Katrina McMullen2, Veena Kumari1, Gareth J Barker1,. Christian Keysers3, and .... the level of self-reflectivity and insight in first episode patients. The role of.
S102 195. RELATIONSHIP BETWEEN PREFRONTAL GLUTAMATE LEVELS AND FUNCTIONAL ACTIVATION DURING EMOTIONAL PROCESSING IN INDIVIDUALS WITH HIGH SCHIZOTYPY Gemma Modinos*,1, Anna McLaughlin1, Alice Egerton1, Katrina McMullen2, Veena Kumari1, Gareth J Barker1, Christian Keysers3, and Steven CR Williams1 1 King’s College London; 2University of British Columbia; 3 University of Amsterdam Background: Empirical evidence shows that healthy individuals with high schizotypy (HS), who show schizophrenia-like characteristics, present similar but attenuated social and emotional disturbances to patients with schizophrenia. Altered glutamatergic neurotransmission in several limbic areas including the anterior cingulate cortex (ACC) has been demonstrated in patients with schizophrenia and individuals at ultra-high risk for psychosis and is associated with abnormalities in brain activation during several cognitive tasks. However, despite animal models of psychosis suggesting an association between prefrontal glutamatergic function and corticolimbic response to stress/emotion, the interactions between these abnormalities in man remain unclear. We examined changes in brain glutamate in subjects with HS and whether any such changes are related to corticolimbic response to emotional processing. Methods: Healthy subjects (n = 48) were selected based on their Oxford and Liverpool Inventory of Feelings and Experiences (O-LIFE) rating. Functional response during an emotional perception task was measured using functional magnetic resonance imaging, and glutamate levels in the ACC using proton magnetic resonance spectroscopy. Results: While viewing emotional pictures, HS individuals showed greater activation than did subjects with low schizotypy (LS) in the caudate, and marginally in the ACC, hippocampus, medial prefrontal cortex, and putamen (P < .05 family-wise error corrected). Within the HS, there was a significant negative association between levels of ACC glutamate and striatal, amygdalar, and prefrontal response to emotion (P < .05 family-wise error corrected), which was not present in the LS group. Conclusion: Our results demonstrate that emotional hyperresponsivity in people with high schizotypy is related to changes in glutamate levels, adding to accumulating evidence that abnormal neurophysiology and neurochemistry within a prefrontal-temporal–striatal system associated with emotional dysfunction may be central to vulnerability for psychosis.
196. SCHIZOPHRENIA PATIENTS SHOW ENHANCED RESPONSES TO LOSS AVOIDANCE IN FRONTOSTRIATAL CIRCUITS James Waltz*,1, Ziye Xu2, Elliot Brown3, Rebecca Ruiz1, and James Gold1 1 Maryland Psychiatric Research Center; University of Maryland School of Medicine; 2Duke University; 3University of Calgary Background: In previous work (Gold et al., 2012), we found that, in the context of a reinforcement learning (RL) task, patients with schizophrenia (SZ) were more likely to subjectively value gains and instances of loss-avoidance similarly, although instances of loss-avoidance were objectively neutral. This finding was most true of avolitional SZ patients and was attributed to maladaptive representations of expected value (EV), in the presence of intact signaling of reward prediction errors (RPEs). In the current study, using fMRI, we investigated the neural basis of this phenomenon, hypothesizing that SZ patients would exhibit aberrant neural signals related to value-signaling in frontostriatal loops, rather than attenuated RPE signals.
Concurrent Oral Presentations Methods: We administered a variant of an RL paradigm (Pessiglione et al. 2006) to 27 chronic SZ patients and 27 controls. Participants learned three probabilistic discriminations (choice of the better stimulus led to better outcome 70% of the time, choice of the worse stimulus led to worse outcome 70% of the time). In a “Gain-Miss” pair, outcomes were either a gain of 25 cents neutral. In a “Loss-Avoid” pair, outcomes were either neutral or a loss of 25 cents. In a “Correct-Incorrect” pair, subjects received only “Correct” and “Incorrect” as pictorial feedback. We examined neural responses to outcomes in nodes of reward and salience networks identified a priori. We also examined contrasts in these areas between outcomes with the same RPE valence but different experienced values (GAIN – LOSS-AVOID, e.g.) and between outcomes with the same experienced value but different RPE valence (LOSS-AVOID – MISS, e.g.). Results: We found that SZ patients showed ENHANCED [LOSS-AVOID – MISS] (RPE-valence) contrasts, relative to controls, in right ventral striatum [VS; t(52) = 2.005, P = .050]. We also observed that SZ patients showed REDUCED [GAIN – LOSS-AVOID] (outcome-valence) contrasts, relative to controls, in dorsal anterior cingulate cortex, dorsomedial prefrontal cortex, and bilateral anterior insula (all t’s > 2.5, all Ps < .02). The between-group differences in these contrasts were largely attributable to ENHANCED responses to loss-avoidance in SZ patients, rather than reduced responses to gains or misses. Finally, we observed significant correlations between neural signals evoked by loss-avoidance in right VS and both Avolition (r = .427) and Anhedonia/Asociality (r = .456) subscores from the SANS. Conclusion: These results provide further evidence for intact RPE signaling in chronic, medicated SZ patients, suggesting that RPE-signaling may even be super-normal, in the case of loss-avoidance. The observation that instances of loss-avoidance evoke stronger frontostriatal responses in individuals with more severe negative symptoms suggests a mechanism by which motivational deficits may emerge from excessive avoidance-learning in SZ.
