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Anomalous Mismatch Negativity (MMN) in psychosis could be a consequence of disturbed neural oscillatory activity at sensory/perceptual stages of stimulus processing. This study investigated effective connectivity within and between the auditory regions during auditory odd-ball deviance tasks. The analyses were performed on two magnetoencephalography (MEG) datasets: one on duration MMN in a cohort with various diagnoses within the psychosis spectrum and neurotypical controls, and one on duration and pitch MMN in first-episode psychosis patients and matched neurotypical controls. We applied spectral Granger causality to MEG source-reconstructed signals to compute effective connectivity within and between the left and right auditory regions. Both experiments showed that duration-deviance detection was associated with early increases of effective connectivity in the beta band followed by increases in the alpha and theta bands, with the connectivity strength linked to the laterality of the MMN amplitude. Compared to controls, people with psychosis had overall smaller effective connectivity, particularly from left to right auditory regions, in the pathway where bilateral information converges toward lateralized processing, often rightward. Blunted MMN in psychosis might reflect a deficit in inter-hemispheric communication between auditory regions, highlighting a "dysconnection" already at preattentive stages of stimulus processing as a model system of widespread pathophysiology., Competing Interests: Declaration of competing interest AB has received lecture fees from Otsuka, Janssen, and Lundbeck, as well as consultant fees from Biogen. GP has received lecture fees from Lundbeck. All other authors report no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Predicting treatment response would facilitate individualized medical treatment in first-episode psychosis (FEP). We examined relationships between auditory-evoked M100 and longitudinal change in positive symptoms in FEP. M100 was measured from source-resolved magnetoencephalography and symptoms were assessed at initial contact and six months later. M100 at baseline significantly predicted symptom change. Larger M100 at baseline predicted symptom improvement, as did shorter untreated psychosis. Shorter untreated psychosis also correlated with larger M100, and M100 mediated the effect of untreated psychosis on treatment response. Thus, M100 may provide a proximal and objective index of untreated psychosis and a viable route to individualized medicine., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Using electroencephalography (EEG) to examine the simple mismatch negativity (MMN), a marker of auditory cortex function, has been of great interest in the exploration of biomarkers for psychotic illness. Despite many studies reporting MMN deficits in chronic schizophrenia, there are inconsistent reports of MMN reductions in the early phases of psychotic illness, suggesting the MMN elicited by traditional paradigms may not be a sensitive enough measure of vulnerability to be used as a biomarker. Recently, a more computationally complex measure of auditory cortex function (the complex mismatch negativity; cMMN) has been hypothesized to provide a more sensitive marker of illness vulnerability. The current study employed a novel dual rule paradigm, in which two pattern rules are established and violated, to examine the cMMN in 14 individuals with early phase psychosis (EPP, < 5 years illness) and 15 healthy controls (HC). Relationships between cMMN waveforms, symptom severity, and measures of functioning were explored. We found reductions of cMMN amplitudes at the site of maximal amplitude in EPP ( p  = .017) with large effect sizes ( Hedges' g  = 0.96). This study is an early step in the exploration of the cMMN as a biomarker for psychosis. Our results provide evidence that the dual rule cMMN paradigm shows promise as a method for cMMN elicitation that captures more subtle neurofunctional changes in the early stages of illness., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Accelerated brain aging is a possible mechanism of pathology in schizophrenia. Advances in MRI-based brain development algorithms allow for the calculation of predicted brain age (PBA) for individuals. Here, we assessed PBA in 70 first-episode schizophrenia-spectrum individuals (FESz) and 76 matched healthy neurotypical comparison individuals (HC) to determine if FESz showed advanced aging proximal to psychosis onset and whether PBA was associated with neurocognitive, social functioning, or symptom severity measures. PBA was calculated with BrainAgeR (v2.1) from T1-weighted MR scans. There were no differences in the PBAs between groups. After controlling for actual age, a "younger" PBA was associated with higher vocabulary scores among all individuals, while an "older" PBA was associated with more severe negative symptom "Inexpressivity" component scores among FESz. Female participants in both groups had an elevated PBA relative to male participants. These results suggest that a relatively younger brain age is associated with a better semantic memory performance. There is no evidence for accelerated aging in FESz with a late adolescent/early adult onset. Despite a normative PBA, FESz with a greater residual PBA showed impairments in a cluster of negative symptoms, which may indicate some underlying age-related pathology proximal to psychosis onset. Although a period of accelerated aging cannot be ruled out with disease course, it does not occur at the time of the first episode.

Infrequent stimulus deviations from repetitive sequences elicit mismatch negativity (MMN) even passively, making MMN practical for clinical applications. Auditory MMN is typically elicited by a change in one (or more) physical stimulus parameters (eg, pitch, duration). This lower-order simple MMN (sMMN) is impaired in long-term schizophrenia. However, sMMN contains activity from release from stimulus adaptation, clouding its face validity as purely deviance-related. More importantly, it is unreliably reduced in samples of first-episode psychosis, limiting its utility as a biomarker. Complex pattern-deviant MMN (cMMN) tasks, which elicit early and late responses, are based on higher-order abstractions and better isolate deviance detection. Their abstract nature may increase the sensitivity to processing deficits in early psychosis. However, both the early and late cMMNs are small, limiting separation between healthy and psychotic samples. In 29 healthy individuals, we tested a new dual-rule cMMN paradigm to assess additivity of deviance. Sounds alternated lateralization between left and right, and low and high pitches, creating a left-low, right-high alternating pattern. Deviants were a repeated left-low, violating lateralization and pitch patterns. Early and late cMMNs on the dual-rule task were significantly larger than those on the one-rule extra tone cMMN task ( P  < .05). Further, the dual-rule early cMMN was not significantly smaller than pitch or duration sMMNs ( P  > .48, .28, respectively). These results demonstrate additivity for cMMN pattern-violating rules. This increase in cMMN amplitude should increase group difference effect size, making it a prime candidate for a biomarker of disease presence at first psychotic episode, and perhaps even prior to the emergence of psychosis., 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.

Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings., (© 2024. The Author(s).)

