PROJECT SUMMARY / ABSTRACT: Cognitive deficits are, arguably, the most prevalent, the most disabling, and the most economically costly symptom of schizophrenia (SZ). There are, however, no FDA-approved medications to improve cognitive function in SZ. Computational models have proposed that cognitive deficits in SZ arise from disruptions to cortical excitation:inhibition (E:I) balance, and these models have inspired new outcome measures for randomized control trials (RCTs), as well as new model paradigms for SZ. Nevertheless, it is unclear whether computational models of E:I balance in SZ will spur innovations in cognitive-enhancing therapeutics. Conventional approaches to modeling of E:I balance in SZ are limited in several ways, which may negatively impact their ability to improve the assessment and treatment of cognitive deficits among those with SZ. The following F31 NRSA proposal seeks to translate a recently-validated modeling approach, which does not exhibit these limitations, to the study of E:I balance in SZ. Mesoscale Individualized Neurodynamic (MINDy) modeling, which was created by members of this NRSA proposal team, is an approach for inferring the biophysical parameters of an individual’s brain using functional magnetic resonance imaging (fMRI) data. MINDy models provide a proxy-measure for E:I balance that is, unlike conventional computational models of E:I balance in SZ, both statistically reliable (Test-Retest R > 0.7) and quick to compute for every region of interest in the brain (~1min compute time). The following NRSA proposal leverages these advantages to investigate disruptions in brain-wide E:I associated dynamics among those with SZ using a wide range of clinically-relevant study designs. For aim one of this NRSA, we will use MINDy to investigate brain wide disruptions to E:I-associated dynamics among individuals with SZ by using resting-state fMRI data from the Human Connectome Project – Early Psychosis (HCP-EP) study. While conventional approaches have demonstrated that SZ is primarily associated with disruptions to E:I balance in association cortical areas such as the prefrontal cortex, there is some evidence that E:I balance may also be disrupted in sensory cortical areas. This has not been explored with computational models of E:I balance. We hypothesize that MINDy will uncover disruptions to E:I-associated dynamics in both association and sensory cortical areas among those with SZ. For aim two of this NRSA, we will use MINDy to investigate genetic contributions to individual differences in brain-wide E:I balance among a sample of approximately 900 monozygotic and dizygotic twin pairs from the Adolescent Brain and Cognitive Development Twin (ABCD-Twin) study. While existing work suggests that general changes in gene expression across the neocortex are related to differences in E:I balance between cortical areas, aim two of this NRSA proposal will be the first study to investigate whether the distribution of E:I balance...