Temporal Interference and Depression

NCT05295888 | Recruiting

• 1 other identifier: 21-152
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Major Depressive Disorder (MDD) has a high prevalence, is the leading cause of disability, and currently available interventions are associated with side effects and high treatment resistance. There is an urgent need for the development of novel interventions for MDD with alternate mechanisms of action. Temporal Interference (TI) stimulation is a newly emerging form of transcranial alternating current stimulation (tACS) that involves the application of two high-frequency currents at slightly different kHz frequencies. Since neurons, due to their intrinsic low-pass filtering, do not respond to high frequencies (i.e. \> 100 Hz), TI relies on the 'beat' interaction leading to neuromodulation at any given location, resulting in a much smaller focus and allowing for better targeting. The subgenual cingulate cortex (SCC) appears to be critical in the pathophysiology of depression and treatment response, especially in treatment-resistant cases. Non-invasive treatments, however, are not able to accurately target SCC due to its deep location within the brain. In this trial, 30 participants meeting the diagnostic criteria for MDD will be randomized to receive 10 sessions of 130 Hz TI delivered daily for 30 minutes, or 10 sessions of sham stimulation. During the stimulation, participants will be watching emotional film clips to enhance target engagement. The investigators will collect metrics of SCC target engagement using the resting-state fMRI and EEG technologies, and determine feasibility, tolerability, safety, and therapeutic efficacy of TI stimulation in MDD. The results of this trial will inform the TI technology as a therapeutic tool for network-based psychiatric disorders, including MDD, and be vital for the design and development of a large-scale randomized-controlled trial.

Conditions

Major Depressive Disorder

Outcome Measures

Primary Outcomes (4)

• Neuroimaging - Signal variance

  Signal variance within SCC to demonstrate SCC target engagement to TI stimulation

  End of 2nd week of intervention

• Neuroimaging - Functional connectivity

  Seed-based resting-state functional connectivity of SCC to demonstrate SCC target engagement to TI stimulation

  End of 2nd week of intervention

• Neuroimaging - Anatomical connectivity

  Anatomical connectivity of SCC to demonstrate SCC target engagement to TI stimulation

  End of 2nd week of intervention

• Neuroimaging - Perfusion metrics

  Cerebral blood flow within SCC to demonstrate SCC target engagement to TI stimulation

  End of 2nd week of intervention

Secondary Outcomes (11)

• Clinical change in depression symptoms

  Baseline, end of 1st week of intervention, end of 2nd week of intervention, 1 week post-intervention, and 4 weeks post-intervention

• Clinical change in depression symptoms

  Baseline, each intervention visit (5 times/week for 2 weeks), 1 week post-intervention, and 4 weeks post-intervention

• EEG Signals - Time domain features

  Baseline, end of 1st week of intervention, and end of 2nd week of intervention

• EEG Signals - Frequency domain features

  Baseline, end of 1st week of intervention, and end of 2nd week of intervention

• EEG Signals - Functional connectivity

  Baseline, end of 1st week of intervention, and end of 2nd week of intervention

Study Arms (2)

Experimental Arm

EXPERIMENTAL

130Hz TI stimulation (total 30 min) + mood induction paradigm: ramp-up (30 sec) =\> stimulation (130Hz, 2mA per electrode pair, 4mA total, 29 min) =\> ramp-down (30 sec)

Device: Temporal Interference stimulation

Sham Arm

SHAM COMPARATOR

Sham stimulation (total 30 min) + mood induction paradigm: ramp-up (30 sec) =\> ramp-down (30 sec) =\> stimulation (130Hz, 0mA, 29 min)

Device: Sham stimulation

Interventions

Temporal Interference stimulation DEVICE

TI involves simultaneous delivery of independent currents to the brain at slightly different kHz frequencies, which are individually too high to recruit neural firing. However, the difference ('beat') frequency where the currents overlap (i.e., temporally interfered) is low enough to drive neural activity. The interferometrically derived low frequencies have been demonstrated to activate neurons at a selected focus without activation of surrounding regions in awake mice. The safety of the TI paradigm has been demonstrated in over 60 healthy human volunteers, and finite element modeling of simulations of TI fields in human anatomical models suggests that large subcortical structures such as the hippocampus or SCC could be selectively targeted. However, the precise TI parameters for selective engagement of SCC in healthy participants and in MDD is currently unknown.

Experimental Arm

Sham stimulation DEVICE

Electrodes will be placed in the same location on the head as that for the TI intervention; 0 mA of electrical current will be delivered to the brain (compared to 2 mA in the active intervention arm), therefore it is expected to elicit no changes in neural activity.

