Individualized fMRI-guided TMS for Depression

This double-blind, randomized, sham-controlled clinical trial will investigate engagement and modulation of brain circuitry involving the subgenual anterior cingulate cortex (sgACC) using individualized resting-state functional magnetic resonance imaging (fMRI)-guided transcranial magnetic stimulation (TMS) in adults with depression. Following screening, participants will undergo a baseline MRI session that includes structural, diffusion, and resting-state imaging. Resting-state functional connectivity will be used to identify individualized cortical stimulation targets that are positively and negatively connected with the sgACC. Participants will also complete baseline clinical assessments, questionnaires, and cognitive testing. Before the 6-week intervention, participants will undergo a TMS/fMRI session to measure sgACC responses to stimulation. Single-pulse TMS will be delivered to three sites: an individualized target positively connected with the sgACC, an individualized target negatively connected with the sgACC, and a vertex control site. TMS/fMRI data will also be collected before and after brief intermittent theta burst stimulation (iTBS) to the positively and negatively connected targets. These procedures will be used to evaluate whether sgACC responses before treatment are associated with subsequent improvement in depressive symptoms. Participants will then be randomized in a 1:1 ratio to receive active or sham iTBS delivered to the individualized positively connected sgACC target every weekday for 6 weeks (30 sessions). Sham procedures will be designed to resemble active stimulation without delivering the intended therapeutic magnetic stimulation to the targeted brain circuit. The TMS/fMRI procedures will be repeated after approximately 3 weeks of treatment and again following the 6-week intervention. Changes in TMS-evoked sgACC responses over the course of treatment will be evaluated in relation to changes in depressive symptoms and compared between the active and sham groups to assess modulation of the targeted brain circuit. Clinical assessments and questionnaires will be conducted throughout the study to evaluate depressive symptoms and related clinical outcomes. The Montgomery-Åsberg Depression Rating Scale (MADRS) will serve as the primary measure of depression severity, and the Patient Health Questionnaire-9 (PHQ-9) will serve as a secondary measure. Participants will also complete the NIH Toolbox Cognition Battery before and after the 6-week intervention to assess cognitive functioning and explore relationships between cognitive performance, clinical outcomes, and neuroimaging measures. Participants will complete remote follow-up assessments at 1, 6, and 12 months after completion of the blinded intervention. After the 1-month follow-up, participants assigned to sham who continue to have clinically significant depressive symptoms and meet study eligibility criteria may be offered an optional open-label active TMS intervention. Data from the open-label phase will be analyzed separately from the randomized sham-controlled phase.