Publications by authors named "Matcheri S Keshavan"

517 Publications

Intermittent theta burst stimulation of cerebellar vermis enhances fronto-cerebellar resting state functional connectivity in schizophrenia with predominant negative symptoms: A randomized controlled trial.

Schizophr Res 2021 Oct 12;238:108-120. Epub 2021 Oct 12.

Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore 560029, Karnataka, India. Electronic address:

Objective: Negative symptoms of schizophrenia are substantially disabling and treatment resistant. Novel treatments like repetitive transcranial magnetic stimulation (TMS) need to be examined for the same using the experimental medicine approach that incorporates tests of mechanism of action in addition to clinical efficacy in trials.

Methods: Study was a double-blind, parallel, randomized, sham-controlled trial recruiting schizophrenia with at least a moderate severity of negative symptoms. Participants were randomized to real or sham intermittent theta burst stimulation (iTBS) under MRI-guided neuro-navigation, targeting the cerebellar vermis area VII-B, at a stimulus intensity of 100% active motor threshold, two sessions/day for five days (total = 6000 pulses). Assessments were conducted at baseline (T0), day-6 (T1) and week-6 (T2) after initiation of intervention. Main outcomes were, a) Scale for the Assessment of Negative Symptoms (SANS) score (T0, T1, T2), b) fronto-cerebellar resting state functional connectivity (RSFC) (T0, T1).

Results: Thirty participants were recruited in each arm. Negative symptoms improved in both arms (p < 0.001) but was not significantly different between the two arms (p = 0.602). RSFC significantly increased between the cerebellar vermis and the right inferior frontal gyrus (p = 0.033), right pallidum (p = 0.042) and right frontal pole (p = 0.047) in the real arm with no change in the sham arm.

Conclusion: Cerebellar vermal iTBS engaged a target belonging to the class of cerebello-subcortical-cortical networks, implicated in negative symptoms of schizophrenia. However, this did not translate to a superior clinical efficacy. Future trials should employ enhanced midline cerebellar TMS stimulation parameters for longer durations that can potentiate and translate biological changes into clinical effects.
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http://dx.doi.org/10.1016/j.schres.2021.10.005DOI Listing
October 2021

Sleep Disturbance in Individuals at Clinical High Risk for Psychosis.

Schizophr Bull 2021 Sep 18. Epub 2021 Sep 18.

Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.

Introduction: Disturbed sleep is a common feature of psychotic disorders that is also present in the clinical high risk (CHR) state. Evidence suggests a potential role of sleep disturbance in symptom progression, yet the interrelationship between sleep and CHR symptoms remains to be determined. To address this knowledge gap, we examined the association between disturbed sleep and CHR symptoms over time.

Methods: Data were obtained from the North American Prodrome Longitudinal Study (NAPLS)-3 consortium, including 688 CHR individuals and 94 controls (mean age 18.25, 46% female) for whom sleep was tracked prospectively for 8 months. We used Cox regression analyses to investigate whether sleep disturbances predicted conversion to psychosis up to >2 years later. With regressions and cross-lagged panel models, we analyzed longitudinal and bidirectional associations between sleep (the Pittsburgh Sleep Quality Index in conjunction with additional sleep items) and CHR symptoms. We also investigated the independent contribution of individual sleep characteristics on CHR symptom domains separately and explored whether cognitive impairments, stress, depression, and psychotropic medication affected the associations.

Results: Disturbed sleep at baseline did not predict conversion to psychosis. However, sleep disturbance was strongly correlated with heightened CHR symptoms over time. Depression accounted for half of the association between sleep and symptoms. Importantly, sleep was a significant predictor of CHR symptoms but not vice versa, although bidirectional effect sizes were similar.

Discussion: The critical role of sleep disturbance in CHR symptom changes suggests that sleep may be a promising intervention target to moderate outcome in the CHR state.
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http://dx.doi.org/10.1093/schbul/sbab104DOI Listing
September 2021

Resting-state functional connectivity predictors of treatment response in schizophrenia - A systematic review and meta-analysis.

Schizophr Res 2021 Sep 15;237:153-165. Epub 2021 Sep 15.

Beth Israel Deaconess Medical Center and Massachusetts Mental Health Center, Harvard Medical School, Boston, MA, United States of America.

