Project Summary / Abstract Acute psychological stressors rapidly and reliably evoke emotional responses, which involve changes in self-reported affect as well as peripheral cardiovascular physiology. These affective and physiological responses to psychological stressors may increase the risk for negative mental and physical health outcomes. However, the neurobiological mechanisms for these processes are not well understood. This K01 proposal will test a novel mechanistic model in which heightened activity in the dorsal anterior cingulate cortex (dACC) in response to acute psychological stress is causally implicated in affective and cardiovascular responses. Human neuroimaging studies show that heightened stressor-evoked activity in the dACC is associated with changes in affect and peripheral physiology, yet to date this evidence has been observational and correlational. Noninvasive neuromodulation methods such as continuous theta burst stimulation (cTBS), an advanced form of transcranial magnetic stimulation (TMS), combined with subject-specific neuronavigational targets, electrical field modeling, and double cone coils targeting deeper cortical structures, can rapidly depotentiate activity in the dACC. This K01 will therefore test the proposed model using a within-subject, sham-controlled, two-armed counterbalanced design in a cohort of 55 midlife adults ranging in mood symptomatology. Participants will undergo single sessions of cTBS to depotentiate dACC activity (i.e., dACC-cTBS) or sham cTBS as a control condition. Immediately following each session, participants will complete a validated psychological stress task with concurrent functional magnetic resonance imaging (fMRI). The proposed K01 will examine effects of dACC-cTBS on stressor-evoked (1) dACC activity, (2) dACC connectivity, (3) affective reactivity, and (4) cardiovascular reactivity. Dr. Kraynak has expertise in stress neurobiology, multimodal functional neuroimaging, and cardiovascular psychophysiology. To successfully complete the proposed study, he will require additional training in (1) clinical affective neuroscience, (2) TMS methodology, and (3) translational experimental study design. Dr. Kraynak will complete this training and research in the Department of Psychiatry at the University of Pittsburgh, a highly collaborative environment that is an ideal fit for his interdisciplinary training and research goals. Completion of the training and research plan in this career development award will enable Dr. Kraynak to transition to an independent investigator focused on the neurobiology of emotional responses to acute psychological stress. Findings from this K01 would significantly add to our understanding of the neurobiology of emotional responses to stressors, potentially confirm the causal contributions of the dACC to emotional reactivity in humans, and inform future independent neuromodulation studies targeting stress-related psychopathology.