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The Effects of Poststroke Aerobic Exercise on Neuroplasticity: A Systematic

Review of Animal and Clinical Studies

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Transl. Stroke Res.
DOI 10.1007/s12975-014-0357-7

REVIEW ARTICLE

The Effects of Poststroke Aerobic Exercise on Neuroplasticity: A

Systematic Review of Animal and Clinical Studies
Michelle Ploughman & Mark W. Austin & Lindsay Glynn &
Dale Corbett

Received: 16 April 2014 / Revised: 2 June 2014 / Accepted: 30 June 2014

# Springer Science+Business Media New York 2014

Abstract Aerobic exercise may be a catalyst to promote Keywords Aerobic exercise . Neurotrophins . BDNF .
neuroplasticity and recovery following stroke; however, the Neuroplasticity . Rehabilitation . Stroke . Cerebrovascular .
optimal methods to measure neuroplasticity and the effects of Review
training parameters have not been fully elucidated. We con-
ducted a systematic review and synthesis of clinical trials and Abbreviations
studies in animal models to determine (1) the extent to which AE Aerobic exercise
aerobic exercise influences poststroke markers of BDNF Brain-derived neurotrophic factor
neuroplasticity, (2) the optimal parameters of exercise re- EEG Electroencephalography
quired to induce beneficial effects, and (3) consistent out- FE Forced exercise
comes in animal models that could help inform the design of fMRI Functional magnetic resonance imaging
future trials. Synthesized findings show that forced exercise at GAP43 Growth-associated protein-43
moderate to high intensity increases brain-derived neurotroph- IGF-I Insulin-like growth factor-I
ic factor (BDNF), insulin-like growth factor-I (IGF-I), nerve NGF Nerve growth factor
growth factor (NGF), and synaptogenesis in multiple brain MAP2 Microtubule-associated protein 2
regions. Dendritic branching was most responsive to moderate MEG Magnetoencephalography
rather than intense training. Disparity between clinical stroke PET Positron emission tomography
and stroke models (timing of initiation of exercise, age, gen- VE Voluntary exercise
der) and clinically viable methods to measure neuroplasticity VEGF Vascular endothelial growth factor
are some of the areas that should be addressed in future
research.

Introduction
M. Ploughman (*) : M. W. Austin
Recovery and Performance Laboratory, Rehabilitation Research With few treatment options available, stroke is the leading
Unit, Faculty of Medicine, Memorial University, Rm 400, L.A. cause of adult neurological disability, affecting one in six
Miller Centre, 100 Forest Rd., St. John’s, NL, Canada
e-mail: michelle.ploughman@med.mun.ca
people worldwide [1, 2]. Although rehabilitative interventions
improve outcome, full recovery is often incomplete [3]. In
L. Glynn animal models, neurotrophins such as brain-derived neuro-
Health Sciences Library, Memorial University of Newfoundland, St. trophic factor (BDNF), insulin-like growth factor-I (IGF-I),
John’s, NL, Canada
and nerve growth factor (NGF) are dramatically upregulated
D. Corbett during the first 4 weeks after stroke [4], creating a
Department of Cellular and Molecular Medicine, University of “neuroplastic milieu” in which cortical remodeling within
Ottawa, Ottawa, ON, Canada the intact brain is optimized [5]. BDNF belongs to a group
of secreted proteins that mediate activity-dependent processes
D. Corbett
Heart and Stroke Foundation Canadian Partnership for Stroke such as synapse formation and neuronal growth [6, 7]. In-
Recovery, Ottawa, ON, Canada creased IGF-I is associated with better neurological recovery

