Repetitive transcranial magnetic stimulation (rTMS) is a powerful tool to non-invasively modulate brain circuits, brain plasticity, and behavior. This proposal will test the hypothesis that controlling behavioral state during focal multi-day rTMS of a brain region involved in grasping movements will enhance the functional specificity of the neuromodulation action among distributed brain regions involved in voluntary motor control and concomitantly improve manual dexterity. Results from this study will be used to optimize rTMS therapy for individuals with neuromotor impairments by controlling behavioral state to improve the efficacy of rTMS treatment. Healthy volunteers that qualify for this study will have motor skill assessments and basic neuromotor testing (using neurophysiology with TMS and functional Magnetic Resonance Imaging (fMRI) scans). Participants will be asked to come in for up to nine sessions that include 1 screening session, 5 consecutive daily rTMS sessions and 3 assessment sessions with resting-state and task-based fMRI, neurophysiology with TMS, and hand motor tasks over the course of 3-4 weeks.
This study will examine a particular type of rTMS, known as theta burst stimulation (TBS), which has been shown to induce longer lasting effects than other forms of rTMS, making TBS an important tool for therapeutic applications. While TBS provides relatively focal stimulation, effects on the brain occur through interconnected networks in ways that are poorly understood. Moreover, stimulation is highly state-dependent, and the use of rTMS in most therapeutic settings, such as the treatment of motor impairments, leaves behavioral state uncontrolled. Augmenting rTMS therapy by inducing specific behavioral states is an attractive idea for improving therapeutic rTMS, but the relevant knowledge base is sparse. To address this critical gap, this exploratory R21 proposal will examine the effects of TBS and behavioral state on brain and motor behavior. The investigators will test the broad hypothesis that when TBS is applied during a controlled behavior state, motor function will be facilitated, compared to stimulation when behavioral state is uncontrolled. The investigators will focus on the posterior parietal cortex (PPC), and associated parietofrontal circuits, which subserve skilled grasp control, an ability known to be impaired in stroke, traumatic brain injury, and other motor disorders. The investigators will collect functional magnetic resonance imaging (fMRI), neurophysiological measures with TMS, and behavioral measures in all subjects for three different interventions. In Aim 1, the investigators will show improvement in action performance by manipulating the behavioral state during PPC stimulation. In Aim 2, the investigators will demonstrate modulation of neurophysiological aftereffects of PPC stimulation on motor output by manipulating behavioral state. In Aim 3, the investigators will assess the relationship between brain connectivity, plasticity and behavior in response to the behavioral state during brain stimulation. Impact: Results will provide insights into the effects of rTMS and behavioral state on the brain and behavior. This knowledge will lay a mechanistic foundation for future studies to show how controlling behavioral state during rTMS can improve therapeutic efficacy in neurological disorders.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
SINGLE
Enrollment
59
A MagPro X100 magnetic stimulator with a 90mm figure-8 coil (MC-B70, MagVenture Inc.) will be utilized to deliver brain stimulation. All participants will receive five consecutive days of stimulation. The 3-minute session of intermittent Theta Burst Stimulation (iTBS) will consist of 10 bursts of high-frequency stimulation (a 2 s train of 3 biphasic waveform pulses at 50 Hz repeated every 200 ms at 80% AMT) repeated every 10 s for a total of 190 s (600 pulses) to the target area. The target area will be located using BrainSight2 neuronavigation system. The baseline structural scan obtained during the scan 1 will be utilized for this localization process.
Subjects will perform a precision grip with the right hand towards either a small or large target object positioned in front of them. The illumination of an LED (green or red) will instruct the subject to plan a precision grip towards either a small or large target object positioned in front of them. After \~1 second, the LED will extinguish and cue subjects to execute the intended object-directed hand action. The presentation of the visual stimuli will be synchronized with the iTBS stimulation, which will occur 800ms before the onset of every "GO" cue in order to modulate cortical activity during both the planning and execution phase of the action.
University of Michigan
Ann Arbor, Michigan, United States
Percentage Change in the Time to Complete the Nine-hole Peg Test (9-HPT) to Immediate Post-intervention
9-hole peg test (9-HPT) is a manual dexterity measure in which a participant must place 9 pegs in board with 9 holes, and remove all 9 pegs upon the insertion of all 9 pegs. This is completed with one peg at a time, and only one hand is used. For our study, only the right hand was used. The performance is estimated as the time required to complete the task (seconds). A lower time in seconds is indicative of a better score. For percent change in performance, a higher positive percent is indicative improved performance.