Background: Gamma-band activity has been the focus of considerable research in schizophrenia. Discrepancies exist regarding the integrity of the early auditory gamma-band response (EAGBR), a stimulus-evoked oscillation, and its relationship to symptoms in early disease. Variability in task design may play a role. This study examined sensitivity of the EAGBR to stimulus intensity and its relation to symptoms and functional impairments in the first-episode schizophrenia spectrum (FESz)., Method: Magnetoencephalography was recorded from 35 FESz and 40 matched healthy controls (HC) during presentation of 3 tone intensities (75 dB, 80 dB, 85 dB). MRIs were collected to localize auditory cortex activity. Wavelet-transformed single trial epochs and trial averages were used to assess EAGBR intertrial phase coherence (ITPC) and evoked power, respectively. Symptoms were assessed using the Positive and Negative Syndrome Scale., Results: Groups did not differ in overall EAGBR power or ITPC. While HC exhibited EAGBR enhancement to increasing intensity, FESz exhibited reduced power to the 80 dB tone and, relative to HC, increased power to the 75 dB tone. Larger power and ITPC were correlated with more severe negative, thought disorganization, and resistance symptoms. Stronger ITPC was associated with impaired social functioning., Discussion: EAGBR showed no overall deficit at disease onset. Rather, FESz exhibited a differential response across tone intensity relative to HC, emphasizing the importance of stimulus characteristics in EAGBR studies. Associations between larger EAGBR and more severe symptoms suggest aberrant synchronization driving overinclusive perceptual binding that may relate to deficits in executive inhibition of initial sensory activity., Competing Interests: Declaration of competing interest None of the authors reported any biomedical financial interests or potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mismatch negativity (MMN) is an auditory event-related response reflecting the pre-attentive detection of novel stimuli and is a biomarker of cortical dysfunction in schizophrenia (SZ). MMN to pitch (pMMN) and to duration (dMMN) deviant stimuli are impaired in chronic SZ, but it is less clear if MMN is reduced in first-episode SZ, with inconsistent findings in scalp-level EEG studies. Here, we investigated the neural generators of pMMN and dMMN with MEG recordings in 26 first-episode schizophrenia spectrum (FE sz ) and 26 matched healthy controls (C). We projected MEG inverse solutions into precise functionally meaningful auditory cortex areas. MEG-derived MMN sources were in bilateral primary auditory cortex (A1) and belt areas. In A1, pMMN FE sz reduction showed a trend towards statistical significance (F (1,50)  = 3.31; p = .07), and dMMN was reduced in FE sz (F (1,50)  = 4.11; p = .04). Hypothesis-driven comparisons at each hemisphere revealed dMMN reduction in FE sz occurred in the left (t (56)  = 2.23; p = .03; d = .61) but not right (t (56)  = 1.02; p = .31; d = .28) hemisphere, with a moderate effect size. The added precision of MEG source solution with high-resolution MRI and parcellation of A1 may be requisite to detect the emerging pathophysiology and indicates a critical role for left hemisphere pathology at psychosis onset. However, the moderate effect size in left A1, albeit larger than reported in scalp MMN meta-analyses, casts doubt on the clinical utility of MMN for differential diagnosis, as a majority of patients will overlap with the healthy individual's distribution., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Mismatch negativity (MMN) to pitch (pMMN) and to duration (dMMN) deviant stimuli is significantly more attenuated in long-term psychotic illness compared to first-episode psychosis (FEP). It was recently shown that source-modeling of magnetically recorded MMN increases the detection of left auditory cortex MMN deficits in FEP, and that computational circuit modeling of electrically recorded MMN also reveals left-hemisphere auditory cortex abnormalities. Computational modeling using dynamic causal modeling (DCM) can also be used to infer synaptic activity from EEG-based scalp recordings. We measured pMMN and dMMN with EEG from 26 FEP and 26 matched healthy controls (HCs) and used a DCM conductance-based neural mass model including α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, N-methyl-D-Aspartate (NMDA), and Gamma-aminobutyric acid receptors to identify any changes in effective connectivity and receptor rate constants in FEP. We modeled MMN sources in bilateral A1, superior temporal gyrus, and inferior frontal gyrus (IFG). No model parameters distinguished groups for pMMN. For dMMN, reduced NMDA receptor activity in right IFG in FEP was detected. This finding is in line with literature of prefrontal NMDA receptor hypofunction in chronic schizophrenia and suggests impaired NMDA-induced synaptic plasticity may be present at psychosis onset where scalp dMMN is only moderately reduced. To the best of our knowledge, this is the first report of impaired NMDA receptor activity in FEP found through computational modeling of dMMN and shows the potential of DCM to non-invasively reveal synaptic-level abnormalities that underly subtle functional auditory processing deficits in early psychosis., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Auditory hallucinations (AH) are a debilitating symptom in psychosis, impacting cognition and real world functioning. Recent thought conceptualizes AH as a consequence of long-range brain communication dysfunction, or circuitopathy, within the auditory sensory/perceptual, language, and cognitive control systems. Recently we showed in first-episode psychosis (FEP) that, despite overall intact white matter integrity in the cortical-cortical and cortical-subcortical language tracts and the callosal tracts connecting auditory cortices, the severity of AH correlated inversely with white matter integrity. However, that hypothesis-driven isolation of specific tracts likely missed important white matter concomitants of AH. In this report, we used a whole-brain data-driven dimensional approach using correlational tractography to associate AH severity with white matter integrity in a sample of 175 individuals. Diffusion Spectrum Imaging (DSI) was used to image diffusion distribution. Quantitative Anisotropy (QA) in three tracts was greater with increased AH severity (FDR < 0.001) and QA in three tracts was lower with increased AH severity (FDR < 0.01). White matter tracts showing associations between QA and AH were generally associated with frontal-parietal-temporal connectivity (tracts with known relevance for cognitive control and the language system), in the cingulum bundle, and in prefrontal inter-hemispheric connectivity. The results of this whole brain data-driven analysis suggest that subtle white matter alterations connecting frontal, parietal, and temporal lobes in the service of sensory-perceptual, language/semantic, and cognitive control processes impact the expression of auditory hallucination in FEP. Disentangling the distributed neural circuits involved in AH should help to develop novel interventions, such as non-invasive brain stimulation., Competing Interests: Declaration of competing interest The 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 © 2023 Elsevier B.V. All rights reserved.)

Psychosis (including symptoms of delusions, hallucinations, and disorganized conduct/speech) is a main feature of schizophrenia and is frequently present in other major psychiatric illnesses. Studies in individuals with first-episode (FEP) and early psychosis (EP) have the potential to interpret aberrant connectivity associated with psychosis during a period with minimal influence from medication and other confounds. The current study uses a data-driven whole-brain approach to examine patterns of aberrant functional network connectivity (FNC) in a multi-site dataset comprising resting-state functional magnetic resonance images (rs-fMRI) from 117 individuals with FEP or EP and 130 individuals without a psychiatric disorder, as controls. Accounting for age, sex, race, head motion, and multiple imaging sites, differences in FNC were identified between psychosis and control participants in cortical (namely the inferior frontal gyrus, superior medial frontal gyrus, postcentral gyrus, supplementary motor area, posterior cingulate cortex, and superior and middle temporal gyri), subcortical (the caudate, thalamus, subthalamus, and hippocampus), and cerebellar regions. The prominent pattern of reduced cerebellar connectivity in psychosis is especially noteworthy, as most studies focus on cortical and subcortical regions, neglecting the cerebellum. The dysconnectivity reported here may indicate disruptions in cortical-subcortical-cerebellar circuitry involved in rudimentary cognitive functions which may serve as reliable correlates of psychosis., 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. Published by Elsevier Inc.)

