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Traditional rehabilitation approaches are time and personnel intensive and costly, and leave ~75% of stroke survivors with residual disability. We propose a clinical trial to determine effects of forced aerobic exercise (FE; i.e., mechanically supplemented) in facilitating upper and lower extremity motor recovery post-stroke in an outpatient rehabilitation setting, to elucidate neural and biochemical substrates of FE-induced motor recovery, and to evaluate cost effectiveness of a FE-centered intervention compared to traditional stroke rehabilitation. The global effect of FE has the potential to enhance recovery in a growing population of stroke survivors in a cost-effective manner, thus accelerating its clinical acceptance.
Traditional rehabilitation approaches following stroke involve 1:1 motor learning-based training to facilitate recovery of upper extremity (UE) and lower extremity (LE) function. These time- and personnel-intensive approaches are costly, yet leave ~75% of stroke survivors with residual disability. More effective alternative approaches to facilitate motor recovery following stroke have not been adopted clinically due to excessive time and cost. To advance clinical care, both effectiveness and cost of a candidate intervention must be considered simultaneously. Aerobic exercise (AE) is known to improve cardiovascular function following stroke and central nervous system (CNS) function in older adults and neurological populations. Strong theoretical arguments suggest that AE may facilitate motor recovery following stroke. A protocol that rigorously tests this theory in the subacute stroke population is warranted. Animal studies, coupled with our preliminary data, indicate a specific type of exercise - forced aerobic exercise (FE), where volitional movements are mechanically supplemented - improves motor recovery following stroke. The mechanical assistance provided by FE enables patients to achieve a more rapid and consistent exercise pattern beyond their volitional capabilities while maintaining their aerobic effort within a beneficial range. In our initial studies, persons completing FE cycling followed by a reduced dose of UE motor task practice exhibited greater recovery of UE motor function compared to those completing unassisted AE and motor task practice or extended sessions of motor task practice alone. Animal studies have shown that FE triggers the release of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1), thought to be critical building blocks for neuroplasticity. Project Hypothesis: FE facilitates high-intensity AE, which triggers growth factors essential for neuroplasticity, thereby 'priming' the CNS to facilitate motor recovery associated with motor retraining therapies. We propose a prospective, pragmatic clinical trial to determine effects of FE in facilitating UE and LE motor recovery post-stroke in an outpatient rehabilitation setting, to elucidate neural and biochemical substrates of FE-induced motor recovery, and to evaluate cost effectiveness of a FE-centered intervention compared to traditional stroke rehabilitation.
Aim 1: Determine effects of FE+rehab vs. time-matched rehab on the recovery of UE motor function.
Aim 2: Determine effects of FE+rehab vs. time-matched rehab on recovery of lower extremity motor function.
Aim 3: Determine effects of FE+rehab vs. rehab on electrophysiological and biochemical markers of neuroplasticity.
Aim 4: Evaluate cost-effectiveness of FE+rehab vs. rehab. The global effect of FE has the potential to enhance recovery in a growing population of stroke survivors in a cost-effective manner, thus accelerating its clinical acceptance. Our mechanistic aim will elucidate the effects of each approach on substrates underlying neuroplasticity.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Forced Rate Exercise + Rehabilitation | Active Comparator | The forced rate exercise+rehab group (N=33) will complete FE on the cycle designed to augment pedaling rate to >75 revolutions per minute (RPM). Target heart rate zone will be set to 60-80% of heart rate (HR) reserve. The session will consist of a 5-min warm-up, 35-min main exercise set, and 5-min cool down. Following FE, abbreviated sessions of motor learning-based training will be administered by a neurologic OT and PT experienced in stroke rehabilitation, with 30 min focused on restoration of UE function (OT) and 15 min focused on LE motor function/ gait training (PT). |
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| Rehabilitation | Active Comparator | The rehab group will receive consecutive, full-length sessions of motor learning-based training, administered by a neurologic OT and PT experienced in stroke rehabilitation, with 45 min focused on restoration of UE function (OT) and 45 min focused on LE motor function/ gait training (PT). |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Forced Rate Exercise + Rehab | Behavioral | The FE+rehab group (N=33) will complete FE on the cycle designed to augment pedaling rate to >75 RPM. Target heart rate zone will be set to 60-80% of HR reserve. The session will consist of a 5-min warm-up, 35-min main exercise set, and 5-min cool down. Following FE, abbreviated sessions of motor learning-based training will be administered by a neurologic OT and PT experienced in stroke rehabilitation, with 30 min focused on restoration of UE function (OT) and 15 min focused on LE motor function/ gait training (PT). |
| Measure | Description | Time Frame |
|---|---|---|
| Upper Extremity Fugl-Meyer Motor Assessment | Impairment-based measure of the upper extremity post-stroke. | Baseline to end of treatment at 12 weeks and end of treatment + 6 months |
| Gait Velocity | Gait velocity obtained using motion capture. | Baseline to end of treatment at 12 weeks and end of treatment + 6 months |
| Plasma IGF-1 | Blood biomarker for neuroplasticity | Before and after first and 24th treatment session |
| Serum BDNF | Blood biomarker for neuroplasticity | Before and after first and 24th treatment session |
| electroencephalograms | Electroencephalograms will be obtained to determine the degree of active engagement of different cortical areas during active/passive UE and LE movements | Baseline and end of treatment at 12 weeks |
| electroencephalograms | Electroencephalograms will be obtained to determine the degree of active engagement of different cortical areas under each cycling condition | Baseline and end of treatment at 12 weeks |
