Fneur 13 804187

HYPOTHESIS AND THEORY
published: 15 February 2022

doi: 10.3389/fneur.2022.804187
Pre-stroke Physical Activity and

Cerebral Collateral Circulation in
Ischemic Stroke: A Potential
Therapeutic Relationship?
Stanley Hughwa Hung 1*, Sharon Kramer 2,3 , Emilio Werden 1,4 , Bruce C. V. Campbell 1,5 and
Amy Brodtmann 1,4
1
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia, 2 Centre for
Quality and Patient Safety Research, Alfred Health Partnership, Melbourne, VIC, Australia, 3 Faculty of Health, School of
Nursing and Midwifery, Deakin University, Geelong, VIC, Australia, 4 Melbourne Dementia Research Centre, The Florey
Institute of Neuroscience and Mental Health, Parkville, VIC, Australia, 5 Department of Medicine and Neurology, Melbourne
Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia
Favorable cerebral collateral circulation contributes to hindering penumbral tissue from

progressing to infarction and is associated with positive clinical outcomes after stroke.
Given its clinical importance, improving cerebral collateral circulation is considered a
therapeutic target to reduce burden after stroke. We provide a hypothesis-generating
Edited by:
Juan Francisco Arenillas,
discussion on the potential association between pre-stroke physical activity and cerebral
Hospital Clínico Universitario de collateral circulation in ischemic stroke. The recruitment of cerebral collaterals in acute
Valladolid, Spain
ischemic stroke may depend on anatomical variations, capacity of collateral vessels
Reviewed by:
to vasodilate, and individual risk factors. Physical activity is associated with improved
Xabier Urra,
Hospital Clínic de Barcelona, Spain cerebral endothelial and vascular function related to vasodilation and angiogenic
Aravind Ganesh, adaptations, and risk reduction in individual risk factors. More research is needed to
University of Calgary, Canada
understand association between cerebral collateral circulation and physical activity. A
*Correspondence:
Stanley Hughwa Hung
presentation of different methodological considerations for measuring cerebral collateral
[email protected] circulation and pre-stroke physical activity in the context of acute ischemic stroke is
included. Opportunities for future research into cerebral collateral circulation, physical
Specialty section:
activity, and stroke recovery is presented.
This article was submitted to
Stroke, Keywords: physical activity, exercise, collateral circulation, stroke, recovery, hypothesis
a section of the journal
Frontiers in Neurology
Received: 29 October 2021 INTRODUCTION

Accepted: 12 January 2022
Published: 15 February 2022 In ischemic stroke, rapid access to targeted treatment is essential to prevent disability and
Citation: mortality (1, 2). Prolonged blood flow disruption as a result of vessel occlusions or stenosis
Hung SH, Kramer S, Werden E, can result in permanent brain tissue damage (i.e., ischemic core) (3). Hypoperfused, electrically
Campbell BCV and Brodtmann A inactive brain tissue surrounding the ischemic core, known as the ischemic penumbra,
(2022) Pre-stroke Physical Activity and
can potentially be salvaged or progress to infarction (2, 4). However, the progression of
Cerebral Collateral Circulation in
Ischemic Stroke: A Potential
ischemic core growth is highly variable (3). One important factor is the level of perfusion
Therapeutic Relationship? in the penumbra (2). Even when reperfusion is not achieved, the ischemic core does not
Front. Neurol. 13:804187. always grow to the full extent of the vascular territory affected (5). The cerebral collateral
doi: 10.3389/fneur.2022.804187 circulation system is recognized as an underlying factor that determines the level of perfusion
Frontiers in Neurology | www.frontiersin.org 1 February 2022 | Volume 13 | Article 804187

Hung et al. Physical Activity and Collateral Circulation
in the penumbra and associated ischemic core growth in ischemic human and animal studies were included. No date restrictions
stroke (6). The level of perfusion offered by the collateral were applied.