We aimed to systematically synthesize and quantify the utility of pre-treatment resting-state functional magnetic resonance imaging (rs-fMRI) in predicting antipsychotic response in schizophrenia. We searched the PubMed/MEDLINE database for studies that examined the magnitude of association between baseline rs-fMRI assessment and subsequent response to antipsychotic treatment in persons with schizophrenia. We also performed meta-analyses for quantifying the magnitude and accuracy of predicting response defined continuously and categorically. Data from 22 datasets examining 1280 individuals identified striatal and default mode network functional segregation and integration metrics as consistent determinants of treatment response. The pooled correlation coefficient for predicting improvement in total symptoms measured continuously was ~0.47 (12 datasets; 95% CI: 0.35 to 0.59). The pooled odds ratio of predicting categorically defined treatment response was 12.66 (nine datasets; 95% CI: 7.91-20.29), with 81% sensitivity and 76% specificity. rs-fMRI holds promise as a predictive biomarker of antipsychotic treatment response in schizophrenia. Future efforts need to focus on refining feature characterization to improve prediction accuracy, validate prediction models, and evaluate their implementation in clinical practice.
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http://dx.doi.org/10.1016/j.schres.2021.09.004DOI Listing
September 2021

Subtyping Schizophrenia Patients Based on Patterns of Structural Brain Alterations.

Schizophr Bull 2021 Sep 11. Epub 2021 Sep 11.

Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.

Schizophrenia is a complex and heterogeneous syndrome. Whether quantitative imaging biomarkers can identify discrete subgroups of patients as might be used to foster personalized medicine approaches for patient care remains unclear. Cross-sectional structural MR images of 163 never-treated first-episode schizophrenia patients (FES) and 133 chronically ill patients with midcourse schizophrenia from the Bipolar and Schizophrenia Network for Intermediate Phenotypes (B-SNIP) consortium and a total of 403 healthy controls were recruited. Morphometric measures (cortical thickness, surface area, and subcortical structures) were extracted for each subject and then the optimized subtyping results were obtained with nonsupervised cluster analysis. Three subgroups of patients defined by distinct patterns of regional cortical and subcortical morphometric features were identified in FES. A similar three subgroup pattern was identified in the independent dataset of patients from the multi-site B-SNIP consortium. Similarities of classification patterns across these two patient cohorts suggest that the 3-group typology is relatively stable over the course of illness. Cognitive functions were worse in subgroup 1 with midcourse schizophrenia than those in subgroup 3. These findings provide novel insight into distinct subgroups of patients with schizophrenia based on structural brain features. Findings of different cognitive functions among the subgroups support clinical differences in the MRI-defined illness subtypes. Regardless of clinical presentation and stage of illness, anatomic MR subgrouping biomarkers can separate neurobiologically distinct subgroups of schizophrenia patients, which represent an important and meaningful step forward in differentiating subtypes of patients for studies of illness neurobiology and potentially for clinical trials.
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http://dx.doi.org/10.1093/schbul/sbab110DOI Listing
September 2021

Confirmatory Efficacy of Cognitive Enhancement Therapy for Early Schizophrenia: Results From a Multisite Randomized Trial.

Psychiatr Serv 2021 Sep 2:appips202000552. Epub 2021 Sep 2.

Jack, Joseph and Morton Mandel School of Applied Social Sciences, Case Western Reserve University, Cleveland (Wojtalik); Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston (Mesholam-Gately, Sandoval, Shashidhar, Keshavan); Department of Psychiatry, Harvard Medical School, Boston (Mesholam-Gately, Sandoval, Guimond, Keshavan); Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh (Hogarty, Greenwald, Litschge, Eack); Department of Psychoeducation and Psychology, Université du Québec en Outaouais, Gatineau, Quebec, Canada (Guimond); School of Social Work, University of Pittsburgh, Pittsburgh (Eack).

Objective: Cognitive enhancement therapy (CET) is an 18-month comprehensive cognitive remediation intervention designed to improve cognition and functioning among patients with schizophrenia. The current study sought to confirm previously observed benefits of CET on cognitive and behavioral outcomes in the early course of the condition in a large multisite trial.

Methods: Overall, 102 outpatients with early-course schizophrenia were randomly assigned to 18 months of CET (N=58) or enriched supportive therapy (EST; N=44). Participants completed cognitive, social adjustment, and symptom assessments at baseline and at 9 and 18 months. Composite indices were calculated for these outcomes. Mixed-effects models investigated differential changes in outcomes between CET and EST. Because of a high attrition rate, sensitivity analyses of data from treatment completers (N=49) were conducted.

