Trial Outcomes & Findings for Theta Burst Transcranial Magnetic Stimulation of Fronto-parietal Networks: Modulation by Mental State (NCT NCT04010461)

NCT ID: NCT04010461

Last Updated: 2023-10-06

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 53 participants
• Primary outcome timeframe: 60 minutes after TMS during fMRI
• Results posted on: 2023-10-06

Participant Flow

Of 59 participants who were screened, 6 were ineligible and 53 were enrolled. With each treatment, regardless of the sequence, an MRI was performed.

Participant milestones

Measure	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.
Overall Study STARTED	53
Overall Study Participants Who Had Baseline Measurements	47
Overall Study TMS to dlPFC, Without a Concurrent Task (Passive)	41
Overall Study TMS to Vertex, Without Concurrent Task (Control)	43
Overall Study TMS to dlPFC, During Task (Active)	40
Overall Study Completed MRI Sessions	40
Overall Study COMPLETED	40
Overall Study NOT COMPLETED	13

Reasons for withdrawal

Measure	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.
Overall Study COVID based withdrawal	5
Overall Study Withdrawal by Subject	5
Overall Study Adverse Event	1
Overall Study No Motor Threshold obtainable	1
Overall Study Physician Decision	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	All Groups n=40 Participants 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.
Age, Continuous	25.5 years STANDARD_DEVIATION 7.4 • n=5 Participants
Sex: Female, Male Female	27 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	37 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	8 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	5 Participants n=5 Participants
Race (NIH/OMB) White	24 Participants n=5 Participants
Race (NIH/OMB) More than one race	3 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	40 Participants n=5 Participants

PRIMARY outcome

Timeframe: 60 minutes after TMS during fMRI

Population: Of the 40 participants, image data from 3 failed quality control.

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.

Outcome measures

Measure	TMS to dlPFC, Without a Concurrent Task (Passive) n=37 Participants 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)	TMS to Vertex, Without Concurrent Task (Control) n=37 Participants 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)	TMS to dlPFC, During Task (Active) n=37 Participants 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)
2-back Minus 1-back Blood Oxygen Level-Dependent (BOLD) Activation, Voxelwise in FPN	0.74 arbitrary units Standard Deviation 0.54	0.75 arbitrary units Standard Deviation 0.45	0.58 arbitrary units Standard Deviation 0.39

PRIMARY outcome

Timeframe: 60 minutes after TMS during fMRI

Population: 3 subjects failed image quality control processing

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.

Outcome measures

Measure	TMS to dlPFC, Without a Concurrent Task (Passive) n=37 Participants 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)	TMS to Vertex, Without Concurrent Task (Control) n=37 Participants 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)	TMS to dlPFC, During Task (Active) n=37 Participants 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)
Frontoparietal Network (FPN) Connectivity to Dorsolateral Prefrontal Cortex (dlPFC) Theta Burst Stimulation (TBS) Target	0 cluster count for connectivity	10 cluster count for connectivity	0 cluster count for connectivity

PRIMARY outcome

Timeframe: 15 minutes after TMS during fMRI

Population: pre-processing failures in 5 participants

Regional cerebral blood flow measured at the site of theta burst stimulation (TBS) in milliliters per 100 mg tissue per minute

Outcome measures

Measure	TMS to dlPFC, Without a Concurrent Task (Passive) n=35 Participants 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)	TMS to Vertex, Without Concurrent Task (Control) n=35 Participants 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)	TMS to dlPFC, During Task (Active) n=35 Participants 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)
Cerebral Blood Flow (rCBF) at Stimulation Target	57.2 ml/100 mg tissue/min Standard Deviation 20.7	57.9 ml/100 mg tissue/min Standard Deviation 28.5	58.4 ml/100 mg tissue/min Standard Deviation 20.3

PRIMARY outcome

Timeframe: 60 minutes after TMS during fMRI

Population: Due to technical failures, data was lost for one participant during control and for 24 during "Active".

Correct responses to letter stimuli, as a percentage of all responses

Outcome measures

Measure	TMS to dlPFC, Without a Concurrent Task (Passive) n=40 Participants 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)	TMS to Vertex, Without Concurrent Task (Control) n=39 Participants 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)	TMS to dlPFC, During Task (Active) n=16 Participants 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)
Accuracy to 2-back	96.7 percentage correct Standard Deviation 3.9	96.7 percentage correct Standard Deviation 3.6	96.2 percentage correct Standard Deviation 4.5

SECONDARY outcome

Timeframe: 60 minutes after TMS during fMRI

Population: 3 participants were not analyzed due to poor data quality

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.

