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Background. Theory of Mind (ToM) refers to the ability to infer another person's mental state based upon interactional information. ToM deficits have been suggested to underlie crucial aspects of social interaction failure in disorders such as autism and schizophrenia, although the development of paradigms for demonstrating such deficits remains an ongoing area of research. Recent studies have explored the use of sarcasm perception, in which subjects must infer an individual's sincerity or lack thereof, as a 'real-life' index of ToM ability, and as an index of functioning of specific right hemispheric structures. Sarcastic detection ability has not previously been studied in schizophrenia, although patients have been shown to have deficits in ability to decode emotional information from speech ('affective prosody').Method. Twenty-two schizophrenia patients and 17 control subjects were tested on their ability to detect sarcasm from spoken speech as well as measures of affective prosody and basic pitch perception.Results. Despite normal overall intelligence, patients performed substantially worse than controls in ability to detect sarcasm (d=2.2), showing both decreased sensitivity (A') in detection of sincerity versus sarcasm and an increased bias (B'') toward sincerity. Correlations across groups revealed significant relationships between impairments in sarcasm recognition, affective prosody and basic pitch perception.Conclusions. These findings demonstrate substantial deficits in ability to infer an internal subjective state based upon vocal modulation among subjects with schizophrenia. Deficits were related to, but were significantly more severe than, more general forms of prosodic and sensorial misperception, and are consistent with both right hemispheric and 'bottom-up' theories of the disorder. [ABSTRACT FROM AUTHOR]

Purpose of review: Current treatments for schizophrenia target the dopamine system. Developments of new treatments that target the glutamate system, however, are under progress, in particular, for the N-methyl-D-aspartate-type glutamate receptor. Compared with dopaminergic treatments, these treatments may show improved efficacy in the treatment of persistent negative symptoms.Recent findings: During the past year, clinical trials have been published with several agonists at the glycine site of the N-methyl-D-aspartate receptor, including glycine, D-serine, D-alanine and with the glycine transport inhibitor, sarcosine. Studies published during the past year indicate highly significant beneficial effects on negative symptoms when these compounds are added to both conventional and newer atypical antipsychotics in efficacy models although an effectiveness trial of current formulations of glycine and D-cycloserine failed to show an overall benefit. Relevant issues across studies may include the compound chosen, its formulation and tolerability, populations studied, and the nature and dose of the base antipsychotic treatment.Summary: The present findings continue to support the use of N-methyl-D-aspartate/glycine site agonists as potential new treatments for persistent negative symptoms of schizophrenia. Ongoing work with novel compounds and new formulations may assist in the translation of these advances into clinic-ready pharmacotherapies. [ABSTRACT FROM AUTHOR]

Patients with schizophrenia show deficits in several neurocognitive domains. However, the relationship between white matter integrity and performance in these domains is poorly understood. The authors conducted neurocognitive testing and diffusion tensor imaging in 25 patients with schizophrenia. Performance was examined for tests of verbal declarative memory, attention, and executive function. Relationships between fractional anisotropy and cognitive performance were examined by using voxelwise correlational analyses. In each case, better performance on these tasks was associated with higher levels of fractional anisotropy in task-relevant regions. [ABSTRACT FROM AUTHOR]

BACKGROUND: Approved therapeutic uses for gamma-hydroxybutyric acid (GHB) (or sodium oxybate), a gamma-aminobutyric acid type B and GHB receptor agonist, include narcolepsy in the United States and Europe and alcohol abuse treatment in Italy. Possible efficacy of GHB in schizophrenia has also been proposed. A tolerability concern regarding use of GHB is its abuse potential. Given the high comorbidity of substance disorders and schizophrenia, a systematic assessment of the published literature is crucial. OBJECTIVE: The aim of this review was to assess the tolerability and abuse liability of GHB in the context of future clinical studies as a potential treatment for insomnia in patients with schizophrenia. Methods: A literature search in English (inception through April 2009, inclusive) was conducted of MEDLINE, EMBASE, and PsycINFO using the search term GHB. All articles whose abstracts mentioned human use of GHB were read in their entirety. The reference sections of identified articles were reviewed for publications that might have been missed by the initial search. RESULTS: GHB is abused by a small percentage of people (<1%) as a 'club drug' and is commonly associated with enhanced sexual experiences (65%), euphoria (41%), somnolence (71%), and confusion (24%), according to a recent study. A review of all available emergency room case series suggests that while GHB can be associated with serious coma necessitating intubation, the number of reported fatal cases associated with GHB appears limited. Clarity on the lethality of GHB is complicated by instability of GHB in postmortem samples and frequent concomitant ingestions. Furthermore, formal abuse liability studies do not support high abuse propensity for GHB, mainly because oversedation and dizziness may lead most individuals to find GHB unpleasant at high doses. As supported by 2 large studies, there is limited evidence to suggest widespread use as an agent in sexual assault. Years of clinical use in narcolepsy do not support the development of tolerance or withdrawal in those subjects without substance dependence. CONCLUSIONS: Tolerability and abuse liability issues, while a concern with GHB given its abuse potential, do not preclude further study of the potential use for insomnia in nondually diagnosed schizophrenia. Full cognizance must be taken of risk/benefit tradeoffs, and to the development of improved formulations with decreased abuse liability. [ABSTRACT FROM AUTHOR]

