INTRODUCTION
Stroke is among the leading causes of death and disability worldwide[1]. Atherothrombotic etiology is the main cause of ischemic stroke, and the main risk
factors for this are hypertension, diabetes, dyslipidemia, smoking and sedentarism.
Particularly, a sedentary lifestyle is increasingly adopted after the event, thus
further compromising physical fitness and cardiovascular function[2]. The functional consequences of stroke depend on the extent, location and area affected[3], and on whether appropriate therapeutic interventions are implemented for each stage
of the disease.
Interventions for rehabilitation of post-stroke patients aim to minimize sequelae,
promote these individuals’ independence and potentially recover functional damage,
based on three basic principles: adaptation, regeneration and neuroplasticity. Individuals’
recovery capacity is proportional to central nervous system neuroplasticity, defined
as changes to or reconnection of the neural networks that were interrupted by the
ischemic/hemorrhagic event. According to individuals’ predisposition and favorable
stimuli, these networks can reconnect to adjacent areas and perform similar functions
in total or partial replacement of the compromised functions[4].
One of the best-known facilitators for neuroplasticity is aerobic exercise. In experimental
stroke models, moderate-intensity aerobic exercise induces neural responses that optimize
motor recovery through plasticity[5]. One proposed mechanism for this relates to increases in neurotrophin levels associated
with neuroprotection, neurogenesis and neuroplasticity, particularly the brain-derived
neurotrophic factor (BDNF), which is induced in the brain directly through aerobic
exercise. This could possibly be potentialized when combined with other forms of rehabilitation[6]. BDNF is a key mediator of motor learning and post-stroke rehabilitation[7].
Despite the plausibility demonstrated in animal models, the facilitator role of aerobic
exercise with regard to post-stroke neuroplasticity in humans is still questionable.
Approximately 30% of humans have BDNF genetic polymorphism (Val66Met)[8], which has been associated with impaired motor learning among post-stroke individuals[9]. Thus, stroke extent and localization, genetic variations such as BDNF polymorphisms
and the types of intervention can all affect the response to rehabilitation and potentially
modulate the effects of aerobic training on neuroplasticity[7].
The objective of this systematic literature review was to identify the impact of aerobic
exercise on neuroplasticity among patients with stroke sequelae.
METHODS
A systematic review was conducted between November 27, 2019, and February 4, 2020,
with searches in the following databases: PUBMED, EMBASE, LILACS and PeDRO. The study
types included were randomized clinical trials and crossover studies. The search was
done by one of the authors (LGP) and was checked by another author (JPP). Any disagreements
regarding inclusion were resolved by reaching a consensus. Studies in English, conducted
only on humans, were included. The PRISMA protocol was followed. The search aimed
to identify studies relating to stroke, aerobic exercise, cognition, neuroplasticity
and functional recovery.
The search strategy was defined based on keywords and through using the Boolean operators
AND and OR. The keywords used were defined based on the PICO strategy, which was used
for selecting articles as follows:
-
(P) - Population: Studies on post-stroke patients at any stage, of any age and gender,
were included regardless of the severity of the sequelae and functionality. Key words
used: “stroke” and “cerebrovascular accident”.
-
(I) - Intervention: Aerobic exercise, of any intensity or duration, either belonging
to a training program or consisting just of aerobic training sessions. Keywords used:
“exercise”, “endurance training”, “aerobic exercise”, “physical activity” and “training
exercise”.
-
(C) Comparison with a control group (conventional rehabilitation), or with interventions
such as strength exercises, physiotherapy, flexibility exercises or functional exercises,
provided that these did not involve aerobic exercises.
-
(O) Outcomes: Results relating to neuroplasticity assessment were evaluated, including
neurotrophic markers such as BDNF, IgF1 and VEGF1, assessment of neuronal excitability,
assessment from neuroimaging such as functional magnetic resonance (fMRI) or use of
recovery scales that indicated neurofunctional improvement. Keywords used: “neuronal
plasticity”, “brain-derived neurotrophic factor”, “recovery” and “nerve growth factor”.
The articles identified through the search strategy were selected according to their
titles and then according to their abstract; and lastly according to reading of the
full text, as defined through the eligibility criteria of the protocol (prospective
registration number CRD42020160865).
The following types of articles were excluded: systematic revies of the literature,
meta-analyses and articles that did not meet the requirements of the research strategy.
RESULTS
[Figure 1] summarizes the search and selection process for the studies included, in accordance
with the PRISMA protocol. Out of the 569 articles extracted from the databases, 22
were selected and six were later excluded because they did not meet the eligibility
criteria or because they were prospective studies without a control group.
Figure 1 Study selection process in accordance with the PRISMA statement.
Among the 16 articles that thus were selected for this systematic review, nine reported
on aerobic physical training programs, among which eight were randomized studies and
one was a crossover study. The other seven studies each evaluated single aerobic training
sessions, among which five studies were randomized and two were crossover.
