Browsing by Subject "Schizophrenia"

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Altered Visuospatial Context Processing in Psychotic Psychopathology
(2024-05) Pokorny, Victor
The present dissertation examines atypical use of visuospatial context in psychotic psychopathology. There is a large literature suggesting individuals with schizophrenia, and to a lesser extent bipolar disorder, perceive visuospatial illusions differently than healthy controls. Such work has the potential to identify behavioral and neural markers of psychotic disorders. The first chapter is a meta-analysis that aims to quantify and summarize more than 50 years of research on atypical use of visuospatial context in psychotic psychopathology. When pooling across all task types, we found weak evidence of reduced use of visuospatial context in schizophrenia (Hedges’ g=0.25), and bipolar disorder (g=0.25). The strongest evidence was observed for altered contrast perception paradigms in schizophrenia (g=0.72). We propose altered feedback to the primary visual cortex as a potential neural mechanism underlying this effect. The second chapter is an original study of atypical orientation-dependent surround suppression of perceived contrast in people with schizophrenia (SCZ, n=31) and bipolar disorder (BP, n=29), first-degree biological relatives of these patient groups (SREL, n=28; BPREL, n=21) and healthy controls (CON, n=29). Individuals with schizophrenia exhibited reduced surround suppression across orientations, consistent with weakened untuned gain control. Group differences in orientation-dependent surround suppression magnitude were moderated by visual acuity. These findings clarify the mechanisms of weakened contextual modulation of perceived contrast in psychosis and suggest that visual acuity is an important driver of atypical orientation-dependent suppression in schizophrenia. The third and final chapter is an fMRI examination of brain responses associated with atypical orientation-dependent surround suppression of contrast in the same sample as Chapter 2. We examined BOLD responses to center-surround gratings in individuals with schizophrenia (SCZ, n= 34), bipolar disorder (BP, n = 25), unaffected first-degree relatives of SCZ (SREL, n = 20), unaffected first-degree relatives of BP (BPREL, n = 13) and healthy controls (CON, n = 23). We observed orientation-dependent modulation of V1 BOLD activation to near surrounds across groups. In particular, the SCZ and CON groups exhibited roughly equivalent orientation-dependent contextual modulation (Cohen’s dz SCZ= .56; CON = .63). Surprisingly, the direction of the contextual modulation for near surrounds was opposite of predicted: greater BOLD activation for the condition that was expected to produce suppression. Our unexpected results suggest that spatial attention and figure-ground modulation are important to consider when studying orientation-dependent surround suppression. By disentangling these effects, clinical studies may become more informative with respect to the neural pathophysiology of mental health disorders. Taken together, the findings described in the present dissertation suggest that atypical suppression of perceived contrast holds great potential for clarifying the neural pathophysiology of schizophrenia. In particular, our pattern of results are most suggestive of altered feedback mechanisms driving this effect rather than V1-intrinsic mechanisms. Future research will seek to further disentangle the degree to which spatial attention, figure-ground modulation and attentional lapses contribute to altered surround suppression of contrast in psychotic psychopathology.
