margaret McKinnon for her
continual support, guidance, and encouragement in developing my skills and pursuing my goals
throughout my graduate school career. I would also like to thank Dr. Michael Kiang who invited
me to help with the study presented in Chapter 3 of this thesis, and for providing excellent
guidance and encouragement throughout the analysis and writing processes. Dr. Ruth Lanius has
also played an integral part in my graduate education, and I would like to thank her for her
support and encouragement as well as helpful feedback and guidance. In addition, I would like to
thank the members of my committee, Dr. Geoff Hall and Dr. Luciano Minuzzi, for their ideas
and contributions to my thesis.
I would also like to thank the members of the Mood Disorders Research Unit who have
provided endless encouragement and laughter. I would especially like to thank Laura Garrick and
Cyndi Gee for all of their help with scheduling and much more. In addition, I would like to thank
the staff at the Homewood Research Institute for welcoming me as part of the team.
Finally, I would like to thank my family and friends who continue to be wonderfully
supportive of all of my goals and who continue to provide a solid base from which I can achieve
these goals.
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Table of Contents
Abstract
Acknowledgements
List of Tables
List of Figures
List of Abbreviations
Declaration of Academic Achievement
Chapter 1
General Introduction
1.1 Cognitive Deficits in Psychiatric Disorders
1.2 Cognitive Deficits in Schizophrenia
1.3 Cognitive Deficits in PTSD
1.4 Relative Severity of Cognitive Deficits
1.5 Overview of Presented Work
Chapter 2
Abstract
Introduction
Methods
Participants
Neuropsychological assessment
Assessment of Dissociative Symptomatology
Statistical Analyses
Results
Correlations between neuropsychological and clinical
measures
Discussion
Conclusions
References
Figures
Tables
Chapter 3
Abstract
Introduction
Methods
Participants
Stimuli
Task
Electroencephalographic data collection and analysis
Statistical analyses
Results
Correct response rates
Percentage of Accepted ERP Trials
ERPs
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Correlations between time 1 and time 2 for N400
measures
Correlations between N400 measures and SANS/SAPS
factor scores
Discussion
References
Figures
Tables
Chapter 4
4.1 Future Directions
4.2 Conclusions
Additional References
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List of Tables
Chapter 2
Table 1: Clinical and demographic characteristics of the study sample
Table 2: Correlational analysis between RBANS total and subscale scores and clinical measures
Chapter 3
Table 3: Demographic and clinical characteristics of the study participants
Table 4: Mean percentage of correct lexical-decision responses
Table 5: Mean percentage of accepted ERP trials
Table 6: Pairwise correlations for each SOA averaged across Time 1 and Time 2 for electrodes
Fz and Cz between N400 amplitudes for related and unrelated targets, and N400
semantic primig effects vs. SANS/SAPS factor scores
Table 7: Pearson’s r and intraclass correlation coefficients (ICC) between mean N400 amplitudes
at Time 1 and Time 2 for each SOA/target type combination at electrode sites Fz, Cz,
and Pz
Table 8: Mean N400 amplitudes and semantic priming effect for electrodes Fz, Cz, and Pz, for
each SOA/target combination at Time 1 and Time 2
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List of Figures
Chapter 2
Figure 1a-d: Scatterplots of correlations (spearman’s rho) between scores on the RBANS
immediate memory subscale and a) MDI total scores, b) MDI
depersonalization/derealization subscales, c) MDI disengagement subscale, and d) MDI
memory lapse subscale
Chapter 3
Figure 2a-d: Grand average ERPs to target words at all electrode sites for all SOA/target
combinations
Figure 3: Mean N400 amplitudes for related and unrelated targets and short and long SOAs at
Time 1 and Time 2
Figure 4a-d: Scatterplots of values at Time 2 vs. Time 1 at electrode Fz for all SOA/target
combinations
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List of Abbreviations
ANOVA
BAI
BDI
CAPS
CRT
CTQ
dACC
EEG
ERP
ES
fMRI
GMT
ICC
MATRICS
MDD
MDI
MINI
mPFC
MTL
OCD
PTSD
QOL
RBANS
SANS
SAPS
SD
SOA
Analysis of Variance
Beck Anxiety Inventory
Beck Depression Inventory
Clinician Administered PTSD Scale
Cognitive Remediation Therapy
Childhood Trauma Questionnaire
Dorsal Anterior Cingulate Cortex
Electroencephalography
Event-related Potential
Effect Size
Functional Magnetic Resonance Imaging
Goal Management Training
Intraclass Correlation Coefficient
Measurement and Treatment Research to Improve Cognition in
Schizophrenia
Major Depressive Disorder
Multiscale Dissociation Inventory
Mini International Neuropsychiatric Interview
Medial Prefrontal Cortex
Medial Temporal Lobe
Obsessive Compulsive Disorder
Post-traumatic Stress Disorder
Quality of Life
Repeatable Battery for the Assessment of Neuropsychological Status
Scale for the Assessment of Negative Symptoms
Scale for the Assessment of Positive Symptoms
Standard Deviation
Stimulus Onset Asynchrony
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Declaration of Academic Achievement
This thesis consists of 4 chapters: Chapter 1 provides background information on cognitive
dysfunctions in psychiatric disorders with a focus on schizophrenia and PTSD; Chapters 2 and 3
are manuscripts of original work completed during the tenure of my Masters degree, one of
which has been published and one of which is about to be submitted for publication; Chapter 4
discusses the results of the two studies in the context of research on cognitive dysfunctions in
psychiatric disorders and the future directions of this research. The study in Chapter 2 was
conceived and designed by Dr. Margaret McKinnon and Dr. Ruth Lanius, the participants were
recruited and data was collected in London, Ontario by London Health Sciences. I completed all
of the data analysis for this study. I performed the literature reviews and wrote the first draft of
the manuscript for this paper. The study in Chapter 3 was designed by Dr. Michael Kiang, and
Iulia Patriciu carried out the participant recruitment and data collection at the Schizophrenia
Research program at St. Joseph’s Healthcare Hamilton. I performed all of the data analysis and
literature searches and wrote the first draft of the manuscript for this paper. I presented portions
of this work at the 2014 Society of Biological Psychiatry annual conference in New York, NY.
This paper has been published in Schizophrenia Research, as of July 2014. The paper in Chapter
2 will be submitted to the Journal of Trauma and Dissociation.
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Chapter 1
General Introduction
This thesis outlines neurophysiological and neuropsychological research aimed at
expanding our knowledge of cognitive dysfunction in psychiatric disorders, namely,
schizophrenia and post-traumatic stress disorder (PTSD). We aim to provide research that
will aid in the development and testing of novel treatments with the capability to
remediate cognitive deficits in schizophrenia and PTSD, a research priority that has been
identified in both research communities (Marder & Fenton, 2004; Aupperle et al., 2011).
Cognitive deficits in schizophrenia have long been an active area of research, and recent
years have seen the emergence of work aimed at identified biomarkers for the cognitive
difficulties observed in this disorder. In the current thesis, we present research supporting
the utility of a novel biomarker for deficits in semantic processing in this population.
Comparatively, research on cognitive deficits in PTSD is in its infancy, and a further
understanding of the deficits in this population is needed before effective treatment
strategies can be developed. Here we present work aimed at elucidating at least one
explanatory mechanism, dissociative symptomatology, involved in the development or
maintenance of cognitive deficits in this disorder.
The following overview is divided into five sections to provide a comprehensive
review of the current state of research on cognitive deficits in psychiatric disorders. In the
first section we review the literature regarding the existence of cognitive deficits across
psychiatric disorders as well as current initiatives related to enhancing our knowledge of,
and developing treatments for, these deficits in various disorders. In the second section,
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we review the literature pertaining to the cognitive deficits present in schizophrenia, their
course of development, and current research initiatives for developing cognitive disease
biomarkers. In section three, we turn our attention to the existing literature on cognitive
deficits in PTSD, their course of development, and research regarding the factors
underlying their development and maintenance. In section four, we compare the
magnitude of cognitive deficits in schizophrenia and PTSD and review their functional
impacts in order to ascertain the relative need for cognition focused interventions in these
two disorders. Finally, in section five we provide a brief overview of the original
research to be presented in chapters two and three.
1.1 Cognitive Deficits across Psychiatric Disorders and their Potential Clinical Utility
Psychiatric disorders are widely known for their pervasive affective, social, and/or
psychotic features, however, it has become increasingly evident that the majority of these
disorders feature additional deficits in cognitive functioning (Millan et al., 2012).
Neurocognitive deficits have been most consistently reported in psychotic disorders,
namely schizophrenia (Fioravanti et al., 2012), but research over the past three decades
has demonstrated that they are present across a range of other psychiatric disorders
including affective disorders (major depressive disorder (MDD) and bipolar disorder
(BD)), obsessive compulsive disorder (OCD), PTSD, panic disorder, and generalized
anxiety disorder (Millan et al., 2012). Despite the relative certainty of the existence of
cognitive deficits in psychiatric disorders, the factors influencing their development and
maintenance, and the directionality of this relation, remain unclear. Undoubtedly, various
genetic, epigenetic, developmental, and environmental factors influence this relation,
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creating difficulty in gaining a clear picture of the etiology of cognitive dysfunction in
psychiatric populations (Millan et al., 2012). Gaining an understanding of what aspects or
characteristics of each disorder influence these impairments provides the opportunity to
tailor treatment approaches that are effective in ameliorating both the affective or
psychotic features of the illness in question and the accompanying cognitive deficits,
which may lead to better functional outcomes overall.
In an effort to add to the literature investigating the factors underlying cognitive
dysfunction in psychiatric disorders, we investigate the relation between one aspect of
PTSD symptomatology, dissociation, and cognitive dysfunction in a sample of combattrauma exposed individuals with and without PTSD, in Chapter two. Individuals with
PTSD have been reported to experience a range of cognitive deficits including difficulties
with long-term declarative memory (Merckelbach et al., 2003; Moradi et al., 2012; van
der Kelk & Fisler, 1995), short-term memory (Johnsen & Asbjornsen, 2008), attention
(Aupperle et al., 2012), and executive functioning (Polak et al., 2012). At present, the
factors underlying the presence of these cognitive dysfunctions are not known, and
dissociation has been suggested as one such factor that may be implicated. Limited
previous research has lent evidence to this conjecture, where dissociative symptoms have
been found to be correlated with impaired performance on measures of attention,
reasoning tasks, and short- and long-term memory (De Bellis et al., 2013; Roca et al.,
2006; Twamley et al., 2009). In Chapter two, we provide evidence congruent with these
previous findings by demonstrating the presence of a relation between immediate short-
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term memory and dissociative symptomatology in individuals with PTSD as a result of
combat-related trauma exposure.
In addition to providing treatment targets, our increased understanding of
cognitive deficits in psychiatric disorders has the potential to aid in identifying
physiological biomarkers of illness severity, if it is demonstrated that cognitive
functioning improves with successful treatment of the disorder in question. Not
surprisingly, as cognitive deficits in schizophrenia are relatively well defined, research
aimed at elucidating biomarkers of cognitive functioning in this disorder has been
identified as a priority in the schizophrenia research community (Cho et al., 2005; Luck et
al., 2011). Preliminary electroencephalography (EEG) research has contributed to this
goal, demonstrating the stability of EEG measures of cognitive processes over time, and
thus their potential utility as biomarkers. Specifically, mismatch negativity (a measure of
auditory processing) and the P300 (a measure of stimulus evaluation or categorization),
two event-related potential (ERP) measures that have been identified as potential
biomarker for schizophrenia, have been validated in healthy individuals (Hall et al., 2006;
Lew et al., 2007), and in patients with schizophrenia (Light & Braff, 2005). The potential
utility of cognitive deficits as biomarkers of illness severity in psychiatric disorders has
also been identified for individuals with OCD through neuroimaging research, where
neural substrates of specific symptom dimensions of OCD such as washing, checking,
and hoarding (associated with alterations in activity in the ventromedial prefrontal regions
/right caudate, putamen/globus pallidus/thalamus, and left pre-central gyrus/right orbitofrontal cortex, respectively), symptoms indicative of impairments in inhibitory processes,
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have been identified (Chamberlain et al., 2005). Research in affective disorders has also
employed neuroimaging in establishing biomarkers of cognitive dysfunction and illness
severity. Specifically, Marquand et al. (2008) determined that functional neuroimaging of
verbal working memory was successful in distinguishing depressed individuals from
healthy controls and therefore may be a useful as a diagnostic biomarker of depression.
