Browsing by Subject "Schizophrenia"
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Item 16.3 Are Visual Motion Perception and Detection of Animacy Critical to Higher-Order Social Cognitive Function in Schizophrenia?(Oxford University Press, 2019-04) Johannesen, Jason; Lysaker, Paul; James, Alison; Kenney, Joshua; Bell, Morris; Medicine, School of MedicineBackground The observation that individuals with schizophrenia tend to misinterpret subtle social cues is often attributed to deficit in Theory of Mind (ToM). While ToM is commonly assessed using videos portraying interaction between actors, recent work in vision science shows that stimuli with no innate animate features can also convey similar social information through motion alone. These simplified stimuli are advantageous for experimental purposes and may provide further insights into perceptual mechanisms supporting social cognitive function. The Social Attribution Task-Multiple Choice (SAT-MC), based on the classic Hieder and Simmel (1944) stimuli, tells a story using three geometric shapes moving about a centrally fixed figure, followed by questions about what the viewer observed. Although there are no explicit social cues, viewers typically detect actions suggestive of relationships between objects, their intentions, and emotions. This talk will present findings from three studies examining psychometric, functional, and neurophysiological aspects on SAT -MC performance in schizophrenia. Methods Study 1 examined psychometric properties of two forms of the SAT-MC in comparison to video-based social cognitive tests using human actors in 32 schizophrenia (SZ) and 30 substance use disorder (SUD) participants. Study 2 examined functional relationships of the SAT-MC and affect recognition (BLERT) performance across neurocognitive, metacognitive, ToM, and symptom domains in 72 adults with SZ. Study 3 is an in-progress investigation of neurophysiological mechanisms of social cognition using test versions adapted for EEG recording. Chronic SZ, clinical high-risk (CHR), and healthy age-matched community samples are being collected. Results SZ scored significantly lower than SUD on two versions of the SAT-MC, each classifying ~60% of SZ as impaired, compared with ~30% of SUD. The two SAT-MC forms demonstrated good test-retest and parallel form reliability, minimal practice effect, high internal consistency, similar patterns of correlation with social cognitive test performance, and compared favorably to social cognitive tests across psychometric features. When examining functional correlates of SAT -MC performance, impairment is found to co-occur with deficits in affect recognition in the majority of cases but relates uniquely to reductions in verbal memory and emotional intelligence measures. Finally, a preliminary analysis (n=8 SZ, n=2 CHR) of EEG collected during SAT-MC video presentation finds significant correlations (r=.66-.72) between occipito-parietal gamma desynchronization and task performance. Additional analyses find task-related EEG during SAT to be predictive of affect recognition (BLERT) and ToM (TASIT) performance, with correlates including alpha desynchronization in frontal, occipital, and temporal regions, and synchronization of temporal theta and occipital gamma (all r > .5). Conclusions SAT-MC performance is found to be reliable using different stimuli, related to affect recognition and ToM in three independent samples, and shows high diagnostic specificity in classifying SZ against a SUD sample. Functional correlates also involve encoding and emotional intelligence abilities tested outside the visual modality. Analysis of neural oscillatory activity related SAT-MC performance to visual and attention processes, as well as engagement of a broader social cognitive network applied to affect recognition and ToM tasks. Impairment in visual motion processing appears integral to schizophrenia pathophysiology and a critical factor influencing social cognitive abilities attributed to higher-order ToM ability.Item 39. Viruses and Schizophrenia: Implications for Pathophysiology and Treatment(Oxford University Press, 2018-04) Breier, Alan; Psychiatry, School of MedicineOverall Abstract: The viral hypothesis of schizophrenia posits that viral infections disrupts cortical circuits that give rise to schizophrenia psychopathology. Prenatal viral exposure during key neurodevelopmental periods, either