Objective: We examined the clinical utility of resting state electroencephalography (rsEEG) by evaluating its temporal stability, discriminant validity for B-SNIP psychosis Biotypes, and suitability as a treatment target for brain stimulation. Methods: We collected 5 minutes of eyes-open rsEEG from 1401 participants with psychosis and 750 healthy persons. A subset of participants was re-tested after 6 months and 12 months (N=109). In a pilot target engagement study (n=5) we collected rsEEG before and after 2 high-definition transcranial direct current stimulation (HD-tDCS) interventions targeting the left dorsolateral prefrontal cortex (dlPFC) and temporoparietal junction (TPJ). Data were reduced with principal component analyses to delta/theta, alpha, beta, and gamma frequency bands, and compared between groups and timepoints. Results: rsEEG frequency bands displayed good-to-excellent stability and significantly distinguished psychosis Biotypes with large effect sizes. Compared to healthy, Biotype-1 had low activity (average ES=-.58), Biotype-2 had high activity (ES=1.07), and Biotype-3 had slightly elevated activity (ES=.33). There were no rsEEG differences between DSM psychosis groups. After anodal dlPFC stimulation, alpha and gamma power slightly increased while positive symptoms and verbal fluency improved. After cathodal TPJ stimulation, delta/theta power slightly increased while psychoticism and digit sequencing improved. Conclusions: Resting state brain activity is a trait-like marker that differentiates B-SNIP psychosis Biotypes, suggesting differing underlying neurophysiology. The pilot intervention supports the feasibility of targeting this underlying neurophysiology with HD-tDCS. Integrating rsEEG in diagnostic procedures and stratified intervention selection may be beneficial for psychosis patients. ### Competing Interest Statement Drs. Pearlson, Gershon, Keedy, Tamminga, McDowell, Keshavan, and Clementz are on B-SNIP Diagnostics Board of Managers. Dr. Gershon is a Consultant for Kynexis Corporation. Dr. Tamminga is on the Kynexis Scientific Advisory Board and receives a retainer and the Karuna Therapeutics Scientific Advisory Board and owns stock. Dr. Keshavan is an advisor for Alkermes. Dr. Clementz is on the Kynexis Corporation Scientific Advisory Board. ### Funding Statement This study was funded by the National Institutes of Health (B-SNIP2: R01MH077851, R01MH103368, R01MH077945, R01MH103366, R01MH078113, PARDIP: R01MH096900, R01MH096942, R01MH096957, R01MH096913, B-SNIP1: R01MH078113, R01MH077945, R01MH077862, R01MH077851, R01MH077852; UL1TR002378, TL1TR002382, F32MH135669). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IRBs of Yale University, University of Illinois at Chicago, University of Maryland Baltimore, Wayne State University, UT Southwestern Medical Center, Beth Israel Deaconess Medical Center, University of Georgia, and University of Chicago gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Cross-sectional and longitudinal data produced in the present work is available online at the NIMH Data Archive. tDCS data produced in the present study is available upon reasonable request to the authors.

BACKGROUND AND HYPOTHESIS:The visual system is a significant site of pathology in psychosis spectrum disorders (PSD). However, there is limited research investigating visual cortex (VC) subregions in this population. Using data from the Bipolar-Schizophrenia Network on Intermediate Phenotypes Consortium (BSNIP-1/BSNIP-2/PARDIP), this study examined structural measures in VC subregions in individuals with PSD (IwP). STUDY DESIGN:Cortical surface area and thickness in 5 VC subregions (hOc1, hOc2, hOc3v, hOc4v, MT) were quantified using FreeSurfer v7.1.0 and compared between IwP (n = 1211) and healthy controls (HC, n = 734). Regional specificity was examined by controlling for total surface area or mean thickness. ComBat was used to harmonize scanner effects. Associations between VC measures and symptom severity, cognition, and childhood trauma scores were assessed. STUDY RESULTS:IwP demonstrated smaller surface area in hOc1, hOc2, and hOc3v, and lower cortical thickness in all 5 VC subregions compared to HC. Thickness reductions in hOc1, hOc4v, and MT were regionally specific. hOc4v and MT were among the top 3 regions exhibiting the most robust thickness deficits (d = -0.38 to -0.40) across all VC and Desikan-Killiany brain regions. Lower thickness in mid-level visual subregions was associated with greater positive symptoms and poorer cognition. Childhood trauma scores were related to thickness alterations in VC subregions. CONCLUSIONS:This study demonstrates that the VC is among the most profoundly affected brain regions in PSD. Different patterns of area and thickness alterations across early and mid-level visual subregions, along with varying associations with clinical measures, suggest distinct developmental and disease-related influences.