[8], while NGF promotes the growth and survival of sensory
and sympathetic neurons: processes that are likely beneficial
to poststroke plasticity and recovery [9]. Animal models of
stroke have elucidated the postischemic molecular events in
which growth of new synapses (synaptogenesis) and dendritic
branching modify the intact sensorimotor cortex and subcor-
tical structures contributing to recovery of cognitive and mo-
tor performance [10]. Much less is known about plasticity
events in human stroke.
Aerobic exercise (AE) is one of several behavioral
interventions known to influence neurotrophins,
neuroplasticity, and cognition [11]. “Aerobic exercise”
is defined by the Consensus Panel recommending AE
for stroke, as “planned, structured and repetitive physical
activity performed for extended periods of time and at
sufficient intensity to improve or maintain physical fit-
ness” [12]. In healthy humans and animals, AE increases
a variety of plasticity-promoting factors including BDNF
[13] and IGF-I [14]. AE also increases synaptogenesis
[15] and maintains brain volume in older adults [16], and
two meta-analyses [11, 17] report that AE significantly
enhances several domains of cognitive function.
Chronic stroke survivors demonstrate significant im-
provements in aerobic fitness following AE interventions
[18] and the use of AE to optimize neuroplasticity and
recovery has begun to garner considerable interest [19,
20]. However, due to inadequately powered clinical trials
and lack of standardized outcomes, recent systematic
reviews have reported that there is insufficient evidence
to recommend poststroke AE to augment plasticity and
cognition [18, 21, 22]. Almost all research examining the
effects of AE after stroke have utilized animal models so
the optimal methods to measure neuroplasticity (such as
peripheral blood levels of neurotrophins or noninvasive
brain imaging) in humans are not known. Furthermore,
the effects of training parameters such as time of initia-
tion, frequency, and intensity have not been fully eluci-
dated—important information in order to translate find-
ings to clinical trials.
This review and synthesis of animal and human studies
aimed to determine (1) the extent to which AE influences
poststroke markers of neuroplasticity (e.g., neurotrophin
levels, synaptogenesis), (2) the optimal parameters of exercise
required to induce beneficial effects, and (3) consistent out-
comes in animal models that could help inform the design of
clinical trials. Although there is a body of literature exam-
ining the neuroprotective effects of aerobic exercise, and
hypoxia/hypercapnia instituted before stroke [23, 24], we
focused on AE initiated post-stroke. This paper, which
synthesizes data from studies examining neuroplasticity,
is the second of three reviews examining the effects of AE
on poststroke repair and recovery (inflammation, cognition,
skilled motor performance, etc.) [25].
Transl. Stroke Res.
Methods
Using PRISMA guidelines [26], a search of English language
articles (up to December 2013) in CINAHL, PubMed,
PsychInfo, and the Cochrane Library was guided by a librar-
ian expert in systematic review (LG). Using a priori search
criteria (Table 1), records were screened at the title and ab-
stract stage by two authors (MP, MWA) who then examined
full-text manuscripts. Experimental methods and results of
studies meeting inclusion criteria were sorted in a spreadsheet
and results were consolidated by the same two authors, who,
by consensus, categorized study outcomes by theme. In order
to compare results across preclinical studies, data derived
from text and graphs were recalculated as a percentage of
sedentary stroke animals. We did not determine statistical
significance of synthesized findings but instead reported when
the p value was <0.05 in the original source study. To protect
against inflation of findings from one or two studies, we only
synthesized outcomes that were examined in three or more
studies.
We divided exercise interventions into voluntary exercise
(VE) or forced exercise (FE). VE used a freely rotating run-
ning wheel which the rodent could propel voluntarily for a
specific duration designated by the experimenter, while FE
utilized a motorized treadmill, wheel, or rod in which the
speed and duration were completely controlled by the
experimenter.
Results
We retrieved 4,250 titles of which 115 were assessed at the
manuscript level (Fig. 1). Thirty measured neuroplasticity
outcomes: neurotrophic factors (BDNF, IGF-I, and NGF),
neuronal morphology (synaptic and dendritic change), and
cortical reorganization (Table 2). All studies except two (ex-
amining brain activity in clinical ischemic stroke) utilized
animal stroke models, with the majority of these employing
ischemic damage within the middle cerebral artery territory
(25 of 28). Two studies used a global ischemia model [50, 51]
and one a hemorrhagic model of striatal stroke [52]. Although
the postinjury events after hemorrhage differ from that of
ischemia [57], we included the study utilizing the hemor-
rhage model since it examined synaptic and dendritic
change (rather than molecular events directly post-
injury). The data from that study is pointed out separate-
ly in the text and in Tables 4 and 5.
We examined the intensity of exercise regimens across
studies, and based on previous research [31] and study con-
sensus, we categorized rodent FE into three levels: low inten-
sity (<10 m/min), moderate intensity (10–17 m/min), and high
intensity (>17 m/min). Based on average and peak heart rate
values [31], VE was classified as low-/moderate-intensity
Transl. Stroke Res.

Table 1 Search inclusion/exclu-

sion criteria Clinical studies Animal models of stroke

1. Adults over the age of 18 1. Utilization of a known model of ischemic

2. Acute, subacute, or chronic stroke
3. Any poststroke AE-based intervention, alone or in
combination with another intervention, including
but not limited to overground locomotion, arm
ergometry, swimming, and treadmill training
4. Exercise lasting more than 2 min to meet aerobic
metabolism threshold [27]
5. At least one component of aerobic fitness
measured (heart rate, perceived exertion, etc.)
6. At least one indicator of neuroplasticity measured
(focal or global) or hemorrhagic stroke
2. Poststroke intervention involving either
voluntary (free access to a running wheel)
or forced (treadmill running, swimming,
etc.) aerobic exercise, alone or in combination
with another intervention
3. At least one indicator of neuroplasticity measured

exercise. All animal studies, with the exception of one [33],
which compared old and young rodents, examined the effects
of exercise in young adult or juvenile animals.
Twelve of the 28 animal studies employed prestroke train-
ing habituation which may help to reduce stress during initi-
ation of poststroke AE, especially in FE protocols. In some
cases, this technique may have affected findings which we
point out in the relevant sections.
The Effects of Exercise on Neurotrophins
22 studies, all employing animal models of stroke. Neuro-
trophic factors examined included BDNF (n=15), IGF-I (n=
4), and NGF (n=4). There were too few studies examining
neurotrophin-4 (NT-4; [59]), vascular endothelial growth fac-
tor (VEGF; [40]), midkine [47], and phosphorylated CREB
[29, 31] to synthesize findings so they were excluded from
further analysis. Other than two studies that examined IGF-I
levels in peripheral blood in animal models [29, 43], all
studies examined neurotrophin levels using histology, West-
ern blot, or other assays of brain tissue.

Levels of neurotrophic factors, proteins that support neuronal

development, function, and survival [58], were measured in BDNF

The 15 studies investigating the effects of AE on BDNF and its

receptor trkB all employed focal ischemic stroke in rodents.
Outside of the two studies investigating BDNF messenger
RNA (mRNA) [28, 32], all studies measured protein levels of
BDNF in the brain by immunoassay or immunohistochemistry.
All study protocols instituted either VE or FE, 1 to 5 days post-
stroke, with the exception of one study [37], which delayed
exercise for 1 week after stroke. Because there were 15 studies
examining BDNF, we report the findings below by brain region
studied (hippocampus, subcortical structures, and cortex).

Hippocampal Levels of BDNF Levels of exercise-induced

changes in BDNF in contralesional and ipsilesional hippo-
campus, important for learning and memory, were examined
in 10 studies. Regardless of timing of exercise onset post-
stroke (1–7 days), mode of exercise, or type and size of stroke,
there are immediate increases in hippocampal levels of BDNF.
A single bout of VE or moderate-intensity FE produces a short
burst of hippocampal BDNF [29, 31]. Short duration training
for 1 week results in similar effects [36].

