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Background: Reduced auditory mismatch negativity (MMN) is robustly impaired in schizophrenia. However, mechanisms underlying dysfunctional MMN generation remain incompletely understood. This study aimed to examine the role of evoked spectral power and phase-coherence towards deviance detection and its impairments in schizophrenia., Methods: Magnetoencephalography data was collected in 16 male schizophrenia patients and 16 male control participants during an auditory MMN paradigm. Analyses of event-related fields (ERF), spectral power and inter-trial phase-coherence (ITPC) focused on Heschl's gyrus, superior temporal gyrus, inferior/medial frontal gyrus and thalamus., Results: MMNm ERF amplitudes were reduced in patients in temporal, frontal and subcortical regions, accompanied by decreased theta-band responses, as well as by a diminished gamma-band response in auditory cortex. At theta/alpha frequencies, ITPC to deviant tones was reduced in patients in frontal cortex and thalamus. Patients were also characterized by aberrant responses to standard tones as indexed by reduced theta-/alpha-band power and ITPC in temporal and frontal regions. Moreover, stimulus-specific adaptation was decreased at theta/alpha frequencies in left temporal regions, which correlated with reduced MMNm spectral power and ERF amplitude. Finally, phase-reset of alpha-oscillations after deviant tones in left thalamus was impaired, which correlated with impaired MMNm generation in auditory cortex. Importantly, both non-rhythmic and rhythmic components of spectral activity contributed to the MMNm response., Conclusions: Our data indicate that deficits in theta-/alpha- and gamma-band activity in cortical and subcortical regions as well as impaired spectral responses to standard sounds could constitute potential mechanisms for dysfunctional MMN generation in schizophrenia, providing a novel perspective towards MMN deficits in the disorder., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Peter J. Uhlhaas reports financial support was provided by German Israeli Foundation for Scientific Research and Development. Abraham Goldstein reports financial support was provided by German Israeli Foundation for Scientific Research and Development., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Emerging evidence suggests that the duration of risk symptoms (DUR) may have an impact on clinical outcomes in clinical high-risk for psychosis (CHRP) participants. To explore this hypothesis, we performed a meta-analysis on studies that examined DUR in CHR-P individuals in relation to their clinical outcomes. This review was conducted in accordance with the PRISMA guidelines and the protocol was registered with PROSPERO on 16th April 2021 (ID no. CRD42021249443). Literature searches were conducted using PsycINFO and Web of Science in March and November 2021, for studies reporting on DUR in CHR-P populations, in relation to transition to psychosis or symptomatic, functional, or cognitive outcomes. The primary outcome was transition to psychosis, while the secondary outcomes were remission from CHR-P status and functioning at baseline. Thirteen independent studies relating to 2506 CHR-P individuals were included in the meta-analysis. The mean age was 19.88 years (SD = 1.61) and 1194 individuals (47.65 %) were females. The mean length of DUR was 23.61 months (SD = 13.18). There was no meta-analytic effect of DUR on transition to psychosis at 12-month follow-up (OR = 1.000, 95%CI = 0.999-1.000, k = 8, p = .98), while DUR was related to remission (Hedge's g = 0.236, 95%CI = 0.014-0.458, k = 4, p = .037). DUR was not related to baseline GAF scores (beta = -0.004, 95%CI = -0.025-0.017, k = 3, p = .71). The current findings suggest that DUR is not associated with transition to psychosis at 12 months, but may impact remission. However, the database was small and further research in this area is required., Competing Interests: Declaration of competing interest PU has received research support from Lilly and Lundbeck outside the submitted work. PFP has received grant fees from Lundbeck and honoraria from Lundbeck, Menarini and Angelini, outside the submitted work., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Poor functional outcomes are common in individuals at clinical high-risk for psychosis (CHR-P), but the contribution of cognitive deficits remains unclear. We examined the potential utility of cognitive variables in predictive models of functioning at baseline and follow-up with machine learning methods. Additional models fitted on baseline