Time frame: Baseline and immediately post-intervention (session 6, up to Day 15), up to 30 minutes
Percentage Change in Amplitude of Motor Evoked Potential (MEP) to Immediate Post-intervention.
Motor cortical excitability is measured by electromyography using MEPs (motor evoked potentials) elicited by TMS (Transcranial magnetic stimulation) to a motor hotspot determined before collection of baseline (baseline occurs before intervention) MEP (motor evoked potential) collection. It was assessed in session 1, 3, 4, 5, 6, and 7, although only session 6 is reported here. An increase in MEPs (motor evoked potentials) is indicative of increased cortical excitability. A positive increase in MEP (motor evoked potential) percent change is indicative of increased cortical excitability.
Time frame: Baseline and immediately post-intervention (session 6, up to Day 15), up to 60 minutes
Change From Baseline Functional Connectivity to PPC Stimulation Target Within the Cortical Grasping Network to Immediate Post-intervention.
Resting-state connectivity of low frequency BOLD (blood oxygenation level dependent) fluctuations for a seed at the PPC (posterior parietal cortex). The original analysis was a time-series correlation (Pearson's R) of resting state fMRI data between two regions of interest. The Z-score a Fisher's r-to-z transform. 0 for the Z value means that the pearson's correlation was also 0, positive means positive correlation and negative means it was a negative correlation. Therefore, standard deviations above the mean represented greater connectivity between the regions of interest. There were no clinically relevant thresholds to consider. The two time points being compared were scans from session 2 and session 7.
Time frame: Baseline (scan acquired during session 2) and immediate post-intervention (scan acquired after intervention during session 7, up to day 20), up to 60 minutes
Change From Baseline Blood Oxygen Level-Dependent (BOLD) Activation, Voxelwise in the Cortical Grasp Network to Immediate Post-intervention.
Parietal-frontal cortical grasping network defined by BOLD change during precision force-tracking task. t-test statistics were acquired for BOLD activation (estimated with univariate GLMs within each individual) from scans pre and post (session 2 and 7) with free surfer software. We ran univariate GLMs for each session for each individual that gave regression coefficients (beta values) for each voxel. We calculated a t-stat for each of those beta-values (each person and session we have a t-stat for our contrast of interest at each voxel). We averaged these across region of interest for each person/session. We ran another paired t-test at the group level to test pre vs post differences. SD shows t-stat variability across people in respective groups. A t-stat of 0 shows no BOLD change, a large positive t-stat shows increase BOLD change (increased connectivity, better outcome), and a large negative t-stat shows decrease BOLD change (decreased connectivity, worse outcome) pre vs post.
Time frame: Baseline (scan acquired during session 2) and immediate post-intervention (scan acquired after intervention during session 7, up to day 20), up to 60 minutes
Percentage Change in the Time to Complete the Nine-hole Peg Test (9-HPT) to 1-week Post-intervention
9-hole peg test (9-HPT) is a manual dexterity measure in which a participant must place 9 pegs in board with 9 holes, and remove all 9 pegs upon the insertion of all 9 pegs. This is completed with one peg at a time, and only one hand is used. For our study, only the right hand was used. The performance is estimated as the time required to complete the task (seconds). A lower time in seconds is indicative of a better score. For percent change in performance, a higher positive percent is indicative improved performance.
Time frame: Baseline and 1-week post intervention (session 8 or 9, approximately 1 week after session 7, up to day 30), up to 30 minutes
Percentage Change in Amplitude of Motor Evoked Potential (MEP) to 1-week Post-intervention.
Motor cortical excitability is measured by electromyography using MEPs (motor evoked potentials) elicited by TMS (Transcranial magnetic stimulation) to a motor hotspot determined before collection of baseline (baseline occurs before intervention) MEP (motor evoked potential) collection. An increase in MEPs (motor evoked potentials) is indicative of increased cortical excitability. A positive increase in MEP (motor evoked potential) percent change is indicative of increased cortical excitability.
Time frame: Baseline and 1-week post-intervention (during session 8 or 9, approximately 1 week after session 7, up to day 30), up to 60 minutes
Change From Baseline Functional Connectivity to PPC Stimulation Target Within the Cortical Grasping Network to 1-week Post-intervention.