Reading fluency deficits in schizophrenia (Sz) have been attributed to dysfunction in both lower-level, oculomotor processing and higher-level, lexical processing, according to the two-hit deficit model. Given that prior work examining reading deficits in individuals with Sz has primarily focused on single-line and single-word reading tasks, eye movements that are unique to passage reading, such as return-sweep saccades, have not yet been examined in Sz. Return-sweep saccades are large eye movements that are made when readers move from the end of one line to the beginning of the next line during natural passage reading. Examining return-sweeps provides an opportunity to examine lower-level, oculomotor deficits during reading under circumstances when upcoming higher-level, lexical information is not available for visual processing because visual acuity constraints do not permit detailed lexical processing of line-initial words when return-sweeps are programmed. To examine the source of reading deficits in Sz, we analysed an existing data set in which participants read multi-line passages with manipulations to line spacing. Readers with Sz made significantly more return-sweep targeting errors followed by corrective saccades compared with healthy controls. Both groups showed similar effects of line spacing on return-sweep targeting accuracy, suggesting similar sensitivities to visual crowding during reading. Furthermore, the patterns of fixation durations in readers with Sz corroborate prior work indicating reduced parafoveal processing of upcoming words. Together, these findings suggest that lower-level visual and oculomotor dysfunction contribute to reading deficits in Sz, providing support for the two-hit deficit model., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Impaired motion perception in schizophrenia has been associated with deficits in social-cognitive processes and with reduced activation of visual sensory regions, including the middle temporal area (MT+) and posterior superior temporal sulcus (pSTS). These findings are consistent with the recent proposal of the existence of a specific 'third visual pathway' specialized for social perception in which motion is a fundamental component. The third visual pathway transmits visual information from early sensory visual processing areas to the STS, with MT+ acting as a critical intermediary. We used functional magnetic resonance imaging to investigate functioning of this pathway during processing of naturalistic videos with explicit (real) motion and static images with implied motion cues. These measures were related to face emotion recognition and motion-perception, as measured behaviorally. Participants were 28 individuals with schizophrenia (Sz) and 20 neurotypical controls. Compared to controls, individuals with Sz showed reduced activation of third visual pathway regions (MT+, pSTS) in response to both real- and implied-motion stimuli. Dysfunction of early visual cortex and pulvinar were also associated with aberrant real-motion processing. Implied-motion stimuli additionally engaged a wide network of brain areas including parietal, motor and frontal nodes of the human mirror neuron system. The findings support concepts of MT+ as a mediator between visual sensory areas and higher-order brain and argue for greater focus on MT+ contributions to social-cognitive processing, in addition to its well-documented role in visual motion processing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Motor learning is a fundamental skill to our daily lives. Dysfunction in motor performance in schizophrenia (Sz) has been associated with poor social and functional outcomes. Transcranial direct current stimulation (tDCS), a non-invasive electrical brain stimulation approach, can influence underlying brain function with potential for improving motor learning in Sz. We used a well-established Serial Reaction Time Task (SRTT) to study motor learning, in combination with simultaneous tDCS and EEG recording, to investigate mechanisms of motor and procedural learning deficits in Sz, and to develop refined non-invasive brain stimulation approaches to improve neurocognitive dysfunction. We recruited 27 individuals with Sz and 21 healthy controls (HC). Individuals performed the SRTT task as they received sham and active tDCS with simultaneous EEG recording. Reaction time (RT), neuropsychological, and measures of global functioning were assessed. SRTT performance was significantly impaired in Sz and showed significant correlations with motor-related and working memory measures as well as global function. Source-space time-frequency decomposition of EEG showed beta-band coherence across supplementary-motor, primary-motor and visual cortex forming a network involved in SRTT performance. Motor-cathodal and visual-cathodal stimulations resulted in significant modulation in coherence particularly across the motor-visual nodes of the network accompanied by significant improvement in motor learning in both controls and patients. Here, we confirm earlier reports of SRTT impairment in Sz and demonstrate significant reversal of the deficits with tDCS. The findings support continued development of tDCS for enhancement of plasticity-based interventions in Sz, as well as source-space EEG analytic approaches for evaluating underlying neural mechanisms., (© 2023. The Author(s).)