Effective Disconnection of Intrinsic Networks in the Prefrontal Cortex: Convergence across Primate and Mouse Models of Schizophrenia
(2018-09) Zick, Jennifer
Individuals who are afflicted with schizophrenia experience a disorienting array of symptoms that include sensations of nonexistent stimuli (hallucinations), fixed beliefs not grounded in reality (delusions), emotional disturbances, and a generalized disorganization of thought. Some of the most fundamental aspects of consciousness can be disrupted in schizophrenia, such as the capacity to maintain a continuous thought process, plan and predict future actions and consequences, discern threatening from beneficial stimuli, and consciously inhibit impulsive or harmful behavior. Descriptions of the subjective experience of schizophrenia often revolve around the idea that the executive “self” of an individual is disconnected or no longer whole. Executive functions are thought to be distributed throughout cortical and subcortical networks, but to the extent that they can be localized they tend to depend on proper functioning of regions within the prefrontal cortex. In particular, the dorsolateral prefrontal cortex (DLPFC) of primates is considered to be vital in the process of organizing thought, and likewise the disorganization of thought in schizophrenia is linked to dysfunction in this region. For example, the DLPFC contains a densely interconnected circuit of pyramidal neurons that can sustain neural activity in the absence of sensory input, which is thought to underlie our ability to maintain a concept “in mind” after it has disappeared. What happens when these fundamental processes are disrupted? The manifestations can range from subtle disturbances in the integration of sensory input to a failure to distinguish reality from imagination. In this dissertation, I describe the contributions I have made to the understanding of schizophrenia during the course of my graduate school training. I was given the opportunity to begin my work on this project by analyzing preexisting neural data obtained from the DLPFC in a pharmacological primate model of schizophrenia . From there, I developed a surgical and recording protocol that allowed me to generate comparable in vivo data from the prefrontal cortex of awake Dgcr8+/- mice, an established genetic model of schizophrenia. Despite the disparities between these two animal models, I report convergent patterns indicating a disruption of neuronal correlations in the prefrontal regions of both monkeys given dissociative drugs and mice carrying a schizophrenia-associated mutation. In both studies, I found evidence that neurons in the disease state were not synchronizing their activity with each other as effectively as in the control state. Furthermore, the effective transfer of information between pairs of neighboring neurons was reduced. These results suggest that the intrinsic circuitry of the prefrontal cortex may be disconnected in schizophrenia, and that this disconnection relates to a reduction in coincident spiking activity of neighboring neurons. It is plausible that such a dissolution of local prefrontal connectivity could result in a failure to achieve the cognitively demanding task of thought organization. While much is yet to be learned about the nature of schizophrenia, my findings have the potential to motivate the development of novel approaches to the restoration of function in this devastating disease.
An fMRI investigation of perceptual impairments on the DS-CPT in Schizophrenia patients.
(2010-12) Force, Rachel Brook
The Degraded-Stimulus Continuous Performance Task (DS-CPT) has been utilized to examine vigilance deficits in schizophrenia patients for decades. However, recent evidence suggests sustained attention may not be the foremost cognitive process underlying task performance. Through the use of functional magnetic resonance imaging (fMRI) and manipulating the perceptual load of the objects in a pseudorandomized order regions of interest that are involved in the creation and maintenance of novel mental representations as well as the implementation of unambiguous cues were identified. Whole-brain exploratory analysis resulted in statistical regions of interest that were further categorized as to their response patterns as involved in task performance, task difficulty, object perception, and the default mode network. Group differences were found in each category of response and correlations with behavioral indices indicated several mechanisms that may underlie cognitive deficits. As areas identified as providing top-down feedback such the dorsolateral prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex exhibited atypical activation, functional compensatory mechanisms may contribute to the lack of performance deficits observed in this sample. Increasing the understanding of the brain mechanisms involved in DS-CPT performance in schizophrenia patients may offer greater insight into the nature of visual perceptual deficits in the disorder.
Functional Brain Networks and the Openness-Psychosis Continuum
(2019-10) Blain, Scott
Psychosis proneness has been linked to heightened Openness to Experience and to cognitive deficits. Openness and psychotic disorders are associated with the default and frontoparietal networks, and the latter network is also robustly associated with intelligence. We tested the hypothesis that functional connectivity of the default and frontoparietal networks is a neural correlate of the openness-psychoticism dimension. Participants in the Human Connectome Project (N = 1003) completed measures of psychoticism, openness, and intelligence. Resting state functional magnetic resonance imaging was used to identify intrinsic connectivity networks. Structural equation modeling revealed relations among personality, intelligence, and network coherence. Psychoticism, openness, and especially their shared variance, were related positively to default network coherence and negatively to frontoparietal coherence. These associations remained after controlling for intelligence. Intelligence was positively related to frontoparietal coherence. Research suggests psychoticism and openness are linked in part through their association with connectivity in networks involving experiential simulation and cognitive control. We propose a model of psychosis risk that highlights roles of the default and frontoparietal networks. Findings echo research on functional connectivity in psychosis patients, suggesting shared mechanisms across the personality-psychopathology continuum.
Functional dysintegration syndrome of schizophrenia: a multimodal neuroimaging study.