Optimal Parameters Longer term exercise durations for two

or more weeks results in changes in hippocampal BDNF
expression that appear to be at least partly intensity dependent.
Fig. 1 PRISMA flow chart of search results For example, low- to moderate-intensity FE for 2 weeks [34]
 Transl. Stroke Res.

Table 2 Search findings by

theme Theme Subtheme (number of articles) References

Neurotrophins BDNF, n=15 [28–42]

IGF-I, n=4 [29, 31, 43, 44]
NGF, n=4 [45–48]
Neuronal modification Synaptic change, n=15 [29, 31–35, 37, 40–42, 45, 49–52]
Dendritic branching, n=8 [32, 33, 40, 41, 48, 52–54]
Brain activity n=3 [49, 55, 56]

or 5 weeks [32] and VE for 4 [28] or 6 weeks [33] do another increased [39], and a third showed no effect
not affect hippocampal BDNF. However, three studies [37]. Careful examination of methodological differences
examining high-intensity FE (18–20 m/min) report con- suggests that longer duration FE (3 weeks) instituted
flicting findings: one showed decreased BDNF [41], 24 h post-stroke may increase hippocampal BDNF [39]

Table 3 BDNF level in cortical regions following exercise (as a percentage of stoke sedentary animals)

Articles Duration of VE VE VE VE+reach FE FE FE FE+reach FE+reach

exercise IL CL PL PL IL CL PL IL CL

Risedal et al. [31]: anterior brain 30 100 90 104

Risedal et al. [31]: posterior brain 30 89 104 71
Ploughman et al. [29]: 30 min 11 m/min 1 115 143*
or VE
Ploughman et al. [29]: 30 min 14 m/min 1 120
Ploughman et al. [29]: 60 min 11 m/min 1 86
Kim et al. [30]: moderate deficit group 12 90 150
Ploughman et al. [31] 1 100 121*
Ploughman et al. [32] 35 104 102 142 132
Maldonado et al. [33]: young group 42 100 100
Maldonado et al. [33]: old group 42 100
Seo et al. [34]: treadmill 14 133 115
Seo et al. [34]: rotorod 14 267 130
Ke et al. [36]: VE or FE 7 155 95
Ke et al. [36]: FE with hindlimb 7 181
stimulation
Sakakima et al. [38] 14 200*
Quirie et al. [37]: mature BDNF lesion rim 14 70
Quirie et al. [37]: mature BDNF lesion 14 206*
border
Quirie et al. [37]: mature BDNF 14 433*
perilesional
Quirie et al. [37]: proBDNF lesion rim 14 70
Quirie et al. [37]: proBDNF lesion border 14 75
Quirie et al. [37]: proBDNF perilesional 14 52*
Quirie et al. [37]: total BDNF 14 100
Zhang et al. [39] 28 200*
Lan et al. [42] 14 230*
Mean 96.3 102.3 110.0 100.0 148.5 120.9 159.3 142.0 132.0
SD 6.4 10.3 42.3 0.0 81.0 20.8 107.9 NA NA

Values are derived and recalculated from the included article text and graphs
VE voluntary exercise, FE forced exercise, IL ipsilesional cortex, CL contralesional cortex, PL perilesional cortex, +Reach combined with skilled reach
training, NA not available
*p<0.05, significantly different from the stroke sedentary group
Table 4 Synthesis of findings from studies reporting the effects of exercise on indicators of synaptic modification (as a percentage of stroke sedentary animals)

Articles Duration VE IL VE VE VE VE VE+ FE IL FE FE PL FE FE FE+ FE+ FE IL FE FE FE FE IL FE CL

of CTX CL PL IL CL reach CTX CL CTX IL CL reach reach STR CL IL CL THAL THAL
exercise CTX CTX HIP HIP IL CTX HIP HIP IL CL STR DG DG
Transl. Stroke Res.

Synapsin-I
Ploughman et al. [29]: 1 84 110 96 106 140 112
30 min 11 m/min or VE
Ploughman et al. [29]: 1 105 97 87
30 min 14 m/min
Ploughman et al. [29, 31]: 1 124 130 131
60 min 11 m/min
Ploughman et al. [32] 35 100 100 100 100
Chang et al. [35] 14 165*
Zhang et al. [40] 24 220* 150*
Shih et al. [41]: 14 112 135*
low intensity
Shih et al. [41]: 14 100 125
high intensity
Lan et al. [42] 14 194*
Synaptophysin
Marin et al. [49] 14 100
Seo et al. [34]: treadmill 14 80 97 183* 140 183* 150 150* 150
Seo et al. [34]: rotorod 14 84 95 206* 135 194* 130 175* 140
Quirie et al. [37] 14 400*
Mean 84 100 110 96 121 105 297 138 124 100 100 158 189 140 163 145
SD 67 10 146 42 19 11 8 14 18 7
Synapse to neuron ratio
Briones et al. [50]: anterior 14 95
Briones et al. [50]: medial 14 96
Briones et al. [51]: 14 96
inner layer
Briones et al. [51]: 14 95
outer layer
Receptor number
Dahlqvist et al. [45]: 30 84
serotonin dentate gyrus
Dahlqvist et al. [45]: 30 85*
serotonin (average dorsal
subregions; sig CA4)
Table 4 (continued)

Articles Duration VE IL VE VE VE VE VE+ FE IL FE FE PL FE FE FE+ FE+ FE IL FE FE FE FE IL FE CL

of CTX CL PL IL CL reach CTX CL CTX IL CL reach reach STR CL IL CL THAL THAL
exercise CTX CTX HIP HIP IL CTX HIP HIP IL CL STR DG DG