Background: We tested the hypothesis that, after initial improvement with intravenous ketamine in patients with bipolar disorder (BD) with severe depression and acute suicidal thinking or behavior, a fixed-dose combination of oral D-cycloserine (DCS) and lurasidone (NRX-101) can maintain improvement more effectively than lurasidone alone., Methods: This was a multi-center, double-blind, twostage, parallel randomized trial. Adult BD patients with depression and suicidal ideation or behavior were infused with ketamine or saline (Stage 1); those who improved were randomized to a fixed-dose combination of DCS and lurasidone vs. lurasidone alone (Stage 2) to maintain the improvement achieved in Stage 1. Depression was measured by the Montgomery Åsberg Depression Rating Scale (MADRS), and suicidal thinking and behavior was measured by the Columbia Suicide Severity Rating Scale (C-SSRS); global improvement was measured by the clinical global severity scale (CGI-S)., Clinicaltrials: gov NCT02974010; Registered: November 22, 2016., Results: Thirty-seven patients were screened and 22 were enrolled, randomized, and treated. All 22 patients treated in Stage 1 (17 with ketamine and 5 with saline) were enrolled into Stage 2, and 11 completed the study. The fixed-dose combination of DCS and lurasidone was significantly more effective than lurasidone alone in maintaining improvement in depression (MADRS LMS Δ-7.7; p = 0.03) and reducing suicidal ideation, as measured by C-SSRS (Δ-1.5; p = 0.02) and by CGI-SS (Δ-2.9; p = 0.03), and with a non-statistically significant decrease in depressive relapse (0% vs. 40%; p = 0.07). This sequential treatment regimen did not cause any significant safety events and demonstrated improvements in patient-reported side effects., Conclusions: Sequential treatment of a single infusion of ketamine followed by NRX-101 maintenance is a promising therapeutic approach for reducing depression and suicidal ideation in patients with bipolar depression who require hospitalization due to acute suicidal ideation and behavior. On the basis of these findings, Breakthrough Therapy Designation was awarded, and a Special Protocol Agreement was granted by the FDA for a registrational trial., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Early auditory processing (EAP) deficits are prevalent in schizophrenia and linked to disturbances in higher order cognition and daily functioning. Treatments that target EAP have the potential to drive downstream cognitive and functional improvements, but clinically feasible means to detect EAP impairment are lacking. This report describes the clinical feasibility and utility of using the Tone Matching (TM) Test to assess EAP in adults with schizophrenia. Clinicians were trained to administer the TM Test as part of a baseline cognitive battery to inform choice of cognitive remediation (CR) exercises. Only if the TM Test indicated EAP impairment, were the recommended CR exercises to include EAP training. Results indicated clinicians included the TM Test in all baseline assessments and identified 51.72% as EAP impaired. There were significant positive relationships between TM Test performance and cognitive summary scores, confirming instrumental validity. All clinicians found the TM Test useful for CR treatment planning. CR participants with impaired EAP spent significantly more training time on EAP exercises compared to CR participants with intact EAP (20.11% vs 3.32%). This study found that it is feasible to use the TM Test in community clinics and the test was perceived as clinically useful for personalizing treatment., Competing Interests: Declaration of Competing Interest DCJ holds equity in Glytech, AASI and NRX pharma. He has served as a consultant for SK Life Sciences, Biogen, Boehringer Ingelheim, Autifony and Anavex. He has received research support from Cerevance. He holds intellectual property for use of NMDAR agonists in treatment of schizophrenia; NMDAR antagonists for treatment of depression; neurophysiological measures for detection of amyloid deposition; and parcel-guided approaches to brain stimulation. AM serves as a consultant at Boehringer Ingelheim and Sumitomo and receives royalties from Oxford University Press. Other authors report no potential COI., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Schizophrenia is a major mental disorder that affects approximately 1% of the population worldwide. Cognitive deficits are a key feature of the disorder and a primary cause of long-term disability. Over the past decades, significant literature has accumulated demonstrating impairments in early auditory perceptual processes in schizophrenia. In this review, we first describe early auditory dysfunction in schizophrenia from both a behavioral and neurophysiological perspective and examine their interrelationship with both higher order cognitive constructs and social cognitive processes. Then, we provide insights into underlying pathological processes, especially in relationship to glutamatergic and N-methyl-D-aspartate receptor (NMDAR) dysfunction models. Finally, we discuss the utility of early auditory measures as both treatment targets for precision intervention and as translational biomarkers for etiological investigation. Altogether, this review points out the crucial role of early auditory deficits in the pathophysiology of schizophrenia, in addition to major implications for early intervention and auditory-targeted approaches., Competing Interests: Conflicts of interest statement DCJ holds equity in Glytech, AASI and NRX pharma. He has served as a consultant for SK Life Sciences, Biogen, Boehringer Ingelheim, Autifony and Anavex. He has received research support from Cerevance. He holds intellectual property for use of NMDAR agonists in treatment of schizophrenia; NMDAR antagonists for treatment of depression; neurophysiological measures for detection of amyloid deposition; and parcel-guided approaches to brain stimulation. JTK reports having received consulting payments within the last 24 months from Alphasights, Medscape, Putnam, techspert.io, Health Monitor, Third Bridge, MEDACorp, Trinity, Globaldata, GKA, Clearview, Clarivate, Health Advances, ECRI Institute, ExpertConnect, Acsel Health, Slingshot, Antheum, Guidepoint, L.E.K., SmartAnalyst, First Thought, Wedbush, Jefferies, Otsuka, Vox Neuro and Reckner. He has served on the MedinCell Psychiatry, Tolmar, Merck, Leal and the Karuna Advisory Boards. He has conducted clinical research supported by the NIMH, Sunovion, Roche, Cerevance, Click, Neurocrine, Corcept, Taisho and Boehringer Ingelheim within the last 24 months. He owns a small number of shares of common stock from GSK. AM serves as a consultant at Boehringer Ingelheim and Sumitomo and receives royalties from Oxford University Press. Other authors report no potential COI., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline., Methods: 81 HV and 80 SZ were tested at one of four study sites. Subjects were administered two ERP/EEG testing sessions on separate visits. Sessions included a mismatch negativity paradigm, a 40 Hz auditory steady-state response paradigm, an eyes-closed resting state EEG, and an active auditory oddball paradigm. SZ subjects were also tested on the Brief Assessment of Cognition (BAC), Positive and Negative Syndrome Scale (PANSS), and Virtual Reality Functional Capacity Assessment Tool (VRFCAT)., Results: Standardized ERP/EEG instrumentation and methods ensured few test failures. The automated data analysis pipeline allowed for near real-time analysis with no human intervention. Test-retest reliability was fair-to-excellent for most of the outcome measures. SZ subjects showed significant deficits in ERP and QEEG measures consistent with published academic literature. A subset of ERP and QEEG measures correlated with functional assessments administered to the SZ subjects., Conclusions: With standardized instrumentation and methods, complex ERP/EEG testing sessions can be reliably performed at clinical and commercial trial sites to produce high-quality data in near real-time., Competing Interests: Declaration of competing interest M. Cecchi is an employee of Cognision. M. Adachi and S. Honda are employees of Astellas Pharma. A. Basile. M.J. Marino, and J.M. Uslaner are employees of Merck & Co. D.L. Buhl is an employee and shareholder of Takeda Pharmaceuticals. H. Chadchankar and M. Rotte are employees of Novartis. S. Christensen is an employee of Lundbeck. E. Christian is an employee of Gilgamesh Pharmaceuticals. J. Doherty and B. Farley are employees and shareholders of Sage Therapeutics. K.C. Fadem is an employee and shareholder of Cognision. M.S. Forman is an employee of Passage Bio. J. Johannesen, P. O'Donnell, and M.C. Quirk are employees of Sage Therapeutics. B.J. Kinon is an employee of Cyclerion Therapeutics. D. Klamer and C. Missling are employees and shareholders of Anavex Life Sciences Corp. T. Piser is an employee of Onsero Therapeutics; T. Piser has financial interest in the development of NMDA receptor modulators owned by Novartis Pharmaceuticals, and is an inventor on issued patents on some of these compounds. C.B. Puryear is an employee of Praxis Precision Medicines. C. Sanchez and D.G. Smith are employees and shareholders of Alkermes. D.C. Javitt has received consulting payments within the last 2 years from Autifony, Biogen, SK Life Sciences, Boehringer Ingelheim, and Biogen; he holds intellectual property rights for use of NMDA modulators in treatment of neuropsychiatric disorders, for parcel-guided TMS treatment of depression, and for EEG-based diagnosis of neuropsychiatric disorders; he also holds equity in Glytech, AASI, and NeuroRx. R.S.E. Keefe is the owner of VeraSci, a for-profit company that supports clinical trials for over 100 business entities, mostly pharmaceutical companies; VeraSci provided paid support for this study. D.P. Walling has received grant funding from Novartis, Janssen, Intracellular, Lyndra, Rovi, Otsuka, Alkermes, Cerevel, Abbvie, Allergan, Noven, Takeda, Indivior, Avanir, Lundbeck, Roche, Boehringer Ingelheim, Biogen, Sunovion and Acadia; he has served on Advisory Boards for Otsuka, Janssen, Biogen, Boehringer Ingelheim and Lyndra. L. Ereshefsky receives support from CenExel, which conducts research for most pharma, and is a performing site for NIH and Alzheimer's Foundation. Moreover, Follow the Molecule LLC receives consulting compensation from Bioxcel, Blackthorn, Neurocrine, Athira, Ceravance, Digestome, Immune Brain Check, Gilgamesh, and Karuna Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Amyloid deposition is a primary predictor of Alzheimer's disease (AD) and related neurodegenerative disorders. Retinal changes involving the structure and function of the ganglion cell layer are increasingly documented in both established and prodromal AD. Visual event-related potentials (vERP) are sensitive to dysfunction in the magno- and parvocellular visual systems, which originate within the retinal ganglion cell layer. The present study evaluates vERP as a function of amyloid deposition in aging, and in mild cognitive impairment (MCI)., Methods: vERP to stimulus-onset, motion-onset, and alpha-frequency steady-state (ssVEP) stimuli were obtained from 16 amyloid-positive and 41 amyloid-negative healthy elders and 15 MCI individuals and analyzed using time-frequency approaches. Social cognition was assessed in a subset of individuals using The Awareness of Social Inference Test (TASIT)., Results: Neurocognitively intact but amyloid-positive participants and MCI individuals showed significant deficits in stimulus-onset (theta) and motion-onset (delta) vERP generation relative to amyloid-negative participants (all p < .01). Across healthy elders, a composite index of these measures correlated highly (r =  - .52, p < .001) with amyloid standardized uptake value ratios (SUVR) and TASIT performance. A composite index composed of vERP measures significant differentiated amyloid-positive and amyloid-negative groups with an overall classification accuracy of > 70%., Discussion: vERP may assist in the early detection of amyloid deposition among older individuals without observable neurocognitive impairments and in linking previously documented retinal deficits in both prodromal AD and MCI to behavioral impairments in social cognition., (© 2023. The Author(s).)