(2009-01) Kang, Seung Suk
Schizophrenia is a serious mental illness with heterogeneous symptoms. Recent neuroimaging studies have suggested that schizophrenic symptoms arise from functional dysintegration in brain network, not from local brain deficits. This study investigates the functional dysintegration in schizophrenia patients using multimodal neuroimaging techniques, integrating functional magnetic resonance imagining (fMRI) and magnetoencephalography (MEG) data collected during spatial working memory task performance. It has been known that schizophrenia patients have deficits in spatial working memory where prefrontal and posterior sensory processing areas should be functionally coordinated. Twelve schizophrenia patients and eleven normal control subjects participated in this study. This study consists of the following four sub-studies; 1) fMRI regional activation study to identify the brain regions involved in spatial working memory and the regions where schizophrenia patients have deficient task-related activations, 2) cortical source MEG study of local gamma energy to identify brain regions where schizophrenia patients have deficient gamma activity, which is an index of functional integration within local brain area, 3) large scale functional connectivity study using temporal correlation analysis of fMRI time-series between regions of interests (ROIs) in the spatial working memory network and interregional gamma phase synchrony analysis of the cortical source MEG signals of the ROIs to identify brain networks showing abnormal functional connectivity during spatial working memory in schizophrenia patients, and 4) association study to investigate the relationships between the fMRI and the cortical source MEG functional connectivity indices and clinical symptoms of schizophrenia. These studies revealed that schizophrenia patients had dysfunctions in prefrontal and posterior association cortices as well as cortico-thlamo-cerebellar system. In addition, they were also found to have local and large-scale functional connectivity deficits in the spatial working memory network. These functional connectivity indices had associations with the spatial working memory task performace. Specific abnormalities in the interregional functional connectivity also showed differential associations with the schizophrenic symptoms, such as positive, negative, and disorganization symptoms. The neurobiological bases of the functional dysintegration syndrome of schizophrenia and the implications of the syndrome in characterizing schizophrenia were discussed.
Functional Magnetic Resonance Imaging of Goal Maintenance in Schizophrenia: Activation, Functional Connectivity, and Reliability
(2016-06) Poppe, Andrew
Cognitive deficits are some of the most debilitating and difficult to treat symptoms of schizophrenia. Goal maintenance is a facet of cognitive control that has been shown to be impaired in schizophrenia patients as well as their unaffected first-degree relatives. Previous fMRI activation studies found less activation in dorsolateral prefrontal cortex (dlPFC) in schizophrenia patients compared with healthy controls during the completion of a goal maintenance task. This dissertation consisted of a series of studies employing a large, multisite retest dataset of schizophrenia patients and healthy control subjects. These studies sought to replicate previous activation findings using a newer goal maintenance task, to use group independent component analysis (ICA) to determine if schizophrenia patients also exhibited dysfunctional functional connectivity or functional network connectivity (FNC) compared with healthy controls during the performance of that task, and to evaluate the test-retest reliability of each of these metrics, directly compare them, and assess the influence of subject group and data collection site on reliability estimates. It replicated previous activation study findings of reduced dlPFC activity during goal maintenance. It additionally found that the temporal association between a frontoparietal executive control network and a salience network was stronger in healthy controls than in schizophrenia patients and that the strength of this relationship predicted performance on the goal maintenance task. It also found that the task-modulation of the relationship between left- and right-lateralized executive control networks was stronger in healthy controls than in schizophrenia patients and that the strength of this task-modulation predicted goal maintenance task performance in healthy controls. Finally, reliability estimates found that ICA and tonic FNC had acceptable overall reliability and that they minimized site-related variance in reliability compared with dynamic FNC and general linear model. These results indicate that ICA and tonic FNC may provide better tools for group contrast fMRI studies examining schizophrenia, especially those that incorporate a multisite design.
"In a shattered language": a feminist poetics of trauma.