circulation has clinical implications. Leng et al. conducted a
systematic review and meta-analysis examining 35 studies on
the association between cerebral collateral circulation and the THE CEREBRAL COLLATERAL
efficacy and safety of endovascular treatments (7). The authors CIRCULATION SYSTEM
reported that favorable collateral circulation was associated with
higher rates of favorable functional outcomes at 3-months post- The cerebral collateral circulation system refers to complex
stroke, reduced risk of symptomatic intracranial hemorrhage networks of supplementary blood vessels that are recruited
during endovascular treatments, and reduced risk of mortality to provide alternative routes to maintain adequate cerebral
at 3-months (7). Other investigators have further reported blood flow when primary blood vessels are obstructed (24).
that unfavorable collateral circulation is associated with many These supplementary blood vessels are particularly important
clinically important stroke outcomes, including faster infarct in ischemic stroke, where inadequate arterial blood flow
growth, larger final infarct volumes, proximal occlusions, higher results from vessel narrowing (i.e., stenosis) or embolism (i.e.,
stroke severity on admission, and poorer functional outcomes occlusion). The anatomical structures of the cerebral collateral
after stroke (8–12). circulation system are complex, and can be subdivided into
Given the established link between favorable collateral primary and secondary collateral systems, illustrated in Figure 1
circulation and improved stroke outcomes, the cerebral collateral (24). Primary collaterals refer to arteries of the Circle of
circulation system is regarded as a potential therapeutic Willis that connect the anterior and posterior circulation of
target to improve outcomes in acute ischemic stroke (6, 13). the brain (24). Specifically, the Circle of Willis is a ring-like
Pharmaceutical and non-pharmaceutical strategies to optimize structure that connects the left and right anterior cerebral arteries
collateral circulation in the acute stroke setting have been (ACA) via the anterior communicating artery, and the middle
proposed, including optimal head position during acute care (14, cerebral arteries (MCA) and posterior cerebral arteries (PCA)
15), medications to induce blood volume expansion, vasodilation via the posterior communicating arteries (Figure 1A) (25). The
or hypertension, neural stimulation, partial occlusion of the secondary collaterals refer to the leptomeningeal arteries, which
aorta, and limb compression devices (6, 13). However, the most form anastomosis between the distal segments of ACA and MCA,
appropriate strategies remain unclear (6). Increasing physical and between the PCA and MCA (Figure 1B) (6).
activity, among other lifestyle factors, may also be a potential
strategy to optimize pre-stroke collateral circulation (16). Pre- Pathophysiology of Cerebral Collateral
stroke physical activity has been associated with lower admission Recruitment
stroke severity, reduced infarct volume, lower risk of mortality, The pathophysiology of cerebral collateral recruitment in
and favorable functional outcomes after stroke (17–23). Yet our ischemic stroke is not well understood in humans, and has
understanding of the association between pre-stroke physical primarily been described in animal models (26). Investigators
activity and collateral circulation in acute ischemic stroke propose that the extent and timing of cerebral collateral
is limited. circulation recruitment are crucial factors, and may be broadly
The purpose of the current article is to provide a hypothetical dependent on the following factors: the anatomical variations in
basis for and discussion of the association between pre-stroke collateral vessels, the capacity of blood vessels to vasodilate in
physical activity and collateral circulation. Specifically, we will (1) response to ischemia, and individual risk factors (13, 24).