Cognitive impairment is a core feature of schizophrenia and a major contributor to poor functional outcomes. Methods for assessment of cognitive dysfunction in schizophrenia are now well established. In addition, there has been increasing appreciation in recent years of the additional role of social cognitive impairment in driving functional outcomes and of the contributions of sensory-level dysfunction to higher-order impairments. At the neurochemical level, acute administration of N -methyl-d-aspartate receptor (NMDAR) antagonists reproduces the pattern of neurocognitive dysfunction associated with schizophrenia, encouraging the development of treatments targeted at both NMDAR and its interactome. At the local-circuit level, an auditory neurophysiological measure, mismatch negativity, has emerged both as a veridical index of NMDAR dysfunction and excitatory/inhibitory imbalance in schizophrenia and as a critical biomarker for early-stage translational drug development. Although no compounds have yet been approved for treatment of cognitive impairment associated with schizophrenia, several candidates are showing promise in early-phase testing.

The extent and nature of cognitive impairment in brief psychotic disorder remains unclear, being rarely studied unlike schizophrenia. The present study hence sought to directly compare the visual cognitive dysfunction and its associated brain networks in brief psychotic disorder and schizophrenia. Data from picture completion (a complex visual task) and whole-brain functional connectome from resting-state fMRI were acquired from a sample of clinically stable patients with an established psychotic disorder (twenty with brief psychotic disorder, twenty with schizophrenia) and twenty-nine healthy controls. Group differences and the inter-relationships in task performances and brain networks were tested. Picture completion task deficits were found in brief psychotic disorder compared with healthy controls, though the deficits were less than schizophrenia. Task performance also correlated with severity of psychotic symptoms in patients. The task performance was inversely correlated with the functional connectivity between peripheral visual and attentional networks (dorsal attention and salience ventral attention), with increased functional connectivity in brief psychotic disorder compared with healthy controls and in schizophrenia compared with brief psychotic disorder. Present findings showed pronounced visual cognitive impairments in brief psychotic disorder that were worse in schizophrenia, underpinned by abnormal interactions between higher-order attentional and lower-order visual processing networks., Competing Interests: Declaration of Competing Interest All authors report no financial conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Hypothesis: Impaired insight into the illness and its consequences is associated with poor outcomes in schizophrenia. While transcranial direct current stimulation (tDCS) may represent a potentially effective treatment strategy to relieve various symptoms of schizophrenia, its impact on insight remains unclear. To investigate whether tDCS would modulate insight in patients with schizophrenia, we undertook a meta-analysis based on results from previous RCTs that investigated the clinical efficacy of tDCS. We hypothesize that repeated sessions of tDCS will be associated with insight improvement among patients., Study Design: PubMed and ScienceDirect databases were systematically searched to identify RCTs that delivered at least 10 tDCS sessions in patients with schizophrenia. The primary outcome was the change in insight score, assessed by the Positive and Negative Syndrome Scale (PANSS) item G12 following active tDCS sessions as opposed to sham stimulation. Effect sizes were calculated for all studies and pooled using a random-effects model. Meta-regression and subgroup analyses were conducted., Study Results: Thirteen studies (587 patients with schizophrenia) were included. A significant pooled effect size (g) of -0.46 (95% CI [-0.78; -0.14]) in favor of active tDCS was observed. Age and G12 score at baseline were identified as significant moderators, while change in total PANSS score was not significant., Conclusions: Ten sessions of active tDCS with either frontotemporoparietal or bifrontal montage may improve insight into the illness in patients with schizophrenia. The effect of this treatment could contribute to the beneficial outcomes observed in patients following stimulation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Deficits in glutamatergic function are well established in schizophrenia (SZ) as reflected in "input" dysfunction across sensory systems. By contrast, less is known about contributions of the GABAergic system to impairments in excitatory/inhibitory balance. We investigated this issue by measuring contrast thresholds for orientation detection, orientation discriminability, and orientation-tilt-aftereffect curves in schizophrenia subjects and matched controls. These measures depend on the amplitude and width of underlying orientation tuning curves, which, in turn, depend on excitatory and inhibitory interactions. By simulating a well-established V1 orientation selectivity model and its link to perception, we demonstrate that reduced cortical excitation and inhibition are both necessary to explain our psychophysical data. Reductions in GABAergic feedback may represent a compensatory response to impaired glutamatergic input in SZ, or a separate pathophysiological event. We also found evidence for the widely accepted, but rarely tested, inverse relationship between orientation discriminability and tuning width., Competing Interests: Declaration of competing interest DCJ: Intellectual property for NMDAR agonists in schizophrenia, NMDAR antagonist in depression, fMRI for prediction of ECT response and ERP biomarkers for aging and schizophrenia. Equity in Glytech, AASI and NeuroRx. Scientific advisory board NeuroRx. Consultant payments Autifony, SK Life Sciences, Biogen, Cadence, and Pfizer. Other authors report no conflicts., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Efficient processing of complex and dynamic social scenes relies on intact connectivity of many underlying cortical areas and networks, but how connectivity anomalies affect the neural substrates of social perception remains unknown. Here we measured these relationships using functionally based localization of social perception areas, resting-state functional connectivity, and movie-watching data., Methods: In 42 participants with schizophrenia (SzPs) and 41 healthy control subjects, we measured the functional connectivity of areas localized by face-emotion processing, theory-of-mind (ToM), and attention tasks. We quantified the weighted shortest path length between visual and medial prefrontal ToM areas in both populations to assess the impact of these changes in functional connectivity on network structure. We then correlated connectivity along the shortest path in each group with movie-evoked activity in a key node of the ToM network (posterior temporoparietal junction [TPJp])., Results: SzPs had pronounced decreases in connectivity in TPJ/posterior superior temporal sulcus (TPJ-pSTS) areas involved in face-emotion processing ( t 81  = 4.4, p  = .00002). In healthy control subjects, the shortest path connecting visual and medial prefrontal ToM areas passed through TPJ-pSTS, whereas in SzPs, the shortest path passed through the prefrontal cortex. While movie-evoked TPJp activity correlated with connectivity along the TPJ-pSTS pathway in both groups ( r  = 0.43, p  = .002), it additionally correlated with connectivity along the prefrontal cortex pathway only in SzPs ( r SzP  = 0.56, p  = .003)., Conclusions: These results suggest that connectivity along the human-unique TPJ-pSTS pathway affects both the network architecture and functioning of areas involved in processing complex dynamic social scenes. These results demonstrate how focal connectivity anomalies can have widespread impacts across the cortex., (© 2022 The Authors.)

