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Background: Paired exercise and cognitive training have the potential to enhance cognition by "priming" the brain and upregulating neurotrophins. Methods: Two-site randomized controlled trial. Fifty-two patients >6 months poststroke with concerns about cognitive impairment trained 50 to 70 minutes, 3× week for 10 weeks with 12-week follow-up. Participants were randomized to 1 of 2 physical interventions: Aerobic (>60% VO2peak using <10% body weight-supported treadmill) or Activity (range of movement and functional tasks). Exercise was paired with 1 of 2 cognitive interventions (computerized dual working memory training [COG] or control computer games [Games]). The primary outcome for the 4 groups (Aerobic + COG, Aerobic + Games, Activity + COG, and Activity + Games) was fluid intelligence measured using Raven's Progressive Matrices Test administered at baseline, posttraining, and 3-month follow-up. Serum neurotrophins collected at one site (N = 30) included brain-derived neurotrophic factor (BDNF) at rest (BDNFresting) and after a graded exercise test (BDNFresponse) and insulin-like growth factor-1 at the same timepoints (IGF-1rest, IGF-1response). Results: At follow-up, fluid intelligence scores significantly improved compared to baseline in the Aerobic + COG and Activity + COG groups; however, only the Aerobic + COG group was significantly different (+47.8%) from control (Activity + Games -8.5%). Greater IGF-1response at baseline predicted 40% of the variance in cognitive improvement. There was no effect of the interventions on BDNFresting or BDNFresponse; nor was BDNF predictive of the outcome. Conclusions: Aerobic exercise combined with cognitive training improved fluid intelligence by almost 50% in patients >6 months poststroke. Participants with more robust improvements in cognition were able to upregulate higher levels of serum IGF-1 suggesting that this neurotrophin may be involved in behaviorally induced plasticity.
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https://doi.org/10.1177/1545968319832605
Neurorehabilitation and
Neural Repair
1 –14
© The Author(s) 2019
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DOI: 10.1177/1545968319832605
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Original Article
Introduction
There is a limited time window of recovery poststroke that
corresponds to biological events involving the upregulation
of growth promoting factors, such as brain-derived neuro-
trophic factor (BDNF) and insulin-like growth factor–1
(IGF-1), and subsequent blocking of postischemic plasticity
by growth-inhibiting factors.1 Large cohort studies examin-
ing poststroke impairment confirm that motor recovery pla-
teaus at about 12 weeks.2-4 The plateau of recovery following
832605NNRXXX10.1177/1545968319832605Neurorehabilitation and Neural RepairPloughman et al
research-article2019
1Memorial University of Newfoundland, St. John’s, Newfoundland and
Labrador, Canada
2Dalhousie University, Halifax, Nova Scotia, Canada NL, Canada
Corresponding Author:
Michelle Ploughman, Faculty of Medicine, Memorial University of
Newfoundland, Recovery & Performance Laboratory, Room 400, L. A.
Miller Centre, 100 Forest Road, St. John’s, Newfoundland and Labrador,
A1A 1E5, Canada.
Email: michelle.ploughman@med.mun.ca
Synergistic Benefits of Combined Aerobic
and Cognitive Training on Fluid Intelligence
and the Role of IGF-1 in Chronic Stroke
Michelle Ploughman, PhD1, Gail A. Eskes, PhD2,
Liam P. Kelly, MSc1, Megan C. Kirkland, MSc1,
Augustine J. Devasahayam, MSc1, Elizabeth M. Wallack, MSc1,
Beraki Abraha, MSc1, S. M. Mahmudul Hasan, MD1,
Matthew B. Downer1, Laura Keeler, MSc2, Graham Wilson2,
Elaine Skene2, Ishika Sharma, MSc2, Arthur R. Chaves1,
Marie E. Curtis1, Emily Bedford2, George S. Robertson, PhD2,
Craig S. Moore, PhD1, Jason McCarthy, MD1, and
Marilyn Mackay-Lyons, PhD2
Abstract
Background. Paired exercise and cognitive training have the potential to enhance cognition by “priming” the brain and
upregulating neurotrophins. Methods. Two-site randomized controlled trial. Fifty-two patients >6 months poststroke
with concerns about cognitive impairment trained 50 to 70 minutes, 3× week for 10 weeks with 12-week follow-up.
Participants were randomized to 1 of 2 physical interventions: Aerobic (>60% VO2peak using <10% body weight–supported
treadmill) or Activity (range of movement and functional tasks). Exercise was paired with 1 of 2 cognitive interventions
(computerized dual working memory training [COG] or control computer games [Games]). The primary outcome for
the 4 groups (Aerobic + COG, Aerobic + Games, Activity + COG, and Activity + Games) was fluid intelligence
measured using Raven’s Progressive Matrices Test administered at baseline, posttraining, and 3-month follow-up. Serum
neurotrophins collected at one site (N = 30) included brain-derived neurotrophic factor (BDNF) at rest (BDNFresting) and
after a graded exercise test (BDNFresponse) and insulin-like growth factor–1 at the same timepoints (IGF-1rest, IGF-1response).
Results. At follow-up, fluid intelligence scores significantly improved compared to baseline in the Aerobic + COG and
Activity + COG groups; however, only the Aerobic + COG group was significantly different (+47.8%) from control
(Activity + Games −8.5%). Greater IGF-1response at baseline predicted 40% of the variance in cognitive improvement. There
was no effect of the interventions on BDNFresting or BDNFresponse; nor was BDNF predictive of the outcome. Conclusions.
Aerobic exercise combined with cognitive training improved fluid intelligence by almost 50% in patients >6 months
poststroke. Participants with more robust improvements in cognition were able to upregulate higher levels of serum IGF-1
suggesting that this neurotrophin may be involved in behaviorally induced plasticity.
Keywords
rehabilitation, fluid intelligence, brain-derived neurotrophic factor, insulin-like growth factor–1, neuroplasticity, cognition
2 Neurorehabilitation and Neural Repair 00(0)
this critical period could also be related to the low inten-
sity interventions provided. Several groups worldwide
have reported the low physical demand of stroke
rehabilitation.5-7
Research groups are examining whether pharmacologi-
cal treatments or high levels of practice can “reopen” the
window to extend stroke recovery.8,9 Aerobic exercise is
one intervention that is underutilized during stroke rehabili-
tation despite the fact that patients have low fitness levels;
often too low to comfortably carry out activities of daily
living without excessive fatigue.10-12 Aerobic exercise has
global direct effects on the brain by increasing levels of
BDNF, IGF-1, and other neurotrophins,13-15 which could
serve to make the brain more amenable to change, particu-
larly when combined with other forms of rehabilitation.16-18
However, the majority of studies examining aerobic exer-
cise and neurotrophin upregulation have employed animal
models.13 Recent research in humans casts doubt on whether
exercise-induced circulating levels of neurotrophins BDNF
and IGF-1 are linked to fitness, cognition, or hippocampal
volume.19-21 Whether an aerobic intervention could enhance
cognition among people with stroke is inconclusive.22,23
Despite the fact that the majority of people with stroke
have cognitive impairment,24 cognition is rarely a target of
rehabilitation interventions.25 Furthermore, patients post-
stroke with cognitive loss, particularly those with impaired
attention and executive function, are unable to fully engage
in sensorimotor training26 and likely do not receive the full
benefits of physical rehabilitation.27 Impairments related to
higher order thinking, especially fluid intelligence, are
important predictors of longer lengths of stay and require-
ment for ongoing services after stroke.28 Furthermore, in
healthy individuals, higher fluid intelligence scores, mea-
sured using Raven’s Progressive Matrices Test (RPMT), are
associated with an efficiently organized and clustered rest-
ing functional brain network.29 Following stroke, such effi-
ciency of activation suggests better recovery.30 When
patients are contacted 2 to 3 years after achieving “success-
ful functional outcomes” at rehabilitation discharge, they
continue to have problems with cognition and reintegra-
tion.31 The fact that cognition and motor recovery are linked
is typically disregarded in rehabilitation and interventions
such as cognitive rehabilitation, speech therapy, and walk-
ing exercise are provided singly and temporally spaced
from one another.32
It is conceivable that aerobic exercise could serve to
“prime” the brain to enhance relearning of subsequent
tasks.18 However, evidence of a priming effect is lacking in
stroke. Quaney et al33 demonstrated enhanced learning of a
hand grip task on the nonhemiparetic side in patients post-
stroke who engaged in exercise. In contrast, Ploughman
et al34 reported that people in the chronic poststroke period
failed to improve their performance on a working memory
task after acute treadmill exercise. Liu-Ambrose and Eng35
showed that among chronic stroke patients with mild cogni-
tive impairment, mixed aerobic, resistance and balance
training combined with enriching recreational and social
activities for 6 months (n = 12) improved cognitive scores
compared with a waitlist control (n = 16). Bo et al36 showed
that combining mixed physical exercise and cognitive train-
ing enhanced cognition more than the interventions pro-
vided on their own among people less than 6 months after
stroke. In terms of nonstroke populations, a recent meta-
analysis confirmed that among older adults with cognitive
impairments, combining physical and cognitive training
improved executive function; however, the benefits seemed
to be less robust when compared with an active control
group.37 The temporal pairing of exercise and cognitive
training to reopen the “window of recovery” beyond 6
months poststroke has yet to be examined.
We aimed to determine whether aerobic exercise com-
bined with cognitive (dual-n-back) training would improve
fluid intelligence compared with the interventions alone
and when compared with an active control group. We also
examined the relationships between cognitive improvement
and change in serum levels of neurotrophins BDNF and
IGF-1. We targeted people who were greater than 6 months
poststroke; beyond the period when major recovery would
occur. Furthermore, by instituting a 12-week follow-up, we
aimed to determine whether combined intervention would
result in sustained improvement in cognition. Since exer-
cise, cognition, and depressive symptoms are linked,38 we
included measurement of depressive symptoms.
Methods
Design
The study was a block-randomized, single-blinded pilot
trial conducted at 2 sites (NC1674790). The study was
approved by the site ethics boards and all participants pro-
vided written informed consent. The second site began
enrolling participants 6 months after the first and due to
resources available, the RPMT was the only prespecified
cognitive outcome that was measured at both sites. Group
assignment to 1 of 4 intervention groups was conducted via
opaque envelope randomization using randomly permuted
blocks of 5 to 8 participants. Outcomes were assessed by an
evaluator blinded to group allocation. With power set at 0.8
and 5% type 1 error rate, sample size was calculated using
data from Mattay et al39 who examined the effects of the
stimulant amphetamine on RPMT scores. Our study was
testing the principle that aerobic exercise could also stimu-
late the brain and provide synergistic benefit using the same
outcome measure (RPMT score).39 Mattay et al39 reported
mean RPMT scores of 78.5% in controls and 87.4% in
drug-treated with 8.7 combined standard deviation. In a
2-group design, sample size was estimated at n = 20. To
Ploughman et al 3
account for attrition and use of four groups with multiple
comparisons, we tripled the estimate to n = 60.
