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Background: The profiles of cortical gyrification across schizophrenia, bipolar I disorder, and schizoaffective disorder have been studied to a limited extent, report discordant findings, and are rarely compared in the same study. Here we assess gyrification in a large dataset of psychotic disorder probands, categorized according to the DSM-IV. Furthermore, we explore gyrification changes with age across healthy controls and probands., Methods: Participants were recruited within the Bipolar-Schizophrenia Network of Intermediate Phenotypes study and received T1-MPRAGE and clinical assessment. Gyrification was measured using FreeSurfer 7.1.0. Pairwise t-tests were conducted in R, and age-related gyrification changes were analyzed in MATLAB. P values <0.05 after false discovery rate correction were considered significant., Results: Significant hypogyria in schizophrenia, bipolar disorder, and schizoaffective disorder probands compared to controls was found, with a significant difference bilaterally in the frontal lobe between schizophrenia and bipolar disorder probands. Verbal memory was associated with gyrification in the right frontal and right cingulate cortex in schizophrenia. Age-fitted gyrification curves differed significantly among psychotic disorders and controls., Conclusions: Findings indicate hypogyria in DSM-IV psychotic disorders compared to controls and suggest differential patterns of gyrification across the different diagnoses. The study extends age related models of gyrification to psychotic disorder probands and supports that age-related differences in gyrification may differ across diagnoses. Fitted gyrification curves among probands categorized by DSM-IV significantly deviate from controls, with the model capturing early hypergyria and later hypogyria in schizophrenia compared to controls; this suggests unique disease and age-related changes in gyrification across psychotic disorders., Competing Interests: Declaration of competing interest The authors Rychagov, Zeng, Oykhman, Dr. del Re, Dr. Yassin, Dr. Lizano, Dr. Sweeny, Dr. Gershon, Dr. Pearlson, Dr. McDowell, and Dr. Clementz reported no potential conflicts of interest. Dr. Keshavan reports serving as an advisor to Alkermes, Takeda, and Vanna Inc. Dr. Tamminga reports the following financial disclosures: American Psychiatric Association – Deputy Editor; Astellas – Ad Hoc Consultant; Autifony – Ad Hoc Consultant; The Brain and Behavior Foundation – Council Member; Eli Lilly Pharmaceuticals – Ad Hoc Consultant; Intra-cellular Therapies (ITI, Inc.) – Advisory Board, drug development; Institute of Medicine – Council Member; National Academy of Medicine – Council Member; Pfizer – Ad Hoc Consultant; Sunovion – Investigator Initiated grant funding., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Enlarged pituitary gland volume could be a marker of psychotic disorders. However, previous studies report conflicting results. To better understand the role of the pituitary gland in psychosis, we examined a large transdiagnostic sample of individuals with psychotic disorders., Methods: The study included 751 participants (174 with schizophrenia, 114 with schizoaffective disorder, 167 with psychotic bipolar disorder, and 296 healthy controls) across six sites in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium. Structural magnetic resonance images were obtained, and pituitary gland volumes were measured using the MAGeT brain algorithm. Linear mixed models examined between-group differences with controls and among patient subgroups based on diagnosis, as well as how pituitary volumes were associated with symptom severity, cognitive function, antipsychotic dose, and illness duration., Results: Mean pituitary gland volume did not significantly differ between patients and controls. No significant effect of diagnosis was observed. Larger pituitary gland volume was associated with greater symptom severity ( F = 13.61, p = 0.0002), lower cognitive function ( F = 4.76, p = 0.03), and higher antipsychotic dose ( F = 5.20, p = 0.02). Illness duration was not significantly associated with pituitary gland volume. When all variables were considered, only symptom severity significantly predicted pituitary gland volume ( F = 7.54, p = 0.006)., Conclusions: Although pituitary volumes were not increased in psychotic disorders, larger size may be a marker associated with more severe symptoms in the progression of psychosis. This finding helps clarify previous inconsistent reports and highlights the need for further research into pituitary gland-related factors in individuals with psychosis.

The Hierarchical Taxonomy of Psychopathology (HiTOP) consortium's transdiagnostic dimensional model of psychopathology has considerable support; however, this model has been underresearched in individuals at clinical high risk for psychosis (CHR-P), a population that may advance the model. CHR-P individuals not only have attenuated psychotic symptoms that vary in severity, but also have many comorbid diagnoses and varied clinical outcomes, including disorders with uncertain relations to HiTOP (e.g., obsessive-compulsive disorder). The present study used self-report and interview data from North American Prodrome Longitudinal Study-3 (710 CHR, 96 controls) to replicate the HiTOP model and test specific hypotheses regarding disorders with uncertain relations to its dimensions. Additionally, the present study examined the HiTOP model in relation to childhood trauma, declines in social functioning, and development of full psychosis. Confirmatory factor analysis indicated that the HiTOP model's fit was nearly adequate (e.g., comparative fit index = .89), though several theory-relevant modifications were indicated. Additionally, specific tests were conducted to gain a more fine-grained perspective on how disorders with less clear prior evidence were related to the HiTOP model. Notable findings from these analyses include bipolar spectrum disorders relating to the psychosis super spectrum (i.e., .39 loading), and obsessive-compulsive disorder showing a complex pattern of loadings (e.g., internalizing and psychosis). The final model parsimoniously accounted for childhood trauma (e.g., super spectra r s = .22-.32), associations with current functioning, and predicted future conversion to a psychotic disorder (e.g., super spectra R ² = .13). Overall, these results inform the HiTOP model and suggest its promise for CHR-P research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual's risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct., Competing Interests: Declaration of competing interest There are no financial or other conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Learning Objective After Participating in This Cme Activity, the Psychiatrist Should Be Better Able to: • Outline and Identify potential benefits of using neurological soft signs (NSS) as biomarkers of schizophrenia., Abstract: Since the late 1960s, NSS have been a focus of study across psychiatric illnesses, including depression, bipolar disorder, and schizophrenia in particular. Utilizing these subtle neurological impairments as biomarkers of illness has numerous benefits; NSS offer a direct connection between clinical presentation and neurological functioning, and assessments are cost-effective. However, incongruent measurement scales, confounding variables, and rating system subjectivity have hindered the advancement and scalability of NSS research and clinical implementation. This article provides a brief overview of the literature on NSS as related to schizophrenia, and proposes utilizing smartphone sensing technology to create standardized NSS assessments with objective scoring. Incorporating digital phenotyping into NSS assessment offers the potential to make measurement more scalable, accessible, and directly comparable across locations, cultures, and demographics. We conducted a narrative search in PubMed and APA PsycInfo using the following keywords: neurological soft signs, schizophrenia spectrum disorders, and psychotic illnesses. No date limitations were used. There is no other direct work on NSS and new smartphone methods like digital phenotyping; though, there is related work in neurology. Harnessing advances in smartphone technology could provide greater insight into and further our understanding of specific aspects of the NSS field. For instance, it could help us distinguish trait vs. state markers and better understand how distinct groups of signs may reflect different aspects of psychiatric illness and neurological impairment. In addition, such technology can help advance research on the capabilities of NSS as an effective diagnostic tool., (Copyright © 2023 President and Fellows of Harvard College.)

Traditional diagnostic formulations of psychotic disorders have low correspondence with underlying disease neurobiology. This has led to a growing interest in using brain-based biomarkers to capture biologically-informed psychosis constructs. Building upon our prior work on the B-SNIP Psychosis Biotypes, we aimed to examine whether structural MRI (an independent biomarker not used in the Biotype development) can effectively classify the Biotypes. Whole brain voxel-wise grey matter density (GMD) maps from T1-weighted images were used to train and test (using repeated randomized train/test splits) binary L2-penalized logistic regression models to discriminate psychosis cases (n = 557) from healthy controls (CON, n = 251). A total of six models were evaluated across two psychosis categorization schemes: (i) three Biotypes (B1, B2, B3) and (ii) three DSM diagnoses (schizophrenia (SZ), schizoaffective (SAD) and bipolar (BD) disorders). Above-chance classification accuracies were observed in all Biotype (B1 = 0.70, B2 = 0.65, and B3 = 0.56) and diagnosis (SZ = 0.64, SAD = 0.64, and BD = 0.59) models. However, the only model that showed evidence of specificity was B1, i.e., the model was able to discriminate B1 vs. CON and did not misclassify other psychosis cases (B2 or B3) as B1 at rates above nominal chance. The GMD-based classifier evidence for B1 showed a negative association with an estimate of premorbid general intellectual ability, regardless of group membership, i.e. psychosis or CON. Our findings indicate that, complimentary to clinical diagnoses, the B-SNIP Psychosis Biotypes may offer a promising approach to capture specific aspects of psychosis neurobiology., (© 2023. Springer Nature Limited.)