Regarding assessment of neuroplasticity, only one study assessed the association of
neurotrophic factors with the aerobic physical training program, while four studies
assessed this association in relation to a single exercise session. The other studies
evaluated neuroplasticity using the following other methods: cortical excitability
from motor evoked potential and electroneuromyography; functional magnetic resonance;
cognitive assessment using specific scales; and motor recovery using the Fugl Meyer
scale or functional recovery scales ([Figure 2]).
Figure 2 Studies included in the review.
The intensity of the exercise that was used as the intervention was a very well-defined
parameter in the studies and was very relevant to the results. This was the main reason
why we included in this review studies involving a single exercise session. Exercise
intensity was measured from heart rate using Karvonen's formula or from the results
of cardiopulmonary exercise tests. Some studies also used the subjective perception
of effort as a way of measuring exercise intensity.
[Tables 1] shows summaries of the studies that used structured aerobic training programs and
[Table 2] shows the studies that used single sessions of exercise. Thus, these tables depict
the associations of chronic and acute effects relating to neuroplasticity, respectively,
that were included in this systematic review.
Table 1
General characteristics of the studies on aerobic training.
|
Author(s) / year / type of study
|
Sampling
|
Experimental intervention
|
Control
|
Outcomes
|
Results
|
|
Linder et al., 2019/ Neurorehabilitation and Neural Repair/ randomized clinical trial[5]
|
N = 40 Patients evaluated: 16 in the “forced exercise group” (FE), 16 in the voluntary
exercise group (VE) and 8 in the control group
|
45 minutes on an exercise bike until reaching 60 to 80% of the reserve heart rate
achieved in the cardiopulmonary exercise test
|
Educational videos and physiotherapy exercises
|
Change in functional scale (FMA)
|
The outcomes evaluated were measurements of improvement of motor recovery through
functional scales. All three groups improved significantly on FMA: by means of 11,
6 and 9 points for the FE, VE and education groups respectively (p = 0.001).
|
|
Ploughman et al., 2019/ Neurorehabilitation and Neural Repair/ randomized clinical
trial[9]
|
N = 52 (4 groups): - Aerobic training with cognitive training: 12 - Aerobic training
with games: 13 - Physiotherapy activities with cognitive training: 15 - Physiotherapy
activities with games: 12
|
20 to 30 minutes of aerobic physical activity with 20 to 30 minutes of cognitive training.
Exercise intensity determined by 60 to 80% of peak VO2 of ergospirometry.
|
Stretching activity or functional training
|
Change in RPMT test
|
Effect of training on intelligent fluidity (RPMT test): difference between groups
with p < 0.05 -> Aerobic + COG = 47% increase -> Aerobic + GAMES = 7% increase ->
Activity + COG = 20% increase -> Activity + GAMES = 8% reduction
|
|
Luft et al., 2008/ Stroke/ randomized clinical trial[11]
|
N = 71 (intervention: 37 versus control: 34)
|
Treadmill training 3 times per week for 40 minutes at the intensity of 60% of the
reserve heart rate (RHR).
|
Stretching with physiotherapist
|
Cerebral activation on fMRI
|
The intervention group improved its peak VO2 by 18% (p < 0.001), test speed by 10 meters and average speed by 19% (p = 0.030)
in the walking test. There was cerebral activation measured by fMRI in the posterior
lobe of the cerebellum in the intervention group and not in the control group (p =
0.005).
|
|
El-Tamawy et al., 2014/ Neurorehabilitation/ randomized clinical trial[19]
|
N = 30 (intervention: 15 versus control: 15)
|
30 minutes of physiotherapy + 15 minutes of rest + 40 minutes by bike (30 minutes
active and 10 minutes of warm-up and cooldown), 3 times per week for 8 weeks
|
Stretching, facilitation, strength, postural control, balance and functional training.
|
Changes in BDNF and ACER score
|
The mean values of subtest domains (attention, memory, verbal fluency, language and
visuospatial ability) in the study group post-treatment were: 16.87, 21.27, 2.6, 25.27
and 15.07 respectively. Comparison of the mean value of each domain with control group
revealed a significant increase in all domains in study group (p < 0.005) except verbal
fluency. Serum level of BDNF increased in study group after intervention (19.18 to
23.83; p = 0.0001) and was unchanged in control group (p = 0.698) Pearson correlation
between the post-treatment changes in ACER total score and BDNF was statistically
significant (r = 0.53; p = 0.044), such that cognitive improvement was associated
with BDNF improvement.
|
|
Shaughnessy et al., 2012/ Journal of Neuroscience Nursing/ randomized clinical trial[23]
|
N = 71 (intervention: 37 versus control: 34).