Dahlqvist et al. [45]: serotonin 30 89

(average ventral subregions)
Maldonado et al. [33]: NMDA 42 100 100
young group
Synaptic spines/boutons
Briones et al. [50]: no. of 14 89
multiple boutons anterior
Briones et al. [50]: no. of 14 97
multiple boutons medial
Briones et al. [50]: no. of 14 105
perforated synpases anterior
Briones et al. [50]: no. of 14 104
perforated synapses medial
Maldonado et al. [33]: 42 176 160
(spinophilin) young group
Takamatsu et al. [52]: PSD-95 11 64 89
synaptic spinesa
Takamatsu et al. [52]: synaptic 11 107 100
spine densitya
Shih et al. [41]: dendritic spine 14 110 126* 135* 118*
density, low intensity
(CA1 apical)
Shih et al. [41]: dendritic spine 14 97 114 110 111
density, high intensity
(CA1 apical)
Shih et al. [41]: dendritic spine 14 120* 114*
density, low intensity
(CA1 basal)
Shih et al. [41]: dendritic spine 14 93 103
density, high intensity
(CA1 basal)
Shih et al. [41]: dendritic spine 14 108 108
density, low intensity
(CA3 apical)
Shih et al. [41]: dendritic spine 14 101 105
density, high intensity
(CA3 apical)
Shih et al. [41]: dendritic spine 14 123* 121*
density, high intensity
Transl. Stroke Res.
Transl. Stroke Res.

FE CL

VE voluntary exercise, FE forced exercise, IL ipsilesional cortex, CL contralesional cortex, PL perilesional cortex, +Reach combined with skilled reach training, CTX cortex, HIP hippocampus, STR
THAL
more than delayed (2 or 7 days) shorter duration
(2 weeks) FE.
THAL
FE IL

Subcortical Levels of BDNF In subcortical regions, the effects

of AE on BDNF levels were variable and were only examined
DG

in five studies: two examining the thalamus [28, 34] and three
CL
FE

the striatum [35–37]. In the ipsilesional or contralesional

thalamus, there was no significant effect of exercise whether
DG
FE
IL

VE for 30 days [28] or low intensity FE for 14 days [34].

STR

High-intensity protocols have not been examined. In the

CL
FE

ipsilesional striatum, 7 days VE [36] beginning 24 h post-

FE IL

stroke did not significantly elevate BDNF while a 2-week

STR

burst of high-intensity FE (without prestroke habituation) or

4 weeks training at moderate intensity commencing 24 h post-
reach
FE+

CL

stroke increased striatal BDNF [35, 40]. When exercise was

accompanied by prestroke habituation [36, 37] or delayed by
reach
FE+

IL

7 days [37], there was no effect on striatal BDNF.

HIP

114
CL
FE

These findings suggest that the thalamus and striatum, even

on the ipsilesional side, are relatively insensitive to exercise-
HIP

110
FE

induced changes in BDNF compared to cortical and hippo-

IL

campal regions, and protocols must be high intensity or mod-

FE PL
CTX

erate intensity/long duration to affect striatal levels of BDNF.

CTX

Cortical Levels of BDNF Of the 12 studies examining cortical

CL
FE

levels of BDNF, five reported increases due to exercise [29,

31, 38, 40, 42], six reported no significant effects [28, 30,
FE IL
CTX

32–34, 36], and one reported mixed findings depending on the

cortical region and form of BDNF examined [37]. In order to
reach
VE+

synthesize study findings, cortical BDNF was recalculated in

IL

all studies as a percentage of BDNF in the corresponding

HIP
VE
CL

region of sedentary, socially housed stroke animals. Our syn-

thesized findings (Table 3) show that VE (1, 30, or 42 days)
HIP
VE
IL

does not alter cortical BDNF levels in the contralesional

Values are derived and recalculated from included article text and graphs

cortex (102.3±10.3 %), the ipsilesional cortex distant from

CTX
VE
PL

the lesion (96.3± 6.4 %), and perilesional cortex (110 ±

*p<0.05, significantly different from the stroke sedentary group

42.3 %) even when combined with skilled reach training [33].

CTX
VE
CL

Optimal Parameters Analysis of the effects of FE regimens

VE IL
CTX

on cortical BDNF levels (Table 3) suggested an effect of

region (proximity to lesion), intensity, and form of BDNF
Duration

exercise

striatum, DG dentate gyrus, THAL thalamus

measured (matureBDNF, proBDNF, or total BDNF). In the

contralesional cortex, exercise-induced changes in BDNF are
14

Utilized hemorrhagic model of stroke

of

only detected after one episode of moderate (30 or 60 min)

wheel running [29] [31]. Exercise for longer periods whether
using wheel, treadmill or rotating rod, or adding skilled reach
Shih et al. [41]: dendritic

intensity (CA3 basal)

training does not significantly affect BDNF levels in the

spine density, high

contralesional cortex (120.9±20.8 %; Table 3). There were

Table 4 (continued)

also no significant effects of FE on the ipsilesional cortex

(CA3 basal)

(148.5±81.0 %; Table 3) even when combined with reach

training [32]. In the perilesional cortex however, FE signifi-
Articles

cantly increased BDNF (159.3±107.9 %) whether measured

by immunostaining (200 %, [38]) or Western blot analysis
a
Table 5 Synthesis of findings from studies reporting effects of exercise on dendritic modification (as a percentage of stroke sedentary animals)

