J Appl Physiol 133: 902–912, 2022.

First published September 15, 2022; doi:10.1152/japplphysiol.00241.2022

RESEARCH ARTICLE

Physical Activity and the Brain

Aerobic exercise training reduces cerebrovascular impedance in older adults: a

1-year randomized controlled trial
Jun Sugawara,1,2,3 Takashi Tarumi,1,2,3 Changyang Xing,1,2,4 Jie Liu,1,2 Tsubasa Tomoto,1,2
Evan P. Pasha,1,2 and Rong Zhang1,2
1
Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, Dallas, Texas; 2University of
Texas Southwestern Medical Center, Dallas, Texas; 3Human Informatics and Interaction Research Institute, National Institute
of Advanced Industrial Science and Technology, Tsukuba, Japan; and 4Department of Ultrasound Diagnostics, Tangdu
Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China

Abstract
Older adults have higher cerebrovascular impedance than young individuals which may contribute to chronic brain hypoperfusion.
Besides, middle-aged athletes exhibit lower cerebrovascular impedance than their sedentary peers. We examined whether aerobic
exercise training (AET) reduces cerebrovascular impedance in sedentary older adults. We conducted a proof-of-concept trial that
randomized 73 older adults to 1 yr of AET (n = 36) or stretching and toning (SAT, n = 37) interventions. Cerebrovascular impedance
was estimated from simultaneous recordings of carotid artery pressure (CAP) via applanation tonometry and cerebral blood flow ve-
locity (CBFV) in the middle cerebral artery via transcranial Doppler using transfer function analysis. Fifty-six participants completed 1-yr
interventions, and 41 of those completed cerebrovascular impedance measurements. AET group showed a significant increase in
V_ O2peak after the intervention [estimated marginal mean (95% confidence interval); from 22.8 (21.6 to 24.1) to 24.9 (23.6 to 26.2)
mL·kg 1·cm 1, P < 0.001], but not SAT [from 21.7 (20.5 to 22.9) to 22.3 (21.1 to 23.7) mL·kg 1·cm 1, P = 0.114]. Coherence between
changes in CBFV and CAP was >0.90 in the frequency range of 0.78–3.12 Hz. The averaged cerebrovascular impedance modulus
(Z) in this frequency range decreased after 1-yr AET [from 1.05 (0.96 to 1.14) to 0.95 (0.92 to 1.06) mmHg·s·cm 1, P = 0.023], but not
SAT [from 0.96 (0.87 to 1.04) to 1.01 (0.92 to 1.10) mmHg·s·cm 1, P = 0.138]. Reductions in Z were correlated positively with reductions
in carotid pulse pressure (r = 0.628, P = 0.004) and inversely with mean CBFV (r = 0.563, P = 0.012) in the AET group. One-year
AET reduces cerebrovascular impedance in older adults, which may benefit brain perfusion.
NEW & NOTEWORTHY Estimation of cerebrovascular impedance is essential for understanding dynamic cerebral blood flow
regulation. This randomized controlled trial demonstrated that aerobic exercise training reduced cerebrovascular impedance in
older adults, which may benefit brain perfusion.

aerobic exercise training; aging; arterial stiffness; cardiorespiratory fitness; transfer function analysis

INTRODUCTION abnormalities and increased risk of Alzheimer disease and

The brain is continuously perfused with high volume of
blood flow because of its high metabolic rate and relatively
low vascular resistance (1, 2). Since cerebrovascular resist-
ance is relatively low compared with the other vascular beds,
small cerebral blood vessels are exposed to high-pressure
fluctuations (3). Thus, the cushioning function of the large
elastic central arteries (e.g., the proximal aorta and carotid
arteries), the so-called Windkessel effects, likely plays an
essential role in maintaining brain health (3). However, with
advancing age, the Windkessel function of the central
arteries may deteriorate due to arterial stiffening (4–6),
which has been related to brain structural and functional
related dementias (3, 7–9). Likewise, the Windkessel function
of the intracranial large cerebral arteries is also likely to be
diminished with aging due to arterial stiffening (10–14). The
precise underlying mechanisms by which central and large
cerebral arterial stiffening lead to brain structural and func-
tional abnormalities remain not fully understood. Recent
studies suggest that the elevated central arterial pressure
and blood flow pulsatility associated with arterial stiffening
are important hemodynamic changes, which may contribute
to cerebral endothelial dysfunction and development of cer-
ebral small vessel disease (15, 16).
Aerobic exercise training (AET) improves central arterial
compliance even in late life (6, 17, 18). However, such

Correspondence: R. Zhang (RongZhang@texashealth.org).

Submitted 2 May 2022 / Revised 17 August 2022 / Accepted 2 September 2022

902 8750-7587/22 Copyright © 2022 the American Physiological Society. http://www.jap.org

Downloaded from journals.physiology.org/journal/jappl at CAPES-USP (143.107.252.134) on November 5, 2022.
 CEREBROVASCULAR IMPEDANCE AND AEROBIC EXERCISE TRAINING
evidence is lacking regarding the large cerebral arteries.
Cross-sectional studies demonstrated that higher aerobic
capacity was associated positively with cerebral arterial com-
pliance among young, healthy adults (10, 19). Our studies also
showed that middle-aged Masters athletes had lower cerebro-
vascular impedance than their sedentary age-matched con-
trols, which suggested higher cerebral arterial compliance in
the athlete group. Moreover, the lower cerebrovascular im-
pedance in athletes was associated with higher cerebral blood
flow velocity (CBFV) with transcranial Doppler (TCD) and cer-
ebral cortical perfusion measured with magnetic resonance
imaging (MRI) arterial spin labeling (ASL) (10). Given the limi-
tations of these cross-sectional studies, it is important to
determine whether AET can reduce cerebrovascular imped-
ance in older adults using interventional design.
Several studies have evaluated the Windkessel function of
the cerebrovasculature with pulsatile changes in cerebral
blood flow (CBF) using MRI ASL (19) or CBFV using TCD (20)
at a given change in blood pressure (BP) measured in the
brachial artery. Although these studies have advanced our
understanding of cerebral arterial compliance in human
subjects, a major limitation was the measurement of periph-
eral rather than cerebral or central arterial pressure in these
studies. Central arterial pressure does not correspond to pe-
ripheral arterial pressure due to the pulse pressure (PP)
amplification as pressure waves propagate from the central
to the periphery arteries (21). Thus, the accuracy of cerebral
arterial compliance reported in these previous studies is a
major concern. In addition, because of the presence of blood
flow inertia, vascular resistance, and arterial distensibility,
measurement of arterial compliance with instantaneous
blood flow through a cardiac cycle divided by the corre-
sponding change in BP may not be appropriate for describ-
ing the dynamic pressure-flow relationship (22). In this
regard, estimation of arterial input impedance, a frequency-
domain approach used to quantify the dynamic pressure-
flow relationship of a vascular bed, reflects not only local ar-
terial properties where BP and flow are measured but also
the properties of the downstream vascular bed (i.e., vascular
resistance and compliance) (21).
The purpose of this study was to determine the effects of
1-yr AET on cerebrovascular impedance in older individuals
and its relationship with changes in mean CBFV and CBFV
pulsatility. We hypothesized that 1) 1-yr AET would reduce
cerebrovascular impedance when compared with the active
control group of stretching and toning (SAT) and 2)
decreases in cerebrovascular impedance are correlated with
increases in mean CBFV measured in the middle cerebral ar-
tery (MCA).
METHODS
Study Design and Subjects
This was a 12-mo open-label randomized controlled trial
(RCT) to investigate the effect of a 1-yr progressive, moder-
ate-to-vigorous AET program on neurocognitive function in
cognitively normal older adults who previously had a seden-
tary lifestyle (22). Neurocognitive function assessments
included the domains of inductive reasoning, long-term epi-
sodic memory, working memory, processing speed, and
J Appl Physiol  doi:10.1152/japplphysiol.00241.2022  www.jap.org
Downloaded from journals.physiology.org/journal/jappl at CAPES-USP (143.107.252.134) on November 5, 2022.
verbal ability which were reported in a previous study (22).
The present study reported changes in cerebrovascular im-
pedance with AET and SAT, which was a secondary outcome
of the parent study. This study was approved by the
Institutional Review Board of the University of Texas
Southwestern Medical Center and Texas Health Presbyterian
Hospital Dallas in accordance with the guidelines of the
Declaration of Helsinki and Belmont Report (STU 102010-
069). All participants gave written informed consent before
participation. This trial was not registered because at the
time of trial initiation, registration of nonpharmacological
interventional studies in healthy adults in a public database
was neither required nor typical.
A flowchart for this RCT characterizing participant
recruitment and inclusion is presented in Supplemental Fig.
S1(all Supplemental material is available at https://doi.org/
10.6084/m9.figshare.19666251). This study targeted cogni-
tively normal sedentary but otherwise healthy men and
women aged 60–80 yr. Recruitment was conducted in the
Dallas-Fort Worth metropolitan area using community-
based advertisements. At an initial telephone screening, par-
ticipants were screened if they had subjective cognitive com-
plaints or a history of major clinical conditions, regularly
engaged in a structured exercise program, and could partici-
pate in a 1-yr AET or SAT program including the required
visits for data collection. Subsequently, participants were
asked to visit our clinical office and screened for the follow-
ing exclusion criteria: 1) clinical diagnosis of major psychiat-
ric or neurological disorders or medications causing major
effects on cognition, 2) a history of active alcoholism or drug
abuse, 3) a history of recurrent epilepsy, stroke, or head
injury/trauma with a loss of consciousness  30 min, 4)
Mini-Mental Status Examination (MMSE) score < 26 to
exclude dementia, 5) uncontrolled hypertension (averaged
three measurements of sitting systolic BP  140 or diastolic
pressure  90 mmHg confirmed by 24-h ambulatory BP mon-
itoring), 6) a diagnosis of diabetes mellitus (fasting glucose >
126 mg/dL or taking antidiabetic medications), 7) severe obe-
sity with body mass index (BMI)  35 kg/m2, 8) smoking
within the past 5 yr of the study, 9) other major or unstable
medical conditions such as a history of coronary bypass sur-
gery or heart attack within the past year, ongoing chemother-
apy, or severe lung, kidney and liver disease, 10) individuals
who spent >90 min of moderate-to-vigorous physical activity
[>4.0 metabolic equivalents (METs)] per week were excluded,
as determined by a 1-wk physical activity monitoring using
an accelerometer (Actical, Philips Respironics), and 11) indi-
viduals with physical disability, metal implants in the body,
or claustrophobia precluding MRI scans were excluded.
Among the 991 candidates screened by phone, 152 older
adults were invited to the clinic for further in-person screen-
ing. Seventy-nine of these were excluded because they either
did not meet the inclusion and exclusion criteria or did not
complete baseline measurements.
Randomization and Blinding
Randomization was performed in SAS V9.2 using two
stratification groups, sex (men and women), and education
(10–14 and 15–20 yr), using a blocking factor of four. The ran-
domization assignments were generated by the study
903
 CEREBROVASCULAR IMPEDANCE AND AEROBIC EXERCISE TRAINING

statistician and placed in a sealed envelope so that the study SAT was used as an active control group to keep partici-
personnel were blinded until opening the envelope for treat- pants engaged with the same level of attention from the
ment assignment of an individual subject. Investigators con- investigators as those for the AET group. The frequency and
ducting the primary and secondary outcome measurements duration of the SAT program were the same as the AET pro-
were blinded to treatment assignment throughout the study. gram. An SAT routine that focuses on the upper and lower
Participants were instructed to maintain normal daily activ- body was used. In this group, participants were asked to
ities aside from the assigned interventions and were keep their heart rate below 50% of the maximal heart rate
instructed not to disclose group assignments or interven- during each session. At week 19, we introduced a second set
tions during outcome measurements or to meet with other of full body stretches that are more advanced than the previ-
participants. Finally, 73 individuals were randomly assigned ous set. At week 26, we introduced a set of low resistance
to SAT (n = 37; 28 women, 68 ± 5 yr of mean age) or AET (n = TheraBand exercise that focuses on strengthening the upper
36; 27 women, 69 ± 6 yr of mean age). Their demographic and lower body.
characteristics at baseline are summarized in Table 1. In both AET and SAT programs, each participant was
supervised by an exercise physiologist for the first 4–6 wk
Intervention
until they could comfortably and safely perform the assigned
AET and SAT programs were conducted with the same program by themselves either at a fitness center or home.
protocol as previously reported (23). The dose and intensity During the study period, they were asked to perform an
of the AET program were based on each individual’s fitness assigned intervention on top of their regular physical activ-
level assessed with peak oxygen uptake (V_ O2peak) testing, and ities. To ensure adherence to each program, participants
progressively increased as participants adapted to previous were required to make a training log in addition to heart rate
workloads. Specifically, the program started with a fre- monitoring. Each month, participants visited the clinic to
quency of 3 exercise sessions per week for 25–30 min per ses- download heart rate data and review their training log to-
sion at the intensity of 75%–85% of maximal heart rate that gether with an exercise physiologist to ensure the implemen-
was measured during V_ O2peak testing at baseline. At week 11, tation of the prescribed training programs. When adherence
participants started alternating between 3 and 4 exercise ses- to exercise programs was not met with the prescribed inten-
sions per week for 30–35 min per session, and at the weeks sity, duration, and frequencies, in-person and/or telephone
in which they performed 3 exercise sessions per week, a meetings were held to solve the issues and encourage partici-
high-intensity exercise session was introduced, which con- pants to continue the program. Training compliance was cal-
sists of 30 min of walking at the intensity of 85%–90% of culated by the ratio of prescribed exercise sessions over the
maximal heart rate (e.g., brisk uphill walking). After week 26, completed exercise sessions in which participants achieved
participants performed 4–5 exercise sessions per week for the prescribed target heart rate (23).
30–40 min, including two high-intensity sessions. Any
modes of aerobic exercise were allowed as long as they main- Data Collection
tained the prescribed training dose and intensity, as moni- In each participant, cardio- and cerebrovascular testing
tored by changes in heart rate during each of the exercise and cardiorespiratory fitness measurement were performed
sessions (Polar RS400, Polar Electro). This AET program before and 1 yr after the start of intervention. This RCT
meets the national physical activity guidelines for older involved MRI, cognitive function, and cerebral autoregula-
adults (24). It has been used in our previous studies that tion measurements in addition to data reported in this arti-
showed significant improvement of cardiorespiratory fitness cle. Each participant continued SAT or AET intervention till
in sedentary individuals older than 65 yr of age (25). the completion of all postmeasurements. All data were col-
lected in an ambient temperature-controlled laboratory
(22 C). Subjects abstained from caffeinated beverages, alco-
Table 1. Participants’ demographics by randomization hol, and vigorous exercise at least 24 h before testing.
groups
Cardio- and Cerebrovascular Testing
Variables SAT AET P Value
All vascular measurements were performed under the
n, men/women 37 (9/28) 36 (10/27) 0.947
Age, yr 68 ± 5 69 ± 6 0.419 supine position after quiet resting for 10 min with nor-
Race, white/black 34/3 36/0 0.947 mal breathing. ECG (via the three-lead system, Hewlett-
Education, yr 16 ± 2 17 ± 2 0.160 Packard), end-tidal CO2 (ETCO2 , via a nasal cannula using
Height, cm 164.8 ± 8.6 165.9 ± 8.3 0.559 capnography, Capnogard; Novametrix), and CBFV in the
Weight, kg 74.0 ± 10.7 71.5 ± 15.6 0.423
Body mass index, kg/m2 27.3 ± 3.6 25.8 ± 4.4 0.120
MCA via TCD were recorded simultaneously. CBFV was
Medications measured over the temporal window using a 2-MHz TCD
Antihypertensives, n 5 8 0.331 probe (Multi-Dop X2; DWL, Singen, Germany). Briefly, the
Cholesterol-lowering, n 12 8 0.328 probe was securely attached to the temporal bone acoustic
Physical activity, min/day
window by using either an individually created mold to fit
Light (<4.0 METs) 240 ± 91 221 ± 81 0.372
Moderate (4.0–5.0 METs) 4±4 4±5 0.938 the facial bone structure or a probe holder (Spencer
Vigorous (>5.0 METs) 2±4 1±3 0.474 Technologies, Seattle, WA) to keep the position and angle
Values represent means ± standard deviation. n is number of
of the probe unchanged during the assessment. To ensure
subjects. AET, aerobic exercise training; METs, metabolic equiva- the same location of TCD recording in each subject before
lents; SAT, stretching and toning. and after the intervention, we recorded the probe location,

904 J Appl Physiol  doi:10.1152/japplphysiol.00241.2022  www.jap.org

Downloaded from journals.physiology.org/journal/jappl at CAPES-USP (143.107.252.134) on November 5, 2022.
 CEREBROVASCULAR IMPEDANCE AND AEROBIC EXERCISE TRAINING

Table 2. Systemic hemodynamics and cardiorespiratory fitness by randomization groups

SAT AET Time Group Interaction
F Value
n EMM 95% CI n EMM 95% CI P value
Weight, kg
Pre 37 73.5 (69.2–77.7) 36 71.8 (67.5–76.2) 0.942 0.608 0.893
Post 28 73.5 (69.1–77.8) 28 70.4 (66.0–74.9) 0.336 0.438 0.349
Body mass index, kg/m2
Pre 37 27.3 (25.8–28.4) 36 25.8 (24.6–27.3) 1.120 2.236 0.390
Post 28 27.0 (25.6–28.4) 28 25.4 (24.1–26.8) 0.294 0.139 0.535
Heart rate, bpm
Pre 37 62 (59–65) 36 64 (61–66) 0.712 0.054 2.981
Post 28 63 (60–65) 28 62 (59–65) 0.403 0.816 0.090
Systolic blood pressure, mmHg
Pre 37 113 (109–117) 36 116 (112–120) 0.202 0.048 2.451
Post 28 115 (111–119) 28 113 (109–117) 0.655 0.828 0.123
Mean arterial pressure, mmHg
Pre 37 88 (85–90) 36 88 (85–90) 2.276 0.274 0.786
Post 28 87 (84–90) 28 85 (82–88) 0.137 0.602 0.379
Diastolic blood pressure, mmHg
Pre 37 70 (67–72) 36 67 (65–70) 1.370 1.174 0.745
Post 28 68 (66–71) 28 67 (65–70) 0.247 0.282 0.392
Pulse pressure, mmHg
Pre 37 43 (40–47) 36 49 (45–52) 0.012 0.879 5.605
Post 28 47 (43–50) 28 46 (42–49) 0.914 0.352 0.021
V_ O2peak, mL/kg/min
Pre 37 21.7 (20.5–22.9) 36 22.8 (21.6–24.1) 22.35 4.681 6.050
Post 28 22.3 (21.1–23.7) 28 24.9 (23.6–26.2) † 0.000 0.034 0.017

Values represent estimated marginal means (EMM) [95% confidence interval (CI)]. F values (upper row) and P values (lower row) were
calculated from the linear mixed model (LMM). n is the number of observations. The Bonferroni correction was applied for multiple pair-
wise comparisons. Significant difference (P < 0.05) vs. baseline within the same group. †Significant difference (P < 0.05) vs. SAT. AET,
aerobic exercise training; SAT, stretching-and-toning; V_ O2peak, peak oxygen uptake.

depth of insonation, gain, and bony landmarks during pre-
measurement and used precisely the same setup for the
postmeasurement, as previously recommended (26). In
addition, brachial cuff pressure (via electrosphygmoma-
nography; Suntech) was acquired three times and calcu-
lated the average systolic and diastolic BP and PP. Using
an applanation tonometry system (SphygmoCor 8.0; AtCor
Medical), the right brachial and the carotid (ipsilateral to
the CBFV measurement) arterial pressure waveforms were
recorded over 10 s at least three times. A pressure sensor
was directly placed on the skin and pressed on the arteries
at a location where the strongest pulse was felt. During ca-
rotid arterial pressure (CAP) measurement, subjects were
asked to raise their chin slightly. The probe was held
directly over the pulse, staying as close to vertical to the
vessel axis as possible, and using light pressure to appla-
nate the underlying vessel wall (27). Recordings were
taken only when a clean signal was obtained with high-
amplitude excursion. Based on the quality-control process
incorporated into the SphygmoCor system, the most repro-
ducible waveforms over 10 s with higher pulse amplitude,
smaller pulse amplitude variation, and smaller diastolic
variation were extracted at the brachial and the carotid
arteries (28). Mean arterial pressure (MAP) was defined as
the time-averaged area under the brachial arterial pressure
waveforms over 10 s, which was corrected by the cuff sys-
tolic and diastolic BP as previously reported (17, 29). CAP
waveform recorded as the change in voltage was calibrated
with the assumption that the mean and diastolic CAPs are
equal to those of brachial arterial pressure (17, 29). CAP
and CBFV waveforms were recorded continually for 10 s
for spectral analysis. All signals were stored on a computer
using a commercial software package for data acquisition
(AcqKnowledge 4.2; Biopac Systems Inc.) with a sampling
frequency of 1k Hz.
Data Analysis
Frequency-domain analysis.
Cerebrovascular impedance was evaluated by the transfer
function method from pulsatile changes in CBFV (as an
input signal) and CAP (as an output signal) for 10 s as we pre-
viously reported (10–12). For this calculation, auto-spectra
and cross-spectra of CBFV and CAP were estimated using the
Welch algorithm (30) as follows. Time series of CBFV and
CAP waveforms were resampled at 100 Hz and were subdi-
vided into 256-point segments (2.56 s) with 50% overlap for
spectral estimation. To reduce the potential effects of includ-
ing fractional cardiac cycles in these data segments on spec-
tral estimation, each data segment was multiplied by a
Hamming window before the periodogram estimation and
average (31). This process resulted in a spectral resolution of
0.39 Hz. Because each data set is short (i.e., 10 s) and does
not include slow fluctuations, results at the frequency
<0.78 Hz were omitted. In cerebrovascular impedance
analysis, the coherence function provides the strength of
the linear relationship between CAP to CBFV. The trans-
fer function method is valid only if the system to be
identified is linear. Previous studies (10–12) demon-
strated that in middle-aged and older subjects, coher-
ence is higher than 0.9 at the frequency <3 Hz where
most of energy was included and decreases gradually
above 3 Hz. These results demonstrated a strong linear
relationship between pulsatile changes in CBFV and CAP
at this frequency range, suggesting the validity of using

J Appl Physiol  doi:10.1152/japplphysiol.00241.2022  www.jap.org 905

Downloaded from journals.physiology.org/journal/jappl at CAPES-USP (143.107.252.134) on November 5, 2022.
 CEREBROVASCULAR IMPEDANCE AND AEROBIC EXERCISE TRAINING

Table 3. Carotid arterial and cerebrovascular measurements by randomization groups

SAT AET P Value (LMM)
Time 3
n EMM 95% CI n EMM 95% CI Time Group Group
Carotid systolic blood pressure, mmHg
Pre 31 113 (108–117) 30 115 (111–120) 0.495 0.762 0.087
Post 23 115 (110–120) 19 110 (105–116)
Carotid pulse pressure, mmHg
Pre 31 43 (39–47) 30 48 (43–52) 0.986 0.756 0.022
Post 23 47 (42–52) 19 44 (39–49)
Systolic CBFV, cm/s
Pre 31 80 (73–87) 30 80 (73–87) 0.617 0.896 0.770
Post 23 81 (74–89) 19 80 (72–88)
Mean CBFV, cm/s
Pre 31 52 (47–56) 30 51 (46–55) 0.613 0.737 0.907
Post 23 51 (46–55) 19 50 (45–55)
Diastolic CBFV, cm/s
Pre 31 31 (28–33) 30 30 (27–33) 0.096 0.685 0.941
Post 23 29 (26–32) 19 28 (25–31)
Pulsatile CBFV, cm/s
Pre 31 49 (44–54) 30 50 (45–55) 0.103 0.988 0.698
Post 23 52 (47–57) 19 52 (46–57)
CVRi, mmHg·s·cm-1
Pre 31 1.8 (1.6–1.9) 30 1.8 (1.7–2.0) 0.868 0.810 0.638
Post 23 1.8 (1.6–2.0) 19 1.8 (1.6–2.0)
Z1, mmHg·s·cm-1
Pre 31 1.02 (0.93–1.11) 30 1.12 (1.03–1.21) 0.697 0.669 0.020
Post 23 1.08 (0.98–1.18) 19 1.03 (0.93–1.14)
ETCO2 , %
Pre 31 37.0 (35.7–38.4) 30 36.7 (35.3–38.1) 0.093 0.294 0.410
Post 17 36.4 (34.7–38.2) 18 35.0 (33.2–36.7)
Values represent estimated marginal means (EMM) [95% confidence interval (CI)] and P values calculated from the linear mixed
model (LMM). n is the number of observations. The Bonferroni correction was applied for multiple pairwise comparisons. AET, aerobic
exercise training; CBFV, cerebral blood flow velocity; CVRi, cerebrovascular resistance index; ETCO2 , end-tidal carbon dioxide; SAT,
stretching-and-toning; Z1, the impedance modulus corresponded to the first harmonics of CBFV and carotid artery pressure (CAP; 0.78–
1.56 Hz).

the transfer function method. Prior to the aforemen-
tioned analysis, we assessed the reproducibility of cere-
brovascular impedance measurement with repeated CAP
and CBFV measurements in nine healthy adults in the
same study session that lasted from 5 to 10 min and con-
firmed that the impedance moduli obtained between
0.78 to 3.12 Hz had excellent reproducibility [R2 = 0.894,
mean difference and standard deviation (SD) of two measure-
ments = 0.03 ± 0.05 mmHg2/(cm/s)2; Supplemental Figs. S2
and S3]. Accordingly, in the present study, we focused on the
frequency range from 0.78 to 3.12 Hz. In addition, to highlight
the cerebrovascular buffering function, we obtained imped-
ance modulus at the frequency range from 0.78 to 1.56 Hz,
where the fundamental first harmonics of CBFV and CABP
corresponding to the resting heart rate were contained, as Z1
(10). Even though CAP is likely to be a good estimate of MCA
pressure given the fact that MCA is a direct branch of the in-
ternal carotid artery (ICA) and the distance between the ICA
and MCA is relatively short (10 cm), a time delay of pressure
wave propagation from the carotid artery to the MCA would
be a confounding factor for the impedance phase estimation.
Therefore, we decided not to report the phase results.
Time-domain analysis.
The averaged values of ETCO2 , heart rate, brachial BP and PP,
carotid BP and PP, and CBFV were obtained from breath-by-
breath or beat-by-beat values during the corresponding period
of cerebrovascular impedance measurement. Cerebrovascular
resistance index (CVRi) was calculated as a ratio of mean CAP
to mean CBFV.
Cardiorespiratory Fitness
V_ O2peak, the gold standard measure of cardiorespiratory
fitness, was collected using a modified Astrand–Saltin pro-
tocol on a treadmill (32, 33). The treadmill grade was
increased by 2% every 2 min until exhaustion while partic-
ipants walked or jogged at a fixed speed, which was deter-
mined by the individual fitness level (34). Specifically, the
treadmill speed was determined during a submaximal
warm-up exercise test before V_ O2peak testing to achieve a
HR response of 65%–75% of an individual’s estimated
maximal HR (25, 34). V_ O2 was measured during the 2nd
minute of each stage using the Douglas bag method. Also,
the breath-by-breath V_ O2, V_ CO2, respiratory exchange ratio
(RER), and ventilation were continuously monitored using
an online computer system. Gas fractions were analyzed
by mass spectrometry (Marquette MGA 1100), and ventila-
tory volume was measured by a Tissot spirometer. BP, 12-
lead ECG, and heart rate were monitored continuously
during exercise testing to assess cardiovascular responses.
V_ O2peak was defined as the highest V_ O2 measured from a >
30-s Douglas bag during the last stage of testing. The crite-
ria to confirm that V_ O2peak was achieved included an
increase in V_ O2 <150 mL despite increasing work rate of
2% grade, an RER > 1.1, and heart rate < 5 beats/min of
age-predicted maximal values (e.g., 220 age). In all cases,

906 J Appl Physiol  doi:10.1152/japplphysiol.00241.2022  www.jap.org

Downloaded from journals.physiology.org/journal/jappl at CAPES-USP (143.107.252.134) on November 5, 2022.
 CEREBROVASCULAR IMPEDANCE AND AEROBIC EXERCISE TRAINING

Group-Time interaction: P=0.164

1.05 1.05
SAT AET
1.00 1.00

Coherence
Coherence

0.95 0.95

0.90 0.90
Pre: n=37 Pre: n=36
Post: n=22 Post: n=19
Figure 1. Group-averaged frequency plots
0.85 0.85 of cerebrovascular impedance modulus
1 2 3 1 2 3
(Z) and coherence before and after 1 yr of
Frequency (Hz) Frequency (Hz) stretching and toning (SAT) and aerobic
exercise training (AET) programs. Solid
Group-Time interaction: P=0.017 and broken lines represent estimated mar-
1.4 1.4 ginal means and 95% confidence inter-
1.3
vals, respectively. Black lines and red lines
SAT 1.3 AET
Z (mmHg·s·cm-1)

are Pre and Post.

Z (mmHg·s·cm-1)

1.2 1.2
1.1 1.1
1.0 1.0
0.9 0.9
P=0.138 P=0.023
0.8 0.8
Pre: n=37 Pre: n=36
0.7 Post: n=22 0.7 Post: n=19
0.6 0.6
1 2 3 1 2 3
Frequency (Hz) Frequency (Hz)

at least two of these criteria were achieved, confirming the
identification of V_ O2peak based on the American College of
Sports Medicine guidelines (24). Our previous study
showed that by using these methods, V_ O2peak can be meas-
ured reliably in sedentary older adults (25, 34).
Statistics Analysis
To compare participants’ demographics between the
AET and SAT groups, independent sample t test was used
for continuous variables and v2 test was used for categori-
cal variables. Data are presented as means and SD for con-
tinuous variables or frequency for categorical variables.
The data analysis for the RCT was based on the intent-to-
treat principle (35) using all available data from the
randomized subjects (SAT: n = 37, AET: n = 36). For the
analysis of cerebrovascular impedance [e.g., coherence
and impedance modulus (Z)], a linear mixed model was
used to analyze the main and interaction effects of group
(AET vs. SAT), time (Pre vs. Post), and frequency (0.39 Hz-
bin from 0.78 to 3.12 Hz). The linear mixed model was also
used to analyze the main and interaction effect of group
(AET vs. SAT) and time (Pre vs. Post) on Z1 as well as other
hemodynamic measures. Post hoc multiple pairwise com-
parisons were corrected by the Bonferroni method in case
of a significant interactions. To confirm the result from the
intent-to-treat analysis, repeated-measures analysis of
variance (ANOVA) was performed on the complete case
data (SAT: n = 22, AET: n = 19). Pearson’s product-moment
correlation was used to determine the relationship
between variables of interest. All statistical analyses were
performed using SPSS 26.0 (Chicago, IL). Results from the
linear mixed model analysis were reported as estimated
marginal means and 95% confidence interval (CI). The sta-
tistical significance level was set to P < 0.05.
RESULTS
Twenty-eight (76%) and 28 (78%) participants completed
the SAT and AET intervention programs, respectively. The
averaged training compliance to aerobic exercise program
was  81.3%, as calculated by the ratio of prescribed exercise
sessions over the exercise sessions completed in which par-
ticipants achieved their target heart rate. The average com-
pliance to stretching program was  70.2%. There was no
group difference in the training compliances. The partici-
pants’ demographic characteristics, who completed hemo-
dynamics assessments, did not differ from those who
participated in the parent study.
Table 2 presents results of systemic hemodynamics and
cardiorespiratory fitness from intent-to-treat analysis. AET
group had higher V_ O2peak after the intervention when com-
pared with their baseline level (P < 0.001) and with SAT (P =
0.006), whereas V_ O2peak did not change with SAT program
(P = 0.114). Change in V_ O2peak in AET was larger than that in
SAT in the complete-case comparison (P = 0.021, Cohen’s d =
0.645). A similar tendency was seen in subjects who were
completed cerebrovascular impedance measurement
(interaction: P = 0.081; Supplemental Table S1). Change in
V_ O2peak in AET tended to larger than that in SAT (P = 0.071,
Cohen’s d = 0.596). Baseline systemic hemodynamics were
similar between the randomization groups. After the 1-yr
intervention, heart rate and brachial BP did not change
significantly. Brachial PP showed a significant group-by-
time interaction effect (P = 0.021), but no significant

J Appl Physiol  doi:10.1152/japplphysiol.00241.2022  www.jap.org 907

Downloaded from journals.physiology.org/journal/jappl at CAPES-USP (143.107.252.134) on November 5, 2022.
 CEREBROVASCULAR IMPEDANCE AND AEROBIC EXERCISE TRAINING

P=0.009 the AET group (P = 0.023) but not in the SAT group (P =
0.6 0.138). Z1 also showed a significant group-by-time interaction
effect (P = 0.020, Table 3). Pairwise comparisons revealed a
Δ Z (mmHg·s·cm-1) 0.4
tendency to reduce Z1 after 1-yr AET (P = 0.075), whereas no
0.2 significant change was observed after the 1-yr SAT (P =
0.191). The complete-case analysis also showed a significant
0
group-by-time interaction on Z1 (P = 0.024; Supplemental
-0.2 Table S1). Average Z in the frequency range from 0.78 to 3.12
-0.4
Hz (P = 0.009, Cohen’s d = 0.753) and Z1 (P = 0.021, Cohen’s
d = 0.856) exhibited significantly larger reductions with 1-yr
-0.6 AET when compared with those of SAT (Fig. 2).
SAT AET Changes in Z and Z1 were positively correlated with
(n=22) (n=19) changes in carotid PP in the AET (r = 0.628, P = 0.004 and r =
0.524, P = 0.022, respectively) and SAT (r = 0.483, P = 0.023
P=0.021 and r = 0.506, P = 0.016) groups, respectively (Fig. 3).
0.6 Changes in Z and Z1 were inversely correlated with
Δ Z1 (mmHg·s·cm-1)

0.4 changes in mean CBFV in the AET (r = 0.563, P = 0.012 and

r = 0.657, P = 0.002, respectively; Fig. 4). Similar trends
0.2 were observed in the SAT (r = 0.401, P = 0.065 and r =
0 0.370, P = 0.090, respectively). In addition, changes in Z
and Z1 were inversely correlated with changes in pulsatile
-0.2 CBFV in the SAT (r = 0.595, P = 0.003 and r = 0.614, P =
-0.4 0.002, respectively; Fig. 4). In the AET group, changes in Z1
(r = 0.479, P = 0.038), but not Z (r = 0.365, P = 0.124),
-0.6 inversely correlated with changes in pulsatile CBFV. The cor-
SAT AET
relation between changes in Z and pulsatile CBFV became
(n=22) (n=19)
significant when one outlying data (pointing with a blue
Figure 2. Changes in cerebrovascular impedance modulus (Z) over 1 yr of arrow) was removed (r = 0.607, P = 0.008).
stretching and toning (SAT, n = 22) and aerobic exercise training (AET, n =
19) programs. Data are means and standard deviation. P value was calcu-
lated by independent t test.

differences were observed from the post hoc pairwise com- ● SAT
parisons after the Bonferroni correction. There was no sig- 0.6
● AET
nificant group-by-time interaction effect in the complete- SAT (n=22)
Δ Z (mmHg·s·cm-1)

case analysis (Supplemental Table S1). r = 0.483

0.3
P = 0.023
Table 3 shows the results of carotid arterial and cerebro-
vascular testing. At the baseline, six participants in the SAT 0
AET (n=19)
and six in the AET group did not complete cerebrovascular
r = 0.628
testing because of technical issues related to the measure- -0.3 P = 0.004
ments of CAT or CBFV. At the postintervention, two partici-
pants in the AET group did not have the cerebrovascular -0.6
measurement and five participants in the SAT and seven in -30 -10 10 30
the AET group did not have reliable TCD measurements. Δ Carotid PP (mmHg)
Thus, 22 participants in the SAT and 19 in the AET group
completed the pre- and postdata collections for cerebrovas- 0.6
Δ Z1 (mmHg·s·cm-1)

cular impedance analysis (Supplemental Fig. S1). SAT (n=22)

There were no significant differences in the baseline ca- 0.3 r = 0.506
P = 0.016
rotid arterial and cerebrovascular measurements between
the randomization groups. After 1-yr intervention, carotid 0 AET (n=19)
SBP, systolic, mean, diastolic, and pulsatile CBFV, CVRi, and r = 0.524
ETCO2 did not show significant group-by-time interactions. -0.3 P = 0.022
In contrast, carotid PP exhibited a significant group-by-time
-0.6
interaction effect (P = 0.022). However, there were no signifi-
-30 -10 10 30
cant differences from post hoc pairwise comparisons after
Δ Carotid PP (mmHg)
the Bonferroni correction.
Figure 1 depicts group-averaged data of cerebrovascular Figure 3. Correlations between changes in carotid pulse pressure (PP)
impedance modulus and coherence. Coherence was higher and cerebrovascular impedance modulus with stretching and toning pro-
grams (SAT, n = 22) and aerobic exercise training (AET, n = 19). Z is the
than 0.9 irrespective of time and groups. Z exhibited a signif- averaged impedance modulus in the frequency range of 0.78–3.12 Hz. Z1
icant group-by-time interaction effect (P = 0.017). Post hoc is the impedance modulus that corresponds to the first harmonics of cere-
pairwise comparisons showed a significant reduction of Z in bral blood flow velocity and carotid arterial pressure.

908 J Appl Physiol  doi:10.1152/japplphysiol.00241.2022  www.jap.org

Downloaded from journals.physiology.org/journal/jappl at CAPES-USP (143.107.252.134) on November 5, 2022.
 CEREBROVASCULAR IMPEDANCE AND AEROBIC EXERCISE TRAINING

● SAT
● AET
Δ Mean CBFV (cm/sec)

Δ Mean CBFV (cm/sec)

30 30
20 SAT (n=22) 20 SAT (n=22)
r = 0.401 r = -0.370
10 P = 0.065 10 P = 0.090
0 0
AET (n=19) AET (n=19)
-10 r = -0.563 -10 r = -0.657
P = 0.012 P = 0.002 Figure 4. Correlations of changes in cere-
-20 -20
brovascular impedance modulus with those
-30 -30 in mean and pulsatile cerebral blood flow
-0.6 -0.3 0 0.3 0.6 -0.6 -0.3 0 0.3 0.6 velocity (CBFV) with stretching and toning
programs (SAT, n = 22) and aerobic exer-
Δ Z (mmHg·s·cm-1 ) Δ Z1 (mmHg·s·cm-1 )
cise training (AET, n = 19). Z is the averaged
impedance modulus in the frequency range
Δ Pulsatile CBFV (cm/sec)

Δ Pulsatile CBFV (cm/sec)

of 0.78–3.12 Hz. Z1 is the impedance modu-
30 30 lus that corresponds to the first harmonics
20 SAT (n=22) 20 SAT (n=22) of cerebral blood flow velocity and carotid
r = 0.595 arterial pressure. A blue arrow points an
10 10 r = -0.614
P = 0.003 outlying data.
P = 0.002
0 0
AET (n=19) AET (n=19)
-10 -10
r = -0.365 r = -0.479
-20 P = 0.124 -20 P = 0.038
-30 -30
-0.6 -0.3 0 0.3 0.6 -0.6 -0.3 0 0.3 0.6
Δ Z (mmHg·s·cm-1 ) Δ Z1 (mmHg·s·cm-1 )

DISCUSSION modulus is determined by both the vascular resistance

and stiffness, our observation of decreased cerebrovascu-
The main findings of this study were twofold. First, 1-yr lar impedance without changes in CVRi suggests that AET
AET, but not SAT, reduced cerebrovascular impedance in reduces cerebral arterial stiffness, which may improve the
older adults. Second, reductions in cerebrovascular im- buffering capability of the cerebral vasculature against
pedance after AET were correlated positively with reduc- dynamic pulsatile changes in arterial pressure and CBF. In
tions of carotid PP, and negatively with elevations in mean support of this hypothesis, a recent study from our group
CBFV. showed that 1-yr AET reduced carotid arterial stiffness,
We have shown that cerebrovascular impedance was higher increased global CBF, and reduced CBFV pulsatility in
in middle-aged and older sedentary than young sedentary patients with mild cognitive impairment (MCI) (39).
adults (10–12). Furthermore, cerebrovascular impedance in We observed that changes in cerebrovascular impedance
middle-aged endurance trained athletes was equivalent to (e.g., Z and Z1) were correlated positively with changes in ca-
that of young sedentary adults (10). These findings together rotid PP (i.e., central arterial PP) in both the AET and SAT
suggest that cerebrovascular impedance increases with aging groups. We speculate that in response to age-related eleva-
and that prolonged engagement in AET may prevent or tions in central arterial stiffness and carotid PP (40, 41), the
reduce increases in cerebrovascular impedance with aging. cerebrovascular bed may undergo compensatory remodeling
The present study extended these previous studies (10–12) by (e.g., arterial hypertrophy, vasoconstriction, and increased
showing that cerebrovascular impedance was reduced by 1-yr cerebrovascular impedance) to protect the downstream
AET in previously sedentary older individuals. Previous stud- microcirculation from the increased mechanical burden of
ies suggested that 3–4 mo of moderate-to-vigorous intensity age-related increases in central arterial PP (16) at the cost of
AET reduced central arterial stiffness in middle-aged and increased brain hypoperfusion risk. Consistently with this
older adults, which was related to improved endothelial func- hypothesis, even no main group effects of AET or SAT on ca-
tion and decreased sympathetic neural activity (17, 36, 37). rotid PP were observed in this study, at the individual level,
Therefore, AET-induced improvements in cerebral endothe- the positive associations between reductions in cerebrovas-
lial function and reductions in sympathetic neural activity cular impedance and carotid PP in both the AET and SAT
may contribute to the observed decreases in cerebrovascular group suggest that changes in cerebrovascular impedance
impedance. are coupled to changes in central arterial PP.
Interestingly, CVRi remained unchanged after the 1-yr Of note, the trend of reduced carotid PP observed in the
AET. Vascular resistance or vascular resistance index, as AET group (Table 3) was consistent with the observations
calculated by dividing MAP by mean blood flow or blood from a large population-based longitudinal study, which
flow velocity, was often used to measure vascular tone or showed that higher physical activity level in late-life, as well
vasoconstriction (38). “Resistance” has an analogous as habitual physical activity during mid- to late-life, was
meaning as “impedance,” but it is only applicable under associated with lower central arterial PP (42). The relatively
nonoscillatory or steady-flow conditions. In this regard, re- small sample size and shorter duration of AET in this and
sistance may be considered as the vascular impedance at previous training studies may have led to inconsistent find-
zero frequency (21). Considering that vascular impedance ings of the effects of AET on central arterial PP (6, 17, 18).

J Appl Physiol  doi:10.1152/japplphysiol.00241.2022  www.jap.org 909

Downloaded from journals.physiology.org/journal/jappl at CAPES-USP (143.107.252.134) on November 5, 2022.
 CEREBROVASCULAR IMPEDANCE AND AEROBIC EXERCISE TRAINING
There is a growing body of evidence suggesting salutary
effects of regular AET on brain perfusion and cerebrovascu-
lar reactivity to changes in arterial CO2 (43), although the cur-
rent findings are inconclusive (44). A cross-sectional study
indicated that habitual physical activity might attenuate the
age-related reduction in CBFV (45, 46). However, Murrell et
al. (47) showed no change in CBFV measured in the MCA at
rest after 3 mo of moderate-intensity AET in previously sed-
entary young and older adults. Conversely, Guadagni et al.
(48) observed an increase in CBFV in the MCA in healthy
middle-aged and older adults after a 6-mo moderate-inten-
sity AET. In our previous studies, we found global CBF and
cerebrovascular reactivity to changes in arterial CO2 were
improved in patients with MCI after 1-yr moderate-vigorous
intensity AET although mean CBFV measured with TCD at
the MCA remained unchanged (49). In addition, we observed
that cerebral cortical perfusion measured with MRI ASL in
middle-aged endurance athletes at rest was similar to those of
age-matched sedentary adults (10) and that lower cerebrovas-
cular impedance was associated with higher mean CBFV and
cerebral perfusion among these subjects (10). These findings
are consistent with the inverse relationship between changes
in mean CBFV and cerebrovascular impedance after 1-yr AET
in older adults, suggesting that AET reduces cerebrovascular
impedance, which may benefit brain perfusion (11).
Although we found no interventional effects on pulsatile
CBFV at the group level (Table 3), at the individual level, we
observed that changes in Z1 were associated inversely with
changes in pulsatile CBFV in the AET and SAT groups. This
is consistent with our previous findings that middle-aged
Masters athletes had significantly lower cerebrovascular im-
pedance than sedentary age-matched controls associated
with higher pulsatile CBFV (10). Of note, excessive pulsatile
flow has been proposed as a risk factor of cerebral microvas-
cular and brain damage in older adults (3, 41, 50, 51). A
recent study also reported that older adults with MCI had a
higher cerebral pulsatility index when compared with the
age-matched normal participants partly due to the increased
systemic vascular stiffness and endothelial dysfunction (52).
In this regard, our previous studies have reported that 1-yr
moderate-to-vigorous AET reduced CBFV pulsatility in older
adults with MCI (39). Thus, under these conditions, whether
AET may reduce high level of pulsatile CBF associated with
reduction in cerebrovascular impedance (i.e., due to reduc-
tions in cerebral arterial stiffness and increases in vascular
buffering effects discussed above) needs to be determined in
future studies.
We acknowledge several limitations in this study. First,
changes in CBFV measured by TCD represent changes in
CBF only when the insonated arterial diameter remains rela-
tively constant. This study did not measure MCA diameter
and could not determine whether volumetric CBF was
altered after the intervention.(41) Second, we measured
CBFV only at the MCA and could not determine how flow ve-
locity or vascular impedance might change in different cere-
bral arteries (e.g., the anterior and posterior cerebral arteries
after AET or SAT). Third, we could not examine the sex-
related differences in exercise training effects because of the
relatively small sample size, although we previously reported
that cerebrovascular impedance differed between men and
women (11). Furthermore, participants were mainly well-
910 J Appl Physiol  doi:10.1152/japplphysiol.00241.2022  www.jap.org
Downloaded from journals.physiology.org/journal/jappl at CAPES-USP (143.107.252.134) on November 5, 2022.
educated Caucasians. Thus, the findings of this study need to
be confirmed in future studies with a large sample of diverse
racial and ethnic backgrounds. Finally, both subject dropout
(23%) and technical issues with TCD have led to a discrep-
ancy in the sample size from the pre- to postintervention,
which may affect the group intervention balance achieved
with the randomization. We conducted both the intent-to-
treat and the complete-case analysis to assess the sensitivity
of the outcome measures to the differences in the sample size
before and after 1-yr interventions.
In conclusion, this RCT found that 1-yr AET reduced cere-
brovascular impedance in sedentary older adults. Given the
importance of cerebrovascular function for brain health, reg-
ular aerobic exercise represents an important lifestyle strat-
egy for preventing or slowing brain aging in our society.
SUPPLEMENTAL DATA
Supplemental Figs. S1–S3 and Supplemental Table S1: https://
doi.org/10.6084/m9.figshare.19666251.
ACKNOWLEDGMENTS
The authors thank all our study participants for willingness,
time, and effort devoted to this study.
GRANTS
This study was supported in part by the National Institute of
Health (NIH, R01HL102457, R.Z.) and the Japan Society for the
Promotion of Science (JSPS, 16KK0011, 17H02186, J.S.).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by
the authors.
AUTHOR CONTRIBUTIONS
T.T. and R.Z. conceived and designed research; T.T., C.X., J.L.,
and R.Z. performed experiments; J.S., T.T., C.X., J.L., T.T., E.P.P.,
and R.Z. analyzed data; J.S., T.T., C.X., J.L., T.T., E.P.P., and R.Z.
interpreted results of experiments; J.S. prepared figures; J.S. and
T.T. drafted manuscript; J.S., T.T., C.X., J.L., T.T., E.P.P., and R.Z.
edited and revised manuscript; J.S., T.T., C.X., J.L., T.T., E.P.P., and
R.Z. approved final version of manuscript.
REFERENCES
1. Williams LR, Leggett RW. Reference values for resting blood flow to
organs of man. Clin Phys Physiol Meas 10: 187–217, 1989.
doi:10.1088/0143-0815/10/3/001.
2. Elia M. Organ and tissue contribution to metabolic rate. In: Energy
Metabolism: Tissue Determinants and Cellular Corollaries, edited by
Kinney JM and Tucker HN. New York: Raven Press, 1992.
3. O'Rourke MF, Safar ME. Relationship between aortic stiffening
and microvascular disease in brain and kidney: cause and logic of
therapy. Hypertension 46: 200–204, 2005. doi:10.1161/01.HYP.
0000168052.00426.65.
4. Sugawara J, Hayashi K, Yokoi T, Cortez-Cooper MY, DeVan AE,
Anton MA, Tanaka H. Brachial-ankle pulse wave velocity: an index
of central arterial stiffness? J Hum Hypertens 19: 401–406, 2005.
doi:10.1038/sj.jhh.1001838.
5. Sugawara J, Tomoto T, Tanaka H. Heart-to-Brachium Pulse Wave
Velocity as a Measure of Proximal Aortic Stiffness: MRI and
Longitudinal Studies. Am J Hypertens 32: 146–154, 2019. doi:10.1093/
ajh/hpy166.
 CEREBROVASCULAR IMPEDANCE AND AEROBIC EXERCISE TRAINING
6. Tanaka H, Dinenno FA, Monahan KD, Clevenger CM, DeSouza CA,
Seals DR. Aging, habitual exercise, and dynamic arterial compliance.
Circulation 102: 1270–1275, 2000. doi:10.1161/01.CIR.102.11.1270.
7. Ding J, Mitchell GF, Bots ML, Sigurdsson S, Harris TB, Garcia M,
Eiriksdottir G, van Buchem MA, Gudnason V, Launer LJ. Carotid ar-
terial stiffness and risk of incident cerebral microbleeds in older peo-
ple: the Age, Gene/Environment Susceptibility (AGES)-Reykjavik
study. Arterioscler Thromb Vasc Biol 35: 1889–1895, 2015. doi:10.1161/
ATVBAHA.115.305451.
8. Mitchell GF, van Buchem MA, Sigurdsson S, Gotal JD, Jonsdottir
MK, Kjartansson O, Garcia M, Aspelund T, Harris TB, Gudnason V,
Launer LJ. Arterial stiffness, pressure and flow pulsatility and brain
structure and function: the Age, Gene/Environment Susceptibility–
Reykjavik study. Brain 134: 3398–3407, 2011. doi:10.1093/brain/
awr253.
9. Pase MP, Beiser A, Himali JJ, Tsao C, Satizabal CL, Vasan RS,
Seshadri S, Mitchell GF. Aortic stiffness and the risk of incident mild
cognitive impairment and dementia. Stroke 47: 2256–2261, 2016.
doi:10.1161/STROKEAHA.116.013508.
10. Sugawara J, Tomoto T, Repshas J, Zhang R, Tarumi T. Middle-
aged endurance athletes exhibit lower cerebrovascular impedance
than sedentary peers. J Appl Physiol (1985) 129: 335–342, 2020.
doi:10.1152/japplphysiol.00239.2020.
11. Sugawara J, Tarumi T, Xing C, Liu J, Tomoto T, Pasha EP, Zhang R.
Older age and male sex are associated with higher cerebrovascular
impedance. J Appl Physiol (1985) 130: 172–181, 2021. doi:10.1152/
japplphysiol.00396.2020.
12. Zhu YS, Tseng BY, Shibata S, Levine BD, Zhang R. Increases in
cerebrovascular impedance in older adults. J Appl Physiol (1985) 111:
376–381, 2011. doi:10.1152/japplphysiol.01418.2010.
13. Diaz-Otero JM, Garver H, Fink GD, Jackson WF, Dorrance AM.
Aging is associated with changes to the biomechanical properties of
the posterior cerebral artery and parenchymal arterioles. Am J
Physiol Heart Circ Physiol 310: H365–H375, 2016. doi:10.1152/
ajpheart.00562.2015.
14. Li Y, Lim C, Schar M, Jiang D, Qiao Y, Pillai JJ, Lu H. Three-dimen-
sional assessment of brain arterial compliance: Technical develop-
ment, comparison with aortic pulse wave velocity, and age effect.
Magn Reson Med 86: 1928–2021, 1917. doi:10.1002/mrm.28835.
15. Tarumi T, Zhang R. Cerebral blood flow in normal aging adults: car-
diovascular determinants, clinical implications, and aerobic fitness. J
Neurochem 144: 595–608, 2018. doi:10.1111/jnc.14234.
16. Thorin-Trescases N, de Montgolfier O, Pinçon A, Raignault A,
Caland L, Labbe  P, Thorin E. Impact of pulse pressure on cerebro-
vascular events leading to age-related cognitive decline. Am J
Physiol Heart Circ Physiol 314: H1214–H1224, 2018. doi:10.1152/
ajpheart.00637.2017.
17. Sugawara J, Komine H, Hayashi K, Yoshizawa M, Otsuki T, Shimojo
N, Miyauchi T, Yokoi T, Maeda S, Tanaka H. Reduction in a-adrener-
gic receptor-mediated vascular tone contributes to improved arterial
compliance with endurance training. Int J Cardiol 135: 346–352,
2009. doi:10.1016/j.ijcard.2008.04.007.
18. Sugawara J, Otsuki T, Tanabe T, Hayashi K, Maeda S, Matsuda M.
Physical activity duration, intensity, and arterial stiffening in post-
menopausal women. Am J Hypertens 19: 1032–1036, 2006.
doi:10.1016/j.amjhyper.2006.03.008.
19. Furby HV, Warnert EAH, Marley CJ, Bailey DM, Wise RG.
Cardiorespiratory fitness is associated with increased middle cere-
bral arterial compliance and decreased cerebral blood flow in young
healthy adults: a pulsed ASL MRI study. J Cerebr Blood F Met 40:
1879–1889, 2020. doi:10.1177/0271678X19865449.
20. Moir ME, Klassen SA, Zamir M, Shoemaker JK. Rapid changes in
vascular compliance contribute to cerebrovascular adjustments dur-
ing transient reductions in blood pressure in young, healthy adults. J
Appl Physiol (1985) 129: 27–35, 2020. doi:10.1152/japplphysiol.00272.
2020.
21. Nichols WW, McDonald DA. McDonald's Blood Flow in Arteries:
Theoretical, Experimental and Clinical Principles. London: Hodder
Arnold, 2011.
22. Tarumi T, Patel NR, Tomoto T, Pasha E, Khan AM, Kostroske K,
Riley J, Tinajero CD, Wang C, Hynan LS, Rodrigue KM, Kennedy
KM, Park DC, Zhang R. Aerobic exercise training and neurocogni-
tive function in cognitively normal older adults: a one-year random-
ized controlled trial. J Intern Med, 2022. doi:10.1111/joim.13534.
J Appl Physiol  doi:10.1152/japplphysiol.00241.2022  www.jap.org
Downloaded from journals.physiology.org/journal/jappl at CAPES-USP (143.107.252.134) on November 5, 2022.
23. Tarumi T, Thomas BP, Tseng BY, Wang C, Womack KB, Hynan L,
Lu H, Cullum CM, Zhang R. Cerebral white matter integrity in
amnestic mild cognitive impairment: a 1-year randomized controlled
trial of aerobic exercise training. J Alzheimers Dis 73: 489–501,
2020. doi:10.3233/JAD-190875.
24. American College of Sports Medicine. ACSM's Guidelines for
Exercise Testing and Prescription. Philadelphia: Wolters Kluwer,
2014, p. 456.
25. Fujimoto N, Prasad A, Hastings JL, Arbab-Zadeh A, Bhella PS,
Shibata S, Palmer D, Levine BD. Cardiovascular effects of 1 year of
progressive and vigorous exercise training in previously sedentary
individuals older than 65 years of age. Circulation 122: 1797–1805,
2010. doi:10.1161/CIRCULATIONAHA.110.973784.
26. Alexandrov AV, Sloan MA, Wong LK, Douville C, Razumovsky
AY, Koroshetz WJ, Kaps M, Tegeler CH; American Society of
Neuroimaging Practice Guidelines Committee. Practice stand-
ards for transcranial Doppler ultrasound: part I–test performance. J
NeuroImaging 17: 11–18, 2007. doi:10.1111/j.1552-6569.2006.00088.x.
27. Kelly R, Fitchett D. Noninvasive determination of aortic input imped-
ance and external left ventricular power output: a validation and
repeatability study of a new technique. J Am Coll Cardiol 20: 952–
963, 1992. doi:10.1016/0735-1097(92)90198-v.
28. Kelly R, Hayward C, Avolio A, O'Rourke M. Noninvasive determina-
tion of age-related changes in the human arterial pulse. Circulation
80: 1652–1659, 1989. doi:10.1161/01.CIR.80.6.1652.
29. Armentano R, Megnien JL, Simon A, Bellenfant F, Barra J,
Levenson J. Effects of hypertension on viscoelasticity of carotid and
femoral arteries in humans. Hypertension 26: 48–54, 1995.
doi:10.1161/01.HYP.26.1.48.
30. Welch P. The use of fast fourier transform for the estimation of
power spectra: a method based on time averaging over short, modi-
fied periodograms. IEEE Trans Audio Electroacoust 15: 70–73, 1967.
doi:10.1109/TAU.1967.1161901.
31. Marple S Jr. Digital Spectral Analysis with Applications. Prentice
Hall, 1987, p. 492.
32. Astrand PO, Saltin B. Oxygen uptake during the first minutes of heavy
muscular exercise. J Appl Physiol 16: 971–976, 1961. doi:10.1152/
jappl.1961.16.6.971.
33. Balke B, Nagle FJ, Daniels J. Altitude and maximum performance in
work and sports activity. JAMA 194: 646–649, 1965.
34. Okazaki K, Iwasaki K, Prasad A, Palmer MD, Martini ER, Fu Q,
Arbab-Zadeh A, Zhang R, Levine BD. Dose-response relationship
of endurance training for autonomic circulatory control in healthy
seniors. J Appl Physiol (1985) 99: 1041–1049, 2005. doi:10.1152/
japplphysiol.00085.2005.
35. Gupta SK. Intention-to-treat concept: a review. Perspect Clin Res 2:
109–112, 2011. doi:10.4103/2229-3485.83221.
36. DeSouza CA, Shapiro LF, Clevenger CM, Dinenno FA, Monahan
KD, Tanaka H, Seals DR. Regular aerobic exercise prevents and
restores age-related declines in endothelium-dependent vasodila-
tion in healthy men. Circulation 102: 1351–1357, 2000. doi:10.1161/01.
CIR.102.12.1351.
37. Sugawara J, Komine H, Hayashi K, Yoshizawa M, Otsuki T,
Shimojo N, Miyauchi T, Yokoi T, Maeda S, Tanaka H. Systemic
alpha-adrenergic and nitric oxide inhibition on basal limb blood
flow: effects of endurance training in middle-aged and older
adults. Am J Physiol Heart Circ Physiol 293: H1466–H1472, 2007.
doi:10.1152/ajpheart.00273.2007.
38. Aaslid R, Lash SR, Bardy GH, Gild WH, Newell DW. Dynamic pres-
sure–flow velocity relationships in the human cerebral circulation.
Stroke 34: 1645–1649, 2003. doi:10.1161/01.STR.0000077927.63758.B6.
39. Tomoto T, Liu J, Tseng BY, Pasha EP, Cardim D, Tarumi T, Hynan
LS, Munro Cullum C, Zhang R. One-year aerobic exercise reduced
carotid arterial stiffness and increased cerebral blood flow in amnes-
tic mild cognitive impairment. J Alzheimers Dis 80: 841–853, 2021.
doi:10.3233/JAD-201456.
40. Kelly R, Hayward C, Avolio A, O'Rourke M. Noninvasive determina-
tion of age-related changes in the human arterial pulse. Circulation
80: 1652–1659, 1989. doi:10.1161/01.cir.80.6.1652.
41. Tarumi T, Ayaz Khan M, Liu J, Tseng BY, Parker R, Riley J, Tinajero
C, Zhang R. Cerebral hemodynamics in normal aging: central artery
stiffness, wave reflection, and pressure pulsatility. J Cereb Blood
Flow Metab 34: 971–978, 2014 [Erratum in J Cereb Blood Flow
911
 CEREBROVASCULAR IMPEDANCE AND AEROBIC EXERCISE TRAINING

Metab 34: 1255, 2014; Tseng, Benjamin M [corrected to Tseng,
Benjamin Y]]. doi:10.1038/jcbfm.2014.44.
42. Tanaka H, Palta P, Folsom AR, Meyer ML, Matsushita K, Evenson KR,
Aguilar D, Heiss G. Habitual physical activity and central artery stiffening
in older adults: the atherosclerosis risk in communities study. J
Hypertens 36: 1889–1894, 2018. doi:10.1097/HJH.0000000000001782.
43. Tomoto T, Tarumi T, Chen JN, Hynan LS, Cullum CM, Zhang R.
One-year aerobic exercise altered cerebral vasomotor reactivity in
mild cognitive impairment. J Appl Physiol (1985) 131: 119–130, 2021.
doi:10.1152/japplphysiol.00158.2021.
44. Smith EC, Pizzey FK, Askew CD, Mielke GI, Ainslie PN, Coombes
JS, Bailey TG. Effects of cardiorespiratory fitness and exercise train-
ing on cerebrovascular blood flow and reactivity: a systematic
review with meta-analyses. Am J Physiol Heart Circ Physiol 321:
H59–H76, 2021. doi:10.1152/ajpheart.00880.2020.
45. Ainslie PN, Cotter JD, George KP, Lucas S, Murrell C, Shave R,
Thomas KN, Williams MJ, Atkinson G. Elevation in cerebral blood
flow velocity with aerobic fitness throughout healthy human ageing.
J Physiol 586: 4005–4010, 2008. doi:10.1113/jphysiol.2008.158279.
46. Bailey DM, Marley CJ, Brugniaux JV, Hodson D, New KJ, Ogoh S,
Ainslie PN. Elevated aerobic fitness sustained throughout the adult
lifespan is associated with improved cerebral hemodynamics.
Stroke 44: 3235–3238, 2013. doi:10.1161/STROKEAHA.113.002589.
47. Murrell CJ, Cotter JD, Thomas KN, Lucas SJ, Williams MJ, Ainslie
PN. Cerebral blood flow and cerebrovascular reactivity at rest and
during sub-maximal exercise: effect of age and 12-week exercise train-
ing. Age (Dordr) 35: 905–920, 2013. doi:10.1007/s11357-012-9414-x.
48. Guadagni V, Drogos LL, Tyndall AV, Davenport MH, Anderson TJ,
Eskes GA, Longman RS, Hill MD, Hogan DB, Poulin MJ. Aerobic
exercise improves cognition and cerebrovascular regulation in older
adults. Neurology 94: e2245–e2257, 2020 [Erratum in Neurology
95: 890, 2020]. doi:10.1212/WNL.0000000000009478.
49. Tomoto T, Tarumi T, Chen JN, Hynan LS, Cullum CM, Zhang R.
One-year aerobic exercise altered cerebral vasomotor reactivity in
mild cognitive impairment. J Appl Physiol (1985) 131: 119–130, 2021.
doi:10.1152/japplphysiol.00158.2021.
50. Vikner T, Eklund A, Karalija N, Malm J, Riklund K, Lindenberger U,
Ba€ckman L, Nyberg L, Wåhlin A. Cerebral arterial pulsatility is linked
to hippocampal microvascular function and episodic memory in
healthy older adults. J Cereb Blood Flow Metab 41: 1778–1790, 2021.
doi:10.1177/0271678X20980652.
51. Wåhlin A, Ambarki K, Birgander R, Malm J, Eklund A. Intracranial
pulsatility is associated with regional brain volume in elderly individu-
als. Neurobiol Aging 35: 365–372, 2014. doi:10.1016/j.neurobiolaging.
2013.08.026.
52. Bailey TG, Klein T, Meneses AL, Stefanidis KB, Ruediger S, Green
DJ, Stuckenschneider T, Schneider S, Askew CD. Cerebrovascular
function and its association with systemic artery function and stiffness
in older adults with and without mild cognitive impairment. Eur J Appl
Physiol 122: 1843–1856, 2022. doi:10.1007/s00421-022-04956-w.

912 J Appl Physiol  doi:10.1152/japplphysiol.00241.2022  www.jap.org

Downloaded from journals.physiology.org/journal/jappl at CAPES-USP (143.107.252.134) on November 5, 2022.