Optimization of Neurophysiologic Biomarkers for Rehabilitation Interventions in Veterans with Chronic Psychosis

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In response to RX-22-017, this Career Development Award-2 (CDA-2) provides a mentored research and training program for an early career psychiatrist, committed to advancing Veteran’s health and wellbeing and to becoming an independent RR&D Investigator. This application develops a novel biomarker linked to cortical function for applications in “precision rehabilitation” trials for Veterans with schizophrenia (SZ). Despite advances in clinical neuroscience, there are no effective treatments for the cognitive impairment in SZ; this impairment is a primary contributor to significant disability for Veterans with SZ and limits their function, independence, and quality of life. Modest clinical benefits can be achieved with specific rehabilitative interventions, e.g., Targeted Cognitive Training (TCT), but such treatments are time- and resource-intensive, and treatment responses are incomplete and variable. Predictive biomarkers could aid in the prospective identification of patients most likely to benefit from TCT and other rehabilitative interventions, but the lack of such biomarkers has limited the effectiveness of these treatments. Recently, an index of cortical excitation and inhibition (“E/I balance”) has been proposed as a translational biomarker for pro-cognitive interventions. Conceptually, E/I balance reflects the integrated activity of specific cell types in the cerebral cortex. Abnormalities in E/I balance have been implicated in the pathophysiology of the cognitive, perceptual, and social impairment associated with SZ. In Molina et al. (2020), we reported the first in vivo evidence of abnormal E/I balance in SZ patients; these electroencephalographic (EEG) abnormalities were transiently ‘normalized’ by a pro-cognitive modulator of cortical excitability. This study provides evidence that E/I balance may index neural mechanisms that support cognitive rehabilitation; conceivably, such a measure might serve as a predictive biomarker for pro-cognitive interventions. This application takes the steps needed to develop E/I balance as a predictive tool for large-scale application in prospective rehabilitation trials of pro-cognitive interventions in Veterans with SZ. To develop this potential biomarker for rehabilitation trials, this application will establish both the reliability and internal consistency of E/I balance in a Veteran clinical cohort. Past studies assessed E/I balance in the context of drug manipulations, using an EEG “session of convenience” with complex sensory stimuli; this application assesses E/I without drug-challenge and under conditions of both sensory stimulation and rest. The relationship of E/I balance to cognition and function will also be assessed. By optimizing the experimental conditions for measuring E/I balance, this application will increase the likelihood that this biomarker will be capable of distinguishing differences between subjects—a prerequisite for matching the “right Veteran” to the “right intervention” in future precision medicine trials. As a “proof of concept”, this application will determine whether the “optimized” E/I measures predict an acute pro-cognitive response to TCT in Veterans with SZ. This CDA-2 is structured with 2 “phases”. Eighty Veterans will undergo rigorous clinical, cognitive, and functional assessments. Phase 1 (Psychometric Optimization; Aims 1 & 2) will characterize E/I measurements in Veterans, acquired with vs. without sensory stimulation. Experimental conditions will then be optimized for E/I internal consistency and test-retest reliability using Generalizability Theory. The optimized paradigms will be carried forward into Phase 2 (Feasibility Study; Aim 3). This CDA-2 has 3 specific aims: Aim 1. Identify the experimental conditions that optimize the psychometric properties (i.e., sensitivity to detect individual differences) of E/I balance. Aim 2. Characterize the relationships of E/I balance with rehabilitation-relevant outcomes. Aim 3. Evaluate the sensitivity of the optimized E/I balance measures for predicting auditory learning after acute exposure to a pro-cognitive challenge (1-h of Targeted Cognitive Training).