describe the collateral circulation system and factors influencing
collateral circulation recruitment, (2) describe physical activity The Anatomical Variations in Collateral Vessels
and the potential association between pre-stroke physical activity The recruitment of primary and secondary collaterals depends
and collateral circulation, (3) discuss how collateral circulation on natural anatomical variations, size, number, and distribution
and pre-stroke physical activity can be measured and (4) discuss of vessels. In response to a large vessel occlusion, the primary
future directions for the potential utility of collateral circulation collateral circulation system provides immediate diversion of
and physical activity assessment in secondary prevention and blood flow to the ischemic region primarily through the
recovery after stroke. anterior and posterior communicating arteries within the Circle
of Willis (24). The involvement of these primary collaterals
depends on the natural, anatomical variations in the Circle
SEARCH STRATEGY of Willis. Using magnetic resonance angiography (MRA) in
874 men and 990 women, Hindenes et al. found 47 unique
For this hypothesis and theory review, we searched the PubMed variations in the Circle of Willis, where the absence of the
electronic database and Google Scholars for peer-reviewed posterior communicating arteries is the most common variation
journal article. The search was conducted using appropriate (27). This is clinically relevant, as acute MCA occlusions in
Boolean connectors where applicable, including individual or patients with a present ipsilateral posterior communicating
combined keywords and concepts associated with physical artery are more likely to have favorable functional outcomes
activity, exercise, collateral circulation, and ischemic stroke. (i.e., modified Rankin score < 2) after successful endovascular
Reference lists of relevant studies were hand searched. Relevant mechanical thrombectomy, compared to those without an

FIGURE 1 | (A) An illustration of the primary collateral circulation system, including the individual arteries of the Circle of Willis. The left and right anterior cerebral
arteries (ACA) are connected by the anterior communicating artery, while the middle cerebral arteries (MCA) and posterior cerebral arteries (PCA) are connected by the
posterior communicating arteries (25). (B) A sagittal, transparent view of selected right cerebral arteries to illustrate an example of the secondary collateral circulation
system, where the MCA (gray arteries) forms leptomeningeal arterial anastomoses with the (1) ACA and (2) PCA. Created with BioRender.com.
ipsilateral posterior communicating artery (28). The recruitment humans, assessing the association between endothelial function
of leptomeningeal collaterals is hypothesized to occur when and collateral recruitment in response to an acute ischemic
the primary collaterals have failed to provide adequate blood stroke is complex due to the priority for establishing rapid
flow to the ischemic regions (24), since leptomeningeal arteries revascularization via administration of hyperacute therapies.
are primarily observable in the later phases of ischemia Inferences can be made from assessing collateral recruitment
(29). Anatomical variations in the presence of leptomeningeal of acute stroke patients with chronic small vessel disease, a
collaterals have also been investigated by numerous authors patient group where poor endothelial function is well-established
using evidence ranging from human cadaver brain dissections to (33). Lin et al. examined the association between collateral
advanced brain imaging, with high inter-individual variability in recruitment and small vessel disease in 100 acute ischemic
the number and size of the leptomeningeal arteries (29). stroke patients who received mechanical thrombectomy (30).
Participants who were categorized as having small vessel disease
The Capacity of Collateral Vessels to Vasodilate (i.e., presence of severe white matter hyperintensities, lacunar
The recruitment of collaterals may also depend on the capacity strokes, microbleeds, or enlarged perivascular space) were twice
of the cerebral vasculature to vasodilate in response to as likely to have poor cerebral collateral circulation (30). The
ischemic stress through endothelial and metabolic mechanisms authors postulated that increased stiffness of arterioles, including
(26, 30). Animal studies have demonstrated the importance leptomeningeal arteries, associated with small vessels disease
of endothelial function (i.e., the ability of endothelial cells may lead to impaired endothelial function of leptomeningeal
to produce vasodilatory factors, such as nitric oxide) for collaterals (30). In support of this finding, Giurgiutiu et al.
collateral recruitment (26). Investigators have inhibited the studied 73 ischemic stroke survivors and found that greater white
production of endothelial-derived nitric oxide in rats, which matter hyperintensity volumes were independently associated
has been shown to reduce cerebral collateral recruitment with poor collateral circulation (34). Mark et al. reported
during ischemia and lead to subsequent larger infarct sizes similar findings when examining 178 stroke survivors who
(31). Additionally, inhalation of nitric oxide during ischemia, received mechanical thrombectomy, where more extensive white
a known cerebrovascular vasodilator, can promote cerebral matter hyperintensities were independently associated with poor
collateral recruitment and reduce infarct size in rats (32). In collateral circulation (35).