|
6 months of treadmill training: 3 times per week, 40 minutes per session, at the intensity
of 60% of RHR. Starting at the individual's capacity, with progression every 2 weeks
up to the goal
|
13 stretching exercises of large muscle groups under physiotherapy supervision
|
Changes in SIS scale
|
There was no significant difference between groups. There was an improvement in expectations
associated with exercise: this was important because it shows that belief in the benefits
of exercise can help in long-term adherence. The results indicated that regardless
of group, all study participants experienced increased self-efficacy (F= 2.95; p =
0.09) and outcome expectations for exercise (F = 13.23; p < 0.001) and improvement
in activities of daily living as reported in the SIS (F = 10.97; p = 0.002).
|
|
Nave et al., 2019/ BMJ/ randomized clinical trial[25]
|
N = 200 (intervention: 105 versus control: 95)
|
50 minutes, 5 times per week, for 4 weeks (20 sessions in total). 25 min doing exercise
with a target for the HR reached (50 to 60% of HR max).
|
25 minutes of relaxation of muscle groups. HR and SPE evaluated during the sessions.
|
Changes in Barthel index score
|
Compared with relaxation, aerobic physical fitness training did not result in a significantly
higher mean change in maximum walking speed (adjusted treatment effect 0.1 m/s (95%
confidence interval 0.0 to 0.2 m/s); p = 0.23) or mean change in Barthel index score
(0 (−5 to 5); p = 0.99) at three months after stroke. A higher rate of serious adverse
events was observed in the aerobic group, compared with the relaxation group (incidence
rate ratio 1.81; 95% confidence interval 0.97 to 3.36).
|
N: number of patients; RHR: reserve heart rate; fRMI: functional magnetic resonance;
VO2: oxygen consumption; FE: forced exercise; VE: voluntary exercise; FMA (scale):
Fugl Meyer scale; RPMT test: Raven progressive matrices test; COG: cognitive training;
GAMES: cognitive training with video games; HR max: maximum heart rate; SPE: subjective
perception of effort; 6MWT: 6-minute walking test; 10MWT: 10-meter walking test; BDNF:
Brain-derived neurotrophic factor; ACER score: Addenbrooke cognitive examination,
revised; SIS: stroke impact scale; TUG test: timed up and go test; EQ-5D scores: visual
analog scale.
Table 2
General characteristics of the studies with a single exercise session.
|
Author(s) and year/ journal/ type of study
|
Sampling
|
Experimental intervention
|
Control
|
Outcomes
|
Results
|
|
Nepveu et al., 2017/ Neurorehabilitation and neural repair/ randomized clinical trial[12]
|
N = 22 (intervention: 11 versus control: 11).
|
Exercise group: 15 minutes of HIIT: 2 min of warm-up at 25% of the peak VO2 (calculated
in the ergospirometry test), followed by 3 minutes of high intensity (100% of peak)
interspersed with 2 minutes of low intensity at 25% of the peak effort.
|
Rest group
|
Changes in Cognitive assessment (MoCA)
|
Skill retention was significantly better in the HIIT group (unpaired t test, t(19)
= 2.20; p = 0.04; effect size d = 0.96), which showed a 9% improvement in skill level,
compared with the end of acquisition, while the control group showed a 4% decay. Specifically,
7 out of 11 participants in the HIIT group improved their mean score in the retention
block, compared with the best block of training, while only 3 participants in the
control group showed improvement.
|
|
Abraha et al., 2018/ Frontiers of Physiology/ crossover[13]
|
N = 12 (MICE group: 6 and HIIT group: 6)
|
HIIT group: heating: 80% of VO2 max; maintained 60 to 80 steps per min alternating
every 2 min with 40% of VO2 max. Total of 5 HIIT cycles, for 20 minutes
|
MICE group: Cadence of 60 to 80 passes per minute, at 60% of VO2 max for 20 minutes.
|
Changes in motor evoked potential (MEP) on electroneuromyography.
|
MEP latency from the ipsilesional hemisphere was lengthened after HIIT (pre: 24.27
± 1.8 ms, and post: 25.04 ± 1.8 ms; p = 0.01) but not MICE (pre: 25.49 ± 1.10 ms,
and post: 25.28 ± 1.0 ms; p = 0.44). There were no significant changes in motor thresholds,
intracortical inhibition or facilitation. Pinch strength of the affected hand decreased
after MICE (pre: 8.96 ± 1.9 kg vs. post: 8.40 ± 2.0 kg, p = 0.02) but not after HIIT
(pre: 8.83 ± 2.0 kg vs. post: 8.65 ± 2.2 kg, p = 0.29). Regardless of type of aerobic
exercise, higher total energy expenditure was associated with greater increases in
pinch strength in the affected hand after exercise (p = 0.04) and decreases in pinch
strength of the less affected hand (p = 0.02)
|
|
Murdoch et al., 2016/ Plos One/ crossover study[15]
|
N = 12 (intervention: 6 and control: 6)
|
Cycloergometer at 50 rpm for 30 minutes and with subjective perception of light exertion
(11-13/20).
