ARTICLE

The Role of Exercise-Induced Cardiovascular

Adaptation in Brain Health
Takashi Tarumi 1,2 and Rong Zhang 1,2,3
Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas; and 2Departments
of Internal Medicine and 3Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center,
Dallas, TX
1

TARUMI, T. and R. ZHANG. The role of exercise-induced cardiovascular adaptation in brain health. Exerc. Sport Sci.
Rev., Vol. 43, No. 4, pp. 181Y189, 2015. Regular aerobic exercise improves brain health; however, a potential dose-response relationship
and the underling physiological mechanisms remain unclear. Existing data support the following hypotheses: 1) exercise-induced cardiovascular
adaptation plays an important role in improving brain perfusion, structure, and function, and 2) a hormetic relation seems to exist between
the intensity of exercise and brain health, which needs to be further elucidated. Key Words: age, master athletes, aerobic exercise
training, cerebral blood flow, cardiovascular function, cognitive function

dysfunction (30,31). In addition, exercise-related reductions in

other cardiovascular risk factors may contribute to the reduced
risk of cognitive impairment and dementia.
Another important question is whether there is a doseresponse relationship between the intensity of exercise and brain
health. We currently do not know whether more exercise would
naturally lead to a better brain health or such benefits would
plateau or even have deleterious effects beyond a certain dose
of exercise. The existing evidence suggests the presence of a
hormetic relation between the intensity of exercise and brain
structure and function, such that strenuous exercise performed without an adequate recovery may be deleterious to
brain health (2,13). To gain insights into these critical questions, we recently investigated master athletes (MA), a
unique group of middle-aged and older adults who have participated in long-term or lifelong endurance exercise training.

INTRODUCTION
We are facing an unprecedented aging of population in the
history of humanity. Life expectancy has nearly doubled during
the past two centuries, whereas birth rate has steadily declined
in developed countries. Advanced age is a major risk factor
for chronic noncommunicable diseases including Alzheimer
disease (AD), the most common type of late-life dementia.
In 2010, AD affected about 33.9 million people worldwide,
and its prevalence is expected to triple by 2050 if no effective
prevention or treatments are developed. Currently, there is no
cure for AD; however, population-based studies revealed that
approximately 30% of AD cases may be related to modifiable
risk factors such as physical inactivity and cardiovascular risk
factors (23).
Compelling evidence suggests that habitual aerobic exercise attenuates age-related cognitive decline that is linked to
the preservation of brain structure (8,12,38). The mechanisms
underlying exercise-related improvements in brain structure
and function are not well understood and likely to be multifactorial. One possible mechanism is that cardiovascular adaptations to endurance exercise ameliorate brain health through
attenuation of age-related arterial stiffness and/or endothelial

COGNITIVE BENEFITS OF AEROBIC EXERCISE TRAINING

Mounting evidence suggests that regular aerobic exercise
attenuates age-related cognitive decline (8). Cognitive performance peaks during early adulthood and gradually decreases
after late 20s to 30s (24). Specifically, the tasks requiring
working memory and attention-executive function such as
reasoning, perceptual speed, and spatial visualization experience an earlier loss, whereas performance on tasks involving
the crystallized intelligence including vocabulary and general
world knowledge is relatively spared until much later (24).
Investigating two independent samples of MA, we found
higher cognitive performance in memory and executive function compared with their sedentary peers (31,36). Figure 1
shows the result of neurocognitive assessments in middle-aged
MA and sedentary adults. In this study (31), besides age, sex,

Address for correspondence: Rong Zhang, Ph.D., Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, University of Texas
Southwestern Medical Center, 7232 Greenville Ave., Dallas, TX 75231 (E-mail:
rongzhang@texashealth.org).
Accepted for publication: June 9, 2015.
Associate Editor: Hirofumi Tanaka, Ph.D., FACSM
0091-6331/4304/181Y189
Exercise and Sport Sciences Reviews
DOI: 10.1249/JES.0000000000000063
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181
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Figure 1. Endurance-trained master athletes demonstrated a higher cognitive performance in episodic memory, attention-executive function, and total
composite scores than age-matched sedentary adults. The sample-specific Z score was calculated for each of the cognitive domains. The numbers inside bar
graphs are mean T standard error. (Reprinted from (31). Copyright * 2013 Wolters Kluwer Health. Used with permission.)