In Chapter three of this thesis, we present research adding to the literature aimed
at determining physiological biomarkers of psychiatric illness severity. Specifically, we
investigate the test-retest reliability of a putative event-related potential (ERP, voltage
fluctuations measured by EEG in response to internal or external events), biomarker of
semantic priming deficits in schizophrenia. Semantic priming occurs when the processing
of a semantic stimulus is aided by the presentation of a preceding related stimulus
(Collins & Loftus, 1975). This phenomenon can be measured using EEG and the ERP
waveform known as the N400. The N400 is a negative wave deflection that occurs after
the presentation of any meaningful stimulus, and its amplitude is reduced when the
stimulus in question is preceded by a related prime stimulus – the semantic priming effect
(Kutas & Hillyard, 1980; 1984; 1989). In schizophrenia, the N400 semantic priming
effect is reduced, suggesting that individuals with this disorder are impaired in using
meaningful context to facilitate processing of related stimuli (Bobes et al., 1996; Kostova
et al., 2005; Salisbury, 2008; Condray et al., 2010; Mathalon et al., 2010; Kiang et al.,
2011, 2012, 2014). Thus, it has been suggested that the N400 semantic priming deficit
may be used as a biomarker of semantic processing abnormalities in schizophrenia (Kiang
et al., 2013). Recent work by Besche-Richard et al. (2014) has lent preliminary evidence
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for the potential clinical utility of N400 semantic priming effects as a biomarker of illness
severity in schizophrenia. Specifically, they report that while semantic priming effects are
absent in patients at initial testing, they are restored at re-test following treatment over a
one-year period, in concert with improvements in clinical symptoms, indicating that the
presence or absence of N400 semantic priming effects may be indicative of illness state or
severity. In the study presented in chapter three, we provide evidence validating this
potential biomarker by determining its’ test-retest reliability over a one-week period in a
group of individuals with schizophrenia.
Although cognitive deficits affect a range of psychiatric disorders, for the
purposes of this thesis, we will focus our discussion to the two populations studied here:
individuals with schizophrenia, and those with PTSD.
1.2 Cognitive Deficits in Schizophrenia
A significant amount of evidence details the presence of cognitive deficits in
schizophrenia, so much so that these deficits are considered characteristic of the disorder
(Fioravanti et al., 2012). In their recent meta-analysis, Fioravanti et al. (2012) describe
247 studies investigating cognitive functioning in schizophrenia, with a large number of
studies reporting deficits in the following cognitive domains: long-term memory (effect
size (ES) = -1.14), short-term memory (ES = -1.05), general IQ (ES = -0.96), language
processing and functioning (ES = -0.99), attention (ES = 0.99), and executive functioning
(ES = -1.10). The large effect sizes seen across a wide array of cognitive functions
demonstrate the severity of these deficits and imply that they may be associated with
significant societal/personal costs. Furthermore, findings that showcase the functional
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impact of these cognitive deficits for individuals with schizophrenia, demonstrate the
importance of understanding their progression and etiology. Indeed, research shows that
cognitive deficits are the strongest clinical predictors of difficulties in every-day living
(such as independence, interpersonal relations, and vocational functioning) and quality of
life (QOL) in individuals with schizophrenia (Green et al., 2000; Alptekin 2005; Bowie et
al., 2006; Ueoka et al., 2010; Fett et al., 2011; Shamsi et al., 2011). More specifically, a
meta-analysis by Fett et al. (2011) reported small to medium effect sizes in the
association between neurocognitive functioning and functional outcomes, with verbal
fluency being the most strongly associated with community functioning, verbal learning
and memory with social functioning, and social problem solving with problem solving
and reasoning deficiencies.
Since accumulating a solid foundation of evidence profiling cognitive deficits in
schizophrenia, schizophrenia researchers have turned their efforts towards determining
the exact course of development of these deficits, as well as the development of
successful treatments and disease biomarkers. In terms of illness course and chronicity,
recent evidence shows that age of onset is a significant factor in the severity of cognitive
deficits seen in individuals with schizophrenia, with earlier age of onset being related to
more pronounced cognitive deficits (Rajji & Mulsant, 2008). Despite previous beliefs that
these cognitive deficits worsen overtime, it appears that illness duration does not
influence severity, in that the magnitude of cognitive impairments in first-episode
psychosis are comparable to those observed in individuals at later stages of the disorder
(Mesholam-Gately et al., 2009). On the contrary, it appears that the time between the
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prodromal phase and the onset of full-blown psychosis is critical in the development of
cognitive deficits, with research showing that the cognitive deficits present during first
episode psychosis are significantly greater than those present in the premorbid and
prodromal phases, indicating that a substantial decline in cognition occurs between the
prodromal phase and the onset of the first episode (Mesholam-Gately et al., 2009).
Additionally, research suggests that cognitive abnormalities may have a genetic
background, and that these deficits may serve as risk factors for the development of
schizophrenia. Specifically, the prevalence of schizophrenia increases from 1% to 6%17% when comparing the general population to individuals that have first-degree relatives
with schizophrenia, indicating a strong genetic component (Tsuang, 2000). Furthermore,
a significant number of studies have demonstrated that first-degree relatives of
schizophrenia patients score lower than healthy controls (with effect sizes in the moderate
range) on measures of cognitive functioning congruent with the cognitive domains most
effected in patients (verbal memory, visuomotor speed, and executive functioning),
suggesting that certain cognitive deficits are familial and may serve as an endophenotype
for schizophrenia (Sitskoorn et al., 2004).
A second top priority in the schizophrenia research community has been to
develop and validate physiological biomarkers of schizophrenia that may aid both in the
early recognition of the disorder and in validating effective novel treatments. In
particular, there has been a general focus on developing treatments and biomarkers for
cognitive dysfunction (Marder & Fenton, 2004). Electrophysiological measures of
cognitive functions have proven to be a prime candidate for this goal, due to their relative
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
ease of use and the wealth of previous research in this area (Luck et al., 2011).
Specifically, ERPs have been suggested as potential cognitive biomarkers, particularly
those that are correlated with symptoms of the disorder. At present, there are a number of
established ERP biomarkers, including those reflecting cognitive processes, such as the
P300 and mismatch negativity (indices of stimulus categorization and auditory
processing, respectively) (Hall et al., 2006; Lew et al., 2007; Javitt et al., 2008; Light et
al., 2011). Neuroimaging biomarkers are less studied in this population but have also been
suggested as potential cognitive biomarkers. Specifically, top researchers in the field have
identified 17 functional MRI (fMRI) paradigms designed to measure brain activity during
cognitive tasks (i.e., the stroop task for measuring executive control) as warranting further
research investigating their utility as biomarkers of cognitive treatment effectiveness in
schizophrenia (Carter et al., 2012). As mentioned previously, in Chapter 3 research that
aims to add to the literature on putative ERP biomarkers for schizophrenia is presented.
Overall, despite being perhaps the most studied psychiatric disorder in terms of
cognitive impairment, there is still a great deal left to discover regarding the course and
cause of cognitive impairment in schizophrenia, highlighting the complexity of cognitive
dysfunction in psychiatric disorders. Additional research is also needed to determine how
this information may be used to further treatment and clinical practice.
1.3 Cognitive Deficits in Post-Traumatic Stress Disorder
Over the past three decades, PTSD researchers have become increasingly more
aware of the presence of cognitive abnormalities and deficits in individuals with PTSD,
and have since discovered that cognitive dysfunctions in PTSD are diverse and wide-
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reaching. Early research in this area focused on memory dysfunction and the processing
of trauma-related stimuli (Buckley, 2000), while later research turned to investigating
more general, non-trauma-related deficits (McNally, 2006; Aupperle et al., 2012). In
general, PTSD has been reliably reported to be associated with deficits in declarative
memory (van der Kelk & Fisler, 1995; Merckelbach et al., 2003; Moradi et al., 2012),
short-term memory (Johnsen & Asbjornsen, 2008), attention (Aupperle et al., 2012), and
executive functioning (Polak et al., 2012). Perhaps the most apparent abnormalities in the
cognition of individuals with PTSD are alterations in memory for traumatic event(s).
However, research in this area has resulted in conflicting reports of overgeneral and
fragmentary memory in some cases (van der Kelk & Fisler, 1995; Merckelbach et al.,
2003; Moradi et al., 2012; Graham et al., 2014) and increasingly vivid memories in others
(Rubin et al., 2004; Glosan et al., 2009). More consistent dysfunctions have been reported
in other domains of cognitive functioning such as short-term memory, which has been
considered the most reliably reported cognitive deficit in the PTSD literature (Johnsen &
Asbjornsen, 2008). More recent research highlights deficits in attention and executive
functioning, specifically reporting that individuals with PTSD are impaired in performing
tasks measuring auditory attention, working memory, sustained and selective attention,
and planning (Aupperle et al., 2012; Polak et al., 2012). It is important to mention that in
addition to deficits in non-trauma-related cognitive functions, individuals with PTSD also
face cognitive difficulty when confronted with tasks involving trauma-related, or other
emotional stimuli. Specifically, attentional biases towards negative or threatening stimuli
have been noted, whereby individuals with PTSD are impaired in tasks in which they are
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
required to direct their attention away from trauma-related stimuli, demonstrating deficits
in disengaging from such stimuli and/or enhanced perception of these stimuli (Aupperle
et al., 2012).
The exact course of cognitive impairment in PTSD is still an area of active
research, with some literature supporting the notion that these deficits may be present
before the onset of illness and other research indicating that cognitive impairments
develop along with the disease. While IQ in individuals with PTSD is generally within
the normal range (Aupperle et al., 2012), pre-trauma cognitive deficits have been reported
to be associated with higher levels of PTSD symptomatology (Parslow & Jorm, 2007;
Marx et al., 2009). For example, Marx et al. (2009) reported that pre-trauma immediate
memory for visual information was associated with post-trauma PTSD symptom severity,
in that worse performance on immediate memory measures was associated with greater
PTSD symptomatology, in a group of combat veterans. Twin studies provide further
evidence for the hypothesis that premorbid IQ and cognitive functioning may serve as
risk factors for the development of PTSD rather than as consequences of the disorder.
Specifically, Gilbertson et al. (2007) report that among monozygotic twins disconcordant
for trauma exposure, twins who scored lower on measures of IQ, verbal memory,
attention, and executive function, were more likely to have a trauma-exposed twin who
developed PTSD than twins who received high scores on these measures.
On the contrary, other evidence indicates that while premorbid IQ and cognitive
functioning may play a factor in the development of cognitive difficulties, they do not
fully account for post-trauma cognitive deficits. In particular, studies have indicated that
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associations between PTSD and neurocognitive deficits remain significant when
estimated current and premorbid intellectual functioning is controlled for, suggesting that
other aspects of PTSD symptomatology independently influence cognitive functioning in
this population (Gilbertson et al., 2001; Vasterling et al. 2002). Other preliminary
evidence indicates that the cognitive deficits observed in PTSD may be affected by the
chronicity of the disorder as well as the age of onset. Specifically, Yehuda et al. (2004)
report that memory dysfunctions observed in aging holocaust survivors are qualitatively
different from those observed in normal aging, dementia, and younger individuals with
PTSD. Similarly, Golier et al. (2006) suggest that the cognitive profile of individuals with
PTSD may change as a function of time, in that the deficits observed in older combat
veterans with PTSD differed from those seen in young and middle-aged individuals with
PTSD, however, they caution that longitudinal studies are needed to clarify these
findings.
It is likely that as well as the existence of premorbid cognitive deficits, certain
aspects of PTSD symptomatology influence cognitive functioning and may exacerbate
prior deficits. Factors such as the classic PTSD symptoms of hyperarousal, reexperiencing, and numbing (Leskin & White, 2007), depressive symptoms (Burris et al.,
2007) and dissociative symptoms (DePrince & Freyd, 2004; Roca et al., 2006; Twamley
et al., 2009; De Bellis et al., 2013) have been proposed to explain or influence the relation
between PTSD and cognitive dysfunction. Hyperarousal, re-experiencing, and numbing
may be involved in mediating deficits in executive functions in particular, as these
symptoms were found to covary with a measure of executive functioning and it has been
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suggested that these symptom clusters may be related to difficulties in response inhibition
(Leskin & White, 2007). Burris et al. (2008) report an alternative explanatory mechanism
for cognitive deficits in PTSD, finding that scores on a depression inventory accounted
for differences between veterans with and without PTSD on learning and memory tasks,
however they did not test for the influence of specific PTSD symptoms on these tasks.
