Publications

Background

Negative symptom severity predicts functional outcomes and quality of life in people with psychosis. However, negative symptoms respond poorly to medication, and existing literature has not converged on their neurobiological basis. Previous work in small schizophrenia samples has observed that lower cerebellar–dorsolateral prefrontal cortex (DLPFC) connectivity is associated with higher negative symptom severity and that increasing cerebellar-DLPFC connectivity with neuromodulation reduces negative symptoms. We extended this finding by testing associations between cerebellar-DLPFC connectivity, negative symptoms, and cognitive performance in a large sample of individuals with psychosis.

Methods

Individuals with psychosis spectrum disorders (N = 260) underwent resting-state functional magnetic resonance imaging and clinical characterization using the Positive and Negative Syndrome Scale and the Screen for Cognitive Impairment in Psychiatry. Using a previously identified cerebellar region as a seed, we measured connectivity to the DLPFC and regressed connectivity against negative symptom severity, covarying for age, sex, and scanner. Then, we tested whether cognitive performance indirectly affected the relationship between connectivity and negative symptom severity.

Results

Across the psychosis spectrum, higher cerebellar-DLPFC connectivity was associated with lower negative symptom severity (r = −0.17, p = .007). This connectivity–negative symptom relationship was not affected by psychosis subtype or duration of illness. Better delayed verbal learning was associated with higher cerebellar-DLPFC connectivity (r = 0.13, p = .034) and had a significant indirect effect on the relationship between connectivity and negative symptoms.

Conclusions

Our results extend relationships between cerebellar-DLPFC connectivity, negative symptom severity, and cognitive performance across the psychosis spectrum. Larger neuromodulation studies should test whether increasing cerebellar-DLPFC connectivity reduces negative symptoms in psychotic disorders.

Objective:

Psychomotor function is a critical marker of risk and outcome of psychosis. Grip strength is one aspect of psychomotor function that is known to be linked to structural neural integrity and well-being. This study sought to determine whether grip strength is a marker of alterations in resting-state connectivity and well-being in psychotic disorders in order to further clarify the mechanisms by which psychosis phenomenology is related to psychomotor processes.

Methods:

The authors analyzed resting-state functional MRI and grip strength in 89 individuals with early psychosis and 51 control subjects without psychiatric disorders from the Human Connectome Project for Early Psychosis. Participants ranged in age from 16 to 35 years. Using multivariate pattern analysis of whole-connectome data, the authors identified brain correlates of grip strength and then replicated this analysis using the NIH Toolbox well-being measures and the Global Assessment of Functioning Scale (GAF).

Results:

The psychosis group exhibited reduced grip strength, well-being, and GAF scores compared to the control group. Grip strength was linked to resting-state connectivity in the sensorimotor cortex, anterior cingulate cortex, and cerebellum. Connectivity correlated with the default mode network (DMN) (r_sensorimotor=0.22, r_cingulate=0.30, r_cerebellum=0.24). When the analysis was repeated for GAF and well-being, overlapping regions in the sensorimotor cortex and cerebellum were connected to the DMN and related to GAF (r_sensorimotor=0.17, r_cerebellum=0.28) and well-being (r_sensorimotor=0.16, r_cerebellum=0.16). Relationships were driven by the psychosis group for cerebellum and cingulate nodes.

Conclusions:

Data-driven, connectome-wide analysis identified shared brain correlates of grip strength, overall function, and well-being in a sample of young adults with psychosis and healthy control subjects. This suggests that grip strength may be a marker of DMN connectivity, which may in turn be an important marker of overall health, even in young adult populations.

Importance  

Transcranial magnetic stimulation (TMS), a form of noninvasive brain stimulation used to treat major depressive disorder, obsessive-compulsive disorder (OCD), and nicotine dependence, has well-established state-dependent effects on brain circuitry. However, a major question for TMS remains: does brain state affect clinical response?

Objective  

To quantify the association between symptom provocation and clinical response to TMS for OCD and nicotine dependence, the only Food and Drug Administration–cleared TMS indications with symptom provocation.

Data Sources  

PubMed, CINAHL, Embase, PsycInfo until August 30, 2024.

Study Selection  

Randomized clinical trials of TMS for OCD or nicotine dependence with a clinical outcome. Of 600 studies identified, 71 met inclusion criteria.