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals., Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder., Design, Setting, and Participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022., Main Outcomes and Measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores., Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (β = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (β = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate)., Conclusions and Relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Introduction: Semantic verbal fluency (SVF) impairments are debilitating and present early in the course of psychotic illness. Deficits within frontal, parietal, and temporal brain regions contribute to this deficit, as long-range communication across this functionally integrated network is critical to SVF. This study sought to isolate disruptions in functional and structural connectivity contributing to SVF deficits during first-episode psychosis in the schizophrenia spectrum (FESz)., Methods: Thirty-three FESz and 34 matched healthy controls (HC) completed the Animal Naming Task to assess SVF. Magnetoencephalography was recorded during an analogous covert SVF task, and phase-locking value (PLV) used to measure functional connectivity between inferior frontal and temporoparietal structures bilaterally. Diffusion imaging was collected to measure fractional anisotropy (FA) of the arcuate fasciculus, the major tract connecting frontal and temporoparietal language areas., Results: SVF scores were lower among FESz compared to HC. While PLV and FA did not differ between groups overall, FESz exhibited an absence of the left-lateralized nature of both measures observed in HC. Among FESz, larger right-hemisphere PLV was associated with worse SVF performance (ρ = -0.51) and longer DUP (ρ = -0.50)., Discussion: In addition to worse SVF, FESz exhibited diminished leftward asymmetry of structural and functional connectivity in fronto-temporoparietal SVF network. The relationship between theta-band hyperconnectivity and poorer performance suggests a disorganized executive network and may reflect dysfunction of frontal cognitive control centers. These findings illustrate an aberrant pattern across the distributed SVF network at disease onset and merit further investigation into development of asymmetrical hemispheric connectivity and its failure among high-risk populations., Competing Interests: Declaration of competing interest None of the authors reported any potential conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Sensory abnormalities are characteristic of autism and schizophrenia. In autism, greater trial-to-trial variability (TTV) in sensory neural responses suggest that the system is more unstable. However, these findings have only been identified in the amplitude and not in the timing of neural responses, and have not been fully explored in schizophrenia. TTV in event-related potential amplitudes and inter-trial coherence (ITC) were assessed in the auditory mismatch negativity (MMN) in autism, schizophrenia, and controls. MMN was largest in autism and smallest in schizophrenia, and TTV was greater in autism and schizophrenia compared to controls. There were no differences in ITC. Greater TTV appears to be characteristic of both autism and schizophrenia, implicating several neural mechanisms that could underlie sensory instability., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Hypothesis: Despite accounting for significant disease morbidity in schizophrenia, the neuropathological basis of negative symptoms remains poorly understood and options for treatment limited. Our recent study identified robust associations between diminished auditory cortex (AC) dynamic range and social functioning impairments and negative symptoms in first episode psychosis (FESz). The current investigation examined the progression of these relationships 4-8 months from baseline testing., Study Design: Twenty-six FESz and 38 healthy controls (HC) were tested at baseline and follow-up. Magnetoencephalography (MEG) was recorded during binaural presentation of tones (75, 80, and 85 dB). Assessments included the MATRICS cognitive consensus battery (MCCB) and Global Functioning: Role and Social scales (GFR/GFS) and the Positive and Negative Syndrome Scale., Study Results: Overall, FESz exhibited a blunted response to increasing tone intensity relative to HC. While this deficit did not change over time at the group level, recovery of right hemisphere AC dynamic range (85-75 dB response) among FESz individuals was associated with reductions in negative symptoms (ρ = -0.50). Diminished dynamic range was also associated with impaired GFS (ρ = 0.65), GFR (ρ = 0.51), and MCCB (ρ = 0.49) at baseline and increased negative symptoms at baseline (ρ = -0.53) and follow-up (ρ = -0.51)., Conclusion: Despite persistent dynamic range impairment in FESz as a group, individual recovery of this AC response property was associated with significant reduction in negative symptoms. Identification of a functional neural deficit that tracts progression of negative symptoms during a critical period for disease modification is essential to the management of these devastating and historically treatment refractory symptoms., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Attentional control of auditory N100/M100 gain is reduced in individuals with first-episode psychosis (FEP). Persistent problems with executive modulation of auditory sensory activity may impact multiple aspects of psychosis. As a follow-up to our prior work reporting deficits in attentional M100 gain modulation in auditory cortex, we examined changes in M100 gain modulation longitudinally, and further examined relationships between auditory M100 and symptoms of psychosis. We compared auditory M100 in auditory sensory cortex between 21 FEP and 29 matched healthy participants and between timepoints separated by 220 ± 100 days. Magnetoencephalography data were recorded while participants alternately attended or ignored tones in an auditory oddball task. M100 was measured as the average of 80-140 ms post-stimulus in source-localized evoked responses within bilateral auditory cortex. Symptoms were assessed using the PANSS and PSYRATS. M100 amplitudes, attentional modulation of M100 amplitudes, and symptom severity all improved in FEP over time. Further, improvement in M100 modulation correlated with improvements in negative symptoms (PANSS) as well as physical, cognitive, and emotional components of hallucinations (PSYRATS). Conversely, improvements in the overall size of the M100, rather than the difference between active and passive M100 amplitudes, were related to worsening of positive symptoms (PANSS) and physical components of hallucinations. Results indicate a link between symptoms (particularly auditory hallucinations) and auditory cortex neurophysiology in FEP, where auditory attention and auditory sensation have opposed relationships to symptom change. These findings may inform current models of psychosis etiology and could provide nonpharmaceutical avenues for early intervention., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Hypothesis: There is growing appreciation for the contribution of sensory disruptions to disease morbidity in psychosis. The present study examined auditory cortex (AC) dynamic range: the scaling of neurophysiological responses to stimulus intensity, among individuals with a schizophrenia spectrum illness (FESz) and its relationship to clinical outcomes at disease onset., Study Design: Magnetoencephalography (MEG) was recorded from 35 FESz and 40 healthy controls (HC) during binaural presentation of tones at three intensities (75 dB, 80 dB, and 85 dB). MRIs were obtained to enhance cortical localization of MEG sensor-level activity. All participants completed the MATRICS cognitive battery (MCCB) and Global Functioning: Role and Social scales (GFR/GFS). Patients were administered the Positive and Negative Syndrome Scale (PANSS)., Study Results: FESz exhibited reduced AC response relative to HC. Enhancement of AC activity to tones of increasing intensity was blunted in FESz relative to HC. Reduced dynamic range (85-75 dB AC response) was associated with lower GFS (r = .58) and GFR (r = .45) scores, worse MCCB performance (r = .45), and increased PANSS Negative symptom subscale scores (r = -.55) among FESz, relationships not observed with AC responses to individual tones., Conclusion: Beyond an impaired AC response to pure tones, FESz exhibit reduced dynamic range relative to HC. This impairment was correlated with markers of disease morbidity including poorer community functioning as well as cognitive and negative symptoms. The relationship with impaired social functioning may reflect the role of AC dynamic range in decoding the emotional content of language and highlights its importance to future therapeutic sensory remediation protocols., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

