Theta Burst Transcranial Magnetic Stimulation of Fronto-parietal Networks: Modulation by Mental State (TMScogMod)

September 14, 2023 updated by: Stephan F. Taylor, University of Michigan

The purpose of this study is to improve understanding of the way transcranial magnetic stimulation (TMS), a form of non-invasive brain stimulation, affects the brain. The study hypothesis that when theta burst stimulation (TBS) is applied during a controlled mental state, network changes will be facilitated, compared to stimulation when mental state is uncontrolled. This study will focus on the dorsolateral prefrontal cortex (dlPFC) and the associated frontoparietal network (FPN), which subserves cognitive control - the ability to flexibly adapt and regulate behavior, an ability known to be impaired in neuropsychiatric conditions such as depression and dementia.

Healthy volunteers that qualify for this study will have psychological assessments and cognitive measures (due to Covid, some of these were done via teleconference), as well as functional Magnetic Resonance Imaging (fMRI) scans, completed after administration of TMS. Participants will be asked to come in for a total of five visits that include; a screening and assessment visit; a baseline functional magnetic resonance imaging (fMRI) scan, followed by TMS session; Visits 3, 4, and 5 will be the experimental TMS session, followed by fMRI scan.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

We will test the broad hypothesis that when TBS is applied during a controlled mental state, network changes will be facilitated, compared to stimulation when mental state is uncontrolled. We will focus on the dorsolateral prefrontal cortex (dlPFC) and the associated fronto-parietal network (FPN), which subserves cognitive control -- the ability to flexibly adapt and regulate behavior, an ability known to be impaired in neuropsychiatric conditions such as depression and dementia. We will use an 'n-back' task tapping cognitive control and the FPN. We will employ a within-subjects design with 40 healthy subjects in 4 MRI sessions. Each MRI session will consist of blood oxygenation level-dependent (BOLD) fMRI during an n-back task, resting state BOLD fMRI to measure connectivity and resting state arterial spin labeling (ASL) MRI to measure cerebral blood flow (rCBF) and examine effects on resting activity level. BOLD activation during the n-back will identify the FPN and the target site for dlPFC TBS. After a baseline fMRI session, subsequent sessions over different days will entail TBS, immediately followed by an MRI session to assess the effects of stimulation. TBS will involve: 1) dlPFC stimulation by active iTBS (600 pulses) alone or 2) while simultaneously performing an n-back cognitive task or 3) vertex (control) iTBS stimulation, alone.

Study Type

Interventional

Enrollment (Actual)

53

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Michigan
      • Ann Arbor, Michigan, United States, 48170
        • University of Michigan

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 50 years (Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • Women of child bearing age can not be pregnant or trying to become pregnant
  • Ability to tolerate small, enclosed spaces without anxiety
  • Size compatible with scanner gantry, e. g. men over 6 feet tall that weigh more than 250 lbs, men under 6 feet tall that weigh over 220 lbs, women over 5'11" tall that weigh more than 220 lbs, or women under 5'10" tall that weigh more than 200 lbs. Subjects of these weights or greater typically have difficult fitting into the fMRI scanner properly
  • Ability and willingness to give informed consent to participate
  • Alcohol or drug dependence (if in remission for greater than 5 years)

Exclusion Criteria

  • History of past or current mental illness (except simple phobias)
  • History of closed head injury, for example, loss of consciousness > approximately 5 minutes, hospitalization, neurological sequela;
  • Metals, implants or metallic substances within or on the body that might cause adverse effects to the subject in a strong magnetic field, or interfere with image acquisition (for example; aneurysm clips, retained particles or metal workers with exposures, neurostimulators, foil-backed transdermal patches, carotid or cerebral stents, cerebral spinal fluid (CSF) shunts; magnetic dental implants, ferromagnetic ocular implants, pacemakers, and automatic implantable defibrillators).
  • Prescription or non-prescription, with psychotropic effects (birth control medications allowed)
  • First-degree family members with a history of epilepsy
  • History of serious neurological illness or current medical condition that could compromise brain function, such as liver failure