(2011-10) Griffiths, Amy Kathleen
In a Shattered Language": A Feminist Poetics of Trauma, fuses theories of traumatic stress with studies of contemporary poetry and poetics. This project intervenes in debates over the ways trauma is experienced, remembered, and represented by positing poetry as an alternative form of discourse--one which endures the pressures of testimonial coherence while simultaneously preserving the aporias of knowledge and memory that characterize traumatization. My analysis also revises trauma theory from a feminist perspective by investigating domestic traumas such as rape, incest, and mental illness as portrayed in poetry by North American women writers in the twentieth century. The dissertation opens with a brief Prologue, which views the 2010 Korean film Poetry as a text through which the major concerns of this project are refracted. The first chapter, "Difficult Word: The Interpretation of `Trauma' and the Trauma of Interpretation," traces a genealogy of trauma as an intellectual concept prone to semantic slippage, and calls for a Poetics of Trauma to reconfigure the role of linguistic form in conceptualizing trauma and its aftermath. The second chapter, "`While Someone Else is Eating': The Dialectic of the Extreme and the Everyday in Frances Driscoll's. The Rape Poems," conducts close readings of poetry by a survivor of intruder rape, and argues that a feminist perspective qualifies the core tenet of trauma theory which locates traumata in extreme external events. The third chapter, "Traumatizing the Lyric `I': Poetic Subjectivity in Betsy Warland's. The Bat Had Blue Eyes," considers theories of the traumatized "self" as they pertain to an adult survivor of childhood incest, and argues that poetry-writing generates a phenomenological selfhood through which survival becomes perpetual revision. The final chapter, "Traumatic Consciousness: The Poetry of Interpretation in Hannah Weiner's Archive," encounters Weiner's work as a means of critiquing the psychopathology model of trauma. This chapter finds that Weiner's avant-garde poetics both does and does not evince symptoms of her struggle with schizophrenia, and as such, suggests how conventional language itself traumatizes consciousness. This chapter weaves together research in Weiner's unpublished journals with a personal narrative to form an implicit theory of the poetics of reading and writing trauma.
Local and Iterative Visual Processing Deficits in Schizophrenia
(2017-05) Espensen-Sturges, Tori
Evidence of dysfunctional visual processing in schizophrenia patients has been noted in all stages of the visual processing pathway. The iterative nature of vision- with hierarchical feedforward signals, modulating feedback signals, and horizontal intracortical connections- makes it difficult to pinpoint exact loci that are driving these deficits. This dissertation uses several contextual modulation paradigms in an effort to isolate and explain the nature of disruptions in iterative visual processing in schizophrenia. Chapter 1 provides an overview of visual processing dysfunctions in schizophrenia, and examines a variety of mechanisms that may play a role. These include neurotransmitters, magnocellular versus parvocellular processing streams, abnormal local connections, and abnormal long-range feedback connections. These are presented in the context of several theoretical perspectives of visual neuroscience. Chapter 2 provides functional magnetic resonance imaging data from a fractured ambiguous object task that probes the role of high-level qualities in primary visual cortex activation and interregional connectivity, and how these may be disrupted in psychosis. Chapter 3 introduces a computational model that attempts to fit parameters to psychophysical data to isolate disrupted mechanisms in schizophrenia. This model focuses on the role of gain control and segmentation of center and surround stimuli in a tilt illusion paradigm. Chapter 4 presents previous work, examining the modulatory effect of the NMDA receptor agonist d-cycoserine on conditioned fear generalization. This work was done in healthy controls as a step in expanding our knowledge of the function of d-cycloserine in increasing specificity and efficacy in the fear learning process.
Multiple Perspectives on the Impact of Cognitive Control Processes on Disorganization in Psychosis
(2023-06) Kwashie, Anita
Disorganization, a psychosis symptom factor denoting abnormal speech and behavior, is thought to reflect impaired cognitive processing. However, despite their theoretical similarities, there appears to be little consistent evidence of a distinctive relationship between disorganization and cognitive control. This dissertation examined the relationship between disorganization and two key cognitive control mechanisms, context processing and prepotent response inhibition, also known as proactive control and reactive control. Chapter 2 compared the functional neuroanatomy of cognitive control in schizophrenia patients and healthy controls. Both context processing and prepotent response inhibition marshaled activity in prefrontal, anterior cingulate, posterior parietal, and middle temporal structures. Controls demonstrated greater prefrontal activity during context processing than did patients. However, BOLD signal did not predict disorganization severity. Due to potential bias in symptom ratings, Chapter 3 controlled for ethnic minority identity while examining the relationship between disorganization and cognitive control in a psychosis sample. Disorganization predicted variance in context processing and prepotent response inhibition, unlike other symptoms. However, the context processing model also found ethnic minority identity predictive, particularly if identifying as Black. Chapter 4 explored the potential influence of visual processing within a new cognitive control task. Behavioral metrics were uncorrelated with either self-report or experimenter-rated disorganization. However, context processing trended with general cognitive impairment in psychosis patients. Visual processing was associated with context processing and prepotent response inhibition in controls, while only the Middle Frontal Gyrus activated in patients. Generalized smooth models suggest visual processing regions may predict cognitive impairment better than traditional regions of interest. Implications and future directions are considered.
