Browsing by Subject "schizophrenia"

Now showing 1 - 7 of 7
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    Altered MD-PFC thalamocortical network dynamics in an NMDAR antagonist animal model of cognitive control deficits in Schizoprenia
    (2019-08) DeNicola, Adele
    Schizophrenia (SZ) is debilitating neuropsychiatric disorder and afflicted patients exhibit an array of symptoms including hallucinations, delusions, flat affect, and deficits in cognitive functioning. Even though the functional outcome of patients with SZ is correlated with the severity of cognitive deficits, current therapeutics do not effectively improve cognitive deficits. However, there is still not a clear understanding of the pathophysiology underlying cognitive deficits, making it difficult to develop therapeutics target at the improvement of cognition in patients. The mediodorsal nucleus of the thalamus (MD) has been thought to play a role in cognitive control behaviors alongside the prefrontal cortex (PFC). This is largely due to the reciprocal connections between the MD and PFC, reports of MD neurons exhibiting similar task-related activity patterns during cognitive behaviors, and that lesions in the MD produce deficits in cognition similar to PFC lesions. Also, in patients with SZ the MD and PFC exhibit correlated reduced activation during cognitive control performance and are function disconnected from each other. In order to further our understanding of the pathophysiology in the MD-PFC thalamocortical network, I trained monkeys to perform a cognitive control task that exposes cognitive control deficits in patients with SZ. First, I relate thalamocortical distributed processing and functional coupling to cognitive control by recording in the MD and PFC simultaneously in the healthy state. Then, I characterize the effects of NMDA receptor (NMDAR) blockade on thalamocortical distributed processing and functional coupling underlying cognitive deficits. I found that MD neurons represent cognitive control state similarly to PFC neurons, but that PFC state neurons contain more information early in the trial, while MD state neurons contain more information late in the trial, MD neurons are more involved in response selection than PFC neurons and neurons in the MD and PFC transmit state and response information reciprocally during cognitive control performance. Following NMDAR blockade, there were less MD and PFC neurons recruited to encode state and response information and the neurons that did encode task information were delayed in their recruitment. Additionally, representation of task state was decreased at the single neuron and population levels in both the MD and PFC, but to a stronger degree in the PFC than the MD, and these changes in state representation predicted task failure on a trial-by-trial basis more strongly in the MD than the PFC. Lastly, NMDAR blockade strongly attenuated transmission of information in local circuits in and between the MD and PFC. Overall, I am the first to characterize MD-PFC cellular level network dynamics underlying cognitive control and the effect of NMDAR blockade on this thalamocortical network that results in pathophysiology and SZ-like cognitive deficits.
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    Cognitive/Neural Compensatory Mechanisms in Schizophrenia: Reaction Times-Brain Activity Correlates
    (2016-12) Elshikh, Ansam
    Abstract Cognitive deficiency in schizophrenia (SZ) was found to be associated with decreased PFC activity compared to healthy controls (HC). Other studies referred to increased / intact patterns of PFC activity. Parallel to those inconsistent neuroimaging findings, schizophrenia patients also showed increased intra-individual reaction times variability (RT_IIV). In the current work, we suggested that inconsistent findings in schizophrenia neuroimaging literature are driven by their increased RT-IIV. We hypothesized that performance with increased reaction times in SZ patients reflects compensatory cognitive/neural mechanisms. To address that general hypothesis, we conducted three studies as follow: 1. Activation likelihood Estimation (ALE) meta analysis of (90 fMRI studies in SZ); In that study we were first concerned with extracting the most consistent neuroimaging findings in the previous SZ literature. Second, we conducted ALE analyses within two categories: experiment with impaired RT (effect sizes > 0.3) vs. experiments with unimpaired RT (effect sizes <0.3); 2. In the second study, we investigated RT_IIV coefficients during AX task performance in four groups, SZ patients (N= 20), SZ.R (N= 33), HC subjects (N =21), HC.R (N= 23). We hypothesized that SZ patients and their relatives would show increased RT_IIV relative to HC within the probe and the cue conditions. 3. In our main study, fMRI study, we tested BOLD response across three levels of RT (slow, medium and fast). We hypothesized that SZ patients and their relatives will show more VLPFC activity during the slow trials than the faster trials relative to HC- reflecting slow reactive compensatory mechanisms.