Emerging evidence also points to dissociative symptoms as an explanatory mechanism
for the relation between PTSD and cognitive deficits. Three studies to date have `aimed to
determine whether this relation is present, and preliminary evidence supports this
assertion. Specifically, De Bellis et al. (2013) and Twamley et al. (2009) report that high
levels of dissociative symptomatology were associated with impaired performance on
attention and reasoning tasks (respectively) in maltreated children and women with PTSD
as a result of intimate partner violence, respectively. Similarly, Roca et al. (2006)
reported that combat veterans with PTSD and a comorbid dissociative disorder (i.e.,
depersonalization or derealization disorder) performed worse on measures of verbal
memory, autobiographical memory, and executive functioning in comparison to veterans
with PTSD and no comorbid dissociative disorder. As described in section 1.1, we present
research that aims to add to the literature regarding the relation between dissociative
symptoms and PTSD in a sample of combat-trauma exposed veterans with and without
PTSD in Chapter 3.
1.4 Relative severity of cognitive deficits in Schizophrenia compared with PTSD
The cognitive deficits seen in schizophrenia are so pervasive they are considered
to be a core feature of the disorder (Fioravanti et al., 2012) and there has been
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consideration for the inclusion of cognitive deficits in the diagnostic criteria for
schizophrenia (Keefe, 2008). Therefore, one can assume that the severity of deficits in
this disorder are of a far greater magnitude than those seen in other Axis I psychiatric
disorders. This conjecture appears to be true if comparing the severity of cognitive
deficits in individuals with schizophrenia versus PTSD. Specifically, in a review by
Millan et al. (2012), it is reported that deficits across a wide range of cognitive functions
are present in schizophrenia and can be considered to be either severe or moderately
severe, whereas the cognitive deficits observed in individuals with PTSD are reported to
cover a narrower range of domains and are either moderately severe or common but not
severe, with the exception of deficits in attention/vigilance and fear extinction, which are
classified as severe. In addition, estimates for effect sizes of deficits in specific cognitive
functions in schizophrenia range from -0.96 to -1.14 (large effect sizes), whereas effect
size estimates in PTSD range from -0.47 to -0.91 (moderate to large), depending on the
cognitive domain assessed (Schuitevoerder et al., 2013; Horner et al., 2013). Thus, it
appears that individuals with schizophrenia suffer from a greater range of more severe
deficits in cognitive functioning than individuals with PTSD.
An alternate way one can assess the magnitude or severity of cognitive deficits is
by determining their level of impact on everyday living and functional outcomes. As was
reviewed in section 1.2, cognitive deficits in schizophrenia are associated with significant
costs in everyday functioning including independence, interpersonal relations, vocational
functioning, and overall QOL, and they are the strongest clinical predictors of difficulties
in these areas (Green et al., 2000; Fett et al., 2011). Unfortunately, there is a general
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paucity of research regarding the individual impact of cognitive deficits on QOL and
everyday functioning in the PTSD literature, despite calls for research to be completed in
this area (Twamley et al., 2004). To date, two studies have investigated the impact of
cognitive deficits on functional outcomes in PTSD. In their study of neuropsychological
functioning and functional outcomes in veterans with PTSD, Gueze et al. (2009) found
that objective assessments of memory performance (immediate and delayed verbal
memory) was able to accurately predict social and occupational outcomes. Similarly, a
more recent study by Kaye et al. (2014) reported that objective measures of cognition and
functional capacity were intercorrelated, and neither was related to PTSD symptom
severity, indicated that worse cognitive functioning was associated with lower functional
capacity. Therefore, despite a fairly limited amount of evidence, it appears that similar to
schizophrenia, deficits in cognitive functioning in PTSD are predictive of poor functional
outcomes, and this relation appears to be independent of PTSD symptom severity.
Determining the relative magnitude of the impact of cognitive deficits on functional
outcomes between these disorders is difficult at this time do to the limited research
available in the PTSD literature. However, if cognitive deficits are a key component to
impaired social and occupational functioning in psychiatric illness, one can assume that
the magnitude of these effects may be more pronounced in individuals with
schizophrenia, as they appear to suffer from more severe cognitive deficits than
individuals with PTSD.
One could assert that therapies targeted at ameliorating cognitive deficits are more
needed in schizophrenia due to the greater magnitude of cognitive deficits in comparison
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with PTSD. However, as these deficits are related to poor functional outcome in both
disorders, the relative severity may not be of particular significance. Functional deficits in
psychiatric disorders create some of the greatest economic costs to society, costing an
estimated 193.2 billion dollars annually in the U.S. (Kessler et al., 2008), and it is worth
pursuing treatments that may increase psychosocial functioning no matter the severity of
deficits present.
1.5 Overview of the Presented Work
The experimental work presented in this thesis is based on data collected during
the course of two distinct studies. Chapter 2 reflects data collected for a study examining
neuropsychological functioning and its correlates in individuals with combat-trauma
related PTSD. The presented analyses of this data reveals that dissociative
symptomatology is the only significant correlate of immediate verbal memory functioning
among various clinical variables tested (including PTSD symptomatology, depressive
symptoms, and anxiety symptoms), suggesting that high levels of dissociation may
account for worse immediate memory functioning in individuals with combat-related
PTSD. Chapter 3 reflects data collected for a study examining the reliability and stability
of a putative ERP biomarker of cognitive functioning in individuals with schizophrenia.
Here, we demonstrate significant test-retest reliability of N400 measures (an indicator of
semantic processing), suggesting that such measures may be useful in determining the
effectiveness of novel treatments aimed at improving cognition in schizophrenia.
Although these seemingly disparate studies focus on different cognitive functions
in different psychiatric populations, they highlight the potential for the development of
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treatment targets and biomarkers of treatment effectiveness that can be gained from our
enhanced understanding of the causes, course, and underlying factors of cognitive deficits
in psychiatric disorders. These studies contribute to areas of research deemed to be of
significant importance in their respective fields. The “Measurement and Treatment
Research to Improve Cognition in Schizophrenia” (MATRICS) initiative by the NIMH
has brought forth a wealth of research regarding cognitive biomarkers and potential
cognition-enhancing treatments for schizophrenia (Marder & Fenton, 2004), and the
research presented here in Chapter 3 adds to this literature and has the potential to aid in
the development of such novel treatments. Although the understanding of cognitive
deficits in PTSD is in its infancy in comparison to schizophrenia, recent years have seen
the emergence of research aimed at understanding the factors underlying cognitive
dysfunction in this population, and the research presented in Chapter 2 is in line with this
goal, and has the potential to inform future studies aimed at incorporating cognitiveenhancing components to treatment for PTSD.
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Chapter 2
The Relation between Dissociative Symptomatology and Immediate
Memory Dysfunction in a Sample of Military Combat Exposed
Individuals with and without PTSD
Jenna E. Boyd, BSc.1,2,3, Paul A. Frewen, PhD., C.Psych4, Ruth Lanius, MD, PhD.4*,
Margaret C. McKinnon, PhD., C.Psych1,2,3*
1
Department of Psychiatry and Behavioural Neurosciences, McMaster University,
Hamilton, Ontario, Canada; 2Mood Disorders Program, St. Joseph’s Healthcare Hamilton,
Hamilton, Ontario, Canada; 3Homewood Research Institute, Guelph, Ontario, Canada;
4
Department of Psychiatry, University of Western Ontario, London, Ontario, Canada
*Shared Senior Authorship
This paper will be submitted for publication in The Journal of Trauma and Dissociation
as of August 2014.
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Abstract
The core affective components of post-traumatic stress disorder (PTSD) are often
accompanied by neurocognitive dysfunction across a wide range of cognitive domains.
The mechanisms by which such cognitive deficits develop and are maintained remain
poorly understood. Here, we investigate the contribution of one potential mechanism,
dissociative symptomatology, as well as other key clinical characteristics, in a sample of
combat-trauma-exposed veterans with and without PTSD. Twenty combat-traumaexposed military veterans who had either a current diagnosis of PTSD, were in recovery
from PTSD, or who had never had a diagnosis of PTSD were recruited for this study.
Among the clinical variables assessed, dissociative symptomatology was the only
significant correlate of neurocognitive functioning in this population. The results of the
current study indicate that dissociative symptomatology may play a key role in the
development and/or maintenance of short-term memory deficits in individuals with PTSD
as a result of combat-related trauma.
Keywords: Post-traumatic Stress Disorder, Combat Trauma, Dissociation,
Neuropsychological Function, Short-term memory
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Introduction
Individuals with PTSD exhibit neurocognitive dysfunction across a host of
cognitive domains, including declarative memory (Merckelbach, Dekkers, Wessel, &
Roefs, 2003; Moradi, Abdi, Fathi-Ashtiani, Dalgleish, & Jobson, 2012; van der Kelk, &
Fisler, 1995), short-term memory (Johnsen, & Asbjornsen, 2008) attention (Aupperle et
al., 2012), and executive functioning (Polak et al., 2012). Multiple factors, including
hyperarousal, re-experiencing and emotional numbing (Leskin & White, 2007),
depressive symptoms (Burriss, Ayers, Ginsberg, & Powell, 2007), and dissociation
((DeBellis, Woolley, & Hooper, 2013; DePrince, & Freyd, 2004; Roca, Hart, Kimbrell, &
Freeman, 2006; Twamley et al., 2009), have been proposed as explanatory mechanisms
for alterations in cognitive functioning in PTSD. In the present study, we examine the
relation between one such seldom-explored factor, the presence of dissociative symptoms,
and neurocognitive deficits in a military sample of combat-trauma-exposed veterans with
and without PTSD. In order to determine the relative contribution of these factors to
neuropsychological dysfunction in this population, we also explore the relation between
cognitive performance and other key clinical variables, including anxiety, PTSD, and
depression severity and level of trauma exposure.
Although neurocognitive dysfunction following trauma exposure likely stems
from the combined effect of several factors, it is probable that dissociative symptoms play
a prominent role in driving this disruption. Given the definition of dissociation as a
disrupted or fragmented integration of consciousness, memory, identity, emotion,
perception, body representation, motor control, and behaviour (American Psychological
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Association, 2013), it follows that the presence of these symptoms disrupts the ability to
attend to cognitively demanding tasks. Critically, dissociation is among the strongest
predictors of poor outcome and symptom severity in the peri-traumatic period, and
immediately following trauma exposure (Galatzer-Levy, Madan, Neylan, Henn-Haase, &
Marmar, 2011; Kumpula, Orcutt, Bardeen, & Varkovitzky, 2011; Ozer, Best, Lipsey, &
Weiss, 2003; Vasquez, De Arellano, Reid-Quinones, Bridges, Rheingold, Stocker, &
Danielson, 2012; Werner, & Griffin, 2012). Indeed, in a recent study of acute trauma
survivors receiving immediate psychological treatment, the only significant predictor of
treatment response at one and three months post incident was level of dissociative
symptoms present at the initial treatment session (Price, Kearns, Houry, & Routhbaum,
2014). Few studies, however, have explored the relation between neurocognitive
dysfunction and dissociative symptoms in PTSD, with three studies reported to date. For
example, De Bellis et al. (2013) found that high levels of dissociation were negatively
correlated with a measure of attention in a sample of maltreated children with and without
PTSD, where children with high symptoms of dissociation were more likely to experience
disrupted attention. In another study involving women with PTSD resulting from intimate
partner violence, impaired performance on reasoning tasks was significantly correlated
with dissociative symptoms (Twamley et al., 2009). Finally, Roca et al. (2006) reported
that when compared to combat veterans with PTSD but no comorbid dissociative
disorder, combat veterans with PTSD and a comorbid dissociative disorder show
impaired performance on measures of verbal memory, autobiographical memory, and
executive functioning.
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Although preliminary evidence points toward a relation between neurocognitive
dysfunction in PTSD and the presence of dissociative symptoms, further characterization
is required across different illness states resulting from trauma exposure. This is
particularly relevant in light of the recent addition of the dissociative subtype of PTSD to
the DSM-5 that identifies specifically symptoms of depersonalization and derealization
(APA, 2013), and recent reports that as many as 14.4% of individuals cross-culturally
with PTSD show symptoms of dissociation involving depersonalization and derealization
(Stein et al., 2013). Understanding factors related to neurocognitive dysfunction among
service members is of particular importance, given the large number of soldiers returning
from recently ending conflicts in Iraq and Afghanistan and estimates of the number of US
Iraq Veterans with PTSD ranging from 4-17% (Richardson, Frueh, & Aciemo, 2010).