functioning variables were used as a benchmark to evaluate model performance. Data were available for 1) 146 CHR-P individuals of whom 118 completed a 6- and/or 12-month follow-up, 2) 47 participants not fulfilling CHR criteria (CHR-Ns) but displaying affective and substance use disorders and 3) 55 healthy controls (HCs). Predictors of baseline global assessment of functioning (GAF) scores were selected by L1-regularised least angle regression and then used to train classifiers to predict functional outcome in CHR-P individuals. In CHR-P participants, cognitive deficits together with clinical and functioning variables explained 41% of the variance in baseline GAF scores while cognitive variables alone explained 12%. These variables allowed classification of functional outcome with an average balanced accuracy (BAC) of 63% in both mixed- and cross-site models. However, higher accuracies (68%-70%) were achieved using classifiers fitted only on baseline functioning variables. Our findings suggest that cognitive deficits, alongside clinical and functioning variables, displayed robust relationships with impaired functioning in CHR-P participants at baseline and follow-up. Moreover, these variables allow for prediction of functional outcome. However, models based on baseline functioning variables showed a similar performance, highlighting the need to develop more accurate algorithms for predicting functional outcome in CHR-P participants., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The current study examined the presence of abnormalities in cortical grey-matter (GM) in a sample of clinical high-risk (CHR) participants and examined relationships with psychosocial functioning and neurocognition. CHR-participants (n = 114), participants who did not fulfil CHR-criteria (CHR-negative) (n = 39) as well as a group of healthy controls (HC) (n = 49) were recruited. CHR-status was assessed using the Comprehensive Assessment of At-Risk Mental State (CAARMS) and the Schizophrenia Proneness Interview, Adult Version (SPI-A). The Brief Assessment of Cognition in Schizophrenia Battery (BACS) as well as tests for emotion recognition, working memory and attention were administered. In addition, role and social functioning as well as premorbid adjustment were assessed. No significant differences in GM-thickness and intensity were observed in CHR-participants compared to CHR-negative and HC. Circumscribed abnormalities in GM-intensity were found in the visual and frontal cortex of CHR-participants. Moreover, small-to-moderate correlations were observed between GM-intensity and neuropsychological deficits in the CHR-group. The current data suggest that CHR-participants may not show comprehensive abnormalities in GM. We discuss the implications of these findings for the pathophysiological theories of early stage-psychosis as well as methodological issues and the impact of different recruitment strategies., Competing Interests: Declaration of competing interest P.J.U. has received research support from Lilly and Lundbeck. S.M.L. has received lecture fees from Janssen, Otsuka and Sunovion. The remaining authors report no biomedical financial interests or potential conflicts of interest. The following are the supplementary data related to this article. Supplementary data to this article can be found online at https://doi.org/10.1016/j.schres.2019.08.034., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Cognitive deficits are a fundamental feature of schizophrenia for which currently no effective treatments exist. This paper examines the possibility to use transcranial direct current stimulation (tDCS) to target cognitive deficits in schizophrenia as evidence from studies in healthy participants suggests that tDCS may improve cognitive functions and associated neural processes. We carried out a systematic review with the following search terms: 'tDCS', 'electric brain stimulation', 'schizophrenia', 'cognitive', 'cognition' until March 2019. 