Intermittent Theta Burst Stimulation (iTBS) for Emotion Regulation in Bipolar Disorder

NCT ID: NCT06274567

Last Updated: 2025-04-20

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 136 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-09-20
• Study Completion Date: 2029-03-31

Brief Summary

The objective of this study protocol is to test whether intermittent theta-burst transcranial magnetic stimulation (iTBS-TMS) to the inferior parietal lobule (IPL) can strengthen functional connectivity with a key region in emotion regulation (ER) neurocircuitry (anterior insula, AI) and improve performance on ER-related tasks in patients with bipolar disorder. Individual IPL sites for stimulation will be identified through baseline, pre-TMS functional magnetic resonance imaging (fMRI) scans. Patient-specific IPL subregions showing positive functional connectivity with the anterior insula and falling within the patient-specific frontoparietal control network will be used as individualized target sites for TMS stimulation. Patients will be randomized to receive 24 sessions of active versus sham iTBS to patient-specific IPL targets (6 sessions/day, 4 days, 43,200 pulses total). Post-iTBS resting-state and task-based fMRI scans will be acquired 3 days after the final day of iTBS administration (Day 4) following identical procedures as baseline. Effects of iTBS-TMS on ER will be evaluated by comparing pre-TMS versus post-TMS functional connectivity and behavior during performance on ER tasks.

Detailed Description

The specific goal of this mechanistic study is to test whether targeted engagement of the inferior parietal lobule (IPL) using a rapid and robust form of transcranial magnetic stimulation, accelerated intermittent theta burst stimulation (aiTBS), will increase emotion regulation (ER) in patients with bipolar disorder (BD). Specifically, the Investigators will experimentally test whether stimulation the IPL with aiTBS can strengthen functional neurocircuitry supporting healthy ER, as indexed by increased IPL and anterior insula (AI) functional connectivity and improved performance on ER-related behavioral tasks. The Investigators will use computer tasks that measure ER and functional magnetic resonance imaging (fMRI) to examine changes in brain function and behavior following real versus sham aiTBS in individuals with BD. Patients will be randomized to either active or sham aiTBS and will receive 6 sessions of high dose (1800 pulses) iTBS per day over a course of 4 days (24 sessions total). Patients will be scanned at baseline and 3 days after Day 4 of aiTBS in order to examine ER-related neuroplastic effects of IPL stimulation. To increase the potential clinical utility of findings from this study, the Investigators will examine the effects of aiTBS to the IPL in a sample of BD patients who are currently depressed, the most common and chronic mood state in this population. Following informed consent, all participants will complete a battery of self-report questionnaires assessing ER and will complete a computer-based ER task (Balloon Analog Risk Task; BART). Participants will then complete a functional magnetic resonance imaging (fMRI) scanning session consisting of (1) structural, (2) resting state, and (3) task-based (Affective Multisource Interference Task; MSIT-IAPS) scans. Participants will then be randomized to either Active (n=60, 30 per site) or Sham (N=60, 30 per site) aiTBS conditions in a double-blind design. Both Active and Sham procedures will consist of 4 days of iTBS (6 sessions/day). Participants will repeat the BART computer-based task and fMRI scanning procedures (structural, resting state, MSIT-IAPS in scanner task) within 3 days after Day 4 stimulation to measure the neuroplastic effects of aiTBS. The Investigators propose to recruit 136 individuals with a diagnosis of BD and a current depressed episode. The study will have 68 per each of the two groups (Active, Sham) at baseline and anticipate approximately 10% loss to attrition by post aiTBS. As the study has a single primary outcome (aiTBS-induced changes in IPL-AI functional connectivity), the Investigators use an alpha-level (Type 1 error rate) of 0.05. In preliminary data (n=8), the Investigators observed an increase in IPL-AI functional connectivity from 0.04 (SD=0.17) to 0.15 (SD=0.22), with correlation of 0.80 after a single day of 10 sessions active iTBS, corresponding to an effect size of Cohen's d=0.57. The Investigators anticipate a small "placebo" effect in the TBS group, of about d=0.10, and conservatively assume a correlation of 0.65, rather than the 0.80 seen in the pilot study. With these assumptions, the study has 80% power for an active aiTBS effect of 0.45, relative to sham aiTBS. The Investigators note that these effect size estimates are based on a much smaller dose of iTBS than the dose to be administered in the proposed study (18,000 pulses versus 43,200 pulses) - thus, it is plausible that the effect sizes seen in the study will be larger than those in the pilot data. See "Statistical Design and Power" for full details of data analysis plan.

Conditions

Bipolar Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Active intermittent theta burst stimulation (iTBS)

The Active intermittent theta burst stimulation (iTBS) arm will receive active iTBS applied to the inferior parietal lobule (IPL)

Group Type: EXPERIMENTAL

Transcranial Magnetic Stimulation (TMS)

Intervention Type: DEVICE

Transcranial magnetic stimulation (TMS) is a non-invasive tool for modulating patterns of brain activation and circuit connectivity. It uses electromagnetic pulses to induce electric currents over the cortex that serve to depolarize or hyperpolarize neurons, thereby changing patterns of synaptic activity. This study uses intermittent theta burst stimulation (iTBS), an efficient TMS protocol that uses high frequency (50Hz) triplets of TMS given every 200 milliseconds (i.e. at 5 Hz).

