The Utilization of Forced-Rate Cycling to Facilitate Motor Recovery Following Stroke: A Randomized Clinical Trial

Abstract

Background

The potential for aerobic exercise (AE) to enhance neuroplasticity post-stroke has been theorized but not systematically investigated. Our aim was to determine the effects of forced-rate AE (FE) paired with upper extremity (UE) repetitive task practice (FE + RTP) compared to time-matched UE RTP (RTP only) on motor recovery.

Methods

A single center randomized clinical trial was conducted from April 2019 to December 2022. Sixty individuals ≥6 months post-stroke with UE hemiparesis were randomized to FE + RTP (N = 30) or RTP only (N = 30), completing 90-minute sessions, 3×/week for 8 weeks. The FE + RTP group underwent 45-minute of FE (5-minute warm-up, 35-minute main set, and 5-minute cool down) followed by 45-minute of UE RTP. The RTP only group completed 90-minute of RTP. Primary outcomes were the Fugl-Meyer Assessment (FMA) and Action Research Arm Test (ARAT). The 6-minute Walk Test (6MWT, secondary outcome) assessed walking capacity.

Results

Sixty individuals enrolled and 56 completed the study. The RTP only group completed more RTP in terms of repetitions (411.8 ± 44.4 vs 222.8 ± 28.4, P < .001) and time (72.7 ± 6.7 vs 37.8 ± 2.4 minutes, P < .001) versus FE + RTP. There was no significant difference between groups on the FMA (FE + RTP, 36.2 ± 10.1-44.0 ± 11.8 and RTP only, 34.4 ± 11.0-41.2 ± 13.4, P = .43) or ARAT (FE + RTP, 32.5 ± 16.6-37.7 ± 17.9 and RTP only, 32.8 ± 18.6-36.4 ± 18.5, P = .88). The FE + RTP group demonstrated greater improvements on the 6MWT (274.9 ± 122.0-327.1 ± 141.2 m) versus RTP only (285.5 ± 160.3-316.9 ± 170.0, P = .003).

Conclusions

There was no significant difference between groups in the primary outcomes. The FE + RTP improved more on the 6MWT, a secondary outcome.

Trial Registration:

ClinicalTrials.gov: NCT03819764.

Keywords

cycling aerobic exercise neuroplasticity

Introduction

Advances in the medical management of stroke have improved survival rates by nearly one-third over the past 20 years; however, disability rates post-stroke have not changed substantially.¹ Despite extensive resources dedicated to rehabilitation, nearly two-thirds of survivors do not regain full use of their hemiparetic upper and lower extremities resulting in the inability to use the more affected hand, deficits in locomotion and mobility, and decreased community reintegration.^2,3 Neuroplasticity, the ability of the central nervous system (CNS) to change in response to stimuli by strengthening existing and forming new neural connections, remains the tenet of motor recovery post-stroke.^1,2,4,5 Motor learning-based therapies to drive the recovery of upper extremity (UE) function are considered the standard of care in post-stroke rehabilitation and include constraint-induced movement therapy and repetitive task practice (RTP).^1,2,5-10 Clinical trials in the past 2 decades have focused on variations to these approaches of motor retraining therapies^7,10,11 and titrating the optimal dosage to drive neural recovery.^8,9 However, the optimal method to facilitate UE motor recovery has not been determined and the causal relationship between dose and recovery remains unclear.^3,9,10

Principles of motor recovery indicate that neuroplasticity is experience-dependent, requiring motor task practice to improve function. Unfortunately, the dose of therapy most individuals post-stroke receive does not meet a level of practice necessary to realize the full recovery potential.^6,8 There is emerging evidence to indicate that aerobic exercise (AE) improves brain function and promotes neuroplasticity.^4,12-17 Studies in animals and humans indicate that AE can increase levels of brain-derived neurotrophic factor and insulin-like growth factor-1, neurotrophins thought to be key facilitators of neuroplasticity, implicated on a molecular level to encourage axonal and dendritic growth and remodeling, synaptogenesis, and synaptic transmission efficacy.^{2,4,13,14,17,18} Numerous systematic reviews of animal and human literature have found that exercise intensity is an important factor in upregulating neurotrophins, with higher intensities eliciting greater responses compared to low-intensity AE approaches.^{13,14,16,17,19-22}

To harness the potential neuroplastic priming effects of AE, studies conducted in animals and neurologically healthy humans indicate that AE administered immediately prior to motor task practice enhances motor skill acquisition.¹⁸ Our underlying hypothesis is that AE primes the CNS to facilitate neuroplasticity and its use in combination with motor task practice will optimize motor recovery.^4,13,15 To evaluate this hypothesis, we conducted successful preliminary studies suggesting AE training can enhance the motor learning benefits associated with UE RTP in individuals with stroke.^23,24 However, a barrier is that persons post-stroke often present with considerable declines in cardiovascular fitness and endurance, which necessarily limits the duration and intensity of AE. To overcome this deconditioning, we utilized a forced-rate exercise (FE) paradigm, an approach in which the voluntary efforts of participants are supplemented to facilitate exercise of greater intensity and duration to trigger potential neuroplastic benefits. During FE, pedaling cadence on a stationary cycle is supplemented by a motor to assist, but not replace, the voluntary efforts of the individual. We previously reported that when comparing FE to voluntary-rate exercise (VE), FE elicited greater improvements in motor recovery associated with UE RTP.^23,24

While our pilot studies demonstrated superiority of FE, the dose–response relationship with UE RTP was not evaluated. The aim of this project was to determine the effects of FE paired with an abbreviated session of UE RTP (FE + RTP) compared to time-matched UE RTP (RTP only) on the recovery of motor function in individuals with chronic stroke. We hypothesized that FE + RTP would yield greater improvements in UE motor recovery compared to time-matched RTP only.