Articles Duration of VE IL VE CL VE PL VE+reach FE IL FE CL FE PL FE IL FE CL FE+reach FE+reach FE IL FE CL FE IL FE CL

exercise CTX CTX CTX PL CTX CTX CTX CTX HIP HIP IL CTX CL CTX STR STR DG DG

Microtubule-associated protein (MAP-2)

Ploughman et al. [32]: 35 84 95 95 109
MAP2 stain (cingulate)
Ploughman et al. [32]: 35 83 88
MAP2 stain (sensory)
Ploughman et al. [32]: 35 101 124
MAP2 stain (motor)
Ploughman et al. [32]: 35 100 100 100 100
MAP2 mRNA
Maldonado et al. [33]: 42 100 100
young group MAP2 stain
Shimada et al. [54]: MAP2 28 131 157* 145* 101
stain, low intensity (CA3)
Shimada et al. [54]: MAP2 28 80 84 90 81
stain, high intensity (CA3)
Shimada et al. [54]: MAP2 28 149 125
stain, low intensity (CA1)
Shimada et al. [54]: MAP2 28 85 63
stain, high intensity (CA1)
Dendritic morphology
Takamatsu et al. [52]: total 11 100 137
dendritic lengtha
Takamatsu et al. [52]: peak 11 100 129
no. intersectionsa
Shih et al. [41]: peak no. 14 114 133* 131* 142*
intersections, low intensity
(CA3)
Shih et al. [41]: peak no. 14 100 107 100 100
intersections, high intensity
(CA3)
Shih et al. [41]: peak no. 14 100 125*
intersections, low intensity
(CA1)
Shih et al. [41]: peak no. of 14 100 105
intersections, high intensity
(CA1)
Mean 100 100 92 95 107 112 98 105 100 133 117 106
SD 11 8 23 29 4 15 0 6 26 26
Dendritic growth indicators
Transl. Stroke Res.
Table 5 (continued)

Articles Duration of VE IL VE CL VE PL VE+reach FE IL FE CL FE PL FE IL FE CL FE+reach FE+reach FE IL FE CL FE IL FE CL

exercise CTX CTX CTX PL CTX CTX CTX CTX HIP HIP IL CTX CL CTX STR STR DG DG

Mizutani et al. [48]: GAP43 14 162*

Transl. Stroke Res.

Mizutani et al. [48]: pSer41- 14 175*

GAP43
Liu et al. [53]: netrin protein 28 113
day 4
Liu et al. [53]: netrin protein 28 140*
day 7
Liu et al. [53]: netrin protein 28 141*
day 14
Liu et al. [53]: netrin protein 28 170*
day 28
Liu et al. [53]: netrin receptor 28 117
DCC day 4
Liu et al. [53]: netrin receptor 28 181*
DCC day 7
Liu et al. [53]: netrin receptor 28 171*
DCC day 14
Liu et al. [53]: netrin receptor 28 188*
DCC day 28
Liu et al. [53]: netrin receptor 28 109
Unc5B day 4
Liu et al. [53]: netrin receptor 28 109
Unc5B day 7
Liu et al. [53]: netrin receptor 28 51*
Unc5B day 14
Liu et al. [53]: netrin receptor 28 47*
Unc5B day 28
Zhang et al. [40]: GAP43 23 87 90
Zhang et al. [40]: NogoA 23 22* 48
(inhibitor)

Values are derived and recalculated from the included article text and graphs
VE voluntary exercise, FE forced exercise, IL ipsilesional cortex, CL contralesional cortex, PL perilesional cortex, +Reach combined with skilled reach training, CTX cortex, HIP hippocampus, STR
striatum, DG dentate gyrus, THAL thalamus
*p<0.05, significantly different from the stroke sedentary group
a
Utilized hemorrhagic model of stroke