Neural Anomalies During Vigilance in Schizophrenia: Diagnostic Specificities and Genetic Associations
(2020-10) Klein, Samuel
Impaired vigilance is a core cognitive deficit in schizophrenia and may serve as an endophenotype (i.e., mark genetic liability). We used a continuous performance task with perceptually degraded stimuli in schizophrenia patients (N=48), bipolar disorder patients (N=26), first-degree biological relatives of schizophrenia patients (N=55) and bipolar disorder patients (N =28), as well as healthy controls (N=68) to clarify whether previously reported vigilance deficits and abnormal neural functions were indicative of genetic liability for schizophrenia as opposed to a generalized liability for severe psychopathology. We also examined variation in the Catechol-O-methyltransferase gene to evaluate whether brain responses were related to genetic variation associated with higher-order cognition. Relatives of schizophrenia patients had an increased rate of misidentification of nontarget stimuli as targets when they were perceptually similar, suggestive of difficulties with contour perception. Larger early visual responses (i.e., N1) were associated with better task performance in patients with schizophrenia consistent with enhanced N1 responses reflecting beneficial neural compensation. Additionally, reduced N2 augmentation to target stimuli was specific to schizophrenia. Both patients with schizophrenia and first-degree relatives displayed reduced late cognitive responses (P3b) that predicted worse performance. First-degree relatives of bipolar patients exhibited performance deficits, and displayed aberrant neural responses that were milder than individuals with liability for schizophrenia and dependent on sex. Variation in the Catechol-O-methyltransferase gene was differentially associated with P3b in schizophrenia and bipolar groups. Poor vigilance in schizophrenia is specifically predicted by a failure to enhance early visual responses, weak augmentation of mid-latency brain responses to targets, and limited engagement of late cognitive responses that may be tied to genetic variation associated with prefrontal dopaminergic availability. Experimental results illustrate specific neural functions that distinguish schizophrenia from bipolar disorder and provides evidence for a putative endophenotype that differentiates genetic liability for schizophrenia from severe mental illness more broadly.
Neural basis of context processing dysfunction in schizophrenia: a monkey model
(2013-08) Blackman, Rachael Keir
Ranking among the top ten causes of years lost due to disability worldwide, schizophrenia is a psychiatric disease whose pathophysiology has not been fully characterized to-date. The objective of my dissertation is to characterize the change in neuronal information processing that leads to cognitive dysfunction in the disease. To this end, I trained monkeys to perform a translational cognitive task that measures context processing deficits in schizophrenia patients. Context processing is the ability to use prior contextual information maintained in working memory to conditionally respond to subsequent stimuli. I then recorded neural activity from the prefrontal (PFC) and posterior parietal (PAR) cortex after administering N-methyl-D-aspartate (NMDA) receptor antagonists that 1) are known to mimic symptoms of schizophrenia in human control subjects, and 2) block the NMDA receptor which is thought to be dysfunctional in the disease. I found that after drug administration, monkeys produced essentially the same pattern of behavioral errors on this task that schizophrenia patients commit. Further, by recording neural activity in PFC and PAR during the period of cognitive impairment, I was able to determine that the maintenance of contextual information in PFC was selectively diminished. In addition, I was able to use trial-by-trial changes in neural activity in both cortical areas to predict errors on the task, linking neuronal activity to behavioral performance. Overall, I have been able to characterize for the first time the change in cortical information processing at a cellular level that could account for context processing dysfunction in schizophrenia.
