Efficacy and Safety of Transcranial Temporal Interference Stimulation for Depression

Major depressive disorder (MDD) is a common and disabling mental disorder. Althoughmedication, psychotherapy, and established brain stimulation methods can help many peoplewith MDD, some participants still have insufficient improvement. Transcranial temporalinterference stimulation (tTIS) is a non‐invasive brain stimulation technique that mayallow modulation of deeper brain regions or pathways. This study is designed to evaluatewhether tTIS can improve depressive symptoms in adults with MDD, assess its safety, andexplore potential neuroimaging mechanisms.This is a single‐center, randomized, double‐blind, sham‐controlled clinical trialconducted at Zhongda Hospital, Southeast University. Eligible participants with MDD willbe randomly assigned in a 1:1:1 ratio to one of three groups: active tTIS targeting theleft anterior limb of the internal capsule (ALIC), active tTIS targeting the leftsubgenual anterior cingulate cortex (sgACC), or sham tTIS. The sham stimulation will bedesigned to provide sensory feedback similar to active stimulation while maintainingblinding.Participants with MDD will receive 10 treatment sessions over 5 consecutive days, withtwo 20‐minute sessions each day. Clinical symptoms and safety will be assessed atbaseline, after treatment, and during follow‐up. The main clinical outcome is the changein the 24‐item Hamilton Depression Rating Scale (HAMD‐24) total score from baseline toafter treatment. Secondary outcomes include follow‐up changes in depressive symptoms,response and remission rates, anxiety symptoms, anhedonia, psychosomatic symptoms, sideeffects, and adverse events.Multimodal 5.0T brain magnetic resonance imaging (MRI) will be collected fromparticipants with MDD before and after treatment. MRI measures will include structuralimaging, resting‐state functional imaging, and diffusion imaging. These data will be usedto explore changes in brain structure, functional connectivity, and diffusion‐relatedmeasures after tTIS, and to identify potential imaging biomarkers related to treatmentresponse.