It is not known how Auditory-Evoked Responses (AERs) comprising Middle Latency Responses (MLRs) and Long Latency Responses (LLRs) are modulated by stimulus intensity and inter-stimulus interval (ISI) in an unpredictable auditory context. Further, intensity and ISI effects on MLR and LLR have never been assessed simultaneously in the same humans. To address this important question, thirty participants passively listened to a random sequence of auditory clicks of three possible intensities (65, 75, and 85 dB) at five possible ISI ranges (0.25 to 0.5 s, 0.5 to 1 s, 1 to 2 s, 2 to 4 s, 4 to 8 s) over four to seven one-hour sessions while EEG was recorded. P0, Na, Pa, Nb, and Pb MLR peaks and N1 and P2 LLR peaks were measured. MLRs P0 (p = .005), Pa (p = .021), and Pb (p = <.001) were modulated by intensity, while only MLR Pb (p = <.001) was modulated by ISI. LLR N1 and P2 were modulated by both intensity and ISI (all p values < .001). Intensity and ISI interacted at Pb, N1, and P2 (all p values < .001), with greater intensity effects at longer ISIs and greater ISI effects at louder intensities. Together, these results provide a comprehensive picture of intensity and ISI effects on AER across the entire thalamocortical auditory pathway, while controlling for stimulus predictability. Moreover, they highlight P0 as the earliest MLR response sensitive to stimulus intensity and Pb (~50 ms) as the earliest cortical response coding for ISIs above 250 ms and showing an interdependence between intensity and ISI effects., (© 2022 Society for Psychophysiological Research.)

Background: Selective attention deficits in first episode of psychosis (FEP) can be indexed by impaired attentional modulation of auditory M100. It is unknown if the pathophysiology underlying this deficit is restricted to auditory cortex or involves a distributed attention network. We examined the auditory attention network in FEP., Methods: MEG was recorded from 27 FEP and 31 matched healthy controls (HC) while alternately ignoring or attending tones. A whole-brain analysis of MEG source activity during auditory M100 identified non-auditory areas with increased activity. Time-frequency activity and phase-amplitude coupling were examined in auditory cortex to identify the attentional executive carrier frequency. Attention networks were defined by phase-locking at the carrier frequency. Spectral and gray matter deficits in the identified circuits were examined in FEP., Results: Attention-related activity was identified in prefrontal and parietal regions, markedly in precuneus. Theta power and phase coupling to gamma amplitude increased with attention in left primary auditory cortex. Two unilateral attention networks were identified with precuneus seeds in HC. Network synchrony was impaired in FEP. Gray matter thickness was reduced within the left hemisphere network in FEP but did not correlate with synchrony., Conclusion: Several extra-auditory attention areas with attention-related activity were identified. Theta was the carrier frequency for attentional modulation in auditory cortex. Left and right hemisphere attention networks were identified, with bilateral functional deficits and left hemisphere structural deficits, though FEP showed intact auditory cortex theta phase-gamma amplitude coupling. These novel findings indicate attention-related circuitopathy early in psychosis potentially amenable to future non-invasive interventions., Competing Interests: The 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 © 2023 Curtis, Sklar, Coffman and Salisbury.)

Selective attention is impaired in first-episode psychosis (FEP). Selective attention effects can be detected during auditory tasks as increased sensory activity. We previously reported electroencephalography scalp-measured N100 enhancement is reduced in FEP. Here, we localized magnetoencephalography (MEG) M100 source activity within the auditory cortex, making novel use of the Human Connectome Project multimodal parcellation (HCP-MMP) to identify precise auditory cortical areas involved in attention modulation and its impairment in FEP. MEG was recorded from 27 FEP and 31 matched healthy controls (HC) while individuals either ignored frequent standard and rare oddball tones while watching a silent movie or attended tones by pressing a button to oddballs. Because M100 arises mainly in the auditory cortices, MEG activity during the M100 interval was projected to the auditory sensory cortices defined by the HCP-MMP (A1, lateral belt, and parabelt parcels). FEP had less auditory sensory cortex M100 activity in both conditions. In addition, there was a significant interaction between group and attention. HC enhanced source activity with attention, but FEP did not. These results demonstrate deficits in both sensory processing and attentional modulation of the M100 in FEP. Novel use of the HCP-MMP revealed the precise cortical areas underlying attention modulation of auditory sensory activity in healthy individuals and impairments in FEP. The sensory reduction and attention modulation impairment indicate local and systems-level pathophysiology proximal to disease onset that may be critical for etiology. Further, M100 and N100 enhancement may serve as outcome variables for targeted intervention to improve attention in early psychosis., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Introduction: Aberrant network connectivity is a core deficit in schizophrenia and may underlie many of its associated cognitive deficits. Previous work in first-episode schizophrenia spectrum illness (FESz) suggests preservation of working memory network function during low-load conditions with dysfunction emerging as task complexity increases. This study assessed visual network connectivity and its contribution to load-dependent working memory impairments., Methods: Magnetoencephalography was recorded from 35 FESz and 28 matched controls (HC) during a lateralized change detection task. Impaired alpha desynchronization was previously identified within bilateral dorsal occipital (Occ) regions. Here, whole-brain alpha-band connectivity was examined using phase-locking (PLV) and bilateral Occ as connectivity seeds. Load effects on connectivity were assessed across participants, and PLV modulation within networks was compared between groups., Results: Occ exhibited significant load modulated connectivity with six regions (FDR-corrected). HC exhibited PLV enhancement with load in all connections. FESz failed to show PLV modulation between right Occ and left inferior frontal gyrus, lateral occipito-temporal sulcus, and anterior intermediate parietal sulcus. Smaller PLVs in all three network connections during both memory load conditions were associated with increased reality distortion in FESz (FDR-corrected.) CONCLUSION: Examination of functional connectivity across the visual working memory network in FESz revealed an inability to enhance communication between perceptual and executive networks in response to increasing cognitive demands. Furthermore, the degree of network communication impairment was associated with positive symptoms. These findings provide insights into the nature of brain dysconnectivity and its contribution to symptoms in early psychosis and identify potential targets for future interventions., (Published by Elsevier Ltd.)

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the 'normativeness' of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation., (© 2022. The Author(s).)

Background: The neurodevelopmental model of psychosis was established over 30 years ago; however, the developmental influence on psychotic symptom expression - how age affects clinical presentation in first-episode psychosis - has not been thoroughly investigated., Methods: Using generalized additive modeling, which allows for linear and non-linear functional forms of age-related change, we leveraged symptom data from a large sample of antipsychotic-naïve individuals with first-episode psychosis ( N = 340, 12-40 years, 1-12 visits), collected at the University of Pittsburgh from 1990 to 2017. We examined relationships between age and severity of perceptual and non-perceptual positive symptoms and negative symptoms. We tested for age-associated effects on change in positive or negative symptom severity following baseline assessment and explored the time-varying relationship between perceptual and non-perceptual positive symptoms across adolescent development., Results: Perceptual positive symptom severity significantly decreased with increasing age ( F = 7.0, p = 0.0007; q = 0.003) while non-perceptual positive symptom severity increased with age ( F = 4.1, p = 0.01, q = 0.02). Anhedonia severity increased with increasing age ( F = 6.7, p = 0.00035; q = 0.0003), while flat affect decreased in severity with increased age ( F = 9.8, p = 0.002; q = 0.006). Findings remained significant when parental SES, IQ, and illness duration were included as covariates. There were no developmental effects on change in positive or negative symptom severity (all p > 0.25). Beginning at age 18, there was a statistically significant association between severity of non-perceptual and perceptual symptoms. This relationship increased in strength throughout adulthood., Conclusions: These findings suggest that as maturation proceeds, perceptual symptoms attenuate while non-perceptual symptoms are enhanced. Findings underscore how pathological brain-behavior relationships vary as a function of development.