Data Extraction and Synthesis  

Data extraction was completed independently by 2 extractors and cross-checked by a third. Standardized mean difference (SMD) and SE were estimated via Hedges g and synthesized data in a 3-level random-effects meta-analysis. Study data were analyzed from August 2023 to March 2025.

Main Outcomes and Measures  

Primary outcomes were clinical response measures.

Results  

A total of 71 studies met inclusion criteria and included 3246 participants (mean [SD] age; 37.8 [8.0] years; mean [SD] percentage female, 44.1% [17.2%]). Included in the meta-analysis were 63 studies with 2998 participants. For OCD studies, active TMS was associated with better clinical response than sham both with (SMD = −0.51; 95% CI, −0.96 to −0.07; P = 0.04) and without (SMD = −0.29; 95% CI, −0.40 to −0.17; P < .001) symptom provocation. For nicotine use, active TMS was associated with better clinical response than sham when used with (SMD = −0.56; 95% CI, −1.12 to 0; P = .05) but not without (SMD = −0.35; 95% CI, −0.74 to 0.04; P = .08) symptom provocation. For OCD studies, the estimated expected added effect of provocation was SMD of −0.22 (95% CI, −0.65 to 0.20; P = .22). In nicotine studies, the estimated expected added effect of provocation was SMD of −0.21 (95% CI, −1.00 to 0.58; P = .57).

Conclusions and Relevance  

Results of this systematic review and meta-analysis suggest that symptom provocation may enhance clinical response to TMS for OCD and nicotine dependence. Studies comparing TMS with and without provocation are critical to establish the causal effect of provocation.

Abstract

Background and Hypothesis

Current treatments for schizophrenia are only partially effective, and there are no medications for negative symptoms or cognitive impairment. Neuromodulation, such as repetitive transcranial magnetic stimulation (rTMS), has potential as a novel intervention for schizophrenia. Prior to clinical use, rTMS should have demonstrated safety in a large schizophrenia population. However, the safety profile of rTMS in schizophrenia is not well characterized, and regulatory agencies have expressed concern about safety in this population.

Study Design

We conducted a systematic review with meta-analysis of rTMS studies in schizophrenia. We searched PubMed, the Cochrane Library, PsycINFO, and Science Citation Index Expanded for rTMS studies in schizophrenia that reported adverse effects. We extracted the number of participants who experienced an adverse effect and calculated the prevalence of each adverse effect for active or sham rTMS. We tested the difference between the prevalence of events in the active and sham conditions. We assessed risk of bias using the Cochrane Handbook.

Study Results

The initial search identified 1472 studies. After screening, 261 full-text studies were assessed, and 126 met inclusion criteria (N = 4122 total subjects). The prevalence of headache or scalp pain, dizziness or syncope, facial twitching, and nausea was higher for active rTMS compared to sham (P < .05). The prevalence of all other adverse effects, including seizure, was not different between active and sham rTMS.

Conclusions

rTMS is safe and well tolerated for people with schizophrenia. Individuals with schizophrenia are not at increased risk for adverse effects, including seizure, compared to the general population.

Background

Psychomotor disturbances are observed across psychiatric disorders and often manifest as psychomotor slowing, agitation, disorganized behavior, or catatonia. Psychomotor function includes both cognitive and motor components, but the neural circuits driving these subprocesses and how they relate to symptoms have remained elusive for centuries.

Methods

We analyzed data from the HCP-EP (Human Connectome Project for Early Psychosis), a multisite study of 125 participants with early psychosis and 58 healthy participants with resting-state functional magnetic resonance imaging and clinical characterization. Psychomotor function was assessed using the 9-hole pegboard task, a timed motor task that engages mechanical and psychomotor components of action, and tasks assessing processing speed and task switching. We used multivariate pattern analysis of whole-connectome data to identify brain correlates of psychomotor function.

Results

We identified discrete brain circuits driving the cognitive and motor components of psychomotor function. In our combined sample of participants with psychosis (n = 89) and healthy control participants (n = 52), the strongest correlates of psychomotor function (pegboard performance) (p < .005) were between a midline cerebellar region and left frontal region and presupplementary motor area. Psychomotor function was correlated with both cerebellar-frontal connectivity (r = 0.33) and cerebellar–presupplementary motor area connectivity (r = 0.27). However, the cognitive component of psychomotor performance (task switching) was correlated only with cerebellar-frontal connectivity (r = 0.19), whereas the motor component (processing speed) was correlated only with cerebellar–presupplementary motor area connectivity (r = 0.15), suggesting distinct circuits driving unique subprocesses of psychomotor function.

