ArticlePDF Available

Abstract and Figures

The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.
Content may be subject to copyright.
Exercise training increases size of hippocampus and
improves memory
Kirk I. Erickson
, Michelle W. Voss
, Ruchika Shaurya Prakash
, Chandramallika Basak
, Amanda Szabo
Laura Chaddock
, Jennifer S. Kim
, Susie Heo
, Heloisa Alves
, Siobhan M. White
, Thomas R. Wojcicki
Emily Mailey
, Victoria J. Vieira
, Stephen A. Martin
, Brandt D. Pence
, Jeffrey A. Woods
, Edward McAuley
and Arthur F. Kramer
Department of Psychology, University of Pittsburgh, Pittsburgh, PA 15260;
Beckman Institute for Advanced Science and Technology, and
Department of
Kinesiology and Community Health, University of Illinois, Champaign-Urbana, IL 61801;
Department of Psychology, University of Illinois, Champaign-Urbana,
IL 61820;
Department of Psychology, Ohio State University, Columbus, OH 43210; and
Department of Psychology, Rice University, Houston, TX 77251
Edited* by Fred Gage, Salk Institute, San Diego, CA, and approved December 30, 2010 (received for review October 23, 2010)
The hippocampus shrinks in late adulthood, leading to impaired
memory and increased risk for dementia. Hippocampal and medial
temporal lobe volumes are larger in higher-t adults, and physical
activity training increases hippocampal perfusion, but the extent to
which aerobic exercise training can modify hippocampal volume in
late adulthood remains unknown. Here we show, in a randomized
controlled trial with 120 older adults, that aerobic exercise training
increases the size of the anterior hippocampus, leading to improve-
ments in spatial memory. Exercise training increased hippocampal
volume by 2%, effectively reversing age-related loss in volume by
1 to 2 y. We also demonstrate that increased hippocampal volume
is associated with greater serum levels of BDNF, a mediator of
neurogenesis inthe dentate gyrus. Hippocampal volume declined in
the control group, but higher preintervention tness partially
attenuated the decline, suggesting that tness protects against
volume loss. Caudate nucleus and thalamus volumes were un-
affected by the intervention. These theoretically important ndings
indicate that aerobic exercise training is effective at reversing hip-
pocampal volume loss in late adulthood, which is accompanied by
improved memory function.
Deterioration of the hippocampus precedes and leads to
memory impairment in late adulthood (1, 2). Strategies to
ght hippocampal loss and protect against the development of
memory impairment has become an important topic in recent
years from both scientic and public health perspectives. Physical
activity, such as aerobic exercise, has emerged as a promising low-
cost treatment to improve neurocognitive function that is acces-
sible to most adults and is not plagued by intolerable side effects
often found with pharmaceutical treatments (3). Exercise
enhances learning and improves retention, which is accompanied
by increased cell proliferation and survival in the hippocampus of
rodents (46); effects that are mediated, in part, by increased
production and secretion of BDNF and its receptor tyrosine ki-
nase trkB (7, 8).
Aerobic exercise training increases gray and white matter vol-
ume in the prefrontal cortex (9) of older adults and increases the
functioning of key nodes in the executive control network (10, 11).
Greater amounts of physical activity are associated with sparing of
prefrontal and temporal brain regions over a 9-y period, which
reduces the risk for cognitive impairment (12). Further, hippo-
campal and medial temporal lobe volumes are larger in higher-t
older adults (13, 14), and larger hippocampal volumes mediate
improvements in spatial memory (13). Exercise training increases
cerebral blood volume (15) and perfusion of the hippocampus
(16), but the extent to which exercise can modify the size of the
hippocampus in late adulthood remains unknown.
To evaluate whether exercise training increases the size of the
hippocampus and improves spatial memory, we designed a single-
blind, randomized controlled trial in which adults were randomly
assigned to receive either moderate-intensity aerobic exercise 3 d/
wk or stretching and toning exercises that served as a control. We
predicted that 1 y of moderate-intensity exercise would increase
the size of the hippocampus and that change in hippocampal
volume would be associated with increased serum BDNF and
improved memory function.
Aerobic Exercise Training Selectively Increases Hippocampal Volume.
One hundred twenty older adults without dementia (Table 1)
were randomly assigned to an aerobic exercise group (n= 60) or
to a stretching control group (n= 60). Magnetic resonance
images were collected before the intervention, after 6 mo, and
again after the completion of the program. The groups did not
differ at baseline in hippocampal volume or attendance rates
(Table 2 and SI Results). We found that the exercise intervention
was effective at increasing the size of the hippocampus. That is,
the aerobic exercise group demonstrated an increase in volume of
the left and right hippocampus by 2.12% and 1.97%, respectively,
over the 1-y period, whereas the stretching control group dis-
played a 1.40% and 1.43% decline over this same interval (Fig.
1A). The moderating effect of aerobic exercise on hippocampal
volume loss was conrmed by a signicant Time ×Group in-
teraction for both the left [F(2,114) = 8.25; P<0.001; η
= 0.12]
and right [F(2,114) = 10.41; P<0.001; η
= 0.15] hippocampus
(see Table 2 for all means and SDs).
As can be seen in Fig. 2, we found that aerobic exercise selec-
tively increased the volume of the anterior hippocampus that in-
cluded the dentate gyrus, where cell proliferation occurs (4, 6, 8),
as well as subiculum and CA1 subelds, but had a minimal effect
on the volume of the posterior section. Cells in the anterior hip-
pocampus mediate acquisition of spatial memory (17) and show
more age-related atrophy compared with the tail of the hippo-
campus (18, 19). The selective effect of aerobic exercise on the
anterior hippocampus was conrmed by a signicant Time ×
Group ×Region interaction for both the left [F(2,114) = 4.05; P<
0.02; η
= 0.06] and right [F(2,114) = 4.67; P<0.01; η
= 0.07]
hippocampus. As revealed by ttests, the aerobic exercise group
showed an increase in anterior hippocampus volume from base-
line to after intervention [left: t(2,58) = 3.38; P<0.001; right:
t(2,58) = 4.33; P<0.001] but demonstrated no change in the
volume of the posterior hippocampus (both P>0.10). In contrast,
Author contributions: K.I.E., M.W.V., R.S.P., C.B., J.A.W., E. McAuley, and A.F.K. designed
research; K.I.E., M.W.V., R.S.P., A.S., L.C., J.S.K., S.H., H.A., S.M.W., T.R.W., E. Mailey, V.J.V.,
S.A.M., B.D.P., E. McAuley, and A.F.K. performed research; K.I.E., M.W.V., and R.S.P. an-
alyzed data; and K.I.E., M.W.V., R.S.P., and A.F.K. wrote the paper.
The authors declare no conict of interest.
*This Direct Submission article had a prearranged editor.
To whom correspondence should be addressed. E-mail:
This article contains supporting information online at
1073/pnas.1015950108/-/DCSupplemental. PNAS Early Edition
the stretching control group demonstrated a selective decline in
volume from baseline to after intervention for the anterior hip-
pocampus [left: t(2,58) = 3.07; P<0.003; right: t(2,58) = 2.45;
P<0.01] but no signicant change in volume for the posterior
hippocampus (both P>0.20).
