An interventional study of TMS and n-back working memory task in Healthy, sponsored by University of Michigan. Completed at 1 site in United States. Open to participants aged 18 Years to 50 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2023-10-06.
Sponsored by University of Michigan · Not applicable, Interventional, and Basic science
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.
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.
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TMS (intermittent theta burst stimulation) will be applied to the dlPFC, when subjects are in a resting state
Device: TMS · Behavioral: n-back working memory task
TMS (intermittent theta burst stimulation) will be applied to the cerebral vertex, when subjects are in a resting state
Device: TMS · Behavioral: n-back working memory 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 · Behavioral: n-back working memory task
Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex
Also known as: intermittent theta burst stimulation (iTBS)
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)
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.
Time frame: 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.
Time frame: 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
Time frame: 15 minutes after TMS during fMRI
Accuracy to 2-back
Correct responses to letter stimuli, as a percentage of all responses
Time frame: 60 minutes after TMS during fMRI
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.
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 60 minutes after TMS during fMRI
| Milestone | All Groups |
|---|---|
| Started | 53 |
| Participants who had baseline measurements | 47 |
| Tms to dlpfc, without a concurrent task (passive) | 41 |
| Tms to vertex, without concurrent task (control) | 43 |
| Tms to dlpfc, during task (active) | 40 |
| Completed mri sessions | 40 |
| Completed | 40 |
| Not completed | 13 |
| Withdrew: Covid based withdrawal | 5 |
| Withdrew: Withdrawal by subject | 5 |
| Withdrew: Adverse event | 1 |
| Withdrew: No motor threshold obtainable | 1 |
| Withdrew: Physician decision | 1 |
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.
| arbitrary units | TMS to dlPFC, Without a Concurrent Task (Passive) | TMS to Vertex, Without Concurrent Task (Control) | TMS to dlPFC, During Task (Active) |
|---|---|---|---|
| 2-back Minus 1-back Blood Oxygen Level-Dependent (BOLD) Activation, Voxelwise in FPN | 0.74 ± 0.54 | 0.75 ± 0.45 | 0.58 ± 0.39 |
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.
| cluster count for connectivity | TMS to dlPFC, Without a Concurrent Task (Passive) | TMS to Vertex, Without Concurrent Task (Control) | TMS to dlPFC, During Task (Active) |
|---|---|---|---|
| Frontoparietal Network (FPN) Connectivity to Dorsolateral Prefrontal Cortex (dlPFC) Theta Burst Stimulation (TBS) Target | 0 | 10 | 0 |
Regional cerebral blood flow measured at the site of theta burst stimulation (TBS) in milliliters per 100 mg tissue per minute
| ml/100 mg tissue/min | TMS to dlPFC, Without a Concurrent Task (Passive) | TMS to Vertex, Without Concurrent Task (Control) | TMS to dlPFC, During Task (Active) |
|---|---|---|---|
| Cerebral Blood Flow (rCBF) at Stimulation Target | 57.2 ± 20.7 | 57.9 ± 28.5 | 58.4 ± 20.3 |
Correct responses to letter stimuli, as a percentage of all responses
| percentage correct | TMS to dlPFC, Without a Concurrent Task (Passive) | TMS to Vertex, Without Concurrent Task (Control) | TMS to dlPFC, During Task (Active) |
|---|---|---|---|
| Accuracy to 2-back | 96.7 ± 3.9 | 96.7 ± 3.6 | 96.2 ± 4.5 |
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.
| voxel count | TMS to dlPFC, Without a Concurrent Task (Passive) | TMS to Vertex, Without Concurrent Task (Control) | TMS to dlPFC, During Task (Active) |
|---|---|---|---|
| 2-back Minus 1-back BOLD Activation, Voxelwise in Whole Brain | 1139 | 1532 | 907 |
Regional cerebral blood flow measured in the FPN in milliliters per 100 mg tissue per minute
| mL/100 mg tissue/min | TMS to dlPFC, Without a Concurrent Task (Passive) | TMS to Vertex, Without Concurrent Task (Control) | TMS to dlPFC, During Task (Active) |
|---|---|---|---|
| Measure Cerebral Blood Flow (rCBF) in FPN | 52.7 ± 11.8 | 52.9 ± 15.6 | 51.9 ± 13.1 |
Median reaction time for subjects responding in the n-back task, for correct responses (1-back and 2-back)
| milliseconds | TMS to dlPFC, Without a Concurrent Task (Passive) | TMS to Vertex, Without Concurrent Task (Control) | TMS to dlPFC, During Task (Active) |
|---|---|---|---|
| Median Reaction Time (RT) in 2-back | 573.2 ± 175.8 | 556.4 ± 164.2 | 572.1 ± 135.4 |
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
| d-prime | TMS to dlPFC, Without a Concurrent Task (Passive) | TMS to Vertex, Without Concurrent Task (Control) | TMS to dlPFC, During Task (Active) |
|---|---|---|---|
| D-prime in 2-back | 3.8 ± 0.7 | 3.8 ± 0.6 | 3.7 ± 0.8 |
Collected over duration of participation in study -- 3- 6 weeks. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Baseline Measurement | 0/47 (0%) | 0/47 (0%) | 4/47 (8.5%) |
| TMS to dlPFC, Without a Concurrent Task (Passive) | 0/41 (0%) | 0/41 (0%) | 2/41 (4.9%) |
| TMS to Vertex, Without Concurrent Task (Control) | 0/43 (0%) | 0/43 (0%) | 0/43 (0%) |
| TMS to dlPFC, During Task (Active) | 0/40 (0%) | 0/40 (0%) | 1/40 (2.5%) |
| Event | Baseline Measurement | TMS to dlPFC, Without a Concurrent Task (Passive) | TMS to Vertex, Without Concurrent Task (Control) | TMS to dlPFC, During Task (Active) |
|---|---|---|---|---|
| Finger/Hand SorenessMusculoskeletal and connective tissue disorders | 2/47 | 0/41 | 0/43 | 0/40 |
| Discomfort During fMRIGeneral disorders | 1/47 | 0/41 | 0/43 | 1/40 |
| HeadacheNervous system disorders | 1/47 | 1/41 | 0/43 | 0/40 |
| LightheadednessNervous system disorders | 0/47 | 1/41 | 0/43 | 0/40 |
| Age, Continuous(years) | All Groups |
|---|---|
| Mean | 25.5 ± 7.4 |
| Sex: Female, Male(Participants) | All Groups |
|---|---|
| Female | 27 |
| Male | 13 |
| Ethnicity (NIH/OMB)(Participants) | All Groups |
|---|---|
| Hispanic or Latino | 3 |
| Not Hispanic or Latino | 37 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | All Groups |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 8 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 5 |
| White | 24 |
| More than one race | 3 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(Participants) | All Groups |
|---|---|
| United States | 40 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — 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.
Supporting information: Study protocol, Statistical analysis plan, Informed consent form
Time frame: De-identified data will be entered into the NDA within 1 year of the conclusion of the study.
Access criteria: No additional access restrictions will be placed on the de-identified data beyond those that are standard for the NDA.
Data sharing details ↗ · nda.nih.gov
Ran from Nov 2019 to primary completion in Mar 2022, 28 months.
Results were first posted in Oct 2023, 1 year 6 months after primary completion. A results delay was requested in Mar 2023.
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