Participants
Participants were recruited from a list of patients discharged
from two rehabilitation hospitals between January 2014 and
June 2016. Inclusion criteria: (a) age 18 years, (b) isch-
emic or hemorrhagic stroke >6 months, (c) self-reported
cognitive problems related to stroke interfering with daily
functioning, (d) ability to perform 2-step instruction, (e)
ambulation with/without aid 10 m, (f) negative high-risk
screening,40 (g) agreement to refrain from aerobic exercise
outside of trial interventions, and (h) time commitment to
participate in the study. Exclusion criteria: (a) moderate/
severe receptive aphasia, (b) life-threatening comorbidity
or concomitant neurological or psychiatric illness, and (c)
participation in other studies that could confound the out-
comes of this trial. Given their active role throughout the
trial, we were unable to blind the participants to their indi-
vidual interventions. However, they were all informed that
they were participating in a study to improve “thinking”
with no information provided on the superiority of particu-
lar groups. Participants were not provided any specific
instructions about ongoing physical or cognitive training
following the 10-week intervention and activity was not
monitored.
Intervention Protocols
Laboratory-supervised sessions were scheduled for 50 to 70
minutes per session, 3 sessions per week for 10 weeks. The
intervention dosage was chosen based on consolidated evi-
dence that aerobic training of sufficient intensity and dura-
tion (3 times per week for >8 weeks at moderate to vigorous
intensity) could increase neurotrophins, improve aerobic
fitness, and enhance cognition.12 Each intervention group
participated in one 20- to 30-minute physical intervention
(Aerobic or Activity) and one 20- to 30-minute cognitive
intervention (cognitive training [COG] or Games). Of the 4
groups (Aerobic + COG, Aerobic + Games, Activity +
COG, and Activity + Games), the Activity + Games group
was considered the active control. Rating of perceived exer-
tion (RPE) and heart rate (HR) was monitored in each ses-
sion to document physical and mental effort.
Aerobic Exercise (Aerobic). Aerobic exercise was performed
on a treadmill that had body weight support (BWS) and
speed/incline was adjusted to maintain the target heart rate
zone corresponding to 60% to 80% of peak oxygen uptake
(VO2peak), which was determined by the symptom-limited
graded exercise text (GXT) performed at baseline. Verbal
instructions were provided to promote stepping symmetry
and proper stepping kinematics, and BWS was reduced
such that the harness provided safety rather than support.
Physical Activity (Activity). Participants engaged in therapeutic
activity including interventions designed to improve range
of motion and comfort of the affected side (massage and
active and passive range of motion exercises) and to relearn
routine mobility tasks such as lying to sitting, rolling, sit to
stand, and standing balance (functional task training).41
Cognitive Training (COG). Computerized dual-n-back training
was performed with level of difficulty adapted to the indi-
vidual’s performance. The working memory task involved
monitoring a series of 2 concurrent stimuli (ie, visual loca-
tions on a screen and auditory single letters) and indicating
whether the current stimuli match those presented n items
back in the series. Value of n started at 1 and gradually
increased, dependent on participant performance.42
Cognitive Games (Games). Participants sat at a workstation
and played a non-adaptive computer-based game that
involved strategically placing descending puzzle pieces.
Assessment Protocol
Participant characteristics (age, sex, education level, and
comorbid conditions), stroke history (date of onset, type
and location of lesion, severity using National Institutes of
Health Stroke Scale [NIHSS]43), cognitive status (Montreal
Cognitive Assessment [MoCA]44), physical function (self-
selected walking speed, Chedoke-McMaster Stages of
Recovery of Leg and Foot45) were collected prior to ran-
domization. Primary and secondary outcome measures
were assessed at baseline, posttraining, and 3-month fol-
low-up by the same independent assessor. All assessments
for each participant were scheduled at a time corresponding
to the intervention time slot for that individual. On testing
day, participants were asked to eat at their regular times and
take their medications as usual.
Primary Outcome. The primary outcome was fluid intelli-
gence (also known as abstract reasoning) measured using
the RPMT; a nonverbal and nonmathematical measure
which tests the ability to solve new visual puzzles indepen-
dently of previously acquired knowledge.46 Participants
were presented with geometric figures of progressing
design complexity and asked to indicate the design that
completed a missing piece. Repeated testing alternated
between “odd” and “even” items to prevent familiarity with
the geometric patterns and testing was preceded by 2 stan-
dard practice blocks to limit any learning effects. RPMT
was scored out of 60 with higher score indicating greater
fluid intelligence.
4 Neurorehabilitation and Neural Repair 00(0)
Secondary Outcomes
Depression score. The Depression subscale of the Hos-
pital Anxiety and Depression Scale (HADS-D) was used,
which consists of 7 items with higher scores indicating
more severe symptoms.47
Aerobic fitness. Symptom-limited maximal GXT’s were
performed on either the treadmill (with 10%-15% BWS)
or total body recumbent stepper (TBRS; NuStep LLC, Ann
Arbor, MI, USA) according to best practice guidelines.48
Expired gas was analyzed via open-circuit spirometry
(SensorMedics 2900, Yorba Linda, CA, USA or Moxus,
AEI Technologies, Pittsburgh, PA, USA) to measure oxy-
gen consumption. Briefly, the treadmill protocol involved
walking at a self-selected speed and 0% incline for 2 min-
utes, followed by a 2.5% increase in grade every 2 min-
utes until an incline of 10% was reached and, thereafter,
a 0.05 m/s increase in speed every 2 minutes, until test
termination.49 The TBRS protocol was adapted from pre-
vious work in this population50 and involved increments
in workload (~20 W) every 2 minutes. Cardiovascular and
ventilatory responses were monitored throughout the GXT
and RPE was taken at the end of each 2-minute stage. All
testing was terminated according to American College of
Sports Medicine criteria.51 Volitional exhaustion was con-
sidered the point at which the participant indicated that
they could no longer proceed. The GXT was conducted
by a trained physiotherapist or exercise physiologist and
electrocardiogram activity was monitored by a physician
when indicated, for example, among participants with
atrial fibrillation.
Walking speed. Self-selected walking speed data were
extracted from an instrumented gait analysis walkway (Pro-
tokinetics, Havertown, PA, USA). Walking speed at post
and follow-up was measured only at one site.
Serum levels of neurotrophins. Other than resting
BDNF, levels of BDNF and IGF-1 were measured from
peripheral blood samples collected at one site. Since
both resting and exercise-induced levels of neurotroph-
ins could be important, samples were taken before the
GXT (BDNFresting, IGF-1resting) and directly following
the GXT (BDNFresponse and IGF-1response change scores)
at pre, post and follow-up. A 10 mL blood sample was
obtained from the antecubital vein using (no additive)
Vacutainer tubes. The blood was left to clot at room tem-
perature for 30 minutes, spun at 2200 rpm for 10 min-
utes, aliquoted into microcentrifuge tubes and placed at
−80°C. Assays were completed in triplicate according to
manufacturer’s instructions (Human/Mouse BDNF and
Human IGF-1 DuoSet enzyme-linked immunosorbent
assay, R&D systems).
Data Analysis
Primary and secondary behavioral outcomes and BDNF/
IGF-1 levels were analyzed using repeated-measures 4
(groups) × 3 (pre, post, follow-up) analysis of variance
(ANOVA) or log transformations/nonparametric equivalent
if assumptions of normality were violated. Normality of
data was tested using Shapiro-Wilk test. When data were
not normally distributed, we log-transformed the data.
Analysis was completed on the primary outcome with site,
baseline cognition (Montreal Cognitive Assessment
[MoCA]), and fitness (VO2peak) as covariates. We employed
Greenhouse, Geisser, and Bonferroni corrections for multi-
ple comparisons (significance set at P < .05). Baseline dif-
ferences were evaluated using ANOVA. Linear regression
was used where appropriate to examine relationships among
variables. Effect sizes were expressed as partial eta squared
(η2) where η2 of 0.01 was considered a small effect, 0.06 a
moderate effect, and 0.14 a large effect.52
Results
Participants
Ninety-three potential participants were screened of whom
60 were randomized with 15 participants per group (see
Figure 1). Eight participants withdrew in the first 4 weeks.
Their data were excluded from the analysis. Two partici-
pants were unable to be contacted at follow-up but were
included in an intention-to-treat analysis with their post
score brought forward using last-observation-carried-for-
ward53; leaving 34 participants in one site and 18 at the sec-
ond. As part of a pilot test to examine feasibility, 4
participants at one site (2 from the Aerobic + COG group
and 2 from the Aerobic + Games group) received the aero-
bic training following the cognitive training (randomly
assigned). Their data were included in the analysis as per
their assigned group. The remainder of the participants
received the physical activity intervention directly before
the cognitive. There were no adverse events such as falls or
other injuries, chest pain or other cardiac related symptoms,
or intolerance to the treatments. Participants were on aver-
age, 63 years of age and 3.4 years poststroke; 69% were
male and 77% were diagnosed with ischemic stroke.
Demographic data are shown in Table 1.
Fifteen participants had no comorbid conditions, 18 par-
ticipants had 1 comorbid condition, 8 had 2 conditions, 7
had 3 conditions, 3 participants had 4 conditions, and 1 par-
ticipant had 7 comorbid conditions. Because of language
difficulties, 33 of 52 participants were able to complete the
MoCA. Fifteen of those (45%) scored below the cutoff for
normal cognition (26/30). In terms of depressive symptoms,
3 participants reported moderate depression and 8 had mild
depression based on the HADS cutoff values.47 Medications
Ploughman et al 5
are described in Table 2. On average, participants were pre-
scribed 4.1 medications (SD = 4.3). At the extreme ranges,
4 participants took no medications while 1 person was pre-
scribed 13 medications. There were no significant baseline
differences between the groups in terms of age, sex, type of
stroke, side of stroke, stroke severity, MoCA, Chedoke
stage of leg and foot impairment, walking speed, aerobic
fitness, depression score, presence of aphasia, or number of
comorbid conditions (P values ranged from .089 [age] to
.864 [Chedoke stage of foot impairment], data not shown).
All participants reached volitional exhaustion during
GXT’s performed on the treadmill (n = 35) and TBRS
(n = 17). In terms of relative indicators of maximal exercise,
maximal HRs achieved during the GXT were within 10% of
age-predicted maximum (91.8%, SD = 12.6) and the aver-
age respiratory expiratory exchange ratio was more than 1.0
(1.10, SD = 0.14). As expected, significantly higher relative
workloads were maintained during the aerobic exercise
interventions compared with the activity groups, F(1, 141)
= 21.12, P < .0001, and participants were able to achieve
Figure 1. Consort diagram. #The last measure of one participant within the group was carried forward as an intention to treat
analysis.