Results: The effects of CET on improved overall cognition were confirmed and tentatively confirmed for social cognition in both intent-to-treat and completer analyses, and beneficial effects on attention/vigilance were also observed. An effect of CET on social adjustment was not confirmed in the analyses, because both CET and EST groups had considerably improved social adjustment. Although not statistically significant, the between-group effect size for CET's effect on social adjustment doubled from the intent-to-treat (Cohen's d=0.23) to completer analyses (Cohen's d=0.51) (p=0.057). Both groups displayed similar symptom improvements.

Conclusions: CET effectively improved cognition among patients with early-course schizophrenia. The functional benefits of CET appeared to increase with treatment retention. Further research is needed to understand predictors of attrition and mechanisms of change during CET for this population.
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http://dx.doi.org/10.1176/appi.ps.202000552DOI Listing
September 2021

Psychosis Biotypes: Replication and Validation from the B-SNIP Consortium.

Schizophr Bull 2021 Aug 19. Epub 2021 Aug 19.

Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.

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.
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http://dx.doi.org/10.1093/schbul/sbab090DOI Listing
August 2021

Auditory Oddball Responses Across the Schizophrenia-Bipolar Spectrum and Their Relationship to Cognitive and Clinical Features.

Am J Psychiatry 2021 10 19;178(10):952-964. Epub 2021 Aug 19.

Departments of Psychology and Neuroscience, Bio-Imaging Research Center, University of Georgia, Athens (Parker, Trotti, McDowell, Clementz); Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago (Keedy, Gershon); Department of Psychology, Rosalind Franklin University of Medicine and Science, Chicago (Hill); Department of Psychiatry, UT Southwestern Medical Center, Dallas (Ivleva, Tamminga); Departments of Psychiatry and Neuroscience, Yale School of Medicine, New Haven, Conn. (Pearlson); Olin Center, Institute of Living, Hartford Healthcare Corporation, Hartford, Conn. (Pearlson); and Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Cambridge, Mass. (Keshavan).

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.
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http://dx.doi.org/10.1176/appi.ajp.2021.20071043DOI Listing
October 2021

Deficits in generalized cognitive ability, visual sensorimotor function, and inhibitory control represent discrete domains of neurobehavioral deficit in psychotic disorders.

Schizophr Res 2021 10 13;236:54-60. Epub 2021 Aug 13.

Rosalind Franklin University of Medicine and Science, Department of Psychology, North Chicago, IL, United States.

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.
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http://dx.doi.org/10.1016/j.schres.2021.07.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464494PMC
October 2021

Proximate markers of cognitive dysfunction in schizophrenia.

Schizophr Res 2021 07 26;233:114-115. Epub 2021 Jul 26.

Department of Psychological & Brain Sciences, Boston University, Boston, MA, United States; Center for Systems Neuroscience, Cognitive Neuroimaging Center, Center for Research in Sensory Communications and Neural Technology, Boston University, Boston, MA, United States. Electronic address:

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http://dx.doi.org/10.1016/j.schres.2021.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380687PMC
July 2021

Improving the predictive potential of diffusion MRI in schizophrenia using normative models-Towards subject-level classification.

Hum Brain Mapp 2021 Oct 29;42(14):4658-4670. Epub 2021 Jul 29.

Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Diffusion MRI studies consistently report group differences in white matter between individuals diagnosed with schizophrenia and healthy controls. Nevertheless, the abnormalities found at the group-level are often not observed at the individual level. Among the different approaches aiming to study white matter abnormalities at the subject level, normative modeling analysis takes a step towards subject-level predictions by identifying affected brain locations in individual subjects based on extreme deviations from a normative range. Here, we leveraged a large harmonized diffusion MRI dataset from 512 healthy controls and 601 individuals diagnosed with schizophrenia, to study whether normative modeling can improve subject-level predictions from a binary classifier. To this aim, individual deviations from a normative model of standard (fractional anisotropy) and advanced (free-water) dMRI measures, were calculated by means of age and sex-adjusted z-scores relative to control data, in 18 white matter regions. Even though larger effect sizes are found when testing for group differences in z-scores than are found with raw values (p < .001), predictions based on summary z-score measures achieved low predictive power (AUC < 0.63). Instead, we find that combining information from the different white matter tracts, while using multiple imaging measures simultaneously, improves prediction performance (the best predictor achieved AUC = 0.726). Our findings suggest that extreme deviations from a normative model are not optimal features for prediction. However, including the complete distribution of deviations across multiple imaging measures improves prediction, and could aid in subject-level classification.
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http://dx.doi.org/10.1002/hbm.25574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410550PMC
October 2021

An opportunity for primary prevention research in psychotic disorders.