|
Resting in a seated position for 30 minutes.
|
Changes in motor evoked potential (MEP) in electroneuromyography.
|
There was no significant effect on neuronal excitability after a single session of
mild-intensity exercise with or without electrical stimulation (iTBs). There was no
significant change in MEP amplitude over time with exercise alone (p = 0.661). Mild-intensity
aerobic exercise does not result in an improvement in excitability.
|
|
Charalambous et al., 2018/ Topics Stroke Rehabilitation/ Randomized clinical trial[20]
|
N = 34 3 groups: - Control: 11 - Treadmill walk: 13 - Total body exercise: 10
|
Treadmill walk (TMW): 13 individuals - 15 minutes of high intensity exercise (75 to
80% of HR max. or 13-15 SPE if using BB). - Total Body exercise (TBE): Subjects pedaled
at high resistance and fast speed, which we modulated throughout so that the exercise
intensity was within the high-intensity range based on either HR or SPE.
|
Control (CON): 11 individuals - walking on the treadmill at 25% of comfortable speed
(low intensity)
|
Changes in BDNF blood level.
|
Intensity significantly changed from the beginning to the end of exercise only in
the exercise groups (CON: p = 0.104; TMW: p < 0.001; TBE: p < 0.001). Lactate levels
were similar between the groups pre-exercise (p > 0.05 in all groups). Only the exercise
groups (p < 0.001 in both groups) showed significant changes from pre- to post-exercise
(CON: p = 0.592). A significant exercise effect was found for all measurements, except
BDNF.
|
|
Boyne et al., 2020/ Neurorehabilitation and Neural/ crossover[21]
|
N = 15 - 3 groups: - HIIT on the treadmill: 5 - Seated stepper HIIT :5 - Continuous
exercise (MCT treadmill): 5
|
- HIIT on the treadmill: 3 min of warm-up + 20 min of HIIT, in which the protocol
was 30'' acceleration with 60'' rest and recovery decreasing to 30'' after the first
5 min. The goal was to achieve a RHR of 60%. - Seated stepper HIIT (ergometer cycle):
3 min of warm-up + 20 min of HIIT, in which the protocol was 30'' acceleration with
60'' rest and recovery decreasing to 30'' after the first 5 min. The goal was to achieve
a RHR of 60%.
|
Continuous exercise (MCT treadmill): from moderate intensity to 45% of RHR
|
Changes in VEGF1, IgF1 and cortisol blood level.
|
- HIIT elicited significantly (P < 0.05) greater mean responses than MCT for blood
lactate (HIT-treadmill, 4.6 mmol/L; HIT-stepper, 6.8 mmol/L; MCT-treadmill, 2.0 mmol/L),
mean heart rate (HIT-treadmill, 59.0% of heart rate reserve; HIT-stepper, 67.5%; MCT-treadmill,
43.8%), and peak treadmill speed (HIT-treadmill, 1.30 m/s; MCT-treadmill, 0.68 m/s)
- VEGF1 significantly increased in HIIT on the treadmill, with no increase in the
other groups - IgF1 increased significantly in both HIIT groups and did not increase
in MICE - Cortisol decreased in all 3 groups
|
|
Boyne et al., 2019/ Journal of Applied Physiology/ crossover[22]
|
N = 15 - 3 groups: - HIIT on the treadmill: 5 - Seated stepper HIIT: 5 - Continuous
exercise (MCT treadmill): 5
|
HIIT on the treadmill: 3 min of warm-up + 20 min of HIIT, in which the protocol was
30'' acceleration with 60'' rest and recovery, decreasing to 30'' after the first
5 min. The goal was to achieve a RHR of 60%. - Seated stepper HIIT (ergometer cycle):
Same HIIT protocol on the treadmill.
|
Continuous exercise: from moderate intensity to 45% of RHR.
|
Changes in BDNF blood level.
|
Serum BDNF significantly increased during the treadmill GXT (4.6 ng/ml [95% confidence
interval: 0.7-8.4]). The increase was significantly greater for HIT-treadmill, compared
with MCT-treadmill (3.9 [0.1-7.8]) but not for HIT-stepper compared with MCT treadmill
(2.9 [1.0-6.7]). The increase in BDNF was positively related to lactate, VO2 and HR.
