Linking enlarged choroid plexus with plasma analyte and structural phenotypes in clinical high risk for psychosis: A multisite neuroimaging study.

BACKGROUND: Choroid plexus (ChP) enlargement exists in first-episode and chronic psychosis, but whether enlargement occurs before psychosis onset is unknown. This study investigated whether ChP volume is enlarged in individuals with clinical high-risk (CHR) for psychosis and whether these changes are related to clinical, neuroanatomical, and plasma analytes. METHODS: Clinical and neuroimaging data from the North American Prodrome Longitudinal Study 2 (NAPLS2) was used for analysis. 509 participants (169 controls, 340 CHR) were recruited. Conversion status was determined after 2-years of follow-up, with 36 psychosis converters. The lateral ventricle ChP was manually segmented from baseline scans. A subsample of 31 controls and 53 CHR had plasma analyte and neuroimaging data. RESULTS: Compared to controls, CHR (d = 0.23, p = 0.017) and non-converters (d = 0.22, p = 0.03) demonstrated higher ChP volumes, but not in converters. In CHR, greater ChP volume correlated with lower cortical (r = -0.22, p < 0.001), subcortical gray matter (r = -0.21, p < 0.001), and total white matter volume (r = -0.28,p < 0.001), as well as larger lateral ventricle volume (r = 0.63,p < 0.001). Greater ChP volume correlated with makers functionally associated with the lateral ventricle ChP in CHR [CCL1 (r = -0.30, p = 0.035), ICAM1 (r = 0.33, p = 0.02)], converters [IL1ß (r = 0.66, p = 0.004)], and non-converters [BMP6 (r = -0.96, p < 0.001), CALB1 (r = -0.98, p < 0.001), ICAM1 (r = 0.80, p = 0.003), SELE (r = 0.59, p = 0.026), SHBG (r = 0.99, p < 0.001), TNFRSF10C (r = 0.78, p = 0.001)]. CONCLUSIONS: CHR and non-converters demonstrated significantly larger ChP volumes compared to controls. Enlarged ChP was associated with neuroanatomical alterations and analyte markers functionally associated with the ChP. These findings suggest that the ChP may be a key an important biomarker in CHR.

A pilot study to investigate the efficacy and tolerability of lesion network guided transcranial electrical stimulation in outpatients with psychosis spectrum illness.

BACKGROUND: Transcranial electrical stimulation (tES) may improve psychosis symptoms, but few investigations have targeted brain regions causally linked to psychosis symptoms. We implemented a novel montage targeting the extrastriate visual cortex (eVC) previously identified by lesion network mapping in the manifestation of visual hallucinations. OBJECTIVE: To determine if lesion network guided High Definition-tES (HD-tES) to the eVC is safe and efficacious in reducing symptoms related to psychosis. METHODS: We conducted a single-blind crossover pilot study (NCT04870710) in patients with psychosis spectrum disorders. Participants first received HD-tDCS (direct current), followed by 4 weeks of wash out, then 2 Hz HD-tACS (alternating current). Participants received 5 days of daily (2×20 min) stimulation bilaterally to the eVC. Primary outcomes included the Positive and Negative Syndrome Scale (PANSS), biological motion task, and Event Related Potentials (ERP) from a steady state visual evoked potential (SSVEP) paradigm. Secondary outcomes included the Montgomery-Asperg Depression Rating Scale, Global Assessment of Functioning (GAF), velocity discrimination and visual working memory task, and emotional ERP. RESULTS: HD-tDCS improved PANSS general psychopathology in the short-term (d=0.47; pfdr=0.03), with long-term improvements in general psychopathology (d=0.62; pfdr=0.05) and GAF (d=-0.56; pfdr=0.04) with HD-tACS. HD-tDCS reduced SSVEP P1 (d=0.25; pfdr=0.005), which correlated with general psychopathology (ß = 0.274, t = 3.59, p = 0.04). No significant differences in safety or tolerability measures were identified. CONCLUSION: Lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via changes in neuroplasticity. These results highlight the need for larger clinical trials implementing novel targeting methodologies for the treatments of psychosis.

Efficacy and Tolerability of Lesion Network Guided Transcranial Electrical Stimulation in Outpatients with Psychosis Spectrum Illness: A Nonrandomized Controlled Trial.

Importance: Transcranial electrical stimulation (tES) may improve psychosis symptoms, but few investigations have targeted brain regions causally linked to psychosis symptoms. We implemented a novel montage targeting the extrastriate visual cortex (eVC) previously identified by lesion network mapping in the manifestation of visual hallucinations. Objective: To determine if lesion network guided HD-tES to the eVC is safe and efficacious in reducing symptoms related to psychosis. Design Setting and Participants: Single-center, nonrandomized, single-blind trial using a crossover design conducted in two 4-week phases beginning November 2020, and ending January 2022. Participants were adults 18-55 years of age with a diagnosis of schizophrenia, schizoaffective or psychotic bipolar disorder as confirmed by the Structured Clinical Interview for DSM-V, without an antipsychotic medication change for at least 4 weeks. A total of 8 participants consented and 6 participants enrolled. Significance threshold set to <0.1 due to small sample size. Interventions: 6 Participants first received HD-tDCS (direct current), followed by 4 weeks of wash out, then 4 received 2Hz HD-tACS (alternating current). Participants received 5 consecutive days of daily (2 × 20min) stimulation applied bilaterally to the eVC. Main Outcomes and Measures: Primary outcomes included the Positive and Negative Syndrome Scale (PANSS) total, positive, negative, and general scores, biological motion task, and Event Related Potential (ERP) measures obtained from a steady state visual evoked potential (SSVEP) task across each 4-week phase. Secondary outcomes included the Montgomery-Asperg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF), velocity discrimination task, visual working memory task, and emotional ERP across each 4-week phase. Results: HD-tDCS improved general psychopathology in the short-term (d=0.47; p fdr =0.03), with long-term improvements in general psychopathology (d=0.62; p fdr =0.05) and GAF (d=-0.56; p fdr =0.04) with HD-tACS. HD-tDCS reduced SSVEP P1 (d=0.25; p fdr =0.005), which correlated with general psychopathology (ß=0.274, t=3.59, p=0.04). No significant differences in safety or tolerability measures were identified. Conclusions and Relevance: Lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via changes in neuroplasticity. These results highlight the need for larger clinical trials implementing novel targeting methodologies for the treatments of psychosis. Trial Registration: ClinicalTrials.gov Identifier: NCT04870710. Key Points: Question: Is lesion network guided neurostimulation an efficacious, safe, and targeted approach for treating psychosis?Findings: In this single-center, nonrandomized, crossover, single-blind trial of 6 outpatients with psychosis, improvement in general psychopathology was seen in the short-term with HD-tDCS (high-definition transcranial direct current stimulation) and long-term with HD-tACS (alternating current) targeting the extrastriate visual cortex (eVC). HD-tDCS reduced early visual evoked responses which linked to general psychopathology improvements. Overall, both stimulations were well tolerated.Meaning: Study findings suggest that lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via neuroplastic changes.