Neural Impact of Cognitive Remediation for Schizophrenia in a Randomized Controlled Trial
(2016-06) Ramsay, Ian
Cognitive remediation training for schizophrenia has been shown to have modest influence on both cognitive and psychosocial functioning, but much is not understood about the neurobiology associated with these interventions. The current randomized placebo-controlled trial and review sought to replicate and expand on previous findings demonstrating that improvements from cognitive remediation are associated with changes in prefrontal brain activation and functional connectivity. Results suggest that cognitive remediation influences both prefrontal and thalamic brain areas, and that changes within the connections between these regions may reflect improvements in overall cognition. The implications of these findings as well as how neuroplastic changes might influence cognition, psychosocial functioning, or symptom profile in schizophrenia will be discussed.
Neural mechanisms of visual context processing in healthy adults and those with Schizophrenia
(2014-12) Schallmo, Michael-Paul
The brain's response to a visual stimulus depends in part on the context in which it appears. For example, objects appearing within similar-looking backgrounds tend to evoke smaller neural responses than those seen in isolation. While it is known that schizophrenia (SZ) may reduce visual context effects, the neural mechanisms involved are not fully understood. This dissertation uses functional magnetic resonance imaging (fMRI) and visual behavioral tasks to examine the role of context during normal visual processing, and how context processing is affected by SZ.Chapter 1 provides an overview of the forms of contextual modulation that will be addressed later, and their impairment in SZ. Chapter 2 describes a series of five experiments probing how factors such as stimulus geometry, presentation timing, and attention affect the fMRI response to small groups of visual stimuli. In primary visual cortex, the relative strength of contextual modulation was found to increase when subjects directed their attention away from the stimuli. Further, fMRI responses to parallel center and surrounding stimuli did not show the predicted sensitivity to center contrast.In Chapters 3 and 4, the effect of spatial context during early visual processing in SZ patients was assessed using behavioral measures. Surround suppression of perceived contrast was examined in Chapter 3 among SZ patients and their unaffected relatives, as well as subjects with bipolar affective disorder (BP), relatives of BP subjects, and healthy controls. Weaker surround suppression was observed in SZ versus control subjects, while BP patients showed an intermediate deficit. These deficits did not depend on the configuration of surrounding stimuli. Normal performance was observed among relatives of SZ and BP subjects, indicating deficits in surround suppression were not associated with a genetic risk for these disorders. Chapter 4 examined how SZ impairs the ability to detect visual contours in cluttered backgrounds. Contours were presented in more- or less-similar backgrounds, in order to assess contextual modulation. While SZ patients performed worse than healthy controls or SZ relatives when detecting contours, performance in SZ was less influenced by background context. These experiments were designed to explore the neural basis of visual context processing in healthy adults, and to help uncover how SZ impairs these processes. The large body of research into the neurophysiology of human vision provides powerful tools with which to study how SZ may disrupt neural processing. Studying visual context processing may ultimately help to uncover computational principles conserved across many neural systems, and aid in identifying new targets for the treatment of mental disorders.
New Estimation and Inferential Methods for Functional Connectivity Analysis
(2021-06) DiLernia, Andrew
Functional magnetic resonance imaging (fMRI) data is increasingly available and provides insight into the physiological mechanisms of the brain. As psychiatric disorders and many neurodegenerative diseases are intrinsically related to the brain, the availability of fMRI presents tremendous opportunities for improving understanding of these disorders and diseases. One approach for analyzing fMRI data is to describe functional connectivity (FC), the dependence of neuronal activity in regions of the brain. FC disruptions have been found in many mental disorders and diseases, so improving understanding of alterations in FC potentially underpinning mechanisms of these diseases is of clinical importance. Several metrics are used to describe FC connections such as marginal correlations, partial correlations, mutual information, and coherence among others. In this dissertation, we propose novel methods for inference and estimation of partial correlations for FC analysis of multi-subject fMRI data. In our first project, we consider heterogeneity of FC patterns and aim to cluster multi-subject fMRI data based on each individual's FC patterns. We propose a novel penalized model-based clustering method which simultaneously estimates FC and clusters subjects into groups with similar FC patterns. The method estimates the precision matrix, the elements of which give partial correlations of all pairs of variables, at both the subject and cluster level for bi-level FC inference. We apply the method to a multi-subject fMRI data set collected on participants diagnosed with schizophrenia and healthy controls finding that participants with schizophrenia were more likely to be clustered into a group with reduced FC connections. In our second project, we consider the issue of autocorrelation in fMRI data which is not accounted for in many existing methods when estimating and conducting inference of partial correlations. We derive an asymptotic joint distribution and novel covariance estimator for the partial correlations of a multivariate Gaussian process given mild regularity conditions. Based on the asymptotic distribution, we develop Wald confidence intervals and testing procedures for inference of individual partial correlations for inference of FC connections in single-subject fMRI data analysis. In our third project, we also use our theoretical result to propose a hierarchical model that directly accounts for the autocorrelation in fMRI data and within group heterogeneity. We then develop a novel testing procedure for two-group comparisons of group-level FC in terms of the partial correlations which is robust to various levels of autocorrelation present in fMRI data.
