Target engagement of the subgenual anterior cingulate cortex with transcranial temporal interference stimulation in major depressive disorder: a protocol for a randomized sham-controlled trial.

Background: Transcranial temporal interference stimulation (tTIS) is a new, emerging neurostimulation technology that utilizes two or more electric fields at specific frequencies to modulate the oscillations of neurons at a desired spatial location in the brain. The physics of tTIS offers the advantage of modulating deep brain structures in a non-invasive fashion and with minimal stimulation of the overlying cortex outside of a selected target. As such, tTIS can be effectively employed in the context of therapeutics for the psychiatric disease of disrupted brain connectivity, such as major depressive disorder (MDD). The subgenual anterior cingulate cortex (sgACC), a key brain center that regulates human emotions and influences negative emotional states, is a plausible target for tTIS in MDD based on reports of its successful neuromodulation with invasive deep brain stimulation. Methods: This pilot, single-site, double-blind, randomized, sham-controlled interventional clinical trial will be conducted at St. Michael's Hospital Discussion: This study is one of the first-ever clinical trials among patients with psychiatric disorders examining the therapeutic potential of repetitive tTIS and its neurobiological mechanisms. Data obtained from this trial will be used to optimize the tTIS approach and design a large-scale efficacy trial. Research in this area has the potential to provide a novel treatment option for individuals with MDD and circuitry-related disorders and may contribute to the process of obtaining regulatory approval for therapeutic applications of tTIS. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05295888.