Materials and Methods

A single-center, parallel group, rater blinded randomized clinical trial with a 1:1 allocation ratio was conducted at the Cleveland Clinic between April 2019 and December 2022. The trial was funded by the National Institutes of Health (K01HD092556), registered prospectively at ClinicalTrials.gov (NCT03819764) and conducted in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines.

Participants and Screening

Sixty individuals were recruited from the community via a stroke research participant registry, clinician outreach, and support group education sessions. Inclusion criteria were: (1) ≥6 months since a single ischemic or hemorrhagic stroke; (2) UE Fugl-Meyer motor score 19 to 55; and (3) ambulatory ≥20 m with no more than contact guard assistance; and (4) 18 to 85 years of age. Exclusion criteria were: (1) hospitalization for myocardial infarction, heart failure, or heart surgery within 3 months, (2) cardiac arrhythmia, (3) hypertrophic cardiomyopathy, (4) severe aortic stenosis, (5) pulmonary embolus, (6) significant contractures, (7) anti-spasticity injection to paretic UE within 3 months of enrollment, and (8) other contraindications to exercise. The study was approved by the Cleveland Clinic Institutional Review Board and the informed consent process was completed with all participants.

After meeting initial screening criteria,²⁵ participants underwent cardiopulmonary exercise (CPX) testing administered by an exercise physiologist blinded to group allocation at baseline and end of treatment (EOT) to determine baseline function and cardiopulmonary response to maximum exertion. Participants completed testing while on all prescribed medications including anti-hypertensives to obtain an accurate measure of heart rate (HR) and blood pressure response. A 12-lead electrocardiogram was assessed prior to exercise and monitored continuously throughout exercise and recovery. An individualized ramp protocol was employed on an electronically controlled Lode cycle ergometer (Lode, Groningen, The Netherlands) using MedGraphics CardioO2/CP system (MCG Diagnostics, St. Paul, MN) with the ramp set to elicit a test duration of approximately 10 minutes. Participants were encouraged to exercise until volitional fatigue or standard test termination criteria according to the American College of Sports Medicine (ACSM) Guidelines for Exercise Testing and Prescription.²⁶ To capture gas analyses during steady state, breath by breath samples were collected and data were averaged during the last 30 seconds of each stage. Peak oxygen consumption (Peak VO₂) was defined as the highest average collected. Results were interpreted by the study cardiologist blinded to group allocation to determine participant safety.

Outcomes

Clinical outcomes evaluating UE motor recovery and walking capacity were obtained at baseline, EOT, and 4 weeks following EOT (EOT + 4) by the same trained physical therapist blinded to group allocation. The primary impairment-based motor outcome was the Fugl-Meyer Assessment (FMA),²⁷ which evaluates the ability of the individual to move out of synergistic patterns toward isolated movement control.²⁸ The primary functional-based motor outcome was the Action Research Arm Test (ARAT) total score.²⁹ The ARAT includes 19 tests of fine and gross motor function, grouped in subscales of grasp, grip, pinch, and gross movement. The ARAT subscale scores were secondary outcomes. The Wolf Motor Function Test served as secondary motor outcome.³⁰

The 6-minute walk test (6MWT) was a secondary outcome administered along a continuous 100-m oval lap as a measure of walking capacity according to methods described by Eng et al.³¹ Specifically, participants were instructed to: “walk as far as possible around the oval path within 6 minutes and do not stop unless you need to.”³¹ Assistive devices and orthoses as prescribed for community ambulation were used, with equipment remaining consistent across testing time points.

Interventions

Following baseline testing, participants (N = 60) underwent concealed randomization stratified by baseline FMA level (≤33 or >33) using a nonreplenished sealed opaque envelope pull method to 1 of 2 time-matched groups: (1) forced-rate AE and RTP (FE + RTP, N = 30) or (2) RTP only (N = 30). Randomization was conducted by the research therapist who was not involved in the collection of outcomes. Participants in both groups completed 24 visits, 3× per week for 8 weeks, and were permitted up to 12 weeks to complete the 24 visits to allow for vacations, illness, or holidays. Study visits for both groups were matched at 90 minutes in length. Participants were asked to refrain from formal therapy or enrolling in other trials until after the 4-week follow up. All were taught specific strategies and advised to incorporate their more affected UE into daily tasks. Those in the FE group did not have access to a FE bike following the 8-week intervention.

Forced Exercise + Repetitive Task Practice

Participants in the FE + RTP group completed a 45-minute session of supervised AE on a custom-engineered motor-assisted stationary semi-recumbent cycle ergometer, followed by 45-minutes of UE RTP. Participants were instructed to exercise within their target HR zone during the 35-minute main exercise set, which occurred between a 5-minute warm-up and 5-minute cool-down. Target HR range was individualized using the Karvonen formula at 60% to 80% of peak HR based on CPX testing.³² Heart rate was monitored and recorded continuously using a Wahoo chest strap (Wahoo Fitness, Atlanta, GA), synced and displayed continuously on an Apple iPad (Apple, Inc, Cupertino, CA), allowing the therapist and participant to monitor aerobic intensity, facilitating adherence to prescribed values. Participants were instructed to actively pedal with the motor to achieve target HR response. Cycling cadence was programmed by the therapist based on the individual’s ability to contribute to the workload with a target cadence of ≥75 revolutions per minute (RPM), based on results from previous studies indicating better outcomes at higher cycling cadence.²³ Exercise intensity was progressed by encouraging a higher aerobic response, increased power output, or increased cycling cadence. Given that cycling cadence was programmed and driven by the motor, the therapist monitored the individual’s ability to contribute to the workload when progressing cycling cadence, ensuring that the motor was not passively spinning the participant’s legs. Average HR during the warm-up, main set, and cool down were recorded. Blood pressure (BP) and rating of perceived exertion were recorded every 10 minutes. Training was conducted under the supervision of a physical therapist or physical therapist assistant certified in Basic Life Support. Participants completed a 45-minute session of UE RTP immediately following their FE session.