659 records were identified initially, 612 of which were excluded after abstract screening. The remaining 47 articles were assessed for eligibility based on our criteria and 26 studies were excluded. In addition, we compared several variables, such as online vs. offline-stimulation protocols, stimulation type and intensity on mediating positive vs. negative study outcomes. The majority of studies (n = 21) identified significant behavioural and neural effects on a range of cognitive functions (versus n = 11 with null results), including working memory, attention and social cognition. However, we could not identify tDCS parameters (electrode montage, stimulation protocol, type and intensity) that clearly mediated effects on cognitive deficits. There is preliminary evidence for the possibility that tDCS may improve cognitive deficits in schizophrenia. We discuss the rationale and strength of evidence for using tDCS for targeting cognitive deficits in schizophrenia as well as methodological issues and potential mechanisms of action., Competing Interests: Declaration of competing interest P.J.U. has received research support from Lilly and Lundbeck. The remaining authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Anomalies in visual and auditory perception represent an important aspect of the symptomatic manifestation of schizophrenia (ScZ). However, there are currently no instruments available that allow the assessment of the full range of auditory and visual abnormalities using a self-report measure., Methods: We developed the 85-item Audio-Visual Abnormalities Questionnaire (AVAQ) to assess abnormalities in auditory and visual processing. The AVAQ was validated in an online-sample of 355 healthy participants to establish the factorial structure, internal consistency and reliability of the instrument. In addition, participants completed the Autism-Spectrum Quotient (AQ) and the Schizotypal Personality Questionnaire (SPQ) to establish convergent validity regarding autistic and schizotypal traits., Results: High internal consistency was observed for the total AVAQ-scale (α = 0.99) as well as for the visual (α = 0.98), auditory (α = 0.96) and the audio-visual subscales (α = 0.83). Principal component analyses demonstrated one factor comprising 78 items. The AVAQ was positively correlated with the SPQ (r = 0.69, p < .001) as well as the AQ (r = 0.38, p < .001). Correlations with the SPQ were highest for unusual perceptual experiences (r = 0.72, p < .001) and lowest for social anxiety (r = 0.30, p < .001)., Conclusion: The AVAQ demonstrated excellent reliability, internal consistency and construct validity. Accordingly, the instrument could be useful for characterizing sensory dysfunctions across the schizophrenia spectrum that could guide interventions as well as aid the development of biomarkers., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The thalamus has recently received renewed interest in systems-neuroscience and schizophrenia (ScZ) research because of emerging evidence highlighting its important role in coordinating functional interactions in cortical-subcortical circuits. Moreover, higher cognitive functions, such as working memory and attention, have been related to thalamo-cortical interactions, providing a novel perspective for the understanding of the neural substrate of cognition. The current review will support this perspective by summarizing evidence on the crucial role of neural oscillations in facilitating thalamo-cortical (TC) interactions during normal brain functioning and their potential impairment in ScZ. Specifically, we will focus on the relationship between NMDA-R mediated (glutamatergic) neurotransmission in TC-interactions. To this end, we will first review the functional anatomy and neurotransmitters in thalamic circuits, followed by a review of the oscillatory signatures and cognitive processes supported by TC-circuits. In the second part of the paper, data from preclinical research as well as human studies will be summarized that have implicated TC-interactions as a crucial target for NMDA-receptor hypofunctioning. Finally, we will compare these neural signatures with current evidence from ScZ-research, suggesting a potential overlap between alterations in TC-circuits as the result of NMDA-R deficits and stage-specific alterations in large-scale networks in ScZ., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Gamma-band oscillations are prominently impaired in schizophrenia, but the nature of the deficit and relationship to perceptual processes is unclear., Methods: 16 patients with chronic schizophrenia (ScZ) and 16 age-matched healthy controls completed a visual paradigm while magnetoencephalographic (MEG) data was recorded. Participants had to detect randomly occurring stimulus acceleration while viewing a concentric moving grating. MEG data were analyzed for spectral power (1-100Hz) at sensor- and source-level to examine the brain regions involved in aberrant rhythmic activity, and for contribution of differences in baseline activity towards the generation of low- and high-frequency power., Results: Our data show reduced gamma-band power at sensor level in schizophrenia patients during stimulus processing while alpha-band and baseline