The regional specicity of the intervention was investigated
further by examining two regions that served as control: thalamus
and caudate nucleus. The volume of the thalamus increased for
both the aerobic exercise and stretching groups (Fig. 1C), but this
increase was not signicant [F(2,114) = 0.65; P<0.52]. Aerobic
exercise did not moderate the increase in thalamic volume, as
demonstrated by a nonsignicant Time ×Group interaction
[F(2,114) = 0.24; P<0.80]. The volume of both the left and right
caudate nucleus declined (Fig. 1B), but only for the stretching
group. Aerobic exercise attenuated the loss of volume, although
the Time ×Group interaction was not signicant for either the left
[F(2,114) = 2.25; P<0.11; η
= 0.03] or right [F(2,114) = 1.63;
P<0.19; η
= 0.02] hemispheres.
Our results demonstrate that the size of the hippocampus is
modiable in late adulthood and that moderate-intensity aerobic
exercise is effective at reversing volume loss. Increased volume with
exercise occurred in a selective fashion, inuencing the anterior
hippocampus but not the posterior hippocampus or the thalamus
or caudate nucleus.
Changes in Fitness Are Associated with Increased Hippocampal Volume.
The intervention was effective at increasing aerobic tness levels.
The aerobic exercise group showed a 7.78% improvement in
maximal oxygen consumption (VO
max) after the intervention,
whereas the stretching control group showed a 1.11% improve-
ment in VO
max (Table 1). This difference between the groups
was conrmed by a Time ×Group interaction [F(2,111) = 4.42;
P<0.01; η
= 0.07]. We examined whether improvements in
tness levels were associated with the magnitude of the change in
hippocampal volume. To test this, we ran correlations between
change in aerobic tness levels and change in hippocampal vol-
ume, collapsing across both groups of participants. We found that
greater improvements in aerobic tness level over the 1-y interval
were associated with greater increases in hippocampal volume for
the left (r= 0.37; P<0.001) and right (r=0.40;P<0.001)
hemispheres, suggesting that larger changes in tness translate to
larger changes in volume (Fig. 3 Aand B). This result is consistent
with several rodent studies of exercise on neurogenesis and BDNF
(20, 21). Improvements in VO
max were correlated with increases
in both anterior (left: r= 0.28; P<0.001; right: r= 0.51; P<0.001)
and posterior (left: r=0.32;P<0.001; right: r=0.39;P<0.001)
hippocampal regions, indicating that changes in aerobic tness
have a global inuence on hippocampal volume. Correlations be-
tween changes in VO
max and change in caudate nucleus and
thalamic volumes were not signicant (all r<0.14; P>0.10).
We reasoned that if higher physical tness is protective against
the loss of brain tissue, then higher tness levels at baseline would
be predictive of less volume loss over the 1-y period. We examined
the participants that declined in volume in the stretching group to
test this hypothesis, because the stretching group, and not the
aerobic exercise group, showed a decline in hippocampal volume
over the 1-y interval. We found results partially consistent with
this prediction. That is, higher tness levels at baseline were as-
sociated with less hippocampal volume loss over the 1-y interval,
for the right (r= 0.50; P<0.002) but not for the left (r= 0.17; P<
0.30) hippocampus. Further, consistent with our expectations, it
was only the right anterior hippocampus (r= 0.48; P<0.003) that
was protected by higher tness levels at baseline; the posterior
hippocampus was not affected by baseline tness (r= 0.21;
BDNF Is Associated with Changes in Hippocampal Volume. Exercise
increases levels of BDNF in the hippocampus (5, 7, 20), which,
along with the trkB receptor, is considered to be a partial medi-
ator of the enhancing effect of exercise on learning and memory
(7, 8). BDNF can be measured in serum, and higher serum levels
of BDNF are associated with both better memory function and
larger hippocampal volumes (22). Here, we examined whether 1 y
of aerobic exercise would change circulating levels of BDNF and
whether increased hippocampal volume would be correlated with
changes in BDNF. The aerobic exercise group did not demon-
strate greater changes in serum BDNF levels compared with the
stretching group, as indicated by a nonsignicant Time ×Group
interaction [F(1,97) = 1.42; P<0.23; η
= 0.01]. We reasoned,
however, that because BDNF mediates cell proliferation in the
dentate gyrus of the hippocampus, increased hippocampal vol-
Table 1. Characteristics for the aerobic exercise and stretching
control groups
n60 60
Age (y), mean (SD) 67.6 (5.81) 65.5 (5.44)
Sex (% female) 73 60
Attendance (%), mean (SD) 79.5 (13.70) 78.6 (13.61)
Fitness improvement (%), mean (SD) 7.78 (12.7) 1.11 (13.9)
Table 2. Means (SD) for both groups at all three time points
Aerobic exercise group Stretching control group
Baseline 6 mo
intervention Baseline 6 mo
max 21.36 (4.71) 22.25 (4.66) 22.61 (4.84) 21.75 (4.87) 21.87 (5.07) 21.87 (4.93)
L hippocampus 4.89 (0.74) 4.93 (0.71) 4.98 (0.69) 4.90 (0.80) 4.86 (0.80) 4.83 (0.80)
R hippocampus 5.00 (0.67) 5.03 (0.63) 5.09 (0.63) 4.92 (0.80) 4.89 (0.83) 4.86 (0.82)
L anterior hippocampus 2.86 (0.42) 2.88 (0.41) 2.93 (0.40) 2.84 (0.48) 2.82 (0.48) 2.78 (0.46)
R anterior hippocampus 2.90 (0.40) 2.93 (0.38) 2.99 (0.38) 2.88 (0.48) 2.87 (0.48) 2.84 (0.49)
L posterior hippocampus 2.03 (0.34) 2.04 (0.31) 2.05 (0.30) 2.05 (0.33) 2.03 (0.34) 2.03 (0.37)
R posterior hippocampus 2.05 (0.30) 2.09 (0.27) 2.09 (0.27) 2.03 (0.35) 2.02 (0.37) 2.01 (0.34)
L caudate nucleus 4.65 (0.57) 4.68 (0.57) 4.67 (0.57) 4.66 (0.57) 4.63 (0.51) 4.63 (0.51)
R caudate nucleus 5.04 (0.54) 5.04 (0.52) 5.05 (0.56) 5.06 (0.56) 5.02 (0.57) 5.02 (0.56)
Thalamus 14.11 (1.28) 14.20 (1.32) 14.16 (1.36) 14.22 (1.41) 14.33 (1.36) 14.26 (1.41)
BDNF 21.32 (9.32) 23.77 (8.04) 23.41 (9.67) 24.04 (10.83)
Accuracy (%) 85.9 (8.2) 84.1 (17.1) 88.2 (7.1) 82.3 (9.9) 82.5 (15.8) 86.0 (8.2)
max was measured as ml/kg per min. Brain volumes were measured as cm
. BDNF was measured as pg/mL. L, left; R, right.
| Erickson et al.
ume could be associated with increased levels of serum BDNF.