Indeed, emerging evidence suggests that veterans with PTSD may be at increased risk of
developing neurocognitive deficits in comparison to other PTSD populations (Polak et al.,
2012).
In the current study, we investigated the relation between performance on
measures of neuropsychological functioning and dissociative symptomatology in a
military sample of combat-exposed individuals with and without PTSD. We also assessed
the relation between measures of other key clinical variables (i.e., PTSD symptom
severity, depressive symptoms, childhood trauma exposure, and anxiety symptoms). We
hypothesized that high levels of dissociative symptoms would be associated with lower
scores on objective measures of frontal-temporally mediated domains of neurocognitive
functioning previously shown to be impacted in PTSD and that this relation would be
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
stronger than those between neurocognitive functioning and other clinical variables
assessed in the current study.
Methods
Participants
The University of Western Ontario’s Health Sciences Research Ethics Board
approved this study. Twenty military-combat-exposed males were recruited to participate
in this study, and informed consent was obtained from all participants. Fourteen
participants had a current diagnosis of PTSD related to military trauma, three were
considered to be in remission from PTSD, and three had no current or past diagnosis of
PTSD and were considered to be resilient. Trauma-exposed control participants were not
on any current or past psychiatric medications. Of the participants who had recovered
from PTSD, two had previously taken psychiatric medication and one was currently
taking psychiatric medication. Twelve of the fourteen participants with a current
diagnosis of PTSD were currently (n=10) or had previously (n=2) taken psychiatric
medication. Participants’ medication status is summarized in Table 1. Participants were
recruited from London Health Sciences Centre (LHSC; London, Ontario, Canada)
through operational stress injury referrals made by military providers.
The Structured Clinical Interview for the DSM-IV-TR (SCID) was used to
confirm diagnosis of psychiatric illness (First et al., 2002). The Clinician-Administered
PTSD Scale (CAPS) was used to confirm diagnosis of PTSD and assess PTSD symptom
severity (Blake et al., 1995). The Beck Depression Inventory (BDI) (Beck, Steer, &
Brown, 1996) and Beck Anxiety Inventory (BAI) (Beck & Steer, 1996) were used to
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
assess depression and anxiety symptom severity, respectively. In addition, exposure to
childhood trauma was probed using the Childhood Trauma Questionnaire (CTQ)
(Bernstein& Fink, 1998). Please refer to Table 1 for demographic and clinical summaries.
The following exclusion criteria was applied to all participants (resilient controls,
recovered, and participants with PTSD): history of head injury and loss of consciousness,
significant untreated illness, history of a neurological disorder, history of any pervasive
developmental disorder lifetime diagnosis of bipolar or psychotic disorder, current or past
DSM-IV-TR AXIS II disorder, current alcohol or substance abuse disorder or dependence
within the last 6 months, history of a pain disorder, history of obsessive compulsive
disorder, or history of electroconvulsive therapy or trauma-focused psychotherapy (e.g.,
exposure therapy).
Neuropsychological Assessment
The Repeatable Battery of the Assessment of Neuropsychological Status
(RBANS) (Randolph, Tierny, Mohr, & Chase, 1998) was used to determine participants’
neuropsychological status. The RBANS is composed of five indexes that comprise the
following index scores: Immediate Memory (short-term memory),
Visuospatial/Constructional, Language, Attention, and Delayed Memory. Raw scores
from each of the five indexes are converted to Index scores based on age and gender
norms. The converted raw scores make up the total index score, and index scores for the
five subscales.
Assessment of Dissociative Symptomatology
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
The Multiscale Dissociation Inventory (MDI) was used to assess dissociative
symptomatology (Briere, 2002). The MDI measures five domains of dissociative
behaviour: Disengagement, Depersonalization, Derealization, Emotional Constriction,
Memory Disturbance, and Identity Dissociation. Disengagement refers to an emotional or
cognitive separation of oneself from one’s surroundings or environment.
Depersonalization and derealization can be described as alterations in self-awareness and
the perception of oneself and alterations in the awareness/perception of one’s
surroundings, respectively. Emotional constriction refers to a dampening or decreased
responsiveness to emotions. Memory disturbances occur when an individual experiences
a reduced ability to recall personal life events. Finally, identity dissociation refers to the
experience and portrayal of more than one personality. The MDI yields six scores, one for
each subscale, and one score for total dissociative symptomatology.
Statistical Analyses
Across participants, pairwise correlational analysis was performed to determine
whether any clinical variables were significantly related to neurocognitive functioning as
assessed by the RBANS. Specifically, pairwise correlations were calculated between
RBANS total and RBANS subscale scores (immediate memory,
visuospatial/constructional, language, attention, and delayed memory) and the following
variables: CAPS (past month), BAI, BDI, CTQ, MDI (total and subscale scores
(disengagement, depersonalization/derealization, emotional constriction, and identity
dissociation)) The depersonalization and derealization subscales of the MDI were
averaged for the purposes of our analyses as previous work has indicated that these two
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
constructs are the most common dissociative symptoms in individuals with PTSD and are
together indicative of the dissociative subtype of PTSD (Lanius et al., 2012). Pearson’s r
or Spearman’s rho (ρ) values were reported, depending on results from the Shapiro-Wilk
test of normality.
Results
Correlations between neuropsychological and clinical measures
Table 2 summarizes the results of the correlational analyses. No significant
correlations were found between RBANS scores and CAPS, CTQ, BDI, or BAI scores.
The immediate memory subscale of the RBANS was significantly correlated with MDI
total scores (ρ = -0.48, P = 0.031), and scores on the following MDI subscales:
disengagement (ρ = -0.60, P = 0.005), depersonalization/derealization (ρ = -0.56, P =
0.01), and memory lapse (ρ = -0.47, P = 0.036). Scatterplots of significant correlations are
shown in Figure 1.
Discussion
In this sample of combat-exposed military personnel with and without PTSD,
dissociation was the only clinical measure that correlated with neuropsychological
functioning; no such correlations emerged for other clinical measures. Specifically, we
found a significant negative correlation between the immediate memory subscale of the
RBANS, and MDI total score, as well as the MDI subscales of disengagement,
depersonalization/derealization, and memory impairment. These results indicate that
higher levels of dissociative symptomatology are associated with worse performance on a
measure of short-term verbal memory. Critically, other factors, such as illness severity
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
and level of trauma exposure putatively associated with cognitive dysfunction following
trauma exposure showed no such relation, supporting strongly the idea that dissociation is
the most significant driver of changes in memory functioning among this military
population.
These results are in line with previous literature demonstrating a relation between
neurocognitive functioning, and more specifically, short-term memory dysfunction, and
dissociative symptomatology in PTSD. A host of studies point towards the presence of
cognitive dysfunction in PTSD (Aupperle et al., 2012; De Bellis et al., 2011; Flaks et al.,
2014; Hayes et al., 2013; LaGarde et al., 2010; Parslow & Jorm, 2007; Polak et al., 2012;
Rivera-Velez et al., 2014; Schuitevoerder et al., 2013; Schweizer & Dalgleish, 2011;
Walter et al., 2010); the results of the present study suggest that specific symptoms of
dissociation including those associated with the dissociative subtype of PTSD (i.e.,
depersonalization and derealization) may those most strongly associated with cognitive
dysfunction, at least in a combat-exposed population.
Previous work indicates that deficits in short-term memory are among the most
consistently reported neurocognitive deficits in PTSD (Brewin et al., 2007; Johnsen &
Asbjernsen, 2008). Critically, encoding information in short-term memory relies heavily
upon attention resources and strategic processes, processes collectively mediated by the
medial temporal lobe (MTL) system (Squire, & Zola-Morgan, 1991) and frontal lobes
(Hensen, Burgess, & Frith, 2000). The results of the current study suggest that
dissociative symptomatology plays a significant role in these deficits in information
acquisition. Neurobiological findings that have been used to characterize the dissociative
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
subtype of PTSD point to a pattern of emotional overmodulation whereby areas of the
brain involved in emotional arousal and emotional regulation such as the medial
prefrontal cortex (mPFC) and the dorsal anterior cingulate cortex (dACC) show
heightened activity, leading to an overmodulation and decreased activity in areas of the
brain involved in emotional processing, such as the amygdala and the right interior insula,
in comparison to non-dissociative PTSD controls (Lanius et al., 2010; Lanius et al.,
2012). In addition to the overmodulation of regions of the brain involved in emotional
processing, the hyperactivity of the mPFC and dACC are also related to overmodulation
of other limbic structures, including the hippocampus, which is highly involved in the
encoding of new information (Lanius et al., 2010). This neurobiological link between the
dissociative subtype and regions of the brain involved in memory encoding further
supports the view that dissociative symptomatology may play an important role the
reported deficits in short-term memory. The suggestion that overmodulation of the
hippocampus by the mPFC may lead to failures in short-term memory is validated by
reports that increased activity in other areas of the default mode network (part of which is
the mPFC) predict lapses in verbal short-term memory (Otten, & Rugg, 2001). In
addition, other forms of hippocampally-dependent memory have been linked to
dissociative states and changes in hippocampal activity. Specifically, in a recent study by
Bergouignan, Nyberg, & Ehrsson (2014), disruptions in declarative memory were been
elicited by an experimentally induced out-of-body illusion during a social interaction.
This dissociative “out-of-body” experience led to lapses in recall for the social interaction
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
as well as abnormal activity in the left posterior hippocampus in comparison to controls
that experienced an “in-body” illusion.
Together the results of the present study, and of prior investigations (De Bellis et
al., 2013; Twamley et al., 2012; Roca et al. 2006), support the involvement of dissociative
symptomatology in the presence of neurocognitive dysfunction in PTSD. This work has
the potential to inform future treatment strategies. For example, cognitive remediation
therapies (CRT) targeting specific cognitive abilities (i.e., attention and memory) have
been applied to other psychiatric disorders, including schizophrenia and affective
disorders, and have resulted in long-term improvements in working memory, executive
functions, and attention (Anaya et al., 2012; Grynzpan et al., 2011; Vinogradov, Fisher, &
Villers-Sidani, 2012; Kluwe-Schiavon, Sanvicente-Vieira, Kristensen, & Grass-Oliverira,
2012). Critically, CRT has also been shown to improve functional outcome (e.g., return
to work and school) when measured immediately post-treatment and at follow-up (Wykes
et al., 2011). To date, no studies have investigated the utility of CRT for individuals with
PTSD despite mounting evidence that this type of therapy might be ideal for this
population. If CMT were to be employed as a therapeutic approach in the PTSD
population, the current evidence for the role of dissociative symptomatology may be used
to tailor techniques so that they include components that will also aid in the reduction of
dissociative symptomatology, such as mindfulness based therapies (Ozer et al., 2008;
Smith et al., 2011) or grounding techniques (Kennerley, 1996; Kriedler, Zupancic, Bell,
& Longo, 2000), which may on their own lead to partial reductions in neurocognitive
deficits. This will be of critical importance to military members returning from the
29
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
combat theatre and seeking re-entry to occupational and educational roles, where the
presence of untreated cognitive dysfunction would be expected to impact negatively on
these re-engagement efforts.
Some limitations of the current study warrant caution. Most notably, the current
analysis was correlational in nature and therefore causality cannot be assumed in the
relation between dissociative symptoms and short-term memory deficits in individuals
exposed to combat related trauma. These provocative findings emerged in a small sample
of returning military members; additional work involving larger samples will be required.
Future work should also aim to determine whether there is a predictive relation between
dissociative symptomatology and neurocognitive functioning in this population through
the use of regression analyses. Unfortunately, the small sample size of the current study
precluded the use of such analyses. In addition, the current study does not elucidate
whether the relation between dissociative symptomatology and short-term memory
dysfunction is present only when PTSD symptomatology is present or if this relation
persists following recovery. Future cross-sectional or longitudinal studies will be
necessary to determine whether this assertion is true. Finally, the results reported here are
specific to individuals with PTSD as a result of exposure to combat-related trauma, and
therefore may not be generalizable to other populations of individuals with PTSD. Future
work will be required to identify the presence of such a relation in the various PTSD
etiologies (i.e., childhood abuse, interpersonal violence, natural disasters).
