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

Primary Purpose

Bipolar Disorder

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Continuous Theta Burst Stimulation (cTBS)
Intermittent Theta Burst Stimulation (iTBS)
Sponsored by
Mary Phillips, MD MD (Cantab)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Bipolar Disorder focused on measuring Bipolar Disorder, Transcranial Magnetic Stimulation, Electroencephalography

Eligibility Criteria

18 Years - 35 Years (Adult)All SexesDoes not accept healthy volunteers

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 for >2 months 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 taken for >2 months, as these are commonly-prescribed medications for BD
  • Right handed
  • 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
  • Left/mixed handedness (Annett criteria)
  • 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 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 allowed psychotropic medication for <2 months
  • Using psychotropic medications other than those allowed in inclusion criteria
  • Unmedicated for <2 months
  • 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

Sites / Locations

  • University of Pittsburgh

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Left vLPFC cTBS/right dlPFC iTBS/left Som cTBS

Left vLPFC cTBS/left Som cTBS/right dlPFC iTBS

left Som cTBS/right dlPFC iTBS/Left vLPFC cTBS

left Som cTBS/Left vLPFC cTBS/right dlPFC iTBS

right dlPFC iTBS/left Som cTBS/Left vLPFC cTBS

right dlPFC iTBS/Left vLPFC cTBS/left Som cTBS

Arm Description

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)

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)

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)

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)

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)

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)

Outcomes

Primary Outcome Measures

Beta power in left vlPFC
The difference in Beta power in left vLPFC from pre TBS to post TBS
Beta power in right vlPFC
The difference in Beta power in right vLPFC from pre TBS to post TBS
Beta power in left dlPFC
The difference in Beta power in left dLPFC from pre TBS to post TBS
Beta power in right dlPFC
The difference in Beta power in right dLPFC from pre TBS to post TBS
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
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
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

Secondary Outcome Measures

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
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
Number of immediate choices made on the delay discounting task
The sum of the immediate choices made on the delay discounting task

Full Information

First Posted
December 16, 2021
Last Updated
October 5, 2023
Sponsor
Mary Phillips, MD MD (Cantab)
Collaborators
Milken Institute
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1. Study Identification

Unique Protocol Identification Number
NCT05179785
Brief Title
Examining the Effect of EEG-guided Theta Burst Stimulation in Bipolar Disorder
Official Title
Establishing the Effect of Electroencephalography (EEG)-Guided Theta Burst Stimulation on Reducing Mania/Hypomania-related Affect and Reward Driven Behavior in Bipolar Disorder
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Completed
Study Start Date
March 23, 2022 (Actual)
Primary Completion Date
July 31, 2023 (Actual)
Study Completion Date
July 31, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Mary Phillips, MD MD (Cantab)
Collaborators
Milken Institute

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bipolar Disorder
Keywords
Bipolar Disorder, Transcranial Magnetic Stimulation, Electroencephalography

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
26 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Left vLPFC cTBS/right dlPFC iTBS/left Som cTBS
Arm Type
Experimental
Arm Description
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)
Arm Title
Left vLPFC cTBS/left Som cTBS/right dlPFC iTBS
Arm Type
Experimental
Arm Description
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)
Arm Title
left Som cTBS/right dlPFC iTBS/Left vLPFC cTBS
Arm Type
Experimental
Arm Description
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)
Arm Title
left Som cTBS/Left vLPFC cTBS/right dlPFC iTBS
Arm Type
Experimental
Arm Description
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)
Arm Title
right dlPFC iTBS/left Som cTBS/Left vLPFC cTBS
Arm Type
Experimental
Arm Description
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)
Arm Title
right dlPFC iTBS/Left vLPFC cTBS/left Som cTBS
Arm Type
Experimental
Arm Description
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)
Intervention Type
Device
Intervention Name(s)
Continuous Theta Burst Stimulation (cTBS)
Other Intervention Name(s)
Transcranial Magnetic Stimulation (TMS)
Intervention Description
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
Intervention Type
Device
Intervention Name(s)
Intermittent Theta Burst Stimulation (iTBS)
Other Intervention Name(s)
Transcranial Magnetic Stimulation (TMS)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Beta power in left vlPFC
Description
The difference in Beta power in left vLPFC from pre TBS to post TBS
Time Frame
Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Title
Beta power in right vlPFC
Description
The difference in Beta power in right vLPFC from pre TBS to post TBS
Time Frame
Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Title
Beta power in left dlPFC
Description
The difference in Beta power in left dLPFC from pre TBS to post TBS
Time Frame
Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Title
Beta power in right dlPFC
Description
The difference in Beta power in right dLPFC from pre TBS to post TBS
Time Frame
Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Title
Beta functional connectivity between left and right vlPFC
Description
The difference in Beta functional connectivity among left and right vLPFC from pre TBS to post TBS
Time Frame
Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Title
Beta functional connectivity between vlPFC and other RNet regions
Description
The difference in Beta functional connectivity among vLPFC and other RNet regions from pre TBS to post TBS
Time Frame
Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Title
Beta functional connectivity between dlPFC with other CEN regions
Description
The difference in Beta functional connectivity among dlPFC and other RNet regions from pre TBS to post TBS
Time Frame
Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Secondary Outcome Measure Information:
Title
Beta power in other RNet and CEN regions
Description
The difference in Beta power among other RNet and CEN regions from pre TBS to post TBS
Time Frame
Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Title
Functional connectivity among other RNet and CEN regions
Description
The difference in Beta functional connectivity among other RNet and CEN regions from pre TBS to post TBS
Time Frame
Change in magnitude immediately before and immediately after each TBS condition at EEG/TBS visits (15-30 mins)
Title
Number of immediate choices made on the delay discounting task
Description
The sum of the immediate choices made on the delay discounting task
Time Frame
15-30 minutes

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
35 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mary L Phillips, MD, MD
Organizational Affiliation
University of Pittsburgh
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Fabio Ferrarelli, MD, PhD
Organizational Affiliation
University of Pittsburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.

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

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