through direct effects on fetal brain or exposure to excessive maternal cytokines and other chemokines, have been implicated. In addition, abnormal activation of dormant neuro-viruses have been linked to the pathophysiology of schizophrenia. Activation of dormant viruses has potentially important treatment implication for therapies, such as valacyclovir, that suppress viral activity. Among the viruses that have been mostly frequently associated with schizophrenia include herpes simplex virus type 1 (HSV1) and Epstein-Barr virus (EBV). The purpose of this symposium is to focus on the role of viruses in the pathophysiology of schizophrenia and results of antiviral treatment trials in this illness.Item A preliminary choroid plexus volumetric study in individuals with psychosis(Wiley, 2023) Senay, Olcay; Seethaler, Magdalena; Makris, Nikos; Yeterian, Edward; Rushmore, Jarrett; Cho, Kang Ik K.; Rizzoni, Elizabeth; Heller, Carina; Pasternak, Ofer; Szczepankiewicz, Filip; Westin, Carl-Frederik; Losak, Jan; Ustohal, Libor; Tomandl, Josef; Vojtisek, Lubomir; Kudlicka, Peter; Kikinis, Zora; Holt, Daphne; Lewandowski, Kathryn E.; Lizano, Paulo; Keshavan, Matcheri S.; Öngür, Dost; Kasparek, Tomas; Breier, Alan; Shenton, Martha E.; Seitz-Holland, Johanna; Kubicki, Marek; Psychiatry, School of MedicineThe choroid plexus (ChP) is part of the blood‐cerebrospinal fluid barrier, regulating brain homeostasis and the brain's response to peripheral events. Its upregulation and enlargement are considered essential in psychosis. However, the timing of the ChP enlargement has not been established. This study introduces a novel magnetic resonance imaging‐based segmentation method to examine ChP volumes in two cohorts of individuals with psychosis. The first sample consists of 41 individuals with early course psychosis (mean duration of illness = 1.78 years) and 30 healthy individuals. The second sample consists of 30 individuals with chronic psychosis (mean duration of illness = 7.96 years) and 34 healthy individuals. We utilized manual segmentation to measure ChP volumes. We applied ANCOVAs to compare normalized ChP volumes between groups and partial correlations to investigate the relationship between ChP, LV volumes, and clinical characteristics. Our segmentation demonstrated good reliability (.87). We further showed a significant ChP volume increase in early psychosis (left: p < .00010, right: p < .00010) and a significant positive correlation between higher ChP and higher LV volumes in chronic psychosis (left: r = .54, p = .0030, right: r = .68; p < .0010). Our study suggests that ChP enlargement may be a marker of acute response around disease onset. It might also play a modulatory role in the chronic enlargement of lateral ventricles, often reported in psychosis. Future longitudinal studies should investigate the dynamics of ChP enlargement as a promising marker for novel therapeutic strategies.Item Abstract thinking and its correlates with insight, metacognition and social cognition in the early and prolonged phases of schizophrenia(Office of the Vice Chancellor for Research, 2016-04-08) Thakkar, Rut; Vohs, JeniferSchizophrenia is a severe mental illness that affects approximately one percent of the population worldwide. Symptoms of the illness include abnormal perceptual experiences, social withdrawal and cognitive impairments, with the mechanisms underlying the illness still being ambiguous. Abstract thinking, a core deficit in schizophrenia, is characterized by adaptability, flexibility, and the use of concepts and generalizations. However, its changes along with the different phases of the illness are still obscure. The limited data available suggests that those in the earlier phases of schizophrenia tend to have a higher capacity for abstraction than those in the prolonged phases (Wang et. al, 2013). In addition to the differences across the illness phase, supplemental studies further suggest that abstract thinking could be related to clinical insight, or the awareness of one’s illness (Dickerson, et. al, 1997). Therefore, in this study we examined the differences in abstract thinking between two groups; patients with chronic schizophrenia and patients with early onset schizophrenia. Furthermore, we conducted exploratory analyses of abstraction with clinical insight, metacognition and social cognition, hypothesizing that patients with better abstract thinking would possess