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| ID | Type | Description | Link |
|---|---|---|---|
| R21MH120633-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Mental Health (NIMH) | NIH |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TMS to dlPFC, without a concurrent task | Experimental | TMS (intermittent theta burst stimulation) will be applied to the dlPFC, when subjects are in a resting state |
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| TMS to vertex, without concurrent task | Experimental | TMS (intermittent theta burst stimulation) will be applied to the cerebral vertex, when subjects are in a resting state |
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| TMS to dlPFC, during task | Experimental | TMS (intermittent theta burst stimulation) will be applied to the dlPFC, when subjects are engaged in the n-back working memory task |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TMS | Device | Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex |
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| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Stephan Taylor, MD | University of Michigan | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Michigan | Ann Arbor | Michigan | 48170 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32613082 | Derived | Taylor SF, Lee TG, Jonides J, Tso IF, Hernandez-Garcia L. Theta Burst Transcranial Magnetic Stimulation of Fronto-Parietal Networks: Modulation by Mental State. J Psychiatr Brain Sci. 2020;5:e200011. doi: 10.20900/jpbs.20200011. Epub 2020 May 26. |
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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.
De-identified data will be entered into the NDA within 1 year of the conclusion of the study.
No additional access restrictions will be placed on the de-identified data beyond those that are standard for the NDA.
Of 59 participants who were screened, 6 were ineligible and 53 were enrolled. With each treatment, regardless of the sequence, an MRI was performed.
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| ID | Title | Description |
|---|---|---|
| FG000 | All Groups | Since participants' data are only analyzed if they completed all assignments, and the order of assignment was immaterial to the trial, as it was a basic experiment studying humans, there was no reason to separate out the participants based on the order of interventions. Hence, the milestones listed below, other than "Completed," do not represent the actual sequential order for all participants. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Groups | Since participants' data are only analyzed if they completed all assignments, and the order of assignment was immaterial to the trial, as it was a basic experiment studying humans, there was no reason to separate out the participants based on the order of interventions. Data is provided for all subjects whose data is analyzed. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Of the 40 participants, image data from 3 failed quality control. | Posted | Mean | Standard Deviation | arbitrary units | 60 minutes after TMS during fMRI |
duration of participation in study -- 3- 6 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Baseline Measurement | Initial assessments, baseline MRI scan, TMS motor threshold |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Finger/Hand Soreness | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
Because of technical problems, performance measure for accuracy and d-prime were not available for 24 subjects in the 'Active' condition.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Stephan Taylor | University of Michigan | (734) 936-4955 | sftaylor@med.umich.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 27, 2022 | Jul 10, 2023 | Prot_SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | Dec 13, 2021 | May 16, 2022 | ICF_000.pdf |
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All participants will have 3 MRI sessions subsequent to the baseline visit and these will occur in a counterbalanced order.
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All subjects will receive all interventions in a cross-over design. The three intervention sessions (visits 3, 4 & 5) will be given in counter-balanced order, stratified by gender. Subjects will be blind to the nature of the questions being asked; however, they will be told that different stimulation paradigms will be used, which will be evident to the subjects as they go through the procedures.