Conclusions

We identified cerebellar-cortical circuits that drive distinct subprocesses of psychomotor function. Future studies should probe relationships between cerebellar connectivity and psychomotor performance using neuromodulation.

Decades of psychosis research highlight the prevalence and the clinical significance of negative emotions, such as fear and anxiety. Translational evidence demonstrates the pivotal role of the amygdala in fear and anxiety. However, most of these approaches have used hypothesis-driven analyses with predefined regions of interest. A data-driven analysis may provide a complimentary, unbiased approach to identifying brain correlates of fear and anxiety. The aim of the current study was to identify the brain basis of fear and anxiety in early psychosis and controls using a data-driven approach. We analyzed data from the Human Connectome Project for Early Psychosis, a multi-site study of 125 people with psychosis and 58 controls with resting-state fMRI and clinical characterization. Multivariate pattern analysis of whole-connectome data was used to identify shared and psychosis-specific brain correlates of fear and anxiety using the NIH Toolbox Fear-Affect and Fear-Somatic Arousal scales. We then examined clinical correlations of Fear-Affect scores and connectivity patterns. Individuals with psychosis had higher levels of Fear-Affect scores than controls (p < 0.05). The data-driven analysis identified a cluster encompassing the amygdala and hippocampus where connectivity was correlated with Fear-Affect score (p < 0.005) in the entire sample. The strongest correlate of Fear-Affect was between this cluster and the anterior insula and stronger connectivity was associated with higher Fear-Affect scores (r = 0.31, p = 0.0003). The multivariate pattern analysis also identified a psychosis-specific correlate of Fear-Affect score between the amygdala/hippocampus cluster and a cluster in the ventromedial prefrontal cortex (VMPFC). Higher Fear-Affect scores were correlated with stronger amygdala/hippocampal-VMPFC connectivity in the early psychosis group (r = 0.33, p = 0.002), but not in controls (r = −0.15, p = 0.28). The current study provides evidence for the transdiagnostic role of the amygdala, hippocampus, and anterior insula in the neural basis of fear and anxiety and suggests a psychosis-specific relationship between fear and anxiety symptoms and amygdala/hippocampal-VMPFC connectivity. Our novel data-driven approach identifies novel, psychosis-specific treatment targets for fear and anxiety symptoms and provides complimentary evidence to decades of hypothesis-driven approaches examining the brain basis of threat processing.

Background

Neurocognitive impairment is a well-known phenomenon in schizophrenia that begins prior to psychosis onset. Connectome-wide association studies have inconsistently linked cognitive performance to resting-state fMRI. We hypothesized a carefully selected cognitive instrument and refined population would allow identification of reliable brain-behavior associations with connectome-wide association studies. To test this hypothesis, we first identified brain-cognition correlations via a connectome-wide association study in early psychosis. We then asked, in an independent dataset, if these brain-cognition relationships would generalize to individuals who develop psychosis in the future.

Methods

The Seidman Auditory Continuous Performance Task (ACPT) effectively differentiates healthy participants from those with psychosis. Our connectome-wide association study used the Human Connectome Project for Early Psychosis (n=183) to identify links between connectivity and ACPT performance. We then analyzed the North American Prodrome Longitudinal Study 2 (n=345), a multi-site prospective study of individuals at risk for psychosis. We tested the connectome-wide association study-identified cognition-connectivity relationship in both individuals at risk for psychosis and controls.

Results

Our connectome-wide association study in early-course psychosis identified robust associations between better ACPT performance and higher prefrontal-somatomotor connectivity (p<.005). Prefrontal-somatomotor connectivity was also related to ACPT performance in at-risk individuals who would develop psychosis (n=17). This finding was not observed in nonconverters (n=196) or controls (n=132).

Conclusions

This connectome-wide association study identified reproducible links between connectivity and cognition in separate samples of psychosis and at-risk individuals who would later develop psychosis. A carefully selected task and population improves the ability of connectome-wide association studies to identify reliable brain-phenotype relationships.