The highest BDNF results were with lactate > 4.7, mean VO2 > 67% peak and RHR > 60%.
|
|
Morton, 2019/ Topics in Stroke Rehabilitation/ crossover[27]
|
N = 13 (HIIT and rest)
|
Two one-week training sessions between them - crossover: - 5 minutes of high intensity
on the treadmill - 70 to 80% of HRmax.
|
Rest
|
Changes in motor evoked potential (MEP) on electroneuromyography.
|
All participants were able to reach the target high-intensity exercise level. Blood
lactate levels increased significantly after exercise (p < 0.001; d = 2.85). Resting
motor evoked potentials from the lesioned hemisphere increased after exercise, compared
with the resting condition (p = 0.046; d = 2.76), but this was not the case for the
non-lesioned hemisphere (p = 0.406; d = 0.25).
|
N: number of patients; HIIT: high-intensity interval training; VO2: oxygen consumption;
MoCA test: Montreal cognitive assessment; MICE: moderate-intensity continuous training;
MEP: motor evoked potential; HR max: max heart rate; iTBS: intermittent theta burst
stimulation; TMW: treadmill walk; SPE: subjective perception of effort; TBE: total
body exercise; CON: control; BDNF: brain-derived neurotrophic factor; MCT treadmill:
moderate continuous training; RHR: reserve heart rate; VEGF1: vascular endothelial
growth factor receptor 1; IgF1: insulin-like growth factor 1; GXT: graded exercise
test.
The quality of the studies was evaluated using the risk assessment tools of the PeDRO
scale (Physiotherapy Evidence Database) and is shown in [Table 3]. Among the 16 articles, four had scores on the PeDRO scale < 6 and four studies
had scores ≥ 8. On average, the overall PeDRO grade was 6. The most common weakness
was unclear blinding assessment. None of the studies blinded patients or therapists,
but the patients were randomized in 11 studies. The most common strengths were the
clear eligibility (a list of criteria was used to determine who was eligible to participate
in the study), similar distribution of the groups (with description of at least one
measurement of the severity of the condition under treatment and at least one (different)
key outcome measurement at baseline), the intergroup comparisons and the measurements
of variability. These statistical assessments were important for reducing the risk
of bias associated with comparisons between the results from the control and intervention
groups.
Table 3
PeDRO assessment of the studies.
|
Author and year
|
Eligibility
|
Subjects were randomly assigned
|
Blind distribution
|
Similar groups
|
Subjects were blinded
|
Therapists were blinded
|
Assessors were blinded
|
Results measured
|
Intention-to-treat analysis
|
Intergroup comparison
|
Measurement of variability
|
Total
|
|
Linder et al., 2019[5]
|
Yes
|
Yes
|
Yes
|
Yes
|
No
|
No
|
Yes
|
Yes
|
No
|
Yes
|
Yes
|
8/11
|
|
Ploughman et al., 2019[9]
|
Yes
|
Yes
|
Yes
|
Yes
|
No
|
No
|
Yes
|
Yes
|
Yes
|
Yes
|
Yes
|
9/11
|
|
Luft et al., 2008[11]
|
Yes
|
Yes
|
No
|
Yes
|
No
|
No
|
Yes
|
No
|
No
|
Yes
|
Yes
|
6/11
|
|
Nepveu et al., 2017[12]
|
No
|
Yes
|
No
|
Yes
|
No
|
No
|
Yes
|
Yes
|
Yes
|
Yes
|
Yes
|
7/11
|
|
Abraha et al., 2018[13]
|
No
|
No
|
No
|
No
|
No
|
No
|
No
|
Yes
|
Yes
|
Yes
|
Yes
|
4/11
|
|
Murdoch et al., 2016[15]
|
Yes
|
Yes
|
No
|
No
|
No
|
No
|
No
|
No
|
No
|
Yes
|
Yes
|
4/11
|
|
Quaney et al., 2009[16]
|
Yes
|
Yes
|
No
|
Yes
|
No
|
No
|
Yes
|
Yes
|
No
|
Yes
|
Yes
|
7/11
|
|
Yang et al., 2014[17]
|
Yes
|
Yes
|
Yes
|
Yes
|
No
|
No
|
Yes
|
Yes
|
No
|
Yes
|
Yes
|
8/11
|
|
El-Tamawy et al., 2014[19]
|
Yes
|
No
|
No
|
Yes
|
No
|
No
|
No
|
Yes
|
Yes
|
Yes
|
Yes
|
6/11
|
|
Charalambous et al., 2018[20]
|
Yes
|
Yes
|
No
|
Yes
|
No
|
No
|
No
|
Yes
|
Yes
|
Yes
|
Yes
|
7/11
|
|
Boyne et al., 2020[21]
|
Yes
|
No
|
No
|
Yes
|
No
|
No
|
No
|
Yes
|
Yes
|
Yes
|
Yes
|
6/11
|
|
Boyne et al., 2019[22]
|
Yes
|
No
|
No
|
Yes
|
No
|
No
|
No
|
Yes
|
Yes
|
Yes
|
Yes
|
6/11
|
|
Shaughnessy et al., 2012[23]
|
No
|
Yes
|
No
|
Yes
|
No
|
No
|
No
|
No
|
No
|
Yes
|
Yes
|
4/11
|
|
Sandberg et al., 2016[24]
|
Yes
|
Yes
|
Yes
|
Yes
|
No
|
No
|
Yes
|
Yes
|
No
|
Yes
|
Yes
|
8/11
|
|
Nave et al., 2019[25]
|
Yes
|
Yes
|
No
|
Yes
|
No
|
No
|
Yes
|
No
|
Yes
|
Yes
|
Yes
|
7/11
|
|
Morton, 2019[27]
|
Yes
|
No
|
No
|
Yes
|
No
|
No
|
No
|
Yes
|
Yes
|
Yes
|
Yes
|
5/11
|
Evaluation of results
The results from the studies included in this systematic review were expressed according
to outcomes represented by each neuroplasticity assessment marker, as follows: 1)
functional magnetic resonance and cortical excitability; 2) cognitive evaluation and
motor recovery (motor relearning); 3) evaluation of neurotrophic factors; and 4) functional
evaluation through functionality scales.