One important aspect for managing social interactions is the ability to perceive and respond to facial expressions rapidly and accurately. This ability is highly dependent upon intact processing within both cortical and subcortical components of the early visual pathways. Social cognitive deficits, including face emotion recognition (FER) deficits, are characteristic of several neuropsychiatric disorders including schizophrenia (Sz) and autism spectrum disorders (ASD). Here, we investigated potential visual sensory contributions to FER deficits in Sz ( n = 28, 8/20 female/male; age 21-54 years) and adult ASD ( n = 20, 4/16 female/male; age 19-43 years) participants compared to neurotypical ( n = 30, 8/22 female/male; age 19-54 years) controls using task-based fMRI during an implicit static/dynamic FER task. Compared to neurotypical controls, both Sz ( d = 1.97) and ASD ( d = 1.13) participants had significantly lower FER scores which interrelated with diminished activation of the superior temporal sulcus (STS). In Sz, STS deficits were predicted by reduced activation of early visual regions ( d = 0.85, p = 0.002) and of the pulvinar nucleus of the thalamus ( d = 0.44, p = 0.042), along with impaired cortico-pulvinar interaction. By contrast, ASD participants showed patterns of increased early visual cortical ( d = 1.03, p = 0.001) and pulvinar ( d = 0.71, p = 0.015) activation. Large effect-size structural and histological abnormalities of pulvinar have previously been documented in Sz. Moreover, we have recently demonstrated impaired pulvinar activation to simple visual stimuli in Sz. Here, we provide the first demonstration of a disease-specific contribution of impaired pulvinar activation to social cognitive impairment in Sz., Competing Interests: DCJ holds equity in Glytech, AASI, and NeuroRx; is part of the scientific advisory board for NRx pharma; and received consultant payments from Concert, Lundbeck, Phytec, Autifony, SK Life Sciences, Biogen, Cadence, Boehringer-Ingelheim, and Pfizer; DCJ has also received research support from Cerevance unrelated to this project., (Copyright © 2022 Martínez, Tobe, Gaspar, Malinsky, Dias, Sehatpour, Lakatos, Patel, Bermudez, Silipo and Javitt.)

Serotonin type-3 receptor (5-HT 3 R) antagonists show potential as a treatment for cognitive deficits in schizophrenia. CVN058, a brain-penetrant, potent and selective 5-HT 3 R antagonist, shows efficacy in rodent models of cognition and was well-tolerated in Phase-1 studies. We evaluated the target engagement of CVN058 using mismatch negativity (MMN) in a randomized, double-blind, placebo-controlled, cross-over study. Subjects were stable outpatients with schizophrenia or schizoaffective disorder treated with antipsychotics. Subjects were not permitted to use other 5-HT 3 R modulators or serotonin reuptake inhibitors. Each subject received a high (150 mg) and low (15 mg or 75 mg) oral dose of CVN058 and placebo in a randomized order across 3 single-day treatment visits separated by at least 1 week. The primary pre-registered outcome was amplitude of duration MMN. Amplitude of other MMN deviants (frequency, intensity, frequency modulation, and location), P50, P300 and auditory steady-state response (ASSR) were exploratory endpoints. 19 of 22 randomized subjects (86.4%) completed the study. Baseline PANSS scores indicated moderate impairment. CVN058 150 mg led to significant improvement vs. placebo on the primary outcome of duration MMN (p = 0.02, Cohen's d = 0.48). A significant treatment effect was also seen in a combined analysis across all MMN deviants (p < 0.001, d = 0.57). Effects on location MMN were independently significant (p < 0.007, d = 0.46). No other significant effects were seen for other deviants, doses or EEG measures. There were no clinically significant treatment related adverse effects. These results show MMN to be a sensitive target engagement biomarker for 5-HT 3 R, and support the potential utility of CVN058 in correcting the excitatory/inhibitory imbalance in schizophrenia., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Schizophrenia is widely seen as a disorder of dysconnectivity. Neuroimaging studies have examined both structural and functional connectivity in the disorder, but these modalities have rarely been integrated directly. We scanned 29 patients with schizophrenia and 25 healthy control subjects, and we acquired resting state fMRI and diffusion tensor imaging. We used the Functional and Tractographic Connectivity Analysis Toolbox (FATCAT) to estimate functional and structural connectivity of the default mode network. Correlations between modalities were investigated, and multimodal connectivity scores (MCS) were created using principal component analysis. Of the 28 possible region pairs, 9 showed consistent (>80%) tracts across participants. Correlations between modalities were found among those with schizophrenia for the prefrontal cortex, posterior cingulate, and lateral temporal lobes, with frontal and parietal regions, consistent with frontotemporoparietal network involvement in the disorder. In patients, MCS correlated with several aspects of the Positive and Negative Syndrome Scale, with higher multimodal connectivity associated with outward-directed (externalizing) behavior and lower multimodal connectivity related to psychosis per se. In this preliminary sample, we found FATCAT to be a useful toolbox to directly integrate and examine connectivity between imaging modalities. A consideration of conjoint structural and functional connectivity can provide important information about the network mechanisms of schizophrenia.