Repetitive Task Practice

RTP emphasizes highly-repetitious UE tasks that are functional, goal-oriented, and relevant to the individual, administered using blocked practice.³³ The RTP approach was identical to our previous studies,^23,24 originally modeled after Birkenmeier and colleagues.^6,9,34 Tasks were individualized to each participant’s goals and abilities and included gross and fine motor components involving proximal and distal motor control; for example, reaching to a shelf positioned at knee height, grasping a plastic cup, and placing it onto a shelf positioned at shoulder height. Task difficulty was progressed according to motor control principles and guided by the manual of Upper Extremity Task Specific Training by Birkenemeier and Lang.³⁵ Specific strategies included increasing the range of movement of the task, adding weight to the object or limb, modifying the size, shape, or pliability of the object, and increasing the complexity of fine motor tasks from gross motor to include object manipulation.³⁵ The RTP activities were administered by a licensed neurologic physical therapist or physical therapist assistant who tailored each task to ensure appropriate difficulty. During a 45-minute RTP session, participants completed 3 to 5 tasks, targeting 60 to 90 repetitions of each task. Time spent completing tasks and number of repetitions were recorded. The RTP intervention was administered in the same manner for both groups; however, to ensure a time-matched intervention, the FE + RTP group participated in a 45-minute session immediately after 45-minute of FE, while the RTP only group completed 2 sequential 45-minute RTP sessions.

Statistical Analysis

The power and sample size calculation was based on FMA scores from our pilot study.²⁴ Assuming a minimal clinically important difference (MCID) value for the FMA of 4.25 points³⁶ and an increase of 2 × MCID for the FE + RTP group and 1 × MCID for the RTP only group, an n = 30 per group provided a 0.87 power at the .05 significance level to detect pairwise group differences equivalent to an effect size of 0.4.

Intention to treat analysis was conducted. Participant demographics, clinical characteristics, intervention parameters, and outcomes were summarized by mean with standard deviation or median with interquartile range for continuous variables, and count with percentage for categorical variables.

Mixed-effects models were used to model outcomes over time. The primary outcome of FMA was measured at baseline, mid-point, EOT, and EOT + 4. All other outcomes were measured at baseline, EOT, and EOT + 4, which were dependent variables. Independent variables included time point (baseline, mid-point as applicable, EOT, and EOT + 4), group, and interaction between time points and group. Subject random effect was included in the model. Interaction term was excluded if it was non-significant (P > .05). There were 5 primary hypotheses of interest which were evaluated in contrast statements in the mixed effects models: group comparisons of change from baseline for FMA at mid-point, EOT, and EOT + 4 and for ARAT Total Score at EOT and EOT + 4. For these 5 primary hypotheses, a Bonferroni correction was applied with significance set at P < .01.

A responder analysis was conducted by determining the number of participants with change scores that exceed the MCID from baseline to EOT, and baseline to EOT + 4, for FMA, ARAT, and 6MWT. The entire distribution of responses for FE + RTP and RTP only groups were graphed using a cumulative distribution function.³⁷

Statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc, Cary, NC) with statistical significance established throughout at P < .05 for secondary analyses.

Results

Sixty participants met participation criteria, were consented, and enrolled. Participants were 60.5 (±10.6) years of age and 58.3% male. Racial distribution included 78.3% White, 20.0% Black/African American, and 1.7% Asian. Median time since stroke was 26.0 [13.0, 69.0] months. Detailed demographics, which were similar across groups, are presented in Table 1. Both interventions were well-tolerated by participants, with an overall retention of 93.3% and no serious adverse events related to study interventions. Twenty-nine participants in the FE + RTP group and 27 in the RTP only group completed the intervention and EOT testing. Two FE + RTP participants impacted by the mandatory COVID-19 shutdown completed 20 and 21 sessions rather than the planned 24 sessions. The study team decided to conduct EOT testing immediately prior to the shutdown to preserve outcomes from their participation. Two additional participants randomized to FE + RTP completed only 2 and 6 sessions prior to the shutdown. Both resumed the intervention 10 and 12 weeks later, restarting with session 1. The CONSORT flow diagram is shown in Figure 1.

Table 1.

Demographics, Clinical Characteristics, and Intervention Parameters of the Study Sample, Stratified by Groups.

