Temporal Interference and Depression (TI)

Evaluation of Temporal Interference in Target Engagement of Subgenual Cingulate Cortex in the Treatment of Major Depressive Disorder

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. 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.

Study Overview

• Status: Not yet recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Device: Temporal Interference stimulation; Device: Sham stimulation

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Venkat Bhat, MD MSc; Phone Number: 76404 416-360-4000; Email: Venkat.Bhat@unityhealth.to
• Study Contact Backup: Name: Walter Sim, BSc; Phone Number: 76404 416-360-4000; Email: walter.sim@unityhealth.to

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria - Patients will be included if they:

1. provide written informed consent before initiation of any study-related procedures
2. are outpatients
3. 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)
4. are male or female, 18 to 65 years of age (inclusive) at screening
5. have a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of ≥ 20 (moderate to severe depression) at screening
6. have had no increase or initiation of any psychotropic medication in the 4 weeks prior to screening
7. able to adhere to the treatment schedule
8. pass the TI adult safety screening questionnaire
9. have normal thyroid functioning based on pre-study blood work
10. are able to understand and comply with the requirements of the study, as judged by the investigator(s)

Exclusion Criteria - Patients will be excluded if they:

1. 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
2. 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
3. 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) assessed at Screening
4. have suicidal ideation or behaviour caused primarily by another non-MDD condition, as obtained from MINI, Module Z (Suicidality Disorders Classification Interview) assessed at Screening
5. have a current clinical diagnosis of autism, dementia, or intellectual disability
6. take medications prohibited by the protocol. Medications will be reviewed by the responsible MD and decisions about inclusion will be made based on a predetermined list of contraindicated medications.
7. are pregnant or lactating
8. have any prior or current Mini-International Neuropsychiatric Interview (MINI) 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
9. have any prior or current Mini-International Neuropsychiatric Interview (MINI) diagnosis of obsessive-compulsive disorder, post-traumatic stress disorder (current or within the last year), anxiety disorder (generalized anxiety disorder, social anxiety disorder, panic disorder), or dysthymia, assessed by a study investigator to be primary and causing greater impairment than MDD
10. have a diagnosis of any personality disorder, and assessed by a study investigator to be primary and causing greater impairment than MDD
11. have failed a course of ECT or intravenous ketamine therapy in the current episode or previous episode
12. have received TI for any previous indication due to the potential compromise of subject blinding
13. 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
14. 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
15. if participating in psychotherapy, must have been in stable treatment for at least 3 months prior to entry into the study, with no anticipation of change in the frequency of therapeutic sessions, or the therapeutic focus over the duration of the study
16. have a clinically significant laboratory abnormality, in the opinion of one of the principal investigators or study physicians
17. currently take medications that potentially limit the TI efficacy
18. have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with an interview)
19. have a clinical finding that is unstable or that, in the opinion of the investigator(s), would be negatively affected by the study medication or that would affect the study medication (e.g., diabetes mellitus, hypertension, unstable angina)
20. have uncorrected hypothyroidism or hyperthyroidism. Subjects needing a thyroid hormone supplement to treat hypothyroidism must have been on a stable dose of the medication for 30 days prior to enrolment.
21. have any other condition that, in the opinion of the investigator(s), would adversely affect the subject's ability to complete the study or its measure
22. wear a hairstyle or headdress that prevents electrode contact with the scalp or would interfere with the stimulation (e.g., thick braids, hair weave, afro, wig)
23. have any contraindications for receiving TI or undergoing MRI scans (e.g., hip circumference <180 cm or metal in the body)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental Arm; 130Hz TI stimulation (total 2700 sec): ramp-up (30-60 sec) => stimulation (130Hz, 2mA per electrode pair, 4mA total, 2580-2640 sec) => ramp-down (30-60sec)	Device: Temporal Interference stimulation; 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.
Sham Comparator: Sham Arm; Sham stimulation (total 2700 sec): ramp-up (30-60 sec) => ramp-down (30-60 sec) => stimulation (130Hz, 0mA, 2520-2610 sec) => ramp-down (30-60 sec)	Device: Sham stimulation; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuroimaging - Signal variance	Signal variance within SCC to demonstrate SCC target engagement to TI stimulation	At 1 week post-intervention (3 weeks from baseline)
Neuroimaging - Functional connectivity	Seed-based resting-state functional connectivity within SCC to demonstrate SCC target engagement to TI stimulation	At 1 week post-intervention (3 weeks from baseline)
Neuroimaging - Anatomical connectivity	Anatomical connectivity within SCC to demonstrate SCC target engagement to TI stimulation	At 1 week post-intervention (3 weeks from baseline)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical change in depression symptoms	Change in symptoms of depression measured by the 17-item Hamilton Depression Rating Scale (HAM-D); scores range from 0 to 53, and higher scores indicate more severe 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	Change in symptoms of depression measured by the 16-item Quick Inventory of Depressive Symptomatology; scores range from 0 to 48, and higher scores indicate more severe 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	Changes in time domain features of alpha oscillation on resting-state EEG Changes in time domain features of beta and theta oscillation on resting-state EEG Changes in time domain features of theta oscillation on resting-state EEG	Baseline, end of 1st week of intervention, and 1 week post-intervention
EEG Signals - Frequency domain features	Changes in frequency domain features of alpha oscillation on resting-state EEG Changes in frequency domain features of beta oscillation on resting-state EEG Changes in frequency domain features of theta oscillation on resting-state EEG	Baseline, end of 1st week of intervention, and 1 week post-intervention
EEG Signals - Functional connectivity	Changes in functional connectivity on resting-state EEG	Baseline, end of 1st week of intervention, and 1 week post-intervention
Correlation between EEG and depression symptoms	Correlation between changes in features of alpha, beta, or theta oscillations (EEG) and changes in depression symptoms measured by the HAM-D	Baseline, end of 1st week of intervention, and 1 week post-intervention

Collaborators and Investigators

• Sponsor: Unity Health Toronto
• Collaborators: Charite University, Berlin, Germany; Centre for Addiction and Mental Health; Beth Israel Deaconess Medical Center; Ryerson University; Northeastern University; Soterix Medical
• Investigators: Principal Investigator: Venkat Bhat, MD MSc, Unity Health Toronto

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2023
• Primary Completion (Anticipated): July 1, 2023
• Study Completion (Anticipated): July 1, 2023

Study Registration Dates

• First Submitted: October 8, 2021
• First Submitted That Met QC Criteria: March 14, 2022
• First Posted (Actual): March 25, 2022

Study Record Updates

• Last Update Posted (Estimate): December 21, 2022
• Last Update Submitted That Met QC Criteria: December 20, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 21-152

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No