Given that the vasodilatory responses in cerebral circulation high triglycerides, low high-density lipoprotein cholesterol, high
occurs from large arteries to the microcirculation, inferences plasma glucose, high blood pressure or medication to control
can also made about collateral vessel recruitment by examining blood pressure, or obesity) (16). Fujita et al. examined the
the evidence of the endothelial function of the larger arteries, association between chronic hypertension (defined as pre-stroke
such as the MCA, or arteries in the Circle of Willis (36). For hypertension diagnosis or use of antihypertensive medications)
instance, the recruitment of primary collaterals may depend on and collateral circulation in 100 acute ischemic stroke patients,
their vasodilatory capacity (37). Kim et al. used transcranial and found that chronic hypertension was associated with poorer
Doppler ultrasonography (TCD) to measure flow diversion in collateral recruitment (47). A meta-analysis by Malhotra et
the ipsilateral ACA and PCA within 24 h of clinical angiography al. including nine studies investigated the association between
in 51 patients with acute M1 MCA stenosis or occlusion, pre-stroke statin treatment, collateral circulation, and infarct
and found that 47% of patient had adequate flow diversion size, and found that pre-stroke statin treatment was associated
(i.e., >30% greater flow velocity compared to contralesionally with smaller infarct size, and inconclusive association with
side) and were associated with recruitment of leptomeningeal collateral circulation status (48). Overall, these studies identified
collaterals (38). Impaired endothelial function assessed at the potential individual, modifiable risk factors associated with poor
MCA or basilar artery is more commonly observed in stroke collateral circulation.
survivors when compared to healthy age-matched controls,
likely due to combined effects of pre-stroke vascular risk (i.e.,
PHYSICAL ACTIVITY AND ITS POTENTIAL
chronic hypertension) and stroke-related tissue injury (39).
Therefore, endothelial function of the MCA post-stroke may ASSOCIATION WITH CEREBRAL
be a surrogate measure of collateral circulation recruitment COLLATERAL RECRUITMENT
in ischemic stroke. However, the evidence relating endothelial
function of the MCA in subacute or chronic phases of stroke Physical activity is defined as “any bodily movement produced
and collateral circulation recruitment in response to ischemia are by skeletal muscle that results in energy expenditure,” and can be
conflicting (40–43). For instance, Hofmeijer et al. investigated sub-typed as leisure-time, household, work, and transportation
the association between collateral circulation and endothelial (49). Exercise is a specific subtype of leisure-time physical
function using TCD at the MCA in 70 patients with symptomatic activity, which involves planned, structured, and repetitive bodily
carotid artery stenosis (40). The authors found that poor movements with the purpose of improving or maintaining one of
endothelial function at the MCA was associated with the more components of physical fitness, such as cardiorespiratory
recruitment of collateral circulation via the ophthalmic (TCD) fitness or muscle strength (49). Exercise can also be further sub-
or leptomeningeal arteries (angiography) on the symptomatic categorized as aerobic or resistance exercise. Aerobic exercise
hemisphere (40), which may be counter-intuitive. To explain this is defined as exercise that involves large muscle groups that
observation, investigators have postulated that the presence of can be maintained continuously in a rhythmic nature (50).
angiogenic adaptations via the development of collateral arteries Resistance exercise is defined as exercise involving periodic
may be a response to post-stroke ischemic injury and chronic bodily movements where external weights provide progressive
hypoperfusion (24). Therefore, these studies may not sufficiently overload to increase skeletal muscles strength and mass (51).
reflect the association between endothelial function and collateral The following section will discuss various cerebrovascular
recruitment in the setting of an acute ischemic stroke, and further responses to physical activity, primarily aerobic exercise, that
investigation is needed. may influence collateral circulation. In Table 1 and Figure 2, we
summarized the factors influencing cerebral collateral circulation
and proposed benefits of physical activity that may improve
Individual Risk Factors for Poor Collateral cerebral collateral circulation.