Background: Cannabis use (CA) and childhood trauma (CT) independently increase the risk of earlier psychosis onset; but their interaction in relation to psychosis risk and association with endocannabinoid-receptor rich brain regions, i.e. the hippocampus (HP), remains unclear. The objective was to determine whether lower age of psychosis onset (AgePsyOnset) is associated with CA and CT through mediation by the HP volumes, and genetic risk, as measured by schizophrenia polygene scores (SZ-PGRS)., Methods: Cross-sectional, case-control, multicenter sample from 5 metropolitan US regions. Participants (n = 1185) included 397 controls not affected by psychosis (HC); 209 participants with bipolar disorder type-1; 279 with schizoaffective disorder; and 300 with schizophrenia (DSM IV-TR). CT was assessed using the Childhood Trauma Questionnaire (CTQ); CA was assessed by self-reports and trained clinical interviewers. Assessment included neuroimaging, symptomatology, cognition and calculation of the SZ polygenic risk score (SZ-PGRS)., Results: In survival analysis, CT and CA exposure interact to be associated with lower AgePsyOnset. At high CT or CA, CT or CA are individually sufficient to affect AgePsyOnset. CT relation with AgePsyOnset is mediated in part by the HP in CA users before AgePsyOnset. CA before AgePsyOnset is associated with higher SZ-PGRS and correlated with younger age at CA usage., Discussion: CA and CT interact to increase risk when moderate; while severe CT and/or CA abuse/dependence are each sufficient to affect AgePsyOnset, indicating a ceiling effect. Probands with/out CA before AgePsyOnset differ on biological variables, suggesting divergent pathways to psychosis., Funding: MH077945; MH096942; MH096913; MH077862; MH103368; MH096900; MH122759., Competing Interests: Declaration of competing interest All the authors declare NO conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Elevated markers of peripheral inflammation are common in psychosis spectrum disorders and have been associated with brain anatomy, pathology, and physiology as well as clinical outcomes. Preliminary evidence suggests a link between inflammatory cytokines and C-reactive protein (CRP) with generalized cognitive impairments in a subgroup of individuals with psychosis. Whether these patients with elevated peripheral inflammation demonstrate deficits in specific cognitive domains remains unclear. To examine this, seventeen neuropsychological and sensorimotor tasks and thirteen peripheral inflammatory and microvascular markers were quantified in a subset of B-SNIP consortium participants (129 psychosis, 55 healthy controls). Principal component analysis was conducted across the inflammatory markers, resulting in five inflammation factors. Three discrete latent cognitive domains (Visual Sensorimotor, General Cognitive Ability, and Inhibitory Behavioral Control) were characterized based on the neurobehavioral battery and examined in association with inflammation factors. Hierarchical clustering analysis identified cognition-sensitive high/low inflammation subgroups. Among persons with psychotic disorders but not healthy controls, higher inflammation scores had significant associations with impairments of Inhibitory Control (R 2  = 0.100, p-value = 2.69e -4 , q-value = 0.004) and suggestive associations with Visual Sensorimotor function (R 2  = 0.039, p-value = 0.024, q-value = 0.180), but not with General Cognitive Ability (R 2  = 0.015, p-value = 0.162). Greater deficits in Inhibitory Control were observed in the high inflammation patient subgroup, which represented 30.2 % of persons with psychotic disorders, as compared to the low inflammation psychosis subgroup. These findings indicate that inflammation dysregulation may differentially impact specific neurobehavioral domains across psychotic disorders, particularly performance on tasks requiring ongoing behavioral monitoring and control., Competing Interests: Declaration of competing interest CAT declares an ad hoc consulting relationship with Sunovion, Astellas and Merck and membership on a Merck DSMB; CAT is on the Clinical Advisory Board at Kynexis and Karuna Therapeutics and holds stock in Karuna. MSK has received support from Sunovion and GlaxoSmithKline; MSK is a consultant to Forum Pharmaceuticals. JAS has received support from VeraSci. JRB has served as a consultant to OptumRx. RSEK receives royalties for the BACS, and has consulting relationships with Merck, Karuna, Sunovion, Biogen and Boehringer-Ingelheim. The other authors report no related disclosures., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Task-evoked pupillary response (TEPR) is a measure of physiological arousal modulated by cognitive demand. Healthy individuals demonstrate greater TEPR prior to correct versus error antisaccade trials and correct antisaccade versus visually guided saccade (VGS) trials. The relationship between TEPR and antisaccade performance in individuals with psychotic disorders and their relatives has not been investigated. Probands with schizophrenia, schizoaffective disorder, psychotic bipolar disorder, their first-degree relatives, and controls from the B-SNIP study completed antisaccade and VGS tasks. TEPR prior to execution of responses on these tasks was evaluated among controls compared to probands and relatives according to diagnostic groups and neurobiologically defined subgroups (biotypes). Controls demonstrated greater TEPR on antisaccade correct versus error versus VGS trials. TEPR was not differentiated between antisaccade correct versus error trials in bipolar or schizophrenia probands, though was greater on antisaccade compared to prosaccade trials. There was no modulation of TEPR in schizoaffective probands. Relatives of schizophrenia and schizoaffective probands and those with elevated psychosis spectrum traits failed to demonstrate differential TEPR on antisaccade correct versus error trials. No proband or relative biotypes demonstrated differential TEPR on antisaccade correct versus error trials, and only proband biotype 3 and relative biotypes 3 and 2 demonstrated greater TEPR on antisaccade versus VGS trials. Our findings suggest that aberrant modulation of preparatory activity prior to saccade execution contributes to impaired executive cognitive control across the psychosis spectrum, including nonpsychotic relatives with elevated clinical risk. Reduced pupillary modulation under cognitive challenge may thus be a biomarker for the psychosis phenotype., 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. Published by Elsevier B.V.)

Background: Antisaccade tasks can be used to index cognitive control processes, e.g. attention, behavioral inhibition, working memory, and goal maintenance in people with brain disorders. Though diagnoses of schizophrenia (SZ), schizoaffective (SAD), and bipolar I with psychosis (BDP) are typically considered to be distinct entities, previous work shows patterns of cognitive deficits differing in degree, rather than in kind, across these syndromes., Methods: Large samples of individuals with psychotic disorders were recruited through the Bipolar-Schizophrenia Network on Intermediate Phenotypes 2 (B-SNIP2) study. Anti- and pro-saccade task performances were evaluated in 189 people with SZ, 185 people with SAD, 96 people with BDP, and 279 healthy comparison participants. Logistic functions were fitted to each group's antisaccade speed-performance tradeoff patterns., Results: Psychosis groups had higher antisaccade error rates than the healthy group, with SZ and SAD participants committing 2 times as many errors, and BDP participants committing 1.5 times as many errors. Latencies on correctly performed antisaccade trials in SZ and SAD were longer than in healthy participants, although error trial latencies were preserved. Parameters of speed-performance tradeoff functions indicated that compared to the healthy group, SZ and SAD groups had optimal performance characterized by more errors, as well as less benefit from prolonged response latencies. Prosaccade metrics did not differ between groups., Conclusions: With basic prosaccade mechanisms intact, the higher speed-performance tradeoff cost for antisaccade performance in psychosis cases indicates a deficit that is specific to the higher-order cognitive aspects of saccade generation.

Background: Impairments of the visual system are implicated in psychotic disorders. However, studies exploring visual cortex (VC) morphology in this population are limited. Using data from the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium, we examined VC structure in psychosis probands and their first-degree relatives (RELs), sex differences in VC measures, and their relationships with cognitive and peripheral inflammatory markers., Methods: Cortical thickness, surface area, and volume of the primary (Brodmann area 17/V1) and secondary (Brodmann area 18/V2) visual areas and the middle temporal (V5/MT) region were quantified using FreeSurfer version 6.0 in psychosis probands (n = 530), first-degree RELs (n = 544), and healthy control subjects (n = 323). Familiality estimates were determined for probands and RELs. General cognition, response inhibition, and emotion recognition functions were assessed. Systemic inflammation was measured in a subset of participants., Results: Psychosis probands demonstrated significant area, thickness, and volume reductions in V1, V2, and MT, and their first-degree RELs demonstrated area and volume reductions in MT compared with control subjects. There was a higher degree of familiality for VC area than thickness. Area and volume reductions in V1 and V2 were sex dependent, affecting only female probands in a regionally specific manner. Reductions in some VC regions were correlated with poor general cognition, worse response inhibition, and increased C-reactive protein levels., Conclusions: The visual cortex is a site of significant pathology in psychotic disorders, with distinct patterns of area and thickness changes, sex-specific and regional effects, potential contributions to cognitive impairments, and association with C-reactive protein levels., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Affective and non-affective psychotic disorders are associated with variable levels of impairment in affective processing, but this domain typically has been examined via presentation of static facial images. We compared performance on a dynamic facial expression identification task across six emotions (sad, fear, surprise, disgust, anger, happy) in individuals with psychotic disorders (bipolar with psychotic features [PBD] = 113, schizoaffective [SAD] = 163, schizophrenia [SZ] = 181) and healthy controls (HC; n = 236) derived from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). These same individuals with psychotic disorders were also grouped by B-SNIP-derived Biotype (Biotype 1 [B1] = 115, Biotype 2 [B2] = 132, Biotype 3 [B3] = 158), derived from a cluster analysis applied to a large biomarker panel that did not include the current data. Irrespective of the depicted emotion, groups differed in accuracy of emotion identification (P < 0.0001). The SZ group demonstrated lower accuracy versus HC and PBD groups; the SAD group was less accurate than the HC group (Ps < 0.02). Similar overall group differences were evident in speed of identifying emotional expressions. Controlling for general cognitive ability did not eliminate most group differences on accuracy but eliminated almost all group differences on reaction time for emotion identification. Results from the Biotype groups indicated that B1 and B2 had more severe deficits in emotion recognition than HC and B3, meanwhile B3 did not show significant deficits. In sum, this characterization of facial emotion recognition deficits adds to our emerging understanding of social/emotional deficits across the psychosis spectrum., (Copyright © 2021 Elsevier B.V. All rights reserved.)

