Bipolar DisorderNCT06274567
Intermittent Theta Burst Stimulation (iTBS) for Emotion Regulation in Bipolar Disorder
A study testing Transcranial Magnetic Stimulation (TMS) in people with Bipolar Disorder, run by Massachusetts General Hospital at 2 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 24 to 65 years
- Conditions the study is for
- Bipolar Disorder
- What is being tested?
- Transcranial Magnetic Stimulation (TMS)
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 136 participants
- Where
- 2 sitesUnited States
- Study dates
- 20 Sep 2024to 31 Mar 2029
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 24 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Individuals of all genders
- ages 24-65
- 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.
- Current depressive episode, assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) score ≥20,
- Ability to provide informed consent and verifiable contact information, including current psychiatric treatment provider
- Stable medication regimen for at least one month, which must include a mood stabilizer
Who cannot join
- current mania/hypomania assessed by the Young Mania Rating Scale (YMRS > 12)
- rapid-cycling bipolar illness, defined as >4 episodes per year, indicating increased risk of switch to mania
- current active suicidality (suicidal ideation with intent or plan), as assessed by a score >4 on the MADRS item #10
- current substance use disorder for the past 6 months; substance use disorder in remission permitted
- history of psychosis
- dementia or other major neurological disorders, as assessed by a Mini-Mental State Exam (MMSE) score <24 and Montreal Cognitive Assessment (MOCA) score <26
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- medical illness or non-psychiatric medical treatment that would likely interfere with study participation
- 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
- a clinical course of a neuromodulatory therapy (e.g. transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy) within the past 6 months
- current use of benzodiazepines, which can interfere with iTBS stimulation
- 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.
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States2 sites, 2 recruiting
- Recruiting
Martinos Center for Biomedical Imaging
Charlestown, Massachusetts, 02129
Kristen K Ellard, PhD, 617-724-3221, kellard@mgh.harvard.edu
Kristen K Ellard, PhD
- Recruiting
University of Pennsylvania, Center for Neuromodulation in Depression and Stress
Philadelphia, Pennsylvania, 19104-4283(215) 573-4229
Yvette Sheline, MD, MS, (215) 573-4229, sheline@pennmedicine.upenn.edu
Walid Makhoul, MD, Walid.Makhoul@pennmedicine.upenn.edu
About this study
Official title: Targeting Emotion Regulation in Bipolar Disorder With Intermittent Theta Burst Stimulation: A Mechanistic Study
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.
Read the 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
- Being tested
- Transcranial Magnetic Stimulation (TMS), Sham (placebo) TMS
- Medical subject headings
- Bipolar Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Transcranial Magnetic Stimulation (TMS)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 (placebo) TMSDevice
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.
| Study group | Role | What they receive |
|---|---|---|
| Active intermittent theta burst stimulation (iTBS) | Experimental | The Active intermittent theta burst stimulation (iTBS) arm will receive active iTBS applied to the inferior parietal lobule (IPL) Receives: Device: Transcranial Magnetic Stimulation (TMS) |
| Sham intermittent theta burst stimulation (iTBS) | Placebo comparator | The Sham intermittent theta burst stimulation (iTBS) arm will receive sham iTBS applied to the inferior parietal lobule (IPL) Receives: Device: Sham (placebo) TMS |
What is being measured
The primary outcome is the main question the study is designed to answer.
