Individualized fMRI-guided TMS for Depression

This double‐blind, randomized, sham‐controlled clinical trial will investigate engagementand 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 includesstructural, diffusion, and resting‐state imaging. Resting‐state functional connectivitywill be used to identify individualized cortical stimulation targets that are positivelyand negatively connected with the sgACC. Participants will also complete baselineclinical assessments, questionnaires, and cognitive testing.Before the 6‐week intervention, participants will undergo a TMS/fMRI session to measuresgACC responses to stimulation. Single‐pulse TMS will be delivered to three sites: anindividualized target positively connected with the sgACC, an individualized targetnegatively connected with the sgACC, and a vertex control site. TMS/fMRI data will alsobe collected before and after brief intermittent theta burst stimulation (iTBS) to thepositively and negatively connected targets. These procedures will be used to evaluatewhether sgACC responses before treatment are associated with subsequent improvement indepressive symptoms.Participants will then be randomized in a 1:1 ratio to receive active or sham iTBSdelivered to the individualized positively connected sgACC target every weekday for 6weeks (30 sessions). Sham procedures will be designed to resemble active stimulationwithout delivering the intended therapeutic magnetic stimulation to the targeted braincircuit.The TMS/fMRI procedures will be repeated after approximately 3 weeks of treatment andagain following the 6‐week intervention. Changes in TMS‐evoked sgACC responses over thecourse of treatment will be evaluated in relation to changes in depressive symptoms andcompared between the active and sham groups to assess modulation of the targeted braincircuit.Clinical assessments and questionnaires will be conducted throughout the study toevaluate depressive symptoms and related clinical outcomes. The Montgomery‐ÅsbergDepression 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 the6‐week intervention to assess cognitive functioning and explore relationships betweencognitive performance, clinical outcomes, and neuroimaging measures.Participants will complete remote follow‐up assessments at 1, 6, and 12 months aftercompletion of the blinded intervention. After the 1‐month follow‐up, participantsassigned to sham who continue to have clinically significant depressive symptoms and meetstudy eligibility criteria may be offered an optional open‐label active TMS intervention.Data from the open‐label phase will be analyzed separately from the randomizedsham‐controlled phase.