An opportunity has opened for research into primary prevention of psychotic disorders, based on progress in endophenotypes, genetics, and genomics. Primary prevention requires reliable prediction of susceptibility before any symptoms are present. We studied a battery of measures where published data supports abnormalities of these measurements prior to appearance of initial psychosis symptoms. These neurobiological and behavioral measurements included cognition, eye movement tracking, Event Related Potentials, and polygenic risk scores. They generated an acceptably precise separation of healthy controls from outpatients with a psychotic disorder. METHODS: The Bipolar and Schizophrenia Network on Intermediate Phenotypes (B-SNIP) measured this battery in an ancestry-diverse series of consecutively recruited adult outpatients with a psychotic disorder and healthy controls. Participants include all genders, 16 to 50 years of age, 261 with psychotic disorders (Schizophrenia (SZ) 109, Bipolar with psychosis (BPP) 92, Schizoaffective disorder (SAD) 60), 110 healthy controls. Logistic Regression, and an extension of the Linear Mixed Model to include analysis of pairwise interactions between measures (Environmental kernel Relationship Matrices (ERM)) with multiple iterations, were performed to predict case-control status. Each regression analysis was validated with four-fold cross-validation. RESULTS AND CONCLUSIONS: Sensitivity, specificity, and Area Under the Curve of Receiver Operating Characteristic of 85%, 62%, and 86%, respectively, were obtained for both analytic methods. These prediction metrics demonstrate a promising diagnostic distinction based on premorbid risk variables. There were also statistically significant pairwise interactions between measures in the ERM model. The strong prediction metrics of both types of analytic model provide proof-of-principle for biologically-based laboratory tests as a first step toward primary prevention studies. Prospective studies of adolescents at elevated risk, vs. healthy adolescent controls, would be a next step toward development of primary prevention strategies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Current clinical phenomenological diagnosis in psychiatry neither captures biologically homologous disease entities nor allows for individualized treatment prescriptions based on neurobiology. In this report, we studied two large samples of cases with schizophrenia, schizoaffective, and bipolar I disorder with psychosis, presentations with clinical features of hallucinations, delusions, thought disorder, affective, or negative symptoms. A biomarker approach to subtyping psychosis cases (called psychosis Biotypes) captured neurobiological homology that was missed by conventional clinical diagnoses. Two samples (called "B-SNIP1" with 711 psychosis and 274 healthy persons, and the "replication sample" with 717 psychosis and 198 healthy persons) showed that 44 individual biomarkers, drawn from general cognition (BACS), motor inhibitory (stop signal), saccadic system (pro- and anti-saccades), and auditory EEG/ERP (paired-stimuli and oddball) tasks of psychosis-relevant brain functions were replicable (r's from .96-.99) and temporally stable (r's from .76-.95). Using numerical taxonomy (k-means clustering) with nine groups of integrated biomarker characteristics (called bio-factors) yielded three Biotypes that were virtually identical between the two samples and showed highly similar case assignments to subgroups based on cross-validations (88.5%-89%). Biotypes-1 and -2 shared poor cognition. Biotype-1 was further characterized by low neural response magnitudes, while Biotype-2 was further characterized by overactive neural responses and poor sensory motor inhibition. Biotype-3 was nearly normal on all bio-factors. Construct validation of Biotype EEG/ERP neurophysiology using measures of intrinsic neural activity and auditory steady state stimulation highlighted the robustness of these outcomes. Psychosis Biotypes may yield meaningful neurobiological targets for treatments and etiological investigations., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Objectives: Affective and psychotic features overlap considerably in bipolar I disorder, complicating efforts to determine its etiology and develop targeted treatments. In order to clarify whether mechanisms are similar or divergent for bipolar disorder with psychosis (BDP) and bipolar disorder with no psychosis (BDNP), neurobiological profiles for both the groups must first be established. This study examines white matter structure in the BDP and BDNP groups, in an effort to identify portions of white matter that may differ between the bipolar and healthy groups or between the bipolar subgroups themselves., Methods: Diffusion-weighted imaging data were acquired from participants with BDP (n = 45), BDNP (n = 40), and healthy comparisons (HC) (n = 66). Fractional anisotropy (FA), radial diffusivity (RD), and spin distribution function (SDF) values indexing white matter diffusivity or spin density were calculated and compared between the groups., Results: In comparisons between both the bipolar groups and HC, FA (FDR < 0.00001) and RD (FDR = 0.0037) differed minimally, in localized portions of the left cingulum and corpus callosum, while reductions in SDF (FDR = 0.0002) were more widespread. The bipolar subgroups did not differ from each other on FA, RD, or SDF metrics., Conclusions: Together, these results demonstrate a novel profile of white matter differences in bipolar disorder and suggest that this white matter pathology is associated with the affective disturbance common to those with bipolar disorder rather than the psychotic features unique to some. The white matter alterations identified in this study may provide substrates for future studies examining specific mechanisms that target affective domains of illness., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Brain-based Biotypes for psychotic disorders have been developed as part of the B-SNIP consortium to create neurobiologically distinct subgroups within idiopathic psychosis, independent from traditional phenomenological diagnostic methods. In the current study, we aimed to validate the Biotype model by assessing differences in volume and shape of the amygdala and hippocampus contrasting traditional clinical diagnoses with Biotype classification., Methods: A total of 811 participants from 6 sites were included: probands with schizophrenia (n = 199), schizoaffective disorder (n = 122), psychotic bipolar disorder with psychosis (n = 160), and healthy controls (n = 330). Biotype classification, previously developed using cognitive and electrophysiological data and K-means clustering, was used to categorize psychosis probands into 3 Biotypes, with Biotype-1 (B-1) showing reduced neural salience and severe cognitive impairment. MAGeT-Brain segmentation was used to determine amygdala and hippocampal volumetric data and shape deformations., Results: When using Biotype classification, B-1 showed the strongest reductions in amygdala-hippocampal volume and the most widespread shape abnormalities. Using clinical diagnosis, probands with schizophrenia and schizoaffective disorder showed the most significant reductions of amygdala and hippocampal volumes and the most abnormal hippocampal shape compared with healthy controls. Biotype classification provided the strongest neuroanatomical differences compared with conventional DSM diagnoses, with the best discrimination seen using bilateral amygdala and right hippocampal volumes in B-1., Conclusion: These findings characterize amygdala and hippocampal volumetric and shape abnormalities across the psychosis spectrum. Grouping individuals by Biotype showed greater between-group discrimination, suggesting a promising approach and a favorable target for characterizing biological heterogeneity across the psychosis spectrum., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Psychotic disorders are characterized by impaired cognition, yet some reports indicate specific deficits extend beyond reduced general cognitive ability. This study utilized exploratory and confirmatory factor analytic methods to evaluate the latent structure of a broad neurocognitive battery used in the Bipolar-Schizophrenia Network of Intermediate Phenotypes (B-SNIP) study, which included neuropsychological and neurophysiological measures in psychotic disorder probands and their unaffected first-degree relatives. Findings indicate that the factor structure of data from this set of assessments is more complex than the unitary factor of global cognitive ability underlying the Brief Assessment of Cognition in Schizophrenia (BACS). In addition to assessing generalized cognitive ability, two other factors were identified: visual sensorimotor function and inhibitory behavioral control. This complex cognitive architecture, derived in controls, generalized to patients across the psychosis spectrum and to their unaffected relatives. These findings highlight the need for a more differentiated assessment of neurobehavioral functions in studies designed to test for diagnostically specific biomarkers, endophenotypes for gene discovery and beneficial effects of therapeutics on cognitive function., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Neural activations during auditory oddball tasks may be endophenotypes for psychosis and bipolar disorder. The authors investigated oddball neural deviations that discriminate multiple diagnostic groups across the schizophrenia-bipolar spectrum (schizophrenia, schizoaffective disorder, psychotic bipolar disorder, and nonpsychotic bipolar disorder) and clarified their relationship to clinical and cognitive features., Methods: Auditory oddball responses to standard and target tones from 64 sensor EEG recordings were compared across patients with psychosis (total N=597; schizophrenia, N=225; schizoaffective disorder, N=201; bipolar disorder with psychosis, N=171), patients with bipolar disorder without psychosis (N=66), and healthy comparison subjects (N=415) from the second iteration of the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP2) study. EEG activity was analyzed in voltage and in the time-frequency domain (low, beta, and gamma bands). Event-related potentials (ERPs) were compared with those from an independent sample collected during the first iteration of B-SNIP (B-SNIP1; healthy subjects, N=211; psychosis group, N=526) to establish the repeatability of complex oddball ERPs across multiple psychosis syndromes (r values >0.94 between B-SNIP1 and B-SNIP2)., Results: Twenty-six EEG features differentiated the groups; they were used in discriminant and correlational analyses. EEG variables from the N100, P300, and low-frequency ranges separated the groups along a diagnostic continuum from healthy to bipolar disorder with psychosis/bipolar disorder without psychosis to schizoaffective disorder/schizophrenia and were strongly related to general cognitive function (r=0.91). P50 responses to standard trials and early beta/gamma frequency responses separated the bipolar disorder without psychosis group from the bipolar disorder with psychosis group. P200, N200, and late beta/gamma frequency responses separated the two bipolar disorder groups from the other groups., Conclusions: Neural deviations during auditory processing are related to psychosis history and bipolar disorder. There is a powerful transdiagnostic relationship between severity of these neural deviations and general cognitive performance. These results have implications for understanding the neurobiology of clinical syndromes across the schizophrenia-bipolar spectrum that may have an impact on future biomarker research.