The 40-Hz auditory steady state response (ASSR) is reduced early in schizophrenia, with differences evident even at the first episode of schizophrenia-spectrum psychosis (FESz). Although robust, there is high variability in effect size across studies, possibly due to differences in experimental control of attention and heterogeneity of symptom profiles across studies, both of which may affect the ASSR. We investigated the relationships among ASSR deficits, attention-mediated sensory gain, and auditory hallucinations in 25 FESz (15 male; 23.3 ± 4.5 years) and 32 matched healthy comparison subjects (HC, 22 male; 24.7 ± 5.8 years). ASSR was measured to 40-Hz click trains at three intensities (75, 80, and 85 dB) while participants attended or ignored stimuli. ASSR evoked power and inter-trial phase coherence (ITPC) were measured using the Morlet wavelet transform. FESz did not show overall ASSR power reduction (p > 0.1), but power was significantly increased with attention in HC (p < 0.01), but not in FESz (p > 0.1). Likewise, FESz did not evince overall ASSR ITPC reduction (p > 0.1), and ITPC was significantly increased with attention in HC (p < 0.01), but not in FESz (p > 0.09). Attention-related change in ASSR correlated with auditory hallucination severity for power (r = -0.49, p < 0.05) and ITPC (r = -0.58, p < 0.01). FESz with auditory hallucinations may have pathologically increased basal excitability of auditory cortex and consequent reduced ability to further increase auditory cortex sensory gain with focused attention. These findings indicate hallucination-related pathophysiology early in schizophrenia and may guide novel intervention strategies aimed to modulate basal activity levels., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Hypothesis: Quantitative models of psychopathology can empirically guide subclassification of heterogeneous clinical presentations such as psychosis; they are particularly well-equipped to capture the nuanced symptomatology observed in first-episode psychosis. As well, components may be better aligned with biological variables. The current study sought to confirm and extend knowledge of the hierarchical structure of psychosis symptoms in first-episode psychosis. Based on past hierarchical work, we hypothesized that a 4 component level would be most closely associated with longitudinal disability., Study Design: Participants with early-stage psychosis (N = 370) underwent clinical assessment with the scale for the assessment of positive symptoms (SAPS), scale for assessment of negative symptoms (SANS), and global assessment scale(GAS). A subset was assessed at 6 months (N = 221) and 1 year (N = 207). Hierarchical symptom components were extracted at 12 levels. The predictive utility of the components for global functioning was tested., Study Results: As predicted, the 4-component model (reality distortion, thought disorder, inexpressivity, apathy/asociality) provided a superior prediction of functioning over other levels of the hierarchy. Baseline apathy/asociality longitudinally predicted functioning beyond the shared variance of the components at 6 months (b = -4.83, t(216) = -5.37, p < .001, R2adj = 0.12) and 1-year (b = -4.49, t(202) = -4.38, p < .001, R2adj = 0.09)., Conclusions: The hierarchical structure of psychotic symptomatology and its external validity have been robustly established in independent, longitudinal first-episode psychosis samples. The established model incorporates multiple levels of granularity that can be flexibly applied based on the level that offers the greatest predictive utility for external validators., (Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2022.)

Individuals with autism typically experience a range of symptoms, including abnormal sensory sensitivities. However, there are conflicting reports on the sensory profiles that characterize the sensory experience in autism that often depend on the type of stimulus. Here, we examine early auditory processing to simple changes in pitch and later auditory processing of more complex emotional utterances. We measured electroencephalography in 24 adults with autism and 28 controls. First, tones (1046.5Hz/C6, 1108.7Hz/C#6, or 1244.5Hz/D#6) were repeated three times or nine times before the pitch changed. Second, utterances of delight or frustration were repeated three or six times before the emotion changed. In response to the simple pitched tones, the autism group exhibited larger mismatch negativity (MMN) after nine standards compared to controls and produced greater trial-to-trial variability (TTV). In response to the prosodic utterances, the autism group showed smaller P3 responses when delight changed to frustration compared to controls. There was no significant correlation between ERPs to pitch and ERPs to prosody. Together, this suggests that early auditory processing is hyper-sensitive in autism whereas later processing of prosodic information is hypo-sensitive. The impact the different sensory profiles have on perceptual experience in autism may be key to identifying behavioral treatments to reduce symptoms., Competing Interests: The 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 © 2022 Haigh, Brosseau, Eack, Leitman, Salisbury and Behrmann.)