Novel Biomarker Identification Approaches for Schizophrenia using fMRI and Retinal Electrophysiology
(2017-11) Moghimi, Pantea
Schizophrenia is a chronic mental illness. The exact cause if schizophrenia is not yet known. Extensive research has been done to identify robust biomarkers for the disease using non-invasive brain imaging techniques. A robust biomarker can be informative about pathophysiology of the disease and can guide clinicians into developing more effective interventions. The aim of this dissertation is two folds. First, we seek to identify robust biomarkers using resting state fMRI activity from a cohort of schizophrenic and healthy subjects in a purely data driven approach. We will calculate multivariate network measures and use them as features for classification of the subjects into healthy and diseased. The network measures will be calculated using nodes defined by the AAL anatomical atlas as well as a functional atlas constructed from the fMRI activity. Network measures with high classification rate may be used as potential biomarkers. We will employ double cross-validation to estimate generalizability of our results to a new population of subjects that were not used in biomarker identification. Second, we seek to identify biomarkers using electroretinogram (ERG). We will use a data driven approach to classify individuals based on the pattern of retinal activity they exhibit in response to visual stimulation. Characteristics of the ERG result in high classification rate are presented as potential biomarkers of schizophrenia.
The Role of Theta- / Gamma-Coupling in Working Memory Dysfunction in Schizophrenia
(2019-04) Lynn, Peter
Background: Prominent working memory (WM) deficits have been repeatedly observed in people with schizophrenia (PSZ) and their unaffected relatives (REL), including in the spatial domain. Given the apparent association between spatial WM dysfunction and genetic liability for schizophrenia, spatial WM deficits have been proposed as a potential endophenotype for the disorder. Deficits in the neural correlates of WM performance have likewise been observed in PSZ and REL. Lisman and Idiart (1995) offered a model delineating a mechanism for the representation of multiple stimuli in WM through systematic interactions between activity in the theta- and gamma- frequency ranges, and much experimental evidence in support of this model has been obtained since. Activity in these frequency ranges has also been proposed as a potential underlying factor in WM dysfunction in PSZ and REL, especially in light of documented deficits in the theta- and gamma- bands independently. Methods: Theta- and gamma-band oscillatory activity recorded during a spatial WM task was examined through time-frequency analyses in PSZ, REL, and CTRL. Indices of power, phase-synchrony, cross-frequency coupling and their relationships to task performance were explored. Results: PSZ demonstrated abnormalities in measures of both theta- and gamma-band power as compared to CTRL and REL, whereas deviance in power measures were limited to gamma-activity in REL. Both PSZ and REL showed reduced phase-synchrony across examined frequencies for electrodes where synchrony was observed in CTRL. Theta-gamma coupling increased significantly in response to WM stimuli, though minimal differences were observed across diagnostic groupings. Behavioral performance was generally predicted by measures of low frequency power and high-frequency phase synchrony, though the predictive ability of focused measures of gamma-band power, synchrony and phase-amplitude coupling was increased for PSZ as compared to CTRL and REL. Discussion: Disturbances in various measures of theta- and gamma-band oscillatory activity was observed in PSZ and to a lesser extent in REL. PSZ showed unique predictive relationships between certain neural indices (including limited indices of cross-frequency coupling) and behavioral performance, even in measures where no group differences were observed, suggesting PSZ are more impaired by normal variability in neural processes related to these measures than CTRL and REL. These findings, in light of preserved WM performance in REL, may further support the presence of a compensatory mechanism in REL that insulates them from deficits in performance. Cross-frequency coupling appears to have some predictive utility regarding WM ability, though further work in determining particular frequency pairs of relevance is needed.