Impaired emotional processing and cognitive functioning are common in schizophrenia, schizoaffective disorder, and bipolar disorders, causing significant socioemotional disability. While a large body of research demonstrates abnormal cognition/emotion interactions in these disorders, previous studies investigating abnormalities in the emotional scene response using event-related potentials (ERPs) have yielded mixed findings, and few studies compare findings across psychiatric diagnoses. The current study investigates the effects of emotion and repetition on ERPs in a large, well-characterized sample of participants with schizophrenia-bipolar syndromes. Two ERP components that are modulated by emotional content and scene repetition, the early posterior negativity (EPN) and late positive potential (LPP), were recorded in healthy controls and participants with schizophrenia, schizoaffective disorder, bipolar disorder with psychosis, and bipolar disorder without psychosis. Effects of emotion and repetition were compared across groups. Results displayed significant but small effects in schizophrenia and schizoaffective disorder, with diminished EPN amplitudes to neutral and novel scenes, reduced LPP amplitudes to emotional scenes, and attenuated effects of scene repetition. Despite significant findings, small effect sizes indicate that emotional scene processing is predominantly intact in these disorders. Multivariate analyses indicate that these mild ERP abnormalities are related to cognition, psychosocial functioning, and psychosis severity. This relationship suggests that impaired cognition, rather than diagnosis or mood disturbance, may underlie disrupted neural scene processing in schizophrenia-bipolar syndromes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Neurovascular abnormalities are relevant to the pathophysiology of bipolar disorder (BD), which can be assessed using cerebral blood flow (CBF) imaging. CBF alterations have been identified in BD, but studies to date have been small and inconclusive. We aimed to determine cortical gray matter CBF (GM-CBF) differences between BD and healthy controls (HC) and to identify relationships between CBF and clinical or cognitive measures., Methods: Cortical GM-CBF maps were generated using Pseudo-Continuous Arterial Spin Labeling (pCASL) for 109 participants (BD, n = 61; HC, n = 48). We used SnPM13 to perform non-parametric voxel-wise two-sample t-tests comparing CBF between groups. We performed multiple linear regression to relate GM-CBF with clinical and cognitive measures. Analysis was adjusted for multiple comparisons with 10,000 permutations. Significance was set at a voxel level threshold of P < .001 followed by AlphaSim cluster-wise correction of P < .05., Results: Compared to HCs, BD patients had greater GM-CBF in the left lateral occipital cortex, superior division and lower CBF in the right lateral occipital, angular and middle temporal gyrus. Greater GM-CBF in the left lateral occipital cortex correlated with worse working memory, verbal memory, attention and speed of processing. We found using voxel-wise regression that decreased gray matter CBF in the bilateral thalamus and cerebellum, and increased right fronto-limbic CBF were associated with worse working memory. No clusters were associated with clinical variables after FDR correction., Conclusions: Cortical GM-CBF alterations are seen in BD and may be related to cognitive function, which suggest neurovascular unit dysfunction as a possible pathophysiologic mechanism., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The B-SNIP consortium identified three brain-based Biotypes across the psychosis spectrum, independent of clinical phenomenology. To externally validate the Biotype model, we used free-water fractional volume (FW) and free-water corrected fractional anisotropy (FA T ) to compare white matter differences across Biotypes and clinical diagnoses. Diffusion tensor imaging data from 167 individuals were included: 41 healthy controls, 55 schizophrenia probands, 47 schizoaffective disorder probands, and 24 probands with psychotic bipolar disorder. Compared to healthy controls, FAt reductions were observed in the body of corpus callosum (BCC) for schizoaffective disorder (d = 0.91) and schizophrenia (d = 0.64). Grouping by Biotype, Biotype 1 showed FAt reductions in the CC and fornix, with largest effect in the BCC (d = 0.87). Biotype 2 showed significant FAt reductions in the BCC (d = 0.90). Schizoaffective disorder individuals had elevated FW in the CC, fornix and anterior corona radiata (ACR), with largest effect in the BCC (d = 0.79). Biotype 2 showed elevated FW in the CC, fornix and ACR, with largest effect in the BCC (d = 0.94). While significant diagnosis comparisons were observed, overall greater discrimination from healthy controls was observed for lower FAt in Biotype 1 and elevated FW in Biotype 2. However, between-group differences were modest, with one region (cerebral peduncle) showing a between-Biotype effect. No between-group effects were observed for diagnosis groupings., (Copyright © 2020. Published by Elsevier B.V.)

Objectives: Smooth pursuit eye movement deficits are an established psychosis biomarker across schizophrenia, schizoaffective and psychotic bipolar disorder (BPwP). Whether smooth pursuit deficits are also seen in bipolar disorder without psychosis (BPwoP) is unclear. Here we present data from the Psychosis and Affective Research Domains and Intermediate Phenotypes (PARDIP) study comparing bipolar patients with and without psychotic features., Methods: Probands with BPwP (N = 49) and BPwoP (N = 36), and healthy controls (HC, N = 71) performed eye tracking tasks designed to evaluate specific sensorimotor components relevant for pursuit initiation and pursuit maintenance., Results: While BPwoP did not differ from either BPwP or HC on initial eye acceleration, they performed significantly better than BPwP on early (P < .01) and predictive (P = .02) pursuit maintenance measures, both without differing from HC. BPwP were impaired compared to HC on initial eye acceleration, and on early and predictive pursuit maintenance (all P < .01). In contrast to the three pursuit measures, BPwP and BPwoP were both impaired on general neurocognitive assessments in relation to HC (both P < .001), without a significant difference between the two bipolar patient groups., Conclusions: Our findings support the model that impairments of sensorimotor and cognitive processing as required for early and later predictive smooth pursuit maintenance are relatively specific to those bipolar patients with a history of psychosis. This suggests that the neural circuitry for developing feed-forward predictive models for accurate pursuit maintenance is associated with the occurrence of psychotic features in bipolar patients. In contrast, generalized neuropsychological impairments did not differentiate the two bipolar patient groups., (© 2019 The Authors. Bipolar Disorders published by Published by John Wiley & Sons Ltd.)

Subtypes of schizophrenia, constructed using clinical phenomenology to resolve illness heterogeneity, have faced criticism due to overlapping symptomatology and longitudinal instability; they were therefore dropped from the Diagnostic Statistical Manual-5. Cognitive and imaging findings comparing paranoid (P-SZ) and non-paranoid (disorganized, residual and undifferentiated; NP-SZ) schizophrenia have been limited due to small sample sizes. We assessed P-SZ and NP-SZ using symptomatology, cognition and brain structure and predicted that there would be few neurobiological differences. P-SZ (n = 237), NP-SZ (n = 127) and controls (n = 430) were included from a multi-site study. In a subset of this sample, structural imaging measures (P-SZ, n = 133; NP-SZ, n = 67; controls, n = 310) were calculated using Freesurfer 6.0. Group contrasts were run using analysis of covariance, controlling for age, sex, race and site, p-values were corrected using False Discovery Rate (FDR) and were repeated excluding the residual subtype. Compared to NP-SZ (with and without the residual subtype), P-SZ displayed fewer negative symptoms, faster speed of processing, larger bilateral hippocampus, right amygdala and their subfield volumes. Additionally, NP-SZ (with residual subtype) displayed fewer depressive symptoms and higher left transverse temporal cortical thickness (CT) but NP-SZ without residual subtype showed lower GAF scores and worse digit sequencing compared to P-SZ. No differences in positive symptoms and functioning (global or social) were detected. Subtle but significant differences were seen in cognition, symptoms, CT and subcortical volumes between P-SZ and NP-SZ. While the magnitude of these differences is not large enough to justify them as distinct categories, the paranoid- nonparanoid distinction in schizophrenia merits further investigation., Competing Interests: Declaration of competing interest The authors have declared that there are no conflicts of interest in relation to the subject of this study., (Copyright © 2020. Published by Elsevier B.V.)