Schizophr Res 2021 Jul 24. Epub 2021 Jul 24.

Rosalind Franklin University of Medicine and Science, United States of America. Electronic address:

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.
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http://dx.doi.org/10.1016/j.schres.2021.07.001DOI Listing
July 2021

Genome-wide association study accounting for anticholinergic burden to examine cognitive dysfunction in psychotic disorders.

Neuropsychopharmacology 2021 09 18;46(10):1802-1810. Epub 2021 Jun 18.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.

Identifying genetic contributors to cognitive impairments in psychosis-spectrum disorders can advance understanding of disease pathophysiology. Although CNS medications are known to affect cognitive performance, they are often not accounted for in genetic association studies. In this study, we performed a genome-wide association study (GWAS) of global cognitive performance, measured as composite z-scores from the Brief Assessment of Cognition in Schizophrenia (BACS), in persons with psychotic disorders and controls (N = 817; 682 cases and 135 controls) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Analyses accounting for anticholinergic exposures from both psychiatric and non-psychiatric medications revealed five significantly associated variants located at the chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene (P = 3.25×E-9). The inclusion of anticholinergic burden improved association models (P < 0.001) and the number of significant SNPs identified. The effect sizes and direction of effect of the top variants remained consistent when investigating findings within individuals receiving specific antipsychotic drugs and after accounting for antipsychotic dose. These associations were replicated in a separate study sample of untreated first-episode psychosis. The chromosome 3p21.1 locus was previously reported to have association with the risk for psychotic disorders and cognitive performance in healthy individuals. Our findings suggest that this region may be a psychosis risk locus that is associated with cognitive mechanisms. Our data highlight the general point that the inclusion of medication exposure information may improve the detection of gene-cognition associations in psychiatric genetic research.
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http://dx.doi.org/10.1038/s41386-021-01057-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358015PMC
September 2021

White matter changes in psychosis risk relate to development and are not impacted by the transition to psychosis.

Mol Psychiatry 2021 May 24. Epub 2021 May 24.

Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Subtle alterations in white matter microstructure are observed in youth at clinical high risk (CHR) for psychosis. However, the timing of these changes and their relationships to the emergence of psychosis remain unclear. Here, we track the evolution of white matter abnormalities in a large, longitudinal cohort of CHR individuals comprising the North American Prodrome Longitudinal Study (NAPLS-3). Multi-shell diffusion magnetic resonance imaging data were collected across multiple timepoints (1-5 over 1 year) in 286 subjects (aged 12-32 years): 25 CHR individuals who transitioned to psychosis (CHR-P; 61 scans), 205 CHR subjects with unknown transition outcome after the 1-year follow-up period (CHR-U; 596 scans), and 56 healthy controls (195 scans). Linear mixed effects models were fitted to infer the impact of age and illness-onset on variation in the fractional anisotropy of cellular tissue (FA) and the volume fraction of extracellular free water (FW). Baseline measures of white matter microstructure did not differentiate between HC, CHR-U and CHR-P individuals. However, age trajectories differed between the three groups in line with a developmental effect: CHR-P and CHR-U groups displayed higher FA in adolescence, and 4% lower FA by 30 years of age compared to controls. Furthermore, older CHR-P subjects (20+ years) displayed 4% higher FW in the forceps major (p < 0.05). Prospective analysis in CHR-P did not reveal a significant impact of illness onset on regional FA or FW, suggesting that transition to psychosis is not marked by dramatic change in white matter microstructure. Instead, clinical high risk for psychosis-regardless of transition outcome-is characterized by subtle age-related white matter changes that occur in tandem with development.
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http://dx.doi.org/10.1038/s41380-021-01128-8DOI Listing
May 2021

Characterizing transdiagnostic premorbid biotypes can help progress in selective prevention in psychiatry.

World Psychiatry 2021 Jun;20(2):231-232

Beth Israel Deaconess Medical Center, Massachusetts Mental Health Center and Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1002/wps.20857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129835PMC
June 2021

Abnormal Function in Dentate Nuclei Precedes the Onset of Psychosis: A Resting-State fMRI Study in High-Risk Individuals.

Schizophr Bull 2021 Aug;47(5):1421-1430

Department of Psychology, Northeastern University, Boston, MA.

Objective: The cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into 3 functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN, precede the onset of psychosis in individuals at risk of developing schizophrenia.

Methods: We used the magnetic resonance imaging (MRI) dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N = 144), with longitudinal follow-up to determine which subjects developed a psychotic episode within 1 year of their functional magnetic resonance imaging (fMRI) scan (converters N = 23). Analysis used the 3 functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis.

Results: RsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the 3 functional territories of the DN that were evaluated.

Conclusions: We show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention.
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http://dx.doi.org/10.1093/schbul/sbab038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379537PMC
August 2021

Motivational Interviewing for Loved Ones in Early Psychosis: Development and Pilot Feasibility Trial of a Brief Psychoeducational Intervention for Caregivers.

Front Psychiatry 2021 1;12:659568. Epub 2021 Apr 1.

Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, United States.

Treatment delay and non-adherence in first episode psychosis is a pressing public health problem. Ambivalence regarding psychiatric intervention and labeling among young people with psychosis is a contributing factor. For these individuals, caregivers often facilitate the pathway to care and support ongoing engagement and adherence. Caregivers describe distress and burden associated with this role. This manuscript describes the development and pilot feasibility testing of a motivational interviewing-derived communication training for caregivers of individuals with untreated or under-treated early course psychosis. Individuals with lived experience were consulted in the intervention development process. The training consisted of four 60-min sessions teaching the philosophy and basic skills of motivational interviewing as well as two brief practice calls. Feasibility was assessed with regard to study enrollment, retention, and completion. Satisfaction was assessed through the Client Satisfaction Questionnaire and qualitative feedback. Thirty-one caregivers consented to this pilot feasibility trial and participated via telehealth over the course of 5 months. Intervention completion and reported satisfaction were high, with 94% of consented participants completing at least three training sessions and 84% reporting that they would "definitely" recommend the training to a friend in similar circumstances. There were no between-clinician differences in MILO session attendance ( = 0.53, = 0.596) or satisfaction total scores ( = 1.03, = 0.371). Brief motivational interviewing skills training appears to be a feasible and valued intervention for caregivers of individuals with poorly managed early course psychosis. ClinicalTrials.gov Identifier: NCT04010747.
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http://dx.doi.org/10.3389/fpsyt.2021.659568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047061PMC
April 2021

Comparison of social cognition using an adapted Chinese version of the Reading the Mind in the Eyes Test in drug-naive and regularly medicated individuals with chronic schizophrenia and healthy controls in rural China.

Psychol Med 2021 Mar 16:1-13. Epub 2021 Mar 16.

Department of Epidemiology, Columbia University Mailman School of Public Health, New York, New York, USA.

Background: Social cognition has not previously been assessed in treatment-naive patients with chronic schizophrenia, in patients over 60 years of age, or in patients with less than 5 years of schooling.

Methods: We revised a commonly used measure of social cognition, the Reading the Mind in the Eyes Test (RMET), by expanding the instructions, using both self-completion and interviewer-completion versions (for illiterate respondents), and classifying each test administration as 'successfully completed' or 'incomplete'. The revised instrument (RMET-CV-R) was administered to 233 treatment-naive patients with chronic schizophrenia (UT), 154 treated controls with chronic schizophrenia (TC), and 259 healthy controls (HC) from rural communities in China.

Results: In bivariate and multivariate analyses, successful completion rates and RMET-CV-R scores (percent correct judgments about emotion exhibited in 70 presented slides) were highest in HC, intermediate in TC, and lowest in UT (adjusted completion rates, 97.0, 72.4, and 49.9%, respectively; adjusted RMET-CV-R scores, 45.4, 38.5, and 34.6%, respectively; all p < 0.02). Stratified analyses by the method of administration (self-completed v. interviewer-completed) and by education and age ('educated-younger' v. 'undereducated-older') show the same relationship between groups (i.e. NC>TC>UT), though not all differences remain statistically significant.

Conclusions: We find poorer social cognition in treatment-naive than in treated patients with chronic schizophrenia. The discriminant validity of RMET-CV-R in undereducated, older patients demonstrates the feasibility of administering revised versions of RMET to patients who may otherwise be considered ineligible due to education or age by changing the method of test administration and carefully assessing respondents' ability to complete the task successfully.
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http://dx.doi.org/10.1017/S003329172100043XDOI Listing
March 2021

Biomarker Profiles in Psychosis Risk Groups Within Unaffected Relatives Based on Familiality and Age.

Schizophr Bull 2021 07;47(4):1058-1067

Department of Psychiatry, the University of Texas Southwestern Medical Center, Dallas, TX.

