2. in progressive MS: a randomized,
controlled pilot trial
S Briken1,2, SM Gold1, S Patra3, E Vettorazzi4, D Harbs3,
A Tallner5, G Ketels6, KH Schulz3,7 and C Heesen1,2
Abstract
Background: Exercise may have beneficial effects on both well-
being and walking ability in multiple sclerosis (MS). Exer-
cise is shown to be neuroprotective in rodents and may also
enhance cognitive function in humans. It may, therefore, be
particularly useful for MS patients with pronounced
neurodegeneration.
Objective: To investigate the potential of standardized exercise
as a therapeutic intervention for progressive MS, in a
randomized-controlled pilot trial.
Methods: Patients with progressive MS and moderate disability
(Expanded Disability Status Scale (EDSS) of 4–6) were
randomized to one of three exercise interventions (arm
ergometry, rowing, bicycle ergometry) for 8–10 weeks or a
waitlist control group. We analyzed the drop-out rate as a
measure of feasibility. The primary endpoint of the study was
aerobic fitness. Secondary endpoints were walking ability,
cognitive function as measured by a neuropsychological test
battery, depression and fatigue.
Results: A total of 42 patients completed the trial (10.6% drop-
out rate). Significant improvements were seen in aero-
bic fitness. In addition, exercise improved walking ability,
depressive symptoms, fatigue and several domains of cognitive
function.
Conclusion: This study indicated that aerobic training is
feasible and could be beneficial for patients with progressive
MS. Larger exercise studies are needed to confirm the effect on
cognition.
Trial Registration: ISRCTN (trial number 76467492)
http://isrctn.org
3. Keywords
Aerobic exercise, clinical trial, cognition, depression, fatigue,
fitness, motor function, multiple sclerosis, progressive
multiple sclerosis, rehabilitation, walking ability
Date received: 15 July 2013; accepted: 8 September 2013
1 Institute for Neuroimmunology and Clinical Multiple
Sclerosis Research
(inims), University Hospital Eppendorf, Hamburg, Germany.
2 Department of Neurology, University Hospital Eppendorf,
Hamburg,
Germany.
3 Competence Center for Sports and Exercise Medicine
(Athleticum),
University Hospital Eppendorf, Hamburg, Germany.
4 Department of Medical Biometry and Epidemiology,
University Medical
Center Hamburg-Eppendorf, Germany.
5 Institute of Sport Science, University of Erlangen-Nürnberg,
Germany.
6 Department of Physiotherapy, University Medical Center
Hamburg-
Eppendorf, Germany.
7 Institute for Medical Psychology, Hamburg, Germany.
Authors Briken, Gold, Schulz and Heesen contributed equally.
Corresponding author:
Christoph Heesen, Institute for Neuroimmunology and Clinical
MS
4. Research (inims), University Medical Center Eppendorf,
Martinistrasse,
Hamburg, Germany.
Email: [email protected]
507358MSJ20310.1177/1352458513507358Multiple Sclerosis
JournalBriken et al.
2013
Research Paper
Briken et al. 383
aerobic exercise in both young healthy and aging adults
demonstrate improved cognitive function.7 Exercise may
therefore have therapeutic potential for improving cogni-
tive function in MS, but empirical evidence from rand-
omized controlled trials is lacking.8
Since the first RCT of exercise in MS by Petajan et al.9,
both improved quality of life and walking ability in MS
after exercise training were confirmed by several RCTs.10,
11 In addition to improving well-being, recent experimental
evidence suggests that exercise might directly affect pathol-
ogy, by showing neuronal protection during experimental
autoimmune encephalomyelitis (EAE).12
Exercise therapy might be a particularly useful approach
for MS patients with progressive disease, as treatment
options are very limited.13 On the other hand, the more
advanced motor impairment in secondary progressive MS
(SPMS) might interfere with the ability of the patients to
perform aerobic exercise training programs. Therefore,
there is a need to rigorously test the feasibility and effec-
tiveness of exercise in progressive MS.
5. In the present pilot-RCT, we aimed to compare three
endurance-training interventions in progressive MS
patients. We expected exercise to improve their physical
fitness, walking ability and cognitive function. Based on a
meta-analysis in non-MS populations7, we expected
improved performance in learning/memory, attention and
executive function.
Materials and methods
Study design, overview and patient recruitment
Our study was a RCT of three different exercise training
tools (arm ergometry, rowing and bicycle ergometry) and a
waitlist control group with progressive MS patients with
moderate disability (see Supplemental Figure). The training
programs consisted of 8–10 weeks of standardized exercise
with 2–3 sessions per week. This time frame was chosen as a
pragmatic approach, to also allow short interruptions of the
training with the aim of obtaining about 20 training sessions.
The training program was tailored to the individual level of
fitness of the participants, as determined by standard ergom-
etry at baseline. The feasibility measure of the study was the
percentage of subjects completing the trial.
Our main hypothesis was that the training program
would increase fitness, as measured by increased peak oxy-
gen consumption (VO2), and would improve walking abil-
ity, as measured by gait tests. The primary endpoint was
aerobic fitness (as defined by peak oxygen consumption
during an exhaustion test). Secondary endpoints were:
walking ability (as defined by the 6-Minute Walk Test
(6MWT)), cognitive function (as measured by a neuropsy-
chological battery), depressive symptoms and fatigue. All
endpoints were assessed at baseline, as well as at the end of
6. the 8–10 week intervention (unblinded to the group).
Patients were recruited through the MS outpatient clinic at
the University Medical Center Hamburg Eppendorf, as
well as through advertisements on the website of the
German MS Society and leaflets left in neurologists’
offices. We also contacted patients from our database who
had agreed to be informed about new studies.
Standard protocol approvals and patient consent
The trial was approved by the ethics committee of the
Chamber of Physicians, City of Hamburg, Germany
(Registration Number PV3689). Participants provided
written informed consent prior to enrollment.
Participant inclusion and exclusion criteria
Patients had to meet diagnostic criteria for clinically defi-
nite MS14 with a secondary-progressive disease course15
and moderate disability (EDSS 4–6). To enhance recruit-
ment, we later also allowed patients with primary-
progressive MS (PPMS) to enter the trial, as long as they
met the EDSS inclusion criterion.
Patients were excluded if they had any medical contrain-
dications for exercise therapy (cardiovascular or major
orthopedic disease, general medical contraindications for
increased aerobic activity) as assessed by self-report using
the revised Physical Activity Readiness Questionnaire
(rPAR-Q).16 We excluded patients if they had started immu-
nomodulatory therapy within the last 6 months, undergone
steroid therapy within the last 4 weeks, documented
relapses within the last 12 months, abnormal liver or kidney
function, immunodeficiency, diagnosis of other serious
medical illnesses, or if they had severe developmental, psy-
7. chiatric and neurological disorders other than MS.
Eligibility was determined by an experienced senior neu-
rologist. As no previous studies were available to power the
exercise trial, its sample size was based on patient availa-
bility, with a recruitment goal of n = 40 (at least n = 10 in
each group).
Randomization
Patients were consecutively randomized to one of the four
groups, using an automated biased coin algorithm.17 This
approach used the a priori defined variables age, sex, EDSS
and previous group size. To ensure a concealed allocation,
we performed randomization after determining eligibility.
Individually-tailored training intervention
The training schedule for each participant was tailored to
the individual results from a bicycle ergometry perfor-
mance test that assessed aerobic fitness levels.18 Since MS
patients might not be able to reach their maximum perfor-
mance in a stepwise exhaustion test, we used a submaximal
performance index (aerobic threshold (AT)) for the adjust-
ment of the training intervention.
384 Multiple Sclerosis Journal 20(3)
The training was then performed with the modalities the
participants were randomized to. We used the following
equipment for training: First Degree Fitness® E-920 Upper
Body arm ergometer, the Ergofit® 3000 bicycle ergometer
and the Waterrower®.
We determined the training levels using a performance
8. test (ramp test) on the specific selected training tool (see
Supplemental Figure). We used the performance in Watts
(W) recorded at the individual AT as an anchor for the fol-
lowing training intensity categories: AT, 120% of AT and
130% of AT. The length of each training interval and the
target performance were steadily increased with every
training session (including regeneration sessions), accord-
ing to a predefined training plan. The performance as well
as subjective work load ratings (Borg scale) were recorded
during each training session.19 The length of the training
sessions steadily increased from 15 to 45 minutes (see
Supplemental Table 1). All training sessions were per-
formed at the Department of Physiotherapy, University
Medical Center Hamburg-Eppendorf, under the supervi-
sion of a licensed physiotherapist.
Outcome measures
Aerobic fitness. Participants started cycling at 25 W and
resistance was steadily increased with an incline of 12.5 W/
min. We obtained VO2 and heart rate continuously and
recorded maximum power. We measured lactate every 2
minutes. As some patients (n = 14) were unable to perform
this standard ergometry, for these participants, an easier
protocol was used starting at 8W with incremental increases
of 8W/min. These tests were conducted at the Competence
Center for Sports and Exercise Medicine in Hamburg, Ger-
many by an experienced sports scientist.
Motor function. We assessed walking ability before and
after the training program, using the 6MWT.20
Neuropsychological function. Cognitive impairment in MS
affects domains including attention, processing speed,
long-term memory and executive function.21 Therefore, we
administered a battery of standardized neuropsychological
9. tests that covered these domains.
The “Symbol Digit Modalities Test” (SDMT)22 was
utilized to measure processing speed. The “Verbal
Learning and Memory Test” (VLMT) was used to evalu-
ate declarative memory and learning abilities.23 Here, a
word list of 15 unrelated words is presented 5 times. The
test provides a measure of learning (sum of correctly
recalled words during the 5 trials), plus delayed recall
after 30 minutes. To assess attention, we used the “alert-
ness” and “shift of attention” subtests of the computerized
“Test Battery of Attention” (TAP).24 The “alertness” TAP
subtest consists of a simple reaction time test, with and
without cue (for “tonic alertness” and “phasic alertness”,
respectively). In the TAP subtest “shift of attention”, a
Posner paradigm with valid and invalid cues is used: After
valid cues, the stimulus is presented in the area, as indi-
cated by the arrow. After invalid cues, the stimulus is pre-
sented on the side opposite to that indicated by the arrow.
We quantified executive function with subtest 3 of the
“Achievement Testing System” (Leistungsprüfsystem
(LPS)).25 In this test, subjects select a symbol that does
not fit a sequence, i.e. they identify the rule behind the
sequence. The LPS was employed as a measure of logical
reasoning. In addition, we assessed verbal fluency using
the “Regensburg Verbal Fluency Test” (RWT), specifi-
cally subtest “letters G-R”.26 In a previous study, we dem-
onstrated that the VLMT, RWT and TAP are sensitive for
detecting cognitive impairment in MS.27
Patient-based outcome measures. We assessed depression
using the self-reported version of the 30-item “Inventory of
Depressive Symptoms” (IDS-SR30).