Background and Hypothesis: Cortical (e.g., Broca's area and Wernicke's area) and subcortical (e.g., putamen) language-related areas and executive control areas (e.g., inferior frontal gyrus (IFG), dorsolateral prefrontal cortex (DLPFC)) show functional and structural dysconnectivity in long-term psychosis. We examined whether resting-state basal perfusion levels revealed selective pathophysiology (likely hypo- and hyper-activation) of language-related and executive areas in first-episode psychosis (FEP)., Study Design: Basal resting-state perfusion was measured using pseudo-continuous Arterial Spin Labeling (pcASL). Relative cerebral blood flow (rCBF) was compared between 32 FEP and 34 matched healthy comparison (HC) individuals. Structural and functional MRI scans were acquired using a 3T Prisma scanner during the same session., Study Results: Whole-brain comparison of resting rCBF identified 8 clusters with significant between-group differences. Reduced rCBF was found in executive control areas in left and right IFG, right DLPFC, and right parietal cortex. Increased rCBF was found in left and right temporal cortex (including Wernicke's area), and left and right putamen. A positive correlation was observed between auditory hallucination severity and rCBF in the left putamen., Conclusions: To the degree that perfusion implies activation, language and auditory processing areas in bilateral temporal lobe and putamen showed pathological hyper-activity, and cognitive control areas (IFG, DLPFC, right parietal) showed pathological hypo-activity in FEP at rest. Pathological basal activity was present across the range of symptom severity, suggesting it may be a common underlying pathology for psychosis that may be targeted with non-invasive brain stimulation to normalize resting activity levels., 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 © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cognitive impairments account for significant morbidity in schizophrenia and are present at disease onset. Controlled processes are particularly susceptible and may contribute to pervasive selective attention deficits. The present study assessed fronto-parietal attention network (FPAN) functioning during cue presentation on a visual search task in first-episode schizophrenia spectrum patients (FE) and its relation to symptom burden and community functioning. Brain activity was recorded with magnetoencephalography from 38 FE and 38 healthy controls (HC) during blocks of pop-out and serial search target detection. Activity during cue presentation was compared between groups across bilateral FPAN regions (frontal eye fields (FEF), inferior frontal gyrus (IFG), midcingulate cortex (MCC), and intraparietal sulcus (IPS)). FE exhibited greater right hemisphere IFG activity despite worse performance relative to HC. Performance and FPAN activity were not correlated in HC. Among FE, however, stronger activity within right hemisphere FEF and IFG was associated with faster responses. Stronger right IPS and left IFG activity in patients was also associated with reduced negative symptoms and improved community functioning, respectively. Increased reliance on the FPAN for task completion suggests an inefficient cognitive control network and might reflect a compensation for impaired attentional deployment during target detection, a strategy employed by those with less severe illness. These findings represent a critical step towards identifying the neural substrates of negative symptoms and impaired neurocognition at disease onset., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Sensation Seeking, the proclivity toward novel and stimulating experiences, is associated with greater left ventrolateral prefrontal cortex (vlPFC) activity during uncertain reward expectancy. Here, we examined relationships between sensation seeking and vlPFC oscillatory dynamics using electroencephalography (EEG)., Methods: In 26 adolescents/young adults (16 female; 22.3 ± 1.7yrs), EEG was measured during uncertain reward expectancy. Event-related spectral perturbations (ERSP) from 15-80 Hz (beta/gamma bands) were compared as a function of uncertain reward expected value and assessed for relationships with feedback-related negativity (FRN) response to outcome feedback and response tendency measures of risk for BD., Results: Event-related synchronization (ERS) between 15-25 Hz (beta) over left vlPFC was sensitive to the expected value of uncertain reward (rho=0.46; p = 0.048), and correlated with sensation seeking (r = 0.49, p < 0.01) and feedback-related negativity (FRN), where greater beta ERS was related to larger FRN (r = -0.39, p = 0.047). FRN was also related to behavioral inhibition (r = 0.49, p < 0.01)., Limitations: It is unknown whether results may extrapolate to clinical populations, given the healthy sample used here. Further, although we have confidence that the beta-band signal we measure in this study arises from left prefrontal cortex, we largely infer a left vlPFC source., Conclusions: These findings highlight the role of left vlPFC in evaluation of immediate rewards. We now provide a link between reward expectancy-related left vlPFC activity and the well-characterized FRN, with a known role in attentive processing. These findings can guide treatment development for mania/hypomania at-risk individuals, including transcranial alternating current stimulation., (Copyright © 2021. Published by Elsevier B.V.)

Importance: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk., Objective: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-)., Design, Setting, and Participants: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020., Main Outcomes and Measures: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group)., Results: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001)., Conclusions and Relevance: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.

Reductions of the auditory N100 are present in schizophrenia, even at the first episode (FESz). Because most studies examine auditory N100 on active target detection oddball tasks, it remains unclear if the abnormality in FESz results from sensory deficits or impaired enhancement of N100 by selective attention, or both. N100 was recorded from 21 FESz and 22 matched healthy controls (HC) on a single-tone task and a two-tone oddball task. Overall, N100 was smaller in FESz (p = .036). Attention enhanced N100 amplitude (p < .001), but this differed between groups, with FESz impaired in N100 modulation (group x attention, p = .012). The oddball task showed greater N100 enhancement than the single-tone task (p < .001) in both groups. Group differences in N100 enhancement in the oddball task were large (Cohen's d = 0.85). Exploratory correlations showed that better N100 enhancement on the oddball task in FESz was associated with better MATRICS Overall Composite scores (cognitive tasks highly sensitive to psychosis), lower PANNS Negative factor and SANS scores, and better interpersonal (social) and role functioning in the last year. N100 during ignore conditions showed no significant difference between groups, albeit smaller in FESz, with small to medium effect sizes. Although sensory deficits in N100 are likely present, they are compounded by a failure to enhance N100 with attention. The failure of N100 enhancement by attentional gain control in FESz suggests functional dysconnection between cognitive control areas and the sensory cortex. N100 amplitude on active attention tasks may be a useful outcome biomarker for targeted enhancement of the cognitive control system., (© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Pitch and duration mismatch negativity (pMMN/dMMN) are related to left Heschl's gyrus gray matter volumes in first-episode schizophrenia (FESz). Previous methods were unable to delineate functional subregions within and outside Heschl's gyrus. The Human Connectome Project multimodal parcellation (HCP-MMP) atlas overcomes this limitation by parcellating these functional subregions. Further, MMN has generators in inferior frontal cortex, and therefore, may be associated with inferior frontal cortex pathology. With the novel use of the HCP-MMP to precisely parcellate auditory and inferior frontal cortex, we investigated relationships between gray matter and pMMN and dMMN in FESz., Methods: pMMN and dMMN were measured at Fz from 27 FESz and 27 matched healthy controls. T1-weighted MRI scans were acquired. The HCP-MMP atlas was applied to individuals, and gray matter volumes were calculated for bilateral auditory and inferior frontal cortex parcels and correlated with MMN. FDR correction was used for multiple comparisons., Results: In FESz only, pMMN was negatively correlated with left medial belt in auditory cortex and area 47L in inferior frontal cortex. Duration MMN negatively correlated with the following auditory parcels: left medial belt, lateral belt, parabelt, TA2, and right A5. Further, dMMN was associated with left area 47L, right area 44, and right area 47L in inferior frontal cortex., Conclusions: The novel approach revealed overlapping and distinct gray matter associations for pMMN and dMMN in auditory and inferior frontal cortex in FESz. Thus, pMMN and dMMN may serve as biomarkers of underlying pathological deficits in both similar and slightly different cortical areas., (© The Author(s) 2021. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Early course schizophrenia is associated with reduced gray matter. The specific structures affected first and how deficits impact symptoms and cognition remain unresolved. We used the Human Connectome Project multimodal parcellation (HCP-MMP) to precisely identify cortical areas and investigate thickness abnormalities in discovery and replication samples of first-episode schizophrenia spectrum individuals (FESz). In the discovery sample, T1w scans were acquired from 31 FESz and 31 matched healthy controls (HC). Thickness was calculated for 360 regions in Freesurfer. In the replication sample, high-resolution T1w, T2w, and BOLD-rest scans were acquired from 23 FESz and 32 HC and processed with HCP protocols. Thickness was calculated for regions significant in the discovery sample. After FDR correction (q < .05), left and right parahippocampal area 3 (PHA3) were significantly thinner in FESz. In the replication sample, bilateral PHA3 were again thinner in FESz (q < .05). Exploratory correlation analyses revealed left PHA3 was positively associated with hallucinations and right PHA3 was positively associated with processing speed, working memory, and verbal learning. The novel use of the HCP-MMP in two independent FESz samples revealed thinner bilateral PHA3, suggesting this byway between cortical and limbic processing is a critical site of pathology near the emergence of psychosis., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Functional connectivity abnormalities between Broca's and Wernicke's areas and the putamen revealed by functional magnetic resonance imaging (fMRI) are related to auditory hallucinations (AH). In long-term schizophrenia, reduced white matter structural integrity revealed by diffusion imaging in left arcuate fasciculus (connecting Broca's and Wernicke's areas) is likely related to AH. The structural integrity of connections with putamen and their relation to AH are unknown. Little is known about this relationship in first-episode psychosis (FEP), although auditory transcallosal connections were reported to play a role. White matter in the Broca's-Wernicke's-putamen language-related circuit and auditory transcallosal fibers was examined to investigate associations with AH in FEP., Methods: White matter connectivity was measured in 40 FEP and 32 matched HC using generalized fractional anisotropy (gFA) derived from diffusion spectrum imaging (DSI)., Results: FEP and HC did not differ in gFA in any fiber bundle. In FEP, AH severity was significantly inversely related to gFA in auditory transcallosal fibers and left arcuate fasciculus. Although the right hemisphere arcuate fasciculus-AH association did not attain significance, the left and right arcuate fasciculus associations were not significantly different., Conclusions: Despite overall normal gFA in FEP, AH severity was significantly related to gFA in transcallosal auditory fibers and the left hemisphere connection between Broca's and Wernicke's areas. Other bilateral tracts' gFA were weakly associated with AH. At the first psychotic episode, AH are more robustly associated with left hemisphere arcuate fasciculus and interhemispheric auditory fibers microstructural deficits, likely reflecting mistiming of information flow between language-related cortical centers., (© 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.)

