Temporal Interference Stimulation Targeting the Right Amygdala in Adolescents With Depression: A Pilot Feasibility Study.

Background: Adolescent depression necessitates the development of novel therapeutic approaches. Temporal interference stimulation (TIS) is a promising noninvasive neuromodulation technique capable of modulating deep-brain circuits; however, its feasibility in adolescent populations has not yet been established. This open-label pilot study evaluated the feasibility, safety, and tolerability of a five-day TIS protocol targeting the right amygdala in adolescents with depression. Clinical outcomes and neuroimaging findings were assessed as exploratory, hypothesis-generating objectives. Methods: Twelve adolescents with depression received five consecutive daily sessions of TIS (2000 Hz carrier frequency with a 100 Hz difference frequency; 20 min/day) targeting the right amygdala. Feasibility was evaluated on the basis of tolerability and adherence rates. Clinical outcomes were assessed using the 17-item Hamilton Depression Rating Scale (HAMD-17), Montgomery-Åsberg Depression Rating Scale (MADRS), 14-item Hamilton Anxiety Rating Scale (HAMA-14), and the THINC-integrated tool (THINC-it) at baseline, post-treatment, and at one-week and four-week follow-up assessments. Exploratory resting-state functional magnetic resonance imaging (fMRI) was performed to investigate neuromodulatory effects. Results: Nine participants completed the study, corresponding to a completion rate of 75%, with a tolerability rate of 100%. No device-related adverse events were reported. Trends toward improvement were observed in depressive symptoms, anxiety symptoms, and subjective cognitive functioning. From baseline to post-treatment, HAMD-17 and HAMA-14 scores decreased by 52.0% and 56.7%, respectively, and these improvements were maintained at the four-week follow-up, with a 53.3% reduction in depression severity. Exploratory fMRI analyses demonstrated acute increases in functional connectivity between the right amygdala and sensorimotor cortical regions during the first stimulation session. Conclusions: A five-day course of right amygdala-targeted TIS was feasible, safe, and well tolerated in adolescents with depression. The observed improvements in depressive and anxiety symptoms, together with acute alterations in amygdala-cortical functional connectivity, provide hypothesis-generating signals that warrant further investigation in rigorously designed sham-controlled trials. However, given the open-label and uncontrolled nature of the study, these improvements cannot be causally attributed to the intervention. Clinical Trial Registration: The study has been registered on https://clinicaltrials.gov/ (registration number: No: NCT06452849; registration link: https://clinicaltrials.gov/study/NCT06452849).