Examining the Effect of EEG-guided Theta Burst Stimulation in Bipolar Disorder

Establishing the Effect of Electroencephalography (EEG)-Guided Theta Burst Stimulation on Reducing Mania/Hypomania-related Affect and Reward Driven Behavior in Bipolar Disorder

Bipolar Disorder (BD) is a common and highly debilitating psychiatric disorder, however, the predisposing brain mechanisms are poorly understood. Here, the investigators will conduct a proof of concept study that will examine the effect of electroencephalography (EEG)-guided theta burst stimulation (TBS) on reducing mania/hypomania-related affect and reward driven behavior in adults with BD. The investigators hypothesize that TBS will reduce mania/hypomania-related affect and reward driven behavior in adults with BD.

Study Overview

• Status: Completed
• Conditions: Bipolar Disorder
• Intervention / Treatment: Device: Continuous Theta Burst Stimulation (cTBS); Device: Intermittent Theta Burst Stimulation (iTBS)

Detailed Description

This study aims to examine the effect of electroencephalography (EEG)-guided theta burst stimulation (TBS) on reducing mania/hypomania-related affect and reward driven behavior in adults with BD. Eligible participants will undergo 6 study visits: a screening visit, a baseline MRI visit, TBS motor thresholding visit, and 3 cTBS/EEG visits. Participants will receive brain stimulation and have brain activity recorded by EEG at each of the 3 cTBS/EEG study visits. The research associates (except for the research associate administering the TBS) and participants will be blinded to the brain area receiving TBS, which will be randomized and counterbalanced beforehand. Certain information is withheld to protect the scientific integrity of the study design.

The goal of the study is to reduce overactivity in the reward neural network (RNet) and increase activity in the central executive control network (CEN) using theta burst stimulation (TBS). The region in the RNet to be targeted by inhibitory (continuous, cTBS) is the left ventrolateral prefrontal cortex (vlPFC); and the region in the CEN to be targeted by excitatory (intermittent, iTBS) is the right dorsolateral prefrontal cortex (dlPFC)

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yiming Wang; Phone Number: 4122466620; Email: wangy40@upmc.edu
• Study Contact Backup: Name: Jill P Morris-Tillman; Phone Number: 4123838206; Email: morristillmanje@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• 18-35 years of age
• Diagnosis of BD (DSM-5 criteria) in remission (euthymic for >2 months) or in a manic/hypomanic episode [manic/hypomanic or euthymic adults with BD (3-fifths manic/hypomanic); euthymic for > 2 months from most recent BD episode OR current manic/hypomanic episode]
• Not psychotic
• Score <3 on delusions, hallucinations, unusual thought content, and conceptual disorganization items of the Positive and Negative Syndrome Scale (PANSS)
• Unmedicated or on any combination 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, as these are commonly-prescribed medications for BD
• Provides the contact information of a medical provider (including but not limited to a PCP) that we may communicate with for any concerns of escalating symptoms of mania

Exclusion criteria:

• Not 18-35 years of age
• Diagnosis of BD in a depressive episode or Diagnosis of BP in partial remission, euthymia that fails to meet full remission criterion of a period of at least 2 months in which there are no significant symptoms, e.g., only partial remission of symptoms or full remission of symptoms but for <2 months
• Diagnosis of BD in a depressive episode
• Personal and family history of epilepsy (TBS exclusion)
• Binge alcohol drinking
• Taking substances in the last month that can elevate seizure risk including but not limited to SNRI antidepressants, bupropion and stimulants (TBS exclusion)
• History of head injury, neurological, pervasive developmental disorder (e.g. autism), systemic medical disease and treatment (medical records, participant report)
• Mini-Mental State Examination score (cognitive state) <24
• Premorbid NAART IQ estimate<85
• Visual disturbance: <20/40 Snellen visual acuity
• History of alcohol/substance use disorder (SUD; all substances, except 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 TBS visit, 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: metallic objects, e.g., surgical implants; claustrophobia; positive pregnancy test for females (at the MRRC) or self-report pregnancy *Unable to understand English
• Scoring greater than or equal to 8 on HRSD at screen visit and depressive episode is confirmed on SCID-5
• Scoring greater than or equal to 18 on HRSD at any study visit
• Psychosis
• Using psychotropic medications other than those allowed in inclusion criteria
• Scoring greater than or equal to 38 on the YMRS at any study visit
• Does not provide the contact information of a medical provider (including but not limited to a PCP) that we may communicate with for any concerns of escalating symptoms of mania