BACKGROUND:Abnormalities in thalamic structure and function are a consistent feature of psychosis spectrum disorders including schizophrenia (SZ), schizoaffective (SAD), and bipolar disorder with psychosis (BDP), yet the extent to which specific thalamic nuclei differ across diagnoses, and how these differences relate to cognition and psychopathology, remains unclear. We examined these questions, focusing on two nuclei - the mediodorsal (MD) and pulvinar (Pu), among individuals with psychosis (n = 2160) in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium. METHODS:Whole thalamus, MD, and Pu were estimated using FreeSurfer. Group comparisons were performed to examine volumetric differences between neurotypical controls (NC) and: (1) traditional diagnostic groups and (2) biologically-defined Biotypes identified through unsupervised clustering of neurophysiological features. Spearman correlations were used to assess the associations between subthalamic nuclei volumes and cognitive performances. RESULTS:The MD volumes were significantly smaller in individuals with SZ, SAD, BDP and BT1 compared to controls (Cohen's d between -0.17 to -0.37). MD and Pu volumes positively correlated with some cognitive functions, notably in the right MD. CONCLUSIONS:This is the largest study to date examining thalamic nuclei volumes across both DSM diagnoses and psychosis Biotypes. We demonstrate that MD reductions are transdiagnostic yet most pronounced in BT1, supporting the Biotype framework over traditional nosology. The links between MD volume and cognitive performance suggest that nucleus-specific thalamic markers may help refine mechanistic models and stratify future treatment targets. Multimodal studies integrating electrophysiology and functional imaging are warranted to clarify nuclei-specific contributions to psychosis.

Individuals at clinical high risk for psychosis (CHR) are cognitively and neurobiologically heterogeneous, which encourages the use of a clustering approach to parse this heterogeneity. Multimodal approaches are assumed to be superior to unimodal approaches in identifying subgroups. With the success of the use of cognition and electrophysiological measures collectively in established psychotic disorders, and the lack of such an approach in CHR, we were motivated to address this gap. Using the North American Psychosis-Risk Longitudinal Study (NAPLS) 2 consortia (CHR (N=764)), we applied unsupervised cluster analysis on the combined cognitive and electrophysiology measures to identify CHR subgroups and assess their relationship with clinical and functional outcomes. A two-cluster solution with modest separability was found, which prompted the use of an alternative probabilistic, rather than discrete, clustering approach. Individuals who were more likely to be in Cluster 1 exhibited poorer cognitive performance, larger N100, mismatch negativity, and P300 amplitudes, and worse functioning, as well as a younger age of onset. These findings were largely replicated in NAPLS 3 (CHR (N=628)). Taken together, the results of our previous study of cognition-only clustering and the current study of combining cognition and electrophysiology indicate that multimodal clustering, if not developmentally informed, may obscure meaningful subtyping.

BACKGROUND:Posttraumatic stress disorder (PTSD) is a common comorbid diagnosis in psychotic disorders. However, little is known about the effect of comorbid PTSD in youth at clinical high risk (CHR) for psychosis. PURPOSE:The purpose of this study was to investigate group differences in symptom severity, risk for psychotic conversion and functioning among youth at CHR for psychosis with and without PTSD. METHODS:This longitudinal study utilized data from N = 693 individuals who met criteria for CHR as part of the North American Prodrome Longitudinal Study 3 (NAPLS-3). Individuals who met criteria for PTSD were compared to those who did not meet criteria for PTSD on demographic, symptom and functional variables. RESULTS:Individuals diagnosed with PTSD (N = 54) reported more severe overall positive symptoms (p = 0.008), negative symptoms (p = 0.043) and general symptoms (p = 0.008) compared to those without the diagnosis (N = 639). These symptom differences were primarily accounted for by more grandiose symptoms (p = 0.026), decreased experience of emotions (p = 0.043), sleep disturbance (p = 0.043), dysphoric mood (p = 0.012) and impaired tolerance to stress (p = 0.008) in those with PTSD. In Cox proportional hazards models using the full sample with censoring at last follow-up, PTSD diagnosis was not associated with time to psychosis conversion. Exploratory analyses of trauma subtype within the PTSD group also did not identify any trauma category significantly associated with conversion risk. Timing of trauma exposure (early childhood, middle childhood, adolescence) was not significantly associated with conversion. CONCLUSIONS:Our findings suggest that a diagnosis of PTSD is associated with more severe overlapping symptoms in individuals meeting the criteria for CHR but not psychotic conversion. Our findings underscore the importance of recognizing and treating comorbid psychiatric conditions including PTSD in CHR populations as a means of reducing symptoms and improving outcomes.