(206 and 433 % [37], 230 % [42], and 200 % [40]). There was
an effect of the form of BDNF with mature BDNF signifi-
cantly increased by FE, while proBDNF was decreased in the
same area [37]. The apparently contradictory effect may be
explained by the different roles of each form; conversion of
proBDNF to matureBDNF by activity assists with synapse
stabilization [60]. Furthermore, Quirie et al. demonstrated that
although FE increased matureBDNF in the perilesional cor-
tex, there was no effect at the rim of the lesion (Table 3; [37]).
Synthesized findings showed that increased BDNF in the
perilesional cortex was elicited using similar FE parameters:
12 to 18 m/min (moderate), 30 min/day for 14 or more days,
3–7 days post-stroke [37, 40, 42], but not high-intensity
protocols (immediate training at 20 m/min for 7 days [36]).
The exception was increased BDNF following rotating rod
exercise reported by Sakakima et al. (low intensity 4.8 m/min
[38]), suggesting a training mode-specific effect. Our findings
also suggest that BDNF changes in the cortex are not uni-
formly distributed so studies in which the entire hemisphere
was homogenized or tissues pooled for analysis [30, 32, 34]
may have been unable to detect subtle differences in BDNF
within ipsilesional areas.
IGF-I
Four studies examined the effects of AE on IGF-I levels
following stroke [29, 31, 43, 44]. Two studies, which mea-
sured both peripheral blood and brain levels [29, 43], con-
firmed the apparent paradoxical relationship between levels of
IGF-I in brain and blood. There was a strong negative corre-
lation between plasma levels of IGF-I [43] or serum [29] and
FE exercise duration [43] or VE distance [29], suggesting that
exercise training depletes circulating IGF-I and enhances its
uptake into the injured brain.
Optimal Parameters In terms of brain levels of IGF-I, a single
bout of moderately high-intensity FE (14 m/min), but not
lower intensity FE (11 m/min) or VE [29, 31], increased
IGF-I levels in contralesional hippocampus (but not the
contralesional cortex or ipsilesional hippocampus). Addition-
ally, 2 weeks of daily high-intensity FE increased IGF-I con-
centration in the ipsilesional motor cortex (about 309 % sed-
entary) and striatum (about 182 % sedentary [43]). The find-
ings were also confirmed by Zhang et al. showing that
moderate-intensity FE increased the number of IGF-I-
positive cells within the peri-infarct cortex after 7 days
(163 % sedentary), 14 days (220 % sedentary), or 21 days
(192 % sedentary) of exercise post-stroke [44].
NGF
Of the four studies investigating NGF or its receptor trkA, all
examined brain tissue levels in animal models of stroke. Three
Transl. Stroke Res.
studies confirmed increased NGF-positive cells in the
ipsilesional cortex after 14 to 28 days of exercise training:
either moderate- to high-intensity FE [46, 47] or 14 days VE
(12 h/day) [48]. Both Chung et al. and Matsuda et al. showed
an effect of exercise duration with increasing NGF-positive
cells over time, peaking at days 16 [46] and 28 [47], but not
earlier (days 1, 3, 5, 7, and 14 [47]). The exceptions to these
findings were those of Dahlqvist and colleagues [45]. They
observed that 1 month of daily VE resulted in lower levels of
mRNA expression of NGF-induced gene A (ipsilesional and
contralesional cortex and hippocampus) than animals exposed
to social housing or environmental enrichment. In contrast to
the previously mentioned studies, animals in the VE group
were provided access to running wheels 24 h/day and were
socially deprived which could have produced unintended
stressful effects.
The Effects of Exercise on Neuronal Modification
After stroke, synaptogenesis (the development of new synap-
ses) and dendritic branching represent examples of
neuroplastic change implicated in stroke recovery [61]. Fif-
teen studies investigated the effects of AE on synaptic modi-
fication after stroke (Table 1) and eight studies investigated
the effects of AE on dendritic change (Table 1).
Synaptic Change
Of the 15 studies examining exercise-induced changes in syn-
apses after stroke, eight reported significant increases in synap-
tic plasticity, one reported a decrease [45], while the remaining
six reported no effect of exercise compared to the control. The
synthesized data from these studies are shown in Table 4.
Notably, the four studies examining the effects of VE [29, 33,
45, 49] showed no benefit of VE on synaptic modification.
Optimal Parameters Synthesized findings (Table 4)
showed that moderate- to high-intensity (8–20 m/min)
FE regimens for 14 or more days increased synapsin-I
or synaptophysin in the perilesional cortex (297±146 %
[37, 42]), ipsilesional cortex distant from the lesion
(121 ± 67 % [40]), ipsilesional hippocampus (124 ±
19 % [34]), ipsilesional striatum (189 ± 8 % [34]),
ipsilesional dentate gyrus (189 ± 8 % [34]), and
ipsilesional thalamus (163±18 % [34]). Only one study
showed an increase in synapsin-I in the contralateral
hemisphere, but the increase was short-lived, dropping
below sedentary levels 30 min after cessation of exer-
cise [29]. Other indicators of synaptic change such as
synapse to spine ratio, number of receptors, or synaptic
spine density were examined in five studies [33, 45,
50–52], and none of these reported any beneficial ef-
fects of poststroke exercise (Table 4).
Transl. Stroke Res.