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    Electrophysiological and Personality Factors Associated with Aberrant Visual Processing in Psychosis
    (2019-08) Longenecker, Julia
    ‘Apophenia’, or the tendency to find patterns in unrelated perceptions, may link normative and pathological sensory experiences. Apophenia has been well-characterized by personality assessment, but has limited behavioral and functional correlates, particularly in clinical populations. Object detection is predicted by apophenia traits in normative populations. Behavioral and neurobiological object detection abnormalities are pervasive in schizophrenia, yet have not been investigated with respect to apophenia. The current set of studies explore multiple levels of perceptual disturbances in normative and psychiatric samples. Study 1 investigated personality and object detection in an undergraduate sample (N=191). The object detection task, Fragmented Ambiguous Object Task (FAOT), controls for low-level visual properties while presenting disjointed object representations of varying difficulty. Personality was comprehensively assessed with the Big Five Aspect Scale (BFAS), Multidimensional Personality Questionnaire (MPQ), and Personality Inventory for DSM-5 (PID-5). Study 2 sought to replicate Study 1 in a clinical population and extend the investigation to EEG in outpatients with psychotic disorders, first-degree biological relatives, and psychiatrically unaffected individuals. Event-related potentials (ERPs) – P1, N1, closure negativity (NCL), and anterior components – were recorded with a 128 channel EEG system. Participants underwent comprehensive clinical assessment, and completed MPQ Absorption and PID-5. In Study 1, object detection was positively associated with BFAS Openness, MPQ Absorption and PID-5 Psychoticism. Additionally, BFAS Conscientiousness and PID-5 Disinhibition predicted object detection. Study 2 did not replicate the association between FAOT and personality, or show an object detection deficit in psychotic disorders. The hypotheses regarding ERPs were largely unsupported. Instead, findings suggested group differences in semantic processing during FAOT, and an anterior component associated with frequent object detection. Personality measures of apophenia were consistently related to experimentally manipulated visual perception in the general population but not persons with psychotic disorders. The present research attempted to unify observations in personality psychology, clinical research, and vision neuroscience of object detection. Deviations in perceptual functions that support the detection of ambiguous visual stimuli reflect normative expressions of trait-level apophenia. However, further investigation is necessary to connect apophenia to psychotic phenomenology in the context of mental illness.
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    An Investigation Into The Neural Nature Of Persecutory Ideation
    (2016-12) Wisner, Krista
    Persecutory ideation is a common and distressing symptom that exists on a continuum with persecutory delusions. Although associated with severe negative consequences the neural mechanisms underlying persecutory ideation remain unclear. Contributing factors in this research deficit include i) low rates of studies specifically examining persecutory ideation, favoring instead broader symptom measurement, and ii) a lack of paradigms that sufficiently engage or examine specific mechanisms associated with the symptom. In this dissertation, a wide range of literature is reviewed to identify brain regions consistently associated with delusions or positive symptoms in order to aid development of a model of persecutory ideation and stimulate research. Brain regions highlighted by the review represented a convergence of neurobiological models of delusions, and were the focus of two empirical studies. In the first study we employed a novel economic social decision-making task in two samples during neuroimaging. We demonstrated a dorsal anterior cingulate and anterior insula (dACC-AI) network, a left frontal-parietal (lF-P) network, and a ventral medial orbital prefrontal (vmPFC/OFC) network were associated with distinct forms of distrust. We then revealed only the connectivity between the vmPFC/OFC and lF-P networks predicted persecutory ideation, suggesting a role of weakened top-down control on subjective valuation. Moreover, we established this mechanism was associated with unique environmental influence in community monozygotic twins. In our second study we aimed to replicate the task-based finding in two resting-state samples to demonstrate generalizability of the mechanism; however, confirmatory analyses did not replicate. In summary, the posited vmPFC/OFC - lF-P interconnectivity mechanism of persecutory ideation appears to be uniquely evoked by the economic social decision-making task. While this provides a novel perspective on persecutory ideation, replications in larger samples are needed.
