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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Theta Burst Transcranial Magnetic Stimulation of Fronto-parietal Networks: Modulation by Mental State

Conditions
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Healthy

Intervention / Treatment
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* Device: TMS
* Behavioral: n-back working memory task


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: All participants will have 3 MRI sessions subsequent to the baseline visit and these will occur in a counterbalanced order.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TMS to dlPFC, without a concurrent task<br>TMS (intermittent theta burst stimulation) will be applied to the dlPFC, when subjects are in a resting state | Device: TMS<br>* Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex<br>* Other names: intermittent theta burst stimulation (iTBS);Behavioral: n-back working memory task<br>* 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)<br>|
| Experimental: TMS to vertex, without concurrent task<br>TMS (intermittent theta burst stimulation) will be applied to the cerebral vertex, when subjects are in a resting state | Device: TMS<br>* Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex<br>* Other names: intermittent theta burst stimulation (iTBS);Behavioral: n-back working memory task<br>* 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)<br>|
| Experimental: TMS to dlPFC, during task<br>TMS (intermittent theta burst stimulation) will be applied to the dlPFC, when subjects are engaged in the n-back working memory task | Device: TMS<br>* Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex<br>* Other names: intermittent theta burst stimulation (iTBS);Behavioral: n-back working memory task<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-back Minus 1-back Blood Oxygen Level-Dependent (BOLD) Activation, Voxelwise in FPN | 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 | 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 | 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 | 
| Accuracy to 2-back | Correct responses to letter stimuli, as a percentage of all responses | 60 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 | 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 | 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 | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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functional magnetic resonance imaging, Transcranial Magnetic Stimulation, dorsolateral prefrontal cortex