	FE + RTP (N = 30)	RTP + RTP (N = 30)
Age	60.8 ± 11.5	60.2 ± 9.8
Sex
Male	18 (60.0)	17 (56.7)
Female	12 (40.0)	13 (43.3)
Race
White	23 (76.7)	24 (80.0)
African American	7 (23.3)	5 (16.7)
Asian	0 (0.00)	1 (3.3)
Stroke type
Ischemic	24 (80.0)	23 (76.7)
Hemorrhagic	6 (20.0)	7 (23.3)
Dominant side affected
Yes	15 (50.0)	14 (46.7)
No	15 (50.0)	16 (53.3)
Side affected
Left	15 (50.0)	13 (43.3)
Right	15 (50.0)	17 (56.7)
Time since stroke (mo)	18.5 [9.5, 60.0]	36.0 [14.0, 72.0]
Co-morbidities
Hypertension	19 (63.3)	19 (63.3)
Hyperlipidemia	20 (66.7)	22 (73.3)
Diabetes	9 (30.0)	9 (30.0)
History of myocardial infarction	1 (3.0)	1 (3.0)
Prescribed medication usage
Anti-hypertensive
Any	20 (66.7)	19 (63.3)
Beta-blocker	10 (33.3)	11 (36.7)
Statin	21 (70.0)	19 (63.3)
Anti-spasticity medication	6 (20.0)	7 (23.3)
Anti-depressant	12 (40.0)	11 (36.7)
Anti-coagulant	21 (70.0)	16 (53.3)
Diuretic	3 (10.0)	6 (20.0)
Diabetes medication	7 (23.3)	9 (30.0)
Anti-seizure medication	6 (20.0)	3 (10.0)
Pain medication	5 (16.7)	5 (16.7)
Baseline function
Fugl-Meyer (UE motor score out of 66)	36.2 ± 10.1	34.4 ± 11.0
Action research arm test
Total score	32.5 ± 16.6	32.8 ± 18.6
Grasp subscale	11.2 ± 5.7	11.4 ± 6.8
Grip subscale	6.8 ± 3.1	6.0 ± 3.9
Pinch subscale	8.0 ± 6.6	8.5 ± 7.0
Gross subscale	6.5 ± 2.3	6.9 ± 2.3
Wolf motor function test
Log performance time	2.4 ± 1.1	2.7 ± 1.2
geometric mean (SD)	11.0 (3.0)	14.9 (3.3)
Functional ability score	2.7 ± 1.3	2.7 ± 1.5
Number of incomplete tasks in 120 s	1.5 ± 2.6	2.4 ± 3.2
Grip strength (kg)	13.8 ± 7.9	13.8 ± 8.9
Weight to box (pounds)	8.2 ± 6.3	8.7 ± 7.2
6-min walk test distance (m)	274.9 ± 122.0	285.5 ± 160.3
Peak VO₂ (mL/kg/min)	16.6 ± 5.3	16.3 ± 5.5
	FE + RTP (N = 30)	RTP + RTP (N = 30)
Intervention variables			P-value
Aerobic intensity (% of heart rate reserve)	56.4 ± 12.1	—
Pedaling cadence (rpm)	74.3 ± 7.3	—
Duration of exercise session (min)	44.8 ± 0.35	—
Power (watts)	46.5 ± 42.7	—
Time spent completing RTP per session (min)	37.8 ± 2.4	72.7 ± 6.7	<.001
Number of repetitions of RTP completed per session	222.8 ± 28.4	411.8 ± 44.4	<.001
Number of tasks practiced per session	4.9 ± 0.49	8.0 ± 0.62	<.001

Abbreviations: FE + RTP, forced-rate exercise plus repetitive task practice; RTP only, repetitive task practice only; UE, upper extremity; VO₂, volume of oxygen consumption; RTP, repetitive task practice.

Statistics presented as Mean ± SD, Median [P25, P75], N (column %); P-values from Satterthwaite t-test.

Figure 1.

CONSORT flow diagram.

Intervention Variables

Average FE session duration was 44.8 (±0.35) minutes, aerobic intensity was 56.4 (±12.1) percent of heart rate reserve (HRR), power output was 46.5 (±42.7) watts, and cycling cadence was 74.3 (±7.3) RPM (Table 1). Mean rating of perceived exertion for the FE group using Borg’s category ratio 10-point scale³⁸ was 3.6 at 10 minutes, 4.1 at 20 minutes, 4.5 at 30 minutes, and 4.7 at 40 minutes, indicative of “moderate” (3) to “somewhat hard” (4) or “hard” (5) perceived exertion. As expected, those in the RTP only group, compared to the FE + RTP group, completed nearly twice the repetitions of RTP (411.8 ± 44.4 vs 222.8 ± 28.4, P < .001) and spent more time completing RTP (72.7 ± 6.7 minutes vs 37.8 ± 2.4 minutes, P < .001).

Given the paucity of data on FE in persons post-stroke, BP was monitored to ensure that exercise was occurring within safe cardiovascular parameters. Systolic and diastolic BP measurements of 200 and 100 mmHg, respectively, were established thresholds for which a FE session was paused. Sessions resumed after BP dropped to below these pre-determined thresholds. There were incidences in 4 participants when BP rose to above threshold values and a brief rest break was provided prior to resuming and completing the exercise session. This was often related to the individual forgetting to take their BP medication, running out of medication, or ceasing to take it against medical advice. These episodes allowed for study staff to monitor and educate patients on the importance of medication adherence, particularly to anti-hypertensives in individuals with a history of stroke.

Upper Extremity Motor Outcomes

Group effects were not significant for the FMA or ARAT in contrast statements for any time-point comparison (Figure 2). Significant improvements in UE motor recovery (Table 2) were measured for both groups from baseline to mid-point in the FMA (FE + RTP, 36.2 ± 10.1-40.4 ± 11.3 and RTP only, 34.4 ± 11.0-37.8 ± 11.7, P < .001), baseline to EOT in the FMA (FE + RTP, 36.2 ± 10.1-44.0 ± 11.8 and RTP only, 34.4 ± 11.0-41.2 ± 13.4, P < .001) and baseline to EOT in the ARAT (FE + RTP, 32.5 ± 16.6-37.7 ± 17.9 and RTP only, 32.8 ± 18.6-36.4 ± 18.5, P < .001).

Figure 2.

Violin dot plots depicting change scores from baseline to end of treatment (EOT, left panel) and baseline to EOT+4 weeks (right panel) with each dot representing a participant. Change scores for the Upper Extremity Fugl-Meyer Motor score (FMA, 3a), Action Research Arm Test (ARAT, 3b), and Six-minute walk test (6MWT, 3c) are shown with the minimal clinically important difference (MCID) range or value depicted by the blue horizontal shading or line, respectively. While both groups made significant improvement on the FMA and ARAT, more participants in the FE+RTP group exceeded MCID thresholds at all time points with the exception of FMA ≥7.25 at EOT+4. With respect to change in walking capacity measured by the 6MWT, only the FE+RTP group made significant improvements at both time points with group means exceeding MCID.

Table 2.

Changes From Baseline to EOT and EOT + 4 by Group.