| electroencephalograms | Electroencephalograms will be obtained to quantify inter-area communication and direction of information flow. | Baseline and end of treatment at 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Action Research Arm Test | Measure of upper extremity gross and fine motor function post-stroke | Baseline to end of treatment at 12 weeks and end of treatment + 6 months |
| Biomechanical Dexterity Task |
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Sixty-six individuals with chronic stroke able to provide informed consent who meet the following criteria for inclusion will be recruited from the Cleveland Clinic:
Exclusion criteria include:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Courtney Miller, PT, DPT | Contact | 216 509-7012 | millerc5@ccf.org | |
| Donayja Harris, BS | Contact | 216 445-2007 | harrisD47@ccf.org |
| Name | Affiliation | Role |
|---|---|---|
| Susan Linder, PT, DPT, PhD | The Cleveland Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cleveland Clinic | Recruiting | Cleveland | Ohio | 44195 | United States |
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| ID | Term |
|---|---|
| D020521 | Stroke |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D012046 | Rehabilitation |
| ID | Term |
|---|---|
| D000359 | Aftercare |
| D003266 | Continuity of Patient Care |
| D005791 | Patient Care |
| D013812 | Therapeutics |
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prospective, single-center, parallel group, rater-blind, pragmatic randomized clinical trial
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Outcomes assessor will be blinded to group allocation
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| Rehabilitation | Behavioral | The rehab group will receive consecutive, full-length sessions of motor learning-based training, administered by a neurologic OT and PT experienced in stroke rehabilitation, with 45 min focused on restoration of UE function (OT) and 45 min focused on LE motor function/ gait training (PT). |
|
| Incremental cost-effectiveness ratio | Incremental cost-effectiveness ratio (ICER) expressed as cost per quality of life years (QALY) will be computed using a healthcare perspective. | baseline to end of treatment at 12 weeks and baseline to end of treatment + 6 months |
| Stroke Impact Scale | Self-reported quality of life measure, normalized to a score from 0-100 with higher scores indicative of better self-reported quality of life | Baseline to end of treatment at 12 weeks and end of treatment + 6 months |
Force tracking task - accuracy within targeted range
| Baseline to end of treatment at 12 weeks and end of treatment + 6 months |
| Biomechanical measure of maximum grasp force | maximum grasp force measured with force transducer | Baseline to end of treatment at 12 weeks and end of treatment + 6 months |
| Bimanual Dexterity Task | Time to complete task when separating 2 force transducers | Baseline to end of treatment at 12 weeks and end of treatment + 6 months |
| Six minute walk test | Measure of walking capacity | Baseline to end of treatment at 12 weeks and end of treatment + 6 months |
| Lower Extremity Fugl-Meyer Motor Assessment | Impairment-based measure of the lower extremity post-stroke. | Baseline to end of treatment at 12 weeks and end of treatment + 6 months |
| Biomechanical Gait Analysis | Biomechanical assessment of the following spatio-temporal components of gait using motion capture: % of gait cycle spent in swing and stance phases, and in single and double limb support. | Baseline, end of treatment at 12 weeks, end of treatment + 6 months |
| Biomechanical Gait Analysis | Biomechanical assessment of gait cadence (steps/minute) | Baseline, end of treatment at 12 weeks, end of treatment + 6 months |
| Biomechanical Gait Analysis | Biomechanical assessment of stride length | Baseline, end of treatment at 12 weeks, end of treatment + 6 months |
| Biomechanical Gait Analysis | Biomechanical assessment of the following components of gait kinetics using motion capture: 1) peak anterior-posterior propulsion forces, 2) peak anterior-posterior braking forces, 3) peak vertical ground reaction forces, 4) peak lateral ground reaction forces. | Baseline, end of treatment at 12 weeks, end of treatment + 6 months |
| Biomechanical Gait Analysis | Biomechanical assessment of the following components of gait kinetics using motion capture: 1) total hip extension moment 2) total knee extension moment, 3) total ankle plantarflexion extension moment | Baseline, end of treatment at 12 weeks, end of treatment + 6 months |
| Biomechanical Gait Analysis | Biomechanical assessment of the following components of gait kinetics during stance phase using motion capture: 1) total hip extension power 2) total knee extension power, 3) total ankle plantarflexion extension power | Baseline, end of treatment at 12 weeks, end of treatment + 6 months |
| Biomechanical Gait Analysis | Biomechanical assessment of the following kinematic components of gait using motion capture: hip flexion/extension, knee flexion/extension, ankle plantar- and dorsi-flexion | Baseline, end of treatment at 12 weeks, end of treatment + 6 months |
| Plasma BDNF | Blood biomarker for neuroplasticity | Before and after first and 24th session |
| Somatosensory evoked potentials | lower extremity somatosensory evoked potentials | Baseline |
| Modified Rankin Scale | Measure of disability | Baseline to end of treatment at 12 weeks and end of treatment + 6 months |
| Peak oxygen consumption (Peak VO2) | Measure of cardiorespiratory function | Baseline to end of treatment at 12 weeks |
| Patient-Reported Outcomes Measurement Information System (PROMIS) Computerized Adaptive Test (CAT) v 2.0 Physical Function | Self-reported quality of life measure of physical function computed as normalized T-scores (1-100 range), with higher scores indicative of greater self-reported quality of life | Baseline to end of treatment at 12 weeks and end of treatment + 6 months |
| Patient-Reported Outcomes Measurement Information System (PROMIS) Computerized Adaptive Test (CAT) v 2.0 Ability to Participate in Social Roles | Self-reported quality of life measure computed as a normalized T-score (0-100 range), with higher scores indicative of greater self-reported participation | Baseline to end of treatment at 12 weeks and end of treatment + 6 months |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006296 |
| Health Services |
| D005159 | Health Care Facilities Workforce and Services |