Schizophrenia, Understanding the Struggle
(2008-02-06) Nguyen, Trung
Schizophrenia is a deteriorative psychological disease that mentally and physically strains the patients who manifest the disease and their families. The etiology of the disease is excess Dopamine, a neurotransmitter. There are two categorization of Schizophrenia; positive symptoms, and negative symptoms. Patients who suffer with positive symptoms experience hallucinations, delusions, and have rambling, incoherent speech. Patients who suffer with negative symptoms have flat affect, decreased mood, and are socially withdrawn. Current treatments for Schizophrenia include neuroleptics and atypical antipsychotics. Both drug categories aim to decrease Dopamine availability at the receptor site. Side effects of these drugs lead to major noncompliance issues. These major side effects include: tardive dyskinesia, Parkinsonian tremor, nausea, and weight gain.
A translational approach to the neurobiology of persecutory ideation in schizophrenia.
(2011-08) Johnson, Melissa Kay
The heterogeneous symptom presentation of schizophrenia has created difficulties in understanding the disease's biological basis. As a result, researchers have adopted dimension or symptom-specific methodologies to identify the disease's etiology. Another successful research method in schizophrenia involves the translation of experimental paradigms designed to study the neurobiology of cognitive mechanisms through multiple levels of inquiry. The current manuscript described the translation of an economic decision-making paradigm into a sample of individuals with schizophrenia. Results showed that patients with schizophrenia in this sample were able to understand the paradigm and as predicted showed behavioral results similar to controls. A symptom measure of persecutory ideation showed a specific relationship to a decision-making bias that has been reliably associated with persecutory ideation in control samples. In terms of neuroimaging results, patients activated the paracingulate cortex, anterior cingulate cortex, orbital frontal cortex, insula and amygdala when deciding whether or not to trust another player. These same regions were not activated when deciding whether or not to let a coin-flip determine their winnings. Of the regions activated when deciding to trust another player, only the anterior cingulate cortex correlated with a measure of persecutory ideation. Results suggest that economic decision-making paradigms can produce fruitful results in psychiatric samples. Additionally, the findings suggest a specific relationship between the self-referential thinking associated with persecutory ideation and the anterior cingulate cortex.
Working memory subprocesses and catechol-O-methyltransferase Val158Met polymorphism in schizophrenia patients, bipolar disorder patients, and their relatives.
(2010-07) Dionisio, Daphne
The present study had several objectives. It sought to determine if deficits in working memory subprocesses of maintenance, monitoring, and manipulation are specific to schizophrenia or are also present in patients with bipolar disorder. It was of interest to additionally determine if working memory deficits are present in the relatives of schizophrenia patients and relatives of bipolar disorder patients. Finally, the association between the COMT Val158Met polymorphism and working memory ability in schizophrenia patients, bipolar disorder patients, and the relatives of these patient groups was investigated. Genotyping data and performance scores for the Spatial Delayed Response Task (i.e. maintenance), Self Ordered Pointing (i.e. monitoring), Digit Span Backwards (i.e. low demand manipulation) and Letter Number Sequencing (i.e. high demand manipulation) were collected for schizophrenia patients, bipolar disorder patients, relatives of schizophrenia patients, relatives of bipolar disorder patients, and nonpsychiatric controls. Results showed worse performance on the maintenance, low demand manipulation, and high demand manipulation working memory subprocesses for schizophrenia patients compared to nonpsychiatric controls and bipolar disorder patients. The relatives of schizophrenia patients also demonstrated impairment in low demand manipulation and high demand manipulation, as well as a trend for worse maintenance performance compared to nonpsychiatric controls. Although no genotype group differences were revealed when examined in a sample combining all diagnostic groups, a few genotype group differences were detected when examined within a sample of schizophrenia patients. These results will be discussed. The results suggest that schizophrenia and bipolar disorder have distinct pathophysiologies, manipulation is promising as an endophenotype for schizophrenia-relevant disease genes, and there may be Val158Met genotype group differences in working memory within schizophrenia patients.

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