The overarching goal of the proposed center is to leverage molecular and circuit biomarkers to advance the understanding of mechanisms and personalized treatment of topiramate treatment of Alcohol Use Disorder comorbid with PTSD. We propose an integrative translational focus on alterations in excitatory and inhibitory signaling, focusing on GABA and glutamate and related circuitry, to model the neurobiology of PTSD comorbid with PTSD and the mitigating effects of topiramate. We will characterize excitatory and inhibitory molecular markers in an animal model of AUD comorbid with PTSD, utilizing genomic markers in the brain and plasma markers in rodents. In clinical trial participants we will characterize excitatory and inhibitory neuronal signaling by ascertaining plasma markers, GRIK 1 genotype and neural circuit markers utilizing TMS evoked potentials in EEG, task-based functional MRI and MR spectroscopy. This goal will be achieved through the activities of three research projects supported by two research cores, the administrative core and the Scientific Advisory Board (Figure1). In Project 1 lead by Silvia Fossati Ph.D. and Jorge Manzanares Robles Ph.D. we will study the behavioral and molecular effects of two doses of topiramate vs. vehicle in animal models of AUD alone, PTSD alone and AUD+PTSD. In Project 2 lead by Michael Bogenschutz M.D. and Joshua Lee M.D. we will study the behavioral, genetic and plasma biomarker effects of topiramate vs. placebo in 150 participants with co-occurring AUD and PTSD. In project 3 lead by Amit Etkin M.D., Ph.D. and Charles R. Marmar M.D. we will ascertain multi-modal imaging markers including task based fMRI, TMS evoked potentials in EEG and MRS. Imaging markers will be used to characterize excitatory and inhibitory circuits in Project 2 clinical trial participants with AUD+PTSD to determine predictors and mechanisms of topiramate vs. placebo treatment outcomes. Plasma biomarkers in Project 2 will be related to the same or homologous plasma biomarkers in Project 1. Circuit markers from Project 3 will be related to genomic markers in the same or homologous brain regions in Project 1. The Biofluids Biomarker Core (BBC) lead by Dr. Fossati will support collection of plasma biomarkers (GABA, glutamate, HPA axis, neuropeptides, neuroinflammatory and oxidative stress) in animals in Project 1 and clinical trial participants in Project 2. The Analytics and Biostatistics Core (ABC) lead by Eugene Laska Ph.D. and Carole Segal Ph.D. will support experimental design, formulation of hypothesis, power calculations, and data integrity, management and analysis for Project 1, 2 and 3, implementing advanced statistical models for individualized prediction of response to topiramate in Project 1 and Project 2.
Overall Narrative We aim to advance personalized topiramate treatment for comorbid AUD and PTSD by focusing on network excitatory and inhibitory imbalances underlying heightened negative emotions and impairments in executive function and emotion regulation. Excitatory and inhibitory targets will be assessed with brain, plasma and circuit markers, where possible harmonizing the approach for optimizing discovery of mechanisms and prediction of topiramate treatment in animal models and in clinical trial participants. We will achieve this aim with a center driven approach to discovery with three integrative design elements and four cross-project center aims, creating translational bridges among animal model, clinical trial and imaging studies.