Conclusion
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
The results of the current study, though preliminary in nature, lend further support
to the emerging relation between dissociative symptomatology and cognitive dysfunction
in individuals with PTSD. Specifically, our results indicate that higher levels of
dissociative symptomatology are associated with worse performance on a measure of
short-term memory in veterans exposed to combat-related trauma; no other clinical
variables, including PTSD symptom severity, showed this relation. The current results are
of critical importance in gaining a more clear understanding of the cognitive profile of
this population, and in determining effective treatment strategies for mitigating the
difficulties experienced by those with PTSD and concomitant neurocognitive deficits as a
result of combat-related trauma. In addition, these findings are important in the
characterization of the newly introduced dissociative subtype, in that individuals with
PTSD and dissociative symptomatology may be at greater risk of experiencing cognitive
difficulties than those with non-dissociative PTSD. Future work should aim to clarify the
causality of the reported relationship through regression analyses and longitudinal studies,
in order to determine the timing of onset of both neurocognitive deficits and dissociative
symptomatology.
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Figures
Figure 1. Scatterplots of correlations (spearman’s rho) between scores on the RBANS
immediate memory subscale and a) MDI total scores, b) MDI
depersonalization/derealization subscales, c) MDI disengagement subscale, and d) MDI
memory lapse subscale
Scores on RBANS Immediate
Memory Subscale
a)
120
100
80
60
40
20
40
60
80
100
15
20
MDI Total Scores
Scores on RBANS Immediate
Memory Subscale
b)
120
100
80
60
40
0
5
10
MDI Depersonalization/Derealization Scores
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Scores on RBANS Immediate
Memory Subscale
c)
120
100
80
60
40
0
5
10
15
20
25
20
25
MDI Disengagement Scores
Scores on RBANS Immediate
Memory Subscale
d)
120
100
80
60
40
0
5
10
15
MDI Memory Lapse Scores
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Tables
Table 1. Clinical and demographic characteristics of study sample with means (SD in
brackets).
Characteristic
Sex
Age
Education
Full Scale IQ (NART)
CAPS
BDI
BAI
CTQ (Total)
MDI (Total)
Disengagement
Depersonalization/Derealization
Emotional constriction
Memory disturbance
Identity dissociation
Medication Status (# of participants)
Current Antidepressant
Past Antidepressant
Current Sedative
Past Sedative
Current Antipsychotic
Past Antipsychotic
Current Mood Stabilizer
Past Mood Stabilizer
Participants (n = 20)
20 male, 0 female
41.0(10.4)
15.0(1.4)
106.8(7.4)
58.8(29.2)
19.0(11.5)
14.8(10.3)
39.5(16.0)
49.7(17.7)
10.9(4.2)
7.4(3.2)
10.5(4.7)
8.6(4.9)
5.0(0.8)
9
7
7
5
3
5
0
1
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Table 2. . Results of the correlational analysis between RBANS total and subscale scores
and clinical measures. Values reflect Pearson’s r or Spearman’s ρ depending on the
normality of clinical variables.
Clinical Measure
r or ρ
RBANS
Total
CAPS (Previous Month)
BAI
BDI
CTQ (Total)
MDI (Total)
Disengagement
Derealization/
Depersonalization
Emotional Constriction
Memory Impairment
Identity Dissociation
r
r
r
ρ
ρ
ρ
ρ
ρ
ρ
ρ
RBANS
visuospatial/
constructional
0.36
0.18
0.35
-0.02
0.07
0.17
-0.03
RBANS
Language
RBANS
Attention
0.13
0.06
0.26
0.14
-0.11
-0.13
-0.23
RBANS
Immediate
Memory
-0.29
0.001
-0.05
0.44
-0.48*
-0.60**
-0.56*
-0.26
-0.27
-0.19
0.09
-0.01
-0.11
-0.06
0.21
0.09
0.38
-0.14
0.20
0.17
0.12
RBANS
Delayed
Memory
0.17
0.03
0.19
0.18
-0.23
-0.23
-0.33
-0.06
-0.05
-0.23
-0.28
-0.47*
-0.29
-0.02
0.19
-0.22
0.11
0.08
-0.36
0.15
0.16
-0.01
-0.11
-0.21
-0.16
*p < 0.05
**p < 0.01
41
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Chapter 3
Test-retest Reliability of N400 Event-Related Brain Potential
Measures in a Word-pair Semantic Priming Paradigm in
Patients with Schizophrenia
Jenna E. Boyd, BSc.1,2,3, Iulia Patriciu, MA2, Margaret C. McKinnon, PhD., C.Psych1,2,3,
Michael Kiang, M.D., PhD.1,2,4
1
Department of Psychiatry and Behavioural Neurosciences, McMaster University,
Hamilton, ON, Canada; 2St. Joseph’s Healthcare Hamilton, Hamilton, ON, Canada;
3
Homewood Research Institute, Guelph, ON, Canada; 4Centre for Addiction and Mental
Health, Toronto, ON, Canada
This paper was published in the journal Schizophrenia Research and has been printed
with permission from the publishers, Elsevier B.V.
Citation: Boyd, J.E., Patriciu, I., McKinnon, M.C., & Kiang, M. (2014). Test-retest
reliability of N400 event-related brain potential measures in a word-pair
semantic priming paradigm in patients with schizophrenia. Schizophrenia
Research, http://dx.doi.org/10.1016/j.schres.2014.06.018
42
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Abstract
The N400 event-related brain potential (ERP), a negative voltage deflection occurring
approximately 400 ms after onset of any meaningful stimulus, is reduced in amplitude
when the stimulus is preceded by related context. Previous work has found this N400
semantic priming effect to be decreased in schizophrenia, suggesting impairment in using
meaningful context to activate related concepts in semantic memory. Thus, N400
amplitude may be a useful biomarker of abnormal semantic processing and its response to
treatment in schizophrenia. To help assess validity of N400 amplitude as a longitudinal
measure in schizophrenia, we aimed to evaluate its test-retest reliability. ERPs were
recorded in sixteen schizophrenia patients who viewed prime words, each followed at
300- or 750-ms stimulus-onset asynchrony (SOA) by a target that was either a related or
unrelated word, or nonword. Participants’ task was to indicate whether or not the target
was a real word. They were retested on the same procedure one week later. Test-retest
reliability was assessed by calculating Pearson’s r and intraclass correlation coefficients
(ICCs) across timepoints for N400 amplitudes for related and unrelated targets, at each
SOA. Consistent with previous results, no significant differences were found between
patients’ N400 amplitudes for related and unrelated targets, at any SOA/timepoint
combination. Pearson’s r (range: 0.52-0.64) and ICCs (range: 0.52-0.63) for N400
amplitudes at Fz across timepoints were significant for both target types at each SOA (all
p < .04). The results suggest potential utility of N400 amplitude as a longitudinal
neurophysiological biomarker of semantic processing abnormalities in schizophrenia.
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Keywords: Schizophrenia, Cognition, Semantics, Neurophysiology, Event-related
potentials, Test-retest reliability
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Introduction
Meaningful stimuli - such as words, pictures, or environmental sounds - facilitate
or prime the processing of related stimuli. For example, after seeing the word SHIP,
people are faster to recognize the related word BOAT than the unrelated word BIRD.
These semantic priming effects can be understood within a network model of long-term
semantic memory, our store of knowledge about the world. In this type of model,
meaningful concepts are represented as nodes in a neural network, with connections
between nodes of related concepts (Collins and Loftus, 1975). When a particular node (in
the example above, our mental concept of a ship) is activated (i.e., by reading the word
SHIP), this activation is thought to spread to related concepts, thereby facilitating
processing of their corresponding stimuli.
A neurophysiological index of semantic priming is the N400 scalp-recorded
event-related brain potential (ERP). The N400 is a negative-going ERP waveform
component peaking between 300 and 500 ms following the onset of any meaningful
stimulus (Kutas and Federmeier, 2011). Its amplitude is reduced (less negative) when the
eliciting stimulus is more related to preceding stimuli (Kutas and Hillyard 1980, 1989;
Chwilla et al., 1995). Within a network model of semantic memory, these N400 semantic
priming effects (N400 amplitude difference between unrelated and related targets) reflect
greater activation of concepts that are more related to preceding context. Thus, N400
semantic priming effects have been used as a neurophysiological probe of abnormal
semantic activation in clinical populations (reviewed by Duncan et al., 2009).
In patients with schizophrenia, a large number of studies have provided evidence
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
of larger than normal N400s in response to target stimuli that are related to preceding
context, and/or smaller than normal N400 semantic priming effects (Bobes et al., 1996;
Strandburg et al., 1997; Ohta et al., 1999; Condray et al., 2003; Kostova et al., 2003;
Iakimova et al., 2005; Kostova et al., 2005; Ditman & Kuperberg, 2007; Kiang et al.,
2008; Salisbury, 2008; Guerra et al., 2009; Condray et al., 2010; Mathalon et al., 2010;
Kiang et al., 2011; Kiang et al., 2012; Kiang et al., 2014). These results suggest that
persons with schizophrenia are impaired in using meaningful contextual stimuli to
activate related concepts. Moreover, several studies have found a correlation between
these N400 semantic priming deficits and patients’ psychotic symptom severity, raising
the possibility that deficits in activating contextually related concepts may underlie the
development and maintenance of delusions (Salisbury et al., 2000; Kiang et al., 2007,
2008).
In contrast, some other studies of schizophrenia patients have found smaller than
normal N400 amplitudes to target stimuli related to preceding prime stimuli, and
increased N400 semantic priming effects (Mathalon et al., 2002; Kreher et al., 2008;
Salisbury, 2008; Kreher et al., 2009). Importantly, this pattern appears specific to short
prime-target stimulus-onset asynchronies (SOAs) of less than approximately 300 ms, and
patients with disorganized speech; and is thus thought to reflect an excess of rapid spread
of activation in the semantic network of disorganized patients in particular (Ditman and
Kuperberg, 2007; Salisbury, 2008; Kreher et al., 2009). Thus, this “hyperpriming” is not
necessarily mutually exclusive with the presence of semantic priming deficits over longer
time intervals in schizophrenia patients more generally.
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Given that N400 semantic priming deficits (at least at SOAs of 300 ms or longer)
have reliably been found in patients with schizophrenia, these deficits may be potentially
useful as a biomarker of semantic processing abnormalities in schizophrenia, and of their
response to treatment in clinical trials (Condray et al., 2003; Kiang et al., 2012). One
necessary step in further validating putative biomarkers of schizophrenia is to establish
their test-retest reliability both in normal individuals and in persons with schizophrenia
(Cho et al., 2005). Previously, Kiang et al. (2013) found excellent test-retest reliability in
healthy individuals for N400 amplitudes to both related and unrelated targets, and for
N400 semantic priming effects, over a one-week period. In the present study we aimed to
examine test-retest reliability of these N400 measures in patients with schizophrenia.
To this end, we recorded ERPs in schizophrenia patients while they viewed the
same sequence of prime words, each followed by a target that was either a related or
unrelated word or a nonword, in two sessions one week apart. Although the procedure
was otherwise similar to that used by Kiang et al. (2013) to examine N400 test-retest
reliability in healthy individuals, that study used a 750-ms prime-target SOA, whereas in
the present study we presented prime-target pairs at SOAs of both 300 and 750 ms. In
light of previous work suggesting that the nature or magnitude of schizophrenia patients‟
N400 semantic priming abnormalities may depend on the interval elapsed since the prime
stimulus, we added the shorter SOA because of the possibility that patients‟ N400
measures or their reliability might vary with SOA.
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Methods
Participants
Participants included 16 outpatients with schizophrenia (n=11) or schizoaffective
disorder (n=5). Patients were recruited in Hamilton, Ontario, Canada from two outpatient
clinics specializing in treatment and rehabilitation of schizophrenia. All participants gave
informed written consent. The protocol was approved by the St. Joseph's Healthcare
Hamilton Research Ethics Board. Participants received cash compensation.
Participants were screened diagnostically with the Mini International
Neuropsychiatric Interview (MINI; Sheehan et al., 1998). Diagnostic and Statistical
Manual of Mental Disorders (4th edition; DSM-IV) diagnoses were established using a
best-estimate approach based on the MINI and information from medical records and
clinician reports. Exclusion criteria included: current manic or depressive episode,
lifetime substance dependence, or substance abuse in the past six months; exposure to a
language other than English at home as a child; history of reading difficulties; and visual
impairment. Table 3 shows group demographic characteristics, and total and factor scores
(Miller et al., 1993) on the Scale for Assessment of Negative Symptoms (SANS;
Andreasen, 1984a) and Scale for the Assessment of Positive Symptoms (SAPS;
Andreasen, 1984b).