Background: Deficits in inhibitory control on a Stop Signal Task (SST) were previously observed to be of similar magnitude across schizophrenia, schizoaffective, and bipolar disorder with psychosis, despite variation in general cognitive ability. Understanding different patterns of performance on the SST may elucidate different pathways to the impaired inhibitory control each group displayed. Comparing nonpsychotic bipolar disorder to the psychosis groups on SST may also expand our understanding of the shared neurobiology of this illness spectrum., Methods: We tested schizophrenia (n = 220), schizoaffective (n = 216), bipolar disorder with (n = 192) and without psychosis (n = 67), and 280 healthy comparison participants with a SST and the Brief Assessment of Cognition in Schizophrenia (BACS), a measure of general cognitive ability., Results: All patient groups had a similar degree of impaired inhibitory control over prepotent responses. However, bipolar groups differed from schizophrenia and schizoaffective groups in showing speeded responses and inhibition errors that were not accounted for by general cognitive ability. Schizophrenia and schizoaffective groups had a broader set of deficits on inhibition and greater general cognitive deficit, which fully accounted for the inhibition deficits. No differences were found between the clinically well-matched bipolar with and without psychosis groups, including for inhibitory control or general cognitive ability., Conclusions: We conclude that 1) while impaired inhibitory control on a SST is of similar magnitude across the schizo-bipolar spectrum, including nonpsychotic bipolar, different mechanisms may underlie the impairments, and 2) history of psychosis in bipolar disorder does not differentially impact inhibitory behavioral control or general cognitive abilities., Competing Interests: Declaration of competing interest M.Y. Gotra, S.K. Hill, E.S. Gershon, C.A. Tamminga, E.I. Ivleva, G.D. Pearlson, B.A. Clementz, J.E. McDowell, P.F. Buckley, J.A. Sweeney, and S.K. Keedy report no financial interests or potential conflicts. M.S. Keshavan has served as an adviser for Alkermes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Psychiatry aspires to the molecular understanding of its disorders and, with that knowledge, to precision medicine. Research supporting such goals in the dimension of psychosis has been compromised, in part, by using phenomenology alone to estimate disease entities. To this end, we are proponents of a deep phenotyping approach in psychosis, using computational strategies to discover the most informative phenotypic fingerprint as a promising strategy to uncover mechanisms in psychosis., Methods: Doing this, the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) has used biomarkers to identify distinct subtypes of psychosis with replicable biomarker characteristics. While we have presented these entities as relevant, their potential utility in clinical practice has not yet been demonstrated., Results: Here we carried out an analysis of clinical features that characterize biotypes. We found that biotypes have unique and defining clinical characteristics that could be used as initial screens in the clinical and research settings. Differences in these clinical features appear to be consistent with biotype biomarker profiles, indicating a link between biological features and clinical presentation. Clinical features associated with biotypes differ from those associated with DSM diagnoses, indicating that biotypes and DSM syndromes are not redundant and are likely to yield different treatment predictions. We highlight 3 predictions based on biotype that are derived from individual biomarker features and cannot be obtained from DSM psychosis syndromes., Conclusions: In the future, biotypes may prove to be useful for targeting distinct molecular, circuit, cognitive, and psychosocial therapies for improved functional outcomes., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: We sought to evaluate whether dynamic Arterial Spin Labeling (dASL), a novel quantitative technique robust to artifacts and noise that especially arise in inferior brain regions, could characterize neural substrates of BD pathology and symptoms., Methods: Forty-five subjects (19 BD patients, 26 controls) were imaged using a dASL sequence. Maps of average perfusion, perfusion fluctuation, and perfusion connectivity with anterior cingulate cortex (ACC) were derived. Patient symptoms were quantified along four symptom dimensions determined using factor analysis of the subjects from the Bipolar and Schizophrenia Network on Intermediate Phenotypes (BSNIP) study. Maps of the perfusion measures were compared between BD patients and controls and correlated with the symptom dimensions in the BD patients only by voxel-level and region-level analyses., Results: BD patients exhibited (i) significantly increased perfusion fluctuations in the left fusiform and inferior temporal regions (P = .020, voxel-level corrected) and marginally increased perfusion fluctuations in the right temporal pole and inferior temporal regions (P = .063, cluster-level corrected), (ii) significantly increased perfusion connectivity between ACC and the occipitoparietal cortex (P = .050, cluster-level corrected). In BD patients, positive symptoms were negatively associated with ACC perfusion connectivity to the right orbitofrontal and superior frontal regions (P = .002, cluster-level corrected) and right orbitofrontal and inferior frontal regions (P = .023, cluster-level corrected)., Conclusion: The abnormal perfusion fluctuations and connectivity alterations may underlie the mood fluctuations and cognitive and emotional dysregulation that characterize BD., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response and provides an index of neural processing speed. Latency is prolonged in schizophrenia, is 90% heritable, and predicts conversion to schizophrenia in a high-risk population. The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) consortium investigates neurobiological features found in psychotic disorders spanning diagnostic criteria for schizophrenia (SCZ), schizoaffective disorder (SAD), and psychotic bipolar disorder (BP). We investigated whether differences in startle latency and prepulse inhibition (PPI) occur in probands, their first-degree relatives, and neurobiologically defined subgroups of the probands (Biotypes)., Methods: 1143 subjects were included from the B-SNIP cohort: 143 with SCZ, 178 SCZ relatives (SCZ-Fam), 123 with SAD, 152 SAD relatives (SAD-Fam), 138 BP, 183 BP relatives (BP-Fam), and 226 controls (CON). A Biopac system recorded the eyeblink component of the startle reflex during startle testing., Results: Latency differed by diagnosis (F(3,620) = 5.10, p = 0.002): SCZ, SAD, and BP probands had slower latency than CON, with relatives intermediate. Biotypes 1 and 2 had slower latency than CON (p < 0.031) but Biotype 3 did not differ from CON. PPI did not separate CON from other subjects when analyzed by diagnoses nor when analyzed by biotype. Biotype 1 relatives had slower latency (F(3,663) = 3.49, p = 0.016) and more impaired PPI than Biotype 2 and 3 relatives (F(3,663) = 2.77, p = 0.041)., Conclusion: Startle latency is prolonged in psychotic disorders that cross traditional diagnostic categories. These data suggest a genetic difference between biotypes that span across clinically defined diagnoses., Competing Interests: Declaration of competing interest Infrastructure support was provided by the Research and Development, the Mental Health Service Lines, and the Center of Visual and Neurocognitive Rehabilitation at the Atlanta Veterans Affairs Medical Center, Decatur, GA. Additional infrastructure support was provided by the Department of Psychiatry and Behavioral Sciences of the Emory University School of Medicine, Atlanta, GA. ED has received research support for work unrelated to this project from Auspex Pharmaceuticals, Inc. and Teva Pharmaceuticals, Inc. Other authors have nothing to disclose. ED is a full time attending psychiatrist in the Mental Health Service Line at the Atlanta Veterans Affairs Medical Center, Decatur, GA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs., (Published by Elsevier B.V.)