better insight and cognition. The results from the 70 patient study indicate that while abstract thinking did not differ across the phases of the illness, it was significantly correlated with insight, metacognition and social cognition. This relationship between abstract thinking and insight and cognition, elucidated by the theory that more fluid and liberal thought patterns would enable patients to contemplate their own illness and its symptoms, could be crucial in developing novel therapeutic approaches for treating psychosis and might lead to better outcomes.Item Acute Phencyclidine Alters Neural Oscillations Evoked by Tones in the Auditory Cortex of Rats(Karger, 2017) Martin, Ashley M. Schnakenberg; O'Donnell, Brian F.; Millward, James B.; Vohs, Jenifer L.; Leishman, Emma; Bolbecker, Amanda R.; Rass, Olga; Morzorati, Sandra L.; Psychiatry, School of MedicineBACKGROUND/AIMS: The onset response to a single tone as measured by electroencephalography (EEG) is diminished in power and synchrony in schizophrenia. Because neural synchrony, particularly at gamma frequencies (30-80 Hz), is hypothesized to be supported by the N-methyl-D-aspartate receptor (NMDAr) system, we tested whether phencyclidine (PCP), an NMDAr antagonist, produced similar deficits to tone stimuli in rats. METHODS: Experiment 1 tested the effect of a PCP dose (1.0, 2.5, and 4.5 mg/kg) on response to single tones on intracranial EEG recorded over the auditory cortex in rats. Experiment 2 evaluated the effect of PCP after acute administration of saline or PCP (5 mg/kg), after continuous subchronic administration of saline or PCP (5 mg/kg/day), and after a week of drug cessation. In both experiments, a time-frequency analysis quantified mean power (MP) and phase locking factor (PLF) between 1 and 80 Hz. Event-related potentials (ERPs) were also measured to tones, and EEG spectral power in the absence of auditory stimuli. RESULTS: Acute PCP increased PLF and MP between 10 and 30 Hz, while decreasing MP and PLF between approximately 50 and 70 Hz. Acute PCP produced a dose-dependent broad-band increase in EEG power that extended into gamma range frequencies. There were no consistent effects of subchronic administration on gamma range activity. Acute PCP increased ERP amplitudes for the P16 and N70 components. CONCLUSIONS: Findings suggest that acute PCP-induced NMDAr hypofunction has differential effects on neural power and synchrony which vary with dose, time course of administration and EEG frequency. EEG synchrony and power appear to be sensitive translational biomarkers for disrupted NMDAr function, which may contribute to the pathophysiology of schizophrenia and other neuropsychiatric disorders.Item Adjunctive yoga training for persons with schizophrenia: who benefits?(Cambridge University Press, 2021) Bhatia, Triptish; Gujral, Swathi; Sharma, Vikas; Kumari, Nupur; Wood, Joel; Wesesky, Maribeth A.; Jones, Jacquelynn; Davis, Louanne W.; Iyenger, Satish; Haas, Gretchen L.; Nimgaonkar, Vishwajit L.; Deshpande, Smita N.; Psychiatry, School of MedicineObjective: The aim of this study was to identify factors associated with acceptability and efficacy of yoga training (YT) for improving cognitive dysfunction in individuals with schizophrenia (SZ). Methods: We analysed data from two published clinical trials of YT for cognitive dysfunction among Indians with SZ: (1) a 21-day randomised controlled trial (RCT, N = 286), 3 and 6 months follow-up and (2) a 21-day open trial (n = 62). Multivariate analyses were conducted to examine the association of baseline characteristics (age, sex, socio-economic status, educational status, duration, and severity of illness) with improvement in cognition (i.e. attention and face memory) following YT. Factors associated with acceptability were identified by comparing baseline demographic variables between screened and enrolled participants as well as completers versus non-completers. Results: Enrolled participants were younger than screened persons who declined participation (t = 2.952, p = 0.003). No other characteristics were associated with study enrollment or completion. Regarding efficacy, schooling duration was nominally associated with greater and sustained cognitive improvement on a measure of facial memory. No other baseline characteristics were associated with efficacy of YT in the open trial, the RCT, or the combined samples (n = 148). Conclusions: YT is acceptable