Stimuli
Stimuli included 80 related (e.g., METAL-STEEL) and 80 unrelated (DONKEYPURSE) prime-target word pairs. For each related pair, the target was among the words
most commonly given as associates to the prime in the University of South Florida word-
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
association norms (Nelson et al., 1999); mean response probability of related targets (i.e.
proportion of individuals producing that word in response to the prime) was 0.42 (SD =
0.23). For each unrelated pair, prime and target were not associates in the norms. Targets
were matched across related and unrelated conditions for mean length and logtransformed frequency, as were primes (Francis & Kucera, 1982). Stimuli also included
160 word-nonword prime-target pairs (DRESS-ZORES), whose targets were
pronounceable nonwords. No word occurred more than once among the stimuli. The
stimulus list included all prime-target pairs in a fixed randomized order, in four blocks of
80 trials each. Two prime-target SOAs were used: 300 and 750 ms. There were two
versions of the list such that order of SOAs was counterbalanced across blocks.
Specifically, in version A, SOA was 300 ms in blocks 1 and 2, and 750 ms in blocks 3
and 4; while in version B, the order was reversed. Each version was presented to half the
participants.
Task
In an electrically shielded, sound-attenuated chamber, participants were seated
100 cm in front of a video monitor on which stimuli were visually presented, with each
letter subtending on average 0.36° of visual angle horizontally, and up to 0.55° vertically.
Words were displayed in yellow letters on a black background.
Each participant was presented with the stimulus list, with short rest breaks
between blocks. Each trial consisted of: (a) a row of preparatory fixation crosses (duration
500 ms); (b) blank screen (250 ms); (c) prime word (175 ms); (d) blank screen (125 ms or
575 ms, resulting in a 300- or 750-ms prime-target SOA, respectively); (e) target (250
49
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
ms); (f) blank screen (1250 ms); (g) the prompt Yes or No? until participants responded
via a button-press; and (h) blank screen (3000 ms) until the onset of the next trial. All
stimuli were centrally presented.
At the prompt, participants were required to press one of two buttons, positioned
under their right and left thumbs, respectively, to indicate whether or not the target was a
word. One button (labeled “Yes”) signaled that it was a word, while the other button
(labeled “No”) signaled it was a nonword; assignment of buttons was counterbalanced
across participants.
Each participant repeated the experimental procedure on two different occasions
(Time 1 and Time 2) separated by approximately one week. The mean interval was 6.5
days (SD = 1.1, range 4-8).
Electroencephalographic data collection and analysis
During the experimental task, EEG was recorded using the ActiveTwo system
(BioSemi BV, Amsterdam), from 32 sites approximately equally spaced across the scalp,
positioned according to a modified International 10-20 System (Fp1-Fp2-AF3-AF4-F7F3-Fz-F4-F8-FC5- FC1-FC2-FC6-T7-T8-C3-Cz-C4-CP5-CP1-CP2-CP6-P7-P3-Pz-P4P8-PO3-PO4-O1-Oz-O2). The EEG was referenced to a left parietal Common Mode
Sense (CMS) active electrode and a right parietal Driven Right Leg (DRL) passive
electrode, which form a feedback loop driving the average potential across the montage as
close as possible to the amplifier zero. The EEG was continuously digitized at 512 Hz and
low-pass filtered at 128 Hz. Blinks and eye movements were monitored via electrodes on
the supraorbital and infraorbital ridges and on the outer canthi of both eyes. Offline, the
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
EEG was re-referenced to the algebraic mean of the mastoids, and bandpassed at 0.01100 Hz. Continuous data was algorithmically corrected for eye-blink artifact (Jung et al.,
2000). ERPs were computed for epochs from 100 ms pre-stimulus to 900 ms poststimulus. Individual trials containing artifacts due to eye movement, excessive muscle
activity or amplifier blocking were rejected off-line by visual inspection before timedomain averaging.
For each participant, separate ERP averages were obtained for trials with related
and unrelated target words, after subtraction of the 100-ms prestimulus baseline.
Consistent with established methods, N400 peak latency was defined as the interval
between target onset and the largest negative peak from 200 to 600 ms post-stimulus and
N400 amplitude was defined as the mean voltage from 200 to 500 ms post-stimulus
(Kiang et al., 2012). N400 semantic priming effects were defined as the mean voltage of
the difference waveform obtained by subtracting the ERP average for related targets from
the average for unrelated targets, from 200 to 500 ms post-stimulus.
Statistical Analyses
P-values in analyses of variance (ANOVAs) with within-subject factors are
reported after Greenhouse-Geisser Epsilon correction. Pairwise comparisons of factorlevel means were made with Tukey simultaneous comparisons, with a family confidence
coefficient of 0.95. All p-values are two-tailed.
Percentage of correct responses was analyzed by repeated-measures ANOVA,
with Target (related vs. unrelated vs. nonword), SOA (300 vs. 750 ms), and Time (1 vs.
2) as within-subject factors.
51
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Percentage of accepted ERP trials was analyzed by repeated-measures ANOVA,
with Target (related vs. unrelated), SOA (300 vs. 750 ms), and Time (1 vs. 2) as withinsubjects factors.
N400 peak latency and mean amplitude were analyzed by repeated-measures
ANOVA with Target (related vs. unrelated), SOA (300 vs. 750 ms), Electrode (13 levels:
F3/FC1/C3/CP1/P3/Pz/P4/CP2/C4/FC2/F4/Fz/Cz, corresponding to a contiguous array of
medial central sites where N400 effects are typically most prominent (Kutas &
Federmeier, 2000), and Time (1 vs. 2) as within-subject factors. N400 semantic priming
effects were analyzed by repeated-measures ANOVA with Electrode (13 levels,
corresponding to the sites listed above), SOA (300 vs. 750 ms), and Time (1 vs. 2) as
within-subject factors.
Across participants, for each SOA, pairwise correlations between values at Time 1
and Time 2 were calculated for N400 amplitudes for related targets, N400 amplitudes for
unrelated targets, and N400 semantic priming effects; for each of the midline sites Fz
(frontal), Cz (central) and Pz (parietal). As convergent measures of test-retest reliability,
Pearson’s correlation coefficients r and intraclass correlation coefficients (ICCs) were
calculated.
In addition, to explore associations between N400 measures and different
symptoms, we calculated pairwise correlations (Pearson’s r) for each SOA between N400
amplitudes for related targets, N400 amplitudes for unrelated targets, and N400 semantic
priming effects vs. SANS/SAPS factor scores. N400 measures were taken as the mean
value over Time 1 and Time 2, at sites Fz and Cz, as these sites were found to have the
52
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
highest test-retest reliability of those tested.
Results
Correct response rates
Participants’ mean correct response rates are shown in Table 4. Overall, the high
correct- response rates indicate that participants were attending to the stimuli and task. No
significant effects of Target, SOA, or Time were found. There was a significant
interaction of SOA x Time [F(1, 15) = 5.05, P = 0.04]; indicating that correct response
percentage was lower for long-SOA trials at Time 1 than for short-SOA trials at Time 1,
or short- or long-SOA trials at Time 2, all three of which did not differ significantly from
one another.
Percentage of accepted ERP trials
The percentage of accepted ERP trials is shown in Table 5. ANOVA did not show
any significant effects of Target, SOA, or Time, or interactions of these factors (all p >
0.19).
ERPs
Grand average ERPs for all electrodes are shown for each SOA at Time 1 and
Time 2 in Figure 2. In the ANOVA of N400 peak latency, there were no significant
effects of Target, SOA, Time, Electrode or significant interactions of these factors (all p >
0.11). Grand mean N400 peak latency was 358 ms (SD = 102, range: 203-594).
N400 mean amplitudes are shown in Figure 3 and in Table 8. There were no
significant effects of Target, SOA, Time, Electrode or significant interactions of these
factors, on N400 mean amplitude (all p > 0.19). Values for N400 semantic priming
53
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
effects are shown in Table 8. In the ANOVA of N400 semantic priming effects, there
were no significant effects of SOA, Time or Electrode, or significant interactions of these
factors (all p > 0.20).
Correlations between Time 1 and Time 2 for N400 measures
Pearson’s r and ICCs for correlations between Time 1 and Time 2 for N400
measures are shown in Table 7. Scatterplots of these correlations at Fz are shown in
Figure 4. Significant correlations between time 1 and time 2 were found at Fz for all
target type/SOA combinations; at Cz for all combinations except unrelated targets at the
short SOA; and at Pz for unrelated targets at the short SOA and related targets at the long
SOA.
Correlations between N400 measures and SANS/SAPS factor scores
Pearson’s r for correlations between N400 measures (averaged across electrodes
Fz and Cz and Times 1 and 2) and SANS/SAPS factor scores are shown in Table 6.
Smaller N400 semantic priming effects were significantly correlated with SAPS/SANS
Positive factor scores at the long SOA (r = -0.66, p = 0.005), indicating that patients with
more severe psychotic symptoms had more similar N400 amplitudes to related and
unrelated targets. No other correlations were significant (all p > 0.10).
Discussion
This study aimed to assess test-retest reliability of N400 ERP measures in patients
with schizophrenia in a word-pair semantic priming paradigm. We recorded ERPs in
schizophrenia patients while they viewed the same series of prime-target word-pairs in
two sessions approximately one week apart. Prime words were followed at either a short
54
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
(300-ms) or long (750-ms) SOA by either a related or an unrelated target word, or a
pronounceable nonword. Participants’ task was to indicate via button-press whether or not
the target was a real word. Across both SOAs, our patient sample exhibited no significant
difference in N400 amplitudes elicited by related vs. unrelated target words, consistent
with previous findings indicating smaller than normal N400 semantic priming effects
(amplitude differences between unrelated and related targets) in schizophrenia over
comparable SOAs (Condray et al., 2003; Kiang et al., 2008; Kiang et al., 2014).
In the current study, schizophrenia patients demonstrated good test-retest
reliability for N400 amplitudes for both related and unrelated targets, at both SOAs. For
example, ICCs for these measures at Fz ranged from 0.52 to 0.63, which is considered
good in the context of clinical trials (Manoach et al., 2001; Fleiss, 1999; Schmidt et al.,
2012). In contrast, patients did not exhibit significant test-retest correlations for N400
semantic priming effects between Time 1 and Time 2. This finding diverged from results
obtained in healthy individuals (Kiang et al., 2013), who exhibited excellent test-retest
reliability for N400 semantic priming effects as well as for N400 amplitudes to related
and unrelated targets. Low test-retest reliability for schizophrenia patients’ N400
semantic priming effects is likely attributable to the fact that these effects were not
significantly different from zero in this group – i.e., there was no difference between
N400 amplitudes for related and unrelated-targets, suggesting that patients were
processing these targets similarly at the neural level. In that case, in contrast to the
situation in healthy individuals, the magnitude of a patient’s N400 semantic priming
effect at Time 2 would depend less on the magnitude of this effect at Time 1, and more on
55
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
other factors that are random with respect to prime-target relatedness, reducing test- retest
reliability.
Notably, in the present study, smaller N400 semantic priming effects at the Long
SOA were significantly correlated with higher SAPS/SANS Positive factor scores (See
Table 6). This result corroborates previous reports that found such a relationship in
patients with schizophrenia (Salisbury et al., 2000; Kiang et al., 2007, 2008) and thus
raises the possibility that semantic priming deficits in schizophrenia may be related to the
development of delusions.
In a recent longitudinal study, Besche-Richard et al. (2014) reported that N400
semantic priming deficits in patients with schizophrenia were not stable, but improved,
over one-year follow-up. Unlike controls, who exhibited similar N400 semantic priming
effects at baseline and one year, the patients exhibited such effects only at one year. The
patient group’s improvement in N400 priming occurred in parallel with a mean reduction
in clinical symptoms (although the authors did not test for associations between
improvements in N400 priming and symptoms). These results suggest that, in addition to
having good reliability, N400 amplitude measures may be a biomarker of clinical
improvements and treatment effectiveness.
A limitation of this study is that the patient sample was not directly compared with
healthy controls on N400 semantic priming effects. Although the literature includes
substantial evidence for smaller than normal N400 semantic priming effects in
schizophrenia patients compared to controls (Bobes et al., 1996; Strandburg et al., 1997;
Ohta et al., 1999; Condray et al., 2003; Kostova et al., 2003; Iakimova et al., 2005;
56
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Kostova et al., 2005; Ditman & Kuperberg, 2007; Kiang et al., 2008; Salisbury, 2008;
Guerra et al., 2009; Condray et al., 2010; Mathalon et al., 2010; Kiang et al., 2011; Kiang
et al., 2012; Kiang et al., 2014), our findings do not allow for a definitive conclusion that
the current sample had smaller than normal N400 semantic priming effects (as suggested
by an absence of significant differences between N400 mean amplitude for contextually
related and unrelated target words).