6 Neurorehabilitation and Neural Repair 00(0)
the target HR range during the aerobic exercise interventions
measured at the first, fifth, and tenth weeks (77%, SD= 12;
80%, SD = 13; and 82%, SD = 12, of age-predicted maxi-
mal HR, respectively). Although not statistically different,
relative HRs were higher in the Aerobic + COG compared
with the Aerobic + Games group at week 1 (11%, SD= 7.07;
P = .110), week 5 (13%, SD = 7.04; P = .151), and week
10 (11%, SD = 6.45; P = .063). Participants attended 28.8
(SD = 1.61) sessions with a range between 25 and 30. There
were no significant differences between the groups in terms
of attendance (P = .750).
Effects of Training on Fluid Intelligence
When controlling for site, baseline cognition, and baseline fit-
ness, there was no significant effect of Time, F(2,88) = 0.83,
P = .440, η2 = 0.020, but there was a significant interaction
of Group × Time, F(6, 88) = 2.84, P = .015, η2 = 0.162,
indicating a large effect; see Figure 2A). Three of the groups
demonstrated nonsignificant trends of improvement in RPMT
between pre- and postassessments (see Table 3 and
Figure 2A). At 12-week follow-up, both the Aerobic + COG
and Activity + COG groups made significant improvements
from baseline. For the raw change in fluid intelligence from
baseline to follow-up, only the performance by the Aerobic +
COG group was significantly greater than that by the active
control group: Activity + Games, F(3, 48) = 4.03, P = .012
(see Figure 2B). Significant differences between Aerobic +
COG/Aerobic + Games (P = .045) and between Activity +
COG/Activity + Games (P = .010) were lost with Bonferroni
corrections (see Figure 2B). In terms of percentage change in
performance, the Aerobic + COG group improved 47.8%
Table 1. Participant Characteristics.
Characteristic All (n = 52)
Aerobic +
COG (n = 12)
Aerobic +
Games (n = 13)
Activity +
COG (n = 15)
Activity + Games
(n = 12)
Age (years, range = 27-81), mean (SD) 63.4 (11.3) 62.1 (14.2) 58.4 (11.7) 63.9 (8.5) 69.7 (8.9)
Sex (male/female), n 36/16 7/5 9/4 12/3 8/4
Months since stroke (range 5-205), mean
(SD)
41.0 (39.8) 40.9 (33.8) 36.0 (53.4) 35.2 (33.9) 53.9 (37.4)
Type of stroke (ischemic/hemorrhagic), n 40/12 9/3 12/1 11/4 8/4
Hemisphere (left/right/bilateral), n 24/25/3 7/4/1 6/6/1 5/10/0 6/5/1
Stroke severity (NIHSS/42; range 0-17),
mean (SD)
4.9 (4.2) 5.5 (3.5) 4.2 (4.2) 5.5 (5.3) 4.4 (3.3)
MoCA (score/30; range 3-30), mean (SD) 23.8 (5.6) 23.3 (7.5) 24.9 (4.8) 24.9 (4.7) 21.9 (5.4)
Chedoke stage of leg impairment (score/7;
range 1-7), mean (SD)
5.2 (1.5) 4.9 (1.3) 5.2 (1.6) 5.6 (1.7) 5.0 (1.5)
Chedoke stage of foot impairment (score/7;
range 1-7), mean (SD)
4.7 (2.0) 4.5 (1.9) 4.4 (2.0) 5.0 (2.3) 4.7 (1.8)
Walking speed (cm/s; range 4.3-190), mean
(SD)
84.5 (40.9) 92.2 (47.9) 92.5 (40.0) 84.5 (39.0) 68.7 (37.7)
Aerobic fitness (VO2peak) (mL/kg/min; range
4.9-27.6), mean (SD)
16.7 (4.8) 15.4 (3.6) 17.5 (6.2) 17.6 (4.6) 15.8 (4.5)
Depression score (HADS-D score/21; range
0-12), mean (SD)
4.6 (3.3) 4.3 (3.6) 3.7 (3.3) 6.1 (2.9) 4.0 (2.9)
Expressive aphasia (number with mild-severe
according to NIHSS)
15 3 3 3 6
Comorbid conditions (n)
None 15 3 6 4 2
Hypertension 26 7 5 7 7
Diabetes 13 4 2 4 3
Dyslipidemia 9 1 2 3 3
Cardiovascular disease, including CHF,
AAA, carotid stenosis, and CABG
6 0 3 2 1
Other cardiac (eg, aortic valve repair or
atrial fibrillation)
5 1 1 1 2
Kidney disease 3 0 1 2 0
Myocardial infarction 1 0 1 0 0
Abbreviations: NIHSS, National Institutes of Health Stroke Scale; MoCA, Montreal Cognitive Assessment; HADS-D, Hospital Anxiety and Depression
Scale–Depression subscale; CHF, congestive heart failure; AAA, abdominal aortic aneurysm; CABG, coronary artery bypass graft.
Ploughman et al 7
(SD = 81.10), Activity + COG 20.7% (SD = 29.97), Aerobic
+ Games 7.0% (SD = 34.19) while the Activity + Games
group declined (−8.5%, SD = 21.49); ANOVA, F(2, 48) =
3.18, P = .032. Data were normally distributed and there were
no significant differences between groups at baseline
(P = .801). Since 4 participants at 1 site received the aerobic
training following the cognitive training, we recalculated the
main results for RPMT with those 4 participants removed.
The results were not substantially changed; no significant
effect of Time, F(2, 80) = 0.52, P = .567, η2 = 0.014, but
significant Group × Time interaction, F(6, 80) = 2.61,
P = .025, η2 = 0.164.
Effects of Training on Depression Score
Overall, the depression score increased over time with no
significant differences between groups (Table 3) There
was a significant effect of Time, F(2, 94) = 3.44,
P = .036, η2 = 0.068, but no interaction of Group ×
Time, F(6, 94) = 0.79, P = .570, η2 = 0.048, indicating
small to moderate effects. Data were normally distributed
and there were no significant differences between groups
at baseline (P = .195).
Effects of Training on Aerobic Fitness and
Walking
In terms of aerobic fitness (Table 3), there was a significant
effect of Time, F(2, 94) = 8.04, P = .001, η2 = 0.146, and
significant Group × Time interaction, F(6, 94) = 2.51,
P = .032, η2 = 0.138, indicating large effects. The Aerobic
+ Games group was the only group to make significant
improvement in VO2peak, which was maintained at follow-
up compared with pre (from 17.46 to 20.21 mL/kg/min at
follow-up; see Figure 3A). The Aerobic + COG made
improvements from pre to post (P = .023) but significance
was reduced to P = .068 with Bonferroni correction.
Notably, both Activity groups demonstrated a trend toward
declines in fitness below baseline values. Data were nor-
mally distributed and there were no significant differences
between groups at baseline (P = .455).
For walking speed (Table 3), there was a significant
effect of Time, F(2, 54) = 4.42, P = .033, η2 = 0.141, and
significant Group × Time interaction, F(6, 54) = 2.80,
P = .042, η2 = 0.237, indicating large effects. Although
both Aerobic + COG and Aerobic + Games groups
increased self-selected walking speed, the improvement
was significant before Bonferroni correction only for the
Aerobic + COG group (Post compared with Pre P = .074;
Follow-up compared with Pre P = .023; see Figure 3B).
Data were normally distributed and there were no signifi-
cant differences between groups at baseline (P = .557).
The Effects of Training on Circulating IGF-1 and
BDNF Levels
IGF-1resting changed during the trial (Table 4) but was not
significantly different across groups—significant effect of
Time, F(2, 46) = 35.11, P < .00001, η2 = 0.604; no Group
× Time interaction F(6, 46) = 1.29, P = .279, η2 = 0.144,
indicating large effects. Data were normally distributed and
Table 2. Medications.
Medication Classification n (%)
Antihypertensive/diuretic 43 (82.7)
Lipid-lowering 40 (76.9)
Antiplatelet/anticoagulant 37 (71.2)
Antidepressant 18 (34.6)
Antianxiety/sedative 12 (23.1)
Diabetic 11 (21.2)
Anticonvulsant 7 (13.5)
Antispasticity/muscle relaxant 7 (13.5)
Analgesic 7 (13.5)
Figure 2. (A) Effects of interventions on Raven’s Progressive Matrices Test performance at Pre, Post (after 10 weeks), and Follow-up
(12 weeks). *Significant difference from pre, P < .05. (B) Change in fluid intelligence score between Pre and Follow-up for each group.
*P < .05. Error bars are standard error of the mean (SEM).
8 Neurorehabilitation and Neural Repair 00(0)
there were no significant differences between groups at
baseline for IGF-1resting (P = .101). Combining the groups,
serum IGF-1resting at pre (3.52, SD = 2.52 ng/mL) was sig-
nificantly lower compared with post levels (7.05 SD = 4.24
ng/mL; P <.001) and dropped to levels lower than pre at
follow-up (1.52 SD = 2.58 ng/mL; P < .00001; Figure 4A).
IGF-1response was the only variable not normally distributed
and therefore was log transformed. There were no signifi-
cant differences between groups at baseline (P = .245).
IGF-1response increased over the trial (see Table 4) but was
not significantly different across groups: significant effect
of Time, F(2, 38) = 6.22, P = .008, η2 = 0.246; no Group
× Time interaction, F(6, 38) = 1.41, P = .249, η2 = 0.181,
indicating large effects. Combining groups, IGF-1response,
expressed as a change in IGF-1 following the GXT, did not
change significantly from pre to post (pre −0.98, SD =
1.76 ng/mL; post 0.72, SD = 4.48 ng/mL; P = 1.00; Figure
4B). Levels at follow-up (3.39, SD = 3.88 ng/mL) were
Table 3. Fluid Intelligence, Depression Score, Aerobic Fitness, and Walking Speed.