Cannabis and tobacco use are highly prevalent among people with psychosis and are associated with medical comorbidities and poor prognosis. Concurrent use of cannabis and tobacco ('co-use') is rising in the general population, but has not been studied in psychosis. Given the devastating consequences of cannabis and tobacco use, it is critical to understand how their co-use affects psychiatric symptoms and the development of psychosis. Here we used the North American Prodrome Longitudinal Study-2, a multisite prospective study of individuals at clinical high risk for psychosis (CHR), and healthy controls to examine baseline differences in psychiatric symptoms and conversion to psychosis across substance groups: (1) CHR tobacco use, (2) CHR cannabis use, (3) CHR co-use, (4) CHR non-tobacco or cannabis use, (5) CHR without substance use and (6) healthy controls. Among 1,012 participants (734 CHR, 278 controls), more frequent cannabis and tobacco use was linked to greater psychiatric symptom severity. In survival analyses, heavy cannabis and light tobacco co-use (HR = 2.93, 95% confidence interval (CI) [1.23-6.97], P = 0.015) was associated with higher risk of conversion than no use of either substance. Co-use of tobacco and cannabis was not associated with psychiatric symptom severity but did predict higher risk of conversion to psychosis. These results highlight the need for strategies that address co-use in CHR populations to mitigate potential long-term psychiatric consequences.

BACKGROUND AND HYPOTHESIS:Adolescents and young adults at clinical high risk for developing psychosis (CHR) show persistent impairments in social and role functioning. Poor social functioning has been linked to greater risk of psychosis, but it remains unclear how functional trajectories differ across clinical outcomes. STUDY DESIGN:Ninety-six healthy controls (HC), 70 CHR-Converters and 415 CHR individuals who did not develop psychosis classified into Remission, Symptomatic, and Progression subgroups were included as part of the third phase of the North American Prodrome Longitudinal Study. Social and role functioning were assessed at baseline, 2, 4, 6, and 8 months using the Global Functioning: Social and Role scales, alongside clinical symptoms and intellectual functioning. STUDY RESULTS:Compared to HCs, all CHR subgroups showed significant social and role functioning impairments across time (Ps < .001). However, the pattern of impairment among the CHR subgroups differed by domain. For social functioning, converters had the lowest functioning compared to both HCs and the 3 non-converter subgroups. In contrast, for role functioning, converters were only significantly different from the progression subgroup. This pattern remained after adjusting for positive and depressive symptoms and intellectual functioning. In follow-up Cox regression analyses adjusting for positive symptoms, depressive symptoms, and intellectual functioning, lower baseline social functioning predicted shorter time to psychosis onset (HR = -0.168, 95%CI, 0.722-0.989; P = .036), but baseline role functioning did not emerge as a significant predictor (P = .057). CONCLUSIONS:CHR individuals who transition to psychosis show enduring impairments in social and role functioning that are evident at baseline and stable across the short-term follow-up period. Poor baseline social, but not role functioning independently predicted time to psychosis onset, underscoring its importance as a prognostic marker in the early identification of psychosis risk.