197. EFFECTIVE CONNECTIVITY DEFICITS IN SCHIZOPHRENIA DURING CEREBELLAR-MEDIATED SENSORIMOTOR SYNCHRONIZATION Alexandra Moussa-Tooks*, Dae-Jin Kim, Amanda Bolbecker, Lisa Bartolomeo, John Purcell, Nancy Lundin, Sharlene Newman, Brian O’Donnell, and William Hetrick Indiana University Background: Temporal processing and sensorimotor synchronization deficits are associated with schizophrenia spectrum disorders (SZ) and may contribute to higher order cognitive deficits (i.e. learning, memory, decision-making) characteristic of these disorders. The cerebellum is implicated in temporal processing and sensorimotor integration, and it projects to brain areas involved in cognition including parietal and frontal cortices. Therefore, behavioral and neural probes of cerebellar function can help assess contributions of the cerebellum, and its associated cortical and subcortical circuits, to cognitive processes involved in temporal processing and sensorimotor integration. It was expected that behavioral impairments in temporal processing be accompanied by a disruption in cerebellar contributions to this cerebellar-subcortical-cortical circuit in an SZ population. Methods: Using a cerebellar-dependent sensorimotor synchronization task that has previously revealed robust differences (Carroll et al., 2009; Bolbecker et al., 2014) between SZ and non-patient controls (HC), we explored differences in neural contributions to task performance in 41 HC and 30 SZ. Participants underwent 3 sessions of a 6-minute fMRI scan during a sensorimotor synchronization finger-tapping task that included tonepaced (synchronization) and self-paced (continuation) tapping at a 500 ms intertap interval (ITI).
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Concurrent Oral Presentations S103 Results: Behavioral data revealed impaired timing in SZ, represented by longer (t(47) = −2.06, P < .05) and more variable (t(47) = −3.04, P < .005) ITIs during the continuation phase in the SZ group. The SZ group also tapped with a greater force (t(43.73) = −3.46, P = .001) throughout the task. WingKristofferson analysis revealed more clock variance than motor variance (t(18) = 8.21, P < .001) in both groups during tapping. During continuation, primary motor (M1), cerebellum, thalamus, supplementary motor area (SMA), putamen, and inferior parietal cortex were activated (FWE P < .05). No group differences were found between SZ and HC with regards to wholebrain activation. In the SZ group compared to HC, we observed decreased effective connectivity during continuation between the cerebellum and M1 (χ2 = 7.26(1), P = .007), but not between cerebellum and thalamus or thalamus and M1. Cerebellar activation during continuation was correlated with Digit-Symbol performance (r = .49, P = .022) in the HC group only. Conclusion: Findings suggest that the cerebellum is heavily involved in the temporal component of sensorimotor continuation, particularly in the millisecond range. Moreover, findings point specifically to impairment in the cortico-cerebellar-thalamic-cortical circuit in schizophrenia, which may contribute to the observed behavioral impairments on this task.