Recruitment
Older age and modifiable risk factors have been identified as Cardiovascular Response to Physical
potential individual risk factors for poor collateral circulation Activity
(13, 24, 29, 44). In animals, aging is associated with a reduction The cardiovascular response to physical activity is highly complex
in the size, number, and diameter of leptomeningeal collateral and has been extensively described (58, 60, 61). Briefly, the
arteries (45), a process that is also thought to occur in humans onset of physical activity causes heart rate and stroke volume
(13, 24). Bullitt et al. assessed cerebrovascular structures using to increase, resulting in increased cardiac output to meet the
MRA in 100 healthy human adults, and found an age-related increased metabolic demands of contracting skeletal muscles
decline in the number of small vessels (<1 mm diameter) and (60). Systolic blood pressure increases with increasing intensity
an abnormal increase in the level of curvature in vessels (46). of physical activity, while diastolic blood pressure remains stable
How these finding may applied to leptomeningeal arteries, or may even decrease (62). Specifically to cerebral circulation,
however, was not specified. In addition to older age, Menon et physical activity acutely increases cerebral blood flow with
al. examined the collateral circulation status of 206 consecutive greater increases with higher intensity physical activity (63).
stroke patients with MCA occlusions, and found that poor This increase in blood pressure and blood flow results in two
collateral circulation status was independently associated with broad types of interactions at arterial walls to further increase in
metabolic syndrome (i.e., having three or more of the following: blood flow through vasodilation: circumference strain and sheer

stress (58). Circumference stress occurs when increases in blood stretches the vascular smooth muscles, and subsequently, induces
pressure stretch and strain the circumference of arterial walls. contraction of the smooth muscles to further increase cerebral
Increased exposure to circumferential strain on endothelial cells blood flow. The second type of interaction is called shear stress,
triggers the production and upregulation of endothelial factors, where increased blood flow results in parallel forces applied by
such as nitric oxide. Furthermore, this circumferential strain also the blood along the vessel endothelium, which also stimulates
the production of endothelial factors, such as nitric oxide.
Among numerous factors, this production and upregulation of
TABLE 1 | Potential association between physical activity and cerebral collateral nitric oxide from these two interactions relaxes vascular smooth
circulation recruitment. muscles, resulting in acute vasodilation and increased blood
Factors influencing Proposed benefits of
flow. In addition to nitric oxide, this circumferential strain and
cerebral collateral physical activity shear stress also induces the production of vascular endothelial
circulation growth factors, responsible for arteriole and capillary growth (i.e.,
angiogenesis), with the purpose of providing more blood flow to
Collateral vessel anatomical Promoting growth of new the required tissues (58, 64).
variations, size, number, and arteriole blood vessels via
distribution (27, 29) vascular endothelial growth
factors (52, 53)
Capacity to vasodilate (30) Cerebrovascular adaptations
Cerebrovascular Adaptations to Physical
• Endothelial function and • Increase nitric oxide Activity
nitric oxide bioavailability (54, 55) Aging is associated with endothelial dysfunction, arterial
bioavailability (26) • Increased cerebral blood stiffening, impaired angiogenesis, and risk of cardiovascular
flow and reactivity (56)
disease (65–67). While mechanisms behind these processes
Individual risk factors Reduce individual risk
• Older age (13, 29) factors (57)
are complex and not fully understood, the reduction in
• Metabolic syndrome (16) • Hypertension bioavailability (i.e., production and release) of nitric oxide with
• Hypertension (47) • Type 2 diabetes age in humans may be a key link (66, 67). Various measures of
• Pre-stroke statin • Cardiovascular disease cerebral endothelial and vascular function also decline with age,
treatment (48) • Obesity
including reduction in global and regional cerebral blood flow
FIGURE 2 | An illustration of the proposed factors influence cerebral collateral recruitment, and how the benefits of physical activity may contribute to favorable
collateral circulation recruitment. Cerebral collateral circulation recruitment depends on individual anatomical variations, number, size, and distribution of blood vessel,
the capacity of blood vessels to vasodilate, and individual risk factors, such as age (13, 24). Physical activity can potentially contribute to arteriogenesis, including
leptomeningeal arteries (52, 58), can improve cerebral endothelial and vascular function (56), and is well-documented in reducing the risk of hypertension, type 2
diabetes mellitus, obesity, and cardiovascular disease (59). Created with BioRender.com.