Background: Schizophrenia (SZ) and bipolar disorder (BD) are characterized by reductions in gray matter and white matter. Limitations in brain imaging have led researchers to use optical coherence tomography (OCT) to explore retinal imaging biomarkers of brain pathology. We examine the retinal layers that may be associated with SZ or BD., Methods: Articles identified using PubMed, Web of Science, Cochrane Database. Twelve studies met inclusion for acutely/chronically ill patients. We used fixed or random effects meta-analysis for probands (SZ and BD), SZ or BD eyes vs healthy control (HC) eyes. We adjusted for sources of bias, cross-validated results, and report standardized mean differences (SMD). Statistical analysis performed using meta package in R., Results: Data from 820 proband eyes (SZ = 541, BD = 279) and 904 HC eyes were suitable for meta-analysis. The peripapillary retinal nerve fiber layer (RNFL) showed significant thinning in SZ and BD eyes compared to HC eyes (n = 12, SMD = -0.74, -0.51, -1.06, respectively). RNFL thinning was greatest in the nasal, temporal, and superior regions. The combined peripapillary ganglion cell layer and inner plexiform layer (GCL-IPL) showed significant thinning in SZ and BD eyes compared to HC eyes (n = 4, SMD = -0.39, -0.44, -0.28, respectively). No statistically significant differences were identified in other retinal or choroidal regions. Clinical variables were unrelated to the RNFL or GCL-IPL thickness by meta-regression., Conclusion: The observed retinal layer thinning is consistent with the classic gray- and white-matter atrophy observed on neuroimaging in SZ and BD patients. OCT may be a useful biomarker tool in studying the neurobiology of psychosis., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Emotional dysfunction is a core feature of bipolar I disorder (BD). Behavioral data suggest that emotional processing may differ based on history of psychosis, but physiological studies frequently disregard this differentiating feature. Face processing studies indicate that emotion-related components of event-related potentials (ERPs) are abnormal in BD, but fMRI data using emotional scenes are mixed. The current study used ERPs to examine emotional scene perception in BD with and without a history of psychosis (BDP, BDNP). 386 participants from the PARDIP consortium (HC = 181, BDP = 130, BDNP = 75) viewed neutral, pleasant, and unpleasant scenes from the International Affective Picture System (IAPS) during continuous EEG recording. The early posterior negativity (EPN) and late positive potential (LPP) were examined for group and stimulus effects. Analyses were conducted for groups on and off medications to examine associations between medication status, psychosis, and ERP response. Group differences were found between HC and BD in emotional modulation of the EPN and between HC and BDP in the LPP to pleasant images. There was a significant interaction between psychosis history and anticonvulsant status in the EPN, but no other medication associations were found. The relationship between neural/self-reported emotional responses and clinical symptoms were examined with canonical correlations, but no significant associations were found. Results from this large well characterized sample indicate mild deviations in neural reactivity related to medication, mood, and psychosis history. However, processing of emotional scenes appears mostly intact in individuals with BD regardless of symptom severity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Recently, a biologically-driven psychosis classification (B-SNIP Biotypes) was derived using brain-based cognitive and electrophysiological markers. Here, we characterized a local functional-connectivity measure, regional homogeneity (ReHo), as a biomarker across Biotypes and conventional DSM diagnoses., Methods: Whole-brain ReHo measures of resting-state functional MRI were examined in psychosis patients and healthy controls organized by Biotype and by DSM-IV-TR diagnosis (n = 737). Group-level ANOVA and individual-level prediction models using support vector machines (SVM) were employed to evaluate the discriminative characteristics in comparisons of 1) DSM diagnostic groups, 2) Biotypes, to controls, and 3) within-proband subgroups with each other., Results: Probands grouped by Biotype versus controls showed a unique abnormality pattern: Biotype-1 displayed bidirectional ReHo differences in more widespread areas, with higher ReHo in para-hippocampus, fusiform, inferior temporal, cerebellum, thalamus and caudate, plus lower ReHo in the postcentral gyrus, middle temporal, cuneus, and middle occipital cortex; Biotype-2 and Biotype-3 showed lesser and unidirectional ReHo changes. Among diagnostic groups, only schizophrenia showed higher ReHo versus control values in the inferior/middle temporal area and fusiform gyrus. For within-patient comparisons, Biotype-1 showed characteristic ReHo when compared to Biotype-2 and Biotype-3. SVM results more accurately identified Biotypes than DSM diagnoses., Conclusion: We characterized patterns of ReHo abnormalities across both Biotypes and DSM sub-groups. Both group-level statistical and machine-learning methods were more sensitive in capturing ReHo deficits in Biotypes than DSM. Overall ReHo is a robust psychosis biomarker., Competing Interests: Declaration of competing interest JAS has served on advisory boards for Bristol-Myers Squibb, Eli Lilly, Pfizer, Roche, and Takeda, and has received grant support from Janssen. MSK has received research support from Sunovion and GlaxoSmithKline. CAT has served on the advisory board for drug development for Intra-Cellular Therapies, Inc.; has served as an ad hoc consultant for Eli Lilly, Sunovion, Astellas, Pfizer, and Merck; has been a council member and unpaid volunteer for the National Alliance on Mental Illness; and has served as deputy editor for the American Psychiatric Association. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Deviant auditory steady-state responses (aSSRs) in the gamma range (30-90 Hz) may be translational biomarkers for schizophrenia (SZ). This study tests whether aSSR deviations are (i) specific to SZ across the psychosis dimension, (ii) specific to particular frequency bands, and (iii) present in bipolar I disorder without psychosis (BDNP)., Methods: Beta (20-), low- (40-), and high-gamma (80-Hz) aSSRs were measured with EEG and compared across 113 SZ, 105 schizoaffective disorder (SAD), 99 bipolar disorder with psychosis (BDP), 68 BDNP, and 137 healthy comparison subjects (HC). Standard aSSR measures (single-trial power [STP] and inter-trial phase coherence [ITC]), as well as evoked responses to stimulus onsets/offsets and pre-stimulus power, were quantified. Multivariate canonical discriminant analysis was used to summarize variables that efficiently and maximally differentiated groups., Results: (i) Psychosis groups showed reduced responses on ITC 20 Hz, STP/ITC 40 Hz, STP/ITC 80 Hz, indicating dimensional reductions in aSSR across the psychosis spectrum not specific to aSSR frequency. For the 40- and 80-Hz ITCs there was greater reduction in SZ compared to SAD, possibly indexing cortical disruptions linked to psychosis without mood symptoms. (ii) All probands had elevated pre-stimulus power, possibly compromising neural entrainment to the steady-state stimuli. (iii) Onset/Offset and 80 Hz ITC responses were most important for group discrimination and showed dimensional reduction across the schizo-bipolar spectrum., Conclusions: Deviant aSSRs were found across the schizo-bipolar spectrum at multiple frequencies with psychosis status and severity linked to greatest reductions at low and high gamma., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Neuroimaging of psychiatric disease is challenged by the difficulty of establishing the causal role of neuroimaging abnormalities. Lesions that cause mania present a unique opportunity to understand how brain network disruption may cause mania in both lesions and in bipolar disorder., Methods: A literature search revealed 23 case reports with imaged lesions that caused mania in patients without history of bipolar disorder. We traced these lesions and examined resting-state functional Magnetic Resonance Imaging (rsfMRI) connectivity to these lesions and control lesions to find networks that would be disrupted specifically by mania-causing lesions. The results were then used as regions-of-interest to examine rsfMRI connectivity in patients with bipolar disorder (n = 16) who underwent imaging longitudinally across states of both mania and euthymia alongside a cohort of healthy participants scanned longitudinally. We then sought to replicate these results in independent cohorts of manic (n = 26) and euthymic (n = 21) participants with bipolar disorder., Results: Mania-inducing lesions overlap significantly in network connectivity. Mania-causing lesions selectively disrupt networks that include orbitofrontal cortex, dorsolateral prefrontal cortex, and temporal lobes. In bipolar disorder, the manic state was reflected in strong, significant, and specific disruption in network communication between these regions and regions implicated in bipolar pathophysiology: the amygdala and ventro-lateral prefrontal cortex., Limitations: There was heterogeneity in the clinical characterization of mania causing lesions., Conclusions: Lesions causing mania demonstrate shared and specific network disruptions. These disruptions are also observed in bipolar mania and suggest a convergence of multiple disorders on shared circuit dysfunction to cause mania., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Cognitive and structural brain abnormalities range from mild to severe in psychosis. The relationships of specific cognitive functions to specific brain structures across the psychosis spectrum is less certain., Methods: Participants (n = 678) with bipolar, schizoaffective, or schizophrenia psychoses and healthy control subjects were recruited via the Bipolar-Schizophrenia Network for Intermediate Phenotypes. The Schizo-Bipolar Scale was used to create a psychosis continuum (from purely affective to purely nonaffective). Canonical correlation between 14 cognitive measures and structural brain measures (gray matter volume, cortical thickness, cortical surface area, and local gyrification indices) for 68 neocortical regions yielded constructs that defined shared cognition-brain structure relationships. Canonical discriminant analysis was used to integrate these constructs and efficiently summarize cognition-brain structure relationships across the psychosis continuum., Results: General cognition was associated with larger gray matter volumes and thicker cortices but smaller cortical surface area in frontoparietal regions. Working memory was associated with larger volume and surface area in frontotemporal regions. Faster response speed was associated with thicker frontal cortices. Constructs that captured general cognitive ability and working memory and their relationship to cortical volumes primarily defined an ordered psychosis spectrum (purely affective, least abnormal through purely nonaffective, and most abnormal). A construct that captured general cognitive ability and its relationship to cortical surface area differentiated purely affective cases from other groups., Conclusions: General cognition and working memory with cortical volume deviations characterized more nonaffective psychoses. Alternatively, affective psychosis cases with general cognitive deficits had deviations in cortical surface area, perhaps accounting for heterogeneous findings across previous studies., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Associations between cannabis use and psychotic disorders suggest that cannabis may be a contributory risk factor in the neurobiology of psychosis. In this study, we examined brain structure characteristics, total and regional gray matter density (GMD), using Voxel Based Morphometry, in psychotic individuals, stratified by history of cannabis use (total n = 109). We also contrasted GMD estimates in individual diagnostic groups (schizophrenia/bipolar I disorder) with and without history of adolescent cannabis use (ACU). Individuals with psychosis as a whole, both with and without history of ACU, had lower total and regional GMD, compared to healthy controls. ACU was associated with attenuated GMD reductions, compared to non-users, especially in the schizophrenia cases, who showed robust GMD reductions in fronto-temporal and parietal cortex, as well as subcortical regions. Notably, total and regional GMD estimates in individuals with psychosis and ACU were not different from controls with no ACU. These data indicate that the history of ACU in psychotic individuals is associated with attenuated GMD abnormalities. Future investigations targeting potential unique etiological and risk factors associated with psychosis in individuals with ACU may help in understanding of the neurobiology of psychotic disorders and novel treatment options for these individuals., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Patients with psychotic disorders are often treated with numerous medications, many of which have anticholinergic activity. We assessed cognition in relation to the cumulative anticholinergic burden of multiple drugs included in treatment regimens of participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study., Method: Clinically stable participants with schizophrenia (n=206), schizoaffective disorder (n=131), and psychotic bipolar disorder (n=146) were examined. Anticholinergic properties of all scheduled drugs were quantified using the Anticholinergic Drug Scale (ADS). ADS scores were summed across individual drugs to create a total ADS burden score for each participant and examined in relation to the Brief Assessment of Cognition in Schizophrenia (BACS)., Results: Anticholinergic burden aggregated across all medications was inversely related to cognitive performance starting at ADS scores of 4 in participants with schizophrenia. Those with ADS scores ≥4 had lower composite BACS scores compared to those with ADS<4 (p=0.004). Among BACS subtests, Verbal Memory was the most adversely affected by high anticholinergic burden. Despite similar anticholinergic burden scores across groups, a significant threshold effect of anticholinergic burden was not detected in schizoaffective or psychotic bipolar disorder., Conclusion: We identified an adverse effect threshold of anticholinergic burden on cognition in clinically stable participants with schizophrenia. This relationship was not identified in affective psychoses. Examination of other medications, doses, and clinical measures did not account for these findings. Patients with schizophrenia may have increased cognitive susceptibility to anticholinergic medications and the aggregate effects of one's medication regimen may be important to consider in clinical practice., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Cognitive dysfunction is a core symptom dimension in bipolar disorder and a strong predictor of functional outcomes. Cognitive remediation (CR) produces moderate, durable effects on cognition in patients with schizophrenia; however, studies of CR in patients with bipolar disorder are sparse and findings have been mixed. Thus, the aim of this study was to evaluate the effects of CR versus active control in patients with bipolar disorder with psychosis., Methods: Patients with a DSM-IV diagnosis of bipolar disorder with psychosis (n = 75) were randomized to a 70-hour computerized CR program or a dose-matched computer control using a parallel design with 1:1 allocation between July 2011 and November 2015. Cognition (primary outcome) and clinical and community functioning (secondary outcomes) were assessed at baseline, at treatment midpoint (after 20-25 hours of training), posttreatment, and at durability (after 6 months of no study contact). Participants and assessment staff were blind to group membership., Results: 75 participants were randomly assigned to a treatment group, and 72 participants initiated the active phase of treatment and were included in the primary, intent-to-treat analysis (CR: n = 39; Control: n = 33). Linear mixed effects models examining the effects of CR versus Control at posttreatment showed medium to large effects of CR on processing speed (d = 0.42), visual learning and memory (d = 0.92), and the composite (d = 0.80). Superiority of CR over Control on processing speed (d = 0.65) and composite (d = 0.83) was maintained or increased at durability. CR was not associated with change in community functioning, although cognitive change was associated with functional change across the sample., Conclusions: Cognitive remediation produced significant improvements over an active control in several cognitive domains and the cognitive composite. While both groups improved on several domains relative to baseline, durability of gains was unique to CR., Trial Registration: ClinicalTrials.gov identifier: NCT01470781., (© Copyright 2017 Physicians Postgraduate Press, Inc.)