Correlated functional magnetic resonance imaging (fMRI) time series (functional connectivity)
Primary outcome will be changes in the correlated time series between brain regions (inferior parietal lobule and anterior insula) from baseline to post intervention
Measured: Baseline, 1-3 days post 4-day intervention (up to 4 weeks post Baseline)
Secondary outcomes (2)
Affective Multisource Interference Task
Secondary outcome will be changes in reaction time responses to an affective interference task
Measured: Baseline, 1-3 days post 4-day intervention (up to 4 weeks post Baseline)
Balloon Analogue Risk Task
Secondary outcome will be changes in number of button presses in response to a risk versus reward task
Measured: Baseline, 1-3 days post 4-day intervention (up to 4 weeks post Baseline)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Feb 2024
- Study start20 Sep 2024
- Primary completion28 Feb 2029 (estimated)
- Study completion31 Mar 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Bipolar DisorderStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Randomized allocation
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 136 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- University of Pennsylvania
- Responsible party
- Principal investigator, Kristen K. Ellard, Ph.D., Massachusetts General Hospital
- Investigators
- Kristen K Ellard, PhD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06274567
- Sponsor's protocol ID
- 2024P000348
- Status last verified
- Jul 2026
- First submitted
- 13 Feb 2024
- Last updated
- 16 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 16 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Targeting Emotion Regulation in Bipolar Disorder With Intermittent Theta Burst Stimulation: A Mechanistic Study
- ClinicalTrials.gov ID
- NCT06274567
- Acronym / sponsor ID
- 2024P000348
- Conditions
- Bipolar Disorder
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 136 participants (estimated)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Collaborators
- University of Pennsylvania
- Study start
- 20 Sep 2024 (actual)
- Primary completion
- 28 Feb 2029 (estimated)
- Study completion
- 31 Mar 2029 (estimated)
- First posted
- 23 Feb 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
- Model description
- Randomized allocation
| Arm | Type | Receives |
|---|---|---|
| Active intermittent theta burst stimulation (iTBS) | Experimental | Device: Transcranial Magnetic Stimulation (TMS)The Active intermittent theta burst stimulation (iTBS) arm will receive active iTBS applied to the inferior parietal lobule (IPL) |
| Sham intermittent theta burst stimulation (iTBS) | Placebo comparator | Device: Sham (placebo) TMSThe Sham intermittent theta burst stimulation (iTBS) arm will receive sham iTBS applied to the inferior parietal lobule (IPL) |
Who may qualify
- Ages
- 24 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Individuals of all genders
- ages 24-65
- 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.
- Current depressive episode, assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) score ≥20,
- Ability to provide informed consent and verifiable contact information, including current psychiatric treatment provider
Key exclusion criteria (12 listed)
- current mania/hypomania assessed by the Young Mania Rating Scale (YMRS > 12)
- rapid-cycling bipolar illness, defined as >4 episodes per year, indicating increased risk of switch to mania
- current active suicidality (suicidal ideation with intent or plan), as assessed by a score >4 on the MADRS item #10
- current substance use disorder for the past 6 months; substance use disorder in remission permitted
- history of psychosis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 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). | Device | Active intermittent theta burst stimulation (iTBS) |
| Sham (placebo) TMSSham 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. | Device | Sham intermittent theta burst stimulation (iTBS) |
Primary outcome
Correlated functional magnetic resonance imaging (fMRI) time series (functional connectivity)
Time frame: Baseline, 1-3 days post 4-day intervention (up to 4 weeks post Baseline)
Primary outcome will be changes in the correlated time series between brain regions (inferior parietal lobule and anterior insula) from baseline to post intervention
2 secondary outcomes
Affective Multisource Interference Task
Time frame: Baseline, 1-3 days post 4-day intervention (up to 4 weeks post Baseline)
Balloon Analogue Risk Task
Time frame: Baseline, 1-3 days post 4-day intervention (up to 4 weeks post Baseline)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Jul 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Kristen K Ellard, PhD principal investigator
Massachusetts General Hospital
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Transcranial Magnetic Stimulation (TMS) in people with Bipolar Disorder, run by Massachusetts General Hospital at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 16 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Kristen K Ellard, PhD (617-724-3221, kellard@mgh.harvard.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Correlated functional magnetic resonance imaging (fMRI) time series (functional connectivity) (time frame: Baseline, 1-3 days post 4-day intervention (up to 4 weeks post Baseline)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jul 2026; AzTrials last refreshed its copy on 26 Oct 2026.