28 We measured fatigue
10. with the “Modified Fatigue Impact Scale” (MFIS). 29
Statistical analyses
We tested the feasibility of the different exercise modali-
ties by analyses of drop-out rates, using Fisher’s exact
test. Based on visual inspection of Quantile-Quantile
(Q-Q) plots, we conducted statistical analyses using para-
metric tests. According to guidelines for statistical analy-
sis of clinical trials, published by The European Agency
for the Evaluation of Medicinal Products (CPMP/
ICH/363/96 and CPMP/EWP/2863/99), we computed the
primary statistical analysis for all outcomes using
ANCOVA (Analysis of covariance) models adjusting for
baseline measurement of the respective outcome variable,
to evaluate treatment effects (measured as change from
baseline). No other covariates were included in this pri-
mary analysis. As recommended, this model also did not
include treatment by covariate interactions. In the case of
significant F values in the ANCOVA model, we conducted
planned pairwise comparisons for each intervention group
(bicycle, arm ergometry and rowing) compared to the
waitlist control group.
A total of 14 ANCOVAs were computed: One for the
primary endpoint (VO2 peak), and one for each of the sec-
ondary endpoints walking ability (6MWT), depressive
symptoms (IDS) and fatigue (MFIS) - for the multidimen-
sional assessment of cognitive function, we computed 10
ANCOVAs, of which four assessed attention. In accord-
ance with European Medicines Agency (EMA) guidelines,
we also computed sensitivity analyses using ANCOVA
models, adjusting for baseline as well as sex, age, EDSS
and patient MS type (SPMS or PPMS), in addition to the
primary analysis. For the ANCOVA models, we used avail-
able data from all our subjects who completed the pre- and
11. post-intervention assessments (n = 42).
Finally, we also computed non-parametric intention-
to-treat (ITT) analyses, using Kruskal-Wallis tests
Briken et al. 385
where the patients who dropped out were assigned the
lowest rank. In the results section, we report p values
from the primary analysis (ANCOVA, adjusted for
baseline). The p values from sensitivity analyses can be
found in Supplemental Table 2. Pre- and post mean
scores, standard deviations as well as confidence inter-
vals are indicated in Supplemental Table 3 and Spearman
correlation coefficients of change scores are indicated
in Supplemental Table 4. We performed statistical anal-
yses and conducted 2-tailed testing, using the statistics
package R 2.15.2.30 A value of p < .05 was considered
statistically significant.
Results
Patient sample
We sent out 423 letters advertising the study. Patients who
indicated interest in participating (n = 80) were contacted
by phone for further screening. We examined 50 MS
patients in person at the MS clinic. After screening, 47
patients met our inclusion criteria and were randomized to
one of the four treatment arms: arm ergometry, rowing,
bicycle ergometry, waitlist control (see flow chart in Figure
1 and Table 1).
Feasibility
12. As a measure of feasibility, we analyzed MS patient drop-
out rates in the four groups. Of the 47 study participants, 42
finished the trial, while five dropped out. The drop-out rate
did not differ between the groups (p = .892; Table 1), indi-
cating that exercise intervention is feasible in progressive
MS with moderate disability (EDSS 4–6). Reasons for not
completing the trial included logistic and mobility difficul-
ties (n = 3), fatigue (n = 1) and injury unrelated to the study
(n = 1). Baseline characteristics for the four groups are
shown in Table 1. On average, the subjects exercised 22 ses-
sions. The average Borg rating during the sessions was 4.6.
Effects of exercise on fitness
Exercise induced significant improvements in aerobic fitness,
as measured by VO2 peak during the bicycle ergometry test
(Figure 2, p = .029). Only the bicycle ergometry group dif-
fered significantly from the control group (p = .003).
Effects of exercise on motor function
Exercise significantly improved distance walked by
patients during the 6MWT (Figure 3; p = .012). Significant
Figure 1. Participant flow chart.
386 Multiple Sclerosis Journal 20(3)
improvements were seen for both the arm ergometry (p =
.003) and bicycle ergometry groups (p = .005), in com-
parison to the control group.
Effects of exercise on neuropsychological function
13. Exercise improved 4 out of 10 neuropsychological
measures. Exercise significantly improved verbal
learning, as measured by the VLMT (p = .011, Figure
4(a)). Improvements were significant for the arm
ergometry (p = .007), the rowing group (p = .001) and
the bicycle group (p = .009), as compared to the waitlist
control group. In addition, a significant effect was found
for VLMT delayed recall (p = .002, Figure 4(b)). Again,
all exercise groups showed significant improvement,
when compared to the waitlist control group (arm
ergometry p = .004; rowing p < .001; bicycle ergometry
p < .001).
Figure 2. Effects of standardized exercise therapy on
aerobic fitness of MS patients. A significant training effect was
observed in VO2 peak consumption during the step-wise bicycle
ergometry exhaustion test, the primary endpoint of the study.
Each dot represents one patient. Asterisks indicate significant
pairwise comparisons (* < .05; ** < .01).
ml: milliliter; min: minutes; MS: multiple sclerosis;VO2 peak:
peak oxygen
consumption.
Figure 3. Effects of standardized exercise therapy on walking
ability in MS patients. Exercise therapy significantly improved
walking ability, as measured by the 6MWT. Each dot represents
one patient. Asterisks indicate significant pairwise comparisons
(* < .05; ** < .01).
ergo: ergometry; MS: multiple sclerosis; 6MWT: 6-Minute
Walking Test.
Table 1. Clinical baseline characteristics and training intensity.
Arm Rowing Bicycle Control
14. Drop-outs (n, %) 2 (16.6%) 1 (8.3%) 1 (8.3%) 1 (10%)
Subjects completing 10 11 11 10
Age (years) 49.1±8.5 50.9±9.2 48.8±6.8 50.4±7.6
Sex (m/f) 5/5 4/7 5/6 4/6
Education (years) 13.7±2.7 12.8±3.7 13.2±3.3 12.9±3.7
Disease duration (years) 17.1±7.2 14.1±6.1 13.3±5.4 18.9±9.8
EDSS (score) 5.2±0.9 4.7±0.8 5.0±0.8 4.9±0.9
MS type (SPMS/PPMS) 8/2 7 / 4 8/3 8/ 2
Number of sessions 21.1±0.5 21.7±0.4 22.6±0.9 N/A
Average Borg rating 4.3±0.5 5.3±0.3 4.3±0.1 N/A
EDSS: Expanded Disability Status Scale, SPMS: secondary
progressive multiple sclerosis, PPMS: primary progressive
multiple sclerosis. Data given as
mean+standard deviation.
Briken et al. 387
Significant group differences were observed for the
TAP subtest “tonic alertness” (p < .001; Figure 4(c)). The
bicycle ergometry group showed significant improve-
ments, compared to waitlist controls (p = .005).
Furthermore, we saw significant effects in the TAP sub-
test “shift of attention” (valid cue p = .007; Figure 4(d)).
Again, the arm ergometry (p = .026), as well as the bicy-
cle ergometry group (p = .002), showed significant
improvements, compared to waitlist controls. No effects
of exercise were seen for the two other TAP subtests,
RWT, LPS and SDMT.
Effects of exercise on mood and fatigue
15. At baseline, 23 patients (49%) had IDS scores of 18 or
higher (indicating moderate to severe clinical depression).
Moreover, 27 patients (64%) had a MFIS score of 38 or
higher at baseline, indicative for substantial fatigue. Exercise
Figure 4. Effects of standardized exercise therapy on
neuropsychological function. (a) Exercise resulted in
significantly
more words remembered in the learning trials 1–5 of the VLMT.
(b) Moreover, significant differences in delayed recall trial 7
were
seen. (c) Exercise significantly improved mean reaction times in
the TAP alertness and (d) TAP shift of attention subtests. Each
dot
represents one patient. Asterisks indicate significant pairwise
comparisons (* < .05; ** < .01).
TAP: Test Battery of Attention; VLMT: Verbal Learning of
Memory Test.
388 Multiple Sclerosis Journal 20(3)
significantly decreased depressive symptoms as per IDS
(p < .001), with arm ergometry (p = .001) and bicycle
ergometry (p = .035) showing significant improvements,
compared to the waitlist control group. Finally, exercise also
significantly improved fatigue, as per MFIS total score
(p = .019), but only the arm ergometry group was signifi-
cantly better than waitlist control (p = .013).
Associations between physical fitness,
walking ability and cognition
We saw significant, albeit small-to-moderate correlations
between improvements in the VO2 peak and the VLMT, as well
16. as walking ability (as measured by the 6MWT) and measures
of attention, fatigue and depression (Supplementary Table 4).
Discussion
In this study, we obtained the first evidence for beneficial
effects of exercise on physical measures (aerobic fitness
and walking ability), as well as neuropsychiatric symptoms
(cognitive impairment, depressive symptoms and fatigue)
in progressive MS.
In MS, exercise studies mostly focused on endpoints,
such as walking ability10 and quality of life11. Given the
high prevalence of neuropsychiatric symptoms such as
depression, fatigue and cognitive impairment in MS31, our
preliminary results obtained in this pilot study indicate
that exercise might have therapeutic potential for these
important symptom domains. Despite the evidence for the
beneficial effects of exercise on brain function provided
by animal models and RCTs in older healthy adults, only
one study to date explored the effects of exercise on cog-
nitive function in MS.32 This trial used a 6 months training
intervention with aerobic exercise at a low intensity (2–3
on the Borg scale), with one class per week plus home
exercise, and found no significant effects on neuropsy-
chological tests, compared to yoga delivered at the same
frequency. In contrast, herein we report significant
improvements in learning, memory and attention after
exercise training at a higher intensity (mean Borg scaling
4.6). Furthermore, for most of our endpoints, namely VO2
peak, depression, fatigue and measures of attention, the
strongest effects were seen in the bicycle group. Therefore,
further studies are needed to determine optimal exercise
intensity, as well as to verify the most effective training
modalities required to gain beneficial effects on neuropsy-
chiatric symptoms in MS.
17. Importantly, we found better performance in aspects of
verbal learning and delayed memory (VLMT), as well as
alertness and shift of attention (TAP), but not in working
memory (SDMT) or executive function (RWT and LPS).
Memory and attention were also shown to be consistently
improved by exercise training in a recent meta-analysis of
RCTs in healthy aging adults.7 On the other hand, this meta-
analysis also reported beneficial effects on executive function
and processing speed, which we did not find in our sample.