even among younger individuals with SZ. It also enhances specific cognitive functions, regardless of individual differences in selected psychosocial characteristics. Thus, yoga could be incorporated as adjunctive therapy for patients with SZ. Importantly, our results suggest cognitive dysfunction is remediable in persons with SZ across the age spectrum.Item Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection(American Society for Pharmacology & Experimental Therapeutics, 2008-09) LIEBERMAN, JEFFREY A.; BYMASTER, FRANK P.; MELTZER, HERBERT Y.; DEUTCH, ARIEL Y.; DUNCAN, GARY E.; MARX, CHRISTINE E.; APRILLE, JUNE R.; DWYER, DONARD S.; LI, XIN-MIN; MAHADIK, SAHEBARAO P.; DUMAN, RONALD S.; PORTER, JOSEPH H.; MODICA-NAPOLITANO, JOSEPHINE S.; NEWTON, SAMUEL S.; CSERNANSKY, JOHN G.; Department of Psychiatry, IU School of MedicineVarious lines of evidence indicate the presence of progressive pathophysiological processes occurring within the brains of patients with schizophrenia. By modulating chemical neurotransmission, antipsychotic drugs may influence a variety of functions regulating neuronal resilience and viability and have the potential for neuroprotection. This article reviews the current literature describing preclinical and clinical studies that evaluate the efficacy of antipsychotic drugs, their mechanism of action and the potential of first- and second-generation antipsychotic drugs to exert effects on cellular processes that may be neuroprotective in schizophrenia. The evidence to date suggests that although all antipsychotic drugs have the ability to reduce psychotic symptoms via D(2) receptor antagonism, some antipsychotics may differ in other pharmacological properties and their capacities to mitigate and possibly reverse cellular processes that may underlie the pathophysiology of schizophrenia.Item Apathy Is Associated With Ventral Striatum Volume in Schizophrenia Spectrum Disorder(American Psychiatric Association, 2016) Roth, Robert M.; Garlinghouse, Matthew A.; Flashman, Laura A.; Koven, Nancy S.; Pendergrass, J. Cara; Ford, James C.; McAllister, Thomas W.; Saykin, Andrew J.; Psychiatry, School of MedicineApathy is prevalent in schizophrenia, but its etiology has received little investigation. The ventral striatum (VS), a key brain region involved in motivated behavior, has been implicated in studies of apathy. We therefore evaluated whether apathy is associated with volume of the VS on MRI in 23 patients with schizophrenia using voxel-based morphometry. Results indicated that greater self-reported apathy severity was associated with smaller volume of the right VS even when controlling for age, gender, depression, and total gray matter volume. The finding suggests that apathy is related to abnormality of brain circuitry subserving motivated behavior in patients with schizophrenia.Item Application of machine learning to predict reduction in total PANSS score and enrich enrollment in schizophrenia clinical trials(Wiley, 2021-09) Podichetty, Jagdeep T.; Silvola, Rebecca M.; Rodriguez-Romero, Violeta; Bergstrom, Richard F.; Vakilynejad, Majid; Bies, Robert R.; Stratford, Robert E., Jr.; Medicine, School of MedicineClinical trial efficiency, defined as facilitating patient enrollment, and reducing the time to reach safety and efficacy decision points, is a critical driving factor for making improvements in therapeutic development. The present work evaluated a machine learning (ML) approach to improve phase II or proof-of-concept trials designed to address unmet medical needs in treating schizophrenia. Diagnostic data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial were used to develop a binary classification ML model predicting individual patient response as either "improvement," defined as greater than 20% reduction in total Positive and Negative Syndrome Scale (PANSS) score, or "no improvement," defined as an inadequate treatment response (<20% reduction in total PANSS). A random forest algorithm performed best relative to other tree-based approaches in model ability to classify patients after 6 months of treatment. Although model ability to identify true positives, a measure of model sensitivity, was poor (<0.2), its specificity, true negative rate, was high (0.948). A second model, adapted from the first, was subsequently applied as a proof-of-concept for the ML approach to supplement trial enrollment by identifying patients not expected to improve based on their baseline diagnostic scores. In three virtual trials applying this screening approach, the percentage of patients predicted to improve ranged from 46% to 48%, consistently approximately double the CATIE response rate of 22%. These results show the promising application of ML to improve clinical trial efficiency and, as such, ML models merit further consideration and development.Item Are Selective Estrogen Receptor Beta Agonists Potential Therapeutics for Schizophrenia?