Effects of Theta Burst Stimulation on the Brain, Behavior, and Clinical Symptoms in Adults With Bipolar Disorder

NCT04696471 | Completed DMC FDA Device

• 2 other identifiers: STUDY20060322R01MH122990
• Study Type: interventional
• Target: 146
• Locations: 1 country
• Sites: 1

Brief Summary

Bipolar Disorder (BD) is a common and highly debilitating psychiatric disorder, however, the predisposing brain mechanisms are poorly understood. Here, the investigators aim to examine the immediate effect of transcranial brain stimulation (TBS) on brain activity and emotions in adults with and without BD as a first stage toward understanding the predisposing brain mechanisms of BD. The investigators hypothesize that TBS will reduce brain activity while playing a game with rewards in all adults, but the TBS will reduce brain activity more in the adults with BD compared to adults without BD. Furthermore, the investigators hypothesize that this reduced brain activity will be associated with reduced BD symptoms, such as negative emotions.

Conditions

Bipolar Disorder

Keywords

Bipolar Disorder; Magnetic Resonance Imaging; Transcranial Magnetic Stimulation

Outcome Measures

Primary Outcomes (19)

• Reward expectancy-related left ventrolateral prefrontal cortex activity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted blood oxygen level-dependent (BOLD) signal from the left ventrolateral prefrontal cortex to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related right ventrolateral prefrontal cortex activity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal from the right ventrolateral prefrontal cortex to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related left ventral striatum activity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal from the left ventral striatum to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related right ventral striatum activity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal from the left ventral striatum to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related left orbitofrontal cortex activity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal from the left orbitofrontal cortex to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related right orbitofrontal cortex activity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal from the left orbitofrontal cortex to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related midline rostral anterior cingulate cortex (rACC) activity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal from the midline rostral anterior cingulate cortex (rACC) to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related midline dorsal anterior cingulate cortex activity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal from the midline dorsal anterior cingulate cortex to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related left amygdala activity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal from the left amygdala to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related right amygdala activity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal from the left amygdala to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related left ventrolateral prefrontal cortex-right ventrolateral prefrontal cortex functional connectivity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimate for functional connectivity between the left and right ventrolateral prefrontal cortices to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related left ventrolateral prefrontal cortex-left ventral striatum functional connectivity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimate for functional connectivity between the left ventrolateral prefrontal cortex and left ventral striatum to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related left ventrolateral prefrontal cortex-right ventral striatum functional connectivity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimate for functional connectivity between the left ventrolateral prefrontal cortex and right ventral striatum to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related left ventrolateral prefrontal cortex-left orbitofrontal cortex functional connectivity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimate for functional connectivity between the left ventrolateral prefrontal cortex and left orbitofrontal cortex to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related left ventrolateral prefrontal cortex-right orbitofrontal cortex functional connectivity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimate for functional connectivity between the left ventrolateral prefrontal cortex and right orbitofrontal cortex to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related left ventrolateral prefrontal cortex-midline rostral anterior cingulate cortex functional connectivity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimate for functional connectivity between the left ventrolateral prefrontal cortex and midline rACC to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related left ventrolateral prefrontal cortex-midline dorsal anterior cingulate cortex functional connectivity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimate for functional connectivity between the left ventrolateral prefrontal cortex and midline dorsal anterior cingulate cortex to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related left ventrolateral prefrontal cortex-left amygdala functional connectivity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimate for functional connectivity between the left ventrolateral prefrontal cortex and left amygdala to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Reward expectancy-related left ventrolateral prefrontal cortex-right amygdala functional connectivity

  The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimate for functional connectivity between the left ventrolateral prefrontal cortex and right amygdala to the uncertain reward expectancy regressor during performance of the reward task

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

Secondary Outcomes (16)

• Reward expectancy-related left ventrolateral prefrontal cortex wholebrain functional connectivity

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Left ventrolateral prefrontal cortex activity

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Right ventrolateral prefrontal cortex activity

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Left ventral striatum activity

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Right ventral striatum activity

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

Other Outcomes (10)

• Left ventrolateral prefrontal cortex-wholebrain resting state functional connectivity

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Left ventrolateral prefrontal cortex-right ventrolateral prefrontal cortex resting state functional connectivity

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

• Left ventrolateral prefrontal cortex-left ventral striatum resting state functional connectivity

  Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)

Study Arms (6)

Left ventrolateral prefrontal cortex (vlPFC)/Left SS/Left vlPFC sham

EXPERIMENTAL

A random number sequence will be generated for randomization of the 3 cTBS scan session order to which each participant is assigned: * left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) * left SS cTBS (cTBS applied to the left somatosensory area) * left vlPFC sham TBS (go through the motions of applying cTBS to the left ventrolateral prefrontal cortex but very low current is administered so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells) Participants will know that one session will be a sham, but they will be blinded to which session is the sham.