Individuals with psychosis have been reported to show either reduced or augmented brain responses under seemingly similar conditions. It is likely that inconsistent baseline-adjustment methods are partly responsible for this discrepancy. Using steady-state stimuli during a pro/antisaccade task, this study addressed the relationship between nonspecific and stimulus-related neural activity, and how these activities are modulated as a function of cognitive demands. In 98 psychosis probands (schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis), neural activity was assessed during baseline and during a 5-s period in preparation for the pro/antisaccade task. To maximize the ability to identify meaningful differences between psychosis subtypes, analyses were conducted as a function of subgrouping probands by standard clinical diagnoses and neurobiological features. These psychosis "biotypes" were created using brain-based biomarkers, independent of symptomatology (Clementz et al., ). Psychosis probands as a whole showed poor antisaccade performance and diminished baseline oscillatory phase synchrony. Psychosis biotypes differed on both behavioral and brain measures, in ways predicted from Clementz et al. (). Two biotype groups showed similarly deficient behavior and baseline synchrony, despite diametrically opposed neural activity amplitudes. Another biotype subgroup was more similar to healthy individuals on behavioral and brain measures, despite the presence of psychosis. This study provides evidence that (a) consideration of baseline levels of activation and synchrony will be essential for a comprehensive understanding of neural response differences in psychosis, and (b) distinct psychosis subgroups exhibit reduced versus augmented intrinsic neural activity, despite cognitive performance and clinical similarities., (© 2017 Society for Psychophysiological Research.)

Background: Using resting-state functional magnetic resonance imaging (rsfMRI), we previously compared cohorts of bipolar I subjects in a manic state to those in a euthymic state to identify mood state-specific patterns of cortico-amygdala connectivity. Our results suggested that mania is reflected in the disruption of emotion regulation circuits. We sought to replicate this finding in a group of subjects with bipolar disorder imaged longitudinally across states of mania and euthymia METHODS: We divided our subjects into three groups: 26 subjects imaged in a manic state, 21 subjects imaged in a euthymic state, and 10 subjects imaged longitudinally across both mood states. We measured differences in amygdala connectivity between the mania and euthymia cohorts. We then used these regions of altered connectivity to examine connectivity in the longitudinal bipolar group using a within-subjects design., Results: Our findings in the mania vs euthymia cohort comparison were replicated in the longitudinal analysis. Bipolar mania was differentiated from euthymia by decreased connectivity between the amygdala and pre-genual anterior cingulate cortex. Mania was also characterized by increased connectivity between amygdala and the supplemental motor area, a region normally anti-correlated to the amygdala in emotion regulation tasks., Limitations: Stringent controls for movement effects limited the number of subjects in the longitudinal sample., Conclusions: In this first report of rsfMRI conducted longitudinally across mood states, we find that previously observed between-group differences in amygdala connectivity are also found longitudinally within subjects. These results suggest resting state cortico-amygdala connectivity is a biomarker of mood state in bipolar disorder., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The current definitions of psychotic illness lack biological validity, motivating alternative biomarker-driven disease entities. Building on experimental constructs-Biotypes-that were previously developed from cognitive and neurophysiologic measures, we contrast brain anatomy characteristics across Biotypes alongside conventional diagnoses, examining gray matter density (GMD) as an independent validator for the Biotypes., Methods: Whole brain GMD measures were examined in probands, their relatives, and healthy subjects organized by Biotype and then by DSM-IV-TR diagnosis (n = 1409) using voxel-based morphometry with subsequent subject-level regional characterization and distribution analyses., Results: Probands grouped by Biotype versus healthy controls showed a stepwise pattern of GMD reductions as follows: Biotype1, extensive and diffusely distributed GMD loss, with the largest effects in frontal, anterior/middle cingulate cortex, and temporal regions; Biotype2, intermediate and more localized reductions, with the largest effects in insula and frontotemporal regions; and Biotype3, small reductions localized to anterior limbic regions. Relatives showed regionally distinct GMD reductions versus healthy controls, with primarily anterior (frontotemporal) effects in Biotype1; posterior (temporo-parieto-cerebellar) in Biotype2; and normal GMD in Biotype3. Schizophrenia and schizoaffective probands versus healthy controls showed overlapping GMD reductions, with the largest effects in frontotemporal and parietal regions; psychotic bipolar probands had small reductions, primarily in frontal regions. GMD changes in relatives followed regional patterns observed in probands, albeit less extensive. Biotypes showed stronger between-group separation based on GMD than the conventional diagnoses and were the strongest predictor of GMD change., Conclusions: GMD biomarkers depicted unique brain structure characteristics within Biotypes, consistent with their cognitive and sensorimotor profiles, and provided stronger discrimination for biologically driven biotypes than symptom-based diagnoses., (Published by Elsevier Inc.)

Background: The adaptability of the human brain to the constantly changing environment is reduced in patients with psychotic disorders, leading to impaired cognitive functions. Brain signal complexity, which may reflect adaptability, can be readily quantified via resting-state functional magnetic resonance imaging (fMRI) signals. We hypothesized that resting-state brain signal complexity is altered in psychotic disorders, and is correlated with cognitive impairment., Methods: We assessed 156 healthy controls (HC) and 330 probands, including 125 patients with psychotic bipolar disorder (BP), 107 patients with schizophrenia (SZ), 98 patients with schizoaffective disorder (SAD) and 230 of their unaffected first-degree relatives (76 BPR, 79 SADR, and 75 SZR) from four sites of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Using multi-scale entropy analysis, we determined whether patients and/or relatives had pathologic differences in complexity of resting-state fMRI signals toward regularity (reduced entropy in all time scales), or toward uncorrelated randomness (increased entropy in fine time scales that decays as the time scale increases) and how these complexity differences might be associated with cognitive impairment., Results: Compared to HC subjects, proband groups showed either decreased complexity toward regularity or toward randomness. SZ probands showed decreased complexity toward regular signal in hypothalamus, and BP probands in left inferior occipital, right precentral and left superior parietal regions, whereas no brain region with decreased complexity toward regularity was found in SAD probands. All proband groups showed significantly increased brain signal randomness in dorsal and ventral prefrontal cortex (PFC), and unaffected relatives showed no complexity differences in PFC regions. SZ had the largest area of involvement in both dorsal and ventral PFC. BP and SAD probands shared increased brain signal randomness in ventral medial PFC, BP and SZ probands shared increased brain signal randomness in ventral lateral PFC, whereas SAD and SZ probands shared increased brain signal randomness in dorsal medial PFC. Only SZ showed increased brain signal randomness in dorsal lateral PFC. The increased brain signal randomness in dorsal or ventral PFC was weakly associated with reduced cognitive performance in psychotic probands., Conclusion: These observations support the loss of brain complexity hypothesis in psychotic probands. Furthermore, we found significant differences as well as overlaps of pathologic brain signal complexity between psychotic probands by DSM diagnoses, thus suggesting a biological approach to categorizing psychosis based on functional neuroimaging data., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Functional magnetic resonance imaging (fMRI) studies have shown altered brain dynamic functional connectivity (DFC) in mental disorders. Here, we aim to explore DFC across a spectrum of symptomatically-related disorders including bipolar disorder with psychosis (BPP), schizoaffective disorder (SAD), and schizophrenia (SZ). We introduce a group information guided independent component analysis procedure to estimate both group-level and subject-specific connectivity states from DFC. Using resting-state fMRI data of 238 healthy controls (HCs), 140 BPP, 132 SAD, and 113 SZ patients, we identified measures differentiating groups from the whole-brain DFC and traditional static functional connectivity (SFC), separately. Results show that DFC provided more informative measures than SFC. Diagnosis-related connectivity states were evident using DFC analysis. For the dominant state consistent across groups, we found 22 instances of hypoconnectivity (with decreasing trends from HC to BPP to SAD to SZ) mainly involving post-central, frontal, and cerebellar cortices as well as 34 examples of hyperconnectivity (with increasing trends HC through SZ) primarily involving thalamus and temporal cortices. Hypoconnectivities/hyperconnectivities also showed negative/positive correlations, respectively, with clinical symptom scores. Specifically, hypoconnectivities linking postcentral and frontal gyri were significantly negatively correlated with the PANSS positive/negative scores. For frontal connectivities, BPP resembled HC while SAD and SZ were more similar. Three connectivities involving the left cerebellar crus differentiated SZ from other groups and one connection linking frontal and fusiform cortices showed a SAD-unique change. In summary, our method is promising for assessing DFC and may yield imaging biomarkers for quantifying the dimension of psychosis. Hum Brain Mapp 38:2683-2708, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Context processing may reflect a specific cognitive impairment in schizophrenia. Whether impaired context processing is observed across psychotic disorders or among relatives of affected individuals, and whether it is a deficit that is independent from the generalized neuropsychological deficits seen in psychotic disorders, are less established., Methods: Schizophrenia, schizoaffective, and psychotic bipolar probands (n = 660), their first-degree relatives (n = 741), and healthy individuals (n = 308) studied by the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium performed an expectancy task requiring use of contextual information to overcome a pre-potent response. Sensitivity for target detection and false alarm rates on trials requiring inhibition or goal maintenance were measured., Results: Proband groups and relatives with psychosis spectrum personality traits demonstrated reduced target sensitivity and elevated false alarm rates. False alarm rate was higher under inhibition vs goal maintenance conditions although this difference was attenuated in schizophrenia and schizoaffective proband groups. After accounting for global neuropsychological impairment, as reflected by the composite score from the Brief Assessment of Cognition in Schizophrenia neuropsychological battery, deficits in schizophrenia and bipolar proband groups were no longer significant. Performance measures were moderately familial., Conclusion: Reduced target detection, but not a specific deficit in context processing, is observed across psychotic disorders. Impairments in both goal maintenance and response inhibition appear to contribute comparably to deficits in schizophrenia and schizoaffective disorder, whereas greater difficulty with response inhibition underlies deficits in bipolar disorder. Yet, these deficits are not independent from the generalized neurocognitive impairment observed in schizophrenia and psychotic bipolar disorder., (© The Author 2016. 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: This study aimed to identify how the activity of large-scale brain networks differs between mood states in bipolar disorder. The authors measured spontaneous brain activity in subjects with bipolar disorder in mania and euthymia and compared these states to a healthy comparison population., Methods: 23 subjects with bipolar disorder type I in a manic episode, 24 euthymic bipolar I subjects, and 23 matched healthy comparison (HC) subjects underwent resting state fMRI scans. Using an existing parcellation of the whole brain, we measured functional connectivity between brain regions and identified significant differences between groups., Results: In unbiased whole-brain analyses, functional connectivity between parietal, occipital, and frontal nodes within the dorsal attention network (DAN) were significantly greater in mania than euthymia or HC subjects. In the default mode network (DMN), connectivity between dorsal frontal nodes and the rest of the DMN differentiated both mood state and diagnosis., Limitations: The bipolar groups were separate cohorts rather than subjects imaged longitudinally across mood states., Conclusions: Bipolar mood states are associated with highly significant alterations in connectivity in two large-scale brain networks. These same networks also differentiate bipolar mania and euthymia from a HC population. State related changes in DAN and DMN connectivity suggest a circuit based pathology underlying cognitive dysfunction as well as activity/reactivity in bipolar mania. Altered activities in neural networks may be biomarkers of bipolar disorder diagnosis and mood state that are accessible to neuromodulation and are promising novel targets for scientific investigation and possible clinical intervention., (Copyright © 2016 Elsevier B.V. All rights reserved.)