Background: Impairments in social cognition contribute significantly to disability in schizophrenia patients (SzP). Perception of facial expressions is critical for social cognition. Intact perception requires an individual to visually scan a complex dynamic social scene for transiently moving facial expressions that may be relevant for understanding the scene. The relationship of visual scanning for these facial expressions and social cognition remains unknown., Methods: In 39 SzP and 27 healthy controls (HC), we used eye-tracking to examine the relationship between performance on The Awareness of Social Inference Test (TASIT), which tests social cognition using naturalistic video clips of social situations, and visual scanning, measuring each individual's relative to the mean of HC. We then examined the relationship of visual scanning to the specific visual features (motion, contrast, luminance, faces) within the video clips., Results: TASIT performance was significantly impaired in SzP for trials involving sarcasm ( p < 10 -5 ). Visual scanning was significantly more variable in SzP than HC ( p < 10 -6 ), and predicted TASIT performance in HC ( p = 0.02) but not SzP ( p = 0.91), differing significantly between groups ( p = 0.04). During the visual scanning, SzP were less likely to be viewing faces ( p = 0.0001) and less likely to saccade to facial motion in peripheral vision ( p = 0.008)., Conclusions: SzP show highly significant deficits in the use of visual scanning of naturalistic social scenes to inform social cognition. Alterations in visual scanning patterns may originate from impaired processing of facial motion within peripheral vision. Overall, these results highlight the utility of naturalistic stimuli in the study of social cognition deficits in schizophrenia.

Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy ( 1 H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using 1 H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlated with more severe depression and lower GABA. MDD severity and diagnosis were both linked to higher Glx in vmPFC/ACC. Low GABA in a subset of these patients is consistent with our hypothesized model of low GABA leading to glutamate disinhibition in MDD. This finding and model are consistent with our previously reported findings that the NMDAR-antagonist antidepressant effect is proportional to the reduction of vmPFC/ACC Glx or Glu levels., (© 2021. The Author(s).)

Schizophrenia is associated with marked impairments in social cognition. However, the neural correlates of these deficits remain unclear. Here we use naturalistic stimuli to examine the role of the right temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS)-an integrative hub for the cortical networks pertinent to the understanding complex social situations-in social inference, a key component of social cognition, in schizophrenia. Twenty-seven schizophrenia participants and 21 healthy control subjects watched a clip of the film The Good, the Bad and the Ugly while high resolution multiband functional MRI images were collected. We used inter-subject correlation to measure the evoked activity, which we then compared to social cognition as measured by The Awareness of Social Inference Test (TASIT). We also compared between groups the TPJ-pSTS blood oxygen level-dependent activity (i) relationship with the motion content in the film; (ii) synchronization with other cortical areas involved in the viewing of the movie; and (iii) relationship with the frequency of saccades made during the movie. Activation deficits were greatest in middle TPJ (TPJm) and correlated significantly with impaired TASIT performance across groups. Follow-up analyses of the TPJ-pSTS revealed decreased synchronization with other cortical areas, decreased correlation with the motion content of the movie, and decreased correlation with the saccades made during the movie. The functional impairment of the TPJm, a hub area in the middle of the TPJ-pSTS, predicts deficits in social inference in schizophrenia participants by disrupting the integration of visual motion processing into the TPJ. This disrupted integration then affects the use of the TPJ to guide saccades during the visual scanning of the movie clip. These findings suggest that the TPJ may be a treatment target for improving deficits in a key component of social cognition in schizophrenia participants., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Deficits in mismatch negativity (MMN) generation are among the best-established biomarkers for cognitive dysfunction in schizophrenia and predict conversion to schizophrenia (Sz) among individuals at symptomatic clinical high risk (CHR). Impairments in MMN index dysfunction at both subcortical and cortical components of the early auditory system. To date, the large majority of studies have been conducted using deviants that differ from preceding standards in either tonal frequency (pitch) or duration. By contrast, MMN to sound location deviation has been studied to only a limited degree in Sz and has not previously been examined in CHR populations. Here, we evaluated location MMN across Sz and CHR using an optimized, multi-deviant pattern that included a location-deviant, as defined using interaural time delay (ITD) stimuli along with pitch, duration, frequency modulation (FM) and intensity deviants in a sample of 42 Sz, 33 CHR and 28 healthy control (HC) subjects. In addition, we obtained resting state functional connectivity (rsfMRI) on CHR subjects. Sz showed impaired MMN performance across all deviant types, along with strong correlation between MMN deficits and impaired neurocognitive function. In this sample of largely non-converting CHR subjects, no deficits were observed in either pitch or duration MMN. By contrast, CHR subjects showed significant impairments in location MMN generation particularly over right hemisphere and significant correlation between impaired location MMN and negative symptoms including deterioration of role function. In addition, significant correlations were observed between location MMN and rsfMRI involving brainstem circuits. In general, location detection using ITD stimuli depends upon precise processing within midbrain regions and provides a rapid and robust reorientation of attention. Present findings reinforce the utility of MMN as a pre-attentive index of auditory cognitive dysfunction in Sz and suggest that location MMN may index brain circuits distinct from those indexed by other deviant types., Competing Interests: DJ reports Intellectual property for NMDAR agonists in schizophrenia, NMDAR antagonist in depression, fMRI for prediction of ECT response, and ERP biomarkers for diagnosis of mental disorders. Equity in Glytech, AASI, and NeuroRx. Scientific advisory board NeuroRx, Promentis, Consultant payments Autifony, SK Life Sciences, Biogen, Cadence, and Pfizer. RG has consulted for Noble Insights and receives royalties for books from Wipf and Stock and Routledge/Taylor and Francis. GP receives income and equity from Pfizer Inc. through family. AM reports intellectual property for ERP biomarkers for diagnosis of mental disorders. JK reports having received consulting payments within the last 24 months from Alphasights, Charles River Associates, Putnam Associates, Third Bridge, Piper Jaffray, MEDACorp, Parexel, GroupH, Simon Kucher, LifeSci Capital, ECRI Institute, ExpertConnect, Parexel, Schlesinger Group, CelloHealth, Acsel Health, Strafluence, Guidepoint, L.E.K. and System Analytic. He has serves on the MedinCell Psychiatry Advisory Board. He has conducted clinical research supported by the NIMH, Sunovion, Roche, Alkermes, the Stanley Foundation, Cerevance, Takeda, Taisho, Lundbeck, Boehringer Ingelheim, NeuroRX, Teva and Lilly within the last 24 months. JK was a co-investigator on a study that receives lumeteperone and reimbursement for safety testing for an investigator-initiated research from Intra-Cellular Therapies Inc. He owns a small number of shares of common stock from GSK. RG has consulted for Noble Insights and receives royalties for books from Wipf and Stock and Routledge/Taylor and Francis. GP receives income and equity from Pfizer Inc. through family. AM reports intellectual property for ERP biomarkers for diagnosis of mental disorders. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sehatpour, Avissar, Kantrowitz, Corcoran, De Baun, Patel, Girgis, Brucato, Lopez-Calderon, Silipo, Dias, Martinez and Javitt.)