Neuroplasticity assessed through functional resonance and cortical excitability
Using functional MRI, other studies have shown increased activation of the contralesional
cortex with movement of the paretic limb in the early post-stroke period[10]. Luft et al.[11] demonstrated that repetitive treadmill training improves cardiorespiratory capacity
and recruits neural circuits in the brainstem and cerebellum as well as in the frontal,
temporal and parietal cortical areas. Such overall changes in brain activation suggests
potential neuroplastic mechanisms through which treadmill training can re-establish
motor capacity and functional ability to walk, among post-stroke hemiparesis patients.
Nepveu et al.[12] showed that a single dose of high-intensity interval training performed immediately
after physical therapy improves motor retention ability, as measured through the Montreal
Cognitive Assessment (MoCA). Despite this, no statistically significant changes were
observed in the assessment of cortical excitability, which could partially be explained
by the older age of the sample being older and use of exercise doses that were lower
than those that would be necessary to produce this effect. That study suggested that
neuroplasticity might be associated with high-intensity exercise potentiated by physical
therapy priming.
Abraha et al.[13] demonstrated that there was greater latency in the motor evoked potential according
to the intensity of the exercise, such that the latency of the motor evoked potential
was greater after high-intensity interval training (HIIT) than after continuous training
of moderate intensity. Their finding may have been related to a tendency to neuromuscular
fatigue with HIIT. Their study brought up the concept that acute changes in corticospinal
excitability after exercise may not be related to clinical changes in paretic limb
strength and dexterity. Therefore, HIIT would not potentiate short term motor neuroplasticity.
Broderick et al.[14] demonstrated that cortical-motor excitability increased after a short dose of high-intensity
exercise among patients with sequelae of VCA. In their study, cortical excitability
changed, as measured through the amplitude of the evoked motor potential in the injured
hemisphere. However, no evaluation was performed with regard to whether motor recovery
also changed with increased excitability.
Murdoch et al.[15] reported that 30 minutes of low-intensity bike exercise did not increase cortical
excitability. Thus, they did find any association with motor cortex neuroplasticity.
Neuroplasticity assessed through cognitive and motor recovery (motor relearning) evaluation
Four studies included in this systematic review evaluated the effects of aerobic physical
training on neuroplasticity using scales and motor assessments before and after the
intervention.
Linder et al.[5] evaluated the effects of a moderate-intensity aerobic training program using two
motor recovery scales: Fugl Meyer scale (FMA) and Wolf Motor Function Test (WMF).
The main finding from their study was that “forced exercise” (defined by the authors
as an exercise modality that augmented but did not replace the voluntary efforts of
a participant to facilitate sustained aerobic exercise training) and moderate-intensity
aerobic exercise facilitated motor recovery. The most plausible explanation for this
was that moderate to high-intensity exercises induce neurophysiological and vascular
changes in the central nervous system.
Ploughman et al.[6] demonstrated that aerobic exercise associated with cognitive training had better
results with regard to cognitive assessment, physical fitness and walking speed. They
also demonstrated that aerobic physical training without cognitive training did not
show the same results. Therefore, their study supports the notion that combined training
can promote neuroplasticity, such that this is able to overcome the recovery plateau
even when there is no benefit regarding improvement of depressed mood. Although BDNF
did not change with this intervention, IgF1 significantly increased.
Quaney et al.[16] demonstrated that patients with chronic stroke who performed aerobic exercise significantly
increased their motor learning. This finding provides evidence that eight weeks of
moderate-intensity aerobic training, three times a week, leads to benefits in cognition,
including improved motor learning.
Yang et al.[17] suggested that a combination of cycling training and conventional rehabilitation
can lead to improved functional recovery of the lower limbs, endurance capabilities,
walking speed and spasticity. The FMA scale was used to assess functional recovery,
with significant improvement observed.
Neuroplasticity assessed through neurotrophic factors
Aerobic training can increase the serum levels of neurotrophic factors in healthy
individuals, which are considered to be potent regulators of plasticity and survival
of adult neurons and glial cells. In animal stroke models, it has been observed that
some neurotrophic factors may increase with moderate to high-intensity aerobic exercise[2],[9],[18].
