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

Bipolar Disorder Clinical Trial

Official title:

Elucidating Neural Mechanisms of Hypo/Mania Using Theta Burst Stimulation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04696471
• Other study ID #: STUDY20060322
• Secondary ID: R01MH122990
• Status: Recruiting
• Phase: N/A
• Start date: April 6, 2021
• Est. completion date: September 2025

Study information

• Verified date: October 2023
• Source: University of Pittsburgh
• Contact: Simona Graur, MSW, LCSW
• Phone: 412-256-8693
• Email: impres[@]upmc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

This study aims to examine the effects of noninvasive stimulation on brain activity as measured by functional magnetic resonance imaging (fMRI) in participants with and without Bipolar I Disorder. Eligible participants will undergo 5 study visits: a screening visit, a baseline MRI visit, and 3 cTBS visits. Participants will receive brain stimulation and undergo fMRI scanning at each of the 3 cTBS study visits, however, at one of the visits, the brain stimulation will be a sham. The research associates and participants will be blinded to when the sham occurs, which will be randomized beforehand. Certain information is withheld to protect the scientific integrity of the study design

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 134
• Est. completion date: September 2025
• Est. primary completion date: September 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 35 Years

Eligibility

Inclusion Criteria:

1. All participants

• 18-35 years of age

• Scoring less than or equal to 8 on the Hamilton Rating Scale for Depression (HRSD) at screen visit

2. 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

3. 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

Exclusion Criteria:

1. All participants

• History of head injury, neurological, pervasive developmental disorder (e.g. autism), systemic medical disease and treatment (medical records, participant report)

• Family history of epilepsy (TBS exclusion criterion)

• 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

• MRI exclusion criteria: metallic objects, e.g., surgical implants; claustrophobia; proneness; positive pregnancy test for females (performed at the MRRC) or self-report pregnancy

• 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

2. Participants with Bipolar Disorder

• BD diagnosis other than BDI/II

• More severe hypo/mania (YMRS>15)

• Psychosis

• Using psychotropic medications other than those allowed in inclusion criteria

3. Participants without Bipolar Disorder

• Present/ lifetime history of any psychiatric disorder other than anxiety and non BD mood disorders

• Family history of of BD

Related Conditions & MeSH terms

• Bipolar Disorder

Intervention

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

Locations

Country	Name	City	State
United States	University of Pittsburgh	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Mary Phillips, MD MD (Cantab)	National Institute of Mental Health (NIMH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Left ventrolateral prefrontal cortex-wholebrain resting state functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of resting state functional connectivity between the left ventrolateral prefrontal cortex and the wholebrain	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Other	Left ventrolateral prefrontal cortex-right ventrolateral prefrontal cortex resting state functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of resting state functional connectivity between the left and right ventrolateral prefrontal cortices	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Other	Left ventrolateral prefrontal cortex-left ventral striatum resting state functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of resting state functional connectivity between the left ventrolateral prefrontal cortex and the left ventral striatum	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Other	Left ventrolateral prefrontal cortex-right ventral striatum resting state functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of resting state functional connectivity between the left ventrolateral prefrontal cortex and the right ventral striatum	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Other	Left ventrolateral prefrontal cortex-left orbitofrontal cortex resting state functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of resting state functional connectivity between the left ventrolateral prefrontal cortex and the left orbitofrontal cortex	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Other	Left ventrolateral prefrontal cortex-right orbitofrontal cortex resting state functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of resting state functional connectivity between the left ventrolateral prefrontal cortex and the right orbitofrontal cortex	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Other	Left ventrolateral prefrontal cortex-midline rostral anterior cingulate cortex resting state functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of resting state functional connectivity between the left ventrolateral prefrontal cortex and the midline rostral anterior cingulate cortex	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Other	Left ventrolateral prefrontal cortex-midline dorsal anterior cingulate cortex resting state functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of resting state functional connectivity between the left ventrolateral prefrontal cortex and the midline dorsal anterior cingulate cortex	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Other	Left ventrolateral prefrontal cortex-left amygdala resting state functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of resting state functional connectivity between the left ventrolateral prefrontal cortex and the left amygdala	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Other	Left ventrolateral prefrontal cortex-right amygdala resting state functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of resting state functional connectivity between the left ventrolateral prefrontal cortex and the right amygdala	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	Reward expectancy-related left ventrolateral prefrontal cortex wholebrain functional connectivity	The difference in magnitude between pre and post cTBS for each cTBS condition of the extracted parameter estimate for functional connectivity between the left ventrolateral prefrontal cortex and the whole brain 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	Left ventrolateral prefrontal cortex activity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal in the left ventrolateral prefrontal cortex to the contrast of possible win vs. neutral control conditions	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Right ventrolateral prefrontal cortex activity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal in the right ventrolateral prefrontal cortex to the contrast of possible win vs. neutral control conditions	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Left ventral striatum activity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal in the left ventral striatum to the contrast of possible win vs. neutral control conditions	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Right ventral striatum activity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal in the right ventral striatum to the contrast of possible win vs. neutral control conditions	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Left orbitofrontal cortex activity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal in the left orbitofrontal cortex to the contrast of possible win vs. neutral control conditions	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Right orbitofrontal cortex activity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal in the right orbitofrontal cortex to the contrast of possible win vs. neutral control conditions	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Midline rostral anterior cingulate cortex activity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal in the midline rostral anterior cingulate cortex to the contrast of possible win vs. neutral control conditions	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	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 in the midline dorsal anterior cingulate cortex to the contrast of possible win vs. neutral control conditions	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Left amygdala activity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal in the left amygdala to the contrast of possible win vs. neutral control conditions	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Right amygdala activity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal in the right amygdala to the contrast of possible win vs. neutral control conditions	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Left ventral lateral prefrontal cortex-wholebrain functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of functional connectivity between the left ventrolateral prefrontal cortex and the wholebrain to the contrast of possible win vs. neutral control conditions	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Prediction error-related left ventral striatum activity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal in the left ventral striatum to the prediction error regressor	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Prediction error-related right ventral striatum activity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted BOLD signal in the right ventral striatum to the prediction error regressor	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Prediction error-related left ventral striatum-wholebrain functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of resting state functional connectivity between the left ventral striatum and the wholebrian to the prediction error regressor	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)
Secondary	Prediction error-related right ventral striatum-wholebrain functional connectivity	The difference in magnitude between pre and post cTBS scans for each cTBS condition of the extracted parameter estimates of resting state functional connectivity between the right ventral striatum and the wholebrain	Change in magnitude immediately before and immediately after each cTBS condition at scan visits (30-60 mins)