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    Neural Abnormalities Related to Visual Working Memory in People with Schizophrenia and their First-Degree Relatives
    (2016-07) Lynn, Peter
    Prominent working memory (WM) deficits have been observed in people with schizophrenia (PSZ) across multiple sensory modalities, including the visuospatial realm. Observed deficits in electrophysiological correlates of early visual processing as well as later cognitive processes in PSZ are thought to underlie deficiencies in WM ability, though the mechanisms linking the two are not well understood. WM deficits and associated electrophysiological abnormalities have also been observed in unaffected relatives of PSZ (REL), suggesting WM dysfunction may be indicative of genetic liability for the disorder. We administered a delayed response visuospatial WM task to 23 PSZ, 30 of their REL, and 37 healthy controls (CTRL) in an effort to better understand the contributions of neural abnormalities to WM performance deficits associated with schizophrenia. PSZ performed more poorly on the WM task and gained less benefit from the presence of irrelevant stimuli than did CTRL and REL. In terms of electrophysiological responses, N1 responses to probes during retrieval differentiated the type and locations of stimuli presented during encoding in CTRL. Retrieval N1 responses in PSZ, however, failed to do so, while retrieval responses in REL showed more pronounced differentiation of stimulus features during encoding. Furthermore, neural responses during retrieval predicted behavioral performance in PSZ and REL, but not CTRL. These results suggest retrieval processes are particularly important to efficient visuospatial WM function in PSZ and REL, and support further investigation of WM retrieval as a potential target for improving overall WM function through clinical intervention.
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    The Role Of D-Serine In Normal Retinal Function And Implications For Psychiatry
    (2019-08) Torres Jimenez, Nathalia
    There is a lack of objective measurements for assessing the progression of mental disorders such as schizophrenia. Biomarkers for schizophrenia would be an invaluable asset to identify at-risk individuals objectively, which should consequently improve the person’s prognosis and treatment. One such candidate for becoming a biomarker for schizophrenia is the flash-electroretinogram (fERG), an ophthalmological tool that assesses retinal integrity. Prior research had conflicting results, with some studies showing that people with schizophrenia have a reduced response from photoreceptors and bipolar cells. However, it has been unclear why abnormalities would occur that early in the retinal pathway when mouse studies that investigated monoamine deprivation, such as dopamine, did not reflect those deficits. An alternative reason for an altered fERG is that it may reflect reduced N-methyl-d-aspartate receptor (NMDAR) function, which has been postulated to explain some of the pathology exhibited in people with schizophrenia. However, no retinal field potentials in the outer retina had been attributed to NMDAR function. One way to induce hypofunction of the NMDAR is by reducing the availability of its co-agonist, either glycine or D-serine, since the NMDAR needs both glutamate and a co-agonist for activation. I examined how D-serine deprivation and its excess affects the outer retinal field potentials, and whether it has implications for psychiatry. We report the first fERG study in a genetic mouse model of schizophrenia characterized by NMDAR hypofunction from genetic silencing of serine racemase expression (SR-/-), an enzyme that converts L-serine to D-serine. We analyzed fERG components under mesopic-adapted conditions that reflect outer retinal function, the a-wave and the b-wave, to determine the resemblance to the human fERG from people with schizophrenia. In all the analyses, I included sex as a factor, due to thevii sex differences underlying the disease. We tested pharmacologically-induced hyperfunction of the NMDAR in WT mice by introducing D-serine. Lastly, we analyzed human fERG and pattern-electroretinogram (PERG) studies to assess outer and inner retinal function. I report that hypo- or hyper-function of the NMDAR, through changes in available D-serine, profoundly affects the temporal scale of photoreceptor and bipolar cell signaling, as well as the amplitude of bipolar cell currents. This work mirrors the deficits observed in people with schizophrenia. Including sex as a factor in analyses showed that D-serine affects male mice more profoundly regardless of genotype, suggesting that NMDAR and D-serine are involved in the retinal field potentials of the outer retina and are dependent on the animal’s sex. These studies also suggest that either there is a functional NMDAR component to the outer retinal field potentials or that D-serine has another role in the retina aside from being an endogenous co-agonist for the NMDAR. This implicates the involvement of gonadal hormones and D-serine in retinal functional integrity. Our human analyses reflect deficits in the retinal ganglion cell layer, and a trending reduction of the signal corresponding to bipolar cells. Furthermore, the human data analyses also showed an interaction between sex, with deficits affecting males with schizophrenia more profoundly. This work elevates the potential of the fERG to differentiate between healthy controls and subjects with schizophrenia, and to detect sex differences known to be present in schizophrenia