Only one study measured the response of an aerobic training program for neuroplasticity
that was measured through neurotrophic factors.
El Tamawy et al.[19] evaluated patients with sequelae of stroke in anterior circulation through aerobic
exercise in association with physical therapy. They showed that aerobic exercise increased
BDNF levels and improved executive function, as assessed through cognitive tests.
There was a positive correlation (r = 0.53) between the increase in BDNF and the improvements
in the tests.
Three studies measured the response of a single session of aerobic exercise regarding
neuroplasticity, through changes in serum neurotrophins.
Charalambos et al.[20] were unable to demonstrate that high-intensity exercises increased serum BDNF levels
after a training session, possibly due to the severe neurological damage and advanced
age in their sample, which thus limited the response to the intervention.
Boyne et al.[21] showed that the neurotrophic factors VEGF1 and IgF1 significantly increased through
high-intensity interval training session, but not with moderate-intensity exercise.
However, they did not measure BDNF, nor did they assess whether such results clinically
impacted rehabilitation goals.
Boyne et al.[22] showed that high-intensity interval exercise promoted a significant increase in
BDNF, in comparison with continuous training of moderate intensity. In addition, they
showed that the increase in BDNF was associated with a decrease in intracortical inhibition.
Since motor relearning has been associated with lower intracortical inhibition, their
findings provide support for the idea that changes in BDNF represent a potential marker
of neuroplasticity.
Neuroplasticity assessed through functional scales
The three articles included in this section used functional scales as outcomes. Indeed,
in assessing overall functionality, scales can provide indirect inferences about neuroplasticity,
albeit not exclusively, given that other rehabilitation mechanisms (e.g. adaptation)
can also improve the functional characteristics of post-stroke individuals.
Shaughnessy et al.[23] evaluated the effects of aerobic training for six months on functional independence
and functional recovery. They showed that there was an increase in the ability to
perform tasks of daily living and an increase in aerobic capacity. Notably, this was
a self-assessment study with no objective measurements.
Sandberg et al.[24] showed that intensive aerobic exercise, twice a week, for 12 weeks, among patients
with stroke in the subacute phase improved their physical performance and quality
of life. There were improvements in aerobic capacity, speed, functional mobility,
balance, quality of life and sense of functional recovery.
Nave et al.[25] evaluated only patients with severe motor sequelae in subacute phases after stroke
and demonstrated that there was no superiority of aerobic physical activity in relation
to relaxation sessions, regarding functional improvement.
DISCUSSION
Neuroplasticity plays a pivotal role in post-stroke recovery processes, through limiting
sequelae and brain damage. A growing body of evidence from experimental stroke models
has shown that physical activity positively impacts neuroplasticity, thus suggesting
that exercise techniques can potentially improve cognition and functionality. However,
there is great variability in the dose-response of exercise prescription and in neuroplasticity
metrics as well. Therefore, the clinical applicability of exercise prescription remains
unknown.
To try to address this relevant clinical question, we conducted the present systematic
review. Our main findings were: a) acute and chronic interventions consisting of moderate
to high-intensity exercise are associated with better neuroplastic responses overall,
except when assessed using functional MRI, from which the results are conflicting;
b) cognitive or physiotherapeutic stimuli after an exercise session seem to provide
additional neuroplastic benefit, which is greater than if these stimuli were applied
without the exercise; c) good quality evidence is still lacking, given the absence
of any gold-standard neuroplasticity metric, the non-uniformity of exercise interventions
and the unknown dose-response relationship.
After a stroke, alterations to brain physiology and organization result in different
brain activation patterns. During functional restructuration, the brain can modify
its connections, thus leading to clinical changes during the rehabilitation period.
Neuroplasticity is defined as the ability of the central nervous system to undergo
structural and functional adaptations as a result of new experiences[4]. Cohort studies on stroke patients have suggested that the motor recovery plateau
occurs around 12 weeks after vascular ictus[6]. Several researchers have implemented forms of rehabilitation that make it possible
to reopen the window of recovery and neuroplasticity after stroke[6]. Thus, aerobic physical exercise has been one of the strategies used for this goal.
The mechanisms through which aerobic exercise can enhance or intensify neuroplasticity
have been described in relation to animals: these involve vascular impact through
angiogenesis, glial restructuration and neurogenesis (with VEGF1 as one of the main
markers); and a direct role for aerobic exercise in neuronal growth and presence of
survival markers (with IgF1 and BDNF). Some authors have speculated that IgF1 elevation
even with unchanged BDNF was associated with better post-stroke functional outcomes[9]. In addition, physical exercise can act on cognitive improvement and, therefore,
have a direct impact on the overall motor relearning process. This can activate accessory
neural networks that assist in improving motor recovery. Lastly, there was an improvement
in expectations associated with doing exercise: this was important because it shows
that belief in the benefits of exercise can help in long-term adherence.