Background . The mismatch negativity (MMN) brainwave indexes novelty detection. MMN to infrequent pitch (pMMN) and duration (dMMN) deviants is reduced in long-term schizophrenia. Although not reduced at first psychosis, pMMN is inversely associated with left hemisphere Heschl's gyrus (HG) gray matter volume within 1 year of first hospitalization for schizophrenia-spectrum psychosis, consistent with pathology of left primary auditory cortex early in disease course. We examined whether the relationship was present earlier, at first psychiatric contact for psychosis, and whether the same structural-functional association was apparent for dMMN. Method . Twenty-seven first-episode schizophrenia-spectrum (FESz) and 27 matched healthy comparison (HC) individuals were compared. EEG-derived pMMN and dMMN were measured by subtracting the standard tone waveform (80%) from the pitch- and duration-deviant waveforms (10% each). HG volumes were calculated from T1-weighted structural magnetic resonance imaging using Freesurfer. Results . In FESz, pMMN amplitudes at Fz were inversely associated with left HG (but not right) gray matter volumes, and dMMN amplitudes were associated significantly with left HG volumes and at trend-level with right HG. There were no structural-functional associations in HC. Conclusions . pMMN and dMMN index gray matter reduction in left hemisphere auditory cortex early in psychosis, with dMMN also marginally indexing right HG volumes. This suggest conjoint functional and structural pathology that affects the automatic detection of novelty with varying degrees of penetrance prior to psychosis. These brainwaves are sensitive biomarkers of pathology early in the psychotic disease course, and may serve as biomarkers of disease progression and as therapeutic outcome measures.

Working memory dysfunction may be central to neurocognitive deficits in schizophrenia. Maintenance of visual information in working memory, or visual short-term memory (vSTM), is linked to general cognitive dysfunction and predicts functional outcome. Lateralized change-detection tasks afford investigation of the contralateral delay activity (CDA), a useful tool for investigating vSTM dysfunction. Previous work suggests "hyperfocusing" of attention in schizophrenia, such that CDA is increased when a single item is maintained in vSTM but reduced for multiple items. If observed early in the disease, vSTM dysfunction may be a key feature of schizophrenia or target for intervention. We investigated CDA during lateralized vSTM of one versus three items using sensor-level electroencephalography and source-level magnetoencephalography in 26 individuals at their first episode of schizophrenia-spectrum psychosis (FESz) and 26 matched healthy controls. FESz were unable to modulate CDA with increased memory load - high-load CDA was reduced and low-load CDA was increased compared to controls. Further, sources of CDA in posterior parietal cortex were reduced in FESz and indices of working memory were correlated with neurocognitive deficits and symptom severity. These results support working memory maintenance dysfunction as a central and early component to the disorder. Targeted intervention focusing on vSTM deficits may be warranted to alleviate downstream effects of this disability., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Little is known about neural oscillatory dynamics in first-episode psychosis. Pathophysiology of functional connectivity can be measured through network activity of alpha oscillations, reflecting long-range communication between distal brain regions., Methods: Resting magnetoencephalographic activity was collected from 31 individuals with first-episode schizophrenia spectrum psychosis and 22 healthy control individuals. Activity was projected to the realistic cortical surface, based on structural magnetic resonance imaging. The first principal component of activity in 40 Brodmann areas per hemisphere was Hilbert transformed within the alpha range. Non-negative matrix factorization was applied to single-trial alpha phase-locking values from all subjects to determine alpha networks. Within networks, energy and entropy were compared., Results: Four cortical alpha networks were pathological in individuals with first-episode schizophrenia spectrum psychosis. The networks involved the bilateral anterior and posterior cingulate; left auditory, medial temporal, and cingulate cortex; right inferior frontal gyrus and widespread areas; and right posterior parietal cortex and widespread areas. Energy and entropy were associated with the Positive and Negative Syndrome Scale total and thought disorder factors for the first three networks. In addition, the left posterior temporal network was associated with positive and negative factors, and the right inferior frontal network was associated with the positive factor., Conclusions: Machine learning network analysis of resting alpha-band neural activity identified several aberrant networks in individuals with first-episode schizophrenia spectrum psychosis, including the left temporal, right inferior frontal, right posterior parietal, and bilateral cingulate cortices. Abnormal long-range alpha communication is evident at the first presentation for psychosis and may provide clues about mechanisms of dysconnectivity in psychosis and novel targets for noninvasive brain stimulation., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Knowledge is lacking regarding deficits in selective attention and their underlying biological mechanisms during early stages of schizophrenia. The present study examined the N2pc, a neurophysiological index of covert spatial attention, and its cortical sources at first psychotic episode in the schizophrenia spectrum (FESz)., Methods: Neurophysiological responses measured simultaneously with magnetoencephalography (MEG) and electroencephalography (EEG) during pop-out and serial search tasks were compared between 32 FESz and 32 matched healthy controls (HC). Mean scalp-recorded N2pc was measured from a cluster of posterior-lateral EEG electrodes. Cortical source-resolved MEG activity contributing to the N2pc signal was derived for the intraparietal sulcus (IPS) and lateral occipital complex (LOC)., Results: Group differences in EEG N2pc varied by task demand. FESz exhibited reduced N2pc amplitude during pop-out (p < .01), but not serial search (p = .11). Furthermore, group differences in N2pc-related MEG cortical activity varied by task demand and cortical region. Compared to HC, FESz exhibited greater IPS during serial search (p < .01)., Discussion: Reductions in EEG N2pc amplitude indicate an impairment of visuo-spatial attention evident at an individual's first psychotic episode, specifically during conditions emphasizing bottom-up processing. Examination of its cortical sources with MEG revealed that, compared to HC, FESz engaged parietal structures to a greater extent during the serial search condition. This pattern suggests a less efficient, more resource intensive strategy employed by FESz in response to a minimal demand on attention. The greater reliance on this controlled attentional network may negatively impact real-world functions with much greater complexity and attentional demands., Competing Interests: Declaration of competing interest None of the authors reported any biomedical financial interests or potential conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cognitive deficits in people with schizophrenia are among the hardest to treat and strongly predict functional outcome. The ability to maintain sensory precepts in memory over a short delay is impacted early in the progression of schizophrenia and has been linked to reliable neurophysiological markers. Yet, little is known about the mechanisms of these deficits. Here, we investigated possible neurophysiological mechanisms of impaired visual short-term memory (vSTM, aka working memory maintenance) in the first-episode schizophrenia spectrum (FESz) using magnetoencephalography (MEG). Twenty-eight FESz and 25 matched controls performed a lateralized change detection task where they were cued to selectively attend and remember colors of circles presented in either the left or right peripheral visual field over a 1 s delay. Contralateral alpha suppression (CAS) during the delay period was used to assess selective attention to cued visual hemifields held in vSTM. Delay-period CAS was compared between FESz and controls and between trials presenting one vs three items per visual hemifield. CAS in dorsal visual cortex was reduced in FESz compared to controls in high-load trials, but not low-load trials. Group differences in CAS were found beginning 100 ms after the disappearance of the memory set, suggesting deficits were not due to the initial deployment of attention to the cued visual hemifield prior to stimulus presentation. CAS was not greater for high-load vs low-load trials in FESz subjects, although this effect was prominent in controls. Further, lateralized gamma (34-40 Hz) power emerged in dorsal visual cortex prior to the onset of CAS in controls but not FESz. Gamma power in this cluster differed between groups at both high and low load. CAS deficits observed in FESz were correlated with change detection accuracy, working memory function, estimated IQ, and negative symptoms. Our results implicate deficits in CAS in trials requiring broad, but not narrow, focus of attention to spatially distributed objects maintained in vSTM in FESz, possibly due to reduced ability to broadly distribute visuospatial attention (alpha) or disruption of object-location binding (gamma) during encoding/consolidation. This early pathophysiology may shed light upon mechanisms of emerging working memory deficits that are intrinsic to schizophrenia., (Copyright © 2020 Coffman, Haas, Olson, Cho, Ghuman and Salisbury.)