Schizophrenia (Sz) is associated with deficits in fluent reading ability that compromise functional outcomes. Here, we utilize a combined eye-tracking, neurophysiological, and computational modeling approach to analyze underlying visual and oculomotor processes. Subjects included 26 Sz patients (SzP) and 26 healthy controls. Eye-tracking and electroencephalography data were acquired continuously during the reading of passages from the Gray Oral Reading Tests reading battery, permitting between-group evaluation of both oculomotor activity and fixation-related potentials (FRP). Schizophrenia patients showed a marked increase in time required per word (d = 1.3, P < .0001), reflecting both a moderate increase in fixation duration (d = .7, P = .026) and a large increase in the total saccade number (d = 1.6, P < .0001). Simulation models that incorporated alterations in both lower-level visual and oculomotor function as well as higher-level lexical processing performed better than models that assumed either deficit-type alone. In neurophysiological analyses, amplitude of the fixation-related P1 potential (P1f) was significantly reduced in SzP (d = .66, P = .013), reflecting reduced phase reset of ongoing theta-alpha band activity (d = .74, P = .019). In turn, P1f deficits significantly predicted increased saccade number both across groups (P = .017) and within SzP alone (P = .042). Computational and neurophysiological methods provide increasingly important approaches for investigating sensory contributions to impaired cognition during naturalistic processing in Sz. Here, we demonstrate deficits in reading rate that reflect both sensory/oculomotor- and semantic-level impairments and that manifest, respectively, as alterations in saccade number and fixation duration. Impaired P1f generation reflects impaired fixation-related reset of ongoing brain rhythms and suggests inefficient information processing within the early visual system as a basis for oculomotor dyscontrol during fluent reading in Sz., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation approach in which low level currents are administered over the scalp to influence underlying brain function. Prevailing theories of tDCS focus on modulation of excitation-inhibition balance at the local stimulation location. However, network level effects are reported as well, and appear to depend upon differential underlying mechanisms. Here, we evaluated potential network-level effects of tDCS during the Serial Reaction Time Task (SRTT) using convergent EEG- and fMRI-based connectivity approaches. Motor learning manifested as a significant (p<.0001) shift from slow to fast responses and corresponded to a significant increase in beta-coherence (p<.0001) and fMRI connectivity (p<.01) particularly within the visual-motor pathway. Differential patterns of tDCS effect were observed within different parametric task versions, consistent with network models. Overall, these findings demonstrate objective physiological effects of tDCS at the network level that result in effective behavioral modulation when tDCS parameters are matched to network-level requirements of the underlying task., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interests to declare., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The term perceptual closure refers to the neural processes responsible for "filling-in" missing information in the visual image under highly adverse viewing conditions such as fog or camouflage. Here we used a closure task that required the participants to identify barely recognizable fragmented line-drawings of common objects. Patients with schizophrenia have been shown to perform poorly on this task. Following priming, controls and importantly patients can complete the line-drawings at greater levels of fragmentation behaviorally, suggesting an improvement in their ability to perform the task. Closure phenomena have been shown to involve a distributed network of cortical regions, notably the lateral occipital complex (LOC) of the ventral visual stream, dorsal visual stream (DS), hippocampal formation (HIPP) and the prefrontal cortex (PFC). We have previously demonstrated the failure of closure processes in schizophrenia and shown that the dysregulation in the sensory information transmitted to the prefrontal cortex plays a critical role in this failure. Here, using a multimodal imaging approach in patients, combining event related electrophysiological recordings (ERP) and functional magnetic resonance imaging (fMRI), we characterize the spatiotemporal dynamics of priming in perceptual closure. Using directed functional connectivity measures we demonstrate that priming modifies the network-level interactions between the nodes of closure processing in a manner that is functionally advantageous to patients resulting in the mitigation of their deficit in perceptual closure., (Copyright © 2020 Sehatpour, Bassir Nia, Adair, Wang, DeBaun, Silipo, Martinez and Javitt.)

Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = -0.41; p = 0.04, d = -0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = -0.36; p = 0.008, d = -0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = -0.56; p = 0.079, d = -0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.

Transcranial magnetic stimulation (TMS) is an approved intervention for treatment-resistant depression (TRD), but current targeting approaches are only partially successful. Our objectives were (1) to examine the feasibility of MRI-guided TMS in the clinical setting using a recently published surface-based, multimodal parcellation in patients with TRD who failed standard TMS (sdTMS); (2) to examine the neurobiological mechanisms and clinical outcomes underlying MRI-guided TMS compared to that of sdTMS. We used parcel-guided TMS (pgTMS) to target the left dorsolateral prefrontal cortex parcel 46. Resting-state functional connectivity (rsfc) was assessed between parcel 46 and predefined nodes within the default mode and visual networks, following both pgTMS and sdTMS. All patients (n = 10) who had previously failed sdTMS responded to pgTMS. Alterations in rsfc between frontal, default mode, and visual networks differed significantly over time between groups. Improvements in symptoms correlated with alterations in rsfc within each treatment group. The outcome of our study supports the feasibility of pgTMS within the clinical setting. Future prospective, double-blind studies of pgTMS vs. sdTMS appear warranted.

