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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental | Experimental | Application of active continuous theta burst stimulation over dorsolateral prefrontal cortex prior to upper limb motor practice. |
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| Control | Placebo Comparator | Application of sham continuous theta burst stimulation over dorsolateral prefrontal cortex prior to upper limb motor practice. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Active continuous theta burst stimulation (cTBS) | Device | Active cTBS over dorsolateral prefrontal cortex that has an effect upon dorsolateral prefrontal cortex brain activity. |
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| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Sean K Meehan, PhD | Sch. of Kinesiology, Univ. of Michigan | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Human Sensorimotor Laboratory, School of Kinesiology, University of Michigan | Ann Arbor | Michigan | 48103 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20725908 | Background | 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. | |
| 21683125 | Background | 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. |
| Label | URL |
|---|---|
| Primary Investigator's Profile Page | View source |
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Enrolled participants were excluded prior to randomization for: known contraindication to the transcranial magnetic stimulation intervention (n=1) and a broken foot, not study related, between enrollment and randomization (n=1).
Recruitment was conducted through mailings to individuals identified as having been admitted to the University of Michigan Health System in the past 5 years (from 01/01/2012 to 01/27/2017) for treatment of middle cerebral artery stroke. Mailings were sent to those individuals with zip codes in the state of Michigan and northwest Ohio.
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| ID | Title | Description |
|---|---|---|
| FG000 | Active+Motor Practice, Then Sham+Motor Practice | Participants first completed four sessions in which motor practice was preceded by ACTIVE continuous theta burst stimulation (cTBS) over dorsolateral prefrontal cortex. After a three-week washout period participants then completed four sessions in which motor practice was preceded by SHAM continuous theta burst stimulation over dorsolateral prefrontal cortex. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| First Intervention |
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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 10, 2018 |
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| Placebo (Sham) continuous theta burst stimulation | Device | 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. |
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| Motor Practice | Behavioral | 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. |
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| 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 |
| 24711790 | Background | 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. |
| FG001 | Sham+Motor Practice, Then Active+Motor Practice | Participants first completed four sessions in which motor practice was preceded by SHAM continuous theta burst stimulation (cTBS) over dorsolateral prefrontal cortex. After a three-week washout period participants then completed four sessions in which motor practice was preceded by ACTIVE continuous theta burst stimulation over dorsolateral prefrontal cortex. |
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| Washout |
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| Second Intervention |
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Baseline analysis was completed on all participants who were randomized.
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| ID | Title | Description |
|---|---|---|
| BG000 | Active+Motor Practice, Then Sham+Motor Practice | Participants first completed four sessions in which motor practice was preceded by ACTIVE continuous theta burst stimulation (cTBS) over dorsolateral prefrontal cortex. After a three-week washout period participants then completed four sessions in which motor practice was preceded by SHAM continuous theta burst stimulation over dorsolateral prefrontal cortex. |
| BG001 | Sham+Motor Practice, Then Active+Motor Practice | Participants first completed four sessions in which motor practice was preceded by SHAM continuous theta burst stimulation (cTBS) over dorsolateral prefrontal cortex. After a three-week washout period participants then completed four sessions in which motor practice was preceded by ACTIVE continuous theta burst stimulation over dorsolateral prefrontal cortex. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | 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 | Number | participants |
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| Fugl-Meyer Assessment of Motor Recovery After Stroke (Upper Limb) | The Fugl-Meyer Assessment of Motor Recovery After Stroke (Upper Limb) scale is a stroke-specific scale designed to assess motor functioning in patients with post-stroke hemiplegia. The upper limb scale ranges between 0 (severe functional impairment) to 66 (minimal functional impairment) | Mean | Standard Deviation | units on a scale |
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| Montreal Cognitive Assessment | The Montreal Cognitive Assessment is a questionnaire used to assess cognitive impairment. The test has a scale that ranges between 0 (severe cognitive impairment) and 30 (typical cognitive function). | Mean | Standard Deviation | units on a scale |