Variable Pre, Mean (SD) Post, Mean (SD) Follow-up, Mean (SD)
Fluid intelligence (RPMT)
Aerobic + COG (n = 12) 28.5 (16.94) 30.7 (15.42) 34.2 (15.98)
Aerobic + Games (n = 13) 31.8 (12.50) 35.3 (10.49) 32.2 (12.26)
Activity + COG (n = 15) 27.5 (9.72) 31.7 (9.25) 31.9 (10.66)
Activity + Games (n = 12) 28.4 (6.52) 27.9 (7.37) 26.3 (8.66)
Depression score (HADS-D)
Aerobic + COG (n = 12) 4.3 (3.62) 3.9 (2.97) 4.4 (2.91)
Aerobic + Games (n = 13) 3.7 (3.33) 4.2 (3.90) 5.5 (4.16)
Activity + COG (n = 14) 6.1 (2.88) 5.1 (2.40) 6.0 (2.69)
Activity + Games (n = 12) 4.0 (3.25) 4.0 (3.10) 5.2 (3.13)
Aerobic fitness (mL/kg/min)
Aerobic + COG (n = 12) 15.3 (3.57) 17.0 (4.96) 16.3 (4.50)
Aerobic + Games (n = 13) 17.5 (6.21) 20.3 (6.45) 20.2 (6.48)
Activity + COG (n = 15) 17.6 (4.60) 18.4 (4.47) 17.6 (4.35)
Activity + Games (n = 11) 16.1 (4.68) 16.4 (4.63) 15.3 (4.65)
Walking speed (cm/s)a
Aerobic + COG (n = 5) 56.6 (17.87) 76.3 (33.88) 76.1 (25.24)
Aerobic + Games (n = 7) 67.5 (30.67) 75.6 (40.65) 79.1 (38.79)
Activity + COG (n = 10) 71.6 (41.17) 68.8 (39.35) 71.3 (38.45)
Activity + Games (n = 9) 62.4 (35.27) 57.1 (27.62) 61.0 (35.26)
Abbreviations: RPMT, Raven’s Progressive Matrices Test; HADS-D, Hospital Anxiety and Depression Scale–Depression subscale.
aValues available only at 1 site. Seven participants required stand-by assistance to walk so speed could not be measured on the walkway.
Figure 3. Effects of training on aerobic fitness and walking. (A) Both Aerobic groups improved from Pre values but only the Aerobic
+ Games significantly so. *P < .05 compared with Pre. (B) The Aerobic + COG and Aerobic + Games groups improved self-selected
walking speed but only the Aerobic + COG group significantly so before Bonferroni correction. *P < .05 compared with Pre. Error
bars are standard error of the mean (SEM).
Ploughman et al 9
significantly higher than those at pre (P = .002) and post
(P = .024).
BDNFresting did not change over the trial (Table 4).
Data were normally distributed and there were no signifi-
cant differences between groups at baseline (P = .922).
There was no effect of Time, F(2, 46) = 0.64, P = .514,
η2 = 0.015 or Group × Time interaction, F(6, 46)
= 0.36, P = .786, η2 = 0.035; indicating small effects.
BDNFresponse was also normally distributed and not
altered, Time, F(2, 42) = 1.00, P = .371, η2 = 0.045;
Group × Time, F(6, 42) = 0.36, P = .884, η2 = 0.049;
indicating small effects. There were no significant
differences in BDNFresponse between groups at baseline
(P = .548).
Table 4. Serum Levels of Brain-Derived Neurotrophic Factor (BDNF) and Insulin-Like Growth Factor–1 (IGF-1).
Serum Neurotrophins (ng/mL) Pre, Mean (SD) Post, Mean (SD) Follow-up, Mean (SD)
BDNFrestinga,b
Aerobic + COG (n = 10) 35.7 (38.11) 32.3 (29.55) 29.1 (26.78)
Aerobic + Games (n = 12) 29.3 (24.50) 26.5 (19.11) 27.3 (21.45)
Activity + COG (n = 13) 29.7 (23.95) 31.4 (22.84) 23.6 (21.38)
Activity + Games (n = 11) 31.7 (29.77) 34.8 (24.78) 34.81 (24.77)
BDNFresponseb
Aerobic + COG (n = 4) −6.6 (32.00) −17.02 (16.16) −14.2 (14.36)
Aerobic + Games (n = 7) 7.1 (16.31) 13.9 (12.82) 2.6 (6.97)
Activity + COG (n = 6) 5.1 (19.42) 2.3 (17.39) −6.1 (14.95)
Activity + Games (n = 8) −0.04 (21.88) −11.8 (15.04) −11.7 (17.10)
IGF-1restingb
Aerobic + COG (n = 4) 2.7 (1.23) 5.3 (5.39) 1.1 (1.70)
Aerobic + Games (n = 8) 5.4 (3.77) 7.9 (4.56) 2.8 (4.12)
Activity + COG (n = 8) 2.8 (1.13) 8.8 (5.32) 1.0 (1.47)
Activity + Games (n = 7) 3.4 (2.51) 6.1 (3.00) 1.7 (2.38)
IGF-1responseb
Aerobic + COG (n = 3) 1.3 (1.74) 1.5 (3.67) 4.3 (3.73)
Aerobic + Games (n = 7) −2.0 (2.42) 1.2 (2.94) 5.7 (5.35)
Activity + COG (n = 6) −1.1 (0.91) −2.7 (6.59) 3.2 (3.05)
Activity + Games (n = 7) −0.3 (1.34) 1.5 (3.35) 2.5 (3.25)
aValues available from both sites.
bSample size is reduced because unable to obtain blood sample from all participants at all time points.
Figure 4. Effects of interventions on serum insulin-like growth factor–1 (IGF-1). (A) Resting IGF-1. *Significantly different from Pre
P < .001, #significantly different from Post P < .0001, significantly different from Pre P < .0001; groups combined. (B) IGF-1 acute
response to exercise significantly different from PRE. *P = .002, #significantly different from Post P = .024; groups combined. Error
bars are standard error of the mean (SEM).
10 Neurorehabilitation and Neural Repair 00(0)
Factors Predicting Intervention Response
Six baseline variables—aerobic fitness (VO2peak), cogni-
tion (RPMT), and serum levels of BDNF (BDNFresting,
BDNFresponse) and IGF-1(IGF-1resting, IGF-1response)—were
examined to determine their relationships with improve-
ment in fluid intelligence (change from pre to follow-up).
We first examined correlations between the 6 baseline vari-
ables and the change in fluid intelligence. Two variables,
higher baseline aerobic fitness (VO2peak) and greater acute
increase in IGF-1 with exercise (IGF-1response), were corre-
lated with improvement in fluid intelligence (R = 0.40,
P = .038 and R = 0.63, P = .016, respectively). To build a
predictive model these significant variables were entered
into a stepwise regression model with change in fluid intel-
ligence as the outcome (see Figure 5A). Only IGF-1response
was retained in the model (see Figure 5A). The model
explained 40% of the variance in change in cognitive
scores in the COG training groups (Aerobic + COG and
Activity + COG; F = 7.94, R2 = 0.40, P = .016) but little
variance in the scores of groups receiving cognitive games
(F = 2.26, R2 = 0.08, P = .155). Since others have reported
that greater increases in aerobic fitness were related to
improvements in cognition,54 we examined the correlation
between these 2 variables (Post-Pre) in the 4 groups com-
bined. There was no relationship between change in fitness
and improvement in cognition (R = 0.07, P = .623; see
Figure 5B).
Discussion
The prevalence of cognitive impairment measured using
sensitive assessments has been reported to be as high as
83% in acute stroke units and 71% at 3-month follow-up.24
We undertook this study to determine whether 10 weeks of
combined aerobic exercise and cognitive training would
improve fluid intelligence among people with chronic
stroke who had cognitive impairment. We compared the
combined training to the interventions provided on their
own (with other control activities in order to match for
treatment duration) and an active control group (Activity +
Games). We found that Aerobic + COG and Activity +
COG made significant improvements in fluid intelligence
although the Aerobic + COG group was the only group in
which the improvement was significantly greater than the
active control group (Activity + Games). Furthermore, par-
ticipants in the Aerobic + COG group also experienced
gains in aerobic fitness and walking (although some signifi-
cant effects were lost after Bonferroni corrections), suggest-
ing that combined interventions have the potential to
improve multiple outcomes at the same time.12 Aerobic
exercise without being combined with cognitive training
(Aerobic + Games) did not improve fluid intelligence.
Finally, levels of serum IGF-1 in response to acute exercise
at baseline (IGF-1response) significantly predicted improve-
ments in fluid intelligence in the groups receiving cognitive
training. The dual-n-back training program we employed
was an adaptive working memory task requiring attentional
maintenance and updating and has been shown to predict
performance on RPMT55 as well as involve a widespread
bilateral frontal-parietal network.56 Our results support that
dual-n-back training aimed at fluid intelligence likely pro-
moted neuroplasticity and could be an important cognitive
training technique in stroke.
Our findings as well as those of Tang et al22 and Bo
et al36 demonstrated that aerobic/physical exercise did not
significantly enhance fluid intelligence poststroke when not
temporally linked with cognitive training (ie, Aerobic +
Figure 5. Predictors of cognitive improvement. (A) IGF-1response at baseline strongly and significantly predicted improvement in
cognition in the cognitive training groups (Aerobic + COG and Activity + COG; open circles). IGF-1response was not associated with
change in fluid intelligence in the groups receiving cognitive games (black inverted triangles). (B) There was no relationship between
change in fitness and improvement in cognition. IGF-1, insulin-like growth factor–1.
Ploughman et al 11
Games group in our study). Others, however, have shown
that 8 weeks of aerobic exercise training during the chronic
period poststroke improved other cognitive functions, such
as attention,57 visual spatial ability,57 and learning.33
Marzolini et al54 reported that 6 months of combined aero-
bic and resistance training resulted in improvement in
MoCA score, specifically in the visuospatial/executive and
attention/concentration domains. Furthermore, Moore
et al,58 in a randomized controlled trial involving 40 indi-
viduals greater than 6 months poststroke, demonstrated that
19 weeks of fitness and mobility training improved execu-
tive function. Quaney et al33 also showed that aerobic exer-
cise improved procedural motor learning. It is important to
appreciate that the participants in the aforementioned stud-
ies were more mildly affected (ie, walking speeds of about
120 cm/s,58 normal MoCA scores33) than our cohort. Moore
et al58 also reported a significant improvement in mood,
which could confound cognitive testing.59 Furthermore,
most studies examining the effects of exercise on cognitive
function did not include follow-up, precluding determina-
tion of the sustainability of effects.22,57,58,60,61 In fact, Quaney
et al33 reported that benefits declined by 8-week follow-up.
We show that with cognitive training (Activity + COG),
and even more robustly with combined aerobic and cogni-
tive training (Aerobic + COG), people poststroke showed
large and significant gains in fluid intelligence measured 12
weeks after the intervention ceased. This finding suggests
that the combined interventions are potent and are able to
overcome the recovery plateau even when there was no
benefit in depressive mood.
Neurotrophins are considered to be potential biomarkers
in stroke recovery.13 BDNF and IGF-1 promote recovery
and repair processes such as angiogenesis, neurogenesis,
synaptogenesis, and long-term potentiation.13 In humans,
serum or plasma levels of BDNF and IGF-1 are used as
proxies of brain levels of these growth factors.23 We found
that resting BDNF and exercise-induced BDNF did not
change significantly during the trial, nor did BDNF predict
improvements in cognition; however, we did not test for
BDNF genotype nor did we require fasting before blood
collection. As well, the serum BDNF values were highly
variable making interpretation difficult.