Because the aerobic exercise group was the only group to show an
increase in volume over the 1-y period, we ran a correlation be-
tween change in BDNF and change in hippocampal volume for
the aerobic exercise group to test this hypothesis. We found that
greater changes in serum BDNF were associated with greater
increases in volume for the left (r= 0.36; P<0.01) and for the
right (r= 0.37; P<0.01) hippocampus (Fig. 3 Cand D). Further,
these effects were selective for the left (r= 0.30; P<0.03) and
right anterior hippocampus (r= 0.27; P<0.04) and only marginal
with the left (r= 0.25; P<0.06) and right (r= 0.22; P<0.08)
posterior hippocampus. There were no associations between
changes in serum BDNF and changes in caudate nucleus or
thalamus volumes (all P>0.50); nor were there any associations
between hippocampal volume and serum BDNF for the stretching
control group (all P>0.40). This indicates that exercise-induced
increases in BDNF are selectively related to the changes in an-
terior hippocampal volume resulting from aerobic exercise.
Hippocampal Volume Is Related to Improvements in Spatial Memory.
Spatial memory (13, 22) was tested on both exercise and
stretching groups at baseline, after 6 mo, and again after the
completion of the 1-y intervention to determine whether changes
in hippocampal volume translate to improved memory. Both
groups showed improvements in memory, as demonstrated by
signicant increases in accuracy between the rst and last testing
sessions for the aerobic exercise [t(2,51) = 2.08; P<0.05] and the
stretching control [t(2,54) = 4.41; P<0.001] groups. Response
times also became faster for both groups between the baseline and
postintervention sessions (all P<0.01), indicating that improve-
ments in accuracy were not caused by changes in speedaccuracy
tradeoff. However, the aerobic exercise group did not improve
performance above that achieved by the stretching control group,
as demonstrated by a nonsignicant Time ×Group interaction
[F(1,102) = 0.67; P<0.40; η
= 0.007]. Nonetheless, we found
that higher aerobic tness levels at baseline (r= 0.31; P<0.001)
and after intervention (r= 0.28; P<0.004) were associated with
better memory performance on the spatial memory task. Change
in aerobic tness levels from baseline to after intervention, how-
ever, was not related to improvements in memory for either the
entire sample (r= 0.15; P<0.12) or when considering each group
separately (both P>0.05). Furthermore, changes in BDNF were
not associated with improvements in memory function for either
group (r<0.15; P>0.20). On the other hand, larger left and right
hippocampi at baseline (both P<0.005) and after intervention
(both P<0.005) were associated with better memory perfor-
mance (12). Therefore, we reasoned that increased hippocampal
Fig. 1. (A) Example of hippocampus
segmentation and graphs demonstrat-
ing an increase in hippocampus volume
for the aerobic exercise group and
a decrease in volume for the stretching
control group. The Time ×Group in-
teraction was signicant (P<0.001) for
both left and right regions. (B) Example
of caudate nucleus segmentation and
graphs demonstrating the changes in
volume for both groups. Although the
exercise group showed an attenuation
of decline, this did not reach signi-
cance (both P>0.10). (C) Example of
thalamus segmentation and graph
demonstrating the change in volume
for both groups. None of the changes
were signicant for the thalamus. Error
bars represent SEM.
Fig. 2. The exercise group showed a selective increase in
the anterior hippocampus and no change in the posterior
hippocampus. See Table 2 for Means and SDs.
Erickson et al. PNAS Early Edition
volume after the exercise intervention should translate to im-
proved memory function. In support of this hypothesis, we found
that, in the aerobic exercise group, increased hippocampal volume
was directly related to improvements in memory performance. The
correlation between improvement in memory and hippocampal
volume reached signicance for left (r= 0.23; P<0.05) and right
(r= 0.29; P<0.02) hemispheres (Fig. 3 Eand F). This indicates
that increases in hippocampal volume after 1 y of exercise aug-
ments memory function in late adulthood. In contrast, changes in
caudate nucleus and thalamus volumes were unrelated to changes
in memory performance for either group (all P>0.10).
Hippocampal volume shrinks 12% annually in older adults
without dementia (1), and this loss of volume increases the risk for
developing cognitive impairment (2). We nd results consistent
with this pattern, such that the stretching control group demon-
strated a 1.4% decline in volume over the 1-y interval. With es-
calating health care costs and an increased proportion of people
aged >65 y, it is imperative that low-cost, accessible preventions
and treatments for brain tissue loss are discovered. In this ran-
domized controlled study of exercise training, we demonstrate
that loss of hippocampal volume in late adulthood is not in-
evitable and can be reversed with moderate-intensity exercise. A
1-y aerobic exercise intervention was effective at increasing hip-
pocampal volume by 2% and offsetting the deterioration associ-
ated with aging. Because hippocampal volume shrinks 12%
annually, a 2% increase in hippocampal volume is equivalent to
adding between 1 and 2 y worth of volume to the hippocampus for
this age group.
On the basis of the several regions we examined, the effect of
exercise was rather selective, inuencing only the anterior hippo-
campus and neither the thalamus nor the caudate nucleus. This
indicates that exercise does not inuence all brain regions uni-
formly. In fact, research from human cognitive studies and rodents
indicates some specicity, such that exercise inuences some brain
regions and behaviors but has minimal inuence on others (3, 5, 9,
12, 20, 21, 2325). Such selectivity suggests that there are regionally
dependent molecular pathways inuenced by exercise. In fact, we
found here that changes in serum BDNF levels were associated
with changes in anterior hippocampal volume; an important link
because the hippocampus is rich in BDNF, and BDNF levels in-
crease with exercise treatments in both rodents (5, 7, 20) and
humans (26, 27). BDNF is a putative mediator of neurogenesis and
contributes to dendritic expansion (28, 29) and is also critical in
memory formation (3032). Our results suggest that cell pro-
liferation or increased dendritic branching might explain increased
hippocampal volume and improvements in memory after exercise;
however, increased vascularization (15, 16, 33) and dendritic
complexity (34) may also be contributing to increased volume.
Aerobic exercise increased anterior hippocampal volume but
had little effect on the posterior hippocampus. Neurons in the
anterior hippocampus are selectively associated with spatial
memory acquisition (17) and show exacerbated age-related at-
rophy compared with the posterior hippocampus (18, 19). It is
possible that regions demonstrating less age-related decay might
also be less amenable to growth. Thus, aerobic exercise might
elicit the greatest changes in regions that show the most pre-
cipitous decline in late adulthood, such as the anterior hippo-
Fig. 3. All scatterplots are of the aerobic
exercise group only because it was the only
group that showed an increase in volume
across the intervention. (Aand B) Scatter-
plots of the association between percent
change in left and right hippocampus vol-
ume and percent change in aerobic tness
level from baseline to after intervention.
(Cand D) Scatterplots of percent change in
left and right hippocampus volume and
percent change in BDNF levels. (Eand F)
Scatterplots of percent change in left and
right hippocampus and percent change in
memory performance.
| Erickson et al.
campus and prefrontal cortex (9). Overall, these data suggest that
the anterior hippocampus remains amenable to augmentation.
