Dataset Information

Effect of Cannabidiol on Medial Temporal, Midbrain, and Striatal Dysfunction in People at Clinical High Risk of Psychosis: A Randomized Clinical Trial.

ABSTRACT: Importance:Cannabidiol (CBD) has antipsychotic effects in humans, but how these are mediated in the brain remains unclear. Objective:To investigate the neurocognitive mechanisms that underlie the therapeutic effects of CBD in psychosis. Design, Setting, and Participants:In this parallel-group, double-blind, placebo-controlled randomized clinical trial conducted at the South London and Maudsley NHS Foundation Trust in London, United Kingdom, 33 antipsychotic medication-naive participants at clinical high risk (CHR) of psychosis and 19 healthy control participants were studied. Data were collected from July 2013 to October 2016 and analyzed from November 2016 to October 2017. Interventions:A total of 16 participants at CHR of psychosis received a single oral dose of 600 mg of CBD, and 17 participants at CHR received a placebo. Control participants were not given any drug. All participants were then studied using functional magnetic resonance imaging (fMRI) while performing a verbal learning task. Main Outcomes and Measures:Brain activation during verbal encoding and recall, indexed using the blood oxygen level-dependent hemodynamic response fMRI signal. Results:Of the 16 participants in the CBD group, 6 (38%) were female, and the mean (SD) age was 22.43 (4.95) years; of 17 in the placebo group, 10 (59%) were female, and the mean (SD) age was 25.35 (5.24) years; and of 19 in the control group, 8 (42%) were female, and the mean (SD) age was 23.89 (4.14) years. Brain activation (indexed using the median sum of squares ratio of the blood oxygen level-dependent hemodynamic response effects model component to the residual sum of squares) was analyzed in 15 participants in the CBD group, 16 in the placebo group, and 19 in the control group. Participants receiving placebo had reduced activation relative to controls in the right caudate during encoding (placebo: median, -0.027; interquartile range [IQR], -0.041 to -0.016; control: median, 0.020; IQR, -0.022 to 0.056; P?

SUBMITTER: Bhattacharyya S

PROVIDER: S-EPMC6248101 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Effect of Cannabidiol on Medial Temporal, Midbrain, and Striatal Dysfunction in People at Clinical High Risk of Psychosis: A Randomized Clinical Trial.

Bhattacharyya Sagnik S Wilson Robin R Appiah-Kusi Elizabeth E O'Neill Aisling A Brammer Michael M Perez Jesus J Murray Robin R Allen Paul P Bossong Matthijs G MG McGuire Philip P

JAMA psychiatry 20181101 11

<h4>Importance</h4>Cannabidiol (CBD) has antipsychotic effects in humans, but how these are mediated in the brain remains unclear.<h4>Objective</h4>To investigate the neurocognitive mechanisms that underlie the therapeutic effects of CBD in psychosis.<h4>Design, setting, and participants</h4>In this parallel-group, double-blind, placebo-controlled randomized clinical trial conducted at the South London and Maudsley NHS Foundation Trust in London, United Kingdom, 33 antipsychotic medication-naive ...[more]

PMID: 30167644

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Project description:To bring biomarkers closer to clinical application, they should be generalizable, reliable, and maintain performance within the constraints of routine clinical conditions. The functional striatal abnormalities (FSA), is among the most advanced neuroimaging biomarkers in schizophrenia, trained to discriminate diagnosis, with post-hoc analyses indicating prognostic properties. Here, we attempt to replicate its diagnostic capabilities measured by the area under the curve (AUC) in receiver operator characteristic curves discriminating individuals with psychosis (n=101) from healthy controls (n=51) in the Human Connectome Project for Early Psychosis. We also measured the test-retest (run 1 vs 2) and phase encoding direction (i.e., AP vs PA) reliability with intraclass correlation coefficients (ICC). Additionally, we measured effects of scan length on classification accuracy (i.e., AUCs) and reliability (i.e., ICCs). Finally, we tested the prognostic capability of the FSA by the correlation between baseline scores and symptom improvement over 12 weeks of antipsychotic treatment in a separate cohort (n=97). Similar analyses were conducted for the Yeo networks intrinsic connectivity as a reference. The FSA had good/excellent diagnostic discrimination (AUC=75.4%, 95%CI=67.0%-83.3%; in non-affective psychosis AUC=80.5%, 95%CI=72.1-88.0%, and in affective psychosis AUC=58.7%, 95%CI=44.2-72.0%). Test-retest reliability ranged between ICC=0.48 (95%CI=0.35-0.59) and ICC=0.22 (95%CI=0.06-0.36), which was comparable to that of networks intrinsic connectivity. Phase encoding direction reliability for the FSA was ICC=0.51 (95%CI=0.42-0.59), generally lower than for networks intrinsic connectivity. By increasing scan length from 2 to 10 minutes, diagnostic classification of the FSA increased from AUC=71.7% (95%CI=63.1%-80.3%) to 75.4% (95%CI=67.0%-83.3%) and phase encoding direction reliability from ICC=0.29 (95%CI=0.14-0.43) to ICC=0.51 (95%CI=0.42-0.59). FSA scores did not correlate with symptom improvement. These results reassure that the FSA is a generalizable diagnostic - but not prognostic - biomarker. Given the replicable results of the FSA as a diagnostic biomarker trained on case-control datasets, next the development of prognostic biomarkers should be on treatment-response data.

Project description:Repeated encounters with the same event typically lead to decreased activation in the medial temporal lobe (MTL) and dopaminergic midbrain, a phenomenon known as repetition suppression. In contrast, encountering an event that overlaps with prior experience leads to increased response in the same regions. Such increased responding is thought to reflect an associative novelty signal that promotes memory updating to resolve differences between current events and stored memories. Here, we married these ideas to test whether event overlap significantly modulates MTL and midbrain responses-even when events are repeated and expected-to promote memory updating through integration. While undergoing high-resolution functional MRI, participants were repeatedly presented with objects pairs, some of which overlapped with other, intervening pairs and some of which contained elements unique from other pairs. MTL and midbrain regions showed widespread repetition suppression for nonoverlapping pairs containing unique elements; however, the degree of repetition suppression was altered for overlapping pairs. Entorhinal cortex, perirhinal cortex (PRc), midbrain, and PRc-midbrain connectivity showed repetition-related increases across overlapping pairs. Notably, increased PRc activation for overlapping pairs tracked individual differences in the ability to reason about the relationships among pairs-our behavioral measure of memory integration. Within the hippocampus, activation increases across overlapping pairs were unique to CA1 , consistent with its hypothesized comparator function. These findings demonstrate that event overlap engages MTL and midbrain functions traditionally implicated in novelty processing, even when overlapping events themselves are repeated. Our findings further suggest that the MTL-midbrain response to event overlap may promote integration of new content into existing memories, leading to the formation of relational memory networks that span experiences. Moreover, the results inform theories about the division of labor within MTL, demonstrating that the role of PRc in episodic encoding extends beyond familiarity processing and item-level recognition. © 2016 Wiley Periodicals, Inc.

Dataset Information

Effect of Cannabidiol on Medial Temporal, Midbrain, and Striatal Dysfunction in People at Clinical High Risk of Psychosis: A Randomized Clinical Trial.

Publications

Effect of Cannabidiol on Medial Temporal, Midbrain, and Striatal Dysfunction in People at Clinical High Risk of Psychosis: A Randomized Clinical Trial.

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