The good test-retest reliability of N400 mean amplitudes in a word-pair priming
paradigm in this study supports their potential clinical utility as longitudinal biomarkers
of semantic processing dysfunction in patients with schizophrenia. In particular, testretest reliabilities of N400 amplitudes at midline frontal and central sites appeared to be
within the range of values that have been obtained in healthy individuals for other
proposed cognitive ERP biomarkers for schizophrenia, such as the amplitudes of the
mismatch negativity (Hall et al., 2006; Jemel et. al., 2002; Kathman et al., 1999; Lew et
al., 2007) and P300 (Fabiani et al., 1987; Hall et. al., 2006; Lew et al., 2007; Kinoshita et
al., 1996). Although N400 amplitude test-retest reliabilities in the current study appear to
fall in the lower part of that range, those other studies examined healthy individuals
whereas, in general, reliabilities for patient populations may be lower due to noisier ERP
data (Luck, 2005). Contrary to this conjecture, however, test-retest ICCs for P300
amplitude over a mean of 11 days ranged from 0.77-0.85 (depending on electrode site) in
patients with primary psychotic disorders, compared to 0.74-0.77 in healthy control
participants (Simons et al., 2011). There have been few studies of short-term (days to
weeks) test-retest reliability of cognitive ERP components in psychotic disorders, even
57
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
though characterizing reliability has been identified as a research priority in developing
appropriate ERP and other biomarkers for schizophrenia (Barch & Mathalon, 2011, Cho
et al., 2005). Further research on test-retest reliabilities of different ERP components in
schizophrenia, encompassing different age groups, stimulus parameters, and test-retest
intervals, would improve our understanding of how these values compare with each other
and with their counterparts in healthy individuals.
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
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Figures
Figure 2. Grand average ERPs to target words at all electrode sites, at (a) Time 1, Short
SOA, (b) Time 1, Long SOA, (c) Time 2, Short SOA, and (d) Time 2, Long SOA.
Negative voltage is plotted upward.
a)
TIME 1 - SHORT SOA
Fp1
AF3
0
2
4
0
2
4
0
0
200 400 600
F3
0
2
4
0
2
4
200 400 600
0
200 400 600
0
2
4
0
200 400 600
FC2
0
2
4
0
2
4
0
2
4
0
200 400 600
0
2
4
0
2
4
0
2
4
200 400 600
0
200 400 600
200 400 600
0
2
4
FC1
200 400 600
0
F8
FC5
0
0
2
4
200 400 600
0
2
4
Cz
0
0
0
2
4
200 400 600
200 400 600
T8
0
2
4
0
200 400 600
CP6
0
2
4
0
2
4
0
2
4
0
2
4
P3
0
2
4
0
2
4
200 400 600
PO3
0
0
200 400 600
200 400 600
0
200 400 600
Pz
P4
0
2
4
0
2
4
0
200 400 600
O1
0
200 400 600
0
0
200 400 600
0
2
4
0
200 400 600
Unrelated
Related
68
200 400 600
200 400 600
0
2
4
200 400 600
0
200 400 600
PO4
O2
0
2
4
0
0
P8
Oz
0
2
4
200 400 600
200 400 600
0
2
4
CP2
200 400 600
0
C4
CP1
0
0
FC6
N400
0
200 400 600
CP5
P7
0
2
4
0
F4
C3
0
AF4
Fz
T7
0
0
2
4
200 400 600
F7
0
Fp2
0
2
4
0
200 400 600
0
200 400 600
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
b)
TIME 1 - LONG SOA
Fp1
AF3
0
2
4
0
2
4
0
Fp2
0
200 400 600
0
2
4
AF4
0
0
2
4
200 400 600
200 400 600
0
200 400 600
F7
F3
Fz
F4
F8
0
2
4
0
2
4
0
2
4
0
2
4
0
2
4
0
200 400 600
0
200 400 600
200 400 600
FC6
0
2
4
0
2
4
0
2
4
0
2
4
0
200 400 600
0
200 400 600
Cz
0
2
4
0
2
4
0
2
4
200 400 600
0
200 400 600
0
200 400 600
N400
0
200 400 600
0
2
4
0
2
4
0
200 400 600
CP2
CP6
0
2
4
0
2
4
0
2
4
0
2
4
200 400 600
P7
0
2
4
0
2
4
200 400 600
PO3
0
0
200 400 600
200 400 600
0
200 400 600
Pz
P8
0
2
4
0
2
4
0
2
4
0
200 400 600
0
200 400 600
0
2
4
O2
0
200 400 600
0
2
4
0
2
4
0
200 400 600
0
200 400 600
µV
0
2
4
69
ms
200 400 600
0
200 400 600
PO4
Oz
200 400 600
0
200 400 600
P4
O1
0
0
200 400 600
200 400 600
T8
CP1
0
0
0
C4
CP5
P3
0
2
4
0
FC2
C3
0
200 400 600
FC1
T7
0
0
FC5
0
2
4
0
200 400 600
0
200 400 600
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
TIME 2 - SHORT SOA
c)
Fp1
AF3
0
2
4
0
2
4
0
Fp2
0
200 400 600
0
2
4
AF4
0
0
2
4
200 400 600
200 400 600
0
200 400 600
F7
F3
Fz
F4
F8
0
2
4
0
2
4
0
2
4
0
2
4
0
2
4
0
200 400 600
0
200 400 600
200 400 600
FC6
0
2
4
0
2
4
0
2
4
0
2
4
0
200 400 600
0
200 400 600
Cz
0
2
4
0
2
4
0
2
4
200 400 600
0
200 400 600
0
200 400 600
N400
0
200 400 600
0
2
4
0
2
4
0
200 400 600
CP2
CP6
0
2
4
0
2
4
0
2
4
0
2
4
200 400 600
P3
0
2
4
0
2
4
200 400 600
PO3
0
0
200 400 600
200 400 600
0
200 400 600
Pz
P4
0
2
4
0
2
4
0
200 400 600
O1
0
0
200 400 600
0
200 400 600
0
2
4
0
200 400 600
Unrelated
Related
70
200 400 600
200 400 600
0
2
4
200 400 600
0
200 400 600
PO4
O2
0
2
4
0
P8
Oz
0
2
4
0
200 400 600
200 400 600
T8
CP1
0
0
0
C4
CP5
P7
0
2
4
0
FC2
C3
0
200 400 600
FC1
T7
0
0
FC5
0
2
4
0
200 400 600
0
200 400 600
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
d)
TIME 2 - LONG SOA
Fp1
AF3
0
2
4
0
Fp2
0
200 400 600
0
2
4
AF4
0
0
2
4
200 400 600
200 400 600
0
200 400 600
F7
F3
Fz
F4
F8
0
2
4
0
2
4
0
2
4
0
2
4
0
2
4
0
200 400 600
0
200 400 600
0
200 400 600
FC6
0
2
4
0
2
4
0
2
4
0
2
4
0
200 400 600
0
200 400 600
C3
Cz
0
2
4
0
2
4
0
200 400 600
0
CP2
0
2
4
0
2
4
0
2
4
200 400 600
0
200 400 600
PO3
0
2
4
0
200 400 600
200 400 600
200 400 600
200 400 600
CP1
0
0
N400
CP5
P3
0
2
4
200 400 600
FC2
P7
0
0
FC1
200 400 600
0
2
4
0
FC5
T7
0
2
4
0
2
4
0
T8
0
2
4
0
2
4
200 400 600
P4
0
2
4
0
2
4
200 400 600
O1
200 400 600
0
2
4
200 400 600
0
2
4
0
0
200 400 600
0
2
4
0
200 400 600
0
200 400 600
µV
0
2
4
71
ms
0
200 400 600
200 400 600
0
2
4
200 400 600
0
200 400 600
PO4
O2
0
2
4
0
P8
Oz
0
200 400 600
C4
0
200 400 600
CP6
Pz
0
0
0
0
2
4
0
200 400 600
0
200 400 600
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Figure 3. Mean N400 amplitudes for related and unrelated targets and short and long
SOAs (averaged across 13 medial central sites: F3, FC1, C3, CP1, P3, Pz, P4, CP2, C4,
FC2, F4, Fz, Cz) at Time 1 and Time 2. Error bars indicate the standard deviation.
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Figure 4. Scatterplots of values at Time 2 vs. values at Time 1 at electrode Fz for: (a)
N400 amplitudes for related targets at the short SOA; (b) N400 amplitudes for unrelated
targets at the short SOA; (c) N400 amplitudes for related targets at the long SOA; and (d)
N400 amplitudes for unrelated targets at the long SOA.
a)
b)
c)
d)
73
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Tables
Table 3. Demographic and clinical characteristics of the study participants with mean and
SD (range provided in brackets).
Participants (n = 16)
Age, years
45.2 ± 8.1 (28-57)
Sex
5 female, 11 male
Handedness (Oldfield, 1971)
2 left, 13 right
Parental socioceconomic status (Blishen et al., 1987)
41.6 ± 4.8 (30.9-48.4
Years of education
13.8 ± 2.0 (11-17)
National Adult Reading Test (O’Carroll et al., 1992)
estimated IQ
107.7 ± 12.4 (87.2-124.7)
SANS total score
8.3 ± 4.7 (0-17)
SAPS total score
4.2 ± 3.8 (0-12)
SANS/SAPS factor scores
Negative
5.5 ± 3.0 (0-11)
Positive
2.6 ± 2.8 (0-8)
Disorganized
1.6 ± 1.4 (0-4)
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Table 4. Mean percentage of correct lexical-decision responses by experimental session,
SOA, and target condition (SDs in parentheses).
Time 1
Time 2
Short SOA Long SOA Short SOA Long SOA
Related
97.4(4.3)
95.7(8.2)
98.9(2.8)
97.9(2.6)
Unrelated 96.8(5.5)
92.8(10.2) 95.4(8.9)
94.8(15.9)
Nonwords 96.9(4.2)
95.7(6.3)
97.3(3.8)
98.4(1.8)
Table 5. Mean trial rejection rate (%) averaged across participants (n = 16) by
experimental session, SOA, and target condition (SDs in parentheses).
Time 1
Time 2
Short SOA Long SOA Short SOA Long SOA
Related
11.1(8.5)
15.4(14.3) 16(13.7)
Unrelated
9.7(7.4)
15.1(14.4) 14.6(16.1) 13.8(11.0)
75
14.4(11.0)
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Table 6. Pairwise correlations (Pearson’s r) for each SOA, averaged across Time 1 and
Time 2 for electrodes Fz and Cz between N400 amplitudes for related targets and
unrelated targets, and N400 semantic priming effects vs. SANS/SAPS factor scores.
N400 Mean Amplitudes
Semantic Priming
Effects
Related
targets, Short
SOA
Related
targets, long
SOA
Unrelated
targets, short
SOA
Unrelated
targets, long
SOA
Short
SOA
Long
SOA
SANS/SAPS
negative
-0.25
-0.41
-0.36
-0.22
-0.02
0.39
SANS/SAPS
positive
0.31
0.39
0.41
0.02
-0.41
-0.66**
SANS/SAPS
disorganized
0.08
-0.06
-0.10
-0.24
-0.23
-0.25
**P < 0.01
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Table 7. Pearson’s r and intraclass correlation coefficients (ICC) between mean N400 amplitudes at Time 1 and Time 2 for each
SOA/target type combination at electrode sites Fz, Cz, and Pz (n = 16 participants).
N400 amplitudes,
related targets,
short SOA
N400 amplitudes,
related targets, long
SOA
N400 amplitudes,
unrelated targets,
short SOA
N400
N400 priming
amplitudes,
effects, short
unrelated targets, SOA
long SOA
N400 priming
effects, long
SOA
r
ICC
r
ICC
r
ICC
r
ICC
r
ICC
r
ICC
Cz
0.60*
0.60**
0.67**
0.66**
0.40
0.39
0.54*
0.53*
0.02
0.02
-0.12
-0.10
Fz
0.52*
0.52*
0.64**
0.63**
0.61*
0.61**
0.61*
0.59**
0.08
0.08
0.28
0.25
Pz
0.30
0.30
0.50*
0.50*
0.43
0.43*
0.36
0.35
-0.041
-0.04
0.10
0.07
Electrode
* P < 0.05
** P < 0.01
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Table 8. Mean (SDs in parentheses) N400 mean amplitudes and semantic priming effects averaged across participants for electrodes
Fz, Cz, and Pz for each SOA/target combinations at times 1 and 2.
