Temporal Interference Stimulation for Depression

(TI Trial)

Overseen By Ilya Demchenko, MSc

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Unity Health Toronto

Must not be taking: Psychotropics, Migraine preventives

Disqualifiers: Substance use, Suicidal intent, Psychotic disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 12

Duration: 2 weeks

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not clearly specify if you must stop taking your current medications, but it mentions that medications will be reviewed by the responsible doctor. Some medications that could limit the effectiveness of the treatment might be prohibited.

What data supports the effectiveness of Temporal Interference stimulation for depression?

Research on transcranial direct current stimulation (tDCS), a similar brain stimulation technique, shows it can help reduce symptoms of depression, especially when targeted to specific brain areas. While the effects are generally small to moderate, combining tDCS with other treatments like medication or therapy may improve outcomes. ^{1 2 3 4 5}

Is Temporal Interference Stimulation safe for humans?

Temporal Interference Stimulation, similar to other low-intensity transcranial electrical stimulations like tDCS, appears to be safe in humans. No serious adverse events have been reported, and only minor side effects like headaches or skin sensations are common. It has been tested in various conditions, including depression, with a good safety profile. ^{6 7 8 9 10}

How does Temporal Interference Stimulation differ from other treatments for depression?

Temporal Interference Stimulation is unique because it aims to target deep brain regions non-invasively by using high-frequency electric fields that interfere with each other, potentially modulating brain activity without affecting the surface of the brain. This approach is different from other treatments like transcranial direct current stimulation (tDCS), which primarily affects superficial brain areas. ^{8 11 12 13 14}

What is the purpose of this trial?

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.

Research Team

Venkat Bhat, MD MSc

Principal Investigator

Unity Health Toronto

Eligibility Criteria

This trial is for adults aged 18-65 with Major Depressive Disorder (MDD) experiencing a current episode without psychotic features. Participants must have moderate to severe depression, not have changed their psychotropic medication in the last 4 weeks, and be able to follow the study schedule. They need normal thyroid function and pass a safety questionnaire specific to Temporal Interference (TI).

Inclusion Criteria

Be able to adhere to the treatment schedule

Pass the TI adult safety screening questionnaire

Provide written informed consent before initiation of any study-related procedures

Exclusion Criteria

Have a clinically significant laboratory abnormality, in the opinion of one of the principal investigators or study physicians

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

Wear a hairstyle or headdress at the time of the stimulation that prevents electrode contact with the scalp or would interfere with the stimulation (e.g., thick or curly hair)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 10 sessions of 130 Hz Temporal Interference stimulation or sham stimulation, delivered daily for 30 minutes

2 weeks

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Sham stimulation
• Temporal Interference stimulation

Trial Overview The trial tests Temporal Interference stimulation—a new type of brain stimulation—against sham (fake) treatment in people with MDD. It involves applying two high-frequency currents that interact at targeted brain locations. The focus is on whether this can safely alter mood-related brain activity.

Participant Groups

Group I: Experimental Arm Experimental Treatment 1 Intervention

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)

Group II: Sham Arm Placebo Group 1 Intervention

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

Who Is Running the Clinical Trial?

Unity Health Toronto

Lead Sponsor

Trials

572

Recruited

470,000+

Ryerson University

Collaborator

Trials

77

Recruited

7,800+

Soterix Medical

Industry Sponsor

Trials

12

Recruited

410+

Toronto Metropolitan University

Collaborator

Trials

95

Recruited

19,300+

Beth Israel Deaconess Medical Center

Collaborator

Trials

872

Recruited

12,930,000+

Northeastern University

Collaborator

Trials

103

Recruited

72,600+

Centre for Addiction and Mental Health

Collaborator

Trials

388

Recruited

84,200+

Charite University, Berlin, Germany

Collaborator

Trials

1,071

Recruited

3,739,000+

Findings from Research

Transcranial direct current stimulation (tDCS) is a promising non-invasive treatment for Major Depression Disorder (MDD) that can modulate cortical excitability for hours after stimulation, potentially addressing the underlying dysfunction in brain networks associated with depression.