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| Mini-Mental State Examination | The Mini-Mental State Examination is used in clinical and research settings to measure cognitive impairment. The scale ranges from 0 (severe cognitive impairment) to 30 (no cognitive impairment). | Mean | Standard Deviation | units on a scale |
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| Trail Making Test A | Trail Making Test A is a timed test that assesses cognitive processing speed. The participant is required to draw lines to connect a sequence of twenty-five consecutively numbered targets (1, 2, 3, etc.) on a sheet of paper. If the subject makes an error, the test administrator corrects them before the subject moves on to the next numbered target. | Mean | Standard Deviation | seconds |
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| Trail Making Test B | Trail Making Test B is a timed test used to assess executive functioning. The participant is required to draw lines to connect a series of targets labelled by either a number or letter in sequential order. When connecting the targets the participant alternates between numbers and letters (1, A, 2, B, etc.). If the subject makes an error, the test administrator corrects them before the participant moves on to the next dot. | Mean | Standard Deviation | seconds |
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| Stroke Affected Hemisphere | Count of stroke affected hemisphere | Count of Participants | Participants |
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| 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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | 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. | All participants who completed at least one arm of the study | Posted | Mean | Standard Deviation | seconds | Baseline and post-intervention |
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| Secondary | 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. | All participants who completed at least one arm of the study | Posted | Mean | Standard Deviation | seconds | Baseline and post-intervention |
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| Secondary | 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. | All participants who completed at least one arm of the study | Posted | Mean | Standard Deviation | seconds | Within session baseline to ~8 minutes post-application of non-invasive stimulation within the same session |
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| Secondary | 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. | All participants who completed at least one arm of the study | Posted | Mean | Standard Deviation | microvolts | Baseline and post-intervention |
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| Secondary | 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. | All participants who completed at least one arm of the study | Posted | Mean | Standard Deviation | percentage change | Baseline and post-intervention |
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Duration of study (9 weeks)
The total numbers reported reflect all participants who completed at least one session of the intervention.
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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 | Active+Motor Practice | Participants who received motor practice preceded by ACTIVE continuous theta burst stimulation (cTBS) over dorsolateral prefrontal cortex in either the first three weeks or last three weeks of the study. | 0 | 5 | 0 | 5 | 0 | 5 |
| EG001 | Sham+Motor Practice | Participants who received motor practice preceded by SHAM continuous theta burst stimulation (cTBS) over dorsolateral prefrontal cortex in either the first three weeks or last three weeks of the study. | 0 | 5 | 0 | 5 | 0 | 5 |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Sean K Meehan, PhD | University of Waterloo, Waterloo, Ontario, Canada | 5198884567 | 39278 | skmeehan@uwaterloo.ca |
| Mar 12, 2020 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D020521 | Stroke |
| D000092122 | Bronchiolitis Obliterans Syndrome |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D000092124 | Organizing Pneumonia |
| D001989 | Bronchiolitis Obliterans |
| D001988 | Bronchiolitis |
| D001991 | Bronchitis |
| D001982 | Bronchial Diseases |
| D012140 | Respiratory Tract Diseases |
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D006086 | Graft vs Host Disease |
| D007154 | Immune System Diseases |
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| >=65 years |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Right Hemisphere |
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| Change in Time (Pre to Post) |
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| Magnitude of change in sequence completion time from pre-baseline to post-intervention for the Sham arm. Cohen's d was calculated as a measure of effect size. | Effect Size - Cohen's d | 0.69 | 2-Sided | Cohen's d was calculated as time to complete the sequence at the pre-baseline assessment minus the time it took to complete the sequence at the post-intervention assessment. The denominator reflected pooled variance. | Other |
| Effect Size - Cohen's d | -0.80 | 2-Sided | Cohen's d was calculated as the change from pre- to post-intervention for the Active arm minus change from pre- to post-intervention for the Sham arm. The denominator reflected pooled variance. | Other | Cohen's d effect size was calculated to compare the magnitude of change in time to complete the movement sequence from pre-baseline to post-intervention across the Active and Sham arms. |
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