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| n-back working memory task | Behavioral | 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) |
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| Accuracy to 2-back | Correct responses to letter stimuli, as a percentage of all responses | 60 minutes after TMS during fMRI |
| 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 |
| No Motor Threshold obtainable |
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| Physician Decision |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Count of Participants | Participants |
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| ID | Title | Description |
|---|
| OG000 | TMS to dlPFC, Without a Concurrent Task (Passive) | TMS (intermittent theta burst stimulation) will be applied to the dlPFC, when subjects are in a resting state TMS: Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex 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) |
| OG001 | TMS to Vertex, Without Concurrent Task (Control) | TMS (intermittent theta burst stimulation) will be applied to the cerebral vertex, when subjects are in a resting state TMS: Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex 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) |
| OG002 | TMS to dlPFC, During Task (Active) | TMS (intermittent theta burst stimulation) will be applied to the dlPFC, when subjects are engaged in the n-back working memory task TMS: Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex 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) |
|
|
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| Primary | 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. | 3 subjects failed image quality control processing | Posted | Number | cluster count for connectivity | 60 minutes after TMS during fMRI |
|
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|
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| Primary | 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 | pre-processing failures in 5 participants | Posted | Mean | Standard Deviation | ml/100 mg tissue/min | 15 minutes after TMS during fMRI |
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| Primary | Accuracy to 2-back | Correct responses to letter stimuli, as a percentage of all responses | Due to technical failures, data was lost for one participant during control and for 24 during "Active". | Posted | Mean | Standard Deviation | percentage correct | 60 minutes after TMS during fMRI |
|
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| Secondary | 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. | 3 participants were not analyzed due to poor data quality | Posted | Number | voxel count | 60 minutes after TMS during fMRI |
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| Secondary | Measure Cerebral Blood Flow (rCBF) in FPN | Regional cerebral blood flow measured in the FPN in milliliters per 100 mg tissue per minute | 5 subjects with poor data quality had to be excluded | Posted | Mean | Standard Deviation | mL/100 mg tissue/min | 15 minutes after TMS during fMRI |
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| Secondary | 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) | Due to technical failures, data was lost for one participant during control and for 24 participants during "Active". | Posted | Mean | Standard Deviation | milliseconds | 60 minutes after TMS during fMRI |
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| Secondary | 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 | Due to technical failures, data was lost for one participant during control and for 24 participants during "Active". | Posted | Mean | Standard Deviation | d-prime | 60 minutes after TMS during fMRI |
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|
| 0 |
| 47 |
| 0 |
| 47 |
| 4 |
| 47 |
| EG001 | TMS to dlPFC, Without a Concurrent Task (Passive) | TMS (intermittent theta burst stimulation) will be applied to the dlPFC, when subjects are in a resting state TMS: Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex 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) | 0 | 41 | 0 | 41 | 2 | 41 |
| EG002 | TMS to Vertex, Without Concurrent Task (Control) | TMS (intermittent theta burst stimulation) will be applied to the cerebral vertex, when subjects are in a resting state TMS: Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex 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) | 0 | 43 | 0 | 43 | 0 | 43 |
| EG003 | TMS to dlPFC, During Task (Active) | TMS (intermittent theta burst stimulation) will be applied to the dlPFC, when subjects are engaged in the n-back working memory task TMS: Intermittent theta burst stimulation TMS applied to the cortex to excite cerebral cortex 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) | 0 | 40 | 0 | 40 | 1 | 40 |
| Headache | Nervous system disorders | Non-systematic Assessment |
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| Lightheadedness | Nervous system disorders | Non-systematic Assessment |
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| Discomfort During fMRI | General disorders | Non-systematic Assessment |
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Number indicates the number of clusters above the threshold of significance for the contrast between two arms (passive vs active) |
| Other |
Group-level analyses were performed using a General Linear Model (GLM). For each individual voxel, a separate GLM was estimated, with first-level connectivity measures at this voxel as dependent variables, and groups or other subject-level identifiers as independent variables. Voxel-level hypotheses were evaluated using multivariate parametric statistics with random effects across subjects and sample covariance estimation across multiple measurements. |
| Results were thresholded using a combination of a cluster-forming p < 0.001 voxel-level threshold, and a corrected false discovery rate (FDR) p < 0.05 cluster-size threshold. | random field theory | 1 | random field theory | 0 | 2-Sided | Number indicates the number of clusters above the threshold of significance for the contrast between two arms (passive vs control) | Other | The applied test with random field theory uses a metric of spatial dispersion, testing against the null hypothesis that spatial clusters of difference across the analyzed region are no different from chance clustering. |
| Superiority |
| Other |
| Statistical thresholding using a random field model adjusted for multiple comparisons, with initial voxel magnitude/height threshold set at p < 0.001 and peak and cluster-corrected significance levels obtained (false discovery rate [FDR]corrected), across the entire brain.. | random field theory | 0.93 | P-value above represents the lowest (most significant) value of the largest cluster, for the contrast of Passive > Control, testing whether the size of this cluster is greater than one would expect by chance alone. | cluster size | 16 | 2-Sided | The estimated parameter is the size, in voxels, of the largest cluster. The applied test with random field theory tests whether the size of cluster difference across are no different from chance clustering. | Superiority |
| F-ratio |
| 0.17 |
| 2-Sided |
| Superiority |
| Superiority |