This systematic review evaluated the impacts of aerobic exercise on neuroplasticity
through assessment of neural networks and neuronal excitability, through neurotrophic
factors and through cognitive and functional assessment.
We found that the studies that evaluated the effects of aerobic exercise on neuroplasticity
after stroke, as measured through functional MRI or cortical excitability, had divergent
but promising results. Lack of uniformity in training (intensity, frequency or duration)
can be the main driver of conflicting results. One important finding was that light-intensity
exercises did not change cortical excitability. Conversely, moderate-intensity exercise
training was associated with changes in functional MRI and excitability, thus suggesting
that neuroplastic adaptations are triggered by rehabilitation programs that include
higher-intensity exercise intervention. Additionally, interval and high-intensity
exercises can lead to better results regarding neuroplastic outcomes, especially if
associated temporally with motor physical therapy. However, it is important to note
that changes in functional MRI and neuronal excitability may not correlate with clinical
changes.
It is known that cognitive impairment hinders the sensory-motor learning that is necessary
for post-stroke recovery. In the studies included in this review that used cognitive
assessment and motor recovery (motor relearning), there was evidence that moderate-intensity
aerobic exercise and “forced exercise” were able to improve motor learning among patients
with stroke sequelae who were undergoing rehabilitation. The mechanisms through which
these improvements occur were not evaluated in these studies, but there were suggestions
that the potential mechanisms involved were increased BDNF, increased IgF1, improved
synaptogenesis and cerebral flow[26]. When the results regarding the association between aerobic training and cognitive
training were analyzed, additional benefits were seen. Thus, there is evidence that
associating aerobic exercise with cognitive training is better for improving certain
cognitive domains linked to motor learning and is a strategy that can be implemented
in a rehabilitation program.
The four studies that involved analysis of neurotrophic factors as an assessment of
neuroplasticity had conflicting results. Notably, all of them evaluated moderate to
high-intensity aerobic exercise. The study that involved a moderate-intensity aerobic
exercise program[19] showed that there was an increase in BDNF after exercise combined with motor physiotherapy.
One of the studies involving a single exercise session[20] did not show any increase in BDNF after a high-intensity training session. Two studies[21],[22] showed that a high-intensity interval training session was able to increase circulating
VEGF, IgF1 and BDNF.
Factors relating to age, genetics, exercise intensity and severity of the neurological
condition could directly attenuate the response of neurotrophic factors to aerobic
physical exercise. BDNF, which is currently the most studied neurotrophic factor,
is abundant in the central nervous system and is involved in activity-induced neuroplasticity.
It is upregulated by exercise in animal models. In healthy adults, the increase in
BDNF during high-intensity activity has been linked to improved cognition. Although
beyond the objective of this review, genetic variation of BDNF can affect the response
to rehabilitation training and, potentially, modulate the effects of aerobic exercise
on neuroplasticity. Helm et al.[8] found that high-intensity exercises can lead to significant increases in BDNF in
patients with Val66Met polymorphism, which can be blunted at lower intensities. Therefore,
greater intensity of exercise may be able to reduce the damaging effects of lower
release of BDNF in individuals with this polymorphism. Thus, although the studies
included in this review did not mention the important contribution of the Val66Met
polymorphism in relation to circulating BDNF after aerobic exercise, the presence
of better results from evaluations on high-intensity exercises may be related to this
fact.
Given that knowledge in this field is still growing, the quality of evidence remains
restricted. The studies analyzed had significant limitations such as small sample
size and risk of selection bias; and absence of well-established correlations between
laboratory/imaging findings and the clinical outcomes.
The heterogeneous interventions and outcomes precluded extraction of more objective
data to calculate effect sizes and dose-response relationships. Additionally, the
lack of a uniform gold-standard method for accurately measuring neuroplasticity, still
limits the ability to expand its clinical applicability.
Despite these limitations, we were able through this review to compile a series of
new findings that may guide the possibilities for further studies in this field, in
order to systematize and optimize rehabilitation programs for patients with stroke
consequences.
As a conclusion for this work, it can be stated that aerobic physical exercise is
a therapeutic intervention in rehabilitation programs that, beyond the known benefits
relating to physical conditioning, functionality, mood and cardiovascular health,
may potentiate the neuroplasticity process. Good-quality evidence is still lacking,
with regard to the limited uniformity of aerobic training prescription, the drivers
of attenuation of individual responses and the equivocal metrics of matching between
plasticity and clinical outcomes. Nonetheless, overall neuroplasticity responses seem
more robust in moderate to high-intensity exercise training programs, to which adherence
and safety are critical to achieving such benefits. A combination of cognitive training
or physiotherapy training, implemented immediately after an aerobic workout, may provide
additive benefit towards neuroplasticity in rehabilitation programs.