IGF-1 is primarily produced in the liver and crosses the
blood-brain barrier following exercise.62 We showed that
higher exercise-induced levels of serum IGF-1 at baseline
predicted 40% of the variability in improvement of fluid
intelligence. It is noteworthy that exercise-induced levels,
but not resting levels of IGF-1, were predictive of this
response. Furthermore, the ability to upregulate circulating
levels of IGF-1 with exercise increased over time in all the
groups. Serum IGF-1 concentrations have been shown to cor-
relate with enhanced brain vascular activation63 and with better
functional outcomes after stroke.64 The transport of circulating
IGF-1 into the brain is enhanced by an activity-driven process
triggered by the release of glutamate in active brain regions
that promotes vasodilation and increases movement of this
growth factor across the blood-brain barrier.65 Neuronal
release of glutamate leads to calcium fluxes in astrocytes
that promote the release of diffusible mediators such as
nitric oxide and arachidonic acid derivatives, which pro-
mote vasodilation.66 These messengers also stimulate
matrix metalloproteinase-9 activity resulting in cleavage of
IGF binding protein-3 and release of IGF-1.65 The com-
bined actions of these 2 events results in the increased local
availability of free serum IGF-1.67 The elevation of serum
IGF-1 concentrations by exercise coupled with the stimula-
tion of activity-dependent entrance of IGF-1 from the circu-
lation into the brain by cognitive training may contribute to
the benefits of combining aerobic and cognitive interven-
tions on fluid intelligence.
Several groups have confirmed that participants post-
stroke with the greatest gains in cognition also had the larg-
est improvements in fitness54,68 and that the 2 outcomes are
linked. Marzolini et al54 showed that improvements in atten-
tion and concentration after 6 months of aerobic and resis-
tance training were correlated with improvement in fitness.
Kluding et al68 also reported a relationship between improved
aerobic fitness with 12 weeks of aerobic and resistance exer-
cise and better performance on the Flanker task.68 We found
no such relationship between fitness and cognitive gains.
Our participants were similar in terms of severity and time
since stroke; however, our intervention included cognitive
training whereas the aforementioned studies did not, poten-
tially lessening the impact of fitness on outcome.54,68
Intensity and structure of cognitive training may be
important in order to maximize cognitive gains. Stroke best
practices recommend taking either a compensatory or
restorative approach to cognitive rehabilitation depending
on patient-specific goals.69 Within the guidelines, thera-
pist-supervised computerized cognitive training was
advised but with no specific intensity or duration recom-
mended. Computerized cognitive training is an attractive
method to enhance cognition considering the pleasurable
gaming format and ability to log on at home with no
requirement for health care personnel. Whether these types
of interventions actually improve cognition is a topic under
scrutiny. In this study, we showed that 15 hours of comput-
erized dual-n-back working memory training (with control
activity, Activity + COG) translated into a 20.7% (SD =
29.97) improvement in fluid intelligence. Although instruc-
tion and coaching were provided for the first 2 weeks, par-
ticipants completed the training in a laboratory environment
with minimal degree of monitoring thereafter. van de Ven
et al70 examined the effects of 30 hours of home-based
computerized training and found that people poststroke
showed a trend in improving cognitive outcomes, albeit not
significant, compared with a waitlist control group. Bo
et al36 showed that 12 weeks of computer-based cognitive
12 Neurorehabilitation and Neural Repair 00(0)
training improved some but not all cognitive domains
among people less than 6 months poststroke. In another
trial, people in the chronic stage of stroke with self-per-
ceived cognitive impairment who participated in 8 weeks
of cognitive training with a commercial Lumosity showed
short-term improvements in reaction time but no changes
in objective and subjective measures of cognition.61 Rather
than targeting working memory specifically, Lumosity pro-
vided practice in a broad range of cognitive domains such
that the working memory aspects of the intervention were
diluted compared with our focused laboratory intervention.
Furthermore, only half of the participants successfully
completed the computerized cognitive training at the rec-
ommended dose.61 As with other forms of exercise, the
intensity and type of cognitive training are likely factors
that mediate outcome so monitoring would be required to
ensure compliance and performance.71
Even though we showed robust and clinically meaningful
gains in cognition, there were some limitations to the study.
First of all, the study took place at 2 sites but data on serum
neurotrophins and walking speed were only available at 1
site, reducing an already limited sample size. Second, we did
not assess presence of the BDNF val66met polymorphism,
which limited interpretation of serum BDNF values.72
Carriers (at least 1 Met allele) of the BDNF polymorphism
have shown decreased brain activation during movement of
the hemiparetic side73 and seem to benefit less from brain
stimulation techniques aimed at improving limb recovery.74
Future research should include genetic analysis. Furthermore,
the relatively high levels of neurological impairment
observed among participants in the current study may have
precluded assessment of true physiological maximum dur-
ing the GXT, which could have influenced our ability to
detect an association between change in aerobic fitness and
fluid intelligence. Although we randomly assigned partici-
pants to groups, there were (nonsignificant) baseline differ-
ences between them (such as age and walking speed), which
may have accounted for some aerobic exercise response dif-
ferences between the aerobic groups. Last, variability was
introduced in control group activities because activity selec-
tion was based on the participant’s level of impairment.
Conclusion
Cognitive impairment is common after stroke26 and inter-
feres with successful sensorimotor rehabilitation.27 In our
trial, aerobic exercise combined with cognitive training
improved fluid intelligence by almost 50% in patients >6
months poststroke who were presumed to have reached
their recovery plateau. Participants in the Aerobic + COG
group also experienced gains in aerobic fitness and walk-
ing, suggesting that combined interventions have the poten-
tial to address several recovery domains.12 Aerobic exercise
without being combined with cognitive training (Aerobic +
Games) did not improve fluid intelligence. Levels of serum
IGF-1 in response to acute exercise at baseline (IGF-1response)
significantly predicted improvements in fluid intelligence
among the groups receiving cognitive training, supporting
its usefulness as a recovery biomarker in stroke.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: This
project was supported by grants from the Heart and Stroke
Foundation Canadian Partnership for Stroke Recovery (MP, JM),
the Canada Research Chairs program (MP), the Canada Foundation
for Innovation (MP), The Newfoundland and Labrador Research
and Development Corporation (MP), the Nova Scotia Health
Research Foundation (MM-L), Capital Health Research Foundation,
Halifax Nova Scotia (MM-L) and the Dalhousie University Faculty
of Health Professions Innovation Fund (MM-L).
ORCID iDs
Michelle Ploughman https://orcid.org/0000-0002-4594-0077
Marie E. Curtis https://orcid.org/0000-0002-6221-1634
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... A total of seven [60][61][62][63][64][65][66] clinical trials involving 200 patients (95 subjected to a single bout of EA, 53 subjected to long-term EA, and 52 subjected to a single bout of EA as well as long-term EA) were included in the systematic review. The characteristics of the papers are displayed in Table 1. ...
... ± 13.9 (23.75 ± 12.7 participants for studies including a single bout of EA and 26.5 ± 4.95 participants for studies including a long-term EA). Only one trial included more than 50 patients [60]. Regarding the EA duration, four studies (57.1%) investigated a single bout of activity, two studies (28.6%) investigated a regular programme of activity, and only one study investigated a single bout as well as long-term activity (14.3%). ...
... The mean age was 58.06 ± 6.51 years (60.27 ± 3.55 years for studies including a single bout of EA, 52.10 ± 5.23 years for studies including long-term EA, and 63.4 ± 11.3 years for studies including a single bout of EA as well as studies including long-term EA). Out of the seven studies, four [60][61][62][63] described power calculations to estimate the requisite sample size. ...
Article
Full-text available
Research in modern neurorehabilitation focusses on cognitive and motor recovery programmes tailored to each stroke patient, with particular emphasis on physiological parameters. The objectives of this review were to determine whether a single bout of endurance activity or long-term endurance activity regulates exercise-dependent serum brain-derived neurotrophic factor (BDNF) levels and to evaluate the methodological quality of the studies. To assess the effectiveness of endurance exercise among patients in the chronic post-stroke phase, a systematic review was performed, including searching EBSCOhost, PEDro, PubMed, and Scopus for articles published up to the end of October 2021. The PRISMA 2020 outline was used, and this review was registered on PROSPERO. Of the 180 papers identified, seven intervention studies (comprising 200 patients) met the inclusion criteria. The methodological quality of these studies was evaluated by using the Physiotherapy Evidence Database (PEDro) criteria. The effect of exercise was evaluated in four studies with a single bout of endurance activity, two studies with long-term endurance activity, and one study with a single bout of endurance activity as well as long-term endurance activity. The results of our systematic review provide evidence that endurance exercise might augment the peripheral BDNF concentration in post-stroke individuals.
... Among the PA training conditions, the duration of intervention ranged from 4 to 72 weeks, the average duration lasted for 15 weeks and the average frequency was 3.8 times every week. Most notably, 10 trials consisted only of aerobic exercise training (10,14,18,23,25,27,28,30,32,33), 2 of which adopted traditional exercises (25,33). Moreover, 4 articles involved strength/balance/stretching/physiotherapy without a primary aerobic component (11,21,22,26) and 8 studies included combined PA trainings (9,15,17,19,20,24,29,31). ...
... From the perspective of the type of control group, 10 trials included control groups that received usual care, daily routines, or wait-list control, without any PA component (10, 11, 15, 17, 21-24, 31, 33). In addition, 9 studies contained control group that included PA components without a primary aerobic component (muscle relaxation, stretching, balance, and physiotherapy) (9,14,19,20,(26)(27)(28)(29)32) and the rest of 3 studies recruited control groups that accepted additional intervention without any form of PA (rhythm-and-music-based therapy, cognitive training, and social communication) (18,25,30). Further details about the characteristics of included studies are shown in the Supplementary Table 1. ...
... We further explored the long-term effects of PA and found that 9 studies took 1-7 months of follow-up to observe the longterm effects of PA (10,14,17,18,21,(27)(28)(29)33). The results of 6 studies supported that the benefits of PA on cognitive performance were sustained (14,21,(27)(28)(29)33), but some studies showed it on overall cognitive function, several studies showed it on different cognitive subdomains, and another 3 studies did not show the long-term effects of PA (10,17,18). ...
