High-Intensity Interval Training After Stroke: An Opportunity to Promote Functional Recovery,Cardiovascular Health,and Neuroplasticity

Abstract

Introduction. Stroke is the leading cause of adult disability. Individuals poststroke possess less than half of the cardiorespiratory fitness (CRF) as their nonstroke counterparts, leading to inactivity, deconditioning, and an increased risk of cardiovascular events. Preserving cardiovascular health is critical to lower stroke risk; however, stroke rehabilitation typically provides limited opportunity for cardiovascular exercise. Optimal cardiovascular training parameters to maximize recovery in stroke survivors also remains unknown. While stroke rehabilitation recommendations suggest the use of moderate-intensity continuous exercise (MICE) to improve CRF, neither is it routinely implemented in clinical practice, nor is the intensity always sufficient to elicit a training effect. High-intensity interval training (HIIT) has emerged as a potentially effective alternative that encompasses brief high-intensity bursts of exercise interspersed with bouts of recovery, aiming to maximize cardiovascular exercise intensity in a time-efficient manner. HIIT may provide an alternative exercise intervention and invoke more pronounced benefits poststroke. Objectives. To provide an updated review of HIIT poststroke through (a) synthesizing current evidence; (b) proposing preliminary considerations of HIIT parameters to optimize benefit; (c) discussing potential mechanisms underlying changes in function, cardiovascular health, and neuroplasticity following HIIT; and (d) discussing clinical implications and directions for future research. Results. Preliminary evidence from 10 studies report HIIT-associated improvements in functional, cardiovascular, and neuroplastic outcomes poststroke; however, optimal HIIT parameters remain unknown. Conclusion. Larger randomized controlled trials are necessary to establish (a) effectiveness, safety, and optimal training parameters within more heterogeneous poststroke populations; (b) potential mechanisms of HIIT-associated improvements; and (c) adherence and psychosocial outcomes.

Keywords

high-intensity interval training stroke cardiovascular health neuroplasticity stroke recovery

Introduction

In 2013, the global prevalence of stroke was 25.7 million with a pooled cumulative 10-year risk of 39.2%.¹ Stroke survivors have approximately half the cardiovascular fitness (CRF)² and a 40% to 50% greater energy cost of walking compared with nonstroke individuals.³ These limitations facilitate an inactive lifestyle that results in further deconditioning and an increased risk of future cardiovascular events.⁴

Maintaining cardiovascular health is the most important strategy for lowering the risk of recurrent stroke,⁵ but historically, stroke rehabilitation programs provide limited opportunity for cardiovascular training,⁶ especially for high-intensity cardiovascular training. Physical activity and exercise recommendations poststroke include moderate-intensity continuous cardiovascular exercise (MICE) to improve CRF with a suggested intensity of 40% to 70% maximal oxygen consumption ( ${\dot{V} O}_{2 Peak}$ ) or heart rate reserve (HRR) or 50% to 80% of maximum heart rate (HRmax).⁷ While moderate-intensity cardiovascular exercise has been shown to improve different aspects of cognition⁸ and motor recovery,⁹ it may be difficult to perform at higher ranges of intensity, particularly for individuals with more severe motor impairments. This may limit their ability to achieve and sustain sufficiently high intensities to optimize benefit.¹⁰ Cardiovascular exercise is a cost-effective intervention poststroke that improves different aspects of cognition⁸ and motor recovery.⁹ In individuals without known disability, cardiovascular exercise induces profound changes in the structure and function of different areas of the brain,¹¹ however, such changes have yet to be examined poststroke. Optimal training parameters to maximize neuroplasticity and functional recovery poststroke also remain unknown.¹²

High-intensity interval training (HIIT) has emerged as a powerful time-efficient alternative to MICE for individuals without known disability,¹³ as well as clinical populations.^14-16 HIIT is characterized by high-intensity bursts of cardiovascular exercise interspersed between bouts of recovery and aims to maximize exercise intensity with a lower time commitment and total exercise volume.¹³ HIIT has been shown to be more time-efficient¹⁶ and an effective alternative to traditional MICE training, with evidence showing similar or even superior adaptations despite substantially lower exercise volumes in both clinical and non-clinical populations.¹³ Current evidence suggests that HIIT is superior to MICE in individuals with heart disease,¹⁴ with greater ${\dot{V} O}_{2 Peak}$ improvement observed in HIIT groups. Arguably, recent findings from a large randomized controlled trial in 261 individuals with heart failure reported that both HIIT and MICE may provide similar benefits, although the authors acknowledged that the less compelling findings may be due to contamination issues (HIIT participants not attaining target exercise intensities and MICE participants exceeding targets),²⁰ making comparisons between groups difficult. More research, therefore, is required.

HIIT could supplement the low cardiovascular intensity typically achieved in stroke rehabilitation programs by achieving higher intensities required to optimize recovery.¹⁰ Importantly, the exercise parameters in HIIT may be adapted to suit the needs of different populations and training objectives.²¹ Despite the perceived benefits, there exist noteworthy barriers to the implementation of HIIT within the stroke population, including cardiovascular deconditioning,²² stroke-related neurological sequelae such as motor and balance impairments²³ and an even greater cardiovascular stress on individuals with stroke²⁴ compared with MICE. Safety, therefore, needs to be assured through rigorous trials.

Poststroke HIIT protocols may be categorized into 3 main types depending on high-intensity burst duration, recovery duration, and recovery type.²² Short-interval HIIT maximizes time spent at a high percentage of ${\dot{V} O}_{2 Peak}$ with short, supramaximal high-intensity bursts (100%-120% ${\dot{V} O}_{2 Peak}$ ) lasting 15 to 60 seconds at a 1:1 burst to recovery ratio.²² Low-volume HIIT yields high neuromuscular intensity, with short, high-intensity bursts of 10 to 60 seconds at a near maximal or maximal absolute or anaerobic workload and burst to recovery ratios at 1:2 or 1:4 minutes with active recovery to mitigate any potential symptoms of dizziness secondary to venous blood pooling.²² Long-interval HIIT is also designed to maximize time spent at a high percentage of ${\dot{V} O}_{2 Peak}$ , but encompasses longer high-intensity bursts (3-4 minutes) at lower workloads (80%-90% ${\dot{V} O}_{2 Peak}$ ) and a burst to recovery ratio of 1:1 or 4:3 with active recovery.²²

Albeit preliminary, recent evidence suggests effectiveness in HIIT-associated functional,^17-19 cardiovascular,¹⁷ and neuroplastic^25,26 outcomes in individuals poststroke. HIIT may provide an alternative exercise option with the potential to invoke more pronounced cardiovascular and cerebrovascular benefits.

The aim of this article is to provide an updated review of HIIT in stroke rehabilitation practice by (a) synthesizing the current evidence regarding the safety and effectiveness of HIIT on functional mobility and novel outcomes of neuroplasticity and cardiovascular outcomes poststroke; (b) offering considerations for optimizing exercise parameters for HIIT within the stroke population; (c) exploring potential mechanisms underlying improvements in functional, cardiovascular, and neuroplastic outcomes following HIIT; and (d) discussing clinical implications and informing directions for future research for HIIT in stroke rehabilitation.

Current Evidence Surrounding the Safety and Effectiveness of HIIT in Stroke

Is HIIT Safe in Individuals With Stroke?

Among individuals with coronary artery disease,¹⁴ myocardial infarction^14,27 and heart failure,²⁸ there have been only 2 nonfatal cardiac arrests in more than 46 000 hours of HIIT during cardiac rehabilitation, with occurrences similar to MICE.²⁹ To reduce the risk of adverse events during HIIT training poststroke, preemptive medical screening and careful monitoring of heart rate, blood pressure and rating of perceived exertion (RPE) during exercise has been implemented.²² In addition, because of the high occurrence of silent myocardial ischemia rates reported within the stroke population, exercise testing with electrocardiography is recommended prior to initiating cardiovascular exercise.⁷ Continuous telemetry may be used but may not be available in many stroke rehabilitation settings.²² In research studies, the risk of orthopedic injury has been minimized by excluding individuals with primary orthopedic conditions (eg, fractures, active rheumatoid arthritis) or severe motor impairments (eg, inability to walk without assistance^18,19,30) and incorporating the use of body weight support, orthotic devices (eg, splints and ankle-foot orthoses) or providing handrail support as needed during training.²² With such prospective safety monitoring in place, no serious adverse events were observed in the 10 studies that were identified to date,^{17-19, 23, 25, 26, 30-33} and only 2 occurrences of symptomatic hypotension and near syncope during recovery.³¹

Important to consider is the response within the cerebrovasculature, which is different than the periphery.⁷² High-intensity exercise has the potential to provoke rapid increases in blood pressure that may be transferred to the cerebrovasculature.⁷² This might, theoretically, increase the risk of hyperperfusion injury⁷² subsequent to functional impairments in dynamic cerebral autoregulation. While this may be of concern, whether the degree of hypertensive response induced with high-intensity exercise is potentially damaging has not been confirmed. Intense exercise in individuals without disability has the potential to increase blood-brain barrier permeability without causing structural brain damage.³⁵ From a practical perspective, however, it appears prudent to mitigate this potential risk on the cerebrovasculature by gradually increasing the exercise intensity over the first 10 seconds of every high-intensity burst.⁷²

There is also the potential for hypotensive responses secondary to venous pooling during recovery periods,³¹ which highlights the importance of adequate hydration, and considering the use of seated recovery positions over standing positions to minimize fall risk. While using active, rather than passive, recovery may be applied to mitigate hypotensive responses, clinicians should be aware that active recovery may decrease HIIT tolerance.²²

Collectively, the evidence suggests that HIIT is a safe approach with no reports of serious adverse events poststroke. However, implementing large randomized controlled trials to investigate safety in a broader range of stroke populations, such as subacute and chronic stroke and with and without comorbid conditions, would be beneficial.

Is HIIT Effective in People Poststroke?

To date, 10 studies including 5 training studies^17-19,23,30 (3 randomized controlled trials^17-19) and 5 single-session studies^25,26,31-33 have investigated the potential application of HIIT within the context of stroke. To summarize the evidence around the effectiveness of HIIT after stroke, findings from these 3 randomized trials are presented in Table 1, panel A. Additionally, studies examining outcomes of tolerance and feasibility^31-33 (of which one was an abstract³¹) and markers of neuroplasticity^25,26 are presented in Table 1, panel B. Together, preliminary results from randomized trials suggest that HIIT may be effective in improving mobility and gait outcomes and cardiovascular health and shows preliminary evidence of positively influencing neuroplasticity.

Table 1.

Summary of (A) Training Studies and (B) Single-Session Studies Investigating HIIT in Individuals Poststroke.

Study, Design, and Population	Groups (n)	Frequency, Intensity, Time, Type Parameters		Results
A. Training studies:
Boyne et al (2016)¹⁷ • Randomized controlled trial • Ambulatory stroke survivors • >6 months poststroke	HIIT n = 13 MICE n = 5	HIIT: Frequency: • 3 times per week for 4 weeks Intensity: • HIIT: Started at 0.1 mph below maximum safe speed and held for 30 seconds. • Recovery: rest for 60 seconds (sessions 1-3); rest for 60 seconds for initial 3 HIIT bursts then rest for 30 seconds for remainder of HIIT bursts (sessions 4-12) Time: • Total HIIT time: 8 minutes (sessions 1-3), 12.5 minutes for sessions 4-12) • Total session time: 25 minutes Type: • Treadmill	MICE: Frequency: • 3 times per week for 4 weeks Intensity: • Speed adjusted to maintain 45% ± 5% HRR for weeks 1-2 • Progressed to 50% ± 5% HRR after 2 weeks for weeks 3-4 Time: • 25 minutes Type: • Treadmill	Significant findings: • Ventilatory threshold ES 1.95* compared with MICE • Fractional utilization of O₂ ES 1.74* compared with MICE • Fastest treadmill speed ES 1.68* compared with MICE • 10MWT ES 1.44* compared to MICE Nonsignificant findings: • No pre-post changes observed within MICE group • 6MWT between groups Other • No serious adverse events • 85% attendance for HIIT sessions • In HIIT, 3 participants not able to complete all 25 minutes of training for 1 to 2 sessions, (ranging from 22 to 23 minutes)
Lau et al (2011)¹⁸ • Randomized controlled trial • <1 month poststroke	HIIT n = 13 MICE n = 13	HIIT: Frequency: • 5 times per week for 2 weeks Intensity: • HIIT: maximum safe speed for 30 seconds • Recovery: rest for 2 minutes Time: • Total HIIT time: 4-5 minutes • Total session time: 30 minutes Type: Treadmill	MICE: Frequency: • 5 times per week for 2 weeks Intensity: • Treadmill belt speed adjusted to fastest overground walking speed Time: • 30 minutes Type: • Treadmill	Significant Findings: • Gait speed P = .014* compared with MICE • Stride length P = .027* compared with MICE Nonsignificant findings: • Walking cadence • Berg Balance Scale Other: • No adverse events • All subjects completed each session
Pohl et al (2002)¹⁹ • Randomized controlled trial • >4 weeks poststroke with hemiparesis	HIIT (Speed-dependent treadmill training) n = 20 MICE (Limited progressive treadmill training) n = 20 Control (Conventional gait therapy) n = 20	HIIT: Frequency: • 3 times per week for 4 weeks Intensity: • HIIT: Increase to maximum safe speed for 1-2 minutes, then held for 10 seconds • Recovery: Active recovery until HR to return to rest Time: • Total HIIT time: Dependent on recovery time (time to resting HR) • Total session time: 30 minutes Type: • Treadmill	MICE: Frequency: • 3 times per week for 4 weeks Intensity: • Speed increased <5% of maximum initial walking speed each week Time • 30 minutes Type • Treadmill Control: • 45 minutes of gait training using proprioceptive neuromuscular facilitation and Bobath concepts	Significant findings: • Walking speed HIIT vs MICE P < .001; HIIT vs Control, P < .001 • Cadence HIIT vs MICE P < .007; HIIT vs. Control P < .001 • Stride length HIIT vs MICE P < .001; HIIT vs Control P < .001 • Functional Ambulation Category score HIIT vs MICE P < .007; HIIT vs Control P < .001 Nonsignificant findings: • Not reported Other: • No adverse events
B. Single-session studies:
Boyne et al (2014)³² • Single session crossover • >6 months poststroke	HIIT n = 18 3 single-session HIIT protocols with differing recovery periods: 30 seconds (P30), 60 seconds (P60), 120 seconds (P120)	HIIT: Frequency: • Single sessions for each of 3 protocols, each scheduled 1 week apart Intensity: • HIIT: 0.1 mph below fastest safe walking speed for 30 seconds • Recovery: Rest for 30 seconds (P30), 60 seconds (P60) or 120 seconds (P120) Time: • Total HIIT time: P30 = 10 minutes, P60 = 7 minutes, P120 = 4 minutes • Total session time: 20 minutes Type: • Treadmill		Significant findings • Highest mean ${\dot{V} O}_{2 Peak}$ , HR, and step count with P30 • Reduced exercise tolerance and lower treadmill speed with P30 compared with P60 or P120 • Treadmill speed and exercise tolerance similar between P60 and P120, but higher mean ${\dot{V} O}_{2 Peak}$ , HR, and step count. Nonsignificant findings: • Time spent at or above moderate intensity between P30 and P60 Other • No serious adverse events • Fewer subjects able to complete P30 compared with P120
Carl et al (2017)³³ • Single session crossover • >6 months poststroke	HIIT n = 18 3 single-session HIIT protocols with differing recovery periods: 30 seconds (P30), 60 seconds (P60), or 120 seconds (P120)	HIIT Frequency: • Single session Intensity: • HIIT: 0.1 mph below fastest safe walking speed and held for 30 seconds • Recovery: Rest for 30 seconds (P30), 60 seconds (P60) or 120 seconds (P120) Time: • Total HIIT time: P30 = 10 minutes, P60 = 7 minutes, P120 = 4 minutes • Total session time: 20 minutes Type: • Treadmill		Significant findings: • Maximal HRs during P30, P60, and P120 were 97%, 95%, and 88% of HRpeak from the GXT and 78%, 77%, and 71% of age-predicted HRmax, respectively • P30 and P60 had higher % HR peak than P120 • 44% of participants exceeded HRpeak from the GXT for P30, 33% for P60, and 11% for P120 (P < .01). Other: • No arrhythmias, myocardial ischemia, uncontrolled hypertension, symptomatic hypertensive responses, or orthopedic injury observed with electrocardiography pre-screening • No serious adverse events on 54 HIIT sessions
Carl et al (2016)³¹ • Single session crossover • >1 year poststroke	HIIT n = 16 3 sessions 1. Moderate treadmill (Mod-TM) 2. High-intensity interval training treadmill (HIIT-TM) 3. High-intensity interval training recumbent stepper (HIIT-RS)	HIIT Frequency: • Single session Intensity: • HIIT: Maximal safe walking speed (treadmill) or maximal power output (recumbent stepper) for 30 seconds • Recovery: Rest 60 seconds Time: • Total session time: 20 minutes Type: • Treadmill (Mod-TM and HIIT-TM) and recumbent stepper (HIIT-RS)		Significant findings: • With original HIIT-RS, hypotension and near syncope observed in 2 of 9 participants. Revised HIIT-RS included HR limitations with 7 of 7 subjects completed with no adverse events • Blood lactate accumulation response to original HIIT-RS higher than HIT-TM and Mod-TM (P = .001)* • Hematocrit in original HIIT-RS greater than HIT-TM (P = .035)* but revised HIIT-RS not different from HIIT-TM (P = .51) and Mod-TM (P = .12). Nonsignificant findings: • BLA response to the revised HIT-RS from original HIIT Other: • No adverse events with Mod-TM or HIIT-TM
Madhavan et al (2016)²⁵ • Single session crossover • Chronic stroke (9 ± 1.8 years poststroke)	HIIT n = 11 2 HIIT sessions: HIIT alone and HIIT + transcranial direct current stimulation	HIIT Frequency: • Single session, 1 week apart Intensity: • HIIT: 1-2 minutes at fastest speed tolerated, then held for 10 seconds • Recovery: Active recovery until HR to return to rest Time: • Total HIIT time: Dependent on time to resting HR • Total session time: 30 minutes Type: • Treadmill		Significant findings: • Interaction for RPE (P = .015) • Main effect of time for HR (P < .001) • HIIT alone reduced paretic M1 excitability in 7 of 11 participants by ≥10%. • Transcranial direct current stimulation + HIIT increased paretic tibialis anterior M1 excitability and decreased nonparetic tibialis anterior M1 excitability. Nonsignificant findings: • Overground gait speed • Baseline MEP slopes for the NP TA and P TA between the 2 sessions. Other: • No adverse events • All participants could complete their treadmill training sessions without a need to discontinue • No adverse effects of transcranial direct current stimulation or treadmill training
Nepveu et al (2017)²⁶ • Randomized controlled trial • Chronic stroke (26.2 ± 15 months poststroke)	HIIT n = 22 3 Experimental sessions 1. GXT and transcranial magnetic stimulation to evaluate corticospinal excitability, intracortical facilitation, short-interval intra-cortical inhibition and the cortical silent period 2. Practice of motor task then performed either HIIT or Control 3. Test of motor task to assess skill retention	HIIT Frequency: • Single session Intensity: • HIIT: 3 minutes at 100% peak workload from GXT • Recovery: 2 minutes at 25% peak workload from GXT Time: • Total session time: 15 minutes Type: • Recumbent stepper	Control • No exercise: Rested for same time period as HIIT training	Significant findings: • Short-interval intracortical inhibition interhemispheric ratio (P = .05) • Better skill retention in HIIT group (P = .04) Nonsignificant findings: • Resting and active corticospinal excitability measures • Intracortical facilitation, cortical silent period and interhemispheric ratios Other: • No adverse events

Abbreviations: HIIT, high-intensity interval training; MICE, moderate-intensity continuous exercise; ES, effect size; 6MWT, 6-minute walk test; HRR, heart rate reserve; 10MWT, 10-meter walk test; ${\dot{V} O}_{2 Peak}$ = oxygen consumption; RPE, rating of perceived exertion; GXT, graded exercise test.

P < .05.

HIIT Is Associated With Mobility and Gait Improvements

Of the 3 randomized controlled trials, Pohl et al¹⁹ reported that low-volume treadmill HIIT resulted in the greatest improvements in fastest overground walking speed, cadence, stride length, and functional ambulation compared with a more conventional limited progressive treadmill training protocol and a control group. Lau and Mak¹⁸ reported that a low-volume treadmill HIIT protocol was effective at improving overground gait speed and step length compared with steady speed and Boyne et al¹⁷ reported that a short-interval treadmill HIIT protocol resulted in greater improvements in fastest treadmill speed compared to MICE training. Two additional single-group pre-post studies demonstrated that long-interval treadmill HIIT was effective in improving fastest overground walking speed, Timed Up and Go, gait economy,³⁰ and 6-Minute Walk Test distance.^23,30 While the aforementioned studies were conducted across multiple phases of stroke recovery (<1 month poststroke, >4 weeks poststroke, and 3 months to 9 years poststroke) studies with larger sample sizes and examining the effects of HIIT on different markers of neuroplasticity across all stages of stroke recovery appear to be the primary need.

HIIT Improves Cardiovascular Health

Exercise intensity has been shown to influence cardiovascular health in young nonclinical populations, with evidence showing that, with consistent exercise volumes, higher exercise intensities are more effective in improving CRF.³⁴ CRF plays a critical role in managing cardiovascular risk, with a 1-MET (metabolic equivalent; 3.5 mL/kg/min) increase translating into a 10% to 25% improvement in survival.³⁶ It is crucial to identify the most effective ways to improve and maintain CRF in the stroke population. Improvements in ${\dot{V} O}_{2 Peak}$ ³⁰ and ventilatory threshold,¹⁷ markers of CRF, have been observed following short-interval¹⁷ and long-interval HIIT³⁰ poststroke. More rigorous research is warranted, however, to determine the relative effectiveness of HIIT versus MICE to improve CRF, as only one study examining markers of CRF was a randomized controlled trial.¹⁷

Taken together, the aforementioned body of evidence reveals the following early trends: (a) preliminary feasibility and effectiveness of low-volume HIIT on improving gait parameters in ambulatory individuals in the subacute phase of stroke^18,19; (b) initial effectiveness of long-interval HIIT among very high-functioning people poststroke³⁰ or individuals with mild-moderate chronic stroke²³ where long burst intervals and active walking recovery provides the most stepping practice²²; and (c) short-interval HIIT on a treadmill improves ventilatory threshold and walking speed,¹⁷ outcomes attributable to the high exercise intensity and task-specific walking practice.²²

HIIT May Promote Neuroplasticity

Establishing strategies to enhance neuroplasticity is critical to promote motor recovery poststroke.⁴² HIIT may facilitate neuroplasticity and motor learning after stroke, although to date, studies are limited to either poststroke animal models,¹² single-session exercise sessions poststroke^25,26 or healthy populations.³⁸

In animal models of stroke, a recent review suggests that higher exercise intensities were necessary to optimize the expression of neurotrophins and modify synapses and dendrites to promote neuroplasticity.¹² Within healthy humans, a single 20-minute bout of HIIT at 90% of maximal power output enhanced corticospinal excitability, a marker of neuroplasticity within the motor cortex,³⁸ whereas another study found no effects following a single 30-minute bout of MICE training at 60% ${\dot{V} O}_{2 Peak}$ .³⁹ Skriver et al⁴⁰ demonstrated that a single bout of HIIT was associated with an elevated level of peripheral concentration of brain-derived neurotrophic factor, a neurotrophin that plays an important role in many functional and structural processes of neuroplasticity. A single bout of HIIT has also shown to improve motor skill retention in healthy individuals⁴¹ as well as individuals poststroke²⁶ with effects appearing to be intensity dependent.⁴²

Within a stroke population, a single bout of HIIT performed immediately after motor practice improved skill retention after 24 hours, demonstrating the potential for HIIT to trigger modest neuroplastic changes and accelerate neurorecovery.²⁶ Notably, skill level was increased at retention, suggesting that a single bout of HIIT may not only strengthen procedural memories but also foster off-line gains occurring between practice sessions.²⁶ It is possible that repeated bouts of HIIT combined with motor practice may show a cumulative effect on motor learning gains and thus accelerate functional recovery.^26,43

In summary, the exercise intensity and ideal time poststroke to initiate cardiovascular exercise to optimally influence neuroplasticity following a stroke remain unknown.¹² In poststroke animal models, delaying rehabilitation to 30 days postevent have failed to show beneficial effects compared to 5 to 14 days poststroke, implying that there is an early window of opportunity to influence neuroplasticity.¹² There may be a critical period within the first few months poststroke in humans where neuroplasticity is most influenced by exercise.⁴⁴ However, exercise very acutely postevent may not be beneficial for recovery.⁴⁵ Determining more definitively when the brain is most responsive to change would be an important consideration for future trials.

HIIT and the Potential to Promote Exercise Enjoyment and Influence Exercise Adherence

A unique feature of HIIT is its potential to improve exercise enjoyment, and ultimately adherence.⁴⁶ HIIT interventions may have limited reach, effectiveness, adoption, and maintenance secondary to its potentially unpleasant stimulus.⁴⁶ However, adherence to HIIT and exercise enjoyment has been shown to be similar or superior to that of MICE in healthy individuals⁴⁷ and those with cardiometabolic disease.¹⁶ The ability to vary the exercise parameters of HIIT makes it an adaptable exercise option for many ages and populations.²² In addition, because of its high time-efficiency, HIIT may appeal to both clinicians and patients who are often under time constraints. However, whether HIIT may be an effective strategy to promote long-term exercise adherence and effectiveness, greater physical activity enjoyment and improved psychosocial outcomes poststroke remains unknown.

Considerations for Optimizing Exercise Parameters for HIIT Poststroke

Frequency

Although limited, current evidence from 3 randomized controlled trials^17
-19 suggests that the health benefits of HIIT after stroke can be achieved by exercising 2-3 times per week for 4 weeks. Delivering HIIT 5 times per week for as little as 2 weeks has led to greater improvements in gait speed and stride length,¹⁸ while training 3 times per week for 4 weeks resulted in greater improvements compared with MICE protocols in gait (gait speed,^17,19 gait economy,¹⁷ cadence,¹⁹ stride length¹⁹), function (Functional Ambulation Category¹⁹), and CRF (ventilatory threshold¹⁷).

Recovery time following a HIIT session is important to consider, as recent evidence suggests a minimum of 3 days between training sessions in older adults (mean age 63 ± 3.4 years) to recover optimally and reduce the risks associated with accumulated fatigue, both of which may hinder exercise adherence.⁴⁸ It may be prudent, therefore, to initially prescribe 2 days per week of training particularly in older adults with stroke, and increasing as tolerated.

Intensity

Prescribing exercise intensity based on % ${\dot{V} O}_{2 Peak}$ or HRR may be well suited for prolonged and submaximal exercise bouts used in conventional MICE training and long-interval HIIT, but may have limited effectiveness for short interval and low-volume HIIT protocols because of the short time intervals during high-intensity blocks to achieve the desired HR.²¹ Rather, prescribing intensity according to the power output associated with a percentage of ${\dot{V} O}_{2 Peak}$ may be a more effective method for HIIT.²¹ This approach combines ${\dot{V} O}_{2 Peak}$ and the energy cost of the activity into a single metric, and thus is more representative of an individual’s motor ability.²¹ This method of prescribing intensity uses the lowest power output required to elicit ${\dot{V} O}_{2 Peak}$ as a reference point for prescribing intensity for HIIT.²¹ Workload is also easier to control when a cycle or recumbent stepper is used, which are commonly available in stroke rehabilitation settings.

Intensity appears critical to modulate the effects of cardiovascular training on neuroplasticity and motor learning.^38,39 In individuals without disability, pairing an acute bout of high-intensity exercise at workloads associated with 90% of peak power output with skilled motor practice was effective in improving motor learning,³⁸ while moderate-intensity exercise at a power output associated with 60% ${\dot{V} O}_{2 Peak}$ was not.³⁹ Moreover, cardiovascular exercise performed at very high work intensities (ranging from 200 to 315 W) stimulated the release of biomarkers, such as BDNF, involved in memory and learning processes.⁴⁰ More mechanistic studies, however, are needed to determine specific roles of biomarkers in the formation of motor memory. It is unclear whether BDNF is a valid marker of central nervous system plasticity^40,49 or whether an increase in peripheral BDNF means an increase in BDNF found within the brain.⁵⁰

Modalities that allow clinicians to directly monitor and easily adjust power output, such as cycle ergometers or steppers, may be preferred particularly in the early stages of HIIT training, as power output can be easily and immediately changed. Moreover, these types of seated modalities are safer than a treadmill and allow for individuals with a broad range of function to participate. In principle, if the goal is to increase cardiovascular intensity, steppers are more appropriate, especially for patients with biomechanical limitations or balance impairments affecting gait. Treadmills are beneficial if balance or biomechanical limitations are not present at high intensities of walking. Also, due to the type of movement, treadmills could possibly lead to a larger transfer of locomotor gains. It is important to note, however, that changes in gait efficiency commonly observed after stroke⁷ may confound intensity prescription during walking exercise. Thus, it may be more appropriate to prescribe treadmill HIIT based on maximum safe walking speed.^17-19,31,33

RPE may also be used in conjunction with measures such as HR, blood pressure, or power output, to ensure that exercise intensity is maintained within tolerable limits.^17,25,26 The RPE method allows for a simple and versatile way of measuring an individual’s subjective level of exertion. An RPE of 14 to 16 on the BORG 6 to 20 scale is considered to be “high-intensity.”¹⁰ Given that 62% of individuals with stroke have been found to have silent coronary artery disease and may be prescribed beta-blockers,⁵¹ the RPE allows individuals the option to self-regulate their exercise intensity when HR is not a viable option and when a high-quality symptom-limited exercise test measuring peak HR on the beta-blocker is not available. The RPE can be a universal “exercise regulator” that can be used regardless of environment,²¹ with special consideration given to individuals with communication impairment (eg, aphasia) following stroke where the scale may need to be represented in pictorial form.⁵² Alternatively, another method to prescribe exercise HR with beta-blocker use is a modified Karvonen equation equal to 0.8 × (maximum heart rate − resting heart rate) + resting heart rate.⁵³

Time

Within the literature on HIIT in stroke, session durations ranged from 20 to 30 minutes^17-19,23,30 but burst to recovery ratios were highly variable amongst studies, ranging from 30 seconds:30 seconds¹⁷ to 4 minutes:3 minutes.²³ Arguably, these studies examining HIIT poststroke enrolled higher functioning participants who had the ability to walk independently with or without assistive devices^{17-19,25,26,33} and could walk safely on a treadmill.^17,18,32,33 For individuals who are not able to walk independently or who may not be able to withstand longer intervals and longer session durations, protocols may require adaptation, particularly at the commencement of the exercise training.¹⁰

Type

Most studies to date of HIIT in stroke have focused on the use of treadmill walking,^17-19,23,30 either with^19,23 or without¹⁷ body weight support while one study (abstract) of single-session HIIT used a recumbent stepper.³¹ While the task-specificity nature of treadmill training has led to improvements in gait and functional outcomes after stroke,^17-19,23,30 its application in the literature to date has been limited to individuals who are able to walk without physical assistance from another individual or when the necessary resources, such as body weight support apparatus and trained staff, are available. Supported modalities, such as the recumbent stepper, have been studied less but offer the opportunity to include individuals with a broader range of functional abilities and have been shown to increase CRF.⁵⁴ Thus, given the task-specificity of treadmill walking, this modality would be recommended for functional gains in walking ability if safety permits, whereas a seated modality such as recumbent stepper may be more feasible for increasing CRF in people with lower functional abilities that are not able to safely walk on a treadmill.

In summary, while various combinations of the FITT parameters may lead to a range of benefits, individualized protocols are warranted. While the above considerations appear to yield improvements in gait, function, and cardiovascular health, they are based on limited evidence regarding HIIT in the stroke population and a wide range of dosing. Based on the current body of evidence, Table 2 offers considerations for FITT parameters for clinicians to consider when prescribing HIIT poststroke.

Table 2.

Frequency, Intensity, Time, and Type Dosing Within Current Literature.

Parameter	Dosing Range
Frequency	2-5 days per week for 2-4 weeks
Intensity	Fastest safe walking speed (for mobility gains) or 85%-95% heart rate reserve or power output associated with 90%-100% ${\dot{V} O}_{2 Peak}$
Time	Session time: • 25-30 minutes Burst-to-recovery ratio: • 30 seconds:30-60 seconds to 3 minutes:4 minutes
Type	Treadmill if safe, or recumbent stepper with careful monitoring of intensity to mitigate potential hypotensive responses

Potential Mechanisms Underlying Improvements in Functional, Cardiovascular, and Neuroplastic Outcomes With HIIT

While there exists little research to date examining specific mechanisms underlying the benefits of HIIT poststroke, evidence of potential mechanisms from other populations may be extrapolated.

Potential Mechanisms Underlying Improved Functional Outcomes

An increase in neuromuscular recruitment during treadmill training in nondisabled individuals may lead to improved oxidative capacity and efficiency within skeletal muscle.⁵⁵ This may also be a potential mechanism by which treadmill HIIT aids in improved functional outcomes following stroke where decreased oxidative capacity in skeletal⁵⁶ can be a result of decreased neuromuscular recruitment.⁵⁷ Indeed, it has been shown that, after controlling for training frequency and duration, higher treadmill speeds yield more positive functional outcomes after stroke than general rehabilitation exercises alone.^18,19 Moreover, the rest periods provided in HIIT allow opportunities for feedback from therapists and mental practice during the training session, which involves a high level of cognitive processing and may lead to enhanced motor practice.⁵⁸

Potential Mechanisms Underlying Improved Cardiovascular Health

Studies investigating HIIT versus MICE in individuals with cardiometabolic disease have shown that amelioration of peripheral mitochondrial dysfunction (typically present in many chronic diseases) may play a role in improving CRF.¹⁶ Increased mitochondrial biogenesis, essential to the structural integrity of skeletal muscle,⁵⁹ occurs even after a single bout of low-volume HIIT in nondisabled individuals through increased PGC-1α, which is correlated with improved CRF.¹³ Additionally, increases of 50% to 60% in maximal rate of Ca²⁺ uptake into the sarcoplasmic reticulum have been observed in individuals with cardiometabolic disease following HIIT.⁶⁰ This may decrease muscle fatigue and improve skeletal muscle function, ultimately leading to improvements in CRF. Repeated bouts of deoxygenation that occur during HIIT compared with MICE may also contribute to adaptations in skeletal muscle oxidative capacity.¹⁶

Centrally, HIIT has been shown to improve cardiac ejection fraction in individuals with heart failure, showing the potential for HIIT to influence left ventricular remodeling.⁶¹ Compared with MICE, HIIT has also lead to greater improvements in stroke volume, mitral annular excursion, ejection velocity and systolic mitral annular velocity in individuals with metabolic syndrome.¹⁶ Arguably, whether these mechanisms apply to the poststroke population is not known. Given that individuals poststroke typically yield a lower absolute power output and a dose-response with intensity and improvements in cardiovascular health in stroke is unknown, we are proposing that similar possible mechanisms may be seen after stroke, but further research is needed.

Shear stress–mediated improvements in endothelial function within the systemic vasculature may also provide insight into improved cerebrovascular function.⁶² Animal models show strong evidence of shear stress–mediated improvements in endothelial function within the cerebrovasculature⁶² brought on through chronic exercise. In healthy adults, HIIT has been shown to induce acute improvements in systemic flow–mediated vasodilation.⁶³ As well, nitric oxide bioavailability is greater following HIIT compared with MICE,⁶⁴ suggesting that there may be other mechanisms contributing to improved vascular function beyond increases in shear stress stimulus. Arguably, an acute bout of exercise at high-intensity stimulates oxidative stress and transient endothelial dysfunction, but the overall improvements to endothelial function prevail as greater nitric oxide bioavailability is observed a few hours later.⁶⁵ It is unclear, however, whether such systemic effects of arterial function can be extrapolated to the cerebrovasculature, and the role of exercise intensity in mediating these effects remains unknown.⁶⁶

Potential Mechanisms Underlying Changes in Neuroplasticity

Evidence surrounding whether cardiovascular exercise can have positive effects on cognition shows mixed results. Cardiovascular exercise has been shown to improve cognition in healthy individuals⁶⁴ through positive changes in the structure and function of different areas of the brain, including gray matter and hippocampal neurogenesis.¹¹ However, a recent Cochrane review suggests no evidence that aerobic physical activities that improve cardiorespiratory ﬁtness, have any cognitive beneﬁt in healthy older adults.⁶⁷ Cardiovascular exercise also promotes changes within the primary motor cortex (M1), a key target area to improve motor recovery following a stroke.⁶⁸ Even a single bout of cardiovascular exercise activates neuroplastic mechanisms responsible for motor learning.⁶⁹

Intensity has been shown to be critical in modulating the neuroplastic and motor learning effects of cardiovascular training in healthy individuals. Higher intensities of cardiovascular exercise are required to increase the expression of brain-derived neurotrophic factor and insulin-like growth factor I, neurotrophins that modulate neural repair processes in animal models,¹² leading to neuroplastic and motor recovery benefits.^12,70 HIIT-associated increases in corticospinal excitability³⁸ and brain-derived neurotrophic factor⁴⁰ may explain the improvements in motor learning in healthy individuals³⁸ and retention of motor skills after stroke.²⁶ An additional key characteristic of HIIT is the sinusoidal high-low flow through the brain and across the cerebrovascular endothelium, which may be a candidate stimulus that optimizes release of vasoactive/growth factors.⁷¹

Overall, while we can extrapolate potential mechanisms underlying HIIT-associated improvements from other populations, further research is warranted to establish mechanisms that may be responsible for the effects of HIIT within the stroke population and to align mechanistic changes with meaningful improvement in cognitive or motor recovery.

HIIT: Clinical Implications and Considerations for Future Direction of HIIT Poststroke

HIIT has shown to be effective at enhancing functional recovery,^17,23,30 CRF,^17,30 and gait parameters^17-19,23,30 within stroke survivors. HIIT has the potential to be integrated into clinical practice to remediate functional impairments following stroke, however, further pragmatic study is warranted to establish the feasibility, safety, and efficacy to guide implementation. HIIT has the potential to contribute to enhanced neuroplasticity and motor recovery poststroke, as higher exercise intensities are required to enhance the expression of neurotrophins that augment neural repair processes.^36-38 Training parameters to optimize functional and health benefits still need to be established. Moreover, future research should address the effectiveness of HIIT among individuals with a broader range of functional abilities, along with larger trials to establish the effectiveness of HIIT across all phases of stroke recovery.

The application of HIIT in individuals with stroke has been shown to improve cardiovascular function and motor performance.^17-19,23,30 Optimal HIIT parameters, as well as HIIT-associated benefits to neuroplasticity and cerebrovascular function, and for those with lower functional abilities who are unable to walk, remain largely unknown. Larger randomized controlled trials are necessary to establish (a) the safety and effectiveness of HIIT within a broader range of functional abilities in the stroke population; (b) potential mechanistic pathways underlying HIIT-associated improvements in functional mobility, cardio- and cerebrovascular function, and neuroplasticity; and (c) adherence, motivation, and enjoyment rates of HIIT compared with MICE training protocols.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Canadian Stroke Trials for Optimized Results (CaSTOR), a joint initiative of the Canadian Stroke Consortium and HSF Canadian Partnership for Stroke Recovery. MR was supported with funds from the Reseau Provincial de Recherche en Adaptation-Readaptation (Recherche Clinique), the Canada Foundation for Innovation (John R. Evans Leaders Fund) and the Montreal Centre for Interdisciplinary Research in Rehabilitation (New Investigator Fund). AT was supported by a personnel award from the Heart and Stroke Foundation, Ontario Provincial Office (CS I 7468). DMB is supported by a Royal Society Wolfson Research Merit Award (No. WM170007) and has also received support from the Higher Education Funding Council of Wales. MP is funded by the Canada Research Chairs program. We acknowledge support from the Canada Research Chair Program (to JJE).

ORCID iD

Ada Tang

References

Mohan

Wolfe

CDA

Rudd

Heuschmann

Kolominsky-Rabas

Grieve

AP.

Risk and cumulative risk of stroke recurrence: a systematic review and meta-analysis. Stroke. 2011;42:1489-1494. doi:10.1161/STROKEAHA.110.602615.

MacKay-Lyons

Makrides

Exercise capacity early after stroke. Arch Phys Med Rehabil. 2002;83:1697-1702.

Baert

Daly

Dejaeger

Vanroy

Vanlandewijck

Feys

Evolution of cardiorespiratory fitness after stroke: a 1-year follow-up study. Influence of prestroke patients’ characteristics and stroke-related factors. Arch Phys Med Rehabil. 2012;93:669-676.

Billinger

Coughenour

MacKay-Lyons

Ivey

FM.

Reduced cardiorespiratory fitness after stroke: biological consequences and exercise-induced adaptations. Stroke Res Treat. 2012;2012:959120. doi:10.1155/2012/959120.

Pase

Beiser

Enserro

, et al. Association of ideal cardiovascular health with vascular brain injury and incident dementia. Stroke. 2016;47:1201-1206.

MacKay-Lyons

Makrides

Cardiovascular stress during a contemporary stroke rehabilitation program: is the intensity adequate to induce a training effect?

Arch Phys Med Rehabil. 2002;83:1378-1383. doi:10.1053/apmr.2002.35089.

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;45:2532-2553. doi:10.1161/STR.0000000000000022.

Cumming

Tyedin

Churilov

Morris

Bernhardt

The effect of physical activity on cognitive function after stroke: a systematic review. Int Psychogeriatr. 2012;24:557-567. doi:10.1017/S1041610211001980.

Quaney

Boyd

McDowd

, et al. Aerobic exercise improves cognition and motor function poststroke. Neurorehabil Neural Repair. 2011;23:879-885. doi:10.1177/1545968309338193.

10.

Billinger

Boyne

Coughenour

Dunning

Mattlage

Does aerobic exercise and the FITT principle fit into stroke recovery?

Curr Neurol Neurosci Rep. 2014;15:519. doi:10.1007/s11910-014-0519-8.

11.

Thomas

Dennis

Bandettini

Johansen-Berg

The effects of aerobic activity on brain structure. Front Psychol. 2012;3:86. doi:10.3389/fpsyg.2012.00086.

12.

Ploughman

Austin

Glynn

Corbett

The effects of poststroke aerobic exercise on neuroplasticity: a systematic review of animal and clinical studies. Transl Stroke Res. 2015;6:13-28. doi:10.1007/s12975-014-0357-7.

13.

Gibala

Little

Macdonald

Hawley

JA.

Physiological adaptations to low-volume; high-intensity interval training in health and disease. J Physiol. 2012;590:1077-1084.

14.

Rognmo

Hetland

Helgerud

, et al. High intensity aerobic interval exercise is superior to moderate intensity exercise for increasing aerobic capacity in patients with coronary artery disease. Eur J Cardiovasc Prev Rehabil. 2004;11:216-222. doi:10.1097/01.hjr.0000131677.96762.0c.

15.

Kortianou

Nasis

Spetsioti

Daskalakis

Vogiatzis

Effectiveness of interval exercise training in patients with COPD. Cardiopulm Phys Ther J. 2010;21:12-19.

16.

Weston

Wisloff

Coombes

JS.

High-intensity interval training in patients with lifestyle-induced cardiometabolic disease: a systematic review and meta-analysis. Br J Sports Med. 2013;48:1227-1234. doi:10.1136/bjsports-2013-092576.

17.

Boyne

Dunning

Carl

, et al. High-intensity interval training and moderate-intensity continuous training in ambulatory chronic stroke: feasibility study background. Phys Ther. 2016;96:1533-1544.

18.

Lau

KWK

Mak

MKY.

Speed-dependent treadmill training is effective to improve gait and balance performance in patients with sub-acute stroke. J Rehabil Med. 2011;43:709-713. doi:10.2340/16501977-0838.

19.

Pohl

Mehrholz

Ritschel

Rückriem

Speed-dependent treadmill training in ambulatory hemiparetic stroke patients: a randomized controlled trial. Stroke. 2002;33:553-558. doi:10.1161/hs0202.102365.

20.

Ellingsen

Halle

Conraads

, et al; SMARTEX Heart Failure Study (Study of Myocardial Recovery After Exercise Training in Heart Failure) Group. High-intensity interval training in patients with heart failure with reduced ejection fraction. Circulation. 2017;135:839-849. doi:10.1161/CIRCULATIONAHA.116.022924.

21.

Buchheit

Laursen

PB.

High-intensity interval training, solutions to the programming puzzle: part I: cardiopulmonary emphasis. Sport Med. 2013;43:313-338. doi:10.1007/s40279-013-0029-x.

22.

Boyne

Dunning

Carl

Gerson

Khoury

Kissela

High-intensity interval training in stroke rehabilitation. Top Stroke Rehabil. 2013;20:317-330. doi:10.1310/tsr2004-317.

23.

Askim

Dahl

Aamot

Hokstad

Helbostad

Indredavik

High-intensity aerobic interval training for patients 3-9months after stroke: a feasibility study. Physiother Res Int. 2014;19:129-139. doi:10.1002/pri.1573.

24.

Bjuro

Fugl-Meyer

Grimby

Hook

Lundgren

Ergonomic studies of standardized domestic work in patients with neuromuscular handicap. Scand J Rehabil Med. 1975;7:106-113.

25.

Madhavan

Stinear

Kanekar

Effects of a single session of high intensity interval treadmill training on corticomotor excitability following stroke: implications for therapy. Neural Plast. 2016;2016:1686414. doi:10.1155/2016/1686414.

26.

Nepveu

Thiel

Tang

, et al. A single bout of high-intensity interval training improves motor skill retention in individuals with stroke. Neurorehabil Neural Repair. 2017;31:726-735.

27.

Moholdt

Aamot

Granoien

, et al. Aerobic interval training increases peak oxygen uptake more than usual care exercise training in myocardial infarction patients: a randomized controlled study. Clin Rehabil. 2012;26:33-44. doi:10.1177/0269215511405229.

28.

Freyssin

Verkindt

Prieur

Benaich

Maunier

S BP

. Cardiac rehabilitation in chronic heart failure: effect of an 8-week, high-intensity interval training versus continuous. Arch Phys Med Rehabil. 2012;93:1359-1364.

29.

Rognmo

Moholdt

Bakken

, et al. Cardiovascular risk of high- versus moderate-intensity aerobic exercise in coronary heart disease patients. Circulation. 2012;126:1436-1440. doi:10.1161/CIRCULATIONAHA.112.123117.

30.

Gjellesvik

Brurok

Hoff

Torhaug

Helgerud

Effect of high aerobic intensity interval treadmill walking in people with chronic stroke: a pilot study with one year follow-up. Top Stroke Rehabil. 2012;19:353-360. doi:10.1310/tsr1904-353.

31.

Carl

Boyne

Meyrose

, et al. Feasibility and intensity of recumbent stepper in high intensity interval training (HIT) in chronic stroke. Med Sci Sport Exerc. 2016;48(5 suppl 1):256.

32.

Boyne

Dunning

Carl

Gerson

Khoury

Kissela

Within-session responses to high-intensity interval training in chronic stroke. Med Sci Sport Exerc. 2014;47:476-484. doi:10.1249/MSS.0000000000000427.

33.

Carl

Boyne

Rockwell

, et al. Preliminary safety analysis of high-intensity interval training (HIIT) in persons with chronic stroke. Appl Physiol Nutr Metab. 2017;42:311-318. doi:10.1139/apnm-2016-0369.

34.

Gormley

Swain

High

, et al. Effect of intensity of aerobic training on VO 2max. Med Sci Sports Exerc. 2008;40:1336-1343. doi:10.1249/MSS.0b013e31816c4839.

35.

Moraine

Lamotte

Berre

Niset

Leduc

Naeije

Relationship of middle cerebral artery blood flow velocity to intensity during dynamic exercise in normal subjects. Eur J Appl Physiol Occup Physiol. 1993;67:35-38.

36.

Kaminsky

Arena

Beckie

, et al. The importance of cardiorespiratory fitness in the United States: the need for a national registry: a policy statement from the American Heart Association. Circulation. 2013;127:652-662. doi:10.1161/CIR.0b013e31827ee100.

37.

Murphy

Corbett

Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci. 2009;10:861-872. doi:10.1038/nrn2735.

38.

Mang

Snow

Campbell

Ross

Boyd

LA.

A single bout of high-intensity aerobic exercise facilitates response to paired associative stimulation and promotes sequence-specific implicit motor learning. J Appl Physiol (1985). 2014;117:1325-1336. doi:10.1152/japplphysiol.00498.2014.

39.

Snow

Mang

Roig

McDonnell

Campbell

Boyd

LA.

The effect of an acute bout of moderate-intensity aerobic exercise on motor learning of a continuous tracking task. PLoS One. 2016;11:e0150039. doi:10.1371/journal.pone.0150039.

40.

Skriver

Roig

Lundbye-Jensen

, et al. Acute exercise improves motor memory: exploring potential biomarkers. Neurobiol Learn Mem. 2014;116:46-58. doi:10.1016/j.nlm.2014.08.004.

41.

Thomas

Line

Geertsen

Christiansen

Roig

Lundbye-Jensen

Acute exercise and motor memory consolidation: the role of exercise timing. Neural Plast. 2016;2016:6205452.

42.

Thomas

Johnsen

Geertsen

, et al. Acute exercise and motor memory consolidation: the role of exercise intensity. PLoS One. 2016;11:e0159589. doi:10.1371/journal.pone.0159589.

43.

Statton

Encarnacion

Celnik

Bastian

AJ.

A single bout of moderate aerobic exercise improves motor skill acquisition. PLoS One. 2015;10:e0141393. doi:10.1371/journal.pone.0141393.

44.

Ploughman

Kelly

LP.

Four birds with one stone? Reparative, neuroplastic, cardiorespiratory, and metabolic benefits of aerobic exercise poststroke. Curr Opin Neurol. 2016;29:684-692. doi:10.1097/WCO.0000000000000383.

45.

Avert Trial Collaboration Group. Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial. Lancet. 2015;386:46-55. doi:10.1016/S0140-6736(15)60690-0.

46.

Biddle

SJH

Batterham

AM.

High-intensity interval exercise training for public health: a big HIT or shall we HIT it on the head?

Int J Behav Nutr Phys Act. 2015;12:95. doi:10.1186/s12966-015-0254-9.

47.

Knowles

Herbert

Easton

Sculthorpe

Grace

FM.

Impact of low-volume, high-intensity interval training on maximal aerobic capacity, health-related quality of life and motivation to exercise in ageing men. Age (Dordr). 2015;37:25. doi:10.1007/s11357-015-9763-3.

48.

Herbert

Sculthorpe

Baker

Grace

FM.

Exercising caution: prolonged recovery from a single session of high-intensity interval training in older men. J Am Geriatr Soc. 2015;63:817-818. doi:10.1080/15438627.2015.1005294.

49.

Helm

Matt

Kirschner

Pohlig

Kohl

Reisman

DS.

The influence of high intensity exercise and the Val66Met polymorphism on circulating BDNF and locomotor learning. Neurobiol Learn Mem. 2017;144:77-85. doi:10.1016/j.nlm.2017.06.003.

50.

Mang

Campbell

Ross

CJD

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;93:1707-1716.

51.

Amarenco

Lavallée

Labreuche

, et al. Prevalence of coronary atherosclerosis in patients with cerebral infarction. Stroke. 2011;42:22-29. doi:10.1161/STROKEAHA.110.584086.

52.

Garrett

Huth

The impact of graphic contextual information and instruction on the conversational behaviours of a person with severe aphasia. Aphasiology. 2002;16:523-536. doi:10.1080/02687030244000149.

53.

Tabet

Meurin

Ben Driss

, et al. Determination of exercise training heart rate in patients on beta-blockers after myocardial infarction. Eur J Cardiovasc Prev Rehabil. 2006;13:538-543.

54.

Billinger

Mattlage

Ashenden

Lentz

Harter

Rippee

MA.

Aerobic exercise in subacute stroke improves cardiovascular health and physical performance. J Neurol Phys Ther. 2012;36:159-165. doi:10.1097/NPT.0b013e318274d082.

55.

Bartlett

Hwa Joo

Jeong

T-S

, et al. Matched work high-intensity interval and continuous running induce similar increases in PGC-1α mRNA, AMPK, p38, and p53 phosphorylation in human skeletal muscle. J Appl Physiol (1985). 2012;112:1135-1143. doi:10.1152/japplphysiol.01040.2011.

56.

Ivey

Hafer-Macko

Macko

RF.

Exercise training for cardiometabolic adaptation after stroke. J Cardiopulm Rehabil Prev. 2008;28:2-11. doi:10.1097/01.HCR.0000311501.57022.a8.

57.

Pak

Patten

Strengthening to promote functional recovery poststroke: an evidence-based review. Top Stroke Rehabil. 2008;15:177-199. doi:10.1310/tsr1503-177.

58.

Hanlon

RE.

Motor learning following unilateral stroke. Arch Phys Med Rehabil. 1996;77:811-815. doi:10.1016/S0003-9993(96)90262-2.

59.

Daussin

Ponsot

Dufour

, et al. Improvement of Vo₂max by cardiac output and oxygen extraction adaptation during intermittent versus continuous endurance training. Eur J Appl Physiol. 2007;101:377-383. doi:10.1007/s00421-007-0499-3.

60.

Tjønna

Lee

Rognmo

, et al. Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: a pilot study. Circulation. 2008;118:346-354. doi:10.1161/CIRCULATIONAHA.108.772822.

61.

Wisløff

Støylen

Loennechen

, et al. Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study. Circulation. 2007;115:3086-3094. doi:10.1161/CIRCULATIONAHA.106.675041.

62.

Bolduc

Thorin-Trescases

Thorin

Endothelium-dependent control of cerebrovascular functions through age: exercise for healthy cerebrovascular aging. Am J Physiol Heart Circ Physiol. 2013;305:H620-H633. doi:10.1152/ajpheart.00624.2012.

63.

Ramos

Dalleck

Tjonna

Beetham

Coombes

JS.

The impact of high-intensity interval training versus moderate-intensity continuous training on vascular function: a systematic review and meta-analysis. Sport Med. 2015;45:679-692. doi:10.1007/s40279-015-0321-z.

64.

Hillman

Erickson

Kramer

AF.

Be smart, exercise your heart: exercise effects on brain and cognition. Nat Rev Neurosci. 2008;9:58-65. doi:10.1038/nrn2298.

65.

Haram

Adams

Kemi

, et al. Time-course of endothelial adaptation following acute and regular exercise. Eur J Cardiovasc Prev Rehabil. 2006;13:585-591. doi:10.1097/01.hjr.0000198920.57685.76.

66.

Bailey

Evans

McEneny

, et al. Exercise-induced oxidative-nitrosative stress is associated with impaired dynamic cerebral autoregulation and blood-brain barrier leakage. Exp Physiol. 2011;96:1196-1207. doi:10.1113/expphysiol.2011.060178.

67.

Young

Angevaren

Rusted

Tabet

Aerobic exercise to improve cognitive function in older people without known cognitive impairment. Cochrane Database Syst Rev. 2015;(4):CD005381. doi:10.1002/14651858.CD005381.pub4.

68.

Singh

Staines

WR.

The effects of acute aerobic exercise on the primary motor cortex. J Mot Behav. 2015;47:328-339. doi:10.1080/00222895.2014.983450.

69.

Ostadan

Centeno

Daloze

Frenn

Lundbye-Jensen

Roig

Changes in corticospinal excitability during consolidation predict acute exercise-induced off-line gains in procedural memory. Neurobiol Learn Mem. 2016;136:196-203. doi:10.1016/j.nlm.2016.10.009.

70.

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. doi:10.1016/j.neures.2014.06.007.

71.

Burley

Bailey

Marley

Lucas

SJE

. Brain train to combat brain drain; focus on exercise strategies that optimize neuroprotection. Exp Physiol. 2016;101:1178-1184. doi:10.1113/EP085672.

72.

Lucas

SJE

Cotter

Brassard

Bailey

. High-intensity interval exercise and cerebrovascular health: curiosity, cause, and consequence. J Cereb Blood Flow Metab. 2015;35:902-911. doi:10.1038/jcbfm.2015.49.