Investigating biomarkers in unaffected relatives (UR) of individuals with psychotic disorders has already proven productive in research on psychosis neurobiology. However, there is considerable heterogeneity among UR based on features linked to psychosis vulnerability. Here, using the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) dataset, we examined cognitive and neurophysiologic biomarkers in first-degree UR of psychosis probands, stratified by 2 widely used risk factors: familiality status of the respective proband (the presence or absence of a first- or second-degree relative with a history of psychotic disorder) and age (within or older than the common age range for developing psychosis). We investigated biomarkers that best differentiate the above specific risk subgroups. Additionally, we examined the relationship of biomarkers with Polygenic Risk Scores for Schizophrenia (PRSSCZ) in a subsample of Caucasian probands and healthy controls (HC). Our results demonstrate that the Brief Assessment of Cognition in Schizophrenia (BACS) score, antisaccade error (ASE) factor, and stop-signal task (SST) factor best differentiate UR (n = 169) from HC (n = 137) (P = .013). Biomarker profiles of UR of familial (n = 82) and non-familial (n = 83) probands were not significantly different. Furthermore, ASE and SST factors best differentiated younger UR (age ≤ 30) (n = 59) from older UR (n = 110) and HC from both age groups (age ≤ 30 years, n=49; age > 30 years, n = 88) (P < .001). In addition, BACS (r = -0.175, P = .006) and ASE factor (r = 0.188, P = .006) showed associations with PRSSCZ. Taken together, our findings indicate that cognitive biomarkers-"top-down inhibition" impairments in particular-may be of critical importance as indicators of psychosis vulnerability.
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http://dx.doi.org/10.1093/schbul/sbab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266584PMC
July 2021

Neural Processing of Repeated Emotional Scenes in Schizophrenia, Schizoaffective Disorder, and Bipolar Disorder.

Schizophr Bull 2021 Aug;47(5):1473-1481

Department of Psychology, University of Georgia, 613 Psychology Building, 125 Baldwin St., Athens, GA 30602, USA.

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.
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http://dx.doi.org/10.1093/schbul/sbab018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379546PMC
August 2021

Building resilience in the COVID-19 era: Three paths in the .

Indian J Psychiatry 2020 Sep-Oct;62(5):459-461. Epub 2020 Oct 10.

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

The COVID-19 pandemic has emerged as a major stressor of a global scale, affecting all aspects of our lives, and is likely to contribute to a surge of mental ill health. Ancient Hindu scriptures, notably the Bhagavad Gita, have a wealth of insights that can help approaches to build psychological resilience for individuals at risk, those affected, as well as for caregivers. The (Jnana yoga) promotes accurate awareness of nature of the self, and can help reframe our thinking from an "I" to a "we mode," much needed for collectively mitigating the spread of the coronavirus. The path of action (Karma yoga) teaches the art of selfless action, providing caregivers and frontline health-care providers a framework to continue efforts in the face of uncertain consequences. Finally, the path of meditation (Raja yoga) offers a multipronged approach to healthy lifestyle and mindful meditation, which may improve resilience to the illness and its severe consequences. While more work is needed to empirically examine the potential value of each of these approaches in modern psychotherapy, the principles herein may already help individuals facing and providing care for the COVID-19 pandemic.
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http://dx.doi.org/10.4103/psychiatry.IndianJPsychiatry_829_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909017PMC
October 2020

Hyperactivation of Posterior Default Mode Network During Self-Referential Processing in Children at Familial High-Risk for Psychosis.

Front Psychiatry 2021 9;12:613142. Epub 2021 Feb 9.

Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, United States.

Patients with schizophrenia spectrum disorders show disturbances in self-referential processing and associated neural circuits including the default mode network (DMN). These disturbances may precede the onset of psychosis and may underlie early social and emotional problems. In this study, we examined self-referential processing in a group of children (7-12 years) at familial high risk (FHR) for psychosis ( = 17), compared to an age and sex-matched group of healthy control (HC) children ( = 20). The participants were presented with a list of adjectives and asked to indicate whether or not the adjectives described them (self-reference condition) and whether the adjectives described a good or bad trait (semantic condition). Three participants were excluded due to chance-level performance on the semantic task, leaving = 15 FHR and = 19 HC for final analysis. Functional MRI (fMRI) was used to measure brain activation during self-referential vs. semantic processing. Internalizing and externalizing problems were assessed with the Child Behavior Checklist (CBCL). Evaluating main effects of task (self > semantic) showed activation of medial prefrontal cortex in HC and precuneus/posterior cingulate cortex (PCC) in FHR. Group-comparison yielded significant results for the FHR > HC contrast, showing two clusters of hyperactivation in precuneus/ PCC ( = 0.004) and anterior cerebellum / temporo-occipital cortex ( = 0.009). Greater precuneus/PCC activation was found to correlate with greater CBCL internalizing ( = 0.60, = 0.032) and total ( = 0.69, = 0.009) problems. In all, this study shows hyperactivity of posterior DMN during self-referential processing in pre-adolescent FHR children. This finding posits DMN-related disturbances in self-processing as a developmental brain abnormality associated with familial risk factors that predates not just psychosis, but also the prodromal stage. Moreover, our results suggest that early disturbances in self-referential processing may be related to internalizing problems in at-risk children.
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http://dx.doi.org/10.3389/fpsyt.2021.613142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900488PMC
February 2021