Impairments in early-stage visual processing are observed in chronic psychosis. However, their presence, localization within the brain, and contribution to cognitive symptoms remain less well established early in disease course. The present study utilized magnetoencephalography (MEG) to examine sensory responses within primary visual cortex (V1). MEG was recorded from 38 individuals diagnosed with a schizophrenia spectrum illness at first psychotic episode (FESz) and 38 matched healthy controls (HC) during visual search tasks. The inverse solution for cortical activity contributing to the M100 visual evoked field was derived. Task performance and V1 activation were compared between groups. FESz exhibited a reduced V1 response relative to HC. This group deficit, however, was selective for the left hemisphere (LH). A similar interaction was observed for response time with FESz exhibiting slower responses to right visual field targets, a difference not observed among HC. Among FESz, larger LH V1 activity was associated with larger hallucination subscale scores on the Scale for the Assessment of Positive Symptoms. Early-stage visual processing deficits localized to V1 are present at disease onset in the schizophrenia spectrum. This impairment appears to be restricted to the LH, consistent with previous reports detailing a predominantly LH disease process in early psychosis, and activity within this region was associated with an increased experience of hallucinations. These findings detail the cortical responses contributing to visual processing impairments and their relationship with symptoms at disease onset, advancing our understanding of their developmental trajectory over the course of psychotic illness., (© 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.)

The N1, P2, and P3 event-related potentials (ERPs) are impaired in first-episode schizophrenia (FESz). Reduced pitch-deviant mismatch negativity (MMN) is present in chronic schizophrenia but not FESz. We examined effect sizes of, and correlations between, N1, P2, P3, and MMN in 106 FESz and 114 matched psychiatrically well controls to determine which ERPs maximally differentiated groups, and whether late sensory/perceptual deficits (N1, P2) affected preattentive memory (MMN) and conscious attention (P3). Furthermore, we compared hallucinators and nonhallucinators within FESz. Participants completed 1 of 3 oddball tasks, silently counting target tones among standard tones. Sixty-seven FESz and 72 matched participants also completed pitch-deviant MMN testing. Measures were z -scored from task appropriate controls before merging samples. Mean z -scores for N1, P2, and P3 were significantly abnormal in FESz, while pitch-deviant MMN was not. N1 showed the largest deficit ( z = 0.53), and only N1 was smaller in hallucinators (n = 71) than nonhallucinators (n = 27). Among all participants, early sensory processing (N1, P2) correlated with later cognitive processing (P3), and P2 and P3 also correlated with automatic preattentive memory (pitch-deviant MMN). In well individuals, N1 was associated with MMN. These data are consistent with bottom-up sensory/perceptual processes affecting more cognitive processes. However, N1 and MMN were not associated in FESz, suggesting different auditory cortex physiology underlie these ERPs, which is differentially affected in FESz. Larger P2 and P3 with greater estimated premorbid intellect in patients indicate a possible neuroprotective effect of intellect in FESz.

Mismatch negativity (MMN) is elicited by infrequent physical parameter sound changes. MMN to pitch-deviants (pMMN) and duration-deviants (dMMN) are severely reduced in long-term schizophrenia (Sz). Although symptom factors (positive, negative, cognitive) are inconsistently associated with MMN amplitude in Sz, several studies have shown smaller dMMN is associated with impaired social functioning in Sz. MMN is less reduced at the first psychotic episode in the schizophrenia spectrum (FESz). Meta-analyses demonstrate that pMMN is not reduced, while dMMN is moderately impaired. Correlations of pMMN and dMMN with symptom factors in FESz are also equivocal. Associations with social functioning have not been reported. FESz and matched controls (n = 40/group), and Sz and matched controls (n = 50/group) were assessed for baseline and current cognitive functioning, symptoms, and social functioning, and pMMN and dMMN were recorded. Sz showed reductions in pMMN (p = 0.001) and dMMN (p = 0.006) amplitude. By contrast, pMMN (p = 0.27) and dMMN (p = 0.84) were not reduced in FESz. However, FESz showed associations between both MMNs and negative symptoms and social functioning. More impaired MMNs in FESz were associated with increased negative symptoms and impaired social functioning, both current and in the year prior to the emergence of psychosis. These data suggest that the extent of pathological process occurring before first psychosis as reflected in compromised social behavior prior to first break and reduced interpersonal communication and increased alogia at first break is indexed by pMMN and dMMN, putative biomarkers of disease progression sensitive to functional impairment., (Copyright © 2020 Murphy, Haigh, Coffman and Salisbury.)