Objective Tobacco use is the top preventable cause of early mortality in schizophrenia, but the underlying pathophysiology remains unknown. In schizophrenia, small studies have linked default mode network (DMN) organization to tobacco use and showed that nicotine normalizes DMN disorganization. We sought to 1) validate the relationship between DMN organization and tobacco use using a large psychosis-spectrum sample (Bipolar-Schizophrenia Network on Intermediate Phenotypes 2, B-SNIP2); and 2) test if targeting this network with single and multiple sessions of transcranial magnetic stimulation (TMS) would affect craving. Methods In B-SNIP2 (n = 596), we tested associations between DMN connectivity and tobacco use. In the Single Session DMN-targeted TMS study, 10 individuals received single TMS sessions (intermittent theta burst stimulation, iTBS; continuous theta burst stimulation, cTBS; sham) with pre-/post-neuroimaging and craving assessment. In the Accelerated, Multi-Session DMN-targeted cTBS study, 12 individuals received 5 cTBS sessions with pre-/post-neuroimaging and craving assessment. Results In B-SNIP2 (n = 596), current smokers had lower DMN connectivity than former (p = .017) and never smokers (p = .021). These differences were also observed in the psychosis group (current vs. former p = .044; current vs. never p = .011). In the Single Session DMN-targeted TMS study (n = 10), there was a treatment∗time interaction (p = .020) where iTBS increased craving (padj = 0.018) compared to cTBS. In the Accelerated, Multi-Session DMN-targeted cTBS study (n = 12), DMN-targeted cTBS reduced craving after each session (p < .001) and reduced DMN connectivity (p = .047). Conclusions We identified a potential mechanism of nicotine use in psychosis and demonstrated that engaging this target reduces craving, suggesting a novel target for nicotine interventions in psychosis.

Thalamocortical circuits regulate information flow between sensory inputs and higher-order processing, and their disruption is increasingly implicated in psychotic disorders. However, scalable biomarkers of this circuitry remain limited. We assessed P50 sensory gating, 40 Hz auditory steady-state responses (ASSRs) and sleep spindles in relation to resting-state thalamocortical connectivity in early-course psychosis (EC, n = 19), first-degree relatives (FHR, n = 24), and demographically matched non-psychiatric comparison subjects (NC, n = 28). Compared to NC, EC, and FHR exhibited hyperconnectivity of the thalamus with the primary auditory cortex. Patients showed spindle deficits and impaired sensory gating and ASSRs, while FHR showed abnormal ASSR. In the entire sample, sleep spindles and sensory gating were associated with distinct thalamic connectivity patterns involving sensorimotor and dorsolateral prefrontal cortices, respectively. Our multimodal, circuit-informed approach points to thalamocortical pathways as potential biomarkers of risk and targets for treatment in psychosis. These findings should be interpreted in light of the modest sample sizes and the cross-sectional design, and suggest that wake EEG measures, though scalable, may not fully capture sleep-related thalamic abnormalities.

Objective:Tobacco and cannabis are the most used substances among individuals at clinical high risk for psychosis (CHR-P), but it remains controversial whether substance use drives symptom exacerbation and psychosis transition, or vice versa. We investigated longitudinal dose-response relationships of tobacco and cannabis use with clinical presentation in a CHR-P population. Methods:Data was obtained from the North American Prodrome Longitudinal Study (NAPLS2) CHR-P cohort (n=764). Participants were assessed every 6 months over two years. Substance use frequency, psychiatric symptoms (psychosis, depression, anxiety, and social anxiety), global social and role functioning, and neurocognitive performance were measured. Linear mixed effect models were used to model the relationship between substance use and clinical measurements across visits, and that between baseline use and trajectory of symptoms, functioning, and cognition. Results:Psychiatric symptoms, functioning, and cognitive performance improved, while tobacco and cannabis use frequency did not change over two years for CHR-P individuals in NAPLS2. Heavier tobacco and cannabis use at current visit predicted worse anxiety at next visit (tobacco: β=0.178, p=0.033; cannabis: β=0.162, p=0.018). Better social functioning predicted heavier tobacco (β=0.178, p<0.001) and cannabis: (β=0.162, p<0.001) use at next visit. We observed a significant baseline cannabis-by-time interaction, where heavier baseline cannabis use predicted slower improvement of negative symptoms (β=0.159, p=0.0017, FDRp=0.0067) and deterioration of role function (β=-0.046, p=0.018). Conclusions:In CHR-R, current tobacco and cannabis use predicted worse anxiety at future visits. Baseline cannabis use frequency predicts worse clinical trajectory, especially for negative symptoms.