Article
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Background and Purpose This study investigates the effect of physical activity (PA) on cognition in patients with cerebrovascular disease and explored the maximum benefit of different PA characteristics. Methods Databases, such as Pubmed, Web of Science, Embase, and Cochrane Library, were searched from their inception to May 31, 2021. Standardized mean difference (SMD) and 95% confidence intervals ( CI s) were calculated to generate a forest plot. In addition, subgroup analysis, moderation analysis, and regression analysis were performed to explore the possible adjustment factors. Results In total, 22 studies that met the criteria were included, demonstrating data from 1,601 participants. The results indicated that PA produced a positive effect on the global cognition for patients with cerebrovascular disease (SMD: 0.20 [95% CI : 0.12–0.27]), at the same time, PA training prominently improved executive function (SMD: 0.09 [95% CI : 0.00–0.17]) and working memory (SMD: 0.25 [95% CI : 0.10–0.40]). Furthermore, patients with baseline cognitive impairment received the greater benefit of PA on cognition (SMD: 0.24 [95% CI : 0.14–0.34]) than those without cognitive impairment before intervention (SMD: 0.15 [95% CI : 0.04–0.26]). For patients in the acute stage (≤ 3 months), PA did not rescue impairment dysfunction significantly (SMD: 0.08 [95% CI : −0.04–0.21]) and remarkable cognitive gains were detected in the chronic stage of participants (>3 months) (SMD: 0.25 [95% CI : 0.16–0.35]). Moderate intensity PA showed a larger pooled effect size (SMD: 0.23 [95% CI : 0.11–0.36]) than low intensity (SMD: −0.01 [95% CI : −0.44–0.43]) and high intensity (SMD: 0.16 [95% CI : 0.03–0.29]). However, the different types, duration, and frequency of PA resulted in no differences in the improvement of cognitive function. Further regression analysis demonstrated that the beneficial effects of PA on cognition are negatively correlated with age ( p < 0.05). Conclusions This study revealed that PA can prominently improve the cognitive ability in patients with cerebrovascular diseases and strengthened the evidence that PA held promise as a widely accessible and effective non-drug therapy for vascular cognitive impairment (VCI).
... IGF-1 levels can increase via exercise in the periphery and can cross the blood-brain barrier to mediate the trigger of neurogenesis in the brain [11]. Ploughman et al. (2019) indicated that after the aerobic (treadmill running) and cognitive exercises (working memory task or computer games), participants who provided better cognition status showed higher levels of serum IGF-1 [12]. Cho and Roh (2019) showed that taekwondo training (physical exercise which requires cognitive demand, 50-80% maximum heart rate for 60 min, 5d/w for 16 weeks) training enhances IGF-1 levels in women aged 65 or older [13]. ...
... IGF-1 levels can increase via exercise in the periphery and can cross the blood-brain barrier to mediate the trigger of neurogenesis in the brain [11]. Ploughman et al. (2019) indicated that after the aerobic (treadmill running) and cognitive exercises (working memory task or computer games), participants who provided better cognition status showed higher levels of serum IGF-1 [12]. Cho and Roh (2019) showed that taekwondo training (physical exercise which requires cognitive demand, 50-80% maximum heart rate for 60 min, 5d/w for 16 weeks) training enhances IGF-1 levels in women aged 65 or older [13]. ...
Article
Full-text available
This study aimed to investigate acute effects of table tennis (physical+cognitive exercise), aerobic running (physical exercise), and chess (cognitive exercise) exercise sessions of veteran male athletes in their branches on the serum homocysteine (Hcy), insulin growth factor-1 (IGF-1), and cortisol (Cor) levels. Thirty veteran athletes [10 table tennis players (TT), 10 long-distance runners (LR), 10 chess players (CP)] and 10 sedentary controls (SC) between 50 and 65 years of age participated in the study. Blood samples were obtained before and immediately after exercise to determine serum Hcy, IGF-1, and Cor levels. According to their branch, each veteran athlete performed exercise sessions (70-75% of the participants' heart rate reserve) of 10-min of warm-up followed by 40-min of table tennis, aerobic running, or chess. TT and LR groups demonstrated significant increases in the serum IGF-1, Cor, and Hcy levels from pre to post-exercise (p<0.05). In contrast, the CP group showed significant increases only in the serum Hcy levels (p<0.05). Serum IGF-1 and Hcy, in response to exercise, were not significantly different between exercise groups (p>0.05). LR group had a greater serum Cor increase than all exercise groups (p<0.05). The TT group showed significantly greater changes in serum Cor levels than the CP group (p<0.05). In conclusion, although a single bout of aerobic running and table tennis exercise induces a remarkable increase in all measured biomarkers, chess exercise only elicits an increase in Hcy levels. Although aerobic running is more effective in increasing Cor levels than other types of exercise, the current study's findings suggest that serum Hcy and IGF-1 levels in veteran male athletes are not affected by the type of exercise.
... Working memory was trained with N-IGMA (Ploughman et al., 2019), a proprietary naturalistic adaptive spatial n-Back (ANBACK) task designed to stimulate participants' engagement (see Supplementary material for an example of the stimuli used). Participants were requested to track a series of locations and indicate whether the current location was a match or not of the location presented at "n" trials ago, following the method of Verhaeghen and Basak (2005). ...
Article
Full-text available
Aging is a very diverse process: successful agers retain most cognitive functioning, while others experience mild to severe cognitive decline. This decline may eventually negatively impact one’s everyday activities. Therefore, scientists must develop approaches to counteract or, at least, slow down the negative change in cognitive performance of aging individuals. Combining cognitive training and transcranial direct current stimulation (tDCS) is a promising approach that capitalizes on the plasticity of brain networks. However, the efficacy of combined methods depends on individual characteristics, such as the cognitive and emotional state of the individual entering the training program. In this report, we explored the effectiveness of working memory training, combined with tDCS to the right dorsolateral prefrontal cortex (DLPFC), to manipulate working memory performance in older individuals. We hypothesized that individuals with lower working memory capacity would benefit the most from the combined regimen. Thirty older adults took part in a 5-day combined regimen. Before and after the training, we evaluated participants’ working memory performance with five working memory tasks. We found that individual characteristics influenced the outcome of combined cognitive training and tDCS regimens, with the intervention selectively benefiting old-old adults with lower working memory capacity. Future work should consider developing individualized treatments by considering individual differences in cognitive profiles.
... insulin-like growth factor (IGF-1) [346][347][348][349] . Further, aerobic exercise could have direct effects on the neuro-immune axis in MS 347,350 . ...
Thesis
Multiple Sclerosis (MS) is an auto-immune mediated inflammatory and degenerative disease of the central nervous system characterized by loss of myelin and axonal integrity. MS often leads to an accrual of walking disability and worsening of fatigue. Exercise-dependent plasticity in the central nervous system, which involves upregulation of growth-promoting neurotrophins and suppression of inflammatory cytokines, may help restore lost ability to walk. Although aerobic training is an intervention that can potentially improve walking disability and reduce fatigue, these factors are also significant barriers to participating in exercise. Furthermore, because of thermal dysregulation, exercise-induced increases in body temperature leads to temporary worsening of symptoms in some MS patients. The purpose of my doctoral work was to develop and determine the feasibility of implementing a progressively intense aerobic treadmill training, in a room cooled to 16°C, for people with MS having walking disability, fatigue, and heat sensitivity. In the first study, I critically appraised and consolidated the research in animal models and clinical trials in order to determine the optimal training dosage and outcomes for a future exercise trial. The second study showed that people with MS-related disability consumed about three times more oxygen to complete relatively simple mobility activities such as rolling in bed, when compared to age and sex-matched healthy controls. The results of this study supported the importance of testing therapeutic aerobic training for this cohort of patients with barriers to exercise, such as fatigue. The third study outlined the effects of maximal aerobic exercise on neurotrophins and inflammatory cytokines iii among people with MS and controls. The final study established preliminary evidence for the feasibility of conducting progressively intense aerobic training on a bodyweight supported treadmill in a room cooled to 16°C. The benefits included significant improvements in walking speed, fatigue, aerobic fitness, and quality of life, while simultaneously altering serum levels of blood biomarkers of recovery such as brain-derived neurotrophic factor and interleukin-6, shifting the balance between repair and inflammation. Randomized controlled trials are needed to substantiate these preliminary findings, which in turn could lead to effective training options for people living with MS-related barriers to exercise participation.
... After the removal of duplicates, we screened 16,071 unique records. Fifty studies with 60 intervention arms were included in the meta-analyses (Antunes et al., 2015;Best et al., 2015;Bolandzadeh et al., 2015;Briken et al., 2016;Burzynska et al., 2017;Cassilhas et al., 2007;Cheng et al., 2018;Coelho-Junior et al., 2020;Erickson et al., 2011;Feys et al., 2019;Fisher et al., 2008;Flodin et al., 2017;Fragala et al., 2014;Frazzitta et al., 2014;Hejazi, 2017;Hsu et al., 2021;Jonasson et al., 2016;Kang et al., 2020;Landers et al., 2019;Langeskov-Christensen et al., 2021;Liu-Ambrose et al., 2012;Luft et al., 2008;Maass et al., 2016Maass et al., , 2015Martins et al., 2010;Marx et al., 2001;Matura et al., 2017;Mokhtarzade et al., 2018;Moore et al., 2015;Mortimer et al., 2012;Muscari et al., 2010;Nagamatsu et al., 2016;Niemann et al., 2014;Nindl et al., 2010;Ploughman et al., 2019;Renteria et al., 2020;Sacheli et al., 2019;Sandroff et al., 2017;Savsek et al., 2021;Seifert et al., 2010;Sexton et al., 2020;So et al., 2013;Svatkova et al., 2015;Tsai et al., 2017Tsai et al., , 2015Umutlu et al., 2020;Voss et al., 2013bVoss et al., , 2010Zhu et al., 2021;Zimmer et al., 2018). Table 1 summarizes the study characteristics and Supplement 2 details these characteristics. ...
Article
Objective To determine the effects of low- vs. high-intensity aerobic and resistance training on motor and cognitive function, brain activation, brain structure, and neurochemical markers of neuroplasticity and the association thereof in healthy young and older adults and in patients with multiple sclerosis, Parkinson’s disease, and stroke. Design Systematic review and robust variance estimation meta-analysis with meta-regression. Data sources Systematic search of MEDLINE, Web of Science, and CINAHL databases. Results Fifty studies with 60 intervention arms and 2,283 in-analyses participants were included. Due to the low number of studies, the three patient groups were combined and analyzed as a single group. Overall, low- (g=0.19, p=0.024) and high-intensity exercise (g=0.40, p=0.001) improved neuroplasticity. Exercise intensity scaled with neuroplasticity only in healthy young adults but not in healthy older adults or patient groups. Exercise-induced improvements in neuroplasticity were associated with changes in motor but not cognitive outcomes. Conclusion Exercise intensity is an important variable to dose and individualize the exercise stimulus for healthy young individuals but not necessarily for healthy older adults and neurological patients. This conclusion warrants caution because studies are needed that directly compare the effects of low- vs. high-intensity exercise on neuroplasticity to determine if such changes are mechanistically and incrementally linked to improved cognition and motor function.
Article
Executive function is frequently impaired among people who have sustained stroke. This review provides an overview of definitions, concepts, and measures. The review also summarizes current best evidence examining executive function impairment and recovery trajectories after stroke, correlates of change over time, and emerging intervention research. Finally, this review provides recommendations for research and clinical practices, as well as priorities for future executive function research.
Article
BACKGROUND BDNF (brain-derived neurotrophic factor) is a biomarker of neuroplasticity linked with better functional outcomes after stroke. Early evidence suggests that increased concentrations after exercise may be possible for people with stroke, however it is unclear how exercise parameters influence BDNF concentration. METHODS This systematic review and meta-analysis searched 7 electronic databases. Experimental or observational studies measuring changes in BDNF concentration after exercise in people poststroke were included. Data were extracted including characteristics of the study, participants, interventions, and outcomes. Several fixed and random effects meta-analyses were completed. RESULTS Seventeen studies including a total of 687 participants met the eligibility criteria (6 randomized trials). Significant improvements were observed in BDNF concentration following a single session (mean difference, 2.49 ng/mL; [95% CI, 1.10–3.88]) and program of high intensity aerobic exercise (mean difference, 3.42 ng/mL; [95% CI, 1.92–4.92]). CONCLUSIONS High intensity aerobic exercise can increase circulating BDNF concentrations, which may contribute to increased neuroplasticity. REGISTRATION URL: https://www.crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42021251083.
Article
Importance: A stroke doubles one's risk for dementia. How to promote cognitive function among persons with chronic stroke is unclear. Objective: To evaluate the effect of exercise (EX) or cognitive and social enrichment activities (ENRICH) on cognitive function in adults with chronic stroke. Design, setting, and participants: This was a 3-group parallel, single-blinded, single-site, proof-of-concept randomized clinical trial at a research center in Vancouver, British Columbia, Canada. Participants included community-dwelling adults with chronic stroke, aged 55 years and older, able to walk 6 meters, and without dementia. The trial included a 6-month intervention and a 6-month follow-up. Randomization occurred from June 6, 2014, to February 26, 2019. Measurement occurred at baseline, 6 months, and 12 months. Data were analyzed from January to November 2021. Interventions: Participants were randomly allocated to twice-weekly supervised classes of: (1) EX, a multicomponent exercise program; (2) ENRICH, a program of cognitive and social enrichment activities; or (3) balance and tone (BAT), a control group that included stretches and light-intensity exercises. Main outcomes and measures: The primary outcome was the Alzheimer Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-Plus), which included the 13-item ADAS-Cog, Trail Making Test Parts A and B, Digit Span Forward and Backward, Animal Fluency, and Vegetable Fluency. Results: One-hundred and twenty participants, with a mean (range) of 1.2 (1-4) strokes, a mean (SD) of 66.5 (53.8) months since the most recent stroke, mean (SD) baseline age of 70 (8) years, mean (SD) baseline ADAS-Cog-Plus of 0.22 (0.81), and 74 (62%) male participants, were randomized to EX (34 participants), ENRICH (34 participants), or BAT (52 participants). Seventeen withdrew during the 6-month intervention and another 7 during the 6-month follow-up. Including all 120 participants, at the end of the 6-month intervention, EX significantly improved ADAS-Cog-Plus performance compared with BAT (estimated mean difference: -0.24; 95% CI, -0.43 to -0.04; P = .02). This difference did not persist at the 6-month follow-up (estimated mean difference: -0.08; 95% CI, -0.29 to 0.12; P = .43). For the 13-item ADAS-Cog, the EX group improved by 5.65 points over the 6-month intervention (95% CI, 2.74 to 8.57 points; P < .001), exceeding the minimally clinical difference of 3.0 points. Conclusions and relevance: These findings suggest that exercise can induce clinically important improvements in cognitive function in adults with chronic stroke. Future studies need to replicate current findings and to understand training parameters, moderators, and mediators to maximize benefits. Trial registration: ClinicalTrials.gov identifier: NCT01916486.
Article
Background: Cognitive impairment is a frequent consequence of stroke and can impact on a person's ability to perform everyday activities. Occupational therapists use a range of interventions when working with people who have cognitive impairment poststroke. This is an update of a Cochrane Review published in 2010. Objectives: To assess the impact of occupational therapy on activities of daily living (ADL), both basic and instrumental, global cognitive function, and specific cognitive abilities in people who have cognitive impairment following a stroke. Search methods: We searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, Embase, four other databases (all last searched September 2020), trial registries, and reference lists. Selection criteria: We included randomised and quasi-randomised controlled trials that evaluated an intervention for adults with clinically defined stroke and confirmed cognitive impairment. The intervention needed either to be provided by an occupational therapist or considered within the scope of occupational therapy practice as defined in the review. We excluded studies focusing on apraxia or perceptual impairments or virtual reality interventions as these are covered by other Cochrane Reviews. The primary outcome was basic activities of daily living (BADL) such as dressing, feeding, and bathing. Secondary outcomes were instrumental ADL (IADL) (e.g. shopping and meal preparation), community integration and participation, global cognitive function and specific cognitive abilities (including attention, memory, executive function, or a combination of these), and subdomains of these abilities. We included both observed and self-reported outcome measures. Data collection and analysis: Two review authors independently selected studies that met the inclusion criteria, extracted data, and assessed the certainty of the evidence. A third review author moderated disagreements if consensus was not reached. We contacted trial authors for additional information and data, where available. We assessed the certainty of key outcomes using GRADE. MAIN RESULTS: We included 24 trials from 11 countries involving 1142 (analysed) participants (two weeks to eight years since stroke onset). This update includes 23 new trials in addition to the one study included in the previous version. Most were parallel randomised controlled trials except for one cross-over trial and one with a two-by-two factorial design. Most studies had sample sizes under 50 participants. Twenty studies involved a remediation approach to cognitive rehabilitation, particularly using computer-based interventions. The other four involved a compensatory and adaptive approach. The length of interventions ranged from 10 days to 18 weeks, with a mean total length of 19 hours. Control groups mostly received usual rehabilitation or occupational therapy care, with a few receiving an attention control that was comparable to usual care; two had no intervention (i.e. a waiting list). Apart from high risk of performance bias for all but one of the studies, the risk of bias for other aspects was mostly low or unclear. For the primary outcome of BADL, meta-analysis found a small effect on completion of the intervention with a mean difference (MD) of 2.26 on the Functional Independence Measure (FIM) (95% confidence interval (CI) 0.17 to 4.22; P = 0.03, I2 = 0%; 6 studies, 336 participants; low-certainty evidence). Therefore, on average, BADL improved by 2.26 points on the FIM that ranges from 18 (total assist) to 126 (complete independence). On follow-up, there was insufficient evidence of an effect at three months (MD 10.00, 95% CI -0.54 to 20.55; P = 0.06, I2 = 53%; 2 studies, 73 participants; low-certainty evidence), but evidence of an effect at six months (MD 11.38, 95% CI 1.62 to 21.14, I2 = 12%; 2 studies, 73 participants; low-certainty evidence). These differences are below 22 points which is the established minimal clinically important difference (MCID) for the FIM for people with stroke. For IADL, the evidence is very uncertain about an effect (standardised mean difference (SMD) 0.94, 95% CI 0.41 to 1.47; P = 0.0005, I2 = 98%; 2 studies, 88 participants). For community integration, we found insufficient evidence of an effect (SMD 0.09, 95% CI -0.35 to 0.54; P = 0.68, I2 = 0%; 2 studies, 78 participants). There was an improvement of clinical importance in global cognitive functional performance after the intervention (SMD 0.35, 95% CI 0.16 to 0.54; P = 0.0004, I2 = 0%; 9 studies, 432 participants; low-certainty evidence), equating to 1.63 points on the Montreal Cognitive Assessment (MoCA) (95% CI 0.75 to 2.52), which exceeds the anchor-based MCID of the MoCA for stroke rehabilitation patients of 1.22. We found some effect for attention overall (SMD -0.31, 95% CI -0.47 to -0.15; P = 0.0002, I2 = 20%; 13 studies, 620 participants; low-certainty evidence), equating to a difference of 17.31 seconds (95% CI 8.38 to 26.24), and for executive functional performance overall (SMD 0.49, 95% CI 0.31 to 0.66; P < 0.00001, I2 = 74%; 11 studies, 550 participants; very low-certainty evidence), equating to 1.41 points on the Frontal Assessment Battery (range: 0-18). Of the cognitive subdomains, we found evidence of effect of possible clinical importance, immediately after intervention, for sustained visual attention (moderate certainty) equating to 15.63 seconds, for working memory (low certainty) equating to 59.9 seconds, and thinking flexibly (low certainty), compared to control. Authors' conclusions: The effectiveness of occupational therapy for cognitive impairment poststroke remains unclear. Occupational therapy may result in little to no clinical difference in BADL immediately after intervention and at three and six months' follow-up. Occupational therapy may slightly improve global cognitive performance of a clinically important difference immediately after intervention, likely improves sustained visual attention slightly, and may slightly increase working memory and flexible thinking after intervention. There is evidence of low or very low certainty or insufficient evidence for effect on other cognitive domains, IADL, and community integration and participation. Given the low certainty of much of the evidence in our review, more research is needed to support or refute the effectiveness of occupational therapy for cognitive impairment after stroke. Future trials need improved methodology to address issues including risk of bias and to better report the outcome measures and interventions used.
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Motor function may be enhanced if aerobic exercise is paired with motor training. One potential mechanism is that aerobic exercise increases levels of brain-derived neurotrophic factor (BDNF), which is important in neuroplasticity and involved in motor learning and motor memory consolidation. This study will examine the feasibility of a parallel-group assessor-blinded randomised controlled trial investigating whether task-specific training preceded by aerobic exercise improves upper limb function more than task-specific training alone, and determine the effect size of changes in primary outcome measures. People with upper limb motor dysfunction after stroke will be allocated to either task-specific training or aerobic exercise and consecutive task-specific training. Both groups will perform 60 h of task-specific training over 10 weeks, comprised of 3 × 1 hour sessions per week with a therapist and 3 × 1 hours of home-based self-practice per week. The combined intervention group will also perform 30 min of aerobic exercise (70–85%HRmax) immediately prior to the 1 h of task-specific training with the therapist. Recruitment, adherence, retention, participant acceptability, and adverse events will be recorded. Clinical outcome measures will be performed pre-randomisation at baseline, at completion of the training program, and at 1 and 6 months follow-up. Primary clinical outcome measures will be the Action Research Arm Test (ARAT) and the Wolf Motor Function Test (WMFT). If aerobic exercise prior to task-specific training is acceptable, and a future phase 3 randomised controlled trial seems feasible, it should be pursued to determine the efficacy of this combined intervention for people after stroke.