and cerebrovascular reactivity (i.e., capacity of blood vessels to reported by some authors (78–80), but there results were
response to physiological stress) (68). Wu et al. cross-sectionally inconsistent (81, 82). The authors highlight the results may
assessed global cerebral blood flow using MRI and transcranial have been influenced by heterogenous exercise intervention
4D flow imaging in 82 people ranging between 7.2 months and designs, including intervention lengths (2-12 months), exercise
60.7 years old, and found that cerebral blood flow declines with types, and lack of reporting on attendance and adherence to
age, starting at 18 years old (69). Similarly, Miller et al. cross- intervention training (56). Taken together, the authors concluded
sectionally assessed cerebrovascular reactivity in 39 participants that their findings suggested that higher cardiorespiratory
between the age 21-67 years old using MRI and transcranial fitness with life-long exercise is associated with improved
4D flow imaging, and found that older participants had lower cerebrovascular function, and enhances our understanding of
cerebrovascular reactivity compared with younger participants in exercise as a potential approach to decrease age-related changes
global and individual vessel blood flow in the MCA, intracranial in cerebrovascular function (56). Higher quality, randomized
artery and basilar artery (70). This age-related decline in blood controlled trials are needed to conclusively determine the benefits
flow and cerebrovascular reactivity may be associated with poor of physical activity intervention on cerebrovascular function, as
collateral recruitment observed in older ischemic stroke patients well as determining exact duration, intensity, type and timing of
previously discussed. interventions (56). Overall, this evidence highlights the potential
Life-long physical activity in humans may prevent age- effect of physical activity on improved capacity for vasodilation
related decreases in nitric oxide bioavailability. Nyberg et associated with collaterals recruitment.
al. assessed bioavailability of nitric oxide in 32 people of Physical activity can potentially influence the growth of
various age and physical activity levels, and found that older, new arteriole blood vessels (i.e., arteriogenesis) through the
sedentary participants had reduced nitric oxide bioavailability production and upregulation of vascular endothelial growth
compared with active, older participants (71). Based on these factors (52, 58). Vital et al. conducted a systematic review
findings, physical activity is regarded as a potential strategy examining the effect of exercise interventions on peripheral
to increase nitric oxide bioavailability (54, 55). A recent concentrations of vascular endothelial growth factors in humans
review conducted by Facioli et al. included 16 studies and (83). Of the 10 studies included, four studies (two randomized
found that various exercise types (aerobic, resistance, Pilates, controlled and two non-randomized controlled trials) reported
Tai Chi), intensities and durations of exercise interventions an increase in vascular endothelial growth factors in various
were associated with increased production of nitric oxide in elderly populations after the interventions, primarily involving
people with hypertension (72). The effects of physical activity aerobic exercise (83). While the six remaining studies (four
may also translate to improvements in multiple measures of randomized controlled, one non-randomized controlled, and one
cerebrovascular function. Smith et al. (56) conducted a systematic randomized uncontrolled trial) found no change in vascular
review and meta-analysis including 34 studies and examined endothelial growth factor concentrations, the heterogeneity in
the association between cardiorespiratory fitness (i.e., objectively type of physical activity, duration and length included across
measured peak oxygen [VO2peak ] consumption during a graded interventions made it difficult to effectively determine optimal
exercises test) and cerebrovascular function, and the effect of dose of exercise (83). Boyne et al. examined 16 chronic stroke
exercise training on cerebrovascular function in healthy and survivors and found an the acute increase in circulating vascular
clinical populations. In this review, cerebrovascular function endothelial growth factors after a single bout of high intensity
was quantified as cerebral blood flow, reactivity (i.e., change in interval treadmill training (84). However, visible changes in
MCA blood flow given a change in hypercapnic conditions), and vasculature in cerebral collateral circulation as a result of physical
resistance (i.e., ratio of mean arterial pressure to cerebral blood activity has primarily been demonstrated in animal models (52).
flow). The authors found that higher cardiorespiratory fitness One known human, cross-sectional study conducted by Bullitt
was associated with improved cerebrovascular resistance and et al. examined the association between self-reported physical
reactivity compared to lower fitness. However, only participants activity and cerebral vascular structure (i.e., vessel number,
who were categorized as extreme levels of high cardiorespiratory average vessel radius, and vessel shape) of the MCA, ACA, and
fitness were associated with higher cerebral blood flow compared PCA assessed using MRA in 14 healthy older adults (53). The
with lower fitness levels. In two studies, improvements in authors found that participants categorized as “high activity” (i.e.,
cerebrovascular reactivity were associated with corresponding engaged in regular aerobic activities for at least 180 min per week
increases in cardiorespiratory fitness after taking part in an for the past 10 years) trended toward having greater number of
aerobic exercise interventions (73, 74). One study reported small vessels (<1 mm diameter), but not larger diameter vessels,
improvements in cerebrovascular reactivity in healthy older and smoother vessel curvature compared to inactive participants
adults using a combined aerobic and resistance training exercise (53). While not mentioned by the authors, these greater number
program (75). However, these results were inconsistent in of small vessels associated with higher physical activity levels may
three other studies including stroke, breast cancer, and chronic also include leptomeningeal arteries. The authors were unable
kidney disease survivors using aerobic exercise training (73, to detect arteries smaller than 0.5 diameter due to limitations
76, 77). While meta-analysis results suggested that exercise in voxel size in MRA techniques, potentially excluding the
interventions were not associated with changes in global cerebral leptomeningeal arteries (53). Overall, this provides promising
blood flow, improvements in cerebral blood flow to specific evidence that physical activity may help prevent age-related
regions (hippocampus and anterior cingulate cortex) were attrition in collateral arteries in humans.

Physical Activity Guidelines and Individual circulation, using angiography or the Collateral Flow Index (i.e.,
Risk Factors considered the “gold standard” for assessing coronary collateral
The wide range of physical and mental health benefits of physical flow) (96). In particular, Möbius-Winkler et al. randomized 60
activity are well-documented and evidenced by numerous patients with severe coronary artery disease to high intensity
systematic reviews and meta-analyses (59, 85–89). In particular, or moderate intensity aerobic exercise training, and showed
Warburton et al. conducted a comprehensive systematic review increased coronary collateral circulation compared with usual
that included 254 articles, primarily observational studies, care patients using Collateral Flow Index and angiographic
highlighting consistent evidence for the independent association evidence (97). Stoller et al. examined muscle tissue in 110 patients
between physical activity and reduced risk of all-cause mortality undergoing diagnostic coronary angiography, and found that
and prevalence for a variety of chronic diseases, such as patients with greater self-reported leisure-time physical activity
cardiovascular disease, hypertension, stroke, obesity, and type levels had greater femoral artery collateral circulation (98). While
II diabetes mellitus (57). Numerous additional meta-analyses of no studies have been conducted in humans, these studies provide
randomized controlled trials have also reported that physical evidence in mammalian models to motivate further investigation
activity interventions are effective in the prevention and in the associations between cerebral collateral circulation and
treatment of hypertension (54 trials, 2,419 participants) (90), physical activity in human acute ischemic stroke.
type 2 diabetes mellitus (11 trials, 846 participants) (91), and
favorable modification of numerous cardiometabolic biomarkers
(160 trials, 7,487 participants), including lipid profiles, fasting MEASURING CEREBRAL COLLATERAL
insulin, and glycosylated hemoglobin A1c (92). As such, the CIRCULATION
American Heart Foundation and American College of Sports
Medicine recommend older adults to engage in at least 30- Measurement considerations for cerebral collateral circulation
min of moderate-to-vigorous physical activity per day to are summarized in Table 2. The conventional method of
prevent and manage chronic diseases (93). The American Heart evaluating the collateral circulation status in acute ischemic
Association Stroke Council have similar recommendations for stroke involves using visual grading systems, often assessing
stroke survivors to improve physical function and reduce risk the presence, extent and/or timing of collateral vessels (namely
factors for stroke for secondary prevention (94). Given these leptomeningeal arteries) relative to the ischemic region (99).
benefits, physical activity may help reduce individual risk factors Different collateral recruitment grading systems have been
associated with poor collateral circulation. developed using brain imaging to visual collateral vessels
(99). The most commonly used grading systems (106) are
those developed by the American Society of Interventional
STUDIES DIRECTLY ASSESSING THE and therapeutic Neuroradiology and Society of Interventional
ASSOCIATION BETWEEN PHYSICAL Radiology (ASITN/SIR) (107), Alberta Stroke Program Early
ACTIVITY AND CEREBRAL COLLATERAL CT (ASPECT) Score for collaterals (108), Christoforidis et al.
CIRCULATION (109, 110), and Miteff et al. (111). Seker et al. compared
these four grading systems using dynamic CTA, and found
The effect of physical activity on cerebral collateral circulation that ASITN/SIR and the ASPECT score to be superior to
has been studied primarily in animals. Rzechorzek et al. Christoforidis and Miteff systems in predicting infarct volumes
showed that voluntary wheel-running in mice (i.e., equivalent in 30 acute stroke patients with M1 or terminal carotid artery
to incidental physical activity in humans) reduced age-related occlusions (106). Furthermore, ASITN/SIR grading system has
decrease cerebral collateral artery diameter, length, and number, been used by multiple investigators to predict stroke outcomes
and infarct size after middle cerebral artery occlusion, compared in acute ischemic stroke patients, where favorable collateral
to sedentary mice (95). Furthermore, these adaptions were grading has been associated with smaller infarct core volume and
associated with upregulation of endothelial nitric oxide (95). favorable functional outcomes (8, 112, 113).
No identified studies have evaluated the association between The “gold standard” imaging modality to visualize cerebral
pre-stroke physical activity and cerebral collateral circulation in collateral circulation in ischemic stroke is digital subtraction
human acute ischemic stroke. Although the association between angiography (13, 114). However, digital subtraction angiography
nitric oxide and cerebral collateral circulation in human ischemic is invasive and costly, so other methods may be preferred
stroke remains unclear, one of the mechanisms underlying the (13, 114, 115). Furthermore, in current clinical practice, the
potential effects of pre-stroke statin treatment on collateral imperative for rapid revascularisation means that a full set
circulation in humans includes the upregulation of endothelial of angiographic images, with injection of multiple arteries, is
nitric oxide (48). However, the effect of physical activity not obtained prior to treatment. This limits the assessment of
interventions on coronary collateral circulation in people with collateral flow largely to MCA occlusion. The anterior cerebral,
coronary artery disease has been examined (96). Nickolay et but not posterior cerebral, collateral pathways can be assessed
al. summarized the evidence from seven studies that examined based on an internal carotid artery injection. However, non-
the effect of aerobic exercise interventions to increase coronary invasive multi-modal brain imaging techniques performed as
collateral flow in humans, and revealed consistent evidence that part of standard clinical care for acute stroke provide numerous
aerobic exercise is beneficial in promoting coronary collateral opportunities for cerebral collateral circulation assessment,

TABLE 2 | Measurement considerations for cerebral collateral circulation and pre-stroke physical activity.
Outcome Methodology Strengths Limitations
Cerebral collateral circulation Visual grading scales using “Gold Standard” (namely DSA) Requires expert input (100)
angiography (DSA, MRI, (13)
CTA, CTP) (99)
Hypoperfusion intensity ratio Automated; requires minimal Indirect measure (101)
(101) expert input (100)
Transcranial Doppler (99) Can be completed post-stroke Unclear clinical relevance to
(40–43) acute ischemic stroke (13)
Pre-stroke physical activity Self-report questionnaires • Suitable of retrospective and Risk of recall bias (102, 103)
case-control studies (17)
• Inexpensive and easy to
administer (102)
Objective measurements • Suitable for prospective cohort Expensive and time consuming
(accelerometers and studies (13, 105)
pedometers) • Reduced risk of bias and
improve accuracy (104)
CTA, computed tomography angiography; CTP, computed tomography perfusion; DSA, digital subtraction angiography; MRI, magnetic resonance imaging.
including MRI, MRA, computed tomography angiography grading in acute ischemic stroke patients (127). Finally, while
(CTA) and perfusion (CTP) (13, 99, 100, 116). For MRI, not routinely assessed, TCD can be used to measure flow