Whether this is due to chance, limited statistical power in our
study or whether there might be domain-specific differences
in the effects of exercise, depending on the patient population
and exercise conditions, remains to be elucidated.
Higher levels of fitness in MS patients are found to be
correlated cross-sectionally with higher structural connec-
tivity33 and higher gray matter density34, using neuroimag-
ing. Together, these data suggested that physical fitness
may be related to less severe CNS damage and higher struc-
tural integrity of brain networks that are important for cog-
nitive function, such as learning and memory in MS.
Our study suggested that exercise may improve walk-
ing ability in progressive MS. This corroborates and
expands the evidence from one recent uncontrolled trial
resulting in increased walking ability after 8 weeks of
mixed aerobic, resistance, and balance training in pro-
gressive patients with EDSS 4–6.35 Intriguingly, we found
improved walking ability, not only in the bicycle ergom-
etry group, but also for the arm ergometry training. The
underlying mechanisms for improved walking ability
after upper limb training in MS are unclear and warrant
further investigation. One possibility is that the increased
walking ability may be due to contributions of improved
18. cardiorespiratory function toward walking, as was previ-
ously shown for patients with peripheral arterial disease36,
37; however, since in our study the arm ergometry group
did not show significant improvement in the VO2 peak,
this explanation seems less likely. Another possibility is
that better core stability, through the training of abdomi-
nal and back muscles by arm ergometry, could help to sta-
bilize the body during movement, thereby improve
walking ability. Alternatively, improved walking ability
could be a non-specific result of the frequent trips to the
training facility, which may have provided some walking
training, but the rowing group had the same frequence of
trips without these significant improvements. This should
be investigated in future studies.
Some other limitations of our study need to be consid-
ered: First, the study sample was small and the findings,
particularly on cognitive function, require replication in
larger samples. The significant increase in fitness might
have, at least in part, been due to the decreased VO2 peak
in the control group; however, other outcomes remained
stable (6MWT) or slightly improved in controls (VLMT).
Therefore, we believe that the intervention effects are not
in general based on a worsening of the control group.
Secondly, our control condition consisted of a waitlist
group, rather than a non-exercise control condition deliv-
ered at the same frequency. Therefore, we cannot entirely
rule out that some of the effects, particularly those seen
in patient self-reporting measures such as the IDS and
MFIS, may be contributed by non-specific factors, such as
attention from the therapist or social support from other
Briken et al. 389
19. patients. However, the three different intervention groups
received the same frequency of visits, yet they did not
show the same pattern of therapeutic effects in the objec-
tive tests of aerobic fitness, walking ability and neuropsy-
chological function. This makes such non-specific effects
unlikely to explain our findings.
A related limitation might be that we had multiple sec-
ondary endpoints, particularly in the neuropsychological
domain. This was because of the lack of previous data
regarding the question which MS-related cognitive impair-
ments might be most likely to be affected by exercise.
Our study should therefore be considered a pilot trial;
however, the consistent pattern of improvements across
endpoints (with strongest improvements always in the
bicycle group) would argue against a chance finding
based on multiple testing.
While the short-term effects of our exercise training
study are encouraging, it remains unknown whether these
effects can be sustained over longer periods of time.
Maintenance of exercise in MS remains a major issue38 and
a better understanding of the barriers involved, as well as
development of effective strategies to overcome these, are
needed.39 Moreover, our findings were obtained in a sample
of progressive MS patients with moderate disability (EDSS
4–6). It therefore remains to be seen if our results can be
extended to higher disability ranges.
In summary, this trial provided the first evidence for ben-
eficial effects of standardized exercise training on aerobic fit-
ness, walking ability, cognitive function and neuropsychiatric
symptoms in patients with progressive MS and moderate-to-
advanced disability. Given the limited pharmacological treat-
20. ment options for progressive MS, further investigation of
exercise interventions in progressive MS is clearly warranted.
Conflict of interest
The authors declare that there are no conflicts of interest.
Funding
This work was supported by the “Bundesministerium für …
ORIGINAL PAPER
The Effect of a Community-Based Exercise Program
on Inflammation, Metabolic Risk, and Fitness Levels
Among Persons Living with HIV/AIDS
Stacy E. Cutrono1,2 • John E. Lewis3 • Arlette Perry1 • Joseph
Signorile1 •
Eduard Tiozzo3 • Kevin A. Jacobs1
Published online: 25 November 2015
� Springer Science+Business Media New York 2015
Abstract The human immunodeficiency virus (HIV)
pandemic remains a top national health priority. Chronic
inflammation may be a critical component in the disease
course of HIV as C-reactive protein (CRP) is elevated and
21. associated with increased mortality. This study examined
the effect of 3 months of combined aerobic and resistance
exercise training among a diverse cohort of HIV-infected
men and women. The fixed effect of time for CRP was
found to be non-significant (F[1,57.3] = 1.7, p = 0.19).
There was a significant fixed effect for time for upper body
(F[1,51.6] = 18.1, p 0.05) and lower body strength
(F[1,48.0] = 15.7, p 0.05) and significant declines in
diastolic blood pressure (p = 0.002) and waist circumfer-
ence (p = 0.027). Though levels of CRP were not impac-
ted after 3 months training, participants demonstrated a
significant increase in muscular strength as well as bene-
ficial changes in metabolic risk factors. Future studies
should focus on determining the optimal exercise inter-
vention length and mode to reduce inflammation among
individuals living with HIV.
Keywords Human immunodeficiency virus � Aerobic
exercise � Resistance training � C-reactive protein �
Inflammation � Metabolic risk
Introduction
22. Globally, the rate of new human immunodeficiency virus
(HIV) infections has fallen by 33 % since 2001 [1], but has
held steady in the United States (U.S.) at an estimated
50,000 new cases per year [2]. As such, the HIV/acquired
immune deficiency syndrome (AIDS) pandemic continues
to affect millions worldwide and remains a top health
priority in the U.S. Recent reports indicate that the state of
Florida has one of the highest rates of newly reported HIV
infections and newly reported AIDS cases in the country
[3]. Furthermore, the burden of HIV/AIDS continues to
disproportionately affect individuals of minority race/eth-
nicity, such as African Americans and Hispanics who
represent 44 and 20 % of new HIV infections, respectively,
as well as individuals with lower socioeconomic status
(SES) and reduced access to quality health care [2].
The use of combination antiretroviral therapy (ART) has
significantly reduced the risk of mortality and morbidity in
persons living with HIV (PLWH) since its introduction in
23. the mid-1990s [4–7]. However, the extensive use of ART
has given rise to serious and adverse side effects including
hyperlipidemia, insulin resistance, and lipodystrophy thus
increasing the risk for non-AIDS events such as cardio-
vascular disease and the development of metabolic syn-
drome (MetS) [8, 9]. The pathogenic mechanism for
metabolic changes secondary to combination ART have yet
to be fully elucidated, however, current investigations
indicate a greater risk of negative side effects are associ-
ated with use of drug combinations containing protease
& Stacy E. Cutrono
[email protected]
1
Department of Kinesiology and Sports Sciences, School of
Education and Human Development, University of Miami,
Coral Gables, FL, USA
2
Sylvester Comprehensive Cancer, University of Miami,
Miller School of Medicine, 1475 NW 12th Avenue, Suite
C-021, Miami, FL 33136, USA
24. 3
Department of Psychiatry & Behavioral Sciences, University
of Miami, Miller School of Medicine, Miami, FL, USA
123
AIDS Behav (2016) 20:1123–1131
DOI 10.1007/s10461-015-1245-1
http://crossmark.crossref.org/dialog/?doi=10.1007/s10461-015-
1245-1&domain=pdf
http://crossmark.crossref.org/dialog/?doi=10.1007/s10461-015-
1245-1&domain=pdf
inhibitors or nucleoside reverse transcriptase inhibitors
[10]. The risks associated with widespread and prolonged
use of ART may be managed through effective lifestyle
interventions incorporating exercise and weight
management.
Current research suggests that chronic inflammation
may be a critical component in the course of disease states.
The American Heart Association and the Centers for Dis-
ease Control and Prevention support the use of C-reactive
protein (CRP), an acute, non-specific inflammatory bio-
25. marker, as an independent predictor of increased coronary
risk and recommends using 3.0 mg/L as the minimum
threshold for high risk classification [11]. In healthy young
adults the median level of CRP is 0.8 mg/L [12]. However,
among PLWH, CRP levels are elevated [9, 13] with
reported ranges of 1.94–4.80 mg/L [14–16] and are asso-
ciated with opportunistic infections, progression to AIDS,
and mortality. Individuals enrolled in the Multicenter AIDS
Cohort Study with CRP levels B1.2 mg/L were found to
have a 47 % reduction in time to AIDS progression com-
pared to those with [2.3 mg/L [17]. Individuals in the
Strategies for Management of Anti-Retroviral Therapy trial
with CRP levels C5 mg/L had 7.6-fold higher odds of
developing an opportunistic infection than those with
CRP B 1.0 mg/L [18]. Thus, interventions that reduce
CRP levels may improve the cardiovascular risk profiles
and disease prognosis among PLWH.
The physiological and psychological benefits of regular
26. exercise are numerous and well established. The available
literature supports the therapeutic use of aerobic and
resistance exercise for improving health and fitness out-
comes among PLWH [19, 20]. For this reason, the Amer-
ican College of Sports Medicine (ACSM) recommends that
PLWH engage in a regular exercise program consisting of
aerobic exercise and resistance exercise on most days of
the week [21]. A reduction in systemic inflammation may
be one of the mechanisms driving the protective effects of
regular exercise for chronic disease risk [22], though the
specific mechanisms by which exercise training may
reduce systemic inflammation has not yet been established.
Recent research examining the effects of exercise inter-
ventions on circulating inflammatory biomarkers has pro-
duced inconsistent results. The third National Health and
Nutrition Examination Survey found that 21 % of seden-
tary individuals had elevated CRP levels compared to 13 %
of moderately active individuals [23]. Several other studies
27. have reported significant declines in CRP levels after aer-
obic exercise interventions among older individuals [24],
obese women [25] and breast cancer survivors [22]. Yet, a
recent meta-analysis of randomized controlled trials
reported a non-significant decrease in CRP levels among
subjects in aerobic exercise interventions [26]. The pro-
inflammatory changes secondary to treatment with ART
are accepted as a necessary risk in an effort to reduce
progression to AIDS and AIDS mortality, yet inflammatory
changes measured by elevated CRP increase the risk of
non-AIDS events, cardiovascular mortality, as well as
progression to AIDS. Interventions with potential to man-
age treatment side effects and reduce inflammation are
necessary among PLWH. The effect of exercise on CRP
levels has not been well examined among PLWH, how-
ever, given the severity of treatment side effects its
potential beneficial impact warrants further investigation.