and education level, lifestyle factors such as daily nutritional

intake and sleep quality were similar between the groups. MA
have participated in vigorous endurance exercise training for
more than 1 h d-1. According to an age- and sex-adjusted regression analysis established by the American College of Sports
Medicine, cardiorespiratory fitness of these MA, as assessed by
O2max), was more than 90 percenmaximal oxygen uptake (V
tile whereas that of sedentary participants was approximately
15 percentile of the general population. In this study, the effect
size of MA, as estimated by the standardized difference between
the two groups (Cohen d), was 0.75, 0.61, and 0.84 in episodic
memory, attention-executive function, and total cognitive composite scores, respectively. This suggests a medium to large
effect size of vigorous aerobic exercise training on improving
cognitive function, consistent with a previous meta-analysis
and systematic review of exercise training and cognition (8).
Another study of older MA with similar levels of cardiorespiratory fitness also exhibited better cognitive performance
in global intelligence and executive function when compared
with age, sex, and education level-matched sedentary older
adults (36).
In addition, a systematic review of prospective studies demonstrated that efficacy of exercise training on cognitive function increased when performed longer than 6 months, with
each exercise session lasting 30 to 45 min (8). The favorable
effect of exercise training was greater when performed earlier
than later in life and when combined with strength exercise
compared with aerobic exercise alone (8).

BRAIN STRUCTURAL ADAPTATIONS TO AEROBIC

EXERCISE TRAINING
The human brain contains approximately 100 billion neurons and consists of the gray (GM) and white (WM) matter.
The GM is composed mainly of neuronal cell bodies with
182 Exercise and Sport Sciences Reviews

branched projections (dendrites). The dendrites receive

electrochemical stimuli from the neighboring and remote
neurons via synapse and propagate them to the cell body.
Subsequently, the neuronal axons in WM transmit electrical
impulse to the surrounding neurons and function as a relay
between the adjacent and remote brain areas as well as between the brain and peripheral organs. The axons are covered by myelin, which increases the conduction velocity of
electrical impulse and plays a critical role for efficient neuronal communications. With advancing age, brain atrophy,
beginning as early as ones 20s to 30s of age, combined with
axonal demyelination that commensurately slows propagation of electrical impulses, results in a loss of cognitive efficiency. In contrast, habitual aerobic exercise may prevent or
at least in part attenuate these age-related deteriorations of
GM and WM physiological and cellular functions, therefore
improving cognitive performance.

Brain Volume
Regular aerobic exercise may increase or preserve regional
brain volume at areas affected by aging and associated with cognitive impairment. Tseng et al. (36) acquired high-resolution
T1 magnetic resonance (MR) images to examine brain volume
in MA. Using a voxel-based morphometric approach, MA
exhibited greater volume at several cortical areas associated
with motor control and visuospatial function than sedentary
older adults (Fig. 2). Specifically, these regions were the
Brodmann areas 7 (parietal lobe) and 19 (visual cortex) and
the culmen (anterior portion of the cerebellum). They also
found a greater concentration of WM at the parietal, occipi O2max was correlated posital, and temporal lobes. Finally, V
tively with the precuneus GM volume as well as the subgyral
frontal and occipital WM volume, when analyzed in all study
participants (36).
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Figure 2. Master athletes exhibited higher gray matter volume in the (A) SII/SPL, (B) V2/IOG, and (C) higher white matter volume in the O3-WM than agematched sedentary adults. The color bar illustrates t statistic scores. The neurological coordinates are based on the Montreal Neurological Institute (MNI)
space. SII, secondary sensorimotor cortex; SPL, superior parietal lobule; V2, secondary visual cortex; IOG, inferior occipital gyrus; O3-WM, inferior occipital
gyrus white matter; A, anterior; and P, posterior. (Reprinted from (36). Copyright * 2013 Wiley Online Library. Used with permission.)

Regional brain volume may increase after a relatively short

period of moderate-intensity aerobic exercise. Sedentary older
adults who participated in 6 to 12 months of a walking program demonstrated greater volume of the hippocampus as well
as several regions of the frontal lobe, including anterior cingulate cortex, supplementary motor area, and middle frontal
gyrus, when compared with the control group that performed
stretching (9,12). In addition, volume of anterior WM tracts,
particularly the genu of the corpus callosum, increased in the
walking but not the stretching group (9).
Brain WM Neuronal Fiber Integrity
The structural integrity of WM neuronal fibers can be
assessed by diffusion tensor imaging (DTI). Using the motion
of water molecules in the brain tissues as an endogenous probe,
DTI provides diffusion metrics that reflect an overall integrity
as well as biological characteristic of WM fiber tracts. Specifically, fractional anisotropy (FA) and mean diffusivity (MD)

provide a measure of water diffusive directionality and magnitude respectively, in that a higher FA and/or a lower MD generally reflect a better integrity of WM fiber tracts. These DTI
metrics have been used to detect early abnormalities which may
precede WM lesions (22).
MA demonstrated higher FA and lower MD in the WM tracts
associated with motor control and coordination when compared
with their sedentary peers (Fig. 3) (35). Specifically, these tracts
included superior corona radiata, superior longitudinal fasciculus,
superior longitudinal fasciculus, inferior fronto-occipital fasciculus, and posterior thalamic radiation. In addition, FA measured from the left superior and inferior longitudinal fasciculi
O2max in all subjects. Furtherwas correlated positively with V
more, these MA exhibited better WM tract integrity in the
cingulum, which carries and integrates memory information
from the hippocampus. Damage to this tract is associated with
mild cognitive impairment and AD. Finally, subcortical WM
lesion volume was smaller in MA than in the control group.

Figure 3. Master athletes exhibited higher fractional anisotropy (AYD) and lower mean diffusivity (EYF) of brain white matter neuronal fiber tracts. These
tracts are (A) right superior corona radiata, (B) right superior longitudinal fasciculus, (C) left superior longitudinal fasciculus, (D) right inferior fronto-occipital
fasciculus, (E) left posterior thalamic radiation, and (F) left cingulum hippocampus. The white matter tracts are shown by green pixels, whereas the red pixels
show disruptions of white matter fiber tracks in sedentary elderly compared with master athletes. A scatter plot (G) shows the correlation of maximal oxygen
uptake (VO2max) with fractional anisotropy (FA) measured from the left superior longitudinal fasciculus (SLF) and left inferior longitudinal fasciculus (ILF). A,
anterior; P, posterior; L, left; R, right. [Adapted from (35). Copyright * 2013 Elsevier. Used with permission.]
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To date, there are few studies that investigated the effect

of aerobic exercise training on WM structural integrity using
DTI. Voss et al. (38) conducted a randomized controlled trial
of 1-yr walking program in sedentary community-dwelling older
adults. In this study, the exercise group did not show grouplevel improvement in WM integrity or cognitive function compared with the control subjects who performed stretching.
However, within the walking group, there was a positive cor O2max
relation between the individual improvements in V
and FA measured from the frontal and temporal lobe WM.
More recently, Svatkova et al. (27) conducted a 6-month
interventional trial of moderate-intensity cycling in the group
of healthy participants as well as patients with schizophrenia.
After the program, both groups exhibited elevations in FA at
the areas associated with motor function. Collectively, these
findings suggest that brain WM integrity is related to cardiorespiratory fitness and those WM areas responsible for motor
function likely are sensitive to exercise training.
THE ROLE OF CARDIOVASCULAR FUNCTION IN
BRAIN HEALTH
The voluntary contractions of skeletal muscle during dynamic exercise dramatically increase the metabolic demand
and challenge whole-body homeostasis. In response, the body
must coordinate its compensatory mechanisms that deliver
adequate oxygen and nutrients to the working muscles. Such
compensatory responses take place in multiple organs, particularly the cardiovascular system, and minimize the disruptions of homeostasis. During exercise, heart rate and cardiac
contractility increase to augment cardiac output, which is the
systemic source of blood flow distributed to all organs. For

efficient substrate delivery, blood flow is redistributed to the

working muscles during dynamic exercise via an integrative
mechanism of nervous, hormonal, and humoral systems. Consequently, dynamic exercise performed at moderate to high
intensity can increase cardiac output and skeletal muscle blood
flow by eightfold and 100-fold, respectively, whereas brain
blood flow may increase by approximately 10% to 20% above
the resting values during moderate-intensity exercise (16,25).
Repeated bouts of aerobic exercise during a prolonged period improve the cardiovascular control of systemic perfusion
and counteract the degenerative processes of aging and/or
disease (16). Because the brain lacks intracellular energy storage and heavily relies on the vascular supply of oxygen and
nutrients, exercise-related improvements in cardiovascular control of cerebral blood flow (CBF) may play a crucial role in
maintaining normal brain function and structure. Although CBF
is coupled closely with the metabolic demand of neurons, hypoperfusion and/or impaired regulation of CBF attributed to
vascular disease or dysfunction can cause neuronal dysfunction
(17). Below, we discuss the key components of cardiovascular
system that may benefit from aerobic exercise training and confer
the favorable effects on brain structure and function (Fig. 4).
The Ventricular-Central Arterial Coupling
Regular aerobic exercise alters chronotropic and inotropic
control of cardiac output. Specifically, endurance training decreases heart rate at rest by shifting autonomic balance of
sympathetic and parasympathetic innervations to the heart.
This is accompanied by an eccentric remodeling of cardiac
chambers, which increases left ventricular end-diastolic filling
and stroke volume. Because of a close coupling with metabolism,

Figure 4. A hypothetical diagram illustrating the effect of aerobic exercise training on cerebral blood flow (CBF) regulations. Normal CBF is maintained
by the hierarchical layers of hemodynamic support extending from the systemic circulation to the local capillary levels. Although not shown in this diagram,
there are overlaps and interactions between each of the layers. For example, cerebral autoregulation and vasomotor reactivity may also take place at
the level of large conduit arteries (e.g., internal carotid and vertebral arteries). Arterial baroreflex may interact with cerebral autoregulation. Please see
the text for detailed explanations. Arrows next to vascular phenotype represent the change that may occur after aerobic exercise training. Currently,
potential effects of aerobic exercise training on the cerebral vasculature, such as cerebral autoregulation, vasomotor reactivity, and microcirculatory
function, remain largely unknown.

184 Exercise and Sport Sciences Reviews

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cardiac output at rest may not change in healthy individuals

after exercise training.
In contrast, patients with heart failure may benefit from
aerobic exercise training by improving cardiac function at
rest. According to the Framingham Heart Study, systemic
hypoperfusion resulting from depressed cardiac index (i.e.,
cardiac output divided by body surface area) is associated with
an elevated risk of incident dementia and AD (19). Conversely, an 18-wk treadmill program improved cognitive performance in attention and psychomotor speed, accompanied
by increased cardiac index at rest, in patients with severe
congestive heart failure (28).
Habitual aerobic exercise attenuates age-related stiffening
of central elastic arteries (e.g., aorta and carotid arteries) (26),
which may improve the efficiency of left ventricular ejection
of stroke volume. The left ventricle generates systolic blood
pressure (SBP) by ejecting a stroke volume against a hydraulic
load (i.e., aortic impedance). Aortic impedance is determined
by its morphological characteristics such as diameter and wall
elasticity. With age and/or presence of cardiovascular risk
factors, the aorta stiffens; arterial wave reflections returning
from the peripheral vascular beds arrive prematurely to the heart;
and consequently aortic impedance rises. These changes necessitate the left ventricle to increase contractility and maintain
stroke volume and cardiac output. With endurance training,
reductions in central arterial stiffness and cardiac afterload decrease the contractile energy required to generate the equivalent
stroke volume, accompanied by a lower SBP. Importantly, SBP
is an established risk factor for stroke and cognitive impairment.
Exercise-related reductions in central arterial stiffness may
attenuate the transmission of excessive blood pressure pulsatility into the brain (32). Cerebral circulation has low vascular
resistance/impedance and, thus, may be vulnerable to excessive hemodynamic pulsatility transmitted into the microcirculations. In young healthy adults, SBP generated by the left
ventricle is dampened effectively by the Windkessel function
of central arteries that expand and recoil with cardiac pulsations. With arterial stiffening and chronic exposure to high
blood pressure pulsatility, cerebral resistance vessels may adapt
by increasing vascular resistance. This maladaptation has been
shown in animal studies where higher pulse pressure is associated with hypertrophic remodeling of cerebral arterioles (4).
Elevated cerebrovascular resistance may not only increase the
risk of ischemia (7,33) but also impair a clearance of neuronal
waste products (e.g., amyloid-A) (18). Consistent with these
notions, MA demonstrated greater distensibility of the carotid
artery that was correlated positively with a higher cerebral
perfusion in the occipitoparietal area (31).
Regular aerobic exercise may improve blood pressure control via enhanced arterial baroreflex function (1). Arterial
baroreceptors, a type of mechanoreceptor located in the aortic
arch and carotid sinus, monitor changes in blood pressure via
mechanical distortion of the vessel walls. The baroreceptor
afferents are relayed to the brainstem, which in turn sends out
autonomic efferent to the heart and blood vessels to control
blood pressure. The brain is particularly sensitive to changes in
blood pressure because of its low resistant vascular bed. Therefore, baroreflex-mediated control of blood pressure is likely
important for maintaining stable CBF, possibly working together with cerebral autoregulation (discussed below) (37).
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Regular aerobic exercise decreases stiffness of the barosensory

arteries and thereby restores baroreflex sensitivity (1,26,31).
Our recent study exhibited that baroreflex sensitivity is associated with the structural integrity of WM neuronal fibers,
as assessed by DTI, and cognitive performance in executive
function (i.e., Trail Making Test B minus A) in older adults
(Fig. 5) (29).
Collectively, exercise-related increase in central arterial elasticity may have favorable effects on CBF regulations, including
attenuation in the transmissions of excessive blood pressure
pulsatility, reduction in cerebrovascular resistance, and stable
blood pressure control and CBF homeostasis. These data
further suggest that central elastic arteries function as a key
vascular component that bridges the heart to the brain.
Large Conduit Artery: Endothelial Function
and Atherosclerosis
The main function of conduit arteries is the delivery and
regulation of blood flow to the peripheral organs. In the brain,
a large portion of vascular resistance is located outside of the
parenchyma including the pial arterioles as well as the large
extracranial (i.e., internal carotid and vertebral arteries) and
intracranial arteries, whereas cerebral penetrating arterioles
and capillaries account for the remaining (21,39). This necessitates a coordinated regulation of cerebrovascular resistance
both inside and outside of the parenchyma to maintain adequate blood supply to the active neurons (i.e., neurovascular
coupling). In this regard, vascular endothelial cells are situated ideally at the intima of the arterial wall, release vasoactive
substances in response to blood shear stimuli as well as neuronal and blood-borne chemicals, and protect the vessel
walls from atherogenesis.
Regular aerobic exercise improves vascular endothelial function via an upregulation of nitric oxide bioavailability (26). The
nitric oxide regulates vasomotor tone during rest and functional activations and also inhibits atherogenesis by reducing
oxidative modification of low-density lipoprotein cholesterol
and preventing the proliferation of vascular smooth muscle
cells. Atherosclerosis, a pathological condition characterized
by the buildup of cholesterol and inflammatory substances in
the arterial walls, occludes blood flow and is associated with
AD pathology (6). Thus, exercise-related ameliorations in
endothelial function as well as a reduced risk of atherosclerosis may facilitate cerebral perfusion.
Cerebral Resistance Vessel: Cerebral Autoregulation
and Vasomotor Reactivity
Cerebral autoregulation (CA) and vasomotor reactivity
(CVMR) provide a local control of CBF. CA is a protective
function of cerebral resistance vessels that keep CBF relatively constant in the face of changes in cerebral perfusion
pressure. Although uncertain, age and endurance training
seem to have fewer effects on the CA compared with the
peripheral vascular beds (5). For example, MA demonstrated
the presence of similar dynamic CA compared with sedentary adults, as assessed by transfer function analysis of arterial
pressure and CBF velocity measured in the middle cerebral
artery during a repeated sit-stand maneuver (1). Currently, we
do not know whether steady-state CA also is less influenced
by age or exercise training.
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185

Figure 5. Associations among cardiovagal baroreflex sensitivity (BRS), fractional anisotropy measured from brain white matter neuronal fiber tracts, and
Trail Making Test BjA performance in older adults. The BRS was assessed during acute changes in arterial blood pressure using the established pharmacological method (modified Oxford technique). The brain images on the top (A) exhibit the area of neuronal fiber tracts that were significantly associated
with BRS based on voxelwise statistics. The color bar illustrates P value of the association. At the bottom (B), scatter plots show the correlations of BRS (left)
and Trail Making Test BjA performance (right) with individual FA values that were extracted from the significant white matter tracts highlighted by
voxelwise analysis (A). [Adapted from (29). Copyright * 2015 Elsevier. Used with permission.]

There are inconsistent findings on the effects of age and

regular aerobic exercise on CVMR. In our study of MA (40),
CVMR was assessed by transcranial Doppler using a modified rebreathing technique that induces incremental elevations in end-tidal CO2, a proxy of arterial pCO2. We
found a higher CVMR during hypercapnia in sedentary and
endurance-trained older adults than in younger subjects,
whereas no difference was observed between the older
groups. Testing a similar sample using functional MR imaging, blood oxygen level-dependent (BOLD) responses to
steady-state hypercapnia were attenuated in MA compared
with that observed in sedentary older adults (34) (Fig. 6).
In contrast, other studies reported higher CVMR in exercisetrained adults than in sedentary subjects, as assessed by
transcranial Doppler during steady-state hypercapnia (3).
Therefore, these inconclusive findings necessitate the standardization of techniques to assess CVMR. Of note, neither
transcranial Doppler nor BOLD measures CBF per se, and
rebreathing and steady-state hypercapnia may have different
effects on cerebrovascular beds and brain tissues. A recent
study using multimodal methods to quantify CBF (i.e., arterial
spin labeling and BOLD) revealed a significant contribution
of basal cerebrovascular tension to CVMR (15). As such,
elevated cerebrovascular tension under resting conditions may
increase hypercapnic vasodilatory reserve while decreasing
186 Exercise and Sport Sciences Reviews

hypocapnic vasoconstrictor capacity, consistent with our

previous observations (40).
Cerebral Microcirculation: Substrate Exchange and
Waste Clearance
CBF ultimately perfuses neuronal tissues at the level of the
capillary where substrate exchange and waste product clearance occur across the blood-brain barrier. Regional cerebral
perfusion is coupled tightly with metabolic demand of neuronal tissues (neurovascular coupling), which presents a high
level of temporal and spatial heterogeneity. Among the important areas of brain that are highly active during rest and
also involved in AD pathology are the prefrontal lobe, medial
temporal lobe including the hippocampus, posterior cingulate
cortex (PCC), and precuneus. These brain areas function as a
neural network hub in mediating and processing information
flow and also serve as the main components of the DefaultMode-Network that contributes to learning and memory
consolidations (14).
MA demonstrated an enhancement of CBF at the PCC
and precuneus compared with sedentary older adults (34)
(Fig. 7). Using the arterial spin labeling technique, wholebrain and regional CBF were measured. Our initial analysis of whole-brain CBF showed similar levels between the
sedentary and endurance-trained older subjects, whereas
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Figure 6. Panel A shows cerebrovascular reactivity (CVR) to steady-state hypercapnia at regions of interest (ROI), as assessed by blood oxygen level
dependence (BOLD) using functional magnetic resonance imaging. Master athletes (MA) demonstrated lower levels of CVR in all of the ROI than the
sedentary elderly (SE) and young control (YC) groups. The CVR was calculated as a percentage change in BOLD divided by an absolute change in end-tidal
CO2 (in millimeters mercury) relative to the baseline level. Panel B shows the result of voxelwise comparison of CVR between the MA and SE groups.
Consistent with the ROI analysis, MA showed a lower CVR throughout the cortex (red), and there was no cluster in which CVR was greater in MA than in SE
subjects. Fro, frontal lobe; Tem, temporal lobe; Par, parietal lobe; Occ, occipital lobe; Cer, cerebellum; Ins, insula; Sub, subcortical gray matter. Error bars
represent standard error. (Reprinted from (34). Copyright * 2013 Wiley Online Library. Used with permission.)

younger subjects demonstrated higher levels of CBF than the

older groups. Next, we calculated relative CBF, which represents a ratio of regional CBF to the whole-brain value and
normalizes the effect of interindividual differences in global
CBF. This analysis revealed that MA have significant elevations
in relative CBF at the PCC and precuneus compared with young
and older sedentary subjects. Therefore, these findings suggested that aerobic exercise training selectively preserve blood
supply in the PCC and precuneus by attenuating the age effect.
EXERCISE INTENSITY AND BRAIN HEALTH
MA as well as sedentary adults who have undergone aerobic exercise training even for a short period of 6 months to
a year demonstrated a similar magnitude of improvements in

cognitive performance when compared with their control groups

(8,31,36). These improvements appeared mainly in the memory
and executive function. On the other hand, brain structural
adaptations to exercise training seemed somewhat different
between the cross-sectional and longitudinal studies. For example, those sedentary adults who completed a short-term exercise
training program demonstrated increases in hippocampal and
prefrontal volume as well as frontal and temporal WM integrity
(9,12,38). In contrast, MA exhibited preservations of the parietal lobe volume and WM integrity, which is not only limited to
the frontal or temporal areas (35,36). Although it is important
to acknowledge the limitations of different study designs and
MA may differ from the general population in terms of genetic
and/or lifestyle factors, these findings collectively suggest that

Figure 7. In panel A, voxelwise analysis revealed a higher level of relative cerebral blood flow (rCBF) in master athletes (MA) than in sedentary elderly (SE)
subjects (cluster size, 250). The cluster was located in the posterior cingulate cortex (PCC) and precuneus of the Default-Mode-Network. No clusters showed
MA G SE. Results are shown in glass brain view. Panel B shows group-averaged rCBF in the area highlighted by panel A. The rCBF values in MA were higher
than those in the SE and young control (YC) groups. In panel C, absolute CBF in the same area showed a significant reduction in SE compared with YC;
however, MA and YC showed similar levels. These data suggest that aerobic exercise training selectively preserves CBF in the PCC/precuneus region by
attenuating the age effect. The rCBF was calculated as a ratio of regional CBF to the whole-brain value. CBF was measured by arterial spin labeling
technique.*P G 0.05, **P G 0.005. Error bars represent standard error. (Reprinted from (34). Copyright * 2013 Wiley Online Library. Used with permission.)
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aerobic exercise training for both a short and a longer duration

has favorable effects on brain structure and function. Prospective
trials that investigate the lifelong effects of exercise training are
difficult to conduct; however, future studies combining crosssectional and interventional study design may elucidate further
the relation between the duration of exercise training and brain
structure and function.
How is exercise intensity linked with brain health in general and cerebrovascular health in particular? A meta-analysis
of cohort and case-control studies reported a dose-dependent
inverse linear relation between physical activity intensity and
stroke incidence or mortality (11). Specifically, moderately
active individuals had a 20% lower risk and highly active individuals had a 27% lower risk of stroke incidence or mortality
than the low-active individuals (11). However, this metaanalysis was limited by different definitions of physical activity intensity used in individual studies, and a few prospective
studies reported a curvilinear relation between exercise intensity and stroke risk. For example, Harvard University alumni
study showed a U-shape relation between relative risks of stroke
and the estimated weekly energy expenditure accounted for
by physical activity (20). Particularly, the effect of physical
activity on reducing stroke risk steadily increased up to the
energy expenditure of 3000 kcal wk-1 but attenuated thereafter. In addition, physical activity performed with moderate
intensity such as walking 20 km wk-1 or more or stair climbing
(Q4.5 metabolic equivalents) was associated with the nadir
of the U-shape relation.
Emerging evidence suggests that strenuous endurance exercise leads to brain injury when performed without adequate
recovery (2,13). Freund et al. (13) measured global GM volume
of ultramarathon runners before, twice during, and 8 months
after the race using MR imaging. The race took over 4487 km
(2788 miles) in 64 days without a rest day. During the race,
those runners experienced an average of approximately 6%
reduction in global GM volume accompanied by a significant
weight loss. The authors estimated that this magnitude of
the volume reductions equates to approximately 30 yr of agerelated atrophy, which normally progresses at an annual rate
of approximately 0.2%. After 8 months of the race, the reduction in GM volume recovered back to the baseline level. Other
studies also reported the link between prolonged endurance
exercise and an elevated risk of cerebral lesions or edema (2).
The mechanism underlying the adverse effects of strenuous
exercise on the brain is not clear. Strenuous exercise substantially increases systemic catabolic burden, inflammatory
responses, and risks of cardiovascular injury, which may affect
brain structure and function. Under normal physiological
conditions, the brain secures its energy intake to support the
high metabolic demand of neuronal tissues via neurovascular
coupling and a relatively constant blood supply. Conversely,
a prolonged high-intensity exercise can deplete intracellular
energy storage of active skeletal muscles (e.g., phosphocreatine and glycogen). Thereafter, those working muscles need
to rely on oxidative phosphorylation of adenosine triphosphate,
which may not be able to sustain a high exercise intensity
(16). These elevations in metabolic demand can lead to
systemic catabolic conditions, which may compromise brain
structure and function via elevated stress hormone levels (e.g.,
cortisol), changes in electrolyte balance (e.g., hyponatremia),
188 Exercise and Sport Sciences Reviews

inflammation and edema, hypoxia, and oxidative stress (2).

Nevertheless, this apparent hormetic relation between the intensity of exercise and brain health needs to be investigated
further.
Currently, there is no clear evidence of a dose-response
relation or any consensus on the optimal dose of exercise training that may prevent or slow the age-related functional and
structural deteriorations of the brain. It is likely that such an
optimal dose is individually based and determined by the
environmental and genetic factors, including age, sex, cardiovascular disease risk, and presence or absence of brainderived neurotrophic factor Val66Met or apolipoprotein E
polymorphisms (10). Furthermore, most studies to date focused
on older subjects and there are not enough data to support
whether exercise training in middle age, for example, would
modify the trajectory of cognitive aging, although midlife vascular risk factors (e.g., hypertension, obesity) elevate an incidence of late-life dementia (23). For future work, much
research is needed to identify and design a personalized
optimal program of exercise training for heterogeneous
populations, including the individuals who have comorbidities or chronic diseases.
CONCLUSIONS
Current evidence suggests that regular aerobic exercise performed at moderate to high intensity attenuates an age-related
reduction in regional brain volume, deterioration of WM integrity, and cognitive decline. Cardiovascular adaptations to
aerobic exercise training represented by reductions in arterial
stiffness and improvements in endothelial function make a favorable systemic and cerebral hemodynamic environment
(milieu) where the brain may benefit from the improvements in
arterial pressure regulation, blood flow homeostasis, and metabolic waste clearance. However, strenuous exercise performed
without adequate recovery may have deleterious effects as
manifested by GM atrophy and WM lesions, which suggests
the presence of a hormetic relation between the intensity of
exercise and brain health. Currently, there are no effective
prevention and treatment modalities for dementia; however,
improvement of cardiovascular health, particularly via regular
aerobic exercise, may prevent or slow age-related cognitive
decline and delay the onset of dementia, thus improving
quality of life and extending a healthy life span.
Acknowledgments
This work was supported by the National Institutes of Health (R01AG033106,
R01HL102457, and P30AG012300) and the American Heart Association
(14POST20140013). The authors thank Jonathan Riley and Erin Howden for
editing and revising the manuscript.

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Exercise and Brain Health

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