spectrum were intact. Differences in oscillatory activity correlated with reduced behavioral detection rates in the schizophrenia group and higher scores on the "Cognitive Factor" of the Positive and Negative Syndrome Scale. Source reconstruction revealed that extra-striate (fusiform/lingual gyrus), but not striate (cuneus), visual cortices contributed towards the reduced activity observed at sensor-level in ScZ patients. Importantly, differences in stimulus-related activity were not due to differences in baseline activity., Conclusions: Our findings highlight that MEG-measured high-frequency oscillations during visual processing can be robustly identified in ScZ. Our data further suggest impairments that involve dysfunctions in ventral stream processing and a failure to increase gamma-band activity in a task-context. Implications of these findings are discussed in the context of current theories of cortical-subcortical circuit dysfunctions and perceptual processing in ScZ., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: High-frequency oscillations are important for sensory processing and dysfunctions in the amplitude and synchrony of beta- and gamma-band oscillations have been demonstrated in schizophrenia (ScZ). However, the presence of aberrant high-frequency oscillations in first-episode (FE), medication-naive patients during sensory processing is unclear., Methods: Magnetoencephalographic (MEG) data were recorded from 15 never-medicated, FE-ScZ patients and 20 matched healthy controls during the perception of Mooney faces. MEG data were analysed for spectral power and single-sensor phase-locking in the beta (13-25Hz) and gamma- (25-140Hz) frequency range., Results: FE-ScZ patients were characterized by significantly impaired sensory processing as indicated by a reduced discrimination index (A'). Impaired behavioural performance in ScZ-patients was accompanied by decreased spectral power in the high- (60-120Hz) gamma-band range. In contrast, oscillations in the lower (25-60Hz) gamma-band were largely intact and beta-band oscillations were increased. Analysis of cross-frequency coupling showed a reduced correlation between 60 and 120Hz amplitude values and beta-band power in FE-ScZ-patients relative to controls., Discussion: Our findings show that impaired sensory processing in medication-naive, FE-schizophrenia is related to a dysregulation of neural oscillations which involves both an impairment in the generation of high gamma-band activity as well as a failure to downregulate task-irrelevant beta-band activity. Because of the interrelationship of these dysfunctions and the role of inhibitory networks in the shaping of high-frequency activity, aberrant neural oscillations in FE-schizophrenia may be linked to dysfunctions in the excitation-inhibition (E/I)-balance., (© 2013.)

Schizophrenia has been associated with aberrant intrinsic functional organization of the brain but the relationship of such deficits to psychopathology is unclear. In this study, we investigated associations between resting-state networks and individual psychopathology in sixteen patients with paranoid schizophrenia and sixteen matched healthy control participants. We estimated whole-brain functional connectivity of multiple networks using a combination of spatial independent component analysis and multiple regression analysis. Five networks (default-mode, left and right fronto-parietal, left fronto-temporal and auditory networks) were selected for analysis based on their involvement in neuropsychological models of psychosis. Between-group comparisons and correlations to psychopathology ratings were performed on both spatial (connectivity distributions) and temporal features (power-spectral densities of temporal frequencies below 0.06 Hz). Schizophrenia patients showed aberrant functional connectivity in the default-mode network, which correlated with severity of hallucinations and delusions, and decreased hemispheric separation of fronto-parietal activity, which correlated with disorganization symptoms. Furthermore, the severity of positive symptoms correlated with functional connectivity of fronto-temporal and auditory networks. Finally, default-mode and auditory networks showed increased spectral power of low frequency oscillations, which correlated with positive symptom severity. These results are in line with findings from studies that investigated the neural correlates of positive symptoms and suggest that psychopathology is associated with aberrant intrinsic organization of functional brain networks in schizophrenia., ((c) 2010 Elsevier B.V. All rights reserved.)