Resting-state connectivity of low frequency BOLD (blood oxygenation level dependent) fluctuations for a seed at the PPC (posterior parietal cortex). The original analysis was a time-series correlation (Pearson's R) of resting state fMRI data between two regions of interest. The Z-score a Fisher's r-to-z transform. 0 for the Z value means that the pearson's correlation was also 0, positive means positive correlation and negative means it was a negative correlation. Therefore, standard deviations above the mean represented greater connectivity between the regions of interest. There were no clinically relevant thresholds to consider.
Time frame: Baseline (scan acquired during session 2) and 1-week post-intervention (scan during session 8 or 9, approximately 1 week after session 7, up to day 30), up to 60 minutes
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Change From Baseline Blood Oxygen Level-Dependent (BOLD) Activation, Voxelwise in the Cortical Grasp Network to 1-week Post-intervention.
Parietal-frontal cortical grasping network defined by BOLD change during precision force-tracking task. t-test statistics were acquired for BOLD activation (estimated with univariate GLMs within each individual) from scans pre and post (session 2 and 8/9) with free surfer software. We ran univariate GLMs for each session for each individual that gave regression coefficients (beta values) for each voxel. We calculated a t-stat for each of those beta-values (each person and session we have a t-stat for our contrast of interest at each voxel). We averaged these across region of interest for each person/session. We ran another paired t-test at the group level to test pre vs post differences. SD shows t-stat variability across people in respective groups. A t-stat of 0 shows no BOLD change, a large positive t-stat shows increase BOLD change (increased connectivity, better outcome), and a large negative t-stat shows decrease BOLD change (decreased connectivity, worse outcome) pre vs post.
Time frame: Baseline (scan acquired during session 2) and 1-week post-intervention (scan during session 8 or 9, approximately 1 week after session 7, up to day 30), up to 60 minutes
Change From Baseline Blood Oxygen Level-Dependent (BOLD) Activation, Voxelwise in Whole Brain to Immediate Post-intervention.
Parietal-frontal cortical grasping network defined by BOLD change during precision force-tracking task. t-test statistics were acquired for BOLD activation (estimated with univariate GLMs within each individual) from scans pre and post (session 2 and 7) with free surfer software. We ran univariate GLMs for each session for each individual that gave regression coefficients (beta values) for each voxel. We calculated a t-stat for each of those beta-values (each person and session we have a t-stat for our contrast of interest at each voxel). We averaged these across region of interest for each person/session. We ran another paired t-test at the group level to test pre vs post differences. SD shows t-stat variability across people in respective groups. A t-stat of 0 shows no BOLD change, a large positive t-stat shows increase BOLD change (increased connectivity, better outcome), and a large negative t-stat shows decrease BOLD change (decreased connectivity, worse outcome) pre vs post.
Time frame: Baseline (scan acquired during session 2) and immediate post-intervention (scan acquired after intervention during session 7, up to day 20), up to 60 minutes
Change From Baseline Blood Oxygen Level-Dependent (BOLD) Activation, Voxelwise in Whole Brain to 1-week Post-intervention.
Parietal-frontal cortical grasping network defined by BOLD change during precision force-tracking task. t-test statistics were acquired for BOLD activation (estimated with univariate GLMs within each individual) from scans pre and post (session 2 and 8/9) with free surfer software. We ran univariate GLMs for each session for each individual that gave regression coefficients (beta values) for each voxel. We calculated a t-stat for each of those beta-values (each person and session we have a t-stat for our contrast of interest at each voxel). We averaged these across region of interest for each person/session. We ran another paired t-test at the group level to test pre vs post differences. SD shows t-stat variability across people in respective groups. A t-stat of 0 shows no BOLD change, a large positive t-stat shows increase BOLD change (increased connectivity, better outcome), and a large negative t-stat shows decrease BOLD change (decreased connectivity, worse outcome) pre vs post.
Time frame: Baseline (scan acquired during session 2) and 1-week post-intervention (scan during session 8 or 9, approximately 1 week after session 7, up to day 30), up to 60 minutes
Percentage Change in Accuracy to Precision Force-tracking Task to Immediate Post-intervention
The force tracking task measures one's ability to regulate their grip force. For this task, the participant must adjust their grip of an object to move the cursor in order to correspond with a constantly moving target. The outcome of this measure is the squared distance (error) from the cursor to the target in the precision force-tracking task, estimated as the root mean squared error (RMSE). A lower root mean squared error (RMSE) is indicative of better performance and better ability of a participant to regulate their grip force. A higher percent change in root mean squared error (RMSE) accuracy is indicative of better performance and better ability of a participant to regulate their grip force. It was assessed in session 2, 7, and 8/9, although only session 2 and 7 are reported here.
Time frame: Baseline(during fMRI during session 2) and immediate post-intervention (during fMRI following stimulation during session 7, up to day 20), up to 60 minutes
Percentage Change in Accuracy to Precision Force-tracking Task to 1-week Post-intervention
The force tracking task measures one's ability to regulate their grip force. For this task, the participant must adjust their grip of an object to move the cursor in order to correspond with a constantly moving target. The outcome of this measure is the squared distance (error) from the cursor to the target in the precision force-tracking task, estimated as the root mean squared error (RMSE). A lower root mean squared error (RMSE) is indicative of better performance and better ability of a participant to regulate their grip force. A higher percent change in root mean squared error (RMSE) accuracy is indicative of better performance and better ability of a participant to regulate their grip force. It was assessed in session 2, 7, and 8/9, although only session 2 and 8/9 are reported here.
Time frame: Baseline(during fMRI during session 2) and 1-week post-intervention (during fMRI during session 8 or 9, about a week following last intervention, up to day 30), up to 60 minutes
Percentage Change in the Mean Choice Reaction Time to Immediate Post-intervention
The cRT (2-choice reaction time control task) is a measurement of visuomotor abilities that are non specific to the reach-to-grasp movement. The outcome for this measure is the mean reaction time for subjects responding in the cRT (2-choice reaction time control task), for correct responses. A lower mean reaction time in seconds is indicative of better visuomotor performance (non specific to the reach-to-grasp movement). A positive percent change in cRT (2-choice reaction time control task) is indicative of better visuomotor performance (non specific to the reach-to-grasp movement).
Time frame: Baseline and immediately post-intervention (session 6, up to Day 15), up to 30 minutes
Percentage Change in the Mean Choice Reaction Time to 1-week Post-intervention
The cRT (2-choice reaction time control task) is a measurement of visuomotor abilities that are non specific to the reach-to-grasp movement. The outcome for this measure is the mean reaction time for subjects responding in the cRT (2-choice reaction time control task), for correct responses. A lower mean reaction time in seconds is indicative of better visuomotor performance (non specific to the reach-to-grasp movement). A positive percent change in cRT (2-choice reaction time control task) is indicative of better visuomotor performance (non specific to the reach-to-grasp movement).
Time frame: Baseline and 1-week post intervention (session 8 or 9, approximately 1 week after session 7, up to day 30), up to 30 minutes
Percentage Change in the Normalized Motor Evoked Potential (MEP) Size to Immediate Post-intervention.
Parietal-motor functional connectivity is measured by electromyography using MEPs (motor evoked potentials) elicited by dual-site TMS (Transcranial magnetic stimulation) to the motor hotspot and a parietal region determined at baseline (baseline occurs before intervention), while subjects perform an object-directed grasp/subjects are at rest. An increase in MEPs (motor evoked potentials) is indicative of increased cortical excitability. A positive increase in MEP (motor evoked potential) percent change, or normalized MEP (motor evoked potential), is indicative of increased cortical excitability. It was assessed in session 1, 3, 4, 5, 6, and 7, although only session 6 is reported here.
Time frame: Baseline and immediately post-intervention (session 6, up to Day 15), up to 60 minutes
Percentage Change in the Normalized Motor Evoked Potential (MEP) Size to 1-week Post-intervention.
Parietal-motor functional connectivity is measured by electromyography using MEPs (motor evoked potentials) elicited by dual-site TMS (Transcranial magnetic stimulation) to the motor hotspot and a parietal region determined at baseline (baseline occurs before intervention), while subjects perform an object-directed grasp/subjects are at rest. An increase in MEPs (motor evoked potentials) is indicative of increased cortical excitability. A positive increase in MEP (motor evoked potential) percent change, or normalized MEP (motor evoked potential), is indicative of increased cortical excitability.
Time frame: Baseline and 1-week post-intervention (during session 8 or 9, approximately 1 week after session 7, up to day 30), up to 60 minutes