In sum, we found that the hippocampus remains plastic in late
adulthood and that 1 y of aerobic exercise was sufcient for en-
hancing volume. Increased hippocampal volume translates to
improved memory function and higher serum BDNF. We also
demonstrate that higher tness levels are protective against loss of
hippocampal volume. These results clearly indicate that aerobic
exercise is neuroprotective and that starting an exercise regimen
later in life is not futile for either enhancing cognition or aug-
menting brain volume.
Participants. Community-dwelling older adults (n= 842) were recruited, and
179 were enrolled. One hundred forty-ve participants completed the in-
tervention (81.0% of the participants originally enrolled). Five participants
were excluded because they did not attend the 6-mo MRI session, owing to
scheduling conicts; eight participants were excluded because they did not
attend the 12-mo follow-up MRI session; and 12 participants were excluded
because they had excessive head motion that created inaccurate hippo-
campal, caudate nucleus, or thalamus segmentations. Therefore, 120 par-
ticipants had complete MR data from all three sessions (82.7% of the
enrolled sample) and were included in the analyses.
Eligible participants had to (i) demonstrate strong right handedness (35),
(ii) be between the ages of 55 and 80 y, (iii ) score 51 on the modied Mini-
Mental Status Examination (36), (iv), score <3 on the Geriatric Depression
Scale to rule out possible depression (37), (v) have normal color vision, (vi )
have a corrected visual acuity of at least 20/40, (vii ) have no history of neu-
rological diseases or infarcts, including Parkinsons disease, Alzheimers dis-
ease, multiple sclerosis, or stroke, (viii ) have no history of major vasculature
problems, including cardiovascular disease or diabetes, (ix) obtain consent
from their personal physician, and (x) sign an informed consent form ap-
proved by the University of Illinois. In addition, all participants had to report
being currently sedentary, dened as being physically active for 30 min or less
in the last 6 mo. Participants were compensated for their participation.
After completion of the initial blood draw, MR session, and tness as-
sessment, participants were randomized to an aerobic walking group (n=60)
or a stretching control group (n= 60) (Fig. 4).
Fitness Assessments. Participants were required to obtain consent from their
personal physician before cardiorespiratory tness testing was conducted.
Aerobic tness (VO
max) was assessed by graded maximal exercise testing on
a motor-driven treadmill. The participantwalked at a speed slightly faster than
their normal walking pace (30100 m/min), with increasing grade increments
of 2% every 2 min. A cardiologist and nurse continuously monitored oxygen
uptake, heart rate, and blood pressure (see SI Methods for more detail).
MRI Parameters and Segmentation Algorithm. MR images were collected on all
participants within 1 mo of the start of the intervention, after 6 mo, and
within 2 wk after the completion of the intervention. High-resolution (1.3
mm ×1.3 mm ×1.3 mm) T1-weighted brain images were acquired using a 3D
magnetization-prepared rapid gradient echo imaging protocol with 144
contiguous slices collected in an ascending fashion.
For segmentation and volumetric analysis of the left and right hippo-
campus, caudate nucleus, and thalamus we used the Oxford Centre for
Functional MRI of the Brain (FMRIB)s Integrated Registration and Segmen-
tation Tool in FMRIBs Software Library version 4.1 (3840) (see SI Methods
for more detail).
Training Protocol. Aerobic exercise condition. For the aerobic exercise program,
a trained exercise leader supervised all sessions. Participants started by walking
for 10 min and increased walking duration weekly by 5-min increments until
a duration of 40 min was achieved at week 7. Participants walked for 40 min per
session for the remainder of the program. All walking sessions started and
ended with approximately 5 min of stretching for the purpose of warming up
and cooling down. Participants wore heart rate monitors and were encour-
aged to walk in their target heart rate zone, which was calculated using the
Karvonen method (41) according to the resting and maximum heart rates
achieved during the baseline maximal graded exercise test. The target heart
rate zone was 5060% of the maximum heart rate reserve for weeks 1 to 7
and 6075% for the remainder of the program. Participants in the walking
group completed an exercise log at each exercise session. Every 4 wk, par-
ticipants received written feedback forms that summarized the data from
their logs. Participants with low attendance and/or exercise heart rate were
encouraged to improve their performance in the following month.
Stretching and toning control condition. For the stretching and toning control
program, all sessions were led and monitored by trained exercise leaders. All
classes started and ended with warm-up and cool-down stretching. During
each class, participants engaged in four muscle-toning exercises using
dumbbells or resistance bands, two exercises designed to improve balance,
one yoga sequence, and one exercise of their choice. To maintain interest,
a new group of exercises was introduced every 3 wk. During the rst week,
participants focused on becoming familiar with the new exercises, and during
the second and third weeks they were encouraged to increase the intensity by
using more weight or adding more repetitions. Participants in the stretching
and toning control group also completed exercise logs at each exercise session
and received monthly feedback forms. They were encouraged to exercise at
an appropriate intensity of 1315 on the Borg Rating of Perceived Exertion
scale (42) and to attend as many classes as possible.
Spatial Memory Paradigm. To test memory function, all participants com-
pleted a computerized spatial memory task at baseline, after 6 mo, and again
after completion of the intervention (13, 22, 43).
Axation crosshair appeared for 1 s, and participants were instructed to
keep their eyes on the crosshair. After the xation, one, two, or three black
dots appeared at random locations on the screen for 500 ms. The dots were
removed from the display for 3 s. During this time, participants were
instructed to try and remember the locations of the previously presented
black dots. At the end of the 3-s delay, a red dot appeared on the screen in
either one of the same locations as the target dots (match condition) or at
a different location (nonmatch condition). Participants had 2 s to respond to
the red dot by pressing one of two keys on a standard keyboardthe xkey
for a nonmatch trial and the mkey for a match trial (Fig. 5). Forty trials
Fig. 5. Display of the spatial memory task used in this study. The spatial
memory task load was parametrically manipulated between one, two, or
three items (two-item condition shown here). Participants were asked to
remember the locations of one, two, or three black dots. After a brief delay,
a red dot appeared, and participants were asked to respond whether the
location of the red dot matched or did not match one of the locations of the
previously shown black dots. This task was administered to all participants at
baseline, after 6 mo, and again after completion of the intervention.
Fig. 4. Flow diagram for the randomization and assessment sessions for
both exercise and stretching control groups.
Erickson et al. PNAS Early Edition
were presented for each set size (one, two, or three locations), with 20 trials
as match trials and 20 trials as nonmatch trials. Participants were instructed
to respond as quickly and accurately as possible. Several practice trials were
performed before the task began to acquaint the participants with the task
instructions and responses (see SI Methods for more detail).
Serum BDNF Assay. Blood was collected at baseline before the intervention
and again immediately after the completion of the program. Blood sampling
for BDNF analysis was performed approximately 2 wk before the MR sessions.