	EOT		EOT + 4		Group P-value	Time P-value
	FE + RTP	RTP only	FE + RTP	RTP only	Group P-value	Time P-value
Fugl-Meyer (UE motor score)^ɫ	7.8 ± 4.0	6.6 ± 4.9	8.4 ± 4.5	8.2 ± 5.8	.44	<.001
Action research arm test
Total score^ɫ	5.3 ± 6.0	3.8 ± 6.0	5.8 ± 5.9	4.4 ± 6.4	.88	<.001
Grasp subscale^ɫ	1.9 ± 2.5	1.2 ± 2.9	2.2 ± 2.5	1.5 ± 2.9	.89	<.001
Grip subscale^ɫ	0.76 ± 1.6	0.89 ± 1.3	0.81 ± 1.5	1.00 ± 1.6	.46	<.001
Pinch subscale^ɫ	1.9 ± 2.7	1.2 ± 3.3	1.9 ± 2.8	1.6 ± 3.7	.96	<.001
Gross subscaleɫ^ɫ	0.76 ± 1.3	0.48 ± 0.89	0.96 ± 1.3	0.38 ± 1.2	.81	<.001
Wolf motor function test
Log performance time^Ŧ	−0.32 ± 0.35	−0.39 ± 0.50			.39	<.001
Functional ability score^ɫ	0.78 ± 0.50	0.39 ± 0.57			.72	<.001*
Number of incomplete tasks in 120 s^ɫ	−0.14 ± 0.79	−0.56 ± 0.93
Grip strength (kg)^ɫ	0.57 ± 3.2	0.51 ± 2.6			.98	.18
Weight to box (pounds)^ɫ	2.4 ± 2.9	2.1 ± 2.5			.83	<.001
6-min walk test distance (m)^ɫ	51.8 ± 45.9	16.3 ± 39.7	61.5 ± 56.5	20.2 ± 38.6	.76	<.001*
PeakVO₂ (mL/kg/min)^ɫ	1.8 ± 2.2	0.23 ± 2.5			.51	.004*

Abbreviations: EOT, end of treatment; EOT + 4, 4 weeks following end of treatment; FE + RTP, forced-rate exercise plus repetitive task practice; RTP only, repetitive task practice only; UE, upper extremity; PeakVO₂, volume of oxygen consumption.

EOT and EOT + 4 presented as change from baseline (mean ± SD) where ^ɫ positive scores indicate improvement, or ^Ŧ negative scores indicate improvement.

Each row represents results from separate mixed-effect models including group and time (baseline, EOT, and EOT + 4).

Significant interaction effect between group and time, P < .05.

Walking Capacity and Cardiovascular Fitness

The FE + RTP group demonstrated significantly greater improvements in the 6MWT (274.9 ± 122.0-327.1 ± 141.2 m) compared to the RTP only group (285.5 ± 160.3-316.9 ± 170.0, P = .003, Table 2, Figure 2) and aerobic capacity measured by peak oxygen consumption (FE + RTP, 16.6 ± 5.3-18.3 ± 6.4 vs RTP only, 16.3 ± 5.5-17.2 ± 5.6 mL/kg/minute, P = .024, Table 2).

Responder Analysis

Change scores for the FMA, ARAT, and 6MWT that exceeded the respective MCIDs are shown in Table 3 and Figure 3. More participants in the FE + RTP group exceeded MCID thresholds at EOT and EOT + 4 for all outcomes, with the exception of FMA ≥7.25 at EOT + 4. Significantly more FE + RTP participants exceeded MCID on the 6MWT at EOT and EOT + 4 than the RTP only group.

Table 3.

Percentage of Patients With Change Scores Exceeding Minimal Clinically Important Difference.

Change scores exceeding MCIDs at EOT	Total	FE + RTP	RTP only	Chi-square P-value
Change scores exceeding MCIDs at EOT	N (%)	N (%)	N (%)	Chi-square P-value
Fugl-Meyer assessment ≥4.25	41 (73.2)	22 (75.9)	19 (70.4)	.64
Fugl-Meyer assessment ≥7.25	22 (39.3)	14 (48.3)	8 (29.6)	.15
Action research arm test total ≥5.7	19 (33.9)	12 (41.4)	7 (25.9)	.22
6-min walk test ≥34.4	23 (42.6)	17 (60.7)	6 (23.1)	.005
Change scores exceeding MCIDs at EOT + 4^a
Fugl-Meyer assessment ≥4.25	42 (77.8)	23 (82.1)	19 (73.1)	.42
Fugl-Meyer assessment ≥7.25	29 (53.7)	15 (53.6)	14 (53.9)	.98
Action research arm test total ≥5.7	21 (39.6)	13 (48.2)	8 (30.8)	.20
6-min walk test ≥34.4	21 (42.0)	15 (60.0)	6 (24.0)	.010

Abbreviations: FE + RTP, forced-rate exercise plus repetitive task practice; RTP only, repetitive task practice only; MCID, minimal clinically important difference; EOT, end of treatment; EOT + 4; 4 weeks following end of treatment.

Subset of patients with available change scores.

Figure 3.

Change scores for the Upper Extremity Fugl-Meyer Motor score (FMA, 2a), Action Research Arm Test (ARAT, 2b), and Six-minute walk test (6MWT, 2c) are shown with the minimal clinically important difference (MCID) range or value depicted by the blue horizontal shading or line, respectively. The y-axis shows the proportion of patients at each point along the outcome scale (x-axis) who experience change at that point or lower. While both groups made statistically significant improvement on the FMA and ARAT, more participants in the FE+RTP group exceeded MCID thresholds at EOT.

Discussion

An intervention comprised of AE and RTP produced similar improvements in UE motor performance as an RTP intervention that was twice as long. Similar motor response with half the RTP dose suggests that AE may be priming the CNS to optimize neuroplasticity in persons with stroke and should be considered as an adjunct to traditional RTP. While we hypothesized that FE + RTP would yield superior improvements in UE motor recovery, the null hypothesis was not rejected. However, unique to the FE + RTP group, significant and clinically meaningful improvements in locomotion and cardiovascular fitness were elicited that were not observed in the RTP only group.