Antisaccade error rates and gap effects in psychosis syndromes from bipolar-schizophrenia network for intermediate phenotypes 2 (B-SNIP2).

Psychol Med 2021 Feb 24:1-10. Epub 2021 Feb 24.

Departments of Psychology & Neuroscience, University of Georgia, Athens, GA, USA.

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.
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http://dx.doi.org/10.1017/S003329172000478XDOI Listing
February 2021

Theory of Mind impairments in early course schizophrenia: An fMRI study.

J Psychiatr Res 2021 04 13;136:236-243. Epub 2021 Feb 13.

Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA. Electronic address:

Theory of Mind (ToM) refers to the ability to perceive others' mental states. Lower ToM has often been associated with poorer functional outcomes in schizophrenia, making it an important treatment target. However, little is known about the underlying neural mechanisms associated with ToM impairments in early course schizophrenia. This study aimed to validate the False Belief task to measure ToM in schizophrenia and to identify aberrant brain activity associated with impairments. 36 individuals with early course schizophrenia and 17 controls were administered the Hinting Task and performed a functional magnetic resonance imaging (fMRI) False Belief task. Between-group differences were examined in a priori regions of interest (ROIs) known to be associated with ToM tasks: medial prefrontal cortex, ventral medial prefrontal cortex, and both the left and right temporal parietal junction (TPJ). We observed a significant positive association between Hinting Task performance and False Belief accuracy, validating the False Belief task as a measure of ToM. Compared to controls, individuals with schizophrenia exhibited reduced brain activation in all four ROIs during the fMRI False Belief task. Furthermore, task-related activations in bilateral TPJs were shown to be positively associated with ToM abilities regardless of diagnosis. Individuals with schizophrenia with lower performance on the False Belief task showed significant reductions in task-related activation in the bilateral TPJ compared to controls, while reductions were not significant for those with higher performance. Our findings suggest that lower neural activity in the bilateral TPJ are associated with ToM impairments observed in individuals with early course schizophrenia.
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http://dx.doi.org/10.1016/j.jpsychires.2021.02.010DOI Listing
April 2021

Hindsight 2020: Emerging research trends in schizophrenia.

Schizophr Res 2021 03 17;229:22-24. Epub 2021 Feb 17.

Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1016/j.schres.2021.01.025DOI Listing
March 2021

Individualized risk components guiding antipsychotic delivery in patients with a clinical high risk of psychosis: application of a risk calculator.

Psychol Med 2021 Feb 17:1-10. Epub 2021 Feb 17.

Institute of Psychology and Behavioral Science, Shanghai Jiao Tong University, Shanghai, PR China.

Background: Antipsychotics are widely used for treating patients with psychosis, and target threshold psychotic symptoms. Individuals at clinical high risk (CHR) for psychosis are characterized by subthreshold psychotic symptoms. It is currently unclear who might benefit from antipsychotic treatment. Our objective was to apply a risk calculator (RC) to identify people that would benefit from antipsychotics.

Methods: Drawing on 400 CHR individuals recruited between 2011 and 2016, 208 individuals who received antipsychotic treatment were included. Clinical and cognitive variables were entered into an individualized RC for psychosis; personal risk was estimated and 4 risk components (negative symptoms-RC-NS, general function-RC-GF, cognitive performance-RC-CP, and positive symptoms-RC-PS) were constructed. The sample was further stratified according to the risk level. Higher risk was defined based on the estimated risk score (20% or higher).

Results: In total, 208 CHR individuals received daily antipsychotic treatment of an olanzapine-equivalent dose of 8.7 mg with a mean administration duration of 58.4 weeks. Of these, 39 (18.8%) developed psychosis within 2 years. A new index of factors ratio (FR), which was derived from the ratio of RC-PS plus RC-GF to RC-NS plus RC-CP, was generated. In the higher-risk group, as FR increased, the conversion rate decreased. A small group (15%) of CHR individuals at higher-risk and an FR >1 benefitted from the antipsychotic treatment.