Device: Continuous Theta Burst Stimulation (cTBS); Device: Sham Continuous Theta Burst Stimulation (Sham cTBS)

Left vlPFC/Left vlPFC sham/Left SS

EXPERIMENTAL

A random number sequence will be generated for randomization of the 3 cTBS scan session order to which each participant is assigned: * left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) * left SS cTBS (cTBS applied to the left somatosensory area) * left vlPFC sham TBS (go through the motions of applying cTBS to the left ventrolateral prefrontal cortex but very low current is administered so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells) Participants will know that one session will be a sham, but they will be blinded to which session is the sham.

Device: Continuous Theta Burst Stimulation (cTBS); Device: Sham Continuous Theta Burst Stimulation (Sham cTBS)

Left SS/Left vlPFC sham/Left vlPFC

EXPERIMENTAL

A random number sequence will be generated for randomization of the 3 cTBS scan session order to which each participant is assigned: * left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) * left SS cTBS (cTBS applied to the left somatosensory area) * left vlPFC sham TBS (go through the motions of applying cTBS to the left ventrolateral prefrontal cortex but very low current is administered so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells) Participants will know that one session will be a sham, but they will be blinded to which session is the sham.

Device: Continuous Theta Burst Stimulation (cTBS); Device: Sham Continuous Theta Burst Stimulation (Sham cTBS)

Left SS/Left vlPFC/Left vlPFC sham

EXPERIMENTAL

A random number sequence will be generated for randomization of the 3 cTBS scan session order to which each participant is assigned: * left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) * left SS cTBS (cTBS applied to the left somatosensory area) * left vlPFC sham TBS (go through the motions of applying cTBS to the left ventrolateral prefrontal cortex but very low current is administered so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells) Participants will know that one session will be a sham, but they will be blinded to which session is the sham.

Device: Continuous Theta Burst Stimulation (cTBS); Device: Sham Continuous Theta Burst Stimulation (Sham cTBS)

Left vlPFC sham/Left SS/Left vlPFC

EXPERIMENTAL

A random number sequence will be generated for randomization of the 3 cTBS scan session order to which each participant is assigned: * left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) * left SS cTBS (cTBS applied to the left somatosensory area) * left vlPFC sham TBS (go through the motions of applying cTBS to the left ventrolateral prefrontal cortex but very low current is administered so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells) Participants will know that one session will be a sham, but they will be blinded to which session is the sham.

Device: Continuous Theta Burst Stimulation (cTBS); Device: Sham Continuous Theta Burst Stimulation (Sham cTBS)

Left vlPFC sham/Left vlPFC/Left SS

EXPERIMENTAL

A random number sequence will be generated for randomization of the 3 cTBS scan session order to which each participant is assigned: * left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) * left SS cTBS (cTBS applied to the left somatosensory area) * left vlPFC sham TBS (go through the motions of applying cTBS to the left ventrolateral prefrontal cortex but very low current is administered so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells) Participants will know that one session will be a sham, but they will be blinded to which session is the sham.

Device: Continuous Theta Burst Stimulation (cTBS); Device: Sham Continuous Theta Burst Stimulation (Sham cTBS)

Interventions

Continuous Theta Burst Stimulation (cTBS) DEVICE

cTBS is a brief stimulation of a part of the brain with a magnetic field that passes through the scalp and skull safely. It is FDA-approved as a treatment for psychological conditions including depression; however, this device is not approved for the treatment of adults with Bipolar Disorder I or for use in healthy adults. This research study is using the cTBS off label in all participants (those with and without Bipolar Disorder I) to examine research questions

Also known as: Transcranial Magnetic Stimulation (TMS)

Left SS/Left vlPFC sham/Left vlPFC; Left SS/Left vlPFC/Left vlPFC sham; Left ventrolateral prefrontal cortex (vlPFC)/Left SS/Left vlPFC sham; Left vlPFC sham/Left SS/Left vlPFC; Left vlPFC sham/Left vlPFC/Left SS; Left vlPFC/Left vlPFC sham/Left SS

Sham Continuous Theta Burst Stimulation (Sham cTBS) DEVICE

Sham cTBS goes through the motions of applying cTBS to the brain but administers very low current so that the participant feels like cTBS is being administered even though the current is too low to stimulate brain cells. Participants will know that one session will be a sham, but they will be blinded to which session is the sham

Also known as: Sham Transcranial Magnetic Stimulation (Sham TMS)

Left SS/Left vlPFC sham/Left vlPFC; Left SS/Left vlPFC/Left vlPFC sham; Left ventrolateral prefrontal cortex (vlPFC)/Left SS/Left vlPFC sham; Left vlPFC sham/Left SS/Left vlPFC; Left vlPFC sham/Left vlPFC/Left SS; Left vlPFC/Left vlPFC sham/Left SS