Recent pilot studies have shown that optimized tDCS protocols may effectively reduce symptoms of depression, but further research is necessary to determine the best stimulation parameters and which patients are most likely to benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of depression with transcranial direct current stimulation (tDCS): a review. Nitsche, MA., Boggio, PS., Fregni, F., et al.[2022]

The pilot study involving 14 depressed participants found that both alternative electrode montages (Fronto-Occipital and Fronto-Cerebellar) for transcranial direct current stimulation (tDCS) were safe and feasible, with no significant adverse effects reported.

The Fronto-Occipital montage showed a promising mood improvement rate of 43.8% after four weeks, suggesting potential efficacy in treating depression, while the Fronto-Cerebellar montage had a lower improvement rate of 15.9%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of alternative transcranial direct current stimulation electrode montages for the treatment of major depression. Ho, KA., Bai, S., Martin, D., et al.[2018]

Low intensity transcranial electrical stimulation (TES) is considered safe, with no serious adverse events reported in over 18,000 sessions across various populations, including healthy individuals and patients with neurological or psychiatric conditions.

While moderate adverse events like skin burns from tDCS are rare, mild adverse events such as headaches and fatigue are more common, and the safety profile is consistent across different age groups and vulnerable populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. Antal, A., Alekseichuk, I., Bikson, M., et al.[2023]

Transcranial direct current stimulation (tDCS) is generally considered a safe treatment for major depressive disorder, with very low side effects reported, making it a viable option for patients.

While meta-analyses indicate some efficacy of tDCS for acute depression with a moderate effect size, its effectiveness is reduced in treatment-resistant cases, suggesting that more research is needed to establish its overall therapeutic value.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

tDCS for the treatment of depression: a comprehensive review. Palm, U., Hasan, A., Strube, W., et al.[2018]

The DepressionDC trial is a multicenter study involving 152 patients with major depressive disorder (MDD) who have not responded to SSRIs, testing the efficacy and safety of prefrontal transcranial direct current stimulation (tDCS) as an add-on treatment over 6 weeks.

This trial employs a rigorous triple-blind design and advanced monitoring of tDCS parameters, aiming to determine if tDCS can significantly improve depression scores compared to a sham treatment, while also assessing cognitive safety and other psychopathological outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prefrontal transcranial direct current stimulation (tDCS) as treatment for major depression: study design and methodology of a multicenter triple blind randomized placebo controlled trial (DepressionDC). Padberg, F., Kumpf, U., Mansmann, U., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

A review of transcranial direct current stimulation (tDCS) for the individualized treatment of depressive symptoms. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Treatment of depression with transcranial direct current stimulation (tDCS): a review. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Pilot study of feasibility of the effect of treatment with tDCS in patients suffering from treatment-resistant depression treated with escitalopram. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Transcranial direct current stimulation in a patient with therapy-resistant major depression. [2009]

5. Netherlands pubmed.ncbi.nlm.nih.gov

A pilot study of alternative transcranial direct current stimulation electrode montages for the treatment of major depression. [2018]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

tDCS for the treatment of depression: a comprehensive review. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Temporal Interference (TI) Stimulation Boosts Functional Connectivity in Human Motor Cortex: A Comparison Study with Transcranial Direct Current Stimulation (tDCS). [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Transcranial Direct Current Stimulation in the Acute Depressive Episode: A Systematic Review of Current Knowledge. [2019]

10. Germany pubmed.ncbi.nlm.nih.gov

Prefrontal transcranial direct current stimulation (tDCS) as treatment for major depression: study design and methodology of a multicenter triple blind randomized placebo controlled trial (DepressionDC). [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Why Temporal Inference Stimulation May Fail in the Human Brain: A Pilot Research Study. [2023]

12. United States pubmed.ncbi.nlm.nih.gov

Temporal interference stimulation targets deep brain regions by modulating neural oscillations. [2022]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Brain Response to Interferential Current Compared with Alternating Current Stimulation. [2023]

14. United States pubmed.ncbi.nlm.nih.gov

Influence of Temporal Interference Stimulation Parameters on Point Neuron Excitability. [2022]