Connectomic Targeted TMS Target for Refractory Anxiety (ConTRA)

A Novel TMS Target for Anxiety: a Confirmatory Randomized Clinical 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.

Study Overview

• Status: Not yet recruiting
• Conditions: Anxiety Disorders; Psychiatric Disorder; Mental Disorder
• Intervention / Treatment: Procedure: Transcranial magnetic stimulation; Procedure: Sham transcranial magnetic stimulation

Detailed Description

We recently derived a novel TMS target for anxiety via lesion and brain stimulation mapping methods. We prospectively tested this target in a sample of participants with major depressive disorder (MDD) with comorbid anxiety symptoms and found that it was more effective for anxiety (median change 60.0% vs 39.8%, p=0.01) than the conventional TMS target for MDD with comorbid anxiety. While these results are promising, it remains unclear how our target works for anxiety-related disorders as opposed to MDD comorbid anxiety symptoms. Furthermore, we used conventional 10 Hz TMS, but accelerated intermittent theta burst stimulation (aiTBS) has now been shown to improve outcomes and is now an FDA approved treatment protocol. Finally, we tested the translational hypothesis that stimulating different circuits can modify different behaviors; clinical efficacy was a secondary outcome.

This double-blinded, randomized, sham-controlled aiTBS trial will test the efficacy of our novel anxiety target. 80 participants with anxiety-related disorders (i.e., panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder) will receive 50 active or sham TMS treatments over 5 days. Changes in anxiety symptoms/processes will be assessed via validated measures (primary outcome measure: Beck Anxiety Inventory) during treatment and follow-up visits up to one-year post-treatment. Participants randomized to sham who do not respond will be offered an open-label crossover extension.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Emma Jones; Phone Number: 617-525-3536; Email: bwhtmsanxiety@mgb.org

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Emma Jones
      • Contact: Emma Jones; Email: bwhtmsanxiety@mgb.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• English proficiency sufficient for informed consent, questionnaires/tasks, and treatment

• Diagnosis of one of the following anxiety-related disorders per Quick-SCID:

  • Generalized Anxiety Disorder
  • Social Anxiety Disorder
  • Panic Disorder
  • Posttraumatic Stress Disorder
  • Obsessive Compulsive Disorder
• Moderate level of anxiety (BAI >16)
• One failed psychological or pharmacological treatment
• Stable psychiatric medication regimen for 4 weeks prior to treatment and throughout treatment
• Primary clinician (e.g. psychiatrist, psychologist, therapist, APRN, PA, etc.) responsible for psychiatric care before, during, and after 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

  • Recent (within 4 weeks) or concurrent use of rapid acting antidepressant agent (ketamine/esketamine/ECT)

  • History of:

    • Exposure to TMS within the last 3 months
    • Neurosurgical intervention for psychiatric disorders
    • Autism spectrum disorder, intellectual disability, or cognitive impairment that impairs capacity to consent
    • Significant neurological illness deemed to increase risk from treatment
    • Moderate to severe neurodegenerative disease
    • Untreated or insufficiently treated endocrine disorder
    • Treatment with investigational drug or intervention during the study period
    • Bipolar I disorder or schizophrenia

  • Anyone presenting with:

    • Mania or hypomania
    • Psychosis
    • Active suicidal ideation with intent and a plan (defined by Columbia Suicide Severity Rating Scale)
    • Contraindications to either TMS or MRI (e.g., metallic implants, severe insomnia > 4 hours per night with hypnotic, etc.).
    • Current moderate or severe substance use disorder (excluding cannabis or nicotine) or demonstrating signs of acute substance withdrawal
  • Positive urine drug screen for illicit substances for cocaine, amphetamines, phencyclidine, and opioids, except for prescribed medications or known medications with history of resulting in a false positive
  • Existing tinnitus (ringing in the ears)
  • Any other condition deemed by the PI to interfere with the study or increase risk to the participant