Sham intermittent theta burst stimulation (iTBS)

The Sham intermittent theta burst stimulation (iTBS) arm will receive sham iTBS applied to the inferior parietal lobule (IPL)

Group Type: PLACEBO_COMPARATOR

Sham (placebo) TMS

Intervention Type: DEVICE

Sham stimulation works by blocking the magnetic field with an internal spacer on the sham side of the TMS coil, allowing the operator to place the coil surface against the scalp. A brief electric pulse calibrated to the stimulator output is delivered to the scalp simultaneous to the TMS pulse to mimic the scalp sensation during the sham condition. 75 Importantly, the electric pulse is calibrated to the stimulator output to ensure a realistic sham condition.

Interventions

Transcranial Magnetic Stimulation (TMS)

Transcranial magnetic stimulation (TMS) is a non-invasive tool for modulating patterns of brain activation and circuit connectivity. It uses electromagnetic pulses to induce electric currents over the cortex that serve to depolarize or hyperpolarize neurons, thereby changing patterns of synaptic activity. This study uses intermittent theta burst stimulation (iTBS), an efficient TMS protocol that uses high frequency (50Hz) triplets of TMS given every 200 milliseconds (i.e. at 5 Hz).

Intervention Type: DEVICE

Sham (placebo) TMS

Sham stimulation works by blocking the magnetic field with an internal spacer on the sham side of the TMS coil, allowing the operator to place the coil surface against the scalp. A brief electric pulse calibrated to the stimulator output is delivered to the scalp simultaneous to the TMS pulse to mimic the scalp sensation during the sham condition. 75 Importantly, the electric pulse is calibrated to the stimulator output to ensure a realistic sham condition.

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

1. Individuals of all genders

2. ages 24-65

3. Diagnostic Statistical Manual (DSM-5) defined diagnosis of bipolar I or II disorder (BD); assessed using the Mini-International Neuropsychiatric Interview (M.I.N.I.) version 7.0.2.

4. Current depressive episode, assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) score ≥20,

5. Ability to provide informed consent and verifiable contact information, including current psychiatric treatment provider

6. Stable medication regimen for at least one month, which must include a mood stabilizer

Exclusion Criteria

1. current mania/hypomania assessed by the Young Mania Rating Scale (YMRS > 12)

2. rapid-cycling bipolar illness, defined as >4 episodes per year, indicating increased risk of switch to mania

3. current active suicidality (suicidal ideation with intent or plan), as assessed by a score >4 on the MADRS item #10

4. current substance use disorder for the past 6 months; substance use disorder in remission permitted

5. history of psychosis

6. dementia or other major neurological disorders, as assessed by a Mini-Mental State Exam (MMSE) score <24 and Montreal Cognitive Assessment (MOCA) score <26

7. medical illness or non-psychiatric medical treatment that would likely interfere with study participation

8. contraindications for magnetic resonance imaging (MRI) or transcranial magnetic stimulation (TMS), including the presence of metallic implants that would interfere with safety (i.e. cardiac pacemaker, metal plates, non-removable body piercings, etc.), history of seizure disorder, history of head trauma

9. a clinical course of a neuromodulatory therapy (e.g. transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy) within the past 6 months

10. current use of benzodiazepines, which can interfere with iTBS stimulation

11. current pregnancy, to limit potential risks to an unborn child

Other: Given that >86% of BD patients experience lifetime comorbid anxiety, co-occurring anxiety disorders will be allowable for inclusion, thus providing a more representative sample of bipolar patients who typically present at our Clinics for treatment. Comorbid anxiety disorders are not a criteria for inclusion or exclusion.

• Minimum Eligible Age: 24 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Pennsylvania

OTHER

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Kristen K. Ellard, Ph.D.

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kristen K Ellard, PhD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Locations

Martinos Center for Biomedical Imaging

Charlestown, Massachusetts, United States

Site Status: RECRUITING

University of Pennsylvania, Center for Neuromodulation in Depression and Stress

Philadelphia, Pennsylvania, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Kristen K Ellard, PhD

Role: CONTACT

kellard@mgh.harvard.edu

617-724-3221

Christopher Polanco, MS MBA

Role: CONTACT

cjpolanco@mgh.harvard.edu

(617) 643-2776

Facility Contacts

Kristen K Ellard, PhD

Role: primary

kellard@mgh.harvard.edu

617-724-3221

Yvette Sheline, MD, MS

Role: primary

sheline@pennmedicine.upenn.edu

(215) 573-4229

Walid Makhoul, MD

Role: backup

Walid.Makhoul@pennmedicine.upenn.edu

Other Identifiers

2024P000348

Identifier Type: -

Identifier Source: org_study_id