TMS for Anxiety Disorders

(ConTRA Trial)

Overseen By Emma Jones

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Brigham and Women's Hospital

Must not be taking: Rapid antidepressants

Disqualifiers: Pregnancy, TMS exposure, Bipolar, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

Duration: 1 week

80 Participants Needed

Trial Summary

What is the purpose of this trial?

We will perform a randomized sham-controlled trial of aiTBS to an anxiosomatic circuit in patients with anxiety-related disorders (i.e., panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder). 80 participants with an anxiety-related disorder (defined below) will receive 50 active or sham TMS treatments over 5 days (following the SAINT protocol, which is FDA-cleared for MDD. The primary outcome will be the BAI, with a modified recall window to reflect the short treatment interval. Participants randomized to sham will be offered an open-label crossover extension.

Will I have to stop taking my current medications?

The trial requires that you stay on a stable psychiatric medication regimen for 4 weeks before and throughout the treatment. So, you should not stop taking your current medications if they are part of your stable regimen.

What data supports the effectiveness of the treatment Connectomic Targeted TMS for anxiety disorders?

Research shows that low-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the right dorsolateral prefrontal cortex (DLPFC) can reduce anxiety symptoms in patients with Generalized Anxiety Disorder (GAD), with improvements lasting up to one month. Additionally, another study found that slow rTMS at the right DLPFC decreased anxiety and was associated with changes in brain activity, suggesting potential benefits for anxiety treatment. ^{1 2 3 4 5}

Is transcranial magnetic stimulation (TMS) safe for humans?

TMS has been studied for safety in various groups, including healthy adults, clinical populations, and even children. It is generally considered safe, with mild side effects like headaches and nausea being the most common. Safety has been specifically reviewed in conditions like depression, showing good tolerance among patients. ^{2 6 7 8 9}

How is Connectomic Targeted TMS treatment different from other treatments for anxiety disorders?

Connectomic Targeted TMS is unique because it uses a personalized approach by combining brain connectivity patterns and electric-field modeling to target specific brain areas for each individual, potentially improving treatment outcomes for anxiety disorders. ^{1 2 3 6 10}

Research Team

Shan Siddiqi, MD

Principal Investigator

Brigham and Women's Hospital

Eligibility Criteria

This trial is for individuals with anxiety-related disorders, such as panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, and PTSD. Participants will receive either real or sham TMS treatments over a short period.

Inclusion Criteria

My psychiatric medication has been stable for at least 4 weeks.

I have a mental health professional overseeing my care throughout the trial.

Agreement to abstaining from becoming pregnant from screening to two weeks after treatment (the MRI visit)

Exclusion Criteria

Active pregnancy as determined by a urine pregnancy test

I have a condition like autism that affects my ability to make decisions.

History of bipolar I disorder or schizophrenia

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 50 active or sham TMS treatments over 5 days

1 week

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Multiple visits (in-person and virtual)

Open-label crossover extension

Participants randomized to sham who do not respond will be offered an open-label crossover extension

Treatment Details

Interventions

• Connectomic Targeted TMS

Trial Overview The study tests aiTBS (a form of TMS) targeting an anxiosomatic circuit against a sham treatment to see if it can reduce symptoms in patients with various anxiety disorders. The effectiveness will be measured using the BAI scale.

Participant Groups

Group I: Real aiTBS Active Control 1 Intervention

Participants in this group will receive aiTBS with neuronavigation to the anxiosomatic treatment target.

Group II: Sham aiTBS Placebo Group 1 Intervention

Participants in this group will receive sham aiTBS with neuronavigation to the anxiosomatic treatment target.

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Findings from Research

Inhibitory repetitive transcranial magnetic stimulation (rTMS) targeting the intraparietal sulcus (IPS) effectively reduced physiological arousal related to fear and anxiety during shock threat conditions, as evidenced by decreased startle responses in participants.