The purpose of this study was to determine the effect of
28. combined aerobic and resistance exercise training
(CARET) on inflammation, metabolic risk profile, and
aerobic and muscular fitness among PLWH after 3 months
of training using data collected from the Healthy Living for
Better Days program. We hypothesized that 3 months of
CARET would significantly improve aerobic and muscular
fitness, and metabolic risk profile and to a lesser extent
systemic inflammation.
Methods
Study Design
The Healthy Living for Better Days was a 12-month,
community exercise program conducted by research staff
at the University of Miami to improve the health of low
SES individuals with HIV residing in Miami-Dade. This
study specifically analyzed baseline and 3-month data.
Program outcome variables measured at baseline and 3
months included: (1) physical characteristics (body weight,
body mass index, waist and hip circumferences, blood
29. pressure), (2) non-lipid blood markers (high sensitivity
CRP, fasting blood glucose, and insulin), (3) blood lipid
profile (total cholesterol, low-density lipoprotein choles-
terol, high-density lipoprotein cholesterol, and total
triglycerides), and (4) physical fitness variables (estimated
VO2max and one-repetition maximum for upper and lower
body strength).
Participants
Ninety male and female participants were enrolled in
Healthy Living for Better Days through referrals from the
Adult HIV clinic at the University of Miami/Jackson
Health System and other local HIV clinics. Program eli-
gibility criteria included: [1] confirmed HIV infection as
established by external laboratory reports, [2] men or
women C18 years of age, [3] currently receiving
antiretroviral treatment, and [4] ability to attend weekly
exercise sessions at the UHealth Fitness and Wellness
Center. Program exclusion criteria included any medical
30. 1124 AIDS Behav (2016) 20:1123–1131
123
condition or situation for which unsupervised exercise
would be contraindicated. The Institutional Review Board
of the University of Miami approved Healthy Living for
Better Days and all participants gave written informed
consent.
Exercise Program
All exercise sessions for Healthy Living for Better Days
were held at the UHealth Fitness and Wellness Center at
the University of Miami Medical campus. Each participant
was required to swipe an electronic badge to gain admit-
tance to the wellness center allowing attendance to be
recorded and tracked electronically. Participants were
encouraged to attend the supervised exercise sessions held
four times a week, but were also given open access to the
wellness center. Study personnel directed each supervised
31. session and were available to advise participants on their
exercise intensity and progression. Each supervised exer-
cise session was 40–60 min in length and consisted of at
least 30 min of aerobic exercise completed on a treadmill,
elliptical machine, or stationary bike and resistance exer-
cises completed on stacked weight machines (bench press,
shoulder press, biceps curl, triceps extension, leg extension,
leg curls, leg press, squat, lateral raises, lat pull downs,
back extension, and abdominal crunches). Aerobic exercise
was performed at 60–80 % of each individual’s age-pre-
dicted maximum heart rate (HRmax). The duration of
exercise sessions progressed from 40 to 60 min over the
first 2 weeks of the program. Two to four sets of 8 to 15
repetitions were performed for each upper and lower body
exercise.
Physical Characteristics
Research staff used standard techniques to obtain anthro-
pometric measurements. Weight and height were recorded
32. to the nearest 0.1 kg and 0.1 cm, respectively, to calculate
body mass index (BMI). Waist circumference was mea-
sured in inches at the narrowest portion between the lowest
rib and the iliac crest. Systolic blood pressure (SBP) and
diastolic blood pressure (DBP) were measured by use of
the automatic oscillometric device (Omron HEM-712CN2,
Omron Healthcare, Inc., Bannockburn, Illinois).
Blood Sampling and Analyses
Blood samples were drawn from participants in the
morning in a fasted condition and processed by the Dia-
betes Research Institute Clinical Laboratory. Chemistry
and immunoassays were performed by automated analyzer
(Roche Cobas-6000; Roche Diagnostics, Indianapolis, IN)
utilizing the manufacturer’s reagents and following the
manufacturer’s instructions. High sensitivity CRP (hsCRP)
was quantified in serum by a high sensitivity latex-particle
enhanced immunoturbidimetric assay with a detection limit
of 0.1 mg/L with an intra- and inter-assay coefficients of
33. variation (CV) of 1.1 and 2.2 %, respectively. Fasting
glucose (FG) was measured by the hexokinase method with
intra- and inter-assay CVs of 1.9 and 2.7 %, respectively.
Total cholesterol and triglycerides were determined in
serum or plasma by enzymatic, colorimetric assay with
intra- and inter-assay CVs are 0.7 and 1.8 %, respectively
for total cholesterol and 0.9 and 2.3 %, respectively for
triglycerides. High density lipoprotein cholesterol (HDL-
C) was measured using a third generation homogenous
enzymatic colorimetric assay with intra- and inter-assay
CVs of 0.6 and 1.9 %, respectively. Low density lipopro-
tein cholesterol (LDL-C) was calculated using the Friede-
wald equation.
Physical Fitness
Cardiorespiratory fitness was measured using a Rockport
One-Mile Fitness Walking Test [21], which has been val-
idated in healthy adults aged 30–69 years [27] and been
used in other clinical populations [28]. The test was
34. modified for use indoors with participants performing the
one-mile walk on a treadmill rather than on an outdoor
track. Participants were instructed to walk for one mile on
the treadmill as quickly as possible and were allowed to
modify speed at their discretion throughout the test. Heart
rate was measured for 10 s immediately upon completion
by palpating the radial artery. Age, gender, body weight,
and walk time were also recorded and used in a regression
equation to predict maximal oxygen consumption
(VO2max).
Muscular strength was measured using the ACSM pro-
tocol for one-repetition maximum (1-RM) testing [21].
Program participants completed a maximum of four trials
of 10, 8, 6, and 3 repetitions with rest periods between 2
and 4 min between trials. The initial weight was selected
within the subject’s perceived capacity (50–70 % of
capacity) and resistance was progressively increased until
the participants reached their maximum. The final maxi-
35. mum weight lifted successfully one time for bench press
and leg press was recorded as the 1-RM.
Metabolic syndrome was defined using ATPIII criteria
[29]. Three or more criteria had to be met to be classified as
having MetS: (1) high fasting serum triglycerides(C150 mg/
dL), (2) abnormal waist circumference ([102 cm for men
and[88 cm for women), (3) low HDL-C level (40 mg/dL
for men and50 mg/dL for women), (4) high blood pressure
(BP) (C130/85 mmHg), and (5) high FG level (C110 mg/
dL). Participants who self-reported being diagnosed with
diabetes or who were receiving treatment for diabetes were
AIDS Behav (2016) 20:1123–1131 1125
123
classified as having a high FG level. The same criteria were
used for high BP.
Statistical Analysis
Statistical analyses were performed with the Statistical
Package for Social Sciences (SPSS) version 22 for Win-
dows (IBM Inc., Chicago, IL, USA). Statistical analyses
36. included descriptive statistics and frequencies for each
variable. Linear Mixed Modeling (LMM) was used to
assess the fixed effect of time on changes in the outcome
variables (hsCRP, estimated VO2max, 1-RM bench press,
and 1-RM leg press) from baseline to 3-months follow
up. The significance level of all analyses was a 0.05.
LMM with heterogeneous compound symmetry covariance
allowed us to account for missing values, subject attrition,
inter-correlated responses between time points, and non-
constant variability. Changes in hsCRP from baseline to
3-months follow up were further examined controlling for
potential confounders, specifically body mass index, waist
circumference, aerobic fitness, and individuals with
hsCRP [ 3 mg/L classified as high risk at baseline. Paired
t tests were used to assess changes in metabolic risk factors
(BP, BMI, FG, HDL-C, LDL-C, waist circumference and
triglycerides) from baseline to 3-months follow up. Chi
square analysis was used to assess the change in MetS
prevalence from baseline to 3-months follow up.
37. Given that the exercise program consisted of four ses-
sions per week, participants were stratified into exercise
compliance groups based on average exercise sessions
attended as follows: (a) Non-compliant (average of 19/
week for 3 months), (b) Somewhat compliant (average
1–29/week for 3 months), and (c) Compliant (C29/week
for 3 months), where compliant individuals completed at
least 50 % of the prescribed exercise. Comparisons
between groups from baseline to 3 months were analyzed
using LMM for outcome variables.
Results
Demographic data are presented in Table 1. Ninety PLWH
were enrolled in Healthy Living for Better Days. The
majority of participants were women (53.9 %), Black/
African American (65.2 %), and unemployed or disabled at
the time of participation (83.1 %). Nearly one-third of
participants were classified as having MetS at baseline.
Fifty-five percent of total participants were non-compliant
38. (49/89), 20.2 % were somewhat compliant (18/89), and
24.7 % were compliant (22/89) with the prescribed exer-
cise. After 3 months participation in Healthy Living for
Better Days, nearly one-quarter (24.7 %) of our partici-
pants were meeting physical activity recommendations
defined as a combination of moderate- and vigorous-in-
tensity aerobic exercise at least 75 min/week and resistance
training twice per week.
The fixed effect of time for hsCRP was found to be non-
significant (F[1,57.3] = 1.7, p = 0.19) (Fig. 1). Mean
hsCRP at baseline was 5.75 ± 7.62 mg/L (median 2.30)
and 7.54 ± 14.19 mg/L (median 2.95) at 3-months follow
up. Comparing hsCRP across categories of exercise com-
pliance groups (see Fig. 1) revealed non-significant fixed
effects for time (F[1,55.5] = 2.4, p = 0.13), exercise
compliance (F[2,62.1] = 0.06, p = 0.94) and exercise
compliance 9 time (F[2,55.5] = 0.99, p = 0.38). When
examining the effect of the exercise intervention on
39. changes in hsCRP from baseline to 3-months follow up
only among individuals classified as high risk
(hsCRP [ 3 mg/dL) at baseline, the fixed effect for time
was still found to be non-significant (F[1,30.3] = 0.20
p = 0.657). Comparing hsCRP levels by gender group
revealed a significant fixed effect for gender
(F[1,68.6] = 4.08, p 0.05]), with women displaying an
overall higher mean hsCRP (8.50 ± 12.69 mg/L) than men
(4.46 ± 13.65 mg/L). The fixed effect for time
(F[1,57.4] = 1.75, p = 0.19]) and gender 9 time was non-
significant (F[1,57.4] = 0.06, p = 0.80]). The fixed effect
of time on changes in CRP from baseline to 3-months
follow up controlling for the use of protease inhibitors
(F[1,55.6] = 1.7, p = 0.200), BMI (F[1,53.2] = 1.7,
p = 0.199), aerobic fitness (F[1,50.1] = 1.1, p = 0.304),
and sleep duration (F[1,56.1] = 2.4, p = 0.129) was found
to be non-significant.
Changes in participant’s metabolic risk profile can be
found in Table 2. Diastolic BP (t(52) = 3.247, 95 % CI
40. 1.55–6.58, p = 0.002) and waist circumference
(t(58) = 2.268, 95 % CI 0.06–1.02, p = 0.027) signifi-
cantly decreased from baseline to 3 months. There were no
significant changes from baseline to 3 months for body
weight (t(58) = 0.405, 95 % CI -1.24 to 1.86, p = 0.687),
SBP (t(52) = 1.796, 95 % CI -0.41 to 7.31, p = 0.078),
BMI (t(58) = 0.196, 95 % CI -0.24 to 0.29, p = 0.845),
triglycerides (t(61) = 0.806, 95 % CI -9.69 to 22.79,
p = 0.423), total cholesterol (t(61) = 0.065, 95 % CI
-7.22 to 7.70, p = 0.948), HDL-C (t(61) = 1.875, 95 %
CI -0.17 to 5.37, p = 0.066), VLDL-C (t(61) = 0.845,
95 % CI -1.87 to 4.62, p = 0.401), LDL-C
(t(61) = -1.186, 95 % CI -10.01 to 2.55, p = 0.240), or
FG (t(61) = 1.226, 95 % CI -3.49 to 14.56, p = 0.225).
There was a non-significant decline in individuals with
MetS from baseline to 3 months (32 vs. 19 %, v2(1,
Nbaseline = 89, N3months = 63) = 3.43, p = 0.06).
The fixed effect of time for changes in VO2max was
found to be non-significant (F[1,36.3] = 3.5, p = 0.07)
41. (Table 3). For upper body 1-RM, a significant fixed
effect was found for time (F[1,51.6] = 18.1, p 0.05)
1126 AIDS Behav (2016) 20:1123–1131
123
and the parameter estimate between baseline and 3
months follow up was also significant (t[51.6] = -4.3,
p 0.05). Likewise, for lower body 1-RM a significant
fixed effect was found for time (F[1,48.0] = 15.7,
p 0.05) and the parameter estimate between baseline
and 3 month follow up was also significant
(t[48.0] = -4.0, p 0.05).
Discussion
Among our participants, changes in hsCRP were not
impacted by 3 months of CARET, even among individuals
with high hsCRP levels at baseline. The number of indi-
viduals classified as having MetS declined from baseline to
3-months, however these results were found to be non-
Table 1 Demographic and
42. baseline population
characteristics by gender
Overall (n = 89) Men (n = 41) Women (n = 48)
Age (years) 48 ± 7 48.7 ± 7 47.8 ± 7.6
Body mass index (kg/m
2
) 31.2 ± 7.8 28.7 ± 5.2 33.4 ± 8.9
Duration of HIV (years) 17.6 ± 12.7 15.3 ± 7.6 19.5 ± 15.7
Ethnic, n (%)
Non-Hispanic White 9 (10.1) 7 (17.1) 2 (4.2)
African-American 58 (65.2) 21 (51.2) 37 (77.1)
Hispanic 20 (22.5) 12 (29.3) 8 (16.7)
Current smoker, n (%) 32 (36.0) 16 (39.0) 16 (33.3)
Antiretroviral therapy, n (%)
Protease inhibitors 46 (51.7) 22 (53.7) 24 (50.0)
Non-protease inhibitors 36 (40.4) 16 (39.0) 20 (41.7)
Employment, n (%)
Unemployed 74 (83.1) 30 (73.2) 44 (91.7)
Employed (part or full time) 14 (15.7) 11 (26.8) 3 (6.3)
43. Yearly household income, n (%)
$5000 27 (30.3) 11 (26.8) 16 (33.3)
$5000–$14,999 38 (42.7) 20 (48.7) 18 (37.6)
$15,000–$39,999 12 (13.4) 6 (14.7) 6 (12.5)
Data are mean ± SD or n (%)
0
5
10
15
20
25
30
35
40
Baseline 3-Months
M
ea
n
CR
P
44. (m
g/
L)
Non-compliant Somewhat Compliant Compliant
Fig. 1 Changes in levels of
C-reactive protein across
exercise compliance groups.
Data are mean ± SD. Non-
compliant, average exercise
session of 19/week for
3 months; Somewhat
Compliant, average exercise
session of 1–29/week for
3 months; Compliant, average
exercise session of C29/week
for 3 months; hsCRP, high
sensitivity C-reactive protein
AIDS Behav (2016) 20:1123–1131 1127
123
45. significant. Participants did significantly increase muscular
strength of the upper and lower body and displayed a trend
for improved aerobic capacity.
Disappointingly, a majority of participants (55 %) were
not compliant with the prescribed exercise regime. Previ-
ous literature has documented barriers and challenges to
appointment adherence or research participation among
PLWH [31, 32]. Though few studies have specifically
assessed challenges to participating in exercise programs,
there have been reports of moderate withdrawals (range
3–44 %) and low compliance (range 24–82 %) in other
exercise interventions [19]. Macarthur et al. [33], reported
transportation and difficulty exercising as challenges to
completing exercise testing and training. Similarly, Neidig
et al. [34], reported changes in employment, unreliable
transportation, and family responsibilities as contributors to
withdrawal from an aerobic exercise trial. Nevertheless,
Healthy Living for Better Days was designed as a com-
46. munity-based exercise program in an effort to expand
access to a variety of participants. The program was well
received by most participants (data not reported); however,
the low compliance highlights the challenge of engaging
this population in exercise programs.
Mean levels of hsCRP were elevated at baseline
(5.75 ± 0.82 mg/L, Fig. 1) and 40 % of our participants
had hsCRP values that would be classified as high coronary
risk ([3 mg/L) under AHA and CDC guidelines [11].
Median levels of hsCRP at baseline and 3-months follow
up were greater than values previously reported in the lit-
erature among PLWH (1.20–2.83 mg/L) [14, 17]. Elevated
CRP has been associated with metabolic risk factors such
as obesity, hypertension, and dyslipidemia [35]. Among
our participants BMI and waist circumference were ele-
vated at baseline and additionally a few of our participants
displayed very high CRP values perhaps reflective of the
disease course of the HIV infection. Thus, it is possible that
47. our cohort had more severe inflammation than the general
population of PLWH. Women in our sample were found to
have significantly higher hsCRP levels than men. This is
consistent with data from the third National Health and
Nutrition Examination Survey that found that the odds of
having elevated CRP levels is twofold higher among
women than men [35].
Participants showed a trend for an increase in VO2max of
2.2 mL/kg/min with 3 months of training (Table 3).
Although this trend was not significant, our results were
consistent with previously reported changes in VO2max
(range ?2.6 to ?4.7 mL/kg/min) after 3 months of training
among PLWH [8, 36]. Exercise adherence did not appear
to be a contributing factor as even the compliant cohort of
subjects showed no significant improvement in hsCRP. In
contrast to our 3-month program consisting of CARET,
Lindegaard et al. [37] found that hsCRP levels declined in
a small sample (n = 18) of HIV-positive men who per-
formed 35 min of endurance training 39/week for
48. 16 weeks (baseline hsCRP, 2.42 mg/L [1.01–5.80],
16-week hsCRP, 1.82 mg/L [0.76–4.36]; p 0.0001).
However, the effect of exercise on inflammatory
biomarkers was not the primary variable studied by Lin-
degaard et al. [37]. Nonetheless, we cannot rule out the
possibility that a longer intervention or higher sustained
intensity of aerobic exercise is needed to impact systemic
inflammation.
Table 2 Changes in metabolic risk profile after 3-months of
CARET
Baseline 3 months p value
Total body weight (lbs) 191.9 ± 46.5 191.6 ± 46.6 0.687
Systolic BP (mmHg) 127 ± 12 124 ± 11 0.078
Diastolic BP (mmHg) 82 ± 9 78 ± 8 0.002*
Body mass index (kg/m
2
) 30.7 ± 7.4 30.7 ± 7.4 0.845
Waist circumference (inch) 41.2 ± 7.0 40.7 ± 7.4 0.027*
Total triglycerides (mg/dL) 125.4 ± 72.6 118.8 ± 55.7 0.423
Total cholesterol (mg/dL) 186.7 ± 35.0 186.5 ± 42.0 0.948
49. HDL cholesterol (mg/dL) 52.3 ± 16.1 49.7 ± 13.7 0.066
VLDL cholesterol (mg/dL) 25.1 ± 14.5 23.7.1 ± 11.2 0.401
LDL cholesterol (mg/dL) 109.4 ± 30.2 113.1 ± 38.1 0.240
Fasting glucose (mg/dL) 95.7 ± 35.1 90.2 ± 16.5 0.225
Data are mean ± SD
CARET combined aerobic and resistance exercise training, BP
blood
pressure, VLDL very low density lipoprotein, LDL low density
lipoprotein, HDL high density lipoprotein
* Significant difference from baseline to 3 months (p 0.05,
paired
t test)
Table 3 Changes in
cardiorespiratory fitness and
muscular strength
Baseline 3 months Statistic
VO2max (mL/kg/min) 27.2 ± 8.9 29.4 ± 10.0 F[1,36.3] = 3.5, p
= 0.07
Upper body 1-RM (lbs) 114 ± 51 125 ± 46 F[1,51.6] = 18.1, *p
0.001
Lower body 1-RM (lbs) 225 ± 81 250 ± 96 F[1,48.0] = 15.7, *p
0.001
50. Data are mean ± SD
VO2max maximal volume of oxygen consumed, 1-RM one-
repetition maximum
* Significant fixed effect on time (p 0.05)
1128 AIDS Behav (2016) 20:1123–1131
123
Participants significantly increased both upper and lower
body strength after 3 months of CARET as has been shown
in other studies that involved resistance training among
PLWH [20, 38, 39]. The improvements in strength in our
study, however, were not associated with a significant
improvement in hsCRP levels from baseline to the 3-month
follow up (Fig. 1). Likewise, Lindegaard et al., [37] found
that despite a 30 % improvement in strength after
16 weeks of resistance training, there was no significant
change in CRP levels (baseline CRP: 1.54 mg/L
[1.0–2.37], 16-week CRP: 1.65 mg/L [1.07–2.54];
51. p = 0.44) among HIV-positive men. Similarly, among
older adults assigned to 10-months of strength and flexi-
bility training serum CRP levels were not improved com-
pared to those in an aerobic exercise arm [24]. These
results may indicate that aerobic exercise rather than
resistance training may be the primary mode of exercise by
which systemic inflammation is impacted.
It has been suggested that reduction in systemic
inflammation may be the mechanism driving the pro-
tective effects of regular physical activity and exercise
for chronic disease risk [22]. Yet, a meta-analysis by
Kelley et al., [26] of randomized controlled trials among
adult subjects reported a non-significant 3 % decrease in
CRP levels in aerobic exercise interventions ranging
from 8 weeks to 6 years. On the other hand, CRP levels
were reported to significantly decline in aerobic exercise
trials among older adults [24] and postmenopausal obese
women [25] after 10- and 12-months of training,
52. respectively. Thus, greater gains in aerobic fitness as
measured by VO2max may be necessary to affect hsCRP
levels in PLWH. Future studies examining the role of
exercise interventions on systemic inflammation should
incorporate randomization to an aerobic-only comparison
arm.
The presence of one or more cardiovascular risk fac-
tors, specifically those which contribute to the classifica-
tion of MetS, are associated with a pro-inflammatory
state. Data from the third National Health and Nutrition
Examination Survey indicated that the presence of at least
one abnormal cardiovascular risk factor was associated
with a threefold higher prevalence of elevated CRP [35].
Among PLWH …
BRIEF REPORT
Exercise and Fitness Modulate Cognitive Function in Older
Adults
Chien-Heng Chu
53. National Taiwan Sport University
Ai-Guo Chen
Yangzhou University
Tsung-Min Hung
National Taiwan Normal University
Chun-Chih Wang and Yu-Kai Chang
National Taiwan Sport University
This study investigated the effects of acute exercise on
cognitive function and the modulatory role of
fitness in the relationship between exercise and cognition.
Forty-six healthy older adults, categorized into
higher or lower fitness groups, completed the Stroop test after
both 30 min of aerobic exercise and a
reading control with a counterbalanced order. Our findings
demonstrated that acute exercise leads to
general improvements in 2 types of cognitive functions and to
specific improvements in executive
function. Additionally, older adults with initially higher fitness
levels experienced greater beneficial
effects from acute exercise.
Keywords: aerobic exercise, cognition, executive function,
inhibition, Stroop test
The population over 60 years old has rapidly grown and
changed the worldwide demographic landscape (Gorman, 2002).
This aging population not only experiences the deterioration of
physical functions but also suffers from declining brain and
cog-
nitive functions. Indeed, normal aging is associated with brain
volume atrophy of approximately 15% to 25% (Jernigan et al.,
2001) and with it the degradation of cognitive processes,
54. including
memory, reasoning, and information processing speed
(Salthouse,
2004). The influence of acute exercise, defined as a single bout
of
exercise, on cognitive performance has received substantial
atten-
tion within younger populations, demonstrating positive
changes
with small to moderate effects on various types of cognitive
performance (Chang & Etnier, 2015; Chang, Labban, Gapin, &
Etnier, 2012; Chu, Alderman, Wei, & Chang, 2015; Lambourne
&
Tomporowski, 2010; McMorris, Sproule, Turner, & Hale, 2011).
However, examination of whether the positive effects of acute
exercise extend to older adults has been limited, with
ambiguous
findings.
Pesce and Audiffren (2011) found that switch performance
improved following acute exercise at moderate intensity in both
younger and older adult groups. Given that switching is one of
the
primary executive function aspects, these results suggested that
the
beneficial effects of acute exercise could extend to higher order
cognitive function, regardless of age. In contrast, research that
used a similar paradigm (i.e., Alternate Uses test) found
partially
conflicting findings wherein the positive effects of acute
exercise
in older adults only partially benefited switching (Netz, Tomer,
Axelrad, Argov, & Inbar, 2007). Another study found changes
in
only basic cognition levels in older adults following acute
55. exercise
(i.e., Stroop color condition) and failed to demonstrate an effect
on
the inhibition- and interference-related executive function
aspects
(i.e., Stroop inhibition and interference conditions; Barella,
Etnier,
& Chang, 2010). Notably, these studies measured different
cogni-
tive functions, implying that the cognition type plays a
moderating
role in the relationship between acute exercise and cognition.
Indeed, Etnier and Chang (2009) proposed that acute exercise
effects might differ depending on the specific type of cognitive
function and further studies are required that utilize assessments
that not only are widely used but also posit multiple cognition
subtypes with similar features, such as the Stroop test.
Therefore,
future research should examine the effects of acute exercise on
different cognitive functions derived from similar task
character-
istics to explore these relationships.
Another potential moderator that must be considered is the
participant’s cardiovascular fitness status (Brisswalter,
Collardeau,
& René, 2002; Chang et al., 2012). Longitudinal studies have
indicated that, along with the positive association between
cardio-
vascular fitness and cognitive function (Etgen et al., 2010),
exer-
Chien-Heng Chu, Graduate Institute of Athletics and Coaching
Science,
National Taiwan Sport University, Taoyuan, Taiwan, Republic
of China;
56. Ai-Guo Chen, College of Physical Education, Yangzhou
University, Ji-
angsu, People’s Republic of China; Tsung-Min Hung,
Department of
Physical Education, National Taiwan Normal University,
Taipei, Taiwan,
Republic of China; Chun-Chih Wang and Yu-Kai Chang,
Graduate Insti-
tute of Athletics and Coaching Science, National Taiwan Sport
University.
This research was supported by a portion of Grants NSC 101-
2628-H-
179-002 and NSC 102-2420-H-179-001-MY3 from the Ministry
of Sci-
ence and Technology, Taiwan, to Yu-Kai Chang.
Correspondence concerning this article should be addressed to
Yu-
Kai Chang, Graduate Institute of Athletics and Coaching
Science,
National Taiwan Sport University, No. 250, Wenhua 1st Road,
Guishan
Township, Taoyuan County 333, Taiwan, Republic of China. E-
mail:
[email protected]
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62. attentional tasks involving executive control compared with a
sedentary group during an acute bout of aerobic exercise.
Similar
fitness-moderated effects of acute exercise on cognitive
flexibility
were observed (Netz, Argov, & Inbar, 2009). However, these
studies focused on highly trained individuals and cognitive per-
formance assessed during acute exercise or utilized assessments
that examined a single construct.
Whether the effects of acute exercise have general or specific
effects on the different cognition types and whether fitness
status
moderates the magnitude of favorable acute exercise effects on
these cognitive performances, particularly in older adults,
remain
undetermined. The present study examined the effects of acute
exercise on two types of cognitive processes derived from the
Stroop test (i.e., Stroop congruent and incongruent conditions),
where the Stroop incongruent condition is believed to engage a
greater amount of executive control than does the Stroop
congru-
ent condition, which reflects more-basic information processing
(e.g., perceptual-motor level; Liotti, Woldorff, Perez, &
Mayberg,
2000; Miyake et al., 2000; West & Alain, 1999). Additionally,
the
acute effects on these cognitive functions were compared
between
older adults with higher and lower fitness levels to explore the
modulatory role of fitness. Acute effects were expected to
induce
favorable effects on multiple cognition types, and older adults
with
higher fitness were expected to receive larger acute exercise
ben-
63. efits than were older adults with lower fitness.
Method
Participants
Seventy healthy older adults, ages 60 to 70 years, were
initially recruited in Taoyuan County, Taiwan. The participants
were screened using physical activity readiness and health
screening questionnaires and were required to meet the follow-
ing criteria: (a) right-hand dominant, (b) no history of neuro-
logical or major psychiatric disorders, (c) normal or corrected-
to-normal vision, and (d) no color-blindness to minimize the
confounders between acute exercise and cognition. Eligible
participants completed the Digit Span test (Wechsler, 1997).
Then, the participants were categorized into a higher or a lower
fitness group on the basis of a VO2peak that fell above or below
the 55th percentile (�35.0 ml/kg/min for men and �29.4 ml/
kg/min for women; American College of Sports Medicine,
2013), resulting in 46 participants, with 22 in the higher fitness
group and 24 in the lower fitness group. This study was ap-
proved by the university Institutional Review Board, and all
participants provided informed consent.
Cardiovascular Fitness Test
Cardiovascular fitness was assessed via a submaximal exercise
test according to the YMCA cycle ergometry protocol (Golding,
1989). The protocol was appropriate for adults with a Class A
risk
stratification (Fletcher et al., 2001). The YMCA protocol
includes
two to four consecutive 3-min circuits, which have specific
work-
loads designed to raise the steady-state heart rate between 110
64. beats/min and 85% of the age-predicted maximal heart rate
(e.g.,
220-age). To begin, the participant rode a cycle ergometer (Er-
goselect 100/200, Ergoline GmbH, Germany) with a workload
of
150 kpm/min (25 W) and a 50-rpm pedaling rate. The average
heart rate during the last 15–30 s of the final second and third
minutes determined the subsequent workloads (e.g., 750
kpm/min,
600 kpm/min, or 300 kpm/min). When the target steady-state
heart
rate was observed for two consecutive circuits, the VO2peak
was
calculated on the basis of the slope regarding heart rates,
workload,
and body mass.
The Stroop test
The Stroop test (Stroop, 1935) is a widely used neuropsycho-
logical assessment recommended for adaptation in exercise–
cognition research. The computerized Stroop test consists of
two
types of conditions— congruent and incongruent—and was pre-
sented using Stim2 (Neurosoft Labs, Inc., Sterling, VA). In the
congruent condition, Chinese words (i.e., 紅 [red], 藍 [blue], and
綠 [green]) were presented in the same color as the meaning of
the
words. In the incongruent condition, the name of the color word
was printed in a different font color. Each stimulus word was
presented in equal proportions in the congruent (i.e., 33.3%
each
for red, blue, and green words) and incongruent (e.g., the word
“red” printed in either blue or green color) conditions to
minimize
specific word facilitation. Each block had 60 target stimuli con-
65. sisting of 38 congruent and 22 incongruent stimuli with mixed
presentation. Each 2-cm stimulus was displayed in the center of
a
21-in. (53.3 cm) computer screen. Each trial began with the pre-
sentation of a fixed cross for 500 ms. Then, either a target-
congruent or -incongruent stimulus was presented for 506 ms;
the
interval between the fixed cross and the target stimulus was
383,
583, or 783 ms in a random order to minimize anticipation.
Participants were instructed to respond as quickly and
accurately
as possible to the color of the presented stimulus by pressing
their
thumb on one of three buttons on a response pane. Each trial
was
completed once the target stimulus response was made within
1,000 ms. Response time and accuracy were identified as
primary
indices. Each participant was required to complete six blocks
with
a 2-min rest between each block, resulting in a total testing
period
of approximately 25 min.
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Experimental Procedures
The participants attended the laboratory individually on three
separate days, with at least a 3-day interval between each day
and within a 2-week period. On Day 1, participants meeting the
inclusion criteria were fit with a Polar HR monitor (Sport Tester
PE 3000, Kempele, Finland) and completed a submaximal
exercise test with a YMCA cycle ergometry protocol. The
participants were then assigned to either the high- or low-
fitness
group on the basis of their VO2peak (categorized as good or
poor, respectively).
The experimental conditions for Days 2 and 3 (i.e., exercise
and control days) were performed in a counterbalanced order to
control for potential practice and order effects. Each participant
was tested at a similar time of day on the 2 days to control
confounding due to time of testing (Hasher, Chung, May, &
Foong, 2002). On the exercise day, the resting heart rate (HR)
was measured by having the participants sit quietly in a chair
for 10 –15 min. Then, participants completed practice trials to
become familiarized with the test procedure; once an 85%
correct rate was achieved, they started the experimental trials.
Next, participants were instructed to complete a modified acute
cycling ergometer protocol on the basis of Chang et al. (2011).
The protocol consisted of three stages: a 5-min warm-up, a
20-min primary exercising stage at 65% heart rate reserve
(HRR; the difference between maximal and resting heart rates),
and a 5-min cool-down. The peddling rate was set at 70 rpm,
and the workload began with 15 W and then increased or
decreased gradually until a steady state at the required HR was
71. reached. The participants performed the Stroop test within 5
min of exercise cessation. On the control day, participants
completed procedures similar to those on the exercise day,
except that participants read a book related to exercise and
cognition during treatment. The control condition was intended
to maintain a low arousal level compared to the exercise con-
dition.
A Polar HR monitor and the Rating of Perceived Exertion (RPE)
scale (Borg, 1982) were used to objectively and subjectively
confirm the intensity manipulation, respectively. The RPE scale
ranges from 6 (no exertion at all) to 20 (maximum exertion).
The
experimental session lasted approximately one and a half hours
each day. Participants were informed about the purpose of the
study and compensated with US$15 after completing the overall
experimental session.
Statistical Analyses
This study was a randomized control group posttest design. A
mixed three-way analysis of variance (ANOVA), with a
between-
subjects (i.e., group: lower vs. higher fitness) and two within-
subject (i.e., treatment: control vs. exercise; Stroop condition:
congruent vs. incongruent) were used to analyze response time
and
accuracy. Multiple comparisons were performed using t tests
with
Bonferroni adjustments when appropriate. The effect size of the
partial eta-square was reported for significant effects derived
from
the ANOVA. An alpha of 0.05 was set as significant for all
analyses.
Results
72. Participant Characteristics and Exercise
Intensity Check
Higher scores in the higher fitness group were observed for only
fitness-related variables (see Table 1). The HR values (beats per
minute [bpm]) for the lower and higher fitness groups during
the
primary exercise were 124.8 � 7.2 bpm and 119.5 � 8.8 bpm,
respectively, representing 60% to 65% of HRR. Along with the
RPE range of 12 to 14, these values suggest that the exercise
intensity was appropriate.
Stroop Test Performances
A preliminary analysis was conducted to test the effects of
session order. Neither a main effect of session order nor any
interaction with session order was observed for any dependent
variable, Fs(1, 21) � 1.81, p � .19.
A main effect of the treatment condition revealed a shorter
response time for the exercise compared with that for the
control
condition, F(1, 44) � 169.75, p � .001, partial �2 � 0.79, and a
main effect of the Stroop condition revealed a longer response
time
for the incongruent compared with the congruent condition,(F(1,
44) � 123.91, p � .001, partial �2 � 0.73 (see Table 2).
An interaction between the treatment and fitness was observed,
F(1, 44) � 10.17, p � .03, partial �2 � 0.18. The follow-up
comparisons revealed that the exercise condition had a shorter
response time compared to that of the control condition in both
the
higher (p � .001) and lower (p � .001) fitness groups.
Addition-
73. ally, the higher fitness group demonstrated a shorter response
time
relative to the lower fitness group in the exercise condition (p �
.04) but not the control condition (see Figure 1a).
An interaction between treatment and Stroop condition was also
observed, F(1, 44) � 10.17, p � .001, partial �2 � 0.24. The
follow-up comparisons revealed that the response time for the
incongruent condition was longer than that for the congruent
condition in both the exercise (632 � 102 vs. 587 � 83, respec-
tively, p � .001) and control (695 � 99 vs. 632 � 82,
respectively,
Table 1
Participant Demographics for the Higher and Lower
Fitness Groups
Variable
Higher
fitnessa
Lower
fitnessb
p ESM SD M SD
Age (years) 63.8 2.3 64.9 4.0 .29
Education (years) 9.3 3.5 10.0 4.1 .57
Height (cm) 161.7 8.6 158.2 6.7 .13
Weight (kg) 63.8 8.6 61.8 9.4 .45
BMI (kg.m�2) 24.2 2.5 24.3 3.1 .95
Digit Span Forward 11.5 2.4 11.2 2.5 .69
Digit Span Backward 6.0 2.4 6.7 2.4 .32
VO2peak (mL.kg
74. �1.min�1) 36.0 1.2 23.5 2.8 .01 5.80�
Resting heart rate (bpm) 65.5 8.7 70.0 6.6 .05 0.58�
Note. ES � effect size with the value of Cohen’s d; BMI �
body mass
index; bpm � beats per minute.
a Sample size � 22 (12 female). b Sample size � 24 (10
female).
� p � .05.
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844 CHU, CHEN, HUNG, WANG, AND CHANG
p � .001) conditions. The exercise condition resulted in shorter
response times compared to those for the control condition with
both the congruent and incongruent conditions (p � .001). An
additional paired t test revealed a smaller difference between
the
congruent and incongruent conditions in the exercise condition
relative to the control condition, t(45) � 3.83, p � .001 (see
Figure
1b). No three-way interaction was observed.
79. Regarding accuracy, main effects of treatment and Stroop con-
dition were revealed. Higher accuracy for the exercise condition
compared to the control condition, F(1, 44) � 5.12, p � .03,
partial �2 � 0.11, and lower accuracy for the incongruent
condi-
tion compared to the congruent condition, F � 28.23, p � .001,
partial �2 � 0.41, were observed. Neither the main effect of
fitness
nor any interaction was significant.
Discussion
This study investigated how cardiovascular fitness moderates
two types of cognitive function assessed by the Stroop test, fol-
lowing an acute bout of moderate aerobic exercise in an older
population. Although participants had a shorter response time
and
an increased accuracy rate in both conditions of the Stroop test
following exercise, reflecting general improvements, acute
exer-
cise led to additional benefits for executive function by demon-
strating a smaller difference between the congruent and
incongru-
ent conditions after acute exercise compared to results for the
control condition. Moreover, older adults with a higher fitness
level performed significantly better following acute exercise
than
did those with a lower fitness level, suggesting that the level of
fitness modulates the relationship between acute exercise and
cognition. Thus, older adults with a higher fitness level
received
disproportionally more benefits from acute exercise than did
those
with a lower fitness level.
80. The longer response time and lower accuracy rate in the Stroop
incongruent condition relative to the Stroop congruent
condition,
regardless of treatment conditions, demonstrate the typical
Stroop
effect (Cohen, Dunbar, & McClelland, 1990). Specifically, com-
pared with the congruent condition, in which colors of the char-
acters were named in the absence of interference (i.e.,
presenting
automatic activation), greater attentional demand was required
to
resolve the conflicts between the stimulus meaning and color in
the
incongruent condition to inhibit the automatic nature of word-
reading tendency (Cohen et al., 1990; Milham et al., 2002). Fur-
thermore, the initiating response to inhibit the bias toward word
reading is also believed to reflect an inhibitory aspect of
executive
function (Bugg, Jacoby, & Toth, 2008; Nigg, 2000).
Acute exercise not only reduced the response times for both
Stroop test conditions but also diminished the interference, sug-
gesting that acute exercise led to both general and specific im-
provements in cognitive functions. Our findings that these im-
provements are associated with acute exercise agree with the
findings of many previous studies and confirm that an acute
bout
of moderate exercise increases cognitive performance requiring
different amounts of executive control (Chang, Tsai, Huang,
Wang, & Chu, 2014; Hyodo et al., 2012; Sibley, Etnier, & Le
Masurier, 2006; Tam, 2013; Yanagisawa et al., 2010). For
exam-
ple, Tam (2013) reported that, compared with a response time
reduction of 10.2% in the congruent condition, a 20.6%
reduction
was found in the incongruent condition after acute exercise.
81. Chang, Tsai, et al. (2014) also reported that acute exercise im-
proved performances in five conditions of the Stroop test (i.e.,
Stroop congruent, word, neutral, square, and incongruent), in
which the largest increase was observed in the incongruent con-
dition.
Table 2
Stroop Test Performances of Fitness Groups and
Treatment Conditions
Variable
Higher fitness Lower fitness
Control Exercise Control Exercise
M SD M SD M SD M SD
Response time (ms)
Congruent 622 67 567 61 642 96 608 99
Incongruent 679 86 602 83 711 109 664 110
Accuracy rate (%)
Congruent 92 7 94 5 94 7 95 7
Incongruent 80 15 84 21 86 9 93 6
Figure 1. (a) The response time of the Stroop test is a function
of treatment condition and fitness. (b) Stroop
differences during the congruent and incongruent conditions
between the exercise and control conditions. Error
bars represent standard error of the means. � Represents a
significant difference between treatments. # Represents
a significant difference between fitness group (p � .05).
T
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845ACUTE EXERCISE, FITNESS, COGNITION, OLDER
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General improvement may be attributed to exercise-induced
increases in cerebral blood flow (Heo et al., 2010; Ide &
Secher,
2000). That is, brain neuronal activity and metabolism increase
during exercise (Ide & Secher, 2000), resulting in elevated
cerebral
blood flow (Ogoh & Ainslie, 2009). In contrast, specific
improve-
ments may be interpreted by neuroelectric studies. Acute
exercise
enlarges the P3 amplitude only in tasks reflecting executive
func-
tion (Chu et al., 2015; Hillman, Snook, & Jerome, 2003;
Kamijo,
Nishihira, Higashiura, & Kuroiwa, 2007). These findings from
neuroelectric perspectives suggest that acute exercise may
benefit
cognition through increased attentional resource allocation for
tasks requiring greater executive control processes. Taken to-
gether, increased cerebral blood flow and attention alterations
suggest possible general and specific functional roles in
exercise-
87. induced cognitive enhancement.
Another novel finding from the current study was an interaction
between treatment and fitness level, namely, the more-fit older
adults had superior improvements in the Stroop test than did
their
less-fit counterparts. This finding is consistent with a previous
meta-analysis (Chang et al., 2012) and extends the current
knowl-
edge regarding older adults with extreme higher fitness status
(e.g.,
highly trained) to those with moderate to high fitness status
(Netz
et al., 2009; Pesce & Audiffren, 2011). Although the underlying
mechanisms remain unknown, potential interpretations based on
studies indirectly examining this issue have been proposed.
Older
adults with higher fitness may maintain better brain structures
and
functions, providing the foundation for superior benefits from
acute exercise. Studies associated with structural and functional
magnetic resonance imaging (MRI) have indicated that older
adults with higher fitness or long-term exercise training demon-
strate larger volumes of several brain regions that are the core
of
cognitive functions, such as white and gray matter in the ventro-
lateral and dorsolateral prefrontal cortexes (Colcombe et al.,
2003)
and the hippocampus (Erickson et al., 2009), as well as greater
activations in similar brain regions during cognitive task perfor-
mance (Colcombe et al., 2004). Using an electroencephalogram,
Hogan et al. (2013) found that adolescents with high fitness
levels
experienced greater lower upper alpha and beta coherence after
acute exercise, whereas no beneficial acute effect was observed
for
88. those with lower fitness levels, implying that the individuals
with
higher fitness posited better cortical efficiency.
The present study was restricted by several factors. First, a
causal relationship between fitness and cognitive performance
could not be established because of the cross-sectional design.
Additionally, the Stroop test reflected only the interference
aspect
of inhibition rather than inhibition related to motor suppression
(Aron et al., 2007). Therefore, caution should be taken with the
generalization of the results. Moreover, Boot, Simons, Stothart,
and Stutts (2013) indicated that different expectancy track
benefit
performances were observed when conducting computer-based
games, reflecting that the treatment effect may be confounded
by
expectancy individual posited. Expectancy has yet to be consid-
ered in acute exercise– cognition studies, and future research
that
considers this confounder is suggested. The disproportionate
num-
ber of congruent and incongruent trials may also lead to
potential
bias regarding inhibitory processes. Specifically, more
incongruent
trials than congruent trials may increase the Stroop effect. Al-
though such bias was limited in the present study because the
number of trials was constant across groups and conditions, the
percentage of each trial type is worth considering in future
study
designs.
In conclusion, acute exercise leads to general and specific im-
provements for two types of cognitive functions derived from
89. the
Stroop test, and the beneficial effects of acute exercise are
greater
for older adults with higher fitness. These findings are
important
for older adults and suggest that performing a single bout of
exercise can improve cognitive performance. These results also
indicate that good fitness levels can maximize these beneficial
cognitive effects (i.e., processing speed of cognitive
performance)
induced by acute exercise.
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http://dx.doi.org/10.1523/JNEUROSCI
91. University of Illinois at Urbana-Champaign
Physical inactivity has been shown to increase the risk for
several chronic diseases across the lifespan. How-
ever, the impact of physical activity and aerobic fitness on
childhood cognitive and brain health has only
recently gained attention. The purposes of this article are to: 1)
highlight the recent emphasis for increasing
physical activity and aerobic fitness in children’s lives for
cognitive and brain health; 2) present aspects of
brain development and cognitive function that are susceptible to
physical activity intervention; 3) review neu-
roimaging studies examining the cross-sectional and
experimental relationships between aerobic fitness and
executive control function; and 4) make recommendations for
future research. Given that the human brain is
not fully developed until the third decade of life,
preadolescence is characterized by changes in brain structure
and function underlying aspects of cognition including
executive control and relational memory. Achieving
adequate physical activity and maintaining aerobic fitness in
childhood may be a critical guideline to follow
for physical as well as cognitive and brain health.
Keywords: executive function, relational memory, pediatrics
Regular physical activity has been shown to be pro-
tective against the development of several diseases includ-
ing obesity, cardiovascular disease, certain cancers, and
Type II diabetes (73). Given that these diseases have also
been associated with reduced cognitive and brain health
among older adults (21,35), physical activity is suggested
to indirectly improve cognition and brain health by
attenuating the risk for disease. However, research from
rodent models demonstrates that physical activity is a
potent stimulator of processes underlying neurogenesis,
92. synaptogenesis, as well as brain vasculature (53,72). In
addition, physical activity training has been shown to
counter age-related hippocampal tissue loss and improve
spatial memory function among older adults (31). Taken
together, the findings from both rodent and older human
studies suggest that physical activity may indirectly or
directly modulate cognitive function and brain health.
Converging lines of research indicate that regular
physical activity and enhanced aerobic fitness may
improve cognitive function and brain health in childhood
as well. Higher-fit preadolescent children exhibit greater
attention (42), faster information processing speed (43),
and achieve higher scores on standardized achievement
tests (11,27), relative to their lower-fit counterparts.
These benefits were highlighted by a recent Institute
of Medicine (48) committee charged with examining
the status of physical activity and physical education in
schools, how physical activity and fitness affect health
outcomes, and ways to help schools get students to
become more active. While acknowledging the fiscal and
policy challenges involved, the final committee report
recognized that attaining over 60 min of moderate to
vigorous physical activity (MVPA) during the school
day is necessary for optimal learning in the classroom.
To represent the full scope of the positive contribution of
regular physical activity to overall health and function,
a team of kinesiologists validated the Human Capital
Model (HCM) of physical activity (3). The HCM is sup-
ported by a growing community of public, private, and
civil sector organizations. It considers physical activity
an investment and consolidates the evidence for physi-
cal activity benefits into six domains including physical,
emotional, individual, social, intellectual, and financial.
Taken together, the Institute of Medicine report and the
93. HCM place an emphasis on childhood health and provide
a platform for implementing physical education and other
physical activity opportunities in schools along with
a holistic conceptual model that incorporates physical
activity benefits for cognitive function and brain health.
However, much remains to be learned regarding
the influence of physical activity on specific cognitive
processes and their neural substrates. Knowledge from
the developmental literature is largely based on observa-
tional/cross-sectional studies. Thus, information on the
Official Journal of NASPEM and the
European Group of PWP
www.PES-Journal.com
REVIEWS
Brain and Cognition 139
efficacy of improving physical activity and/or aerobic
fitness for cognitive function and brain health in child-
hood remains limited. It is of particular importance to
examine how the protracted development of specific
brain structures provides opportunities for environmental
modulation by health behaviors including physical activ-
ity. Keeping this in mind, our laboratory and colleagues
have focused efforts on examining physical activity
effects on the cognitive processes of executive control
and relational/associative memory because the key neural
structures subserving these processes—the prefrontal
cortex and hippocampus—continue to develop through-
out childhood. Furthermore, these cognitive processes
and their neural substrates provide the foundation for
94. successful learning and scholastic achievement, thereby
influencing overall health and well-being throughout life.
In this article, we review the brain developmental
trajectory and evaluate observational and intervention
studies examining relationships between physical activity
and fitness with cognitive performance and brain health
in childhood.
Brain Development
The human brain undergoes a fourfold increase in volume
from birth to adolescence resulting in an adult brain that
is highly structured and functionally specialized (49).
Gestation represents a period of rapid brain development
involving several synchronized processes including neu-
rogenesis, migration, programmed cell death, myelina-
tion, and synaptogenesis (56). In addition, sulci and gyri
formation is nearly complete by birth (57) and by 2 years
the brain achieves 80% of its adult weight (25).
Despite the fact that the brain achieves 95% of its
maximum size by 6 years, the processes underlying
functional connectivity—including competitive elimina-
tion of synapses, myelination, and dendritic and axonal
arborization—continues throughout life (56). The early
rapid increase in synaptic density is followed by a period
during which synaptic connections that are not used are
eliminated or pruned (58). This elimination increases both
computational capacity and speed of information process-
ing and serves as a functional mechanism for plasticity,
which supports the hypothesis that the immature brain is
sculpted to fit the individual’s environment (2). Further,
synaptic pruning occurs at varying velocities in different
parts of the brain with sensory regions—such as the visual
cortex—achieving maturity by 7 years while the middle
frontal gyrus—a region involved in executive function—
95. not maturing until 20 years (47). One of the implications
of this hierarchical growth model is that development of
executive control—which consists of inhibition (resisting
distractions or habits to maintain focus), working memory
(mentally holding and manipulating information), and
cognitive flexibility (multitasking)—is guided by the late
maturation of the prefrontal cortex (10). Furthermore,
protracted myelination throughout the cortices supports
the position that childhood and adolescence are periods
of modification in connectivity between distant brain
circuitries as well as prefrontal specialization (38).
In addition to modifications in connectivity, different
regions of the cortices display varying growth trajecto-
ries. Gray matter volume, which consists of neuronal
cell bodies, dendrites, and unmyelinated axons, peaks
between 10 and 12 years in the frontal and parietal lobes
while temporal lobe gray matter volume does not peak
until 16–17 years of age (37). Indeed, the dorsolateral
prefrontal cortex—a cortical area subserving control of
impulses, judgment, and decision-making—reaches adult
levels of cortical thickness last (56).
The relatively delayed rate of maturation of the
human brain, compared with other mammals, may pro-
vide opportunity for postnatal environmental modulation.
The discovery that the dentate gyrus of the hippocampus
in the adult brain continues to undergo neurogenesis—
previously assumed to be complete at birth—may provide
additional support to this theory (1). Thus, the protracted
development of the prefrontal cortex and neurogenic
capacity of the dentate gyrus offer the possibility of excit-
ing mechanisms by which physical activity may affect
cognitive function and brain health. Rodent models have
been particularly useful in examining the role of physical
96. activity in neurogenesis, and older human studies have
provided further empirical support for this relationship
(19,20,31).
Mechanisms Underlying Physical
Activity-Brain Relationships
Although brain development is complete by the third
decade of life, it is now well accepted that that the adult
human brain has the capacity to form new neurons
throughout life. The two brain regions that exhibit adult
neurogenesis are the subventricular zone of the lateral
ventricle and the dentate gyrus in the hippocampus
(59). Evidence from rodent studies has revealed that
several factors affect neurogenesis including stress,
aging, environmental enrichment, and physical activity
(40,50,54,68). However, physical activity has been identi-
fied as a critical neurogenic component of environmental
enrichment (29,67). Indeed, wheel running in rodents
enhances performance on hippocampal-dependent tasks
including spatial memory and novel object recognition
(61,69). Subsequent studies established that the neu-
rogenic effects of exercise are localized to the dentate
gyrus of the hippocampus and not the subventricular
zone/olfactory bulb; thus, providing a model to explain
the enhanced hippocampal function observed following
exercise (6). This is further supported by the observation
that long-term potentiation (LTP)—a persistent increase
in synaptic strength that may underpin certain forms of
learning or memory—is enhanced in the dentate gyrus
of running mice compared with controls (72). However,
the granule cells in the dentate gyrus can be influenced
by a variety of factors including neurotransmitters, neural
peptides, and growth factors.
