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

Ilya Demchenko^{1

2

3}, Sumientra Rampersad^{4

5}, Abhishek Datta^{6

7}, Andreas Horn^{8

9

10}, Nathan W Churchill^{11

12}, Sidney H Kennedy^{2

11

12

13}, Sridhar Krishnan^{3

14}, Alice Rueda^{1

3}, Tom A Schweizer^{2

3

11

12

15}, John D Griffiths^{2

13

16}, Edward S Boyden^{17

18}, Emiliano Santarnecchi^{19

20}, Venkat Bhat^{1

2

3

11

12

13}

Affiliations

¹ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, Toronto, ON, Canada.
² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
³ Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, Toronto, ON, Canada.
⁴ Department of Physics, University of Massachusetts Boston, Boston, MA, United States.
⁵ Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, United States.
⁶ Research and Development, Soterix Medical, Inc., Woodbridge, NJ, United States.
⁷ Department of Biomedical Engineering, City College of New York, New York, NY, United States.
⁸ Department of Neurology, Center for Brain Circuit Therapeutics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
⁹ Department of Neurosurgery & Center for NeuroTechnology and NeuroRecovery (CNTR), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
¹⁰ Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt - Universität zu Berlin, Berlin, Germany.
¹¹ Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, Toronto, ON, Canada.
¹² Neuroscience Research Program, St. Michael's Hospital - Unity Health Toronto, Toronto, ON, Canada.
¹³ Department of Psychiatry, Temerty Faculty of Medicine, Toronto, ON, Canada.
¹⁴ Department of Electrical, Computer, and Biomedical Engineering, Toronto Metropolitan University, Toronto, ON, Canada.
¹⁵ Division of Neurosurgery, Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁶ Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
¹⁷ Department of Brain and Cognitive Sciences, Media Arts and Sciences, and Biological Engineering, McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States.
¹⁸ Howard Hughes Medical Institute, Chevy Chase, MD, United States.
¹⁹ Precision Neuroscience and Neuromodulation Program, Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
²⁰ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

PMID: 39268031
PMCID: PMC11390435
DOI: 10.3389/fnins.2024.1390250

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

Ilya Demchenko et al. Front Neurosci. 2024.

. 2024 Aug 29:18:1390250.

doi: 10.3389/fnins.2024.1390250. eCollection 2024.

Authors

Affiliations

¹ Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto, Toronto, ON, Canada.
² Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
³ Institute for Biomedical Engineering, Science and Technology (iBEST), Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, Toronto, ON, Canada.
⁴ Department of Physics, University of Massachusetts Boston, Boston, MA, United States.
⁵ Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, United States.
⁶ Research and Development, Soterix Medical, Inc., Woodbridge, NJ, United States.
⁷ Department of Biomedical Engineering, City College of New York, New York, NY, United States.
⁸ Department of Neurology, Center for Brain Circuit Therapeutics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
⁹ Department of Neurosurgery & Center for NeuroTechnology and NeuroRecovery (CNTR), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
¹⁰ Movement Disorder and Neuromodulation Unit, Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt - Universität zu Berlin, Berlin, Germany.
¹¹ Keenan Research Centre for Biomedical Science, St. Michael's Hospital - Unity Health Toronto, Toronto, ON, Canada.
¹² Neuroscience Research Program, St. Michael's Hospital - Unity Health Toronto, Toronto, ON, Canada.
¹³ Department of Psychiatry, Temerty Faculty of Medicine, Toronto, ON, Canada.
¹⁴ Department of Electrical, Computer, and Biomedical Engineering, Toronto Metropolitan University, Toronto, ON, Canada.
¹⁵ Division of Neurosurgery, Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁶ Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada.
¹⁷ Department of Brain and Cognitive Sciences, Media Arts and Sciences, and Biological Engineering, McGovern Institute for Brain Research and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States.
¹⁸ Howard Hughes Medical Institute, Chevy Chase, MD, United States.
¹⁹ Precision Neuroscience and Neuromodulation Program, Gordon Center for Medical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
²⁰ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.

PMID: 39268031
PMCID: PMC11390435
DOI: 10.3389/fnins.2024.1390250

Abstract

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, ON, 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.

Clinical trial registration: ClinicalTrials.gov, identifier NCT05295888.

Keywords: brain stimulation; clinical trials; electric stimulation therapy; electroencephalography; feasibility studies; magnetic resonance imaging; mood disorders; temporal interference.

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Conflict of interest statement

AD is an employee of Soterix Medical, Inc. AH was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, 424778381 – TRR 295), Deutsches Zentrum für Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND), the National Institutes of Health (R01 13478451, 1R01NS127892-01, 2R01 MH113929, and UM1NS132358) as well as the New Venture Fund (FFOR Seed Grant), and reports lecture fees for Boston Scientific and is a consultant for Functional Neuromodulation Ltd. and Abbott. SHK has received honoraria or research funds from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, Canadian Institutes of Health Research, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion, Sun Pharmaceuticals, and holds stock in Field Trip Health. ESB is an inventor on the Temporal Interference (TI) Stimulation patent and a co-founder of TI Solutions, a for-profit company. VB is supported by the Academic Scholar Award from the University of Toronto Department of Psychiatry and has received research support from the Canadian Institutes of Health Research, Brain & Behavior Foundation, Ontario Ministry of Health Innovation Funds, Royal College of Physicians and Surgeons of Canada, Department of National Defence (Government of Canada), New Frontiers in Research Fund, Associated Medical Services Inc. Healthcare, American Foundation for Suicide Prevention, Roche Canada, Novartis, and Eisai. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

**FIGURE 1**
Study design of a pilot randomized sham-controlled interventional clinical trial examining the target engagement and therapeutic potential of transcranial temporal interference stimulation (tTIS) in major depressive disorder (MDD). The trial will enroll 30 participants with MDD, who will be randomized to receive active tTIS or sham stimulation in 1:1 allocation. Participants will complete 10 sessions of tTIS or sham stimulation over 2 weeks. A comprehensive clinical assessment with a semi-structured interview will take place on treatment days 5 and 10 after the stimulation (red circles). After randomized treatment, participants will undergo a post-stimulation visit and a delayed follow-up visit (green circles) scheduled 5 and 20 days after the last treatment day 10, respectively.

**FIGURE 2**
Computational optimization of tTIS electrode placement. The image shows one of three head models for which the tTIS field strength and focality were optimized. The color scale represents the optimized tTIS field strength distribution in the head. The target region (sgACC) is marked with a black circle.

See this image and copyright information in PMC

References

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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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Associated data

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous