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Curr Hypertens Rep (2015) 17:82

DOI 10.1007/s11906-015-0593-6

HYPERTENSION AND THE BRAIN (S STOCKER, SECTION EDITOR)

Exercise, the Brain, and Hypertension


Poghni Peri-Okonny 1 & Qi Fu 1,2 & Rong Zhang 1,2 & Wanpen Vongpatanasin 1

# Springer Science+Business Media New York 2015

Abstract Exercise training is the cornerstone in the preven- Introduction


tion and management of hypertension and atherosclerotic car-
diovascular disease. However, blood pressure (BP) response Benefit of exercise on cardiovascular health has long been
to exercise is exaggerated in hypertension often to the range recognized. Exercise is recommended as one of the lifestyle
that raises the safety concern, which may prohibit patients interventions in the treatment of hypertension by many guide-
from regular exercise. This augmented pressor response is lines [1••, 2]. Increasing evidence also suggests benefit of
shown to be related to excessive sympathetic stimulation regular exercise in preventing or slowing age-related decline
caused by overactive muscle reflex. Exaggerated in cognitive function. The benefits of specific exercise training
sympathetic-mediated vasoconstriction further contributes to modalities on the blood pressure, cardiovascular function, and
the rise in BP during exercise in hypertension. Exercise train- brain health as well as the potential underlying mechanisms
ing has been shown to reduce both exercise pressor reflex and are reviewed in this article.
attenuate the abnormal vasoconstriction. Hypertension also
contributes to cognitive impairment, and exercise training Effects of Exercise Training on Blood Pressure
has been shown to improve cognitive function through both
BP-dependent and BP-independent pathways. Additional Exercise training (ET) can be categorized into dynamic endur-
studies are still needed to determine if newer modes of exer- ance or isometric resistance type. Resistance exercise may be
cise training such as high-intensity interval training may offer further categorized into dynamic resistance training, which
advantages over traditional continuous moderate training in involves muscle contraction against the opposing force
improving BP and brain health in hypertensive patients. coupled with a smaller component of dynamic joint move-
ment (e.g., weight lifting or chest press), or isometric resis-
tance type which involved muscle contraction alone (e.g., iso-
Keywords Brain . Exercise . Cognitive function . metric handgrip or leg extension). Blood pressure (BP) low-
Hypertension . Mechanoreceptors . Metaboreceptors ering effects of exercise training varied widely among studies
and are likely related to the specific training modality and
subjects’ characteristics. A recent meta-analysis of 93 ran-
domized controlled trials showed that BP was reduced by
This article is part of the Topical Collection on Hypertension and the Brain 3.5/2.5 mmHg with moderate- to high-intensity endurance
training with duration between 20 and 50 min per session,
* Wanpen Vongpatanasin two to five sessions per week [3••]. Effects of endurance train-
wanpen.vongpatanasin@utsouthwestern.edu ing on BP appear to be larger in the hypertensive than normo-
tensive individuals (8.3/5.2 vs. 0.75/1.1 mmHg, respectively)
1
Hypertension Section, Cardiology Division, University of Texas [3••]. Further subgroup analysis within the endurance training
Southwestern Medical Center, 5323 Harry Hines Blvd., studies indicated that the magnitude of BP reduction was not
Dallas, TX 75390-8586, USA greater with higher intensity training than moderate intensity.
2
Institute of Exercise and Environmental Medicine, Dallas, TX, USA Longer duration of exercise per session of more than >45 min
82 Page 2 of 12 Curr Hypertens Rep (2015) 17:82

did not result in greater BP reduction than 30–45 min per reducing arterial stiffness [17], and blunting the rise in plasma
session, though no change in BP was noted in studies using NE and endothelin-1 during exercise [18].
protocol of less than <30 min per session (Table 1). Dynamic
resistance exercise was shown to reduce BP by 1.8/3.2 mmHg Effects of Exercise Training on Neural Control
in the same meta-analysis. In more recent studies, dynamic of Circulation in Hypertension
resistance exercise training appears to induce larger reduction
as shown in Table 2. Similarly, the average BP reduction ap- Normally, exercise produces intensity-dependent increases in
pears to be larger with isometric resistance training by 10.9/ heart rate, cardiac output, and BP, which are mediated primar-
6.2 mmHg, but only four studies were included in this cate- ily by decreases in parasympathetic and increases in sympa-
gory of exercise [3••]. In these studies, majority of studies thetic neural activity (SNA). These autonomic adjustments, in
used isometric handgrip at 30 % maximal voluntary contrac- turn, are mediated by both the central neural drive associated
tion using 2-min bout repetition for a total of 4–8 min per with the volitional component of exercise, termed central
session, three to five sessions per week (4–10). More recent command, as well as by a reflex arising in the contracting
studies not included in this meta-analysis, however, show skeletal muscle, known as exercise pressor reflex (EPR,
more modest effects of isometric resistance exercise on BP Fig. 1). The reflex mechanism is mediated by thin fiber muscle
[8–10] (last three studies of Table 3). Thus, benefit of isomet- afferents traditionally classified as metaboreceptors, which are
ric resistance exercise in reducing BP remains to be further activated slowly and only during intense or ischemic muscle
determined. contraction, or mechanoreceptors, which respond quickly to
Despite potential long-term benefit of resistance exercise deformation of their receptive fields [19]. Furthermore, these
training in lowering BP, it is contraindicated in patients with autonomic adjustments are modulated by the carotid sinus and
severe uncontrolled hypertension (BP≥180/110 mmHg) due aortic arch baroreceptors, whose discharge is increased by the
to potentially dangerous acute rise in peripheral vascular re- exercise-induced rise in BP even with baroreflex resetting
sistance and BP during muscle contraction. Currently, the [19]. Several studies have shown that increases in BP were
standard exercise prescription for the treatment of hyperten- exaggerated during exercise in patients with hypertension, and
sion according to the American College of Sports Medicine the exaggerated BP responses to exercise are likely due to an
consists of at least 30 min of accumulated physical activity per augmented central command, muscle metaboreflexes and/or
day on most days per week [2]. Endurance exercise training at mechanoreflexes, or impaired baroreflexes [19].
40 to 60 % maximum oxygen uptake was suggested with A wealth of animal studies have shown that skeletal muscle
moderate-intensity resistance training added as an adjunctive contraction activates thin fiber (groups III and IV) muscle
exercise. Although the continuous mode of endurance exer- afferents that reflexively increase sympathetic outflow to in-
cise is recommended by most of guidelines, increasing evi- crease arterial pressure, cardiac output, and blood flow to the
dence suggests the superiority of aerobic interval training exercising muscles [19]. The group IV afferents are slowly
(AIT) associated with intermittent changes of the intensity of activated by metabolic products of muscle contraction such
exercise in improving exercise capacity (Table 1) and vascular as bradykinin, potassium, lactic acid, diprotonated phosphate,
function [11••]. One study showed that AIT was superior to adenosine triphosphate (ATP) [20], prostaglandin E2, and oth-
continuous moderate exercise training (MCT) in reducing er arachidonic acid metabolites [19]. In contrast, the group III
fasting plasma glucose level and expression of fatty acid syn- afferents are more often rapidly adapting mechanoreceptors,
thase in the fat tissue biopsy samples from hypertensive pa- which respond to mechanical perturbation via cation-selective
tients with metabolic syndrome, suggesting reduced lipogen- stretch-activated ion channels [21]. Previous studies in decer-
esis [12]. In the same study, however, similar BP reduction ebrate cats and rats demonstrated that passive tendon stretch
was observed after MCT and AIT (Table 1) [12]. Studies in caused a large increase in renal sympathetic nerve activity and
patients with hypertension [13, 14] suggested greater reduc- BP within 1–2 s without altering muscle metabolites, suggest-
tion in BP with AIT than MCT. However, the numbers of ing a short latency of mechanoreflex [22]. A strict dichotomy
participants in these studies are typically small, and larger between muscle metaboreceptors and muscle mechanorecep-
clinical trials are needed to confirm these observations. tors is an oversimplification since group III muscle afferents
Moderate endurance training was shown to have beneficial can be sensitized to respond in an exaggerated fashion to a
effects on vascular function, including endothelial function given mechanical stimulus by many chemical substances
[12] and large arterial stiffness [15]. Reduction in neurohor- known to activate group IV afferents, such as lactic acid,
monal activation as evidenced by reduction in plasma norepi- ATP, and prostaglandins.
nephrine (NE) and plasma renin activity has also been dem- Our previous studies in hypertensive patients indicated an
onstrated, which may contribute to reduction in systemic vas- augmented increase in BP, heart rate (HR), and sympathetic
cular resistance [16]. In addition, AIT was shown to be more nerve activity (SNA) measured directly using intraneural mi-
effective than MCT in improving endothelial function [12], croelectrodes [23]. This enhanced exercise pressor reflex was
Table 1 Effects of moderate-intensity continuous endurance training (MCT) vs. high-intensity aerobic interval training (AIT) on BP

Investigators, year Patient characteristics Exercise protocol BP Increase in


VO2max

MCT AIT MCT AIT MCT AIT

Nemoto et al. 2007 Men and women 50 % of VO2max, ≥4 70 % of VO2max (3 min on, SBP/DBP reduction SBP/DBP reduction −2 % 9%
[13] (mean age 63) times/week, (n=51, 3 min off, repeat ≥5 sets), −3/−2 mmHg −9/−5 mmHg
8 M/43 F) ≥4 times/week, (n=87,
19 M/68 F)
Curr Hypertens Rep (2015) 17:82

Wisloff et al. 2007 Patients with heart 70–75 % of HRpeak, 90–95 % of HRpeak (4 min SBP/DBP did not SBP/DBP did not 14 % 46 %
[52] failure (mean age 76) 3 times/week, 47 on, 3 min off, repeat 4 sets) change (data not change (data not
min/session for 12 for 12 weeks (n=9) shown) shown)
weeks (n=9)
Tjønna et al. 2008 Patients with metabolic 70 % of HRmax, 90 % of HRmax (4 min on, SBP/DBP reduction SBP/DBP reduction 16 % 35 %
[12] syndrome (mean age 52) 3 times/week, ∼50 3 min off), 3 times/week, −10/−6 mmHg −9/−6 mmHg
min/session for 25 min AIT/session for 16
16 weeks (n=8, weeks (n=11, 4 M/7 F)
4 M/4 F)
Schjerve et al. Obese adults (mean age 45) 60–70 % of HRmax, 85–95 % of HRmax (4 min on, No change in SBP No change in SBP 16 % 33 %
2008 [53] 3 times/week, 47 min/ 3 min off, repeat 4), 3 times/ (data not shown); (data not shown);
session for 12 weeks week for 12 weeks (n=14, DBP reduction DBP reduction
(n=13, 3 M/10 F) 3 M/11 F) −8 mmHg −6 mmHg
Giolac et al. 2010 Young normotensive women 50–60 % of VO2max, 80–90 % of VO2max (1 min 24-h ABPM −3/ 24-h ABPM −2/−2 8% 15 %
[18] at high familial risk for 3 times/week, 40 min/ on, 2 min off), 3 times/week −2 mmHg mmHg
HTN (mean age 25) session for 16 weeks for 16 weeks (n=16)
(n=16)
Molmen-Hansen Patients with essential HTN ∼70 % of HRmax, 3 times/ >90 % of HRmax (4 min on, 24-h ABPM −4.5/ 24-h ABPM −12/ 5% 15 %
et al. 2010 [14] (mean age 52, 44 % women) week, ∼50 min/session 3 min off), 3 times/week, −3.5 mmHg −8 mmHg
for 12 weeks (n=28, 25 min AIT/session for 12
16 M/12 F) weeks (n=31, 16 M/15 F)
Guimarães et al. Patients with HTN (mean 60 % of HR reserve, 3 times/ 80 % of HR reserve (1 min on, 24-h ABPM 0/ 24-h ABPM −2/ Did not Did not
2010 [17] age 45 and 50 for AIT and week, 40 min/session 2 min off), 3 times/week, −1 mmHg −2 mmHg report report
MCT group each, for 16 weeks (n=16, 40 min/session for 16 weeks
65 % women) 7 M/9 F) (n=16, 4 M/12 F)
Currie et al. 2013 Patients with CAD (mean 51–65 % of peak power 80–104 % of peak power Seated SBP/DBP Seated SBP/DBP 19 % 24 %
[54] age 68 and 62 for MCT output, 3 times/week, output (1 min on, 1 min off, reduction reduction −3/−2
and AIT group each) 30–50 min/session repeat 10), 3 times/week for −6/−7 mmHg mmHg
for 12 weeks (n=10, 12 weeks (n=11, sex did
sex did not mention) not mention)
Angadi et al. 2014 Patients with HFpEF 70 % of HRmax 3 times/ 85–0 % of HRmax (4 min on, SBP/DBP reduction SBP/DBP reduction 1% 9%
[55•] (mean age 70) week, 30 min/session 3 min off, repeat 4), 3 times/ −12/−4 mmHg −4/−8 mmHg
for 4 weeks (n=6, week for 4 weeks (n=9,
4 M/2 F) 8 M/1 F)
Mitranun et al. Patients with type II diabetes 60–65 % of VO2peak, 3 80–85 % of VO2peak (1 min on, SBP/DBP reduction SBP/DBP reduction 14 % 25 %
2014 [56] (mean age 62) times/week, 30 min/ 4 min off, repeat 4–6), 3 −5/0 mmHg −12/2 mmHg
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session for 12 weeks times/week for 12 weeks


(n=14, 5 M/9 F) (n=14, 5 M/9 F)
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Table 1 (continued)

Investigators, year Patient characteristics Exercise protocol BP Increase in


VO2max

MCT AIT MCT AIT MCT AIT


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Klonizakis et al. Postmenopausal women 65 % of peak power 100 % of peak power output SBP/DBP reduction SBP/DBP reduction 7% 11 %
2014 [57] (age range 55–85) output, 3 times/week, (1 min on, 1 min off, −2/−3 mmHg −7/−2 mmHg
40 min/session for 2 repeat 10), 3 times/week
weeks (n=14) for 2 weeks (n=11)
Conraads et al. Patients with coronary artery 70–75 % of HRmax, 90–95 % of HRmax, 3 times/ SBP/DBP reduction SBP/DBP reduction 20 % 23 %
2015 [58] disease (mean age 58) 3 times/week, 37 min/ week, 28 min/session for −6/−3 mmHg 0/−1 mmHg
session for 12 weeks 12 weeks (n=100,
(n=100, 89 M/11 F) 91 M/9 F)
Stensvold et al. Elderly people (70–76 years ∼70 % of HRpeak, 2 ∼90 % of HRpeak (4 min on, Still ongoing, will run
2015 [59•] of age, 53 % women) times/week, 50 min/ 4 min off), 2 times/week, until June 2018
session for 5 years ∼40 min/session for 5 years
(n=387) (n=400)

Reserve heart rate was calculated as the difference between peak and resting heart rate, multiplied by the intensity of exercise and added to resting heart rate, according to the Karvonen method
SBP systolic blood pressure, DBP diastolic blood pressure, HRmax maximum heart rate, HRpeak peak heart rate, VO2max maximal oxygen consumption, VO2peak peak oxygen consumption
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Table 2 Effects of dynamic resistance training on blood pressure

Nascimento et al. Hypertensive sedentary elderly Seated bench press, rotary cuff, leg extension, SBP reduction −15.
(2014) [60••] females (mean age 67) leg curl, leg press, and front lat-pull down. Mean BP reduction −11.
3 sets, 8–12 reps. 2 min rest b/w sets. 2×/week.
Duration 14 weeks. (N=12).
No control group
de Freitas Barito et al. Hypertensive females (age 53±3) 3 groups: control, exercise at 50 % of 1RM, Exercise at 80 %:
(2015) [61] exercise at 80 % of 1RM. 10 sets, maximum BP reduction
10 exercises, 90 s rest. (N=16). −29±4/−14±5 mmHg
Exercise at 50 %:
max BP reduction
−18±6/−8±5 mmHg)
Dias et al. (2015) [62] Adolescents. control; n=20; Leg, arm, chest exercise in circuit format. BP reduction −12/−5
mean age 14.7 years old and 30–40 min, 3×/week. 3 sets.
obese n=24; mean age 14.1 years old Reps range 6–15.
Duration 12 weeks (N=44, 24 F)
Morales Milton et al. Males with stage 1 hypertension 3 sets, 12 reps at 60 % 1RM, BP reduction −16/−12
(2012) [63] (mean age 46±3) 3×/week for 12 weeks (N=15)
Ghroubi et al. Post CABG patients (average age 59) AT biking at 70 % HRR at 60 rpm, AT: BP reduction −10/−8.1
(2012) [64] two 10-min sessions, 5-min rest. 2× per week ST: BP reduction −16/−15
ST strength training at 20 % of peak torque.
Duration 8 weeks. (N=32)

AT aerobic training, BP blood pressure, HRR heart rate reserve, RM repetition maximum

noted during low level of rhythmic handgrip exercise that does redistribute to the metabolically active muscles. This function-
not normally trigger increase in SNA in normotensive indi- al sympatholysis is thought to be a protective mechanism to
viduals, suggesting an enhanced mechanoreflex function. allow the working muscles to continue to function in the pres-
Studies in spontaneously hypertensive rats (SHRs) indicated ence of sympathetic activation during exercise [23, 28].
that this exaggerated increase in BP is mediated at least in part Studies from our laboratories indicated that this mechanism
by augmented EPR with important contributions from both is impaired in hypertensive humans and SHRs, which may
mechanical and chemical components [21]. Precise mecha- contribute to the augmented increases in BP during exercise.
nisms underlying enhanced mechanoreflex and metaboreflex For a given level of sympathetic activation, skeletal muscle
function in hypertension are unknown, but increasing evi- blood flow and muscle oxygenation in hypertensive individ-
dence suggests that centrally derived nitric oxide (NO) may uals were reduced at a greater extent than the age-matched
play a role [24•, 25]. NO normally exerts an inhibitory influ- normotensive controls [23, 28]. More recently, ET has been
ence on the central sympathetic discharge. Expression of neu- shown to restore the impaired functional sympatholysis in
ronal isoforms of nitric oxide synthase (nNOS) in the nucleus SHRs, independent of the level of SNA during muscle con-
tractus solitarius (NTS) was found to be reduced in SHRs, traction [28]. This beneficial effect of ET was thought to be
which may influence the integration of sensory information related to increase in peripheral NO production generated
from the skeletal muscle afferent fibers [22]. Administration from the nNOS which is also expressed in the skeletal muscle
of L-arginine within the NTS also significantly attenuated the [28].
pressor response to muscle stretch in hypertensive rats, sug-
gesting inhibitory role of NO pathway in EPR [24•, 25]. More Effects of Exercise Training on Brainstem Neural
recently, both aldosterone and high dietary sodium are shown Plasticity
to contribute to exercise pressor reflex in rats, independent of
renal sodium retention [26•, 27]. Whether the Endurance exercise training has been shown to attenuate the
sympathoexcitatory action of aldosterone and sodium is me- augmented increase in renal SNA during static muscle con-
diated centrally through the NO pathway remains to be further traction, activation of mechanoreflex using muscle stretch,
investigated. and activation of the chemically sensitive muscle afferents
Not only is sympathetic outflow elevated during exercise in with capsaicin in SHRs [29]. This beneficial effect of exercise
the presence of hypertension, the sympathetic-mediated vaso- training is proposed to be mediated by neuroplastic changes in
constriction is also enhanced. In normotensive humans, sym- the brainstem centers involved in cardiovascular regulation
pathetic vasoconstriction is attenuated in the working muscles [30]. It has been demonstrated that ET reduced the number
while sympathetic activation triggers alpha-adrenergic vaso- of dendrites in the brainstem centers involved in regulation of
constriction in the resting muscle, allowing blood flow to sympathetic outflow and/or locomotor activity, such as
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Table 3 Effects of isometric resistance training on blood pressure

Investigators, year Patient characteristics Exercise protocol BP

Wiley et al. 1992 [4] Health individuals (age Study 1: four, 2-IHG contractions at 30 % MVC with 3-min rests Study 1: SBP/DBP reduction −12.5/−14.9 mmHg
20–52), no mention of between contractions, 3 times/week for 8 weeks (n=8) Study 2: SBP/DBP reduction −9.5/−8.9 mmHg
gender Study 2: four, 45-s IHG contractions at 50 % MVC with 1-min rests
between contractions, 5 times/week for 5 weeks (n=10). +Control group
Taylor et al. 2003 [5] Hypertensive patients Four, 2-min IHG contractions at 30 % MVC, 3 times/week for 10 weeks SBP/DBP reduction −19/−7 mmHg
(mean age 69) (n=9, 5 M/4 F). +Control group
Millar et al. 2009 [6] Older subjects (mean age 70) Bilateral, four, 2-min IHG contractions at 30 % MVC, separated by 1-min rest, SBP reduction −3 mmHg Did not report DBP
acutely 5 min post handgrip (n=18, 9 F/9 F). +Control intervention
Wiles et al. 2010 [7] Healthy young males High-intensity leg isometric training, four, 2-min bouts of ∼21 % MVC, High intensity: SBP/DBP reduction −5.2/−2.6 mmHg
(age range 18–34) 3 times/week for 8 weeks (n=11) Low intensity: SBP/DBP reduction −3.7/−2.5 mmHg
Low-intensity leg isometric training, four, 2-min bouts of 10 % MVC,
3 times/week for 8 weeks (n=11). +Control group
Stiller-Moldovan et al. 2012 [8] Medicated hypertensive Four, 2-min IHG contractions at 30 % MVC, 3 times/week for 8 weeks SBP/DBP reduction −1/0 mmHg
patients (mean age 60) (n=11, 7 M/4 F). +Control group
Millar et al. 2013 [9] Medicated hypertensive Four, 2-min IHG contracts at 30 % MVC, separated by 4 min of rest, SBP/DBP reduction −5/−3 mmHg
patients (mean age 66) 3 times/week for 8 weeks (n=13). +Control group
Badrov et al. 2013 [10] Normotensive women Four, 2-min IHG contractions at 30 % MVC, 3 times/week for 8 weeks (n=12) SBP reduction −6 mmHg SBP reduction −6 mmHg
(mean age 24)) Four, 2-min IHG contractions at 30 % MVC, 5 times/week for 8 weeks (n=11).
+Control group

IHG isometric handgrip, MVC maximum voluntary contraction


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Fig. 1 Schematic cartoon


depicting the role of reflex
originating from the skeletal
muscle (metaboreflex and
mechanoreflex), known as the
exercise pressor reflex, in
stimulating central sympathetic
outflow and the inhibitory role of
arterial baroreceptors. SNA
sympathetic nerve activity

periaqueductal gray matter (PAG), posterior hypothalamic normal rats as evidenced by Fos-like immunoreactivity [32],
area (PH), nucleus of the tractus solitarius (NTS), and the cu- which may explain reduction in sympathetic nerve activity
neiform nucleus (CnF) in normal adult rats [30], which was with endurance training in humans.
reversed upon detraining [31]. This reduction in dendritic field In healthy humans, forearm muscle ET decreased sympa-
was associated with an attenuated activation of cardiorespira- thetic activation during non-fatiguing rhythmic handgrip
tory areas such as PH, PAG, NTS, and rostral ventrolateral exercise [33]. Interestingly, handgrip exercise training has
medulla (RVLM) in response to a single bout of exercise in been shown to reduce accumulation of venous lactate level

Fig. 2 Schematic diagram showing mechanisms underlying impaired beta plaque, CBF cerebral blood flow, BDNF brain-derived neurotrophic
cognition associated with hypertension and beneficial role of exercise factor, GDNF glial cell-derived neurotrophic factor, nNOS neuronal nitric
training on learning and memory process in hypertension. Aβ amyloid- oxide synthase, SNA sympathetic nerve activity
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Table 4 Effects of exercise training on cognitive function

Investigators, year Patient characteristics Exercise protocol Cognitive function

Drigny et al. (2014) [65] Obese patients (mean age 49) 2 sessions of AIT (2–3 10-min reps at of 15–30 s at 80 % of maximal aerobic Improved short-term memory, attention,
power (MAP), with 15–30 s rest), 1 session of MICT (1 h at 60 % of peak processing speed, verbal memory
power output) and 2 resistance training sessions per week). Duration 4 months
(N=6). No control group
Chin et al. (2015) [66] Chronic mild-mod non-penetrating TBI patients Treadmill exercise 3 days/week, 30 min/session. 60-min sessions. Improved cognitive function
(mean age 33) Duration 12 weeks (N=7). No control group
Hillman et al. (2014) [67] Healthy 7–9-year-old children 30–40 min mod-vigorous physical activity, 44–55 min rest on 150 days Improved inhibition and cognitive flexibility
out of 170 school days (N=221). +Control group
Nascimento et al. (2014) [60••] Age≥60 with and without MCI (mean age 67) 3, 1-h moderate exercise/week for 16 weeks. Exercise to achieve Improved BDNF and MoCA.
60–80 % of max HR (N=67). +Control group Decreased TNF alpha and IL6
Nouchi et al. (2014) [68] General healthy population (mean age 67) Combination ET (aerobic, strength, and stretching exercise trainings) Improved executive functions, episodic
3 days/week, 30 min/session × 4 weeks. Target HR 60–80 % (N=64). memory, and processing speed
+Control group
Forte et al. (2013) [69] Healthy (mean age 69) 1 h sessions (coordination/balance/strengthening/agility), followed by floor Improved indices of inhibition
exercises including stretching, strengthening, and relaxation. 2×/week
for 3 months (N=42). No control group
David et al. (2015) [70] Mild-moderate dementia patients (mean age 58) mFC for 60–90 min, 2×/week for 24 months VS PRET for 60–90 min, Both exercises improved attention and
2×/week for 24 months (N=46 at first, 38 at second year). No control working memory.
Loprinzi et al. (2015) [71] Young adults (mean age 22) 4 aerobic exercise groups (no exercise), light intensity (40–50 % max HR), Improved concentration-related cognition
moderate intensity (51–70 % max HR), or vigorous intensity (71–85 %
of max HR) (N=87). +Control group
Nagamatsu et al. (2013) [72] Probable MCI, female patients (age 70–80) Resistance training: 60 min. 2×/week. 2 sets, progressively increasing Improved memory with aerobic and
from 6 to 8 repetitions. Aerobics 2×/week is walking at 40–80 % HRR. resistance training
Duration 6 months (N=86). +Control group
Cancela et al. (2015) [73] Dementia patients (mean age 80) Aerobic exercise at least 15 min per day for 15 months (N=104). +Control group Improved cognitive function and memory
Yu et al. (2014) [74] Mild to moderate Alzheimer’s disease patients Moderate intensity cycling, 20–50 min/session, 3× a week for 6 months (N=90) Ongoing. Will measure effect of exercise
(age ≥66) on hippocampus volume, cognitive decline,
and acute cognition

BDNF brain-derived neurotrophic factor, ET exercise training, AIT aerobic interval training, HR heart rate, HRR heart rate response, IL-6 interleukin-6, MICT moderate-intensity continuous training, mFC
modified fitness count, MoCA Montreal Cognitive Assessment, PRET progressive resistance exercise training, TNF tumor necrosis factor
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resulting in an attenuated metaboreceptor-mediated increase Similarly, a prospective cohort study in participants between
in BP in healthy subjects [34]. Whether whole-body ET will 75 and 89 years of age without history of stroke demonstrated
exert similar influence on EPR in hypertensive patients re- that increased 24-h ambulatory systolic BP was associated
mains unknown. Studies which addressed the role of ET on with increased white matter hyperintensity (WMH) as well
EPR in animals have mainly used dynamic form of exercise to as measures of executive function/processing speed over 24-
date [29]. Whether different modes of exercise will have sim- month follow-up [51]. Interestingly, clinic systolic BP was not
ilar effects on the EPR is also unknown. predictive of cognitive decline or increased WMH in the same
study [51], which underscores the importance of using 24-h
Effects of Exercise Training on Brain Structure ambulatory BP to reliably assess the BP-brain health relation-
and Cognitive Function ship in the elderly population. Whether ET improves cognitive
function in hypertensive patients and whether the potential
Endurance exercise training not only has benefits on neural benefit of ET on the brain is independent of its effects on BP
and non-neural regulation of BP but also may improve cogni- reduction remain unknown.
tive function [35]. Studies in hypertensive and normotensive
rats have shown similar benefits of resistance vs. endurance
ET on memory function [36–38]. Similarly, studies in other- Conclusion
wise healthy older adults showed improvement in executive
function and episodic memory. Furthermore, ET for several Exercise training benefits cardiovascular autonomic regula-
months to a year increased regional brain volume involved in tion of BP and improves cognitive function in older adults.
executive function and memory, which includes the gray mat- The optimal dose and modality of exercise to improve BP and
ter volume in the prefrontal and cingulate cortex [39] and the maintain brain health is unknown and may depend on the age,
hippocampus [40]. These changes are thought to be related to sex, and comorbid conditions in individual patients.
exercise-induced increases of neurotrophic factors such as Additional studies are needed to determine if newer modes
brain-derived neurotrophic factor (BDNF), insulin-like of exercise, such as moderate- to high-intensity aerobic inter-
growth factor 1 (IGF-1), or vascular endothelial growth factor val training, interval training, or isometric handgrip exercise,
(VEGF), resulting in increased neurogenesis and brain den- will offer advantage over the traditional moderate-intensity
drites, which is the opposite finding observed in the brainstem continuous endurance training in reducing the burden of hy-
centers [41, 42]. Increase in brain perfusion in the cingulate pertension and hypertensive brain damage.
cortex and hippocampus has also been demonstrated, most
likely reflecting neurovascular coupling as shown in Fig. 2 Compliance with Ethics Guidelines
[43]. ET also may reduce brain amyloid-β burden, a hallmark
of Alzheimer’s disease (A) [44••].
The Bdose-response^ relationship between ET and changes Conflict of Interest Drs. Peri-Okonny, Fu, Zhang, and Vongpatanasin
in brain structure and function is not known. Several studies declare that they have no conflicts of interest.
have shown improvement in cognitive function after 6 months
Human and Animal Rights and Informed Consent This article does
or year-long exercise training (Table 4). However, significant not contain any studies with human or animal subjects performed by any
improvement in memory has been observed with only of the authors.
12 weeks of ET [43]. A shorter duration of ET plus resistance
training (leg press) of 8 weeks, however, was not shown to Funding Support Dr. Vongpatanasin is supported by R01HL078782
improve cognitive function in participants older than 90 years and RO1HL113738.
of age [45]. More recently, the benefit of ET on cognitive
function has been extended to the sedentary middle-aged
adults [46] and young adults with intellectual disability [47]. References
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Hypertension is known to be an independent risk factor for • Of importance
AD and cognitive impairment after stroke [48••]. In transgenic •• Of major importance
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