Multiple lines of evidence across human functional, lesion, and animal data point to a cerebellar role, in particular of crus I, crus II, and lobule VIIB, in cognitive function. However, a mapping of distinct facets of cognitive function to cerebellar structure is missing. We analyzed structural neuroimaging data from the Healthy Brain Network (HBN). Cerebellar parcellation was performed with a validated automated segmentation pipeline (CERES) and stringent visual quality check (n = 662 subjects retained from initial n = 1452). Canonical correlation analyses (CCA) examined regional gray matter volumetric (GMV) differences in association to cognitive function (quantified with NIH Toolbox Cognition domain, NIH-TB), accounting for psychopathology severity, age, sex, scan location, and intracranial volume. Multivariate CCA uncovered a significant correlation between two components entailing a latent cognitive canonical (NIH-TB subscales) and a brain canonical variate (cerebellar GMV and intracranial volume, ICV), surviving bootstrapping and permutation procedures. The components correspond to partly shared cerebellar-cognitive function relationship with a first map encompassing cognitive flexibility (r = 0.89), speed of processing (r = 0.65), and working memory (r = 0.52) associated with regional GMV in crus II (r = 0.57) and lobule X (r = 0.59) and a second map including the crus I (r = 0.49) and lobule VI (r = 0.49) associated with working memory (r = 0.51). We show evidence for a structural subspecialization of the cerebellum topography for cognitive function in a transdiagnostic sample.

Background: The ability to manage emotions is an important social-cognitive domain impaired in schizophrenia and linked to functional outcome. The goal of our study was to examine the impact of cognitive enhancement therapy (CET) on the ability to manage emotions and brain functional connectivity in early-course schizophrenia.

Methods: Participants were randomly assigned to CET (n = 55) or an enriched supportive therapy (EST) control group (n = 45). The resting-state functional magnetic resonance imaging scans and measures of emotion management performances were collected at baseline, 9, and 18 months follow-up. The final sample consisted of 37 CET and 25 EST participants, including 19 CET and 12 EST participants with imaging data. Linear mixed-effects models investigated the impact of treatment on emotion management and functional connectivity from the amygdala to ventrolateral and dorsolateral prefrontal cortex (dlPFC).

Results: The CET group showed significant improvement over time in emotion management compared to EST. Neither functional connectivity changes nor main group differences were observed following treatment. However, a significant between-group interaction showed that improved emotion management ability was associated with increased functional connectivity between the left amygdala and the left dlPFC in the CET group exclusively.

Conclusion: Our results replicate the previous work demonstrating that CET is effective at improving some aspects of social cognition in schizophrenia. We found evidence that improvement in emotion management may be associated with a change in amygdala-dlPFC connectivity. This fronto-limbic circuit may provide a mechanistic link between the biology of emotion management processes that can be enhanced in individuals with schizophrenia.

Trial registration: ClinicalTrials.gov NCT01561859.

Individuals with schizophrenia are 10 times more likely to have a tobacco use disorder than the general population. Up to 80% of those with schizophrenia smoke tobacco regularly, a prevalence three-times that of the general population. Despite the striking prevalence of tobacco use in schizophrenia, current treatments are not tailored to the pathophysiology of this population. There is growing support for use of noninvasive brain stimulation (NIBS) to treat substance use disorders (SUDs), particularly for tobacco use in neurotypical smokers. NIBS interventions targeting the dorsolateral prefrontal cortex have been effective for nicotine dependence in control populations—so much so that transcranial magnetic stimulation is now FDA-approved for smoking cessation. However, this has not borne out in the studies using this approach in schizophrenia. We performed a literature search to identify articles using NIBS for the treatment of nicotine dependence in people with schizophrenia, which identified six studies. These studies yielded mixed results. Is it possible that nicotine has a unique effect in schizophrenia that is different than its effect in neurotypical smokers? Individuals with schizophrenia may receive additional benefit from nicotine's pro-cognitive effects than control populations and may use nicotine to improve brain network abnormalities from their illness. Therefore, clinical trials of NIBS interventions should test a schizophrenia-specific target for smoking cessation. We propose a generalized approach whereby schizophrenia-specific brain circuitry related to SUDs is be identified and then targeted with NIBS interventions.