N400 amplitudes,
related targets, short
SOA
N400 amplitudes,
related targets, long
SOA
N400 amplitudes,
unrelated targets,
short SOA
N400 amplitudes,
unrelated targets,
long SOA
N400 priming effects,
short SOA
N400 priming effects,
long SOA
Time 1
Time 2
Time 1
Time 2
Time 1
Time 2
Time 1
Time 2
Time 1
Time 2
Time 1
Time 2
Fz
0.62(2.89)
0.18(2.93)
-0.71(3.96)
-1.29(4.28)
0.29(2.33)
0.60(2.27)
-0.40(2.96)
-2.03(3.83)
-0.33(2.39)
0.41(2.53)
0.32(2.40)
-0.74(3.83)
Cz
0.69(2.55)
-0.45(3.55)
0.27(2.49)
0.69(2.55)
-0.50(4.04)
-0.63(3.56)
-0.45(3.56)
-1.50(2.98)
-0.41(2.74)
0.24(2.86)
0.04(1.65)
-0.88(3.14)
Pz
0.62(3.23)
0.45(3.14)
-0.54(2.64)
0.21(2.87)
-0.01(2.39)
0.50(2.32)
-0.27(2.64)
-0.29(2.23)
-0.62(2.59)
0.05(2.90)
0.28(1.29)
-0.50(3.31)
78
MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
Chapter 4
Afterword
The work presented in this thesis contributes to a large body of research aimed at
understanding the mechanisms and causes of cognitive deficits in psychiatric disorders, as well
as research aimed at validating measures of cognitive dysfunction that may be used to evaluate
novel cognition-enhancing therapies for psychiatric disorders.
In chapter 2 of this thesis we presented research demonstrating a relation between
dissociative symptomatology and neurocognitive functioning in combat-trauma exposed veterans
with and without PTSD. Our results indicate that among the clinical variables assessed
(including PTSD symptomatology, depressive symptoms, and anxiety symptoms), dissociative
symptomatology was the only significant correlate of neurocognitive functioning. Specifically,
we found a significant negative correlation between scores on the multi-scale dissociation
inventory (MDI) (Briere, 2002), including the subscales measuring symptoms of disengagement,
derealization/depersonalization, and memory impairment, and scores on the repeatable battery of
the assessment of neuropsychological symptoms (RBANS) subscale measuring immediate
memory (Randolph et al., 1998). Although individuals with PTSD display deficits across a wide
range of cognitive functions, short-term memory, specifically for verbal information, is reported
to be the most consistent cognitive deficit in this disorder (Johnsen & Abjornsen, 2008). We
hypothesize that the relation between deficits in short-term memory and dissociative
symptomatology may be explained through the neurobiological signature of the dissociative
subtype of PTSD proposed by Lanius et al (2010; 2012), whereby areas of the brain involved in
emotional arousal and regulation (i.e., the mPFC and dACC) display heightened activity leading
to overmodulation and decreased activity in areas involved in emotional processing (i.e.
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
amygdala). The overactivity of regions such as the mPFC can also cause overmodulation of other
limbic structures important for memory functions such as the hippocampus, therefore creating an
explanatory link between dissociative symptomatology and reduced short-term memory capacity.
We believe that the information presented here has the potential to inform future treatment
strategies aimed at remediating the cognitive deficits in PTSD, in that reducing dissociative
symptomatology may be one strategy for enhancing cognitive remediation therapies.
In chapter 3 we presented evidence for the reliability of an ERP biomarker for semantic
processing abnormalities in individuals with schizophrenia. Specifically, our results indicate that
the ERP known as the N400 is stable over a one-week period in individuals with schizophrenia,
and therefore may be useful in measuring improvements in semantic processing in response to
novel cognition-enhancing treatments for schizophrenia. The N400 is a negative ERP wave that
occurs in response to any meaningful stimulus approximately 400ms after its’ onset. When a
stimulus is preceded by a semantically related prime stimulus, the amplitude of the N400 is
reduced, reflecting semantic priming. A wealth of research indicates that individuals with
schizophrenia display deficits in semantic priming both behaviourally, and at the neural level
(Kuperberg & Heckers, 2000; Mathalon et al., 2010; Kiang et al., 2011, 2012, 2014). The
stability of N400 measures over a one-week period in patients with schizophrenia supports the
hypothesis that these measures may be useful as a neurophysiological biomarker of cognitive
impairment, specifically semantic priming difficulties, in patients with schizophrenia. This
hypothesis is substantiated in a recent study by Besche-Richard et al. (2014), where the authors
found that normal N400 semantic priming effects are restored in individuals with schizophrenia
in conjunction with improvements in clinical symptoms over a one-year period, suggesting that
N400 measures may serve as successful biomarker of treatment response. Future research should
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
work to establish test-retest reliability of these measures over differing time frames, age groups,
and stimulus parameters.
Although the two studies presented in this thesis address two distinct research questions
about two distinct psychiatric populations, they both act toward the common goals of enhancing
our understanding of cognitive dysfunction in psychiatric populations and informing the
development and testing of therapeutic strategies focused on remediating cognitive dysfunctions.
4.1 Future Directions
Throughout this thesis, the goal of developing cognition enhancing treatments for
individuals with either PTSD or schizophrenia has been a recurring theme, and it is a direction in
which the field is moving. To date, the majority of research investigating therapeutic approaches
for cognitive rehabilitation has been completed on individuals with schizophrenia. Cognitive
remediation therapy (CRT) is one such approach that has been tested in schizophrenic
populations. CRT is an intervention that targets cognitive deficits, and generally includes tasks
that provide training focused on functional adaptation for every-day activities, general
stimulation (non-specific training involving multiple cognitive abilities), or process-specific
approaches that focus on direct strengthening of a specific cognitive skill (Kluwe-Schiavon et al.,
2013). In a recent meta-analysis, Wykes et al. (2011) report a small-moderate effect size (0.45)
for the impact of cognitive remediation therapies on overall cognition in schizophrenia. The
study also reports a small to medium effect size on both functioning and clinical symptoms posttreatment. Similarly, in their meta-analytic review of computer-based CRTs, Grynzpan et al.
(2011) report a small but significant effect size of 0.38 for improvements across all cognitive
domains assessed, including speed of processing, attention, working memory, and verbal
learning/memory. Notably, Wykes et al. (2011) state that higher effect sizes for improvements in
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
overall functioning were found when only studies including adjunct psychiatric rehabilitation
were included in the analysis (ES = 0.59) compared to when only studies that did not include
adjunct therapies were included (ES = 0.28), suggesting that improvements in functional
outcomes are better achieved when CRTs are delivered in adjunct with other psychiatric
therapies.
Despite calls for interventions focused on remediating cognitive deficits in PTSD
(Aupperle et al., 2012), no research has been completed in this area, to date. The fact that CRTs
have been successfully implemented for individuals with schizophrenia, as well as in other
psychiatric populations who experience cognitive difficulties (i.e., eating disorders and affective
disorders) (Elgamel et al., 2007; Deckersbach et al., 2009; Bowie et al., 2013; Brockmeyer et al.,
2014), suggests that this type of approach may be of use in the PTSD population. As such, a
major goal of our lab is to initiate a trial investigating the effectiveness of one particular CRT
known as goal management training (GMT) (Levine et al., 2000), in remediating cognitive
deficits in individuals with PTSD. GMT aims to improve goal-directed behaviours that are
dependent on basic cognitive processes and executive functioning through a top-down approach
that provides transferable skills for every-day living. The efficacy of GMT has been
demonstrated in several populations who experience difficulties in executive functioning,
attention and memory (such as individuals with traumatic brain injury, attention-deficit
hyperactivity disorder, and substance abuse disorders), where researchers report long-term
improvements in decision-making, working memory and selective attention (Alfonso et al.,
2011; Levine et al., 2011; In de Braek et al., 2012, Krasny-Pacini et al., 2014). As we discovered
in Chapter two, dissociative symptomatology may play an important role in the cognitive deficits
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
seen in PTSD, and as such, components of therapies aimed at reducing dissociation (such as
mindfulness techniques) will be incorporated into our proposed GMT model.
In recent years, the focus of research in the schizophrenia community has shifted from
validating behavioural cognitive-remediation approaches to identifying cognition-enhancing
pharmacological agents. Since the onset of the MATRICS initiative, the schizophrenia research
community has seen a large number of clinical trials investigating such treatments. In a 2007
report by Buchanon et al., a number of promising pharmacological agents were identified,
including cholinergic agonists (particularly α-7 nicotinic agonists and aceytlcholinesterase
inhibitors), dopaminergic agonists (D1 agonists), and glutamatergic agonists (with NMDA,
AMPA, and metabotropic receptors as targets). In a more recent report, Keefe et al. (2013)
reviewed ongoing and completed clinical trials of some of these agents supported by the
MATRICS initiative and concluded that at present, it is not possible to draw meaningful
conclusions from these trials as many are not completed and those that are completed are limited
in terms of sample size and length of the trial. They do however mention that the majority of
trials appear to be investigating NMDA receptor agonists. They conclude that ongoing trials that
offer larger and more diverse samples may shed light on what mechanisms are successful in
ameliorating cognitive deficits in schizophrenia.
The future potential for research in both the PTSD and schizophrenia research
communities to elucidate new and adjunctive pharmacological or behavioural interventions for
the treatment of cognitive deficits in these disorders is promising. In addition to this, further
research is still needed to improve our knowledge of the contributing factors to cognitive deficits
in these disorders as well as to validate biomarkers for testing treatment effectiveness. More
specifically, in the context of the research discussed in Chapter 2, future research should aim to
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
determine a causal link between dissociative symptomatology and cognitive deficits in
individuals with PTSD. Several methods could be used to achieve this goal including
regressional analyses whereby the ability of dissociative symptomatology to predict changes in
cognitive functioning could be assessed. Additionally, the inclusion of the dissociative subtype in
the DSM-5 could allow for the identification of two groups of individuals with PTSD, those who
can be categorized as belonging to the dissociative subtype and those who do not belong to this
subtype. In this way, one could determine if the level of cognitive dysfunction is greater in
individuals with the dissociative subtype of PTSD compared to individuals without the
dissociative subtype, as well as determining what specific cognitive functions are impacted by
dissociative symptoms.
Similarly, future work should aim to validate the finding that N400 measures may
represent useful biomarkers for semantic processing abnormalities in schizophrenia reported in
Chapter 3 of this thesis. As mentioned above, recent work has supported our findings in that the
N400 semantic priming effect was seen to improve in individuals with schizophrenia
concomitant with improvements in clinical symptomatology following treatment over a one year
period, suggesting that the N400 may be a successful biomarker of treatment response (BescheRichard et al., 2014). Future work should aim to determine the stability of N400 measures in
individuals with schizophrenia over different time frames, similar to those used in clinical trials.
4.2 Conclusions
The primary aim of this thesis was to provide novel research findings that contribute to
our understanding of cognitive deficits in psychiatric disorders and further the application of
correlates of these deficits to evaluating and developing effective treatment strategies. The
results presented in chapter 2 demonstrate that dissociative symptomatology may play a key role
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
in neurocognitive dysfunction (specifically, short-term memory impairment) in veterans exposed
to combat trauma with and without PTSD. These findings have the potential to aid in the
development of effective treatment strategies for remediating the cognitive deficits seen in
individuals with PTSD. The research presented in chapter 3 demonstrates an alternate use for our
knowledge of cognitive deficits in psychiatric disorders in demonstrating that a well-known
correlate of cognitive processing difficulties in schizophrenia may be utilized as a physiological
biomarker for treatment effectiveness. Specifically, in showing that measures of the N400, an
ERP reflective of semantic processing, are stable over a one-week period in individuals with
schizophrenia, its potential clinical utility as a neurophysiological biomarker of semantic priming
abnormalities in schizophrenia is highlighted. Though the two studies presented in this thesis are
different in terms of the psychiatric population assessed and the measures used, together they
demonstrate the usefulness of developing an enhanced understanding of cognitive processes and
their correlates in psychiatric disorders.
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MSc. Thesis – J.E. Boyd, McMaster University - Neuroscience
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