Recommendations for individuals post-stroke to engage in AE are not new; however, the benefits for CNS function have historically not been emphasized.³⁹ Sustained and intensive AE has been shown to elicit vascular and neurochemical responses within the CNS, hypothesized as the mechanism by which AE facilitates neuroplasticity.^{4,15,16,40-46} Based on these data, our scientific premise was that sustained moderate- to high-intensity AE administered through FE would prime the CNS and optimize recovery associated with motor task practice. We used FE to supplement the voluntary efforts of participants to overcome barriers to completing high intensity AE that individuals post-stroke experience, including hemiparesis, fatigue, spasticity, impaired balance, and reduced cardiovascular fitness.⁴⁷ Participants in the FE + RTP group exercised for 45 minutes at an aerobic intensity (56.4% of HRR) that is nearly equivalent to ACSM exercise guidelines for the general population.⁴⁸ Therefore, supplementing the individuals’ voluntary efforts using FE facilitated a relatively intensive exercise duration (ie, 45 minutes/session) without compromising aerobic intensity.

Because FE involved lower limb cycling, it was unlikely to elicit a transfer of training effect to impact UE function; thus, we hypothesize that a global priming effect was induced, enhancing UE recovery. The MCID for the FMA ranges from 4.25 to 7.25 points.³⁶ Despite half the RTP dosage, mean change scores for the FE + RTP group exceeded the upper value of MCID range for the FMA at both time points. Additionally, responder analyses (Table 3) revealed that more participants in the FE + RTP group exceeded the MCID for the ARAT at both time points, although this was not statistically significant between groups. In a previous study investigating RTP dosage, Lang et al⁹ reported change in ARAT scores of 5.8 and 5.1 for participants receiving 13.6 and 20 hours of UE RTP, respectively, while our FE + RTP group demonstrated a 5.3 point change after 18 hours of RTP. By comparison, the RTP only group receiving a total of 36 hours of RTP improved by 3.8 points. While in part our study was designed to investigate the effects of 2 different doses of RTP, a sham non-AE intervention would be an interesting comparator group to evaluate the differential effects of AE on motor recovery. Additionally, investigating different intensities of aerobic training would further elucidate characteristics of AE that prime the brain for neuroplasticity. We acknowledge that a gap is the investigation of mechanisms that may be responsible for the improvements observed. Future studies have been proposed that include neural and biochemical mechanisms that underlie exercise-induced plasticity.

While not designed to improve walking, a significant and meaningful by-product of FE + RTP was improvements in walking capacity, with a change in 6MWT distance of 52.2 m, exceeding the MCID of 34.4 m.⁴⁹ These results approach the robust improvements in 6MWT values recently reported by Boyne et al⁵⁰ after 8 weeks of high-intensity interval treadmill-based gait training administered 3×/week and suggest that FE improves locomotor function by potentially eliciting a transfer of training to walking.⁵¹ An interim analysis of data from the FE + RTP group revealed normalization of gait kinematics and kinetics associated with increased gait velocity following FE, indicating participants improved locomotor control and did not exaggerate existing compensatory strategies to walk faster.⁵² Task-specificity, a fundamental concept in motor learning, has long been considered critical for neuroplasticity; yet our FE + RTP intervention did not involve task-specific gait training. While cycling and walking are different tasks, improvements in LE kinematics and kinetics from cycling may transfer to gait, as both require the rapid reciprocal activation and relaxation of lower extremity muscles synergistically, and some have proposed similar controlling neural networks.^53-60 Pedaling data from our pilot study revealed increased hemiparetic limb torque production, improved symmetry of force production, and diminished roughness index (a measure of motion smoothness) as a result of cycling.^61,62 It is plausible that increased somatosensory input, muscle power, lower limb motor control, and/or endurance may have elicited these gains.⁶³

AE has been recommended for decades to improve physical and psychosocial function in persons post-stroke.^39,47 While lab-based studies have repeatedly demonstrated the value of AE, feasibility, and reimbursement remain as barriers to implementation in clinical settings. The cardiac rehabilitation model has been previously proposed; however, stroke is not a diagnosis for which cardiac rehabilitation is covered in the United States. Additionally, in isolation, AE administered in a cardiac rehab setting would undoubtedly have numerous benefits but is not designed to enhance neuroplasticity. Novel approaches to include AE in stroke rehabilitation settings are warranted to improve clinical and value-based outcomes.

Conclusions, Limitations, and Future Directions

Our findings that an aerobic cycling intervention administered immediately prior to UE RTP can elicit robust improvements in UE function and locomotion comparable to task-specific training approaches can have significant implications on clinical practice. The FE + RTP intervention was tolerated by all participants without serious adverse events and its summative value in improving UE, lower extremity, and cardiovascular outcomes was demonstrated. The 60% to 80% target HR range was calculated based on CPX results; however, FE sessions were not completed at the same time of day as the CPX test. Therefore, participants on beta blockers may have had slight alterations in their target HR range and actual aerobic intensity, based on precise medication half-life and potency. Future studies employing mechanistic and clinical outcomes to elucidate the role of AE in eliciting a global response within the CNS and facilitating neuroplasticity are planned.

Footnotes

Acknowledgements

The authors wish to acknowledge Anson Rosenfeldt, DPT, MBA and Cindy Clark, OT for their contributions in administering study-related interventions.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Alberts has authored intellectual property protecting the algorithm associated with the forced-rate exercise cycle.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The trial was funded by the National Institutes of Health K01HD092556 to Susan Linder.

ORCID iDs

Susan M. Linder

Yadi Li

References

Winstein

Stein

Arena

, et al. Guidelines for adult stroke rehabilitation and recovery: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016;47(6):e98-e169.

Dobkin

BH.

Clinical practice. Rehabilitation after stroke. N Engl J Med. 2005;352(16):1677-1684.

Duncan

Sullivan

Behrman

, et al. Body-weight-supported treadmill rehabilitation after stroke. N Engl J Med. 2011;364(21):2026-2036.

Mang

Campbell

Ross

Boyd

LA.

Promoting neuroplasticity for motor rehabilitation after stroke: considering the effects of aerobic exercise and genetic variation on brain-derived neurotrophic factor. Phys Ther. 2013;93(12):1707-1716.

Langhorne

Bernhardt

Kwakkel

Stroke rehabilitation. Lancet. 2011;377(9778):1693-1702.

Birkenmeier

Prager

Lang

CE.

Translating animal doses of task-specific training to people with chronic stroke in 1-hour therapy sessions: a proof-of-concept study. Neurorehabil Neural Repair. 2010;24(7):620-635.

Wolf

Winstein

Miller

, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. JAMA. 2006;296(17):2095-2104.

Lang

Lohse

Birkenmeier

RL.

Dose and timing in neurorehabilitation: prescribing motor therapy after stroke. Curr Opin Neurol. 2015;28(6):549-555.

Lang

Strube

Bland

, et al. Dose response of task-specific upper limb training in people at least 6 months poststroke: a phase II, single-blind, randomized, controlled trial. Ann Neurol. 2016;80(3):342-354.

10.

Winstein

Wolf

Dromerick

, et al. Effect of a task-oriented rehabilitation program on upper extremity recovery following motor stroke: the ICARE randomized clinical trial. JAMA. 2016;315(6):571-581.

11.

Page

Levine

Leonard

Szaflarski

Kissela

BM.

Modified constraint-induced therapy in chronic stroke: results of a single-blinded randomized controlled trial. Phys Ther. 2008;88(3):333-340.

12.

Ploughman

Exercise is brain food: the effects of physical activity on cognitive function. Dev Neurorehabil. 2008;11(3):236-240.

13.

Ploughman

Austin

Glynn

Corbett

The effects of poststroke aerobic exercise on neuroplasticity: a systematic review of animal and clinical studies. Transl Stroke Res. 2015;6(1):13-28.

14.

Ploughman

Kelly

LP.

Four birds with one stone? Reparative, neuroplastic, cardiorespiratory, and metabolic benefits of aerobic exercise poststroke. Curr Opin Neurol. 2016;29(6):684-692.

15.

Ploughman

McCarthy

Bosse

Sullivan

Corbett

Does treadmill exercise improve performance of cognitive or upper-extremity tasks in people with chronic stroke? A randomized cross-over trial. Arch Phys Med Rehabil. 2008;89(11):2041-2047.

16.

Knaepen

Goekint

Heyman

. R M Neuroplasticity - Exercise-induced response of peripheral brain-derived neurotrophic factor. Sports Med. 2010;40(9):765-801.

17.

Boyne

Meyrose

Westover

, et al. Exercise intensity affects acute neurotrophic and neurophysiological responses poststroke. J Appl Physiol (1985). 2019;126(2):431-443.

18.

Statton

Encarnacion

Celnik

Bastian

AJ.

A single bout of moderate aerobic exercise improves motor skill acquisition. PLoS One. 2015;10(10):e0141393.

19.

Austin

Ploughman

Glynn

Corbett

Aerobic exercise effects on neuroprotection and brain repair following stroke: a systematic review and perspective. Neurosci Res. 2014;87:8-15.

20.

Fernandez-Rodriguez

Alvarez-Bueno

Martinez-Ortega

, et al. Immediate effect of high-intensity exercise on brain-derived neurotrophic factor in healthy young adults: a systematic review and meta-analysis. J Sport Health Sci. 2022;11(3):367-375.

21.

Limaye

Carvalho

Kramer

Effects of aerobic exercise on serum biomarkers of neuroplasticity and brain repair in stroke: a systematic review. Arch Phys Med Rehabil. 2021;102(8):1633-1644.

22.

Zhou

Wang

Zhu

, et al. Effects of different physical activities on brain-derived neurotrophic factor: a systematic review and bayesian network meta-analysis. Front Aging Neurosci. 2022;14:981002.

23.

Linder

Rosenfeldt

Davidson

, et al. Forced, not voluntary, aerobic exercise enhances motor recovery in persons with chronic stroke. Neurorehabil Neural Repair. 2019;33(8):681-690.

24.

Linder

Rosenfeldt

Dey

Alberts

JL.

Forced aerobic exercise preceding task practice improves motor recovery poststroke. Am J Occup Ther. 2017;71(2):7102290020p7102290021-7102290020p7102290029.

25.

Riebe

Franklin

Thompson

, et al. Updating ACSM’s recommendations for exercise preparticipation health screening. Med Sci Sports Exercise. 2015;47(11):2473-2479.

26.

American College of Sports Medicine. ACSM’s Resource Manual for Guidelines for Exercise Testing and Prescription. 7th ed. Wolters Kluwer and Lippincott Williams & Wilkins; 2014.

27.

Sullivan

Tilson

Cen

, et al. Fugl-Meyer assessment of sensorimotor function after stroke: standardized training procedure for clinical practice and clinical trials. Stroke. 2011;42(2):427-432.

28.

Gladstone

Danells

Black

SE.

The Fugl-Meyer assessment of motor recovery after stroke: a critical review of its measurement properties. Neurorehabil Neural Repair. 2002;16(3):232-240.

29.

Lang

Wagner

Dromerick

Edwards

DF.

Measurement of upper-extremity function early after stroke: properties of the action research arm test. Arch Phys Med Rehabil. 2006;87(12):1605-1610.

30.

Wolf

Catlin

Ellis

Archer

Morgan

Piacentino

Assessing Wolf motor function test as outcome measure for research in patients after stroke. Stroke. 2001;32(7):1635-1639.

31.

Eng

Chu

Dawson

Kim

Hepburn

KE.

Functional walk tests in individuals with stroke: relation to perceived exertion and myocardial exertion. Stroke. 2002;33(3):756-761.

32.

Ignaszewski

Lau

Wong

Isserow

The science of exercise prescription: Martti Karvonen and his contributions. BC Med J. 2017;59(1):38-41.

33.

Hubbard

Parsons

Neilson

Carey

LM.

Task-specific training: evidence for and translation to clinical practice. Occup Ther Int. 2009;16(3-4):175-189.

34.

Lang

Birkenmeier

RL.

Upper-Extremity Task-Specific Training After Stroke or Disability. AOTA Press; 2014.

35.

Birkenmeier

Lang

Upper-Extremity Task-Specific Training After Stroke or Disability. AOTA Press; 2013.

36.

Page

Fulk

Boyne

Clinically important differences for the upper-extremity Fugl-Meyer Scale in people with minimal to moderate impairment due to chronic stroke. Phys Ther. 2012;92(6):791-798.

37.

McLeod

Coon

Martin

Fehnel

Hays

RD.

Interpreting patient-reported outcome results: US FDA guidance and emerging methods. Expert Rev Pharmacoecon Outcomes Res. 2011;11(2):163-169.

38.

Foster

Florhaug

Franklin

, et al. A new approach to monitoring exercise training. J Strength Cond Res. 2001;15(1):109-115.

39.

Billinger

Arena

Bernhardt

, et al. Physical activity and exercise recommendations for stroke survivors: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(8):2532-2553.

40.

Petzinger

Fisher

Van Leeuwen

, et al. Enhancing neuroplasticity in the basal ganglia: the role of exercise in Parkinson’s disease. Mov Disord. 2010;25 Suppl 1:S141-S145.

41.

Baker

L FL

Foster-Schubert

Green

, et al. Effects of aerobic exercise on mild cognitive impairment. Arch Neurol. 2010;67(1):71-79.

42.

Pereira

Viana

Taunay

Sales

Lima

Holanda

MA.

Improvement of cognitive function after a three-month pulmonary rehabilitation program for COPD patients. Lung. 2011;189(4):279-285.

43.

Pereira

Huddleston

Brickman

, et al. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci USA. 2007;104(13):5638-5643.

44.

Kinni

Guo

Ding

, et al. Cerebral metabolism after forced or voluntary physical exercise. Brain Res. 2011;1388:48-55.

45.

Hirsch

Farley

Exercise and neuroplasticity in persons living with Parkinson’s disease. Eur J Phys Rehabil Med. 2009;45(2):215-229.

46.

Voss

Prakash

Erickson

, et al. Plasticity of brain networks in a randomized intervention trial of exercise training in older adults. Front Aging Neurosci. 2010;2:32.

47.

Fini

Bernhardt

Said

Billinger

SA.

How to address physical activity participation after stroke in research and clinical practice. Stroke. 2021;52(6):e274-e277.

48.

Garber

Blissmer

Deschenes

, et al. American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med Sci Sports Exerc. 2011;43(7):1334-1359.

49.

Tang

Eng

Rand

Relationship between perceived and measured changes in walking after stroke. J Neurol Phys Ther. 2012;36(3):115-121.

50.

Boyne

Billinger

Reisman

, et al. Optimal intensity and duration of walking rehabilitation in patients with chronic stroke: a randomized clinical trial. JAMA Neurol. 2023;80(4):342-351.

51.

Hornby

Reisman

Ward

, et al. Clinical practice guideline to improve locomotor function following chronic stroke, incomplete spinal cord injury, and brain injury. J Neurol Phys Ther. 2020;44(1):49-100.

52.

Linder

Learman

Miller Koop

, et al. Increased comfortable gait speed is associated with improved gait biomechanics in persons with chronic stroke completing an 8-week forced-rate aerobic cycling intervention: a preliminary study. Am J Phys Med Rehabil. 2023;102(7):619-624.

53.

Brown

Kukulka

CG.

Human flexor reflex modulation during cycling. J Neurophysiol. 1993;69(4):1212-1224.

54.

Ting

Kautz

Brown

Zajac

FE.

Contralateral movement and extensor force generation alter flexion phase muscle coordination in pedaling. J Neurophysiol. 2000;83(6):3351-3365.

55.

Yang

Stein

RB.

Phase-dependent reflex reversal in human leg muscles during walking. J Neurophysiol. 1990;63(5):1109-1117.

56.

Raasch

Zajac

FE.

Locomotor strategy for pedaling: muscle groups and biomechanical functions. J Neurophysiol. 1999;82(2):515-525.

57.

Raasch

Zajac

Levine

WS.

Muscle coordination of maximum-speed pedaling. J Biomech. 1997;30(6):595-602.

58.

Kautz

Brown

DA.

Relationships between timing of muscle excitation and impaired motor performance during cyclical lower extremity movement in post-stroke hemiplegia. Brain. 1998;121 ( Pt 3):515-526.

59.

Liang

Brown

DA.

Foot force direction control during a pedaling task in individuals post-stroke. J Neuroeng Rehabil. 2014;11:63.

60.

Chen

Wang

YL.

Kinesiological and kinematical analysis for stroke subjects with asymmetrical cycling movement patterns. J Electromyogr Kinesiol. 2005;15(6):587-595.

61.

Linder

Rosenfeldt

Bazyk

Koop

Ozinga

Alberts

JL.

Improved lower extremity pedaling mechanics in individuals with stroke under maximal workloads. Top Stroke Rehabil. 2018;25(4):248-255.

62.

Chakraborty

Dey

Mukherjee

Alberts

Linder

SM.

Functional modeling of pedaling kinematics for the Stroke patients. J Biopharm Stat. 2020;30(4):674-688.

63.

Lee

Kilbreath

Singh

, et al. Comparison of effect of aerobic cycle training and progressive resistance training on walking ability after stroke: a randomized sham exercise-controlled study. J Am Geriatr Soc. 2008;56(6):976-985.