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• All participants
• years of age
• Scoring less than or equal to 8 on the Hamilton Rating Scale for Depression (HRSD) at screen visit
• Participants with Bipolar Disorder (BD)
• Diagnosis of Bipolar Disorder I/II (BDI/II) (DSM-5 criteria) in remission (euthymic for \>2 months) or with mild-moderate hypomania
• \<15 on the Young Mania Rating Scale
• Not psychotic
• \<3 on delusions, hallucinations, unusual thought content, and conceptual disorganization items of the Positive and Negative Syndrome Scale (PANSS)
• Unmedicated or on any combination (except antidepressant monotherapy) of anxiolytics (benzodiazepines, buspirone, pregabalin, hydroxyzine) as needed, and/or atypical antipsychotics, and/or lithium, and/or other mood stabilizers, and/or non-SNRI antidepressants and/or non benzodiazepine hypnotics taken for \>2 months, as these are commonly-prescribed medications for BD
• Participants without Bipolar Disorder
• No present or lifetime history of BD or psychiatric disorder other than anxiety or non BD mood disorders
• Not in a current depressive episode
• No family history of BD

You may not qualify if:

• All participants
• History of head injury, neurological, pervasive developmental disorder (e.g. autism), systemic medical disease and treatment (medical records, participant report)
• Use of substances with seizure risk (e.g., stimulants) in the past month, assessed as at screening, baseline, and before each fMRI-cTBS-fMRI session
• Mini-Mental State Examination score (cognitive state) \<24
• Premorbid National Adult Reading Test Intelligent Quotient estimate\<85
• Visual disturbance: \<20/40 Snellen visual acuity
• Left/mixed handedness
• History of alcohol/substance use disorder (SUD; all substances, including nicotine), and/or illicit substance use (except cannabis) over the last 6 months (SCID-5). Note: lifetime/present cannabis use (at non-abuse (\<3 times in the past month) and non SUD levels) will be allowed, given its common usage in BD and young adults. Cannabis SUD over the last 6 months will not be allowed. Urine tests on scan days will exclude current illicit substance use (except cannabis). Salivary alcohol tests on scan days will exclude intoxicated individuals
• Binge drinking in the week before, and/or \>3 units/day for the 3 days before, and/or alcohol in the last 12 hrs before, any cTBS scan day, confirmed at screening and scan days (to avoid TBS during alcohol withdrawal). Alcohol/nicotine/ caffeine/cannabis use (below SCID-5 SUD, binge levels) will be allowed, and used as covariates
• Inability to understand English
• \<18 years of age or \>35 year of age
• SNRI antidepressants and bupropion will not be allowed, as they can elevate seizure risk, a contraindication for TBS
• Scoring greater than or equal to 8 on HRSD and in depressive episode is confirmed on SCID-5 at screen visit
• Scoring greater than or equal to 18 on HRSD at any visit
• In current depressive episode

Sponsors & Collaborators

• Mary Phillips, MD MD (Cantab): lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

MeSH Terms

Conditions

Bipolar Disorder

Interventions

Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Bipolar and Related Disorders; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics

Study Officials

• Mary Phillips, MD, MD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

• Fabio Ferrarelli, MD, PhD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 18, 2020
• First Posted: January 6, 2021
• Study Start: April 6, 2021
• Primary Completion: October 24, 2025
• Study Completion: October 24, 2025
• Last Updated: January 20, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Time Frame: Raw data and data from descriptive/raw measures will be submitted on a semi-annual basis by July 15 and January 15 or the next business day. We also agree to submit to NDA the analyzed data yielded in our project (i.e., 12 months after accomplishment of each primary aim or objective, or immediately upon publication of the project's primary results, whichever occurs first). The PIs reserve the right to publish on the stated aims in a timely manner during the period of the award. Data will be available for addressing other research questions (i.e. which are not described in funded/pending grants) as soon as the data have been checked for accuracy (a period which will be no later than one year after the completion of each assessment). After the award has ended, the study investigators will continue to test the stated aims, but will also continue to solicit collaborations with outside researchers and to consider data requests in a timely manner.
• Access Criteria: Outside investigators must submit a 1)proposal of the study aims, hypotheses, variables/constructs, analytic approach, and estimated duration of the proposed research; 2)resume, qualifications, source of financial support, and conflict of interest statement; 3)sign a data-sharing agreement and confidentiality statement that stipulates using the data for the stated research purposes only, securing the data using appropriate computer technology, not manipulating the data in order to identify participants, acknowledging the grant that supported data collection and management in publications/presentations, and destroying or returning the data after analyses are complete; 4)obtain approval from their Institutional Review Board, and along with other staff members who have access to the data, submit certificates of the University of Pittsburgh Education and Certification Program in Research Practice Fundamentals or provide written documentation pf similar human subjects protection training.

Locations

US (1)