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Background and purpose: Functional outcome after stroke is often only evaluated using the modified Rankin Scale, which primarily assesses activities of daily living. Stroke patients may experience difficulties with social reintegration and mental functions, feel isolated, and experience poor quality of life, even after physical recovery is complete. Functional assessments based solely on activity limitations may not be able to capture the full range of problems experienced by stroke survivors. Methods: Telephone interviews were conducted 2 to 3 years poststroke to assess outcome on multiple levels of functioning as stated in the WHO International Classification of Functioning: body function (Montreal Cognitive Assessment and Patient Health Questionnaire-2), activity (modified Rankin Scale), and participation (Reintegration to Normal Living Index). Results: Ninety-six (68%) patients had a favorable functional outcome (modified Rankin Scale <2). Of these, 79, 91, and 93 patients completed the Montreal Cognitive Assessment, Reintegration to Normal Living Index, and Patient Health Questionnaire-2, respectively. Forty-three (54%) patients were cognitively impaired, 47 (52%) had restrictions in reintegration, and 30 (32%) endorsed symptoms of depression. There was no difference in Montreal Cognitive Assessment or Patient Health Questionnaire-2 scores between those who had activity limitations and those who had not. Conclusions: More than half of stroke patients with excellent functional recovery measured by the modified Rankin Scale continue to have cognitive impairment and participation restrictions, and one third of patients continue to have depression 2 to 3 years later. Current definitions of good functional outcome used in the majority of stroke acute trials focus on activity limitations, but greater attention to multiple levels of recovery is required.
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Brain training is currently widely used in an attempt to improve cognitive functioning. Computer-based training can be performed at home and could therefore be an effective add-on to available rehabilitation programs aimed at improving cognitive functioning. Several studies have reported cognitive improvements after computer training, but most lacked proper active and passive control conditions.Our aim was to investigate whether computer-based cognitive flexibility training improves executive functioning after stroke. We also conducted within-group analyses similar to those used in previous studies, to assess inferences about transfer effects when comparisons to proper control groups are missing.We conducted a randomized controlled, double blind trial. Adults (30-80 years old) who had suffered a stroke within the last 5 years were assigned to either an intervention group (n = 38), active control group (i.e., mock training; n = 35), or waiting list control group (n = 24). The intervention and mock training consisted of 58 half-hour sessions within a 12-week period. Cognitive functioning was assessed using several paper-and-pencil and computerized neuropsychological tasks before the training, immediately after training, and 4 weeks after training completion.Both training groups improved on training tasks, and all groups improved on several transfer tasks (three executive functioning tasks, attention, reasoning, and psychomotor speed). Improvements remained 4 weeks after training completion. However, the amount of improvement in executive and general cognitive functioning in the intervention group was similar to that of both control groups (active control and waiting list). Therefore, this improvement was likely due to training-unspecific effects. Our results stress the importance to include both active and passive control conditions in the study design and analyses. Results from studies without proper control conditions should be interpreted with care.
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Background The mechanisms through which physical activity supports healthy brain function remain to be elucidated. One hypothesis suggests that increased brain-derived neurotrophic factor (BDNF) mediates some cognitive and mood benefits. This meta-analysis sought to determine the effect of exercise training on resting concentrations of BDNF in peripheral blood. Methods MEDLINE, Embase, PsycINFO, SPORTDiscus, Rehabilitation & Sports Medicine Source, and CINAHL databases were searched for original, peer-reviewed reports of peripheral blood BDNF concentrations before and after exercise interventions ≥ 2 weeks. Risk of bias was assessed using standardized criteria. Standardized mean differences (SMDs) were generated from random effects models. Risk of publication bias was assessed using funnel plots and Egger’s test. Potential sources of heterogeneity were explored in subgroup analyses. Results In 29 studies that met inclusion criteria, resting concentrations of peripheral blood BDNF were higher after intervention (SMD = 0.39, 95% CI: 0.17–0.60, p < 0.001). Subgroup analyses suggested a significant effect in aerobic (SMD = 0.66, 95% CI: 0.33–0.99, p < 0.001) but not resistance training (SMD = 0.07, 95% CI: -0.15–0.30, p = 0.52) interventions. No significant difference in effect was observed between males and females, nor in serum vs plasma. Conclusion Aerobic but not resistance training interventions increased resting BDNF concentrations in peripheral blood.
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Objectives: Our objectives were: 1) to determine whether maximal aerobic exercise increased serum neurotrophins in chronic stroke and 2) to determine the factors that predict resting and exercise-dependent levels. Methods: We investigated the potential predictors of resting and exercise-dependent serum insulin-like growth factor-1 and brain-derived neurotrophic factor among 35 chronic stroke patients. Predictors from three domains (demographic, disease burden, and cardiometabolic) were entered into 4 separate stepwise linear regression models with outcome variables: resting insulin-like growth factor, resting brain-derived neurotrophic factor, exercise-dependent change in insulin-like growth factor, and exercise-dependent change brain-derived neurotrophic factor. Results: Insulin-like growth factor decreased after exercise (p = 0.001) while brain-derived neurotrophic factor did not change (p = 0.38). Greater lower extremity impairment predicted higher resting brain-derived neurotrophic factor (p = 0.004, r² = 0.23). Higher fluid intelligence predicted greater brain-derived neurotrophic factor response to exercise (p = 0.01, r² = 0.18). There were no significant predictors of resting or percent change insulin-like growth factor-1. Discussion: Biomarkers have the potential to characterize an individual’s potential for recovery from stroke. Neurotrophins such as insulin-like growth factor-1 and brain-derived neurotrophic factor are thought to be important in neurorehabilitation; however, the factors that modulate these biomarkers are not well understood. Resting brain-derived neurotrophic factor and percent change in brain-derived neurotrophic factor were related to physical and cognitive recovery in chronic stroke, albeit weakly. Insulin-like growth factor-1 was not an informative biomarker among chronic stroke patients. The novel finding that fluid intelligence positively correlated with exercise-induced change in brain-derived neurotrophic factor warrants further research. © 2019
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Objective: This study evaluated the possible effect of the combined intervention of physical exercise and cognitive training on cognitive function in stroke survivals with vascular cognitive impairment. Design: A single-blind (investigator-blinded but not subject-blinded) randomized controlled trial. Setting: Medical Rehabilitation Center of Shanghai General Hospital, China. Subjects: A total of 225 patients (mean age 64.59 years, SD = 4.27) who exhibited vascular cognitive impairment were included in this study. Interventions: Patients were randomly allocated into one of the four groups: (1) physical exercise ( n = 56; 50-minute session), (2) cognitive training ( n = 57; 60-minute session), (3) combined intervention of physical exercise and cognitive training ( n = 55; 50-minute session + 60-minute session), or (4) control groups ( n = 57; 45-minute session). All participants received training for 36 sessions, three days per week, for 12 weeks. Primary measures: Measures were recorded at baseline, after the intervention and at a six-month follow-up. Primary measurements included the Trail Making Part B, Stroop, forward digit span, and mental rotation tests. Results: A total of 179 participants (79.56% response rate) completed the study. Cognitive performances on all four tasks in the combined training group improved significantly after the intervention ( P < 0.01). Changes in cognitive performance were greater in the combined intervention group than those in the physical exercise group (e.g. forward digit span, 13.61% vs. 2.18%, P = 0.003), the cognitive training group (e.g. mental rotation, 17.36% vs. 0.87%, P = 0.002), and the control group (e.g. Stroop, -4.11% vs. -0.72%, P = 0.026). Conclusion: The combined intervention produced greater benefits on cognitive function compared to either training alone in stroke survivors with vascular cognitive impairment.
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Background: Aerobic exercise can improve upper limb motor function in both healthy and stroke populations. Research in animals after stroke has shown that aerobic exercise combined with forelimb motor training improved forelimb motor function more than aerobic exercise or motor training alone. There is a lack of knowledge about this combined intervention in humans after stroke. Purpose: These 2 case reports describe the exploratory implementation of a combined aerobic exercise and task-specific training intervention to improve upper limb motor function in one person in subacute stroke recovery and one person in chronic stroke recovery. Methods: Case descriptions Subacute participant: 45-year-old female, 3 months after ischemic stroke resulting in left-sided hemiparesis affecting her non-dominant upper limb, with a baseline Action Research Arm Test (ARAT) score of 10/57 and Wolf Motor Function Test (WMFT) score of 39/75. Chronic participant: 69-year-old female, 14 years after ischemic stroke resulting in right-sided hemiparesis affecting her non-dominant upper limb, with a baseline ARAT score of 13/57 and WMFT score of 34/75. Intervention Participants performed 30 min of lower limb cycling immediately prior to 30 min of upper limb task-specific training. Sessions were undertaken 3 times a week for 8 weeks in a university rehabilitation laboratory. Results The combined intervention was feasible and perceived as acceptable and beneficial. Participants improved their upper limb motor function on the ARAT (subacute participant = 4 points; chronic participant = 2 points) and WMFT (subacute participant = 5 points; chronic participant = 3 points). Participants improved their aerobic fitness (subacute participant = +4.66 ml O2 /kg/min; chronic participant = +7.34 ml O2 /kg/min) and 6-minute walking distance (subacute participant = +50 m; chronic participant = +37 m). Discussion Combining aerobic exercise with task-specific training may be a worthwhile therapeutic approach to improve upper limb motor function suitable for persons in the subacute or chronic phase after stroke.
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Improving fluid intelligence is an enduring research aim in the psychological and brain sciences that has motivated public interest and scientific scrutiny. At issue is the efficacy of prominent interventions—including fitness training, computer-based cognitive training, and mindfulness meditation—to improve performance on untrained tests of intellectual ability. To investigate this issue, we conducted a comprehensive 4-month randomized controlled trial in which 424 healthy adults (age 18-43 years) were enrolled in one of four conditions: (1) Fitness training; (2) Fitness training and computer-based cognitive training; (3) Fitness, cognitive training, and mindfulness meditation; or (4) Active control. Intervention effects were evaluated within a structural equation modeling framework that included repeated-testing gains, as well as novel tests of fluid intelligence that were administered only at post-intervention. The combination of fitness and cognitive training produced gains in visuospatial reasoning that were greater than in the Active Control, but not in performance on novel tests administered only at post-intervention. Individuals more variably responded to multi-modal training that additionally incorporated mindfulness meditation (and less time spent on cognitive training), and those who demonstrated repeated-testing gains in visuospatial reasoning also performed better on novel tests of fluid intelligence at post-intervention. In contrast to the multi-modal interventions, fitness only training did not produce Active Control-adjusted gains in task performance. Because fluid intelligence test scores predict real-world outcomes across the lifespan, boosting intelligence ability via multi-modal intervention that is effective even in young, healthy adults is a promising avenue to improve reasoning and decision making in daily life.