Although active rTMS did not show a difference in subjective anxiety ratings compared to sham stimulation, the findings suggest that modulating IPS excitability could be a promising approach for developing treatments for clinical anxiety disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-frequency parietal repetitive transcranial magnetic stimulation reduces fear and anxiety. Balderston, NL., Beydler, EM., Goodwin, M., et al.[2022]

In a study with 12 participants, slow repetitive transcranial magnetic stimulation (rTMS) applied to the right dorsolateral prefrontal cortex led to a significant increase in EEG theta activity in the left hemisphere, indicating a potential mechanism of action for mood improvement.

Participants experienced a notable decrease in anxiety immediately after rTMS and at 35 and 65 minutes post-treatment, suggesting that this non-invasive intervention may effectively reduce anxiety symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of slow rTMS at the right dorsolateral prefrontal cortex on EEG asymmetry and mood. Schutter, DJ., van Honk, J., d'Alfonso, AA., et al.[2019]

In a pilot study involving three patients with Panic Disorder who had not responded to other treatments, transcranial magnetic stimulation (TMS) showed only modest and partial symptom improvement after 10 sessions, which was not clinically significant.

An alternate TMS approach using both high and low frequency stimulation was well tolerated but did not lead to additional benefits, suggesting that while TMS is safe, its efficacy in treating Panic Disorder needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Panic disorder and transcranial magnetic stimulation]. García-Toro, M., Salva Coll, J., Crespí Font, M., et al.[2008]

In a study involving 429 pediatric patients undergoing transcranial magnetic stimulation (TMS) for motor and language mapping, most adverse events were benign, with seizures occurring in 5.8% of sessions but not conclusively linked to TMS.

TMS was safely performed in patients with cranial metal, and useful mapping results were achieved in nearly all cases, indicating that TMS is a safe option for functional mapping in pediatric patients with epilepsy or brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Image-guided TMS is safe in a predominately pediatric clinical population. Braden, AA., Weatherspoon, SE., Boardman, T., et al.[2022]

Mild adverse effects (MAEs) from transcranial magnetic stimulation (TMS) occur in about 5% of sessions, with most symptoms like headache and nausea reported after the sessions, particularly during initial treatments.

The study found no significant links between participant characteristics (age and gender) or TMS parameters (frequency and intensity) and the occurrence of MAEs, suggesting that initial participant anxiety may play a role in these reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative incidence rates of mild adverse effects to transcranial magnetic stimulation. Maizey, L., Allen, CP., Dervinis, M., et al.[2022]

Transcranial magnetic stimulation (TMS) is shown to be safe for patients with major depressive disorder, with no significant increase in dropout rates or serious adverse events compared to sham treatment, based on a meta-analysis of 53 trials involving 3,273 participants.

While TMS may lead to some mild and transient non-serious adverse events like headaches and discomfort, these side effects are manageable, suggesting that TMS can be a viable treatment option either alone or alongside other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of transcranial magnetic stimulation in unipolar depression: A systematic review and meta-analysis of randomized-controlled trials. Wang, WL., Wang, SY., Hung, HY., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Mechanistic link between right prefrontal cortical activity and anxious arousal revealed using transcranial magnetic stimulation in healthy subjects. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Proof of concept study to develop a novel connectivity-based electric-field modelling approach for individualized targeting of transcranial magnetic stimulation treatment. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Repetitive Transcranial Magnetic Stimulation Modulates Frontal and Temporal Time-Varying EEG Network in Generalized Anxiety Disorder: A Pilot Study. [2022]

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

Low-frequency parietal repetitive transcranial magnetic stimulation reduces fear and anxiety. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Effects of slow rTMS at the right dorsolateral prefrontal cortex on EEG asymmetry and mood. [2019]

6. Spain pubmed.ncbi.nlm.nih.gov

[Panic disorder and transcranial magnetic stimulation]. [2008]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Image-guided TMS is safe in a predominately pediatric clinical population. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Comparative incidence rates of mild adverse effects to transcranial magnetic stimulation. [2022]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Safety of transcranial magnetic stimulation in unipolar depression: A systematic review and meta-analysis of randomized-controlled trials. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Neurobiology of repeated transcranial magnetic stimulation in the treatment of anxiety: a critical review. [2009]