It is critical for psychiatry as a field to develop approaches to define the molecular, cellular, and circuit basis of its brain diseases, especially for serious mental illnesses, and then to use these definitions to generate biologically based disease categories, as well as to explore disease mechanisms and illness etiologies. Our current reliance on phenomenology is inadequate to support exploration of molecular treatment targets and disease formulations, and the leap directly from phenomenology to disease biology has been limiting because of broad heterogeneity within conventional diagnoses. The questions addressed in this review are formulated around how we can use brain biomarkers to achieve disease categories that are biologically based. We have grouped together a series of vignettes as examples of early approaches, all using the Bipolar and Schizophrenia Network on Intermediate Phenotypes (BSNIP) biomarker database and collaborators, starting off with describing the foundational statistical methods for these goals. We use primarily criterion-free statistics to identify pertinent groups of involved genes related to psychosis as well as symptoms, and finally, to create new biologically based disease cohorts within the psychopathological dimension of psychosis. Although we do not put these results forward as final formulations, they represent a novel effort to rely minimally on phenomenology as a diagnostic tool and to fully embrace brain characteristics of structure, as well as molecular and cellular characteristics and function, to support disease definition in psychosis., (Copyright © 2016. Published by Elsevier Inc.)

Background: We sought to examine resting-state functional magnetic resonance imaging connectivity measures in psychotic patients to both identify cumulative differences across psychosis and subsequently probe deficits across conventional DSM-IV diagnoses and a newly identified classification using cognitive/neurophysiological data (Biotypes)., Methods: We assessed 1125 subjects, including healthy control subjects, probands (schizophrenia, schizoaffective disorder, psychotic bipolar disorder), and relatives of probands. Probands and relatives were also segregated into Biotype groups (B1-B3, B1R-B3R using a method reported previously). Empirical resting-state functional magnetic resonance imaging networks were derived using independent component analysis. Global psychosis-related abnormalities were first identified. Subsequent post hoc t tests were performed across various diagnostic categories. Follow-up linear mixed model compared significance of within-proband differences across categories. Secondary analyses assessed correlations with biological profile scores., Results: Voxelwise tests between proband and control subjects revealed nine abnormal networks. Post hoc analysis revealed lower connectivity in most networks for all proband subgroups (DSM and Biotypes). Within-proband effect sizes of discrimination were marginally better for Biotypes over DSM. Reduced connectivity was noted in relatives of patients with schizophrenia in two networks and relatives of patients with psychotic bipolar disorder in one network. Biotype relatives showed similar deficits in one network. Connectivity deficits across four networks were significantly associated with cognitive control profile scores., Conclusions: Overall, we found psychosis-related connectivity deficits in nine large-scale networks. Deficits in these networks tracked more closely with cognitive control factors, suggesting potential implications for disease profiling and therapeutic intervention. Biotypes performed marginally better in terms of separating out psychosis subgroups compared with conventional DSM or psychiatric diagnoses., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The corpus callosum has been implicated in the pathogenesis of schizophrenia and bipolar disorder. However, it is unclear whether corpus callosum alterations are related to the underlying familial diathesis for psychotic disorders. We examined the corpus callosum and its subregion volumes and their relationship to cognition, psychotic symptoms, and age in probands with schizophrenia (SZ), psychotic bipolar disorder (PBD), and schizoaffective disorder; their first-degree relatives; and healthy control subjects., Methods: We present findings from morphometric and neurocognitive analyses of 1381 subjects (SZ probands, n = 224; PBD probands, n = 190; schizoaffective disorder probands, n = 142; unaffected relatives, n = 483 [SZ relatives, n = 195; PBD relatives, n = 175; schizoaffective disorder relatives, n = 113]; control subjects, n = 342). Magnetization prepared rapid acquisition gradient-echo T1 scans across five sites were obtained using 3-tesla magnets. Image processing was done using FreeSurfer Version 5.1. Neurocognitive function was measured using the Brief Assessment of Cognition in Schizophrenia scale., Results: Anterior and posterior splenial volumes were significantly reduced across the groups. The SZ and PBD probands showed robust and significant reductions, whereas relatives showed significant reductions of intermediate severity. The splenial volumes were positively but differentially correlated with aspects of cognition in the probands and their relatives. Proband groups showed a significant age-related decrease in the volume of the anterior splenium compared with control subjects. Among the psychosis groups, the anterior splenium in probands with PBD showed a stronger correlation with psychotic symptoms, as shown by the Positive and Negative Syndrome Scale. All five subregions showed significantly high familiality., Conclusions: The splenial volumes were significantly reduced across the psychosis dimension. However, this volume reduction impacts cognition and clinical manifestation of the illnesses differentially., Competing Interests: Disclosure/Conflict of Interest Statement: All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Existing models of the pathophysiology of bipolar disorder posit disruption in neural circuits of emotion regulation and reward processing. However, few fMRI studies have compared regional brain activity and connectivity in different mood states in bipolar disorder to determine if manic symptomatology is reflected in specific circuit abnormalities. The purpose of this study was to test the hypothesis that bipolar mania is associated with altered connectivity between cortical regions thought to regulate subcortical structures such as the amygdala and striatum., Methods: 28 subjects with bipolar disorder in a manic state, 24 different bipolar subjects in a euthymic state, and 23 matched healthy comparison subjects underwent resting state fMRI scans. Several cortical and sub-cortical structures implicated in the pathogenesis of bipolar disorder were selected for study. We conducted a whole-brain analysis of functional connectivity of these regions., Results: Bipolar mania was differentiated from euthymia by decreased functional connectivity between the amygdala and anterior cingulate cortex (ACC). Mania was also characterized by increased connectivity between amygdala and dorsal frontal cortical structures that are normally anti-correlated in emotion regulation tasks., Limitations: Both groups of bipolar subjects were prescribed medications. The study was not longitudinal in design., Conclusions: Compared to bipolar subjects in a euthymic state, subjects in the manic state demonstrate disrupted functional connectivity between brain regions involved in the regulation of emotion and the amygdala. This disruption of activity in neural circuits involved in emotion may underlie the emotional dysregulation inherent to a bipolar manic episode., (Copyright © 2016 Elsevier B.V. All rights reserved.)