(Oxford University Press, 2020-05-18) Breier, Alan; Liffick, Emily; Hummer, Tom; Vohs, Jennifer; Mehdiyoun, Nicole; Yang, Ziyi; Saykin, Andrew J.; McDonald, Brenna; Francis, Michael; Medicine, School of MedicineBackground Estrogen therapies, such as estradiol, have shown promise as therapeutics for schizophrenia; however, safety and tolerability concerns, including feminization effects in men and cancer and stroke risk in pre-menopausal women, may limit their broader use. Estradiol binds to both the estrogen alpha (ERA) and beta (ERB) receptors. ERB receptors appear not to mediate many of the concerning side effects of estrogen therapies. In addition, beta receptors have unique localization in cortical regions (i.e., hippocampus), and improve social behaviors and cognition in some animal models, which has led to interests in these compounds for testing in schizophrenia. To our knowledge, there have been no previous clinical trials of selective ERB agonists in schizophrenia. LY500307 is a highly selective agent for beta receptors without effects on estrogen alpha receptors when doses are constrained. Doses that are too high may engage alpha receptors but the alpha engaging threshold dose has not been fully determined in patient groups. The purpose of this dose-response study was to determine: ERB selectivity doses of LY500307 (i.e., without engaging alpha receptors); safety and tolerability; brain target engagement; and effects on cognition and symptoms. Methods A two-staged, double-blind, 8-week, adjunctive to APDs, adaptive phase 1b/2a trial design was conducted in men with schizophrenia (women were not included because of the lack of toxicology, safety, phase 1 and clinical data supporting use in this population). Three LY500307 doses and placebo were evaluated: 25 mg/day, 75 mg/day, and 150 mg/day. The primary markers for estrogen beta receptor selectivity was lack of effects on total testosterone levels (TT) and no feminization signs. Target engagement was assessed with an N-back working memory fMRI task and the electrophysiology measure mismatch negativity (MMN). Cognitive effects were assessed by the MCCB Composite score. Negative and total symptoms were assessed by the NSA-16 and PANSS, respectively. The primary analyses included all subjects and compared the slope from the three LY500307 dosing arms to the placebo slope in order to evaluate the dose responses. The linear mixed model with random intercept was employed and secondary analyses assessed differences between mean changes of the two higher dose arms combined (75 mg and 150 mg) versus placebo. Results Ninety-four patients were randomized across the placebo and three LY500307 dosing arms. There were no effects on plasma TT levels and no evidence of feminization, suggesting all doses were selective for the beta receptor. No significant adverse events were observed. There were no significant differences between the slopes of the three drug doses versus placebo on the brain target engagement variables (fMRI/N-back: F=0.24, p=0.868; MMN (Duration): F=1.08, p=0.358; MMN (Frequency): F=0.89, p=0.446) or on the cognitive/symptom measures (MCCB composite: F=0.87, p=0.458; NSA-16: F=1.79, p=0.148; and PANSS Total: F=0.69, p=0.558.) Secondary analyses also failed to show any significant effects of LY500307 versus placebo on any of the study variables. Discussion Conclusions: This study indicates that the ERB agonist LY500307 was selective, safe, and well tolerated in patients with schizophrenia. This selective ERB agonist, however, failed to demonstrate any significant effects on brain targets, cognition, negative and total symptoms. Potential issues related to dosing and characteristics of the patient population will be discussed. These data suggest that estrogen alpha receptor activation may be necessary to yield positive results in this patient population. Future studies are needed to confirm these findings.