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Left vLPFC cTBS/right dlPFC iTBS/left Som cTBS; A random number sequence will be generated for randomization of the 3 EEG/TBS session order to which each participant is assigned: left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) right dlPFC iTBS (iTBS applied to the right dorsolateral prefrontal cortex) left Som cTBS (cTBS applied to the left somatosensory cortex)	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 that can decrease the excitability of cortical neurons. 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; Other Names: Transcranial Magnetic Stimulation (TMS); Device: Intermittent Theta Burst Stimulation (iTBS); iTBS is a brief stimulation of a part of the brain with a magnetic field that passes through the scalp and skull safely to increase the excitability of cortical neurons. 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.; Other Names: Transcranial Magnetic Stimulation (TMS)
Experimental: Left vLPFC cTBS/left Som cTBS/right dlPFC iTBS; A random number sequence will be generated for randomization of the 3 EEG/TBS session order to which each participant is assigned: left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) left Som cTBS (cTBS applied to the left somatosensory cortex) right dlPFC iTBS (iTBS applied to the right dorsolateral prefrontal cortex)	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 that can decrease the excitability of cortical neurons. 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; Other Names: Transcranial Magnetic Stimulation (TMS); Device: Intermittent Theta Burst Stimulation (iTBS); iTBS is a brief stimulation of a part of the brain with a magnetic field that passes through the scalp and skull safely to increase the excitability of cortical neurons. 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.; Other Names: Transcranial Magnetic Stimulation (TMS)
Experimental: left Som cTBS/right dlPFC iTBS/Left vLPFC cTBS; A random number sequence will be generated for randomization of the 3 EEG/TBS session order to which each participant is assigned: left Som cTBS (cTBS applied to the left somatosensory cortex) right dlPFC iTBS (iTBS applied to the right dorsolateral prefrontal cortex) left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex)	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 that can decrease the excitability of cortical neurons. 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; Other Names: Transcranial Magnetic Stimulation (TMS); Device: Intermittent Theta Burst Stimulation (iTBS); iTBS is a brief stimulation of a part of the brain with a magnetic field that passes through the scalp and skull safely to increase the excitability of cortical neurons. 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.; Other Names: Transcranial Magnetic Stimulation (TMS)
Experimental: left Som cTBS/Left vLPFC cTBS/right dlPFC iTBS; A random number sequence will be generated for randomization of the 3 EEG/TBS session order to which each participant is assigned: left Som cTBS (cTBS applied to the left somatosensory cortex) left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) right dlPFC iTBS (iTBS applied to the right dorsolateral prefrontal cortex)	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 that can decrease the excitability of cortical neurons. 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; Other Names: Transcranial Magnetic Stimulation (TMS); Device: Intermittent Theta Burst Stimulation (iTBS); iTBS is a brief stimulation of a part of the brain with a magnetic field that passes through the scalp and skull safely to increase the excitability of cortical neurons. 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.; Other Names: Transcranial Magnetic Stimulation (TMS)
Experimental: right dlPFC iTBS/left Som cTBS/Left vLPFC cTBS; A random number sequence will be generated for randomization of the 3 EEG/TBS session order to which each participant is assigned: right dlPFC iTBS (iTBS applied to the right dorsolateral prefrontal cortex) left Som cTBS (cTBS applied to the left somatosensory cortex) left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex)	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 that can decrease the excitability of cortical neurons. 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; Other Names: Transcranial Magnetic Stimulation (TMS); Device: Intermittent Theta Burst Stimulation (iTBS); iTBS is a brief stimulation of a part of the brain with a magnetic field that passes through the scalp and skull safely to increase the excitability of cortical neurons. 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.; Other Names: Transcranial Magnetic Stimulation (TMS)
Experimental: right dlPFC iTBS/Left vLPFC cTBS/left Som cTBS; A random number sequence will be generated for randomization of the 3 EEG/TBS session order to which each participant is assigned: right dlPFC iTBS (iTBS applied to the right dorsolateral prefrontal cortex) left vlPFC cTBS (cTBS applied to the left ventrolateral prefrontal cortex) left Som cTBS (cTBS applied to the left somatosensory cortex)	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 that can decrease the excitability of cortical neurons. 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; Other Names: Transcranial Magnetic Stimulation (TMS); Device: Intermittent Theta Burst Stimulation (iTBS); iTBS is a brief stimulation of a part of the brain with a magnetic field that passes through the scalp and skull safely to increase the excitability of cortical neurons. 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.; Other Names: Transcranial Magnetic Stimulation (TMS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beta power in left vlPFC	The difference in Beta power in left vLPFC from pre TBS to post TBS	Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Beta power in right vlPFC	The difference in Beta power in right vLPFC from pre TBS to post TBS	Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Beta power in left dlPFC	The difference in Beta power in left dLPFC from pre TBS to post TBS	Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Beta power in right dlPFC	The difference in Beta power in right dLPFC from pre TBS to post TBS	Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Beta functional connectivity between left and right vlPFC	The difference in Beta functional connectivity among left and right vLPFC from pre TBS to post TBS	Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Beta functional connectivity between vlPFC and other RNet regions	The difference in Beta functional connectivity among vLPFC and other RNet regions from pre TBS to post TBS	Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Beta functional connectivity between dlPFC with other CEN regions	The difference in Beta functional connectivity among dlPFC and other RNet regions from pre TBS to post TBS	Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beta power in other RNet and CEN regions	The difference in Beta power among other RNet and CEN regions from pre TBS to post TBS	Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Functional connectivity among other RNet and CEN regions	The difference in Beta functional connectivity among other RNet and CEN regions from pre TBS to post TBS	Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Number of immediate choices made on the delay discounting task	The sum of the immediate choices made on the delay discounting task	15-30 minutes

Collaborators and Investigators

• Sponsor: Mary Phillips, MD MD (Cantab)
• Collaborators: Milken Institute
• Investigators: Principal Investigator: Fabio Ferrarelli, MD, PhD, University of Pittsburgh; Principal Investigator: Mary L Phillips, MD, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2022
• Primary Completion (Actual): July 31, 2023
• Study Completion (Actual): July 31, 2023

Study Registration Dates

• First Submitted: December 16, 2021
• First Submitted That Met QC Criteria: December 16, 2021
• First Posted (Actual): January 5, 2022

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Bipolar Disorder; Transcranial Magnetic Stimulation; Electroencephalography
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Bipolar and Related Disorders; Bipolar Disorder
• Other Study ID Numbers: STUDY21110077

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Informed consent will be collected from study participants that allows for broad sharing of participants' de-identified data. Data transfer procedures will be in accordance with all Institutional Review Board guidelines and federal regulations including HIPAA.
• IPD Sharing Time Frame: 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.
• IPD Sharing 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No