Dendritic Growth
Eight studies examined the effects of AE on dendritic modi-
fication (Tables 1 and 5), microtubule-associated protein
(MAP2) [32, 33, 54], growth-associated protein-43 (GAP43)
[40, 48], netrin [53], and dendritic length and complexity [41,
52]. Two studies employing VE showed no benefit of VE or
VE combined with skilled reaching on MAP2 levels in the
ipsilesional cortex but evidence of increases in GAP43 and
pSer41-GAP43 in the area directly adjacent to the focal lesion
(Table 5; VE PL CTX [33, 48]). The remaining six studies
used FE paradigms from moderate to high intensity for 11 to
35 days, with differential effects depending on the intensity
and brain region examined.
Optimal Parameters In terms of the effect of FE in cortical
regions, FE increased GAP43, pSer41-GAP43 [48], netrin,
and netrin receptors [53] in the cortical areas adjacent to the
lesion (Table 5; FE PL CTX) but not MAP2 in more distant
cortical regions [32]. Furthermore, both Shimada et al. and
Shih et al. showed that low-intensity (8 m/min), but not high-
intensity (20–22 m/min) AE resulted in greater MAP2 stain-
ing and dendritic arborization within the CA1, CA3, and
dentate gyrus of the contralesional (but not ipsilesional) hip-
pocampus [41, 54]. Only two studies examined the dendritic
change in the perilesional cortex following forced exercise.
Liu et al. demonstrated an increase in the expression of netrin
and netrin receptor (DCC) following 16 days of moderate FE
[53], while Zhang and group [40] showed decreases in out-
growth inhibitor NogoA following 4 weeks of a similar exer-
cise paradigm.
Exercise-induced dendritic change within the striatum has
been examined in only two studies [40, 52]. They showed that
although there was a decrease in NogoA in the ipsilesional
side, dendritic length and complexity was not significantly
increased in either side with FE employed after a striatal
hemorrhagic stroke [52]. However, Takamatsu et al. used only
11 days of training, one of the shortest interventions reported,
and the increase in dendritic length and intersections in the
contralesional striatum, although not significant, was 137 and
129 % of sedentary [52]. In summary, evidence from the
synthesized findings suggests that after stroke, low- to
moderate-intensity FE, but not VE, enhances markers associ-
ated with dendritic branching in brain regions adjacent to and
distant from the lesion.
The Effects of Exercise on Brain Activity
Imaging techniques that map brain activation patterns have the
potential to detect neuroplasticity after stroke [62]. Only three
studies that met inclusion criteria examined the effects of AE
on brain activation, one using electroencephalography (EEG)
following VE in an animal model of stroke [49] and two using
functional magnetic resonance imaging (fMRI) [55, 56] to
map subcortical activation associated with movement of the
affected lower extremity (Table 2). Both clinical studies
employed moderate-intensity treadmill training in patients
about 3 years post-stroke. Longer duration (6 month) training
resulted in increased subcortical activation during movement
of the paretic limb [56] while 4 weeks training did not [55]. In
an animal model, 14 days VE did not alter EEG power in the
ipsilesional parietal cortex [49]. There were no studies that
examined the effects of AE on reorganization in brain areas
responsible for cognition, language, or upper extremity motor
control.
Discussion
Reduced mortality and better poststroke care results in more
stroke survivors with serious poststroke disability [1]. This,
along with anticipated increases in the rate of stroke due to an
aging population and rising rates of obesity coupled with a
sedentary lifestyle, highlights the importance of carefully
designed clinical trials to improve recovery during the reha-
bilitative phase of stroke. As recommended by stroke research
experts, our aims were to identify consistencies and determine
the optimal methods in animal models and preliminary phase I
and II clinical trials in order to advance the field and inform
the design of future phase III and IV clinical trials [63].
Subject Characteristics in Preclinical Trials Compared
to Stroke Patients
All preclinical studies, with the exception of one, which
compared young and old female animals [33], utilized juve-
nile or young adult male rats. The two clinical studies on the
other hand, examined men and women who were on average
63.2 [56] and 59.8 years of age [55]. Over two thirds of
strokes in Canada [64] and the USA [65] occur over the age
of 65, evenly balanced between men and women. The consis-
tent use of young male rodents in stroke models likely limits
the ability to detect age and sex effects that have been dem-
onstrated in other models of neurological injury [66–70].
Future research in animal models should focus on understand-
ing poststroke rehabilitation and plasticity in the older brains
of males and females.
In humans, variants of genetic polymorphisms of BDNF,
apolipoprotein E (APOE), and other genes may alter response
to interventions that would be expected to enhance plasticity
and recovery [71]. About a third of the population has a
variation of the amino acid chain in the proBDNF gene
(val66met) which results in decreased activity-induced secre-
tion of BDNF. The impact of BDNF gene polymorphism has