Fasted subjects reported to the laboratory at 0800 hours, at which time blood
from the antecubital vein was collected in sterile serum separator tubes
(Becton Dickinson). The blood samples were kept at room temperature for
15 min to allow for clotting, after which the samples were centrifuged at
1,100 ×gat 4 °C for 15 min. Serum was then harvested, aliquoted, and stored
at 80 °C until analysis. Serum BDNF was quantied using an enzyme-linked
immunosorbant assay (Human BDNF Quantikine Immunoassay, DBD00, R & D
Systems) according to the manufacturers instructions (see SI Methods for
more detail).
Analyses. All dependent variables were tested and met criteria for normality
and skew before general linear model and Pearson correlations were con-
ducted. Effects of the intervention on VO
, BDNF, and the volume of the
hippocampus,caudate nucleus, and thalamus wereexamined using an ANOVA
with repeated measures with Group (aerobic exercise, stretching control) as
a between-subjectsfactor and Time (baseline, 6 mo, and1 y) as a within-subject
factor. Because the distribution of men and women was slightly different
between the two groups(Table 1) we included sex as a covariate in all analyses.
In addition, as a safeguard against any residual effects of height or head size,
we included intracranial volume (ICV) as a covariate of no interest. Finally,
age was slightly different between the two groups, so we also included age
as a covariate of no interest in all models.
Correlations were calculated using percent change in VO
max, percent
change in left and right hippocampal volumes, percent change in BDNF, and
percent change in memory performance. We also ran correlations between
absolute difference scores while controlling for variation in baseline values.
These results were identical, so the correlations from the percent change
scores are included in this report. For all correlations, we used a partial
correlation approach to control for the possible confounding effects of age,
sex, and ICV.
ACKNOWLEDGMENTS. We thank Susan Herrel, Edward Malkowski, Dawn
Epstein, Zuha Warraich, Nancy Dodge, and Holly Tracy for help with data
collection. This work was supported by National Institute on Aging, National
Institutes of Health Grants RO1 AG25667 and RO1 AG25032. K.I.E. was
supported by a Junior Scholar Award (P30 AG024827) from the Pittsburgh
Claude D. Pepper Older Americans Independence Center and a seed grant
(P50 AG005133) awarded through the University of Pittsburgh Alzheimers
Disease Research Center.
1. Raz N, et al. (2005) Regional brain changes in aging healthy adults: General trends,
individual differences and modiers. Cereb Cortex 15:16761689.
2. Jack CR, Jr., et al.; AlzheimersDisease NeuroimagingInitiative (2010) Brain beta-amyloid
measures and magnetic resonance imaging atrophy both predict time-to-progression
from mild cognitiveimpairment to Alzheimers disease.Brain 133:33363348.
3. Hillman CH, Erickson KI, Kramer AF (2008) Be smart, exercise your heart: Exercise
effects on brain and cognition. Nat Rev Neurosci 9:5865.
4. van Praag H, Shubert T, Zhao C, Gage FH (2005) Exercise enhances learning and
hippocampal neurogenesis in aged mice. J Neurosci 25:86808685.
5. Cotman CW, Berchtold NC (2002) Exercise: A behavioral intervention to enhance brain
health and plasticity. Trends Neurosci 25:295301.
6. Creer DJ, Romberg C, Saksida LM, van Praag H, Bussey TJ (2010) Running enhances
spatial pattern separation in mice. Proc Natl Acad Sci USA 107:23672372.
7. Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efcacy
of exercise on synaptic plasticity and cognition. Eur J Neurosci 20:25802590.
8. Li Y, et al. (2008) TrkB regulates hippocampal neurogenesis and governs sensitivity to
antidepressive treatment. Neuron 59:399412.
9. Colcombe SJ, et al. (2006) Aerobic exercise training increases brain volume in aging
humans. J Gerontol A Biol Sci Med Sci 61:11661170.
10. Colcombe SJ, et al. (2004) Cardiovascular tness, cortical plasticity, and aging. Proc
Natl Acad Sci USA 101:33163321.
11. Rosano C, et al. (2010) Psychomotor speed and functional brain MRI 2 years after
completing a physical activity treatment. J Gerontol A Biol Sci Med Sci 65:639647.
12. Erickson KI, et al. (2010) Physical activity predicts gray matter volume in late
adulthood: The Cardiovascular Health Study. Neurology 75:14151422.
13. Erickson KI, et al. (2009) Aerobic tness is associated with hippocampal volume in
elderly humans. Hippocampus 19:10301039.
14. Honea RA, et al. (2009) Cardiorespiratory tness and preserved medial temporal lobe
volume in Alzheimers disease. Alzheimer Dis Assoc Disord 23:188197.
15. Pereira AC, et al. (2007) An in vivo correlate of exercise-induced neurogenesis in the
adult dentate gyrus. Proc Natl Acad Sci USA 104:56385643.
16. Burdette JH, et al. (2010) Using network science to evaluate exercise-associated brain
changes in older adults. Front Aging Neurosci 2:23.
17. Moser MB, Moser EI, Forrest E, Andersen P, Morris RG (1995) Spatial learning with
a minislab in the dorsal hippocampus. Proc Natl Acad Sci USA 92:96979701.
18. Raji CA, Lopez OL, Kuller LH, Carmichael OT, Becker JT (2009) Age, Alzheimer disease,
and brain structure. Neurology 73:18991905.
19. Hackert VH, et al. (2002) Hippocampal head size associated with verbal memory
performance in nondemented elderly. Neuroimage 17:13651372.
20. Neeper SA, Gómez-Pinilla F, Choi J, Cotman C (1995) Exercise and brain neu-
rotrophins. Nature 373:109.
21. Holmes MM, Galea LA, Mistlberger RE, Kempermann G (2004) Adult hippocampal
neurogenesis and voluntary running activity: Circadian and dose-dependent effects. J
Neurosci Res 76:216222.
22. Erickson KI, et al. (2010) Brain-derived neurotrophic factor is associated with age-
related decline in hippocampal volume. J Neurosci 30:53685375.
23. Kramer AF, et al. (1999) Ageing, tness and neurocognitive function. Nature 400:
24. Colcombe SJ, Kramer AF (2003) Fitness effects on the cognitive function of older
adults: A meta-analytic study. Psychol Sci 14:125130.
25. Smith PJ, et al. (2010) Aerobic exercise and neurocognitive performance: A meta-
analytic review of randomized controlled trials. Psychosom Med 72:239252.
26. Rasmussen P, et al. (2009) Evidence for a release of brain-derived neurotrophic factor
from the brain during exercise. Exp Physiol 94:10621069.
27. Zoladz JA, et al. (2008) Endurance training increases plasma brain-derived
neurotrophic factor concentration in young healthy men. J Physiol Pharmacol 59
(Suppl 7):119132.
28. Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by
secreted proneurotrophins. Science 294:19451948.
29. Pencea V, Bingaman KD, Wiegand SJ, Luskin MB (2001) Infusion of brain-derived
neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in
the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 21:
30. Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B (1996) Regulation of synaptic
responses to high-frequency stimulation and LTP by neurotrophins in the
hippocampus. Nature 381:706709.
31. Kang H, Schuman EM (1996) A requirement for local protein synthesis in
neurotrophin-induced hippocampal synaptic plasticity. Science 273:14021406.
32. Pang PT, et al. (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term
hippocampal plasticity. Science 306:487491.
33. Black JE, Isaacs KR, Anderson BJ, Alcantara AA, Greenough WT (1990) Learning causes
synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of
adult rats. Proc Natl Acad Sci USA 87:55685572.
34. Redila VA, Christie BR (2006) Exercise-induced changes in dendritic structure and
complexity in the adult hippocampal dentate gyrus. Neuroscience 137:12991307.
35. Oldeld RC (1971) The assessment and analysis of handedness: The Edinburgh
inventory. Neuropsychologia 9:97113.
36. Stern Y, et al. (1987) Modied mini-mental state examination: Validity and reliability.
Neurology 37:179.
37. Sheikh JI, Yesavage JA (1986) Geriatric Depression Scale (GDS): Recent evidence and
development of a shorter version. Clinical Gerontology: A Guide to Assessment and
Intervention. (Haworth Press, New York), pp 165173.
38. Patenaude B, et al. (2007) Bayesian Shape and Appearance Models. Technical Report
TR07BP1 (FMRIB Centre, Univ Oxford, UK).
39. Zhang Y, Brady M, Smith S (2001) Segmentation of brain MR images through
a hidden Markov random eld model and the expectation-maximization algorithm.
IEEE Trans Med Imaging 20:4557.
40. Smith SM, et al. (2004) Advances in functional and structural MR image analysis and
implementation as FSL. Neuroimage 23 (Suppl 1):S208.
41. Strath SJ, et al. (2000) Evaluation of heart rate as a method for assessing moderate
intensity physical activity. Med Sci Sports Exerc 32 (9 Suppl):S465S470.
42. Borg G (1985) An Introduction to Borgs RPE-Scale (Mouvement, Ithaca, NY).
43. Heo S, et al. (2010) Resting hippocampal blood ow, spatial memory and aging. Brain
Res 1315:119127.
| Erickson et al.
... Physical activity, particularly aerobic exercise, is known to increase the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF) [7,[32][33][34][35][36]. BDNF is a neurotrophin essential for neuroplasticity, from neurogenesis to neuronal survival and from synaptogenesis to cognition, as well as regulation of energy homeostasis [34]. ...
... Aerobic exercise training increases the size of the anterior hippocampus in older adults, thereby leading to improvements in spatial memory. This increase in hippocampal volume is associated with greater serum BDNF levels [35]. IGF-1 and VEGF play important roles in neurogenesis and angiogenesis and promote BDNF expression in the hippocampus [7]. ...
Full-text available
As there is no curative treatment for dementia, including Alzheimer’s disease (AD), it is important to establish an optimal nonpharmaceutical preventive intervention. Physical inactivity is a representative modifiable risk factor for dementia, especially for AD in later life (>65 years). As physical activity and exercise are inexpensive and easy to initiate, they may represent an effective nonpharmaceutical intervention for the maintenance of cognitive function. Several studies have reported that physical activity and exercise interventions are effective in preventing cognitive decline and dementia. This review outlines the effects of physical activity and exercise-associated interventions in older adults with and without cognitive impairment and subsequently summarizes their possible mechanisms. Furthermore, this review describes the differences between two types of physical exercise—open-skill exercise (OSE) and closed-skill exercise (CSE)—in terms of their effects on cognitive function. Aerobic physical activity and exercise interventions are particularly useful in preventing cognitive decline and dementia, with OSE exerting a stronger protective effect on cognitive functions than CSE. Therefore, the need to actively promote physical activity and exercise interventions worldwide is emphasized.
... TETs are highly expressed in the brain [342,343], with TET1 and TET3 involved in proper brain and cognitive function [103,344,345], while TET2 is associated with neurogenic processes by restoring adult neurogenesis to youthful levels and, thus, enhancing cognitive function [267] (neurogenesis is a process of generating new functional neurons in the brain [346]. For a long time, it was thought that the loss of neurons was irreversible in the adult brain because dying neurons cannot be replaced; however, later it was demonstrated that life-long continuous neurogenesis takes place in almost all mammals, including humans [347]). Vitamin A works synergistically with vitamin C by stimulating TET expression [280] (for the role of other vitamins in epigenetic modification, see Nur et al. [284], and for the effects of vitamins, polyphenols, and minerals on the cells' homeostasis, senescence, telomere length, and counteraction of DNA damage, see Proshkina et al. [283]). ...
... Thus, maintaining higher levels of brain neurogenesis is proposed to be neuroprotective and responsible for a rejuvenating/regenerative capacity in the aging brain [387], as it is linked to enhanced cognition and slower disease progression in the context of Alzheimer's disease [388]. Generally, regular physical exercise plays an essential role in maintaining healthy neurocognitive function (especially in chronologically older individuals) [391], preservation of brain grey matter [392] and hippocampus volume [347], upregulation of neurotrophic factors, including brain-derived neurotrophic factors [393], and maintaining a healthy central nervous system immunometabolism during aging [394]. Similarly, a calorie restriction diet has been systematically demonstrated to extend both the life-and healthspan and to delay many aspects of aging (for example, the well-documented good health and high number of centenarians among the population of the Japanese of Okinawa island have been attributed to calorie restriction [395]) [396][397][398]. ...
Full-text available
Background: There is a growing consensus that chronological age (CA) is not an accurate indicator of the aging process and that biological age (BA) instead is a better measure of an individual's risk of age-related outcomes and a more accurate predictor of mortality than actual CA. In this context, BA measures the "true" age, which is an integrated result of an individual's level of damage accumulation across all levels of biological organization, along with preserved resources. The BA is plastic and depends upon epigenetics. Brain state is an important factor contributing to health- and lifespan. Methods and objective: Quantitative electroencephalography (qEEG)-derived brain BA (BBA) is a suitable and promising measure of brain aging. In the present study, we aimed to show that BBA can be decelerated or even reversed in humans (N = 89) by using customized programs of nutraceutical compounds or lifestyle changes (mean duration = 13 months). Results: We observed that BBA was younger than CA in both groups at the end of the intervention. Furthermore, the BBA of the participants in the nutraceuticals group was 2.83 years younger at the endpoint of the intervention compared with their BBA score at the beginning of the intervention, while the BBA of the participants in the lifestyle group was only 0.02 years younger at the end of the intervention. These results were accompanied by improvements in mental-physical health comorbidities in both groups. The pre-intervention BBA score and the sex of the participants were considered confounding factors and analyzed separately. Conclusions: Overall, the obtained results support the feasibility of the goal of this study and also provide the first robust evidence that halting and reversal of brain aging are possible in humans within a reasonable (practical) timeframe of approximately one year.
... 2 Whether for mere enjoyment or to properly excel, when practiced over extended periods of time, physical exercise, playing video games, or musical training result in individuals improving performance (compared to their starting point), and even becoming experts in the trained domain. According to many authors (e.g., Bialystok & DePape, 2009;Diamond, 2013;Erickson et al., 2011), these popular activities are seemingly appropriate tools for cognitive enhancement. Indeed, one can easily find today, both in the scientific literature and mass media, claims (strong in many cases) about the cognitive benefits of those activities (e.g., Mehr, 2015). ...
Full-text available
The demands of today's society for interventions that optimize cognitive abilities and prevent their decline have motivated the translation of scientific findings into applied programs. Ordinary activities such as physical exercise, chess, meditation, playing video games or a musical instrument, as well as specific cognitive programs, have witnessed the growth of evidence emphasizing their cognitive benefits. Here, we outline several issues that need consideration before speculating on the implications of this literature: (a) the magnitude and costs of the effect, (b) the robustness of the effect, (c) testing causality, (d) the identification of moderator variables, and (e) the underlying mechanisms. We consider that this would contribute to a critical appraisal of the extant findings by the interested researchers, to reduce overstatements in the media reports about the applicability and public relevance of the effects reported in scientific articles, and to potentially help designing new interventions.
... In our study, we discovered that falls were the most common cause of trauma, and the average hospitalization cost for falls was ¥19,809 ($2,934), which was less expensive than the average hospitalization cost of $29, 562 for patients with nonfatal falls in the United States [40] and the range of $5,654 to $42,840 per fall-related hospitalization in the study by Heinrich et al. [41]. Age-related brain shrinkage affects the parts of older people's brains connected to physical activity [42,43], and age-related losses in active muscle strength and cognitive function raise the risk of falls and fractures in older people. Additionally, traffic accidents are another major external cause of trauma. ...
Full-text available
Background Trauma in the elderly is gradually growing more prevalent as the aging population increases over time. The purpose of this study is to assess hospitalization costs of the elderly trauma population and analyze the association between those costs and the features of the elderly trauma population. Methods In a retrospective analysis, data on trauma patients over 65 who were admitted to the hospital for the first time due to trauma between January 2017 and March 2022 was collected from a tertiary comprehensive hospital in Baotou. We calculated and analyzed the hospitalization cost components. According to various therapeutic approaches, trauma patients were divided into two subgroups: non-surgical patients (1320 cases) and surgical patients (387 cases). Quantile regression was used to evaluate the relationship between trauma patients and hospitalization costs. Results This study comprised 1707 trauma patients in total. Mean total hospitalization costs per patient were ¥20,741. Patients with transportation accidents incurred the highest expenditures among those with external causes of trauma, with a mean hospitalization cost of ¥24,918, followed by patients with falls at ¥19,809 on average. Hospitalization costs were dominated by medicine costs (¥7,182 per capita). According to the quantile regression results, all trauma patients' hospitalization costs were considerably increased by length of stay, surgery, the injury severity score (16–24), multimorbidity, thorax injury, and blood transfusion. For non-surgical patients, length of stay, multimorbidity, and the injury severity score (16–24) were all substantially linked to higher hospitalization costs. For surgical patients, length of stay, injury severity score (16–24), and hip and thigh injuries were significantly associated with greater hospitalization costs. Conclusions Using quantile regression to identify factors associated with hospitalization costs could be helpful for addressing the burden of injury in the elderly population. Policymakers may find these findings to be insightful in lowering hospitalization costs related to injury in the elderly population.
... Physical activity and exercise have a lot of benefits for animals. In addition to reducing and ameliorating excessive apoptotic and inflammatory responses caused by various pathological factors [37][38][39], numerous pieces of evidence have also indicated that exercise training can improve the memory function of animals [40,41] and prevent the occurrence of cardiovascular and chronic metabolic disease. Therefore, researchers utilize exercise training as a method of disease prevention and treatment, and the molecular mechanisms involved were explored [42,43]. ...
Full-text available
Hepatotoxicity induced by excessive fluoride (F) exposure has been extensively studied in both humans and animals. Chronic fluorosis can result in liver apoptosis. Meanwhile, moderate exercise alleviates apoptosis caused by pathological factors. However, the effect of moderate exercise on F-induced liver apoptosis remains unclear. In this research, sixty-four three-week-old Institute of Cancer Research (ICR) mice, half male and half female, were randomly divided into four groups: control group (distilled water); exercise group (distilled water and treadmill exercise); F group [100 mg/L sodium fluoride (NaF)]; and exercise plus F group (100 mg/L NaF and treadmill exercise). The liver tissues of mice were taken at 3 months and 6 months, respectively. Hematoxylin-eosin (HE) staining and situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) results showed that nuclear condensation and apoptotic hepatocytes occurred in the F group. However, this phenomenon could be reversed with the intervention of treadmill exercise. The results of QRT-PCR and western blot displayed NaF- induced apoptosis via tumor necrosis factor recpter 1 (TNFR1) signaling pathway, while treadmill exercise could restore the molecular changes caused by excessive NaF exposure.
... The older adults in the Osc+ condition showed a 0.96% increase of volume in the LC-innervatedregions hippocampal ROI across the 5-week training. A review focusing on structural brain plasticity in adult learning (Lovden et al., 2013) reported that studies using various training protocols like exercise, motor, and cognitive training with acceptable quality had net effects of training on hippocampal volume are in the 2-4% range for 5 days to ~ 3-month training (Erickson et al., 2011;Lovden et al., 2012; . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. ...
Full-text available
Using data from a clinical trial, we tested the hypothesis that daily sessions modulating heart rate oscillations affect older adults’ volume of a region-of-interest (ROI) comprised of adjacent hippocampal subregions with relatively strong locus coeruleus (LC) noradrenergic input. Younger (N=106) and older adults (N=56) completed five weeks of heart rate variability biofeedback. Participants were randomly assigned to one of two daily biofeedback practices: 1) engage in slow-paced breathing (around 10-s per breath or 0.10 Hz) while receiving biofeedback to increase their heart rate oscillations (Osc+); 2) engage in self-selected strategies while receiving biofeedback to decrease their heart rate oscillations (Osc−). Biofeedback did not significantly affect younger adults’ hippocampal volume. Among older adults, the two biofeedback conditions affected volume in the LC-targeted hippocampal ROI differentially with the Osc+ condition showing relatively increased volume and Osc− showing relatively decreased volume. Older adults with greater average spectral power of heart rate at around 0.10 Hz during biofeedback sessions showed greater increases in volume across these regions.
Physical activity (PA) has been shown to benefit various cognitive functions and promote neuroplasticity. Whereas the effects of PA on brain anatomy and function have been well documented in older individuals, data are scarce in young adults. Whether high levels of cardiorespiratory fitness (CRF) achieved through regular PA are associated with significant structural and functional changes in this age group remains largely unknown. In the present study, twenty young adults that engaged in at least 8 hours per week of aerobic exercise during the last 5 years were compared to twenty sedentary controls on measures of cortical excitability, white matter microstructure, cortical thickness and metabolite concentration. All measures were taken in the left primary motor cortex and CRF was assessed with VO2max. Transcranial magnetic stimulation (TMS) revealed higher corticospinal excitability in high- compared to low-fit individuals reflected by greater input/output curve amplitude and slope. No group differences were found for other TMS (short-interval intracortical inhibition and intracortical facilitation), diffusion MRI (fractional anisotropy and apparent fiber density), structural MRI (cortical thickness) and magnetic resonance spectroscopy (NAA, GABA, Glx) measures. Taken together, the present data suggest that brain changes associated with increased CRF are relatively limited, at least in primary motor cortex, in contrast to what has been observed in older adults.
Adult hippocampal neurogenesis is important for preserving learning and memory-related cognitive functions. Physical exercise, especially voluntary running, is one of the strongest stimuli to promote neurogenesis and has beneficial effects on cognitive functions. Voluntary running promotes exit of neural stem cells (NSCs) from the quiescent stage, proliferation of NSCs and progenitors, survival of newborn cells, morphological development of immature neuron, and integration of new neurons into the hippocampal circuitry. However, the detailed mechanisms driving these changes remain unclear. In this review, we will summarize current knowledge with respect to molecular mechanisms underlying voluntary running-induced neurogenesis, highlighting recent genome-wide gene expression analyses. In addition, we will discuss new approaches and future directions for dissecting the complex cellular mechanisms driving change in adult-born new neurons in response to physical exercise.
Full-text available
Extensive research on humans suggests that exercise could have benefits for overall health and cognitive function, particularly in later life. Recent studies using animal models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise could provide a simple means to maintain brain function and promote brain plasticity.
Full-text available
Physical activity (PA) has been hypothesized to spare gray matter volume in late adulthood, but longitudinal data testing an association has been lacking. Here we tested whether PA would be associated with greater gray matter volume after a 9-year follow-up, a threshold could be identified for the amount of walking necessary to spare gray matter volume, and greater gray matter volume associated with PA would be associated with a reduced risk for cognitive impairment 13 years after the PA evaluation. In 299 adults (mean age 78 years) from the Cardiovascular Health Cognition Study, we examined the association between gray matter volume, PA, and cognitive impairment. Physical activity was quantified as the number of blocks walked over 1 week. High-resolution brain scans were acquired 9 years after the PA assessment on cognitively normal adults. White matter hyperintensities, ventricular grade, and other health variables at baseline were used as covariates. Clinical adjudication for cognitive impairment occurred 13 years after baseline. Walking amounts ranged from 0 to 300 blocks (mean 56.3; SD 69.7). Greater PA predicted greater volumes of frontal, occipital, entorhinal, and hippocampal regions 9 years later. Walking 72 blocks was necessary to detect increased gray matter volume but walking more than 72 blocks did not spare additional volume. Greater gray matter volume with PA reduced the risk for cognitive impairment 2-fold. Greater amounts of walking are associated with greater gray matter volume, which is in turn associated with a reduced risk of cognitive impairment.
Full-text available
Biomarkers of brain Aβ amyloid deposition can be measured either by cerebrospinal fluid Aβ42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aβ load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer's dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer's Disease Neuroimaging Initiative. The primary outcome was time-to-progression to Alzheimer's dementia. Hippocampal volumes were measured and adjusted for intracranial volume. We used a new method of pooling cerebrospinal fluid Aβ42 and Pittsburgh compound B positron emission tomography measures to produce equivalent measures of brain Aβ load from either source and analysed the results using multiple imputation methods. We performed our analyses in two phases. First, we grouped our subjects into those who were 'amyloid positive' (n = 165, with the assumption that Alzheimer's pathology is dominant in this group) and those who were 'amyloid negative' (n = 53). In the second phase, we included all 218 subjects with mild cognitive impairment to evaluate the biomarkers in a sample that we assumed to contain a full spectrum of expected pathologies. In a Kaplan-Meier analysis, amyloid positive subjects with mild cognitive impairment were much more likely to progress to dementia within 2 years than amyloid negative subjects with mild cognitive impairment (50 versus 19%). Among amyloid positive subjects with mild cognitive impairment only, hippocampal atrophy predicted shorter time-to-progression (P < 0.001) while Aβ load did not (P = 0.44). In contrast, when all 218 subjects with mild cognitive impairment were combined (amyloid positive and negative), hippocampal atrophy and Aβ load predicted shorter time-to-progression with comparable power (hazard ratio for an inter-quartile difference of 2.6 for both); however, the risk profile was linear throughout the range of hippocampal atrophy values but reached a ceiling at higher values of brain Aβ load. Our results are consistent with a model of Alzheimer's disease in which Aβ deposition initiates the pathological cascade but is not the direct cause of cognitive impairment as evidenced by the fact that Aβ load severity is decoupled from risk of progression at high levels. In contrast, hippocampal atrophy indicates how far along the neurodegenerative path one is, and hence how close to progressing to dementia. Possible explanations for our finding that many subjects with mild cognitive impairment have intermediate levels of Aβ load include: (i) individual subjects may reach an Aβ load plateau at varying absolute levels; (ii) some subjects may be more biologically susceptible to Aβ than others; and (iii) subjects with mild cognitive impairment with intermediate levels of Aβ may represent individuals with Alzheimer's disease co-existent with other pathologies.
Full-text available
Literature has shown that exercise is beneficial for cognitive function in older adults and that aerobic fitness is associated with increased hippocampal tissue and blood volumes. The current study used novel network science methods to shed light on the neurophysiological implications of exercise-induced changes in the hippocampus of older adults. Participants represented a volunteer subgroup of older adults that were part of either the exercise training (ET) or healthy aging educational control (HAC) treatment arms from the Seniors Health and Activity Research Program Pilot (SHARP-P) trial. Following the 4-month interventions, MRI measures of resting brain blood flow and connectivity were performed. The ET group's hippocampal cerebral blood flow (CBF) exhibited statistically significant increases compared to the HAC group. Novel whole-brain network connectivity analyses showed greater connectivity in the hippocampi of the ET participants compared to HAC. Furthermore, the hippocampus was consistently shown to be within the same network neighborhood (module) as the anterior cingulate cortex only within the ET group. Thus, within the ET group, the hippocampus and anterior cingulate were highly interconnected and localized to the same network neighborhood. This project shows the power of network science to investigate potential mechanisms for exercise-induced benefits to the brain in older adults. We show a link between neurological network features and CBF, and it is possible that this alteration of functional brain networks may lead to the known improvement in cognitive function among older adults following exercise.
In the ageing process, neural areas¹,² and cognitive processes³,⁴ do not degrade uniformly. Executive control processes and the prefrontal and frontal brain regions that support them show large and disproportionate changes with age. Studies of adult animals indicate that metabolic⁵ and neurochemical⁶ functions improve with aerobic fitness. We therefore investigated whether greater aerobic fitness in adults would result in selective improvements in executive control processes, such as planning, scheduling, inhibition and working memory. Over a period of six months, we studied 124 previously sedentary adults, 60 to 75 years old, who were randomly assigned to either aerobic (walking) or anaerobic (stretching and toning) exercise. We found that those who received aerobic training showed substantial improvements in performance on tasks requiring executive control compared with anaerobically trained subjects.