Deficits in perceptual organization have been consistently reported in schizophrenia, as has an association between these deficits, disorganized symptoms, and poorer premorbid functioning and prognosis, suggesting that they may be an index of illness severity or progression. It is unclear, however, whether the impairment is present at, or before the first psychotic episode. This study examined perceptual organization in young people considered to be at high-risk for schizophrenia, defined by the "close-in" strategy [Yung, A.R., McGorry, P.D., McFarlane, C.A., Jackson, H.J., Patton, G.C., Rakkar, 1996. Monitoring and care of young people at incipient risk of psychosis. Schizophrenia Bulletin, 22, 283-303]. The high-risk group (n=70) was compared to first-episode patients (n=54), and nonpatients (n=24) using a task with known sensitivity to perceptual organization deficits in schizophrenia, and whose scores have predicted long-term outcome and disorganized symptomatology in past studies [Knight, R.A., Silverstein, S.M., 1998. The role of cognitive psychology in guiding research on cognitive deficits in schizophrenia. In Lenzenweger, M., Dworkin, R.H., (Eds.), Origins and Development of Schizophrenia: Advances in Experimental Psychopathology. APA Press, Washington DC, pp. 247-295.; Silverstein, S.M., Knight, R.A., Schwarzkopf, S.B., West, L.L., Osborn, L.M. Kamin, D., 1996b. Stimulus configuration and context effects in perceptual organization in schizophrenia. Journal of Abnormal Psychology 105, 410-420.; Silverstein, S.M., Schenkel, L.S., Valone, C., Nuernberger, S., 1998a. Cognitive deficits and psychiatric rehabilitation outcomes in schizophrenia. Psychiatric Quarterly 69, 169-191.; Silverstein, S.M., Bakshi, S., Chapman, R.M., Nowlis, G., 1998b. Perceptual organization of configural and nonconfigural visual patterns in schizophrenia: effects of repeated exposure. Cognitive Neuropsychiatry 3, 209-223]. There were no differences between groups, and the first-episode group demonstrated non-significantly more sensitivity to stimulus organization than the other groups. When the high-risk group was broken down into its 3 subgroups (A--family history of psychotic illness and recent drop of 30+ points in the GAF scale; B--history of attenuated psychotic symptoms; C--brief limited intermittent psychotic symptoms), only group A demonstrated evidence of impairment, but this group differed significantly only from first- and young, later-episode schizophrenia patients, not from nonpatients. These findings are consistent with recent data on pre-attentive processes in schizophrenia which indicate that performance is not impaired and may even be enhanced, early in the illness, with dysfunctions beginning with increased chronicity.

This study evaluated deficits in visual perceptual organization in schizophrenia over the course of inpatient treatment, in relation to the remission of particular psychotic symptoms. Disorganized (n=14) and non-disorganized (n=33) schizophrenia patients were tested upon admission to an inpatient psychiatric unit, and again after 3 weeks of treatment, on two measures of visual perceptual organization. Performance of schizophrenia patients was compared to groups of patients with psychotic disorders other than schizophrenia (n=19) and non-psychotic psychiatric disorders (n=25). Symptom ratings were collected at both assessment points. Deficits in visual perceptual organization were observed for both tasks in disorganized schizophrenia patients at index and these deficits improved during the course of treatment. Moreover, improvement in visual perceptual organization correlated significantly with reductions in disorganized symptoms in the schizophrenia group. We interpret these data as further support for the hypothesis that the disorganization syndrome in schizophrenia reflects a widespread deficit in the cognitive coordination of contextually related stimuli, leading to dysfunctional organization of stimulus features in vision, thought and language.

Visual context processing was examined in relation to schizotypy in a large nonclinical university population. Schizotypal status was assessed with the Schizotypal Personality Questionnaire (SPQ) [Schizophr. Bull. 17 (1991) 555]. Schizotypal (n=32) and non-schizotypal (n=37) subjects were tested on a contour integration task (where context processing is necessary for good performance) and a visual size perception task (where context processing impairs accurate performance). In addition, a short form of the Thought Disorder Index (TDI) [Psychol. Assess. 5 (1993) 75] was administered to 28 schizotypal subjects. Thought disordered schizotypal subjects showed significantly impaired performance on the contour integration task but more accurate performance on the visual size perception task. These results support the hypothesis that deficits in visual context processing are the manifestation of a larger disturbance of cognitive coordination in schizotypy and schizophrenia.