not been fully elucidated with some studies showing an im-
pairment in memory and cognition and others showing no
effect [20]. Future studies examining the influence of AE post-
stroke will have to consider patient populations with BDNF
and other genetic polymorphisms.
Timing of Interventions
In studies involving animals, exercise training began 1 to
7 days post-stroke compared to 3 years post-stroke in the
two clinical studies included in this review. Treadmill training
during the subacute rehabilitation phase of stroke improves
endurance and fitness [72, 73]; however, how soon to imple-
ment aerobic exercise and the optimal intensity to influence
plasticity after stroke is not known. In an animal model,
delayed initiation of rehabilitation (30 days post-stroke) did
not produce beneficial effects compared to training onset at 5
and 14 days, suggesting that sensitivity to training declines
with time post-stroke [74]. It is likely that the window of time
in humans when the brain is most responsive is within the first
few months post-stroke; therefore, future clinical trials should
focus efforts within this period when the brain is most ame-
nable to change.
Identifying Optimal Biological Indicators of Plasticity
for Clinical Trials
All studies examining the effects of AE on BDNF included in
this review measured protein levels of BDNF in the brain, not
in peripheral blood, which would be more practical in clinical
studies. Although lower BDNF blood levels have been impli-
cated in neurological disorders [75, 76] and higher peripheral
BDNF is associated with exercise [13], there is no correlation
between brain and blood levels of BDNF after stroke [77],
making it difficult to identify clinically appropriate biological
markers of plasticity. Furthermore, there is debate as to which
component of peripheral blood is most sensitive to behavioral
interventions: serum, plasma, or platelets [78, 79]. Future
animal studies must identify and optimize the most sensitive
methods to detect peripheral BDNF that can be translated to
clinical populations.
Voss and group [80] in a review of exercise studies in
elderly people note that in addition to BDNF, other peripheral
markers, such as IGF-I and VEGF, may be useful indicators of
neuroplasticity. Our review did not find any studies examining
peripheral levels of VEGF; however, IGF-I was measured in
either brain or blood in four studies (Table 1). Interestingly,
both Ploughman et al. [29] and Chang et al. [43] showed that
lower peripheral IGF-I and higher brain levels of IGF-I were
associated with exercise duration, suggesting that blood levels
were not positively correlated with brain levels and the re-
sponse of IGF-I is dynamic and time dependent. Although
IGF-I and VEGF have potential as peripheral biomarkers of
Transl. Stroke Res.
plasticity, their dynamics in response to exercise must be more
fully understood.
Our review revealed four studies investigating the effects
of AE on brain tissue levels (but not serum or plasma levels) of
NGF, with three of the four confirming that moderate- to high-
intensity exercise for 2 to 4 weeks increases NGF-positive
cells in the ipsilesional cortex [46–48], suggesting that NGF
may be a potentially important neurobiological marker. How-
ever, the sensitivity of peripheral blood NGF as a marker of
activity-induced plasticity is under debate with some studies
showing increases and others showing no effect with exercise
[81, 82]. Future research should investigate peripheral NGF as
a viable and accessible measure of poststroke plasticity.
Brain imaging likely provides the most accessible and
sensitive indicator of training-induced plasticity in clinical
stroke trials. Using transcranial magnetic stimulation,
rehabilitation-induced changes in motor threshold and map
size of target muscles can be detected [56, 83]. Functional
MRI [84], EEG, magnetoencephalography (MEG) [85], and
positron emission tomography (PET) also hold promise in
identifying brain activity in response to rehabilitative treat-
ments [86, 87]. As PET probes continue to advance [88], there
will be opportunities to map the properties of neurobiological
markers such as VEGF [89].
Regions of Interest in Poststroke Recovery
Early after ischemic stroke, fMRI and neuronal tracing
studies show that motor-related neural activity is en-
hanced in both hemispheres, but that over subsequent
months, good motor performance and recovery of the
affected side is accompanied by more focused activity
in the injured hemisphere particularly the ipsilesional
dorsal premotor cortex and striatum [10]. It was surpris-
ing that only 3 of 30 studies in this review examined
plastic changes in the striatum as a result of AE. Clearly,
more research needs to be undertaken to determine the
role of distal brain regions in poststroke recovery.
In this review, we found a preponderance of studies
examining the effects of AE on hippocampal plasticity
post-stroke. Although the role of the hippocampus in
motor relearning and motor recovery after stroke has
not been examined, recent imaging studies using longi-
tudinal high-resolution MRI suggests that gray matter
volume of the hippocampus and precuneus is positively
correlated with motor recovery [90]. Attention, motiva-
tion, and short- and long-term memory, which are regu-
lated in part by the hippocampus, are likely important
contributors to practice and motor relearning post-stroke
[91]. Whether or not the hippocampus plays a role in
poststroke recovery and its potential as a plasticity target
are important to determine in future research.
Transl. Stroke Res.
Optimal Aerobic Exercise Parameters to Affect Plasticity
The majority of studies examined in this systematic review
employed FE paradigms which are more likely to mimic
poststroke rehabilitation protocols in which the intensity and
duration are modified by the therapist. Overall, VE paradigms
did not significantly alter neurotrophins or synaptic and den-
dritic structure compared to FE protocols. We found that
intensity but not duration of FE was an important parameter
that increased the expression of neurotrophins and modified
synapses and dendrites. The critical threshold of intensity
depended on the outcome and the brain region examined.
Increased BDNF was consistently observed in the perilesional
cortex with moderate-intensity FE, 30 min/day for 14 or more
days beginning 3 to 7 days post-stroke. Our synthesized
findings suggest that brain levels of IGF-I and NGF as well
as markers of synaptic modification were increased consis-
tently across studies using moderate- to high-intensity FE
protocols. Post-AE dendritic change was particularly sensitive
to intensity, with two studies demonstrating that dendritic
modification is less robust and even downregulated with
immediate high-intensity FE (20–22 m/min), suggesting that
moderate-intensity training may be optimal.
Intensity of inpatient stroke rehabilitation varies substan-
tially across hospitals, health authorities, and countries. In the
Netherlands, it has been reported that patients attending stroke
rehabilitation spend 114 min/day in their heart rate training
zone [92], whereas in North America, patients spent less than
4 min per day at an intensity that would lead to a cardiovas-
cular training effect [93]. According to best practices for
aerobic training after stroke [12], treadmill or bicycle
ergometry, 20 min, three or more times per week for at least
8 weeks with graduated intensity (depending on fitness base-
line) is fundamental to obtain cardiovascular fitness in stroke
patients. However, these guidelines were derived from studies
examining cardiovascular fitness, not brain plasticity, so al-
though they may be a reasonable starting point, the optimal
parameters to induce neuroplastic change are not known.
Furthermore, from our understanding of task specificity train-
ing [94], aerobic exercise on its own is unlikely to improve
unrelated skills such as fine motor performance or executive
function. Combined therapy in which aerobic exercise is
paired with other interventions to “prime” the recovering brain
holds promise for future trials [63].
Summary of Recommendations
& Preclinical studies should focus on understanding post-
stroke rehabilitation and plasticity in the older brains of
male and female animals.
& Future clinical trials should move the AE intervention to
the subacute phase of stroke when the brain is most
amenable to change.
& Create a suite of peripheral (blood, saliva, etc.)
neurotrophin markers or noninvasive imaging techniques
to detect exercise-induced repair and recovery.
& Focus on FE protocols in which the timing and dosage can
be titrated in order to translate to post-stroke rehabilitation
trials, aiming to reach moderate- to high-intensity exercise
three to five times a week.
& Explore the combination of AE with skilled task and
cognitive and language training.
& In preclinical and imaging studies, examine the effects of
AE on brain networks that may underlie recovery such as
those in the supplementary motor cortex and subcortical
structures. There is a preponderance of studies of the
hippocampus even though its role in post-stroke recovery
is not known.
& AE effects may differ among certain populations with
BDNF and other genetic polymorphisms. Understanding
this group will help in the application of AE and other
interventions, aimed at modifying plasticity to a broader
group of patients.
Conclusion
Our synthesized findings show that forced exercise at moder-
ate to high intensity increases BDNF, IGF-I, NGF, and
synaptogenesis in multiple brain regions at least in animal
models of stroke. Clinical stroke and animal models need to
become more similar in terms of choice of research subject
(age, sex, time post-stroke) and selection of plasticity indicators
(peripheral vs. brain levels).
Acknowledgments We acknowledge the work of Chelsea Harris, Ste-
phen Hogan, and Michael Monks in obtaining and cataloguing articles.
Conflict of Interest All authors declare that they have no conflicts of
interest.
Compliance with Ethical Requirements This article is a synthesis of
human and animal study findings. Studies included in the review identi-
fied that they were in accordance with institutional and national guide-
lines for clinical and animal research.
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