Project Grant F30MH146473

CHARACTERIZING THE BRAIN MICROSTRUCTURE UNDERLYING REWARD AND MOTIVATION IN MAJOR DEPRESSIVE DISORDER - PROJECT SUMMARY/ABSTRACT MAJOR DEPRESSIVE DISORDER (MDD) IS ONE OF THE LEADING CAUSES OF DISABILITY WORLDWIDE. ONE OF THE DEFINING SYMPTOMS OF MDD IS ANHEDONIA, DEFINED AS A LOSS OF INTEREST AND/OR PLEASURE IN PREVIOUSLY REWARDING ACTIVITIES. ANHEDONIA IS STRONGLY ASSOCIATED WITH DEFICITS IN MOTIVATION, ALSO KNOWN AS APATHY. BOTH ANHEDONIA AND APATHY ARE ASSOCIATED WITH MORE DEBILITATING SYMPTOMS AND A WORSE PROGNOSIS. HOWEVER, DESPITE THEIR HEAVY BURDEN, THE BIOLOGICAL MECHANISMS UNDERLYING THESE SYMPTOMS REMAIN POORLY UNDERSTOOD. REWARD-PROCESSING AND MOTIVATION HAVE BEEN ASSOCIATED WITH A NETWORK OF BRAIN REGIONS IN THE MIDBRAIN, STRIATUM, AND FRONTAL CORTEX. STRUCTURAL AND FUNCTIONAL ABNORMALITIES IN THESE REGIONS HAVE BEEN IDENTIFIED IN PATIENTS WITH DEPRESSION AND ASSOCIATED WITH ANHEDONIA AND APATHY SYMPTOMS. HOWEVER, IT REMAINS UNCLEAR EXACTLY HOW THESE ABNORMALITIES CONTRIBUTE TO SYMPTOMS. SYNAPTIC PLASTICITY MECHANISMS ARE THEORIZED TO UNDERLIE THE PATHOPHYSIOLOGY OF DEPRESSION, AND ARE LIKELY RECRUITED BY EFFECTIVE, RAPID-ACTING ANTIDEPRESSANT TREATMENTS SUCH AS KETAMINE. HOWEVER, SYNAPTIC PLASTICITY IS DIFFICULT TO STUDY IN LIVING HUMANS GIVEN THE TECHNOLOGICAL CONSTRAINTS OF NON- INVASIVE NEUROIMAGING. ONE TOOL TO ADDRESS THIS IS NEURITE ORIENTATION DISPERSION AND DENSITY IMAGING (NODDI), AN ADVANCED MATHEMATICAL MODEL APPLIED TO MULTI-SHELL DIFFUSION MAGNETIC RESONANCE IMAGING (MRI) DATA TO QUANTIFY THE DENSITY AND COMPLEXITY OF AXONS AND DENDRITES. THIS PROPOSAL WILL LEVERAGE NODDI TOGETHER WITH ULTRA-HIGH RESOLUTION MRI, GRAPH THEORY CONNECTOMICS ANALYSES, AND KETAMINE TREATMENT TO RIGOROUSLY INVESTIGATE THE CENTRAL HYPOTHESIS THAT ANHEDONIA AND APATHY IN MDD ARE DRIVEN BY SYNAPTIC PLASTICITY MECHANISMS THAT LEAD TO REVERSIBLE MICROSTRUCTURAL CHANGES IN MIDBRAIN-STRIATAL-FRONTAL REWARD/MOTIVATION NETWORKS. IN THE MIDBRAIN-STRIATAL-FRONTAL NETWORK OF INTEREST, 7T MRI AND NODDI WILL BE USED TO: CHARACTERIZE THE MICROSTRUCTURE OF THE NETWORK'S GRAY MATTER REGIONS AND WHITE MATTER TRACTS (AIM 1); CONSTRUCT NOVEL STRUCTURAL CONNECTOMES WEIGHTED BY MICROSTRUCTURAL INFORMATION (AIM 2); AND CHARACTERIZE MICROSTRUCTURE BEFORE AND AFTER KETAMINE TREATMENT FOR MDD (AIM 3). TOGETHER, THESE APPROACHES WILL ALLOW FOR UNPRECEDENTED INSIGHTS INTO THE ANATOMICAL PROCESSES UNDERLYING MDD SYMPTOMS OF ANHEDONIA AND APATHY, AS WELL AS HOW THESE STRUCTURAL CHANGES MIGHT BE REVERSED WITH TREATMENT. THIS WORK WILL OCCUR UNDER THE MENTORSHIP OF DR. JAMES MURROUGH AND DR. YAEL JACOB AT THE DEPRESSION AND ANXIETY CENTER AT THE ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI. THIS TRAINING ENVIRONMENT WILL BE AN EXCEPTIONAL OPPORTUNITY TO GAIN TECHNICAL EXPERTISE IN NEUROIMAGING ANALYSES, EXPERIENCE IN RUNNING CLINICAL TRIALS, AND INVALUABLE CLINICAL SKILLS, WHICH TOGETHER WILL PROVIDE A CRUCIAL FOUNDATION FOR A FUTURE CAREER AS A PHYSICIAN-SCIENTIST.