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Therapeutic dose prediction of alpha5-GABA receptor modulation from simulated EEG of depression severity
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Therapeutic dose prediction of alpha5-GABA receptor modulation from simulated EEG of depression severity
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Journal Article
Therapeutic dose prediction of alpha5-GABA receptor modulation from simulated EEG of depression severity
2024
Overview
Treatment for major depressive disorder (depression) often has partial efficacy and a large portion of patients are treatment resistant. Recent studies implicate reduced somatostatin (SST) interneuron inhibition in depression, and new pharmacology boosting this inhibition via positive allosteric modulators of [alpha]5-GABA.sub.A receptors ([alpha]5-PAM) offers a promising effective treatment. However, testing the effect of [alpha]5-PAM on human brain activity is limited, meriting the use of detailed simulations. We utilized our previous detailed computational models of human depression microcircuits with reduced SST interneuron inhibition and [alpha]5-PAM effects, to simulate EEG of individual microcircuits across depression severity and [alpha]5-PAM doses. We developed machine learning models that predicted optimal dose from EEG with high accuracy and recovered microcircuit activity and EEG. This study provides dose prediction models for [alpha]5-PAM administration based on EEG biomarkers of depression severity. Given limitations in doing the above in the living human brain, the results and tools we developed will facilitate translation of [alpha]5-PAM treatment to clinical use.
Publisher
Public Library of Science
Subject