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: TMS to dlPFC, without a concurrent task
TMS (intermittent theta burst stimulation) will be applied to the dlPFC, when subjects are in a resting state
Device: TMS
Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex
Other Names:
  • intermittent theta burst stimulation (iTBS)
Behavioral: n-back working memory task
Subjects perform an executive function task, in which they view the serial presentation of letters and decide whether or not a letter matches a letter presented 'n' letters back (2 letters or 1 letter)
Experimental: TMS to vertex, without concurrent task
TMS (intermittent theta burst stimulation) will be applied to the cerebral vertex, when subjects are in a resting state
Device: TMS
Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex
Other Names:
  • intermittent theta burst stimulation (iTBS)
Behavioral: n-back working memory task
Subjects perform an executive function task, in which they view the serial presentation of letters and decide whether or not a letter matches a letter presented 'n' letters back (2 letters or 1 letter)
Experimental: TMS to dlPFC, during task
TMS (intermittent theta burst stimulation) will be applied to the dlPFC, when subjects are engaged in the n-back working memory task
Device: TMS
Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex
Other Names:
  • intermittent theta burst stimulation (iTBS)
Behavioral: n-back working memory task
Subjects perform an executive function task, in which they view the serial presentation of letters and decide whether or not a letter matches a letter presented 'n' letters back (2 letters or 1 letter)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Accuracy to 2-back
Time Frame: 60 minutes after TMS during fMRI
Correct responses to letter stimuli, as a percentage of all responses
60 minutes after TMS during fMRI
2-back Minus 1-back Blood Oxygen Level-Dependent (BOLD) Activation, Voxelwise in FPN
Time Frame: 60 minutes after TMS during fMRI
Fronto-parietal network (FPN) defined by BOLD change while subject performed the n-back working memory task, contrasting high (2-back) versus low (1-back) loads. Using the SPM12 package, data were normalized per standard, open source routines. Using a General Linear Model framework, a model was estimated with regressors (after convolution with hemodynamic response function) for 2-back & 1-back conditions for each subject to predict BOLD change each day (arm).For analysis of group effects, second-level, between-subject analyses on normalized images of the 2-back minus 1-back beta estimate from the first level were entered into regression models, with mean frame displacement as a co-variate of no-interest to test contrasts between the arms/interventions. Using a FPN mask, the eigenvalues from the second-level estimates were extracted and entered into the analysis as an outcome measure. Note: eigenvalues are arbitrary units. Larger values indicate more BOLD signal.
60 minutes after TMS during fMRI
Frontoparietal Network (FPN) Connectivity to Dorsolateral Prefrontal Cortex (dlPFC) Theta Burst Stimulation (TBS) Target
Time Frame: 60 minutes after TMS during fMRI
Analysis of resting-state connectivity was performed used the CONN toolbox, using standard techniques to demonstrate connectivity between a spherical seed placed on each participant's locus of dlPFC stimulation, and the rest of the brain. Connectivity (correlations of BOLD signal) was first calculated for each participant, and then spatially averaged in MNI brain space, between participants. A 'cluster' of connectivity was identified, only if the number of voxels (thresholded at P <0.001) exceeded the count of 25. The outcome measure here is a count of the number of clusters exceeding this threshold, across all subjects. It represents significant connectivity between the site of stimulation and that cluster in the brain, for all subjects.
60 minutes after TMS during fMRI
Cerebral Blood Flow (rCBF) at Stimulation Target
Time Frame: 15 minutes after TMS during fMRI
Regional cerebral blood flow measured at the site of theta burst stimulation (TBS) in milliliters per 100 mg tissue per minute
15 minutes after TMS during fMRI

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
2-back Minus 1-back BOLD Activation, Voxelwise in Whole Brain
Time Frame: 60 minutes after TMS during fMRI
Fronto-parietal network (FPN) defined by BOLD change while subject performed the n-back working memory task, contrasting high (2-back) versus low (1-back) loads. Using the SPM12 package, data were normalized per standard, open source routines. Using a General Linear Model framework, a model was estimated with regressors (after convolution with hemodynamic response function) for 2-back & 1-back conditions for each subject to predict BOLD change each day (arm).For analysis of group effects, second-level, between-subject analyses on normalized images of the 2-back minus 1-back beta estimate from the first level were entered into regression models. With a cluster threshold of voxel magnitude < 0.001, clusters of difference are defined. Because there are often multiple clusters in a contrast, the number below is the size, in voxels, of the largest cluster, across all participants, for each session.
60 minutes after TMS during fMRI
Measure Cerebral Blood Flow (rCBF) in FPN
Time Frame: 15 minutes after TMS during fMRI
Regional cerebral blood flow measured in the FPN in milliliters per 100 mg tissue per minute
15 minutes after TMS during fMRI
Median Reaction Time (RT) in 2-back
Time Frame: 60 minutes after TMS during fMRI
Median reaction time for subjects responding in the n-back task, for correct responses (1-back and 2-back)
60 minutes after TMS during fMRI
D-prime in 2-back
Time Frame: 60 minutes after TMS during fMRI

d-prime = z(H) - z(F) , where z(H) and z(F) are the z transforms of hit rate and false alarm, respectively.

Hit rate = number of correctly identified targets/number of targets presented False alarm = number of incorrectly identified targets/number of non-targets presented
60 minutes after TMS during fMRI

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Michigan

Collaborators

National Institute of Mental Health (NIMH)

Investigators

  • Principal Investigator: Stephan Taylor, MD, University of Michigan

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 11, 2019

Primary Completion (Actual)

March 29, 2022

Study Completion (Actual)

March 29, 2022

Study Registration Dates

First Submitted

July 3, 2019

First Submitted That Met QC Criteria

July 3, 2019

First Posted (Actual)

July 8, 2019

Study Record Updates

Last Update Posted (Actual)

October 6, 2023

Last Update Submitted That Met QC Criteria

September 14, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Other Study ID Numbers

  • HUM00165239
  • R21MH120633-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The PI will share information about this/these trial(s) via timely registration, updates, and results reporting in ClinicalTrials.gov in accordance with NIH policy.

The PI will also upload data gathered in this proposal to an National Institute of Mental Health (NIMH)-designated central data, NIMH Data Archive (NDA), as prescribed by NOT-MH-15-012, working with NIMH program to determine the timing and extent of data sharing. This includes formulation of an enrollment strategy that will obtain the information necessary to generate a Global Unique Identifier (GUID) for each participant.

The consent form will include language indicating the intention to upload de-identified data into the central archive, and permission will be obtained from University of Michigan Institutional Review Board to do so. The budget includes a data manager to cover the costs of managing the data, building the data dictionary and harmonizing it with data structures.

IPD Sharing Time Frame

De-identified data will be entered into the NDA within 1 year of the conclusion of the study.

IPD Sharing Access Criteria

No additional access restrictions will be placed on the de-identified data beyond those that are standard for the NDA.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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