198. IMPAIRED EMOTION REGULATION DURING WORKING MEMORY IN EARLY SCHIZOPHRENIA Synthia Guimond*,1, Shezal Padani2, Olivia Lutz1, Shaun Eack3, Heidi Thermenos1, and Matcheri Keshavan1 1 Harvard Medical School; 2Northeastern University; 3University of Pittsburgh; University of Pittsburgh School of Medicine Background: Patients with schizophrenia (SZ) exhibit deficits in emotion regulation that affect their daily functioning and long-term outcomes. The prefrontal cortex (PFC) plays an important role in emotion regulation. Previous findings are inconsistent and demonstrate either hypo- or hyperactivity in this region in SZ who were instructed to ignore emotional distractors during a working memory task. Methods: Because the PFC is implicated in both emotion regulation and working memory, a key unaddressed question is how emotion regulation deficits interact with different difficulty levels of a working memory task in SZ. To address this question, we examined how different emotional distractors (neutral, positive, and negative) impact performance on working memory tasks of varying difficulty (0-back and 2-back) and associated brain activity using fMRI. Participants were 20 patients with early course schizophrenia and 20 healthy controls matched on age, sex, and race. Results: SZ had a significant lower accuracy in the effortful working memory task only when emotional distractors were involved, but there was no significant difference between neutral distractors. Additionally, significant between-group differences in brain activity were observed in the left ventrolateral PFC. During the effortful working memory task, healthy controls significantly increased brain activity in this region when regulating fearful emotion. In contrast, SZ had increased left ventrolateral PFC activity during the effortful working memory task regardless of the distractor type. Conclusion: These findings indicate that SZ have more difficulty in successfully performing a working memory task when regulating emotion and fail to show the emotion-specific modulation of the left ventrolateral PFC that was seen in controls. These differences in brain activity could reflect how healthy controls and patients are using distinct emotion regulation strategies during an effortful cognitive task, and could explain previous conflicting results. Moreover, it suggests that improving strategies for efficient emotion regulation could be a critical target for cognitive treatments in schizophrenia. This research was funded by the National Institute of Mental Health (NIMH R01 MH09240).
199. DISRUPTED INTEGRATION IN EARLY PSYCHOSIS: A PRELIMINARY EXPLORATION OF THE RELATIONSHIP BETWEEN NEURAL SYNCHRONIZATION AND HIGHER ORDER COGNITION IN A FIRST-EPISODE PSYCHOSIS SAMPLE. Bethany Leonhardt*,1, Jennifer Vohs2, Paul Lysaker3, Lisa Bartolomeo2, Brian O’Donnell2, and Alan Breier2 1 Indiana University School of Medicine; 2Indiana University; 3 Roudebush VA Medical Center, Indiana University School of Medicine Background: Disruptions in the ability to integrate information into complex ideas needed to make sense of and recover from psychiatric challenges are considered a core source of dysfunction in schizophrenia spectrum disorders (SSD). These disruptions are believed to take place at the level of basic brain functioning through neural synchrony and neurocognitive functioning in which information is encountered, encoded and available for memory and at the level of higher order cognition in which ideas are formed and reflected upon. In this study, we sought to explore the link of difficulties in integration at the level of basic brain functioning with integration at the level of self-reflectivity and insight in first episode patients. The role of disrupted integration has particular importance in early phases of illness, as it may impact the likelihood that an individual is able to move toward recovery. As more work is done in early intervention in SSD, it is pivotal that underlying factors that impact ability to recover are investigated. Methods: To assess the ability to integrate information at the level of basic brain function we used electroencephalography (EEG) collected using an Auditory Steady State Response (ASSR) and the Brief Assessment of Cognition in Schizophrenia (BACS). To assess integration at the level of conscious reflection we used the Metacognition Assessment Scale Abbreviated and insight we used the Scale to Assess Awareness of Mental Disorders (SUMD). Participants were 14 adults with first episode psychosis. Results: Pearson correlations were calculated to assess the relationship of EEG power across a range of frequency bands and neurocognition with MAS-A total scores and SUMD insight score. These revealed that the MAS-A total score was significantly negatively correlated with gamma activity, and was positively correlated with BACS total score. SUMD insight was significantly positively correlated with gamma activity, and negatively correlated with BACS total, Verbal Memory, and Tower of London. Conclusion: Difficulties integrating and managing information at the level of basic brain functioning and neurocognition were associated with greater difficulties forming integrated ideas of oneself and others as well as difficulties recognizing psychiatric challenges. This data supports the conclusion that these impairments in integration influence one another such that disruptions in how information is encoded and stored limits person’s abilities to think about themselves and recognize psychiatric challenges.
200. NEUROINFLAMMATION IN INDIVIDUALS AT CLINICAL HIGH RISK FOR PSYCHOSIS: A PET STUDY WITH [(18)F]-FEPPA Sina Hafizi*, Tania Da Silva, Cory Gerritsen, Michael Kiang, R Michael Bagby, Ivana Prce, Alan Wilson, Sylvain Houle, Pablo Rusjan, and Romina Mizrahi Centre for Addiction and Mental Health Background: A growing body of literature suggesting a prominent role of neuroinflammation in schizophrenia. Positron emission tomography (PET) imaging using ligands that bind to mitochondrial translocator protein 18 kDa (TSPO) is a unique way to study microglia activity as an in-vivo
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