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
Active Comparator: Real aiTBS; Participants in this group will receive aiTBS with neuronavigation to the anxiosomatic treatment target.	Procedure: Transcranial magnetic stimulation; Transcranial magnetic stimulation (TMS) is a focal, non-invasive form of brain stimulation that has FDA clearance for depression. In this study, a form of TMS called accelerated intermittent theta burst stimulation will be administered under the supervision of a physician with TMS expertise.
Sham Comparator: Sham aiTBS; Participants in this group will receive sham aiTBS with neuronavigation to the anxiosomatic treatment target.	Procedure: Sham transcranial magnetic stimulation; The sham TMS coil mimics the scalp sensation of real TMS by delivering a small amount of electrical current with a pair of surface electrodes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beck Anxiety Inventory (BAI)	21 item self-report scale that assesses anxiety symptoms, with a particular emphasis on physiological anxiety symptoms	One week and one month after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inventory of Depression and Anxiety Symptoms-II	99 item self-report scale of mood (e.g. dysphoria, suicidality, mania) and anxiety (e.g. social anxiety, panic, checking/ordering, traumatic avoidance/intrusion)	One week and one month after treatment
Hierarchical Taxonomy of Psychopathology (HiTOP)-Self Report, Distress, Fear, and Mania subfactors	HiTOP is a psychiatric nosology that organizes dimensional constructs across multiple levels of abstraction (from broad spectra to specific symptoms). The HiTOP-self report Distress, Fear, and Mania subfactors contain 117 items that capture a broad range of specific mood and anxiety-relevant symptoms	One week and one month after treatment
State-Trait Anxiety Inventory	40 item self-report scale of present anxiety (i.e., state anxiety) and the general tendency toward anxiety	One week and one month after treatment
Penn State Worry Questionnaire (PSWQ)	16 item self-report scale of trait worry and anxious apprehension, a transdiagnostic construct characterized by a persistent pattern of negative future thinking	One week and one month after treatment
Mood/Anxiety Symptoms Questionnaire: Anxious Arousal (MASQ:AA)	90 item self-report with a 17 item scale that measures anxious arousal, a transdiagnostic construct characterized by a persistent pattern of hyperarousal/hypervigilance	One week and one month after treatment
Anxiety Sensitivity Index (ASI)	16 item self-report scale of concern about anxious cognitions/physiological sensations	One week and one month after treatment
Intolerance of Uncertainty Scale (IUS)	27 item self-report scale that measures cognitive, emotional, and behavioral reactions to the potential occurrence and unpredictability of negative future events	One week and one month after treatment
Beck Depression Inventory (BDI)	21 item self-report scale that assesses depression symptoms	One week and one month after treatment
TCI-R140 (Temperament and character inventory, revised 140-question format)	Psychobiologically-based personality inventory which measures seven personality dimensions (harm avoidance, novelty seeking, reward dependence, persistence, self-directedness, cooperativeness, and persistence). For each dimension, this yields a scaled T-score (mean score of 50 with standard deviation of 10). This is an overall estimate of personality traits, and there are no "better" or "worse" traits.	One week and one month after treatment
Emotional Conflict Resolution Task	Computer task measuring accuracy and reaction time	One week after treatment
Laboratory Fear Extinction Paradigm	We will use a validated fear extinction task (24) to assess the effects of anxiosomatic circuit TMS on fear discrimination and fear extinction. This task will consist of two learning phases: fear conditioning and fear extinction. We will measure fear via the skin conductance response.	One week after treatment

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Shan Siddiqi, MD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2024
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): February 1, 2029

Study Registration Dates

• First Submitted: April 17, 2024
• First Submitted That Met QC Criteria: April 17, 2024
• First Posted (Actual): April 19, 2024

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: neuroimaging; anxiety; Transcranial Magnetic Stimulation; neuromodulation; TMS; brain stimulation; theta burst stimulation; accelerated intermittent theta burst stimulation; transcranial; neuronavigation
• Additional Relevant MeSH Terms: Behavioral Symptoms; Problem Behavior; Anxiety Disorders; Mental Disorders
• Other Study ID Numbers: 2024P000900

Drug and device information, study documents

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