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    Understanding Social Functioning Deficits in Health and First Episode Schizophrenia: A Data-driven Approach Towards Improved Identification and Treatment
    (2022-02) Miley, Kathleen
    Background: Schizophrenia and other psychotic disorders are characterized by severe disability in social functioning, reducing quality of life, increasing risk for poor health outcomes, and causing significant personal and societal burden. Remediating social functioning impairments is an urgent clinical need, however progress has been hindered by a poor understanding of bio-behavioral underpinnings of functional decline, and the resulting lack of both prognostic tools to identify individuals at risk for poor outcomes and robustly effective interventions to promote functional recovery. This dissertation has an overarching purpose to improve the understanding, identification, and remediation of social functioning deficits in schizophrenia spectrum disorders by leveraging data-driven approaches. Three manuscripts are presented. Manuscript 1 critically reviews twelve studies to characterize the state of the science of individual prognostic models for functional outcomes in schizophrenia spectrum disorders. Findings indicate that development of prognostic tools is in an early stage, with a wide range of accuracies, and no clear advantage of utilizing one data modality (i.e., neurobiological data, clinical data, or functional data) over another. Results highlight a need to evaluate and directly compare predictive models which utilize different predictor modalities to understand how to optimally balance accuracy and clinical usability. Manuscript 2 presents a study aimed to develop individual prediction models for social functioning from integrated bio-behavioral data and identify which predictors are most important for social functioning using machine learning. With data from the Human Connectome Project Healthy Young Adult sample (age 22-35, N=1,101) and machine learning methods, four prognostic models were built from variable sets of brain morphology to behavior with increasing complexity: 1) brain-only model, 2) brain-cognition model, 3) cognition-behavioral model, and 4) combined brain-cognition-behavioral model. Results show that the combined brain-cognition-behavioral and cognition-behavioral models significantly predicted social functioning with nearly identical accuracy (R2 =0.53, 95% CI [0.38, 0.62] for each model), whereas the brain-only and brain-cognition models performed significantly worse (R2 = 0.06, 95% CI [-0.07, 0.16] and R2 = 0.11 95% CI [-0.05, 0.23], respectively). Negative affect, psychological wellbeing, extraversion, withdrawal, and cortical thickness of the rostral middle-frontal and superior-temporal brain regions were the most important predictors. These results suggest that prognostic models relying on behavioral data may promote clinical usability while maintaining predictive accuracy, and identify potentially important risk markers to be explored in future research. Manuscript 3 shifts the focus to identifying potential causes of functional outcomes that could be high impact treatment targets in first episode schizophrenia. We used demographic, clinical, and psychosocial measures for 276 participants from the Recovery After an Initial Schizophrenia Episode Early Treatment Program (RAISE-ETP) trial and a causal discovery algorithm, Greedy Fast Causal Inference, to model causal relationships across baseline variables and six-month social and occupational functioning. Results were validated in an independent dataset. Our primary finding was a modeled causal pathway from baseline socio-affective capacity to motivation, and from motivation to both social and occupational functioning at six months. These findings indicate that socio-affective abilities and motivation are specific high-impact treatment needs that must be addressed to promote optimal social and occupational recovery and highlight the need to integrate evidenced based treatments for these areas into gold-standard care models to promote social recovery. Conclusions: This dissertation leverages data-driven approaches to provide foundational knowledge for developing individual prognostic models for social functioning and to guide clinical research seeking to fill critical unmet treatment needs for the remediation of functional impairments. Research and clinical agendas must continue to advance the science toward ensuring that social recovery is the expectation of mental health treatment through early identification of individuals at risk for functional decline and innovative treatments which enhance their functioning. Further synthesis and implications of this work are explored in the concluding chapter.