Outcome measures

Measure	TMS to dlPFC, Without a Concurrent Task (Passive) n=37 Participants 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)	TMS to Vertex, Without Concurrent Task (Control) n=37 Participants 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)	TMS to dlPFC, During Task (Active) n=37 Participants 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)
2-back Minus 1-back BOLD Activation, Voxelwise in Whole Brain	1139 voxel count	1532 voxel count	907 voxel count

SECONDARY outcome

Timeframe: 15 minutes after TMS during fMRI

Population: 5 subjects with poor data quality had to be excluded

Regional cerebral blood flow measured in the FPN in milliliters per 100 mg tissue per minute

Outcome measures

Measure	TMS to dlPFC, Without a Concurrent Task (Passive) n=35 Participants 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)	TMS to Vertex, Without Concurrent Task (Control) n=35 Participants 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)	TMS to dlPFC, During Task (Active) n=35 Participants 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)
Measure Cerebral Blood Flow (rCBF) in FPN	52.7 mL/100 mg tissue/min Standard Deviation 11.8	52.9 mL/100 mg tissue/min Standard Deviation 15.6	51.9 mL/100 mg tissue/min Standard Deviation 13.1

SECONDARY outcome

Timeframe: 60 minutes after TMS during fMRI

Population: Due to technical failures, data was lost for one participant during control and for 24 participants during "Active".

Median reaction time for subjects responding in the n-back task, for correct responses (1-back and 2-back)

Outcome measures

Measure	TMS to dlPFC, Without a Concurrent Task (Passive) n=40 Participants 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)	TMS to Vertex, Without Concurrent Task (Control) n=39 Participants 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)	TMS to dlPFC, During Task (Active) n=16 Participants 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)
Median Reaction Time (RT) in 2-back	573.2 milliseconds Standard Deviation 175.8	556.4 milliseconds Standard Deviation 164.2	572.1 milliseconds Standard Deviation 135.4

SECONDARY outcome

Timeframe: 60 minutes after TMS during fMRI

Population: Due to technical failures, data was lost for one participant during control and for 24 participants during "Active".

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

Outcome measures

Measure	TMS to dlPFC, Without a Concurrent Task (Passive) n=40 Participants 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)	TMS to Vertex, Without Concurrent Task (Control) n=39 Participants 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)	TMS to dlPFC, During Task (Active) n=16 Participants 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)
D-prime in 2-back	3.8 d-prime Standard Deviation 0.7	3.8 d-prime Standard Deviation 0.6	3.7 d-prime Standard Deviation 0.8

Adverse Events

Baseline Measurement

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

TMS to dlPFC, Without a Concurrent Task (Passive)

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

TMS to Vertex, Without Concurrent Task (Control)

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

TMS to dlPFC, During Task (Active)

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Baseline Measurement n=47 participants at risk Initial assessments, baseline MRI scan, TMS motor threshold	TMS to dlPFC, Without a Concurrent Task (Passive) n=41 participants at risk 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)	TMS to Vertex, Without Concurrent Task (Control) n=43 participants at risk 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)	TMS to dlPFC, During Task (Active) n=40 participants at risk 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)
Musculoskeletal and connective tissue disorders Finger/Hand Soreness	4.3% 2/47 • Number of events 2 • duration of participation in study -- 3- 6 weeks	0.00% 0/41 • duration of participation in study -- 3- 6 weeks	0.00% 0/43 • duration of participation in study -- 3- 6 weeks	0.00% 0/40 • duration of participation in study -- 3- 6 weeks
Nervous system disorders Headache	2.1% 1/47 • Number of events 1 • duration of participation in study -- 3- 6 weeks	2.4% 1/41 • Number of events 1 • duration of participation in study -- 3- 6 weeks	0.00% 0/43 • duration of participation in study -- 3- 6 weeks	0.00% 0/40 • duration of participation in study -- 3- 6 weeks
Nervous system disorders Lightheadedness	0.00% 0/47 • duration of participation in study -- 3- 6 weeks	2.4% 1/41 • Number of events 1 • duration of participation in study -- 3- 6 weeks	0.00% 0/43 • duration of participation in study -- 3- 6 weeks	0.00% 0/40 • duration of participation in study -- 3- 6 weeks
General disorders Discomfort During fMRI	2.1% 1/47 • Number of events 1 • duration of participation in study -- 3- 6 weeks	0.00% 0/41 • duration of participation in study -- 3- 6 weeks	0.00% 0/43 • duration of participation in study -- 3- 6 weeks	2.5% 1/40 • Number of events 1 • duration of participation in study -- 3- 6 weeks

Additional Information

Stephan Taylor

University of Michigan

Phone: (734) 936-4955

Email: sftaylor@med.umich.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place