Modulating Interaction of Motor Learning Networks in Rehabilitation of Stroke

This study uses a form on non-invasive brain stimulation called transcranial magnetic stimulation to understand 1) understand how the brain learns post-stroke and 2) assess non-invasive brain stimulation as an addition to current stroke rehabilitation approaches. In two study arms the investigators will compare the effect of active transcranial magnetic stimulation paired with motor practice with placebo (or sham) transcranial magnetic stimulation paired with the same motor practice.

Study Overview

• Status: Completed
• Conditions: Stroke; Stroke, Chronic; Stroke, Middle Cerebral Artery With Infarction
• Intervention / Treatment: Device: Active continuous theta burst stimulation (cTBS); Behavioral: Motor Practice; Device: Placebo (Sham) continuous theta burst stimulation

Detailed Description

Stroke is the leading cause of permanent disability in the United States. In the absence of treatments to restore the lost tissue, clinical scientists have focused upon repetitive forced used of the paretic limb to promote neural reorganization in preserved tissue and reduce disability. However, forced use interventions are time intensive and the extent of functional recovery is variable. One potential contributor to this variability is the potential trade-off between compensatory cognitive motor control strategies and the extent of procedural learning that can occur. Compensatory strategies adopted by patients may produce quick short-term increases in performance but retard slower sustained improvements by interfering with development of procedural learning. Consistent with this hypothesis, the investigators' previous work documents an increased reliance upon dorsolateral prefrontal cortex during performance of learned skills post-stoke. However, the investigators' previous work also demonstrates that the effect of increased activity in dorsolateral prefrontal cortex may limit reorganization in important areas involved in the consolidation of practice thereby limiting functional recovery post-stroke.

Transcranial magnetic stimulation offers a unique opportunity to investigate the relationship between dorsolateral prefrontal cortex activity and consolidation of motor practice/rehabilitaion post-stroke. Here the investigators' objective is to determine whether suppression of the contralesional dorsolateral prefrontal cortex, with continuous theta burst transcranial magnetic brain stimulation (cTBS), a form of transcranial magnetic stimulation, prior to motor practice enhances brain reorganization in critical areas and leads to greater sustained improvements in motor ability over time.

The proposed work will enhance the understanding of motor learning post-stroke and provide preliminary evidence for the benefits of dorsolateral prefrontal cTBS as an adjunct to current rehabilitation interventions.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48103
      • Human Sensorimotor Laboratory, School of Kinesiology, University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age between 50-75 years
2. movement-related deficit associated with first time middle cerebral artery stroke
3. greater than 6-months post-stroke
4. Fugl-Meyer score between 15 and 60
5. ability to elicit a motor evoked potential from the ipsilesional cortex

Exclusion Criteria:

1. a score <27 on the Mini-Mental Status Exam
2. a score of <123 on the Mattis Dementia Rating Scale
3. a score of <13 on the Frenchay Aphasia Screen
4. a history of seizure/epilepsy, head trauma, major psychiatric diagnosis, neurodegenerative disorder or substance abuse
5. a history of congestive heart failure
6. systolic blood pressure above 120 mmHg and/or diastolic pressure above 80 mmHg
7. the taking of any GABAergic, NMDA-receptor antagonist or other drug known to influence the neural receptors that facilitate neural plasticity
8. an infarct resulting from ischemic stroke of anterior or posterior cerebral artery OR an infarct that encroaches within 2cm of the site of cTBS stimulation
9. absence of an MEP in response to single pulse transcranial magnetic stimulation over ipsilesional M1 and 10) any other contraindication to TMS or MRI.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Experimental; Application of active continuous theta burst stimulation over dorsolateral prefrontal cortex prior to upper limb motor practice.	Device: Active continuous theta burst stimulation (cTBS); Active cTBS over dorsolateral prefrontal cortex that has an effect upon dorsolateral prefrontal cortex brain activity.; Behavioral: Motor Practice; Upper limb reaching task to be practiced. Practice will be paired with Active/Sham stimulation. Twenty trials will occur before Active/Sham stimulation. 40 trials will be practiced after Active/Sham stimulation.
PLACEBO_COMPARATOR: Control; Application of sham continuous theta burst stimulation over dorsolateral prefrontal cortex prior to upper limb motor practice.	Behavioral: Motor Practice; Upper limb reaching task to be practiced. Practice will be paired with Active/Sham stimulation. Twenty trials will occur before Active/Sham stimulation. 40 trials will be practiced after Active/Sham stimulation.; Device: Placebo (Sham) continuous theta burst stimulation; Sham stimulation over dorsolateral prefrontal cortex that looks and sounds like active cTBS but does not have any effect upon dorsolateral prefrontal cortex brain activity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Sequential Response Time to Post-Intervention	Aggregate time to complete movements between a six sequential targets presented on a computer touch screen in front of the participant. The mean of ten sequences was calculated prior to any practice and at a delayed retention test (e.g. no warm up or preceding practice) post-intervention. Change between the baseline average and post-intervention average was also calculated by subtracting post-intervention score from pre-intervention score. Positive numbers represent improvement in ability.	Baseline and post-intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Time to Complete the Jebsen-Taylor Hand Function Test	The Jebsen-Taylor Hand Function Test is comprised of a series of unimanual tasks required for activities of daily living. Time to complete the Jebsen-Taylor Hand Function Test was assessed at baseline and post-intervention by taking the aggregate time to complete each activity. Change in time to complete the Jebsen-Taylor Hand Function Test between the baseline and post-intervention tests was derived by subtracting post-intervention score from baseline score. Positive scores indicate improvement in functional motor ability.	Baseline and post-intervention
Change in Sequential Response Time Immediately Follow an Individual Bout of Non-invasive Brain Stimulation (e.g. Within Session)	Aggregate time to complete movements between a six sequential targets presented on a computer touch screen in front of the participant. The mean of ten sequences was calculated prior to application of Active+Motor Practice or Sham+Motor Practice for each intervention session and the first ten sequences of practice immediately following the specific form of non-invasive brain stimulation within each session. Change within a session was calculated by subtracting the post-stimulation score from the pre-stimulation score within a session. Positive values represent improved ability.	Within session baseline to ~8 minutes post-application of non-invasive stimulation within the same session
Motor Evoked Potential Amplitude (in Microvolts) at Pre-baseline and Post-Intervention	Motor evoked potential amplitude evoked by transcranial magnetic brain stimulation was recorded using electromyography over the first dorsal interosseous muscle of the stroke-affected hand. The means of ten trials at 120% (linear part of recruitment curve) and ten trials at 150% (recruitment curve plateau) of resting motor threshold were calculated and expressed in microvolts.	Baseline and post-intervention
Change From Baseline in Cortical Excitability Post-Intervention	Motor evoked potential amplitude evoked by transcranial magnetic brain stimulation was recorded using electromyography over the first dorsal interosseous muscle of the stroke-affected hand. The means of ten trials at 120% (linear part of recruitment curve) and ten trials at 150% (recruitment curve plateau) of resting motor threshold were calculated and expressed in microvolts. Change in motor evoked potential amplitude elicited by transcranial magnetic stimulation intensities of 120% (linear part of recruitment curve) and ten trials at 150% (recruitment curve plateau) of resting motor threshold. Values are expressed percent change relative to pre-baseline values. Positive numbers represent an increase motor evoked potential from pre-baseline to post-intervention.	Baseline and post-intervention

Collaborators and Investigators

• Sponsor: University of Michigan
• Investigators: Principal Investigator: Sean K Meehan, PhD, Sch. of Kinesiology, Univ. of Michigan

Publications and helpful links

General Publications

• Meehan SK, Randhawa B, Wessel B, Boyd LA. Implicit sequence-specific motor learning after subcortical stroke is associated with increased prefrontal brain activations: an fMRI study. Hum Brain Mapp. 2011 Feb;32(2):290-303. doi: 10.1002/hbm.21019.
• Meehan SK, Dao E, Linsdell MA, Boyd LA. Continuous theta burst stimulation over the contralesional sensory and motor cortex enhances motor learning post-stroke. Neurosci Lett. 2011 Aug 1;500(1):26-30. doi: 10.1016/j.neulet.2011.05.237. Epub 2011 Jun 12.
• Brodie SM, Meehan S, Borich MR, Boyd LA. 5 Hz repetitive transcranial magnetic stimulation over the ipsilesional sensory cortex enhances motor learning after stroke. Front Hum Neurosci. 2014 Mar 21;8:143. doi: 10.3389/fnhum.2014.00143. eCollection 2014.

Helpful Links

• Primary Investigator's Profile Page

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2016
• Primary Completion (ACTUAL): March 30, 2019
• Study Completion (ACTUAL): March 30, 2019

Study Registration Dates

• First Submitted: March 16, 2017
• First Submitted That Met QC Criteria: March 16, 2017
• First Posted (ACTUAL): March 22, 2017

Study Record Updates

• Last Update Posted (ACTUAL): April 27, 2020
• Last Update Submitted That Met QC Criteria: April 15, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Rehabilitation; Transcranial Magnetic Stimulation; Motor Learning; Motor Impairment
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Brain Infarction; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Cerebral Infarction; Infarction; Stroke; Infarction, Middle Cerebral Artery
• Other Study ID Numbers: 1R03NS096484-01 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes