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HIIT in Stroke Perspective Paper Version 5.0: May 11, 2017

Submission to Neurorehabilitation and Neural Repair

High-Intensity Interval Training After Stroke: An Opportunity to Promote Health and Function

Crozier J1, Roig M, PhD2, Eng J, Mackay-Lyons M, Ploughman M, Fung J, Bailey DM3, Sweet S, Giacomoantonio N, Thiel A, Tang A, PhD1

1 School of Rehabilitation Sciences, Faculty of Health Sciences, McMaster University2 School of Physical & Occupational Therapy, Faculty of Medicine, McGill University

3Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, UK.

Corresponding Author:

Word count 3793 (max 4500)Number of Tables 2Number of Figures 0

Number of References 75 (max 75)


Introduction

Approximately 30 incidences of stroke occur every minute worldwide1. Stroke is the leading cause of death globally for individuals above the age of 60 years, the fifth leading cause of death in people aged 15-59 years2, and the leading cause of adult disability3. The risk of recurrent stroke is high, with a pooled cumulative 10-year risk of 39.2%4. Stroke survivors have approximately half the cardiovascular capacity as their non-stroke counterparts5 and a 40-50% greater energy cost of walking compared to neurologically intact individuals6. This facilitates a sedentary lifestyle that results in further deconditioning7 and an increased risk of future cardiovascular events8.

Maintaining cardiovascular health is the most important strategy for lowering the risk of recurrent stroke9, but historically, stroke rehabilitation programs provide limited opportunity for cardiovascular training, with <2.8 minutes of conventional therapy spent at sufficient intensities for improving cardiorespiratory fitness (CRF)10,11. Conventional models of exercise rehabilitation use moderate-intensity continuous exercise (MICE) to improve CRF8 with guidelines for stroke survivors including recommending 20-60 minutes, 3-7 days per week at an intensity corresponding to 40-70% maximal oxygen consumption (VO2peak) or heart rate reserve (HRR), 50-80% maximum heart rate (HRmax), or 11-14 on the BORG Rating of Perceived Exertion (RPE) scale12. Continuous cardiovascular exercise, however, performed at vigorous intensities and for long periods of time proves to be difficult for individuals with stroke secondary to motor deficits and/or severe deconditioning that limit the intensity required to achieve optimal benefits13. Such limitations result in a ceiling effect on the ability to achieve high exercise intensities needed to establish benefits14.

Within the last decade, high-intensity interval training (HIIT) has emerged as a potent time-efficient alternative to MICE for healthy individuals15, as well as those with coronary artery disease16, chronic obstructive pulmonary disease17, congestive heart failure18, and metabolic syndrome19. HIIT is characterized by high-intensity bursts of aerobic exercise interspersed with periods of active or passive rest, and aims to maximize aerobic exercise intensity despite a lower exercise time15. HIIT could be a solution to supplement the low intensity of aerobic stimuli typically achieved in stroke rehabilitation programs, allowing individuals to achieve higher exercise intensities and thus optimize recovery13. Nice work and well written here Jennifer

To date, five small, feasibility or preliminary training studies20–24 and four acute exercise studies25–28 have investigated the potential application of HIIT within the context of stroke. Collectively, the evidence suggests that HIIT is a safe approach to potentially improve cardiovascular and functional capacity in individuals with stroke, with no reports of serious adverse events related to its application20–24. Albeit preliminary, recent evidence suggests that HIIT-associated neuroplastic cerebrovascular improvements may equally be superior to those induced by MICE29,30. HIIT has the potential to provide a new window of opportunity within stroke rehabilitation to enhance motor recovery, improve cardiorespiratory health and promote neuroplasticity.


The aim of this paper is to provide a clinical perspective of HIIT in stroke rehabilitation practice by 1) synthesizing the current evidence regarding the safety and effectiveness of HIIT on functional mobility and novel outcomes of neuroplasticity and cardiovascular outcomes after stroke, 2) offering considerations for optimizing the use of HIIT within the stroke population, 3) exploring potential mechanisms underlying improvements in functional, cardiovascular and neuroplastic outcomes following HIIT and 4) discussing clinical implications and informing directions for future research for HIIT in stroke rehabilitation.

HIIT Protocols

HIIT parameters may be adapted to suit the needs of different populations and the specific objectives of training31 with different combinations of parameters taxing different metabolic, neuromuscular and musculoskeletal systems31HIIT protocols may be categorized into 3 main types depending on high-intensity burst duration, recovery duration, and recovery type32. Short interval HIIT maximizes time spent at a high percentage of V̇ O2Peak with short high-intensity bursts lasting 15-60 seconds at a supramaximal workload (100-120%VO2Peak) at 1:1 burst to recovery ratio32. Low-volume HIIT yields high neuromuscular intensity, with short, high-intensity bursts of 10-60 seconds at a near maximal or maximal workload associated with VO2Peak and burst to recovery ratios at 1:2 or 1:4 with active recovery to mitigate any potential symptoms of dizziness secondary to venous blood pooling 32. Long-interval HIIT is also designed to maximize time spent at a high percentage of VO2Peak, but encompasses longer high-intensity bursts (3-4 minutes) at lower workloads (80-90% VO2Peak) and a burst to recovery ratio of 1:1 or 4:3 with active recovery32.

1.0 Benefits of HIIT in Stroke

1.1 Is HIIT Safe in Individuals with Stroke?

There have been no reports of serious adverse events of HIIT in coronary artery disease16, myocardial infarction16,33 and heart failure34, and only 2 non-fatal cardiac arrests in over 46,000 hours of HIIT within cardiac rehabilitation, with occurrences similar to that of MICE35.Nevertheless, the risk of both cardiovascular and orthopedic injury may be present within the stroke population36. Safety monitoring during HIIT sessions in stroke has not only included preemptive screening but also careful monitoring of heart rate, blood pressure and RPE ratings32. Continuous telemetry has also been used for safety monitoring, however this form of monitoring may not be available in many stroke rehabilitation settings32. In research studies, the risk of orthopedic injury has been minimized by excluding individuals with primary orthopedic conditions (i.e., fractures, active rheumatoid arthritis and severe motor impairments) and incorporating the use of body-weight support measures, orthotic devices (i.e., splints and AFO’s) or handrail support as needed during training32. With such prospective safety monitoring in place,


no serious adverse events were observed in 41 individuals with stroke during 294 documented HIIT exercise hours32.

The potential risks of HIIT should not, however, be overlooked, since high-intensity exercise has the potential to provoke rapid and possibly dangerous increases in blood pressurethat may be transferred to the cerebrovasculature, possibly increasing the risk of hyperperfusion injury37 subsequent to any functional impairments in dynamic cerebral autoregulation. Given this knowledge, it appears prudent to mitigate this risk by ‘priming’ the cerebrovasculature through the gradual increase of exercise intensity over the first 10 seconds of every high-intensity burst37.

1.2 Is HIIT Effective?

To date, nine small feasibility or non-controlled pilot studies have investigated the effects of HIIT in mobility and gait outcomes in the stroke population20–25,27,28. Of these, five incorporated a training intervention (2-6 weeks)20–24 and four examined single session HIIT responses on outcomes of tolerance and feasibility25–27 and markers of neuroplasticity28, see Table 1.


Table 1: Summary of Studies Investigating High Intensity Interval Training in Individuals with StrokeStudy, Design and Population Groups (n) Session FITT Parameters Effects

TRAINING STUDIES:

Askim et al. (2014) Single group pre-

post Mild to moderate

stroke 3-9 months post-

stroke

HIIT n=15 HIITFrequency: 2 times per week for 6 weeksIntensity: HIIT: 80-95% HRR for 4 minutes Recovery: 70% HRR for 3 minutes Time: Total HIIT Time: 16 min Total Session Time: 25 minType: Treadmill

Pre-Post-training: 6MWT P=0.001*

No serious adverse events (All participants completed all sessions at 85% intensity,

except 1 did not complete last session)

Boyne et al. (2016) Randomized

controlled trial Ambulatory

stroke survivors > 6 months post-

stroke

HIIT n = 13

MICE n = 5

HIIT: Frequency: 3 times per week for 4 weeksIntensity: HIIT: maximum safe speed for 30

seconds Recovery: rest for 30 seconds

(sessions 1-8); 30 seconds (sessions 9-12)

Time: Total HIIT Time: 12.5 or 8 min -

depending on recovery time Total Session Time: 25 minutesType: Treadmill

MICE: Frequency: Times per week for, 4 weeksIntensity: Speed adjusted to maintain 45

± 5% HRR for Weeks 1-2. Progressed to 50 ±5% HRR

after 2 weeks. for Weeks 3-4Time: 25 minutesType: Treadmill

Effect sizes (ES): Ventilatory threshold ES 1.95* Fractional utilization of O2 ES 1.74* Fastest treadmill speed ES 1.68* 10MWT ES 1.44*

No serious adverse events 11 of 13 (84.6%) attended all HIIT sessions


Gjellesvik et al. (2012)

Single group pre-post with 1-year follow up

Time post stroke > 6 months

HIIT n=8 Frequency: 5 times per week for 4 weeksIntensity: HIIT: 85-95% HR Peak for 4 minutes Recovery: Active rest 59% HR Peak for 3 minutes Time: Total HIIT Time: 16 min Total Time: 25 minType: Inclined Treadmill walking

Pre-post-training: VO2 Peak P=0.003* Walking economy P=0.043* 6MWT distance P=0.020* TUG P=0.02* 10 MWT P=0.032*

Post-training to 1-year follow-up: VO2 Peak maintained from post-training P=1.00 Walking economy declined from post P=0.001* 6MWT, TUG and 10MWT maintained from post (Exact P-

values not reported)

No adverse events

Lau et al. (2011)

Randomized Controlled Trial

Subacute stroke participants within 1 month of stroke onset

HIIT n=13MICE n=13

HIIT: Frequency: 5 times per week for 2 weeksIntensity: HIIT: max safe speed for 30

seconds Recovery: rest fro 2 minutes Time: Total HIIT Time: 4-5 minutes Total Session Time: 30 minutesType: Treadmill

MICE: Frequency: 5 times per week for 2weeksIntensity: Walked at belt speed adjusted

according to fastest overground walking speed

Time: 30 minutesType: Treadmill:

Group-time interaction: Gait speed P=0.014* Stride length P=0.027*

No Adverse events


Pohl et al. (2002)

RCT > 4 weeks post-

stroke 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 weeksIntensity: HIIT: 1-2 min at fastest speed

tolerated, then held for 10 sec Recovery: Active recovery until HR

to return to restTime: Total HIIT Time: Dependent on

time to resting HR Total Session Time: 30 minutesType: Treadmill

MICE: Frequency: 3 times per week for 4 weeksIntensity: Speed increased <5% of max

initial walking speed each week

Time: 30 minutes Type: Treadmill

CONTROL: 45 minutes gait training using

proprioceptive neuromuscular facilitation and Bobath concepts

Pre-Post-training: Walking speed HIIT vs. MICE P<0.001*; HIIT vs.

CONTROL, P<0.001* Cadence HIIT vs. MICE P<0.007*; HIIT vs. CON

P<0.001* Stride length HIIT vs. MICE P<0.001*; HIIT vs. CON

P<0.001* Functional Ambulation Category score STT vs. LTT

P<0.007*; STT vs. CGT P<0.001)*

No adverse events

STUDIES WITH SINGLE HIIT SESSION:

Boyne et al. (2002) Single

session crossover

> 6 months post-stroke

HIIT (n=18)

3 HIIT protocols each had 30 sec. burst times. Protocols differed only in length of rest periods, as follows: 30 s (P30), 60 s (P60), or 120 s (P120)

HIIT: Frequency: Single session, 1 week apartIntensity: HIIT: 0.1 mph below fastest safe walking speed for 30 seconds Recovery: Rest for 30, 60 or 120 secondsTime: Total HIIT Time: P30 = 10 min, P60=7 minutes, P120 = 4 minutes Total Session Time: 20 minutesType: Treadmill

Highest mean VO2, HR, and step count with P30 Reduced exercise tolerance and lower treadmill speed with

P30 compared to P60 or P120 Treadmill speed and exercise tolerance similar between

P60 and P120, but higher mean VO2, HR, and step count.

No serious adverse events Fewer subjects able to complete P30 compared with P120.


Carl et al. (2016a)

Single session crossover

> 6 months post stroke

HIIT (n=18)

3 HIIT protocols each had 30 sec. burst times. Protocols differed only in length of rest periods, as follows: 30 s (P30), 60 s (P60), or 120 s (P120)

HIIT Frequency: Single sessionIntensity: HIIT: 0.1 mph below fastest safe walking speed Recovery: RestTime: Total HIIT Time: P30 = 10 min, P60=7 minutes, P120 = 4 minutes Total Session Time: 20 minutesType: Treadmill

Safety Outcomes: No arrhythmias, myocardial ischemia, uncontrolled

hypertension, symptomatic hypertensive responses, or orthopedic injury observed with electrocardiography pre-screening

0 serious adverse events on 54 HIIT sessionsCardiovascular Intensity: 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. 6/18 participants (44%) exceeded HRpeak from the GXT

for P30, 8/18 (33%) for P60, and 2/18 (11%) for P120 (P<0.01).

Carl et al. (2016b)


> 1 year post-stroke

HIIT (n= 16)

3 Sessions1. 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 minutesType: Treadmill (Mod-TM and HIIT-TM) and recumbent stepper (HIIT-RS)

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

No adverse events with Mod-TM or HIIT-TM

Blood lactate accumulation response to original HIIT-RS higher than HIT-TM and Mod-TM (p=0.001) *

Hematocrit in original HIIT-RS greater than HIT-TM *(p=0.035) but revised HIIT-RS not different from HIIT-TM (p=0.51) and Mod-TM (p=0.12).

Madhavan et al. (2016)


Chronic stroke

HIIT (n=11)

2 HIIT sessions:HIIT alone and HIIT + transcranial direct current stimulation

HIIT Frequency: Single session, 1 week apartIntensity: HIIT: 1-2 min at fastest speed tolerated, then held for 10 sec Recovery: Active recovery until HR to return to restTime: Total HIIT Time: Dependent on time to resting HR Total Session Time: 30 minutesType: Treadmill

Interaction for RPE (p=0.015) Main effect of time for HR (p<0.001) HIIT alone reduced paretic M1 excitability in 7 of 11

participants by ≥ 10%. Transcranial direct current stimulation +HIIT increased

paretic TA M1 excitability and decreased non-paretic TA M1 excitability.

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.


* p < 0.05. Abbreviations: 6MWT = 6-Minute-walk-test; HRR = Heart rate reserve; 10MWT = 10 Meter Walk Test; VO2Peak

= Peak oxygen consumption; RPE = BORG Rating of Perceived Exertion ; GXT = Graded Exercise Test.


1.2.1 HIIT Encourages Mobility and Gait Improvements

Pohl et al. (2002) was the first study to report that a low volume HIIT protocol resulted in the greatest improvements in fastest over-ground walking speed, cadence, stride length and functional ambulation 23. Lau and Mak (2011) reported that a low volume HIIT protocol was effective at improving over-ground gait speed and step length22. Long interval HIIT was effective in improving fastest over-ground walking speed, Timed Up and Go, gait economy21 and 6–Minute Maximum Walk Test21,24, but the lack of changes observed in VO2Peak may be due to the small sample size and single-group design24. Lastly, Boyne at al (2016) examined the effects of a short-interval HIIT protocol and reported between-group differences in fastest treadmill speed20.

1.2.2 HIIT Improves Cardiovascular Health

CRF plays a critical role in managing cardiovascular risk, with a 1-MET (3.5 mL/kg/min) increase translating into a 10–25% improvement in survival38. It is, therefore, crucial to identify the most effective ways to improve and maintain CRF in the stroke population. Exercise intensity is shown to influence cardiovascular health benefits, where, when volume is constant, higher cardiovascular exercise intensities are more effective at improving CRF39. Improvements in VO2peak21and ventilatory threshold20, markers of CRF, have been observed following short-interval20 and long-interval HIIT21 in individuals with stroke, however, more rigorous research is warranted to investigate the effectiveness of HIIT to improve CRF over MICE, as only one of these studies examining markers of CRF was a randomized controlled study20.

1.2.3 HIIT May Promote Neuroplasticity

Establishing strategies to enhance neuroplasticity is critical to promote motor recovery after stroke40. To date, studies examining the effectiveness of HIIT on neuroplasticity are limited to either animal models of stroke41–43 or single session exercise sessions in healthy populations28,44,45 but nonetheless suggest that intensity appears to play a critical role in facilitating neuroplasticity and motor learning.

In animal models of stroke, higher exercise intensities were necessary to optimize the expression of neurotrophins while also modifying synapses and dendrites to promote neuroplasticity43. Within healthy humans, a single 20-minute bout of HIIT at 90% of VO2peak enhanced corticospinal excitability (CSE), a marker of neuroplasticity within the motor cortex46, whereas another study found no effects of CSE following a single 30-minute bout of MICE training at 60% VO2peak29. Skriver et al.47 demonstrated that a single bout of HIIT was associated with higher peripheral concentration of brain-derived neurotrophin factor (BDNF), 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 individuals30 with effects appearing to be intensity-dependent48.


Within a stroke population, a single bout of HIIT performed immediately after motor practice improved skill retention, demonstrating the potential for HIIT to trigger modest neuroplastic changes and accelerate neurorecovery45. Notably, skill level was increased at retention rather than at the end of practice, suggesting that even a single bout of HIIT may not only strengthen procedural memories but also foster gains occurring between practice sessions45. It is possible that repeated bouts of HIIT combined with motor practice may show a cumulative effect on motor learning gains and enhance functional recovery49,45.

How early to apply cardiovascular exercise and at the ideal intensity required to optimally influence neuroplasticity following a stroke remains unknown43. In animal models of stroke, delaying rehabilitation to 30 days post-event have failed to show beneficial effects compared to 5-14 days post-stroke, implying that there is an early window of opportunity to influence neuroplasticity43. There is likely an optimal window of time of the first few months post-stroke in humans where neuroplasticity is most influenced by exercise14, but establishing the timeframe when the brain is most responsive to change would be an important consideration for future trials.

Summary

A unique feature of HIIT relates to its potential to improve exercise enjoyment, and ultimately adherence50, but it may be argued that HIIT interventions will have limited reach, effectiveness and adoption in addition to poor maintenance secondary to analyses of opinions of competence and HIIT’s psychologically unpleasant stimulus50. Despite this, evidence has demonstrated that adherence to HIIT and exercise enjoyment is similar to or indeed superior to that of MICE in healthy individuals51, including patients with cardiometabolic disease19. The variability that HIIT offers makes it an adaptable exercise option for many different ages and populations32. In addition, due to its high time-efficiency, HIIT may appeal to both clinicians and patients who are often under time constraints. Whether HIIT may be an effective strategy to promote long-term adherence to exercise regime in individuals with stroke remains unknown. Investigating whether HIIT shows greater physical activity enjoyment and exercise adherence is valuable to evaluate its long-term application and effectiveness.

Taken together, this body of evidence appears to show the following trends; (1) preliminary feasibility and effectiveness of low-volume HIIT on improving gait parameters in ambulatory individuals in the sub-acute phase of stroke22,23 where the large amount of recovery between bursts may allow time for feedback for mental practice32 which involves a high level of cognitive processing and may lead to enhanced motor practice52 (2) initial effectiveness of long-interval HIIT among very high-functioning people with stroke21 or individuals with mild-moderate chronic stroke24 where long burst intervals and active walking recovery provides the most stepping practice32, (3) short-interval HIIT on treadmill improving ventilatory and walking speed20, with the high exercise intensity and task-specific walking practice owing to the results32.


2.0 FITT Parameters to Optimize the use of HIIT within the stroke population

2.1 FrequencyCurrent evidence suggests that the health benefits of HIIT in stroke can be achieved

through exercising for 12 weeks, 2-3 times per week. HIIT 2 times per week for as little as 6 weeks has led to improvements in function and 6MWT distance24 while training 3 times per week for 4 weeks resulted in improvements in gait23 and CRF20.

One important aspect to consider, however, is the recovery time following a HIIT session. Recent evidence suggests that a minimum of three days is required in older adults for optimal recovery and to decrease the risks associated with accumulated fatigue, each of which may potentially hinder exercise adherence53. Therefore, it may be clinically prudent to initially incorporate two days per week of training, then increase to three per week as tolerance and adaptations improve.

2.2 Intensity

HIIT intensities that incorporate fastest safe walking speed20,22,23 or 80-95% of HRR21,24 appear to yield improvements in functional outcomes (such as the Timed-Up-and-Go test and the 10 Meter Walk Test21) and gait parameters20–23 (such as gait economy21 and walking speed20,22,23, cadence23).

Prescribing exercise intensity based on %VO2peak or HRR may be well suited for prolonged and submaximal exercise bouts but may have limited effectiveness for HIIT due to the short time intervals during high-intensity blocks to achieve the desired heart rate31. Rather, prescribing HIIT intensity using a power output associated with a percentage of VO2peak may be a more effective method, as it combines VO2peak and the energetic cost of the activity into a single metric, and thus is more representative of an individuals’ motor ability31. Theoretically, this method of prescribing intensity is the lowest power required to elicit VO2peak, and it therefore seems rational that this marker be used to represent an ideal intensity reference for HIIT training, however, the application of this method may be limited when utilizing a treadmill.

In addition, the RPE using the BORG scale should always be implemented31, as this method allows for a simple and versatile way of measuring a patient’s subjective level of exertion. The RPE allows individuals to self-regulate their exercise intensity, even when individuals take beta-blockers (62% to 75% of individuals with stroke54,55) and HR is not a viable option. The RPE method has the potential to reflect the conscious sensation of how hard and strenuous exercise is perceived31. RPE has been described as a universal ‘exercise regulator’ and can be used regardless of environment31, however, given the potential communication impairment (e.g. aphasia) following stroke, the RPE method may need to be adapted.

While evidence shows that low-intensity exercise can be prescribed for most individuals following a stroke, higher intensities should be implemented when no contraindications, or signs or symptoms suggestive of exercise intolerance are present13. Intensity appears critical to


modulate the effects of cardiovascular training on neuroplasticity and motor learning29,46. Furthermore, intensity also seems possible as a key modulator of complex motor behavior in individuals with stroke, as evidence shows that pairing an acute bout of high-intensity exercise at workloads associated with 100% of VO2peak with skilled motor practice was effective in improving motor learning, while moderate-intensity exercise at a power output associated with 60% VO2peak did not29. In addition, in individuals with stroke, HIIT performed at 90% maximal power output stimulates the release of peripheral BDNF , a marker of neuroplasticity47.

When prescribing HIIT, it is important to note that the cerebrovascular response to exercise differs from that of the peripheral vasculature37. Increased systemic perfusion during high-intensity exercise are likely responsible for improved peripheral vascular function, but may pose a threat to the cerebrovasculature37 where potentially damaging exposure to elevated perfusion pressure may occur37.

2.3 TimeWithin the literature on HIIT in stroke, total durations ranged from 20 to 30 minutes,20–24

but burst to recovery ratios were highly variable amongst studies , ranging from 30 seconds:30 seconds20 to 4 minutes:3 minutes24. Arguably, these studies examining HIIT in stroke enrolled higher functioning participants that were able to ambulate and walk safely on a treadmill. Thus in clinical practice, protocols may require adaptation for individuals with lower functional abilities who may not be able to withstand longer intervals and longer durations, particularly at the commencement of the exercise training13.

2.4 ModeMost studies to date of HIIT in stroke have focused on the use of treadmill walking20–24,

either with23,24 or without21,22,23 body-weight support while one study of single-session HIIT used a recumbent stepper26. While the task-specificity nature of treadmill training has led to improvements in gait and functional outcomes after stroke20–24, its application may be limited to those with higher functional abilities, or when the necessary resources are available to successfully implement this exercise modality. 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 has been shown to increase CRF56. Thus, given the task-specificity of treadmill walking, this modality would be recommended for functional gains if safety permits, whereas a recumbent stepper may be more effective for increasing CRF.

While various combinations of the FITT parameters may benefit individuals with stroke from a functional, cardiovascular and neuroplastic perspective, individualized protocols are warranted as every individual with stroke will present differently. Based on current evidence on HIIT in the stroke population, Table 2 offers general clinical recommendations.

Table 2: FITT Recommendation for HIIT in Stroke


FITT Parameter RecommendationFrequency 2-3 days per week for a minimum of 12

weeksIntensity Fastest Safe Walking Speed (mobility gains)

or 85-95% HRR (for CRF gains) or workload associated with 90-100% VO2peak (for potential improved neuroplasticity)

Time Session Time: o At least 16-25 minutes

Burst-to-Recovery ratio: o 30Seconds:30-60Seconds to

3Minutes:4Minutes Type Treadmill if safe, or recumbent stepper

3.0 Potential Mechanisms of HIIT

While there has been little study conducted to date examining specific mechanisms underlying the benefits of HIIT observed post-stroke, evidence of potential mechanisms from other populations may be extrapolated.

3.1 Potential Mechanisms Underlying Improved Functional Outcomes

Conventional therapeutic treadmill training protocols in individuals with stroke have focused on the normalization of gait kinematics through treadmill walking with body weight support and/or physical assistance13. It has been proposed that an increase in neuromuscular recruitment during treadmill training in healthy individuals may allow for increased oxidative capacity and efficiency within skeletal57 and cardiac muscle18. This may also be a potential mechanism by which treadmill HIIT aids in improved functional outcomes, as post-stroke decreases in oxidative capacity in skeletal58 and cardiac muscle59 can be a result of decreased neuromuscular recruitment60. Neuromuscular recruitment intensity is proposed as being critical for positive outcomes following a stroke with studies showing that, when training frequency and duration are controlled for, higher treadmill speeds22,23 yield more positive functional outcomes than general rehabilitation exercises alone61.

Furthermore, the positive effects of treadmill training on gait performance in individuals with stroke22,23 may be attributed to the activation of the central gait pattern generator62, ultimately leading to a more symmetrical and energy efficient gait pattern22. Lastly, 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 practice52,63.


3.2 Potential Mechanisms Underlying Improved Cardiovascular Health

Studies investigating HIIT vs. MICE in patients with cardiometabolic disease has shown that peripheral improvements in mitochondrial dysfunction that are typically present in many chronic diseases, may play a role in improving CRF19. Increased mitochondrial biogenesis, essential to the structural integrity of skeletal muscle64, occurs even after a single bout of low-volume HIIT through increased PGC-1α65, which is correlated with improved CRF65. Additionally, increases of 50-60% in maximal rate of Ca2

+ uptake into the sarcoplasmic reticulum observed following HIIT66 may serve to decrease the muscle fatigue and improve skeletal muscle function, ultimately leading to improvements in CRF. Repeated bouts of deoxygenation that occur during HIIT compared to MICE may also contribute to adaptations in skeletal muscle oxidative capacity19.

Centrally, HIIT improves cardiac ejection fraction in individuals with heart failure, showing the potential for HIIT to influence left ventricular re-modeling18. In addition, compared to MICE, HIIT has shown greater improvements in stroke volume, mitral annular excursion, ejection velocity and systolic mitral annular velocity in individuals with metabolic syndrome19.

Shear-stress mediated improvements in endothelial function within the systemic vasculature may also provide insight into improved vascular function within the cerebrovasculature67. Animal models show strong evidence for shear-stress mediated improvements in endothelial function within the cerebrovasculature68 brought on through chronic exercise, while in healthy adults, HIIT69 has shown acute improvements in systemic flow-mediated vasodilation. Nitric oxide bioavailability has also been shown to be increased following HIIT compared to MICE70, suggesting that there is the potential for other mechanisms responsible for improved vascular function in HIIT beyond increasing the shear-stress stimulus. Furthermore, since oxidative stress is a factor affecting nitric oxide bioavailability, the anti-oxidant effects of HIIT suggest greater nitric oxide bioavailability following this form of training70. It is unknown, however, whether such systemic effects of arterial function can be extrapolated to the cerebrovasculature, and the role of exercise intensity in mediating these effects37.

3.3 Potential Mechanisms Underlying Changes in Neuroplasticity

Cardiovascular exercise has been shown to improve cognition in healthy individuals71 through positive changes in the structure and function of different areas of the brain, including grey matter and hippocampal neurogenesis72. Cardiovascular exercise also promotes changes within the primary motor cortex (M1), a key target area to improve motor recovery following a stroke73. Even a single bout of cardiovascular exercise activates neuroplastic mechanisms responsible for motor learning74.

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 BDNF and insulin-like growth factor I,


neurotrophins that modulate neural repair processes in animal models43, leading to neuroplastic and motor recovery benefits42,43. HIIT-associated increases in CSE44 and BDNF47 may explain the improvements in motor learning in healthy individuals46 and retention of motor skills after stroke75.

Overall, while we can extrapolate potential mechanisms underlying HIIT-associated improvements from other populations, further research is warranted to establish specific mechanisms that may be responsible for the effects of HIIT within the stroke population.

4.0 HIIT: Clinical Implications for Stroke Rehabilitation

HIIT has shown to be effective at enhancing functional recovery20,21,24, CRF20,21, and gait parameters 20–24 within stroke survivors through a time-efficient approach. HIIT can be integrated into clinical practice, providing an integrative approach to remediating functional impairments following stroke. Specific training parameters need to be individualized for each client, where functional abilities and exercise tolerance are considered. HIIT has the potential to provide a new window of opportunity to enhance neuroplasticity and motor recovery post stroke with studies showing that higher exercise intensities are required to enhance the expression of neurotrophins that augment neural repair processes41–43. Optimizing training parameters to maximize functional and health benefits still needs to be established, particularly for those with lower functional abilities.

5. 0 Conclusions and Considerations for Future Directions

The application of HIIT in stroke patients has been shown to improve cardiovascular-cerebrovascular function and motor performance20–24 and preliminary evidence shows that HIIT may also show superior improvements in neuroplasticity compared to traditional MICE43. However, optimal HIIT parameters to maximize specific benefits, particularly for those with lower functional abilities, remains largely unknown. Larger, randomized controlled trials are necessary to investigate 1) the safety and effectiveness of HIIT within the stroke population, 2) potential mechanistic pathways linked to improved vascular, neuroplastic and functional recovery, and 3) adherence rates of HIIT compared to MICE training protocols. Few q’s: [1] Could we retrospectively assess the power of the trials previously conducted (suspect they are quite weak). Can we suggest a prospective sample size from these data? That would be a useful practical recommendation based on the observed SMD’s as outlined in the Tables.[2] I wonder if it would be worth pooling the studies and conducting a meta-analysis? May prove a step too far but if we don’t do it, someone will! Just a thought.[3] We should consider adding at least a single figure, but up to 3 would be perfect. It helps break the narrative down.


References

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