Sham Arm

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• provide written informed consent before initiation of any study-related procedures
• are outpatients
• meet the DSM-5 criteria for major depressive disorder (MDD) with a current major depressive episode (MDE) without psychotic features as confirmed at Screening by the Mini International Neuropsychiatric Interview (MINI)
• are male or female, 18 to 65 years of age (inclusive) at screening
• have a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of ≥ 20 (moderate to severe depression) at screening
• have had no increase or initiation of any psychotropic medication in the 4 weeks prior to screening
• able to adhere to the treatment schedule
• pass the TI adult safety screening questionnaire
• are able to understand and comply with the requirements of the study, as judged by the investigator(s)

You may not qualify if:

• have an acute alcohol or substance use disorder, withdrawal symptoms requiring detoxification, or went through detoxification treatment (inpatient or outpatient) within 3 months before Screening, as obtained from MINI, Module I (Alcohol Use Disorder) and Module J (Substance Use Disorder, Non-Alcohol) assessed at Screening
• have a concomitant major unstable medical illness, active hepatitis B virus (HBV), hepatitis C virus (HPC), human immunodeficiency virus (HIV), active COVID-19 infection, cardiac pacemaker or implanted medication pump, as per medical history provided by the participant
• have active suicidal intent, confirmed by a 'Yes' response to Question B3 AND either Question B10 or B11, obtained from the MINI Suicidality, Module B (Suicidality), OR confirmed by the MADRS item #10 score ≥ 4, both assessed at Screening
• have a current clinical diagnosis of autism, dementia, or intellectual disability
• take medications prohibited by the protocol. Medications will be reviewed by the responsible MD
• are pregnant or lactating
• have any prior or current diagnosis of bipolar I or II disorder, MDD with psychotic features, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms as obtained from MINI, Module C (Manic and Hypomanic Episodes) and Module K (Psychotic Disorders and Mood Disorders with Psychotic Features) assessed at Screening
• have any prior or current diagnosis of obsessive-compulsive disorder, post-traumatic stress disorder (current or within the last year), confirmed by MINI and assessed by a study investigator to be primary and causing greater impairment than MDD
• have a diagnosis of any personality disorder, and assessed by a study investigator to be primary and causing greater impairment than MDD
• have received TI for any previous indication due to the potential compromise of subject blinding
• have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space-occupying brain lesion, any history of seizure except those therapeutically induced by ECT or a febrile seizure of infancy, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than 5 minutes, current history of poorly controlled migraines including chronic medication for migraine prevention
• have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed
• if participating in psychotherapy, have NOT been in stable treatment for at least 3 months prior to entry into the study or anticipate change in the frequency of therapeutic sessions or therapeutic focus over the duration of the study
• have a clinically significant laboratory abnormality, in the opinion of one of the principal investigators or study physicians
• currently take medications that potentially limit the TI efficacy

Sponsors & Collaborators

• Unity Health Toronto: lead
• Beth Israel Deaconess Medical Center: collaborator
• Northeastern University: collaborator
• Centre for Addiction and Mental Health: collaborator
• Charite University, Berlin, Germany: collaborator
• Toronto Metropolitan University: collaborator

Study Sites (1)

Interventional Psychiatry Program, St. Michael's Hospital - Unity Health Toronto

Toronto, Ontario, M5B 1W8, Canada

RECRUITING

Related Publications (1)

• Demchenko I, Rampersad S, Datta A, Horn A, Churchill NW, Kennedy SH, Krishnan S, Rueda A, Schweizer TA, Griffiths JD, Boyden ES, Santarnecchi E, Bhat V. 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. Front Neurosci. 2024 Aug 29;18:1390250. doi: 10.3389/fnins.2024.1390250. eCollection 2024.

  PMID: 39268031 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Study Officials

• Venkat Bhat, MD MSc

  Unity Health Toronto

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Venkat Bhat, MD MSc

CONTACT

416-360-4000; Venkat.Bhat@unityhealth.to

Ilya Demchenko, MSc

CONTACT

416-360-4000; Ilya.Demchenko@unityhealth.to

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The following roles will be blinded: i) Investigators and care providers; ii) Enrolled participants; iii) Outcome assessors; iv) MRI technician
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a pilot, sham-controlled, quadruple-blind clinical trial to demonstrate target engagement of SCC with TI, as well as assess feasibility, safety, tolerability, and preliminary therapeutic efficacy of TI stimulation in patients with MDD.

Study Record Dates

• First Submitted: October 8, 2021
• First Posted: March 25, 2022
• Study Start: May 15, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: April 24, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)