Brain State-dependent Stimulation to Improve Movement

Not Applicable

Completed

Conditions: Healthy

Interventions: Device: TMS
Behavioral: Object directed grasping

Registration Number: NCT05103176

Lead Sponsor: University of Michigan

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 59

Inclusion Criteria

Women of child bearing age cannot be pregnant or trying to become pregnant
Ability to tolerate small, enclosed spaces without anxiety
Ability and willingness to give informed consent to participate
No history of neurological disorder
Right handed
English speaking

Exclusion Criteria

Are left-handed
Are younger than 18 or older than 50 years old
Women who are pregnant, suspect they are pregnant, or are attempting to become pregnant
Have metal anywhere in the head, excluding the mouth
Have a pacemaker, deep brain stimulator, vagus nerve stimulator or any other medically implanted device
Have cochlear hearing implants
Are taking GABAergic, NDMA-receptor antagonist, or other drug known to influence neural receptors
Have any of the below conditions that would put participants at increased risk of having a seizure: a personal or family history of seizure/epilepsy, taking prescription drugs that lower the threshold for seizures, recent history of excessive alcohol consumption, history of alcohol addiction/dependence, recent history of recreational drug use, history of drug addiction/dependence
Have been diagnosed with any of the following: a stroke, brain hemorrhage, brain tumor, encephalitis, multiple sclerosis, Parkinson's disease or Alzheimer's disease, depression in the past 6 months, attention deficit disorder, schizophrenia, manic depressive (bipolar) disorder, normal pressure hydrocephalus or increased intra-cranial pressure, diabetes requiring insulin treatment, any serious heart disorder or liver disease
Have had a migraine in the past month
MRI specific exclusion criteria: Any relevant history of open-heart surgery, artificial heart valve, brain aneurysm surgery, braces or extensive dental work, cataract surgery or lens implant, or artificial limb or joint. History of foreign metallic object in the body such as bullets, BB's, pellets, shrapnel, or metalwork fragments. Claustrophobia, have uncontrollable shaking, or cannot lie still for one hour.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
To PPC, with concurrent task	TMS	This arm will receive intermittent theta bust stimulation to the PPC site while subjects perform a grasp task
To PPC, without a concurrent task	TMS	This arm will receive intermittent theta bust stimulation to the PPC site without a concurrent task
To PPC, with concurrent task	Object directed grasping	This arm will receive intermittent theta bust stimulation to the PPC site while subjects perform a grasp task
To vertex, with concurrent task	Object directed grasping	This arm will receive intermittent theta bust stimulation to the vertex site (control condition) while subjects perform a grasp task
To vertex, with concurrent task	TMS	This arm will receive intermittent theta bust stimulation to the vertex site (control condition) while subjects perform a grasp task

Primary Outcome Measures

Name	Time	Method
Percentage Change in the Time to Complete the Nine-hole Peg Test (9-HPT) to Immediate Post-intervention	Baseline and immediately post-intervention (session 6, up to Day 15), up to 30 minutes	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.
Percentage Change in Amplitude of Motor Evoked Potential (MEP) to Immediate Post-intervention.	Baseline and immediately post-intervention (session 6, up to Day 15), up to 60 minutes	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.
Change From Baseline Functional Connectivity to PPC Stimulation Target Within the Cortical Grasping Network to Immediate Post-intervention.	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	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.
Change From Baseline Blood Oxygen Level-Dependent (BOLD) Activation, Voxelwise in the Cortical Grasp Network to Immediate Post-intervention.	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	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.

Secondary Outcome Measures

Name	Time	Method
Percentage Change in the Time to Complete the Nine-hole Peg Test (9-HPT) to 1-week Post-intervention	Baseline and 1-week post intervention (session 8 or 9, approximately 1 week after session 7, up to day 30), up to 30 minutes	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.
Change From Baseline Functional Connectivity to PPC Stimulation Target Within the Cortical Grasping Network to 1-week Post-intervention.	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	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.
Percentage Change in Amplitude of Motor Evoked Potential (MEP) to 1-week Post-intervention.	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	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.
Change From Baseline Blood Oxygen Level-Dependent (BOLD) Activation, Voxelwise in the Cortical Grasp Network to 1-week Post-intervention.	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	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.
Change From Baseline Blood Oxygen Level-Dependent (BOLD) Activation, Voxelwise in Whole Brain to Immediate Post-intervention.	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	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.
Change From Baseline Blood Oxygen Level-Dependent (BOLD) Activation, Voxelwise in Whole Brain to 1-week Post-intervention.	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	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.
Percentage Change in Accuracy to Precision Force-tracking Task to Immediate Post-intervention	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	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.
Percentage Change in Accuracy to Precision Force-tracking Task to 1-week Post-intervention	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	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.
Percentage Change in the Mean Choice Reaction Time to Immediate Post-intervention	Baseline and immediately post-intervention (session 6, up to Day 15), up to 30 minutes	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).
Percentage Change in the Mean Choice Reaction Time to 1-week Post-intervention	Baseline and 1-week post intervention (session 8 or 9, approximately 1 week after session 7, up to day 30), up to 30 minutes	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).
Percentage Change in the Normalized Motor Evoked Potential (MEP) Size to Immediate Post-intervention.	Baseline and immediately post-intervention (session 6, up to Day 15), up to 60 minutes	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.
Percentage Change in the Normalized Motor Evoked Potential (MEP) Size to 1-week Post-intervention.	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	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.