New treatment development for psychiatric disorders depends critically upon the development of physiological measures that can accurately translate between preclinical animal models and clinical human studies. Such measures can be used both as stratification biomarkers to define pathophysiologically homogeneous patient populations and as target engagement biomarkers to verify similarity of effects across preclinical and clinical intervention. Traditional "time-domain" event-related potentials (ERP) have been used translationally to date but are limited by the significant differences in timing and distribution across rodent, monkey and human studies. By contrast, neuro-oscillatory responses, analyzed within the "time-frequency" domain, are relatively preserved across species permitting more precise translational comparisons. Moreover, neuro-oscillatory responses are increasingly being mapped to local circuit mechanisms and may be useful for investigating effects of both pharmacological and neuromodulatory interventions on excitatory/inhibitory balance. The present paper provides a roadmap for development of neuro-oscillatory responses as translational biomarkers in neuropsychiatric treatment development.

Despite their theoretical rationale, nicotinic alpha-7 acetylcholine (nα 7 ) receptor agonists, have largely failed to demonstrate efficacy in placebo-controlled trials in schizophrenia. AVL-3288 is a nα 7 positive allosteric modulator (PAM), which is only active in the presence of the endogenous ligand (acetylcholine), and thus theoretically less likely to cause receptor desensitization. We evaluated the efficacy of AVL-3288 in a Phase 1b, randomized, double-blind, placebo-controlled, triple cross-over study. Twenty-four non-smoking, medicated, outpatients with schizophrenia or schizoaffective disorder and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) ≥62 were randomized. Each subject received 5 days of AVL-3288 (10, 30 mg) and placebo across three separate treatment weeks. The primary outcome measure was the RBANS total scale score, with auditory P50 evoked potential suppression the key target engagement biomarker. Secondary outcome measures include task-based fMRI (RISE task), mismatch negativity, the Scale for the Assessment of Negative Symptoms of Schizophrenia (SANS) and the Brief Psychiatric Rating Scale (BPRS). Twenty-four subjects were randomized and treated without any clinically significant treatment emergent adverse effects. Baseline RBANS (82 ± 17) and BPRS (41 ± 13) scores were consistent with moderate impairment. Primary outcomes were negative, with non-significant worsening for both active groups vs. placebo in the P50 and minimal between group changes on the RBANS. In conclusion, the results did not indicate efficacy of the compound, consistent with most prior results for the nα 7 target.

Alterations in glutamatergic function are well established in schizophrenia (Sz), but new treatment development is hampered by the lack of translational pathophysiological and target engagement biomarkers as well as by the lack of animal models that recapitulate the pathophysiological features of Sz. Here, we evaluated the rodent auditory steady state response (ASSR) and long-latency auditory event-related potential (aERP) as potential translational markers. These biomarkers were assessed for their sensitivity to both the N-methyl-d-aspartate receptor (NMDAR) antagonist phencyclidine (PCP) and to knock-out (KO) of Serine Racemase (SR), which is known to lead to Sz-like alterations in function of parvalbumin (PV)-type cortical interneurons. PCP led to significant increases of ASSR that were further increased in SRKO-/-, consistent with PV interneuron effects. Similar effects were observed in mice with selective NMDAR KO on PV interneurons. By contrast, PCP but not SRKO reduced the amplitude of the rodent analog of the human N1 potential. Overall, these findings support use of rodent ASSR and long-latency aERP, along with previously described measures such as mismatch negativity (MMN), as translational biomarkers, and support SRKO mice as a potential rodent model for PV interneuron dysfunction in Sz., Competing Interests: Declaration of competing interest Within the last 3 years, Dr. Javitt has received consulting payments from Concert, Lundbeck, Phytec, Pfizer, Cadence, Biogen, SK Life Science, Autifony and Boeringer-Ingelheim and research support from Cerevance he holds equity in Glytech, AASI, and NeuroRx. He serves on the Scientific Advisory Board of NeuroRx and Promentis. He holds intellectual property for the use of d-serine combinations in the treatment of neuropsychiatric disorders, and for NMDAR antagonists in the treatment of depression. Other authors declare no conflicts of interest.

During normal visual behavior, individuals scan the environment through a series of saccades and fixations. At each fixation, the phase of ongoing rhythmic neural oscillations is reset, thereby increasing efficiency of subsequent visual processing. This phase-reset is reflected in the generation of a fixation-related potential (FRP). Here, we evaluate the integrity of theta phase-reset/FRP generation and Guided Visual Search task in schizophrenia. Subjects performed serial and parallel versions of the task. An initial study (15 healthy controls (HC)/15 schizophrenia patients (SCZ)) investigated behavioral performance parametrically across stimulus features and set-sizes. A subsequent study (25-HC/25-SCZ) evaluated integrity of search-related FRP generation relative to search performance and evaluated visual span size as an index of parafoveal processing. Search times were significantly increased for patients versus controls across all conditions. Furthermore, significantly, deficits were observed for fixation-related theta phase-reset across conditions, that fully predicted impaired reduced visual span and search performance and correlated with impaired visual components of neurocognitive processing. By contrast, overall search strategy was similar between groups. Deficits in theta phase-reset mechanisms are increasingly documented across sensory modalities in schizophrenia. Here, we demonstrate that deficits in fixation-related theta phase-reset during naturalistic visual processing underlie impaired efficiency of early visual function in schizophrenia., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Mismatch negativity (MMN) is an extensively validated biomarker of cognitive function across both normative and clinical populations and has previously been localized to supratemporal auditory cortex. MMN is thought to represent a comparison of the features of the present stimulus versus a mnemonic template formed by the prior stimuli., Methods: We used concurrent thalamic and primary auditory cortical (A1) laminar recordings in 7 macaques to evaluate the relative contributions of core (lemniscal) and matrix (nonlemniscal) thalamic afferents to MMN generation., Results: We demonstrated that deviance-related activity is observed mainly in matrix regions of auditory thalamus, MMN generators are most prominent in layer 1 of cortex as opposed to sensory responses that activate layer 4 first and sequentially all cortical layers, and MMN is elicited independent of the frequency tuning of A1 neuronal ensembles. Consistent with prior reports, MMN-related thalamocortical activity was strongly inhibited by ketamine., Conclusions: Taken together, our results demonstrate distinct matrix versus core thalamocortical circuitry underlying the generation of a higher-order brain response (MMN) versus sensory responses., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)