Ilya Demchenko ^1,2,3 Sumientra Rampersad ^4,5 Abhishek Datta ^6,7 Andreas Horn ^10,8,9 Nathan W. Churchill ^11,12 Sidney Kennedy ^11,12,13,2 Sri Krishnan ^14,3 Alice Rueda ^1,3 Tom A. Schweizer ^11,12,15,2,3 John D. Griffiths ^13,16,2 Edward S. Boyden ^17,18,19,20 Emiliano Santarnecchi ^21,22 Venkat Bhat ^{1,11,12,13,2,3*}

• ¹ Interventional Psychiatry Program, Centre for Depression & Suicide Studies, St. Michael’s Hospital, Toronto, Ontario, Canada
• ² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
• ³ Institute for Biomedical Engineering, Science, and Technology (iBEST), Keenan Research Center for Biomedical Science, St. Michael’s Hospital – Unity Health Toronto, Toronto, Ontario, Canada
• ⁴ Department of Physics, College of Science and Mathematics, University of Massachusetts Boston, Boston, Massachusetts, United States
• ⁵ Department of Electrical and Computer Engineering, College of Engineering, Northeastern University, Boston, Massachusetts, United States
• ⁶ Soterix Medical Inc., New York, New York, United States
• ⁷ Department of Biomedical Engineering, The City College of New York, New York, New York, United States
• ⁸ Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Boston, Massachusetts, United States
• ⁹ Center of Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
• ¹⁰ Movement Disorder and Neuromodulation Unit, Clinic for Neurology with Experimental Neurology, Charité University Medicine Berlin, Berlin, Baden-Württemberg, Germany
• ¹¹ Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada
• ¹² Neuroscience Research Program, St. Michael’s Hospital – Unity Health Toronto, Toronto, Ontario, Canada
• ¹³ Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
• ¹⁴ Department of Electrical, Computer and Biomedical Engineering, Faculty of Engineering and Architectural Science, Ryerson University, Toronto, Ontario, Canada
• ¹⁵ Division of Neurosurgery, Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
• ¹⁶ Krembil Center for Neuroinformatics, Center for Addiction and Mental Health, Toronto, Canada
• ¹⁷ McGovern Institute for Brain Research, School of Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
• ¹⁸ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
• ¹⁹ Department of Brain and Cognitive Sciences, School of Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
• ²⁰ Howard Hughes Medical Institute (HHMI), Chevy Chase, Maryland, United States
• ²¹ Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
• ²² Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States

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 – Unity Health Toronto in Toronto, Canada. The primary objective is to demonstrate target engagement of the sgACC with 130 Hz tTIS using resting-state magnetic resonance imaging (MRI) techniques. The secondary objective is to estimate the therapeutic potential of tTIS for MDD by evaluating the change in clinical characteristics of participants and electrophysiological outcomes and providing feasibility and tolerability estimates for a large-scale efficacy trial. Thirty participants (18-65 years) with unipolar, non-psychotic MDD will be recruited and randomized to receive 10 sessions of 130 Hz tTIS or sham stimulation (n = 15 per arm). The trial includes a pre- vs. post-treatment 3T MRI scan of the brain, clinical evaluation, and electroencephalography (EEG) acquisition at rest and during the auditory mismatch negativity (MMN) paradigm. 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.