Conclusions: Through applying a personal risk assessment, the administration of antipsychotics should be limited to CHR individuals with predominantly positive symptoms and related function decline. A strict antipsychotic prescription strategy should be introduced to reduce inappropriate use.
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http://dx.doi.org/10.1017/S0033291721000064DOI Listing
February 2021

Reduced white matter microstructure in bipolar disorder with and without psychosis.

Bipolar Disord 2021 Feb 7. Epub 2021 Feb 7.

Departments of Psychology and Neuroscience, University of Georgia, Athens, GA, USA.

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.
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http://dx.doi.org/10.1111/bdi.13055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514149PMC
February 2021

Regression dynamic causal modeling for resting-state fMRI.

Hum Brain Mapp 2021 05 4;42(7):2159-2180. Epub 2021 Feb 4.

Translational Neuromodeling Unit (TNU), Institute for Biomedical Engineering, University of Zurich & ETH Zurich, Zurich, Switzerland.

"Resting-state" functional magnetic resonance imaging (rs-fMRI) is widely used to study brain connectivity. So far, researchers have been restricted to measures of functional connectivity that are computationally efficient but undirected, or to effective connectivity estimates that are directed but limited to small networks. Here, we show that a method recently developed for task-fMRI-regression dynamic causal modeling (rDCM)-extends to rs-fMRI and offers both directional estimates and scalability to whole-brain networks. First, simulations demonstrate that rDCM faithfully recovers parameter values over a wide range of signal-to-noise ratios and repetition times. Second, we test construct validity of rDCM in relation to an established model of effective connectivity, spectral DCM. Using rs-fMRI data from nearly 200 healthy participants, rDCM produces biologically plausible results consistent with estimates by spectral DCM. Importantly, rDCM is computationally highly efficient, reconstructing whole-brain networks (>200 areas) within minutes on standard hardware. This opens promising new avenues for connectomics.
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http://dx.doi.org/10.1002/hbm.25357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046067PMC
May 2021

Genetic and clinical analyses of psychosis spectrum symptoms in a large multiethnic youth cohort reveal significant link with ADHD.

Transl Psychiatry 2021 01 28;11(1):80. Epub 2021 Jan 28.

Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.

Psychotic symptoms are not only an important feature of severe neuropsychiatric disorders, but are also common in the general population, especially in youth. The genetic etiology of psychosis symptoms in youth remains poorly understood. To characterize genetic risk for psychosis spectrum symptoms (PS), we leverage a community-based multiethnic sample of children and adolescents aged 8-22 years, the Philadelphia Neurodevelopmental Cohort (n = 7225, 20% PS). Using an elastic net regression model, we aim to classify PS status using polygenic scores (PGS) based on a range of heritable psychiatric and brain-related traits in a multi-PGS model. We also perform univariate PGS associations and evaluate age-specific effects. The multi-PGS analyses do not improve prediction of PS status over univariate models, but reveal that the attention deficit hyperactivity disorder (ADHD) PGS is robustly and uniquely associated with PS (OR 1.12 (1.05, 1.18) P = 0.0003). This association is driven by subjects of European ancestry (OR = 1.23 (1.14, 1.34), P = 4.15 × 10) but is not observed in African American subjects (P = 0.65). We find a significant interaction of ADHD PGS with age (P = 0.01), with a stronger association in younger children. The association is independent of phenotypic overlap between ADHD and PS, not indirectly driven by substance use or childhood trauma, and appears to be specific to PS rather than reflecting general psychopathology in youth. In an independent sample, we replicate an increased ADHD PGS in 328 youth at clinical high risk for psychosis, compared to 216 unaffected controls (OR 1.06, CI(1.01, 1.11), P = 0.02). Our findings suggest that PS in youth may reflect a different genetic etiology than psychotic symptoms in adulthood, one more akin to ADHD, and shed light on how genetic risk can be investigated across early disease trajectories.
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http://dx.doi.org/10.1038/s41398-021-01203-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844241PMC
January 2021

White matter microstructure across brain-based biotypes for psychosis - findings from the bipolar-schizophrenia network for intermediate phenotypes.

Psychiatry Res Neuroimaging 2021 02 16;308:111234. Epub 2020 Dec 16.

Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, United States.

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) 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.
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http://dx.doi.org/10.1016/j.pscychresns.2020.111234DOI Listing
February 2021
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