PROJECT SUMMARY/ABSTRACT My career goal is to be an independent investigator in clinical trials of transcranial magnetic stimulation (TMS) focusing on the relationship between depressive symptoms and the blood-brain barrier (BBB). The central hypothesis of this proposal is that BBB function is significantly abnormal in treatment-resistant depression (TRD) and is associated with depressive symptoms, with region specificity that underwrites core depressive symptom domains, and are clinically improvable using TMS. The specific aims are to: 1) test if BBB abnormalities occur in specific symptom domains of TRD; and 2) test if TMS-induced BBB functional improvements explain symptom responses in TRD patients. To investigate these aims, the hypotheses are: 1) the TRD group will have specific BBB dysfunctions compared to a group of age-, sex-, and metabolically-matched controls, and will be correlated to core depressive symptom domains; and 2) BBB function, in subsets of patients, will predict core depressive symptom domain outcomes to accelerated TMS (aTMS) treatment a priori. Underlying regional BBB patterns will be tested with using measurements obtained before and after a course of aTMS. We propose that aTMS improves BBB function in the target region (dorsolateral prefrontal cortex or connected frontostriatal/limbic areas) and that the same regions will not reveal BBB changes similarly in non-responders. More broadly, my goal is to uncover BBB functions implicating a biological mechanism linked to TRD and improved by aTMS to build new, testable, mechanistic insights for future clinical trial work. This Mentored Patient-Oriented Research Career Development Award (K23) builds upon a firm background in BBB cellular and molecular biology and clinical expertise in psychiatry to bridge these areas in highly translational ways. Weill Cornell Medicine/New York- Presbyterian Hospital is a premier institution, with top-ranked clinical and research programs on which to support and build my career. The primary mentor, Dr. Conor Liston, is a psychiatrist who has made major scientific contributions to psychiatric neuroimaging and TMS research, detailing mechanisms and that have propelled the field forward. The co-mentor, Dr. Danny J. J. Wang, is an expert in MRI physics/engineering widely prized in the field, with key advancements to methods of BBB measurements used in this study. Critical progress to our understanding of BBB functioning in TRD, symptom domains, and its ability to be improved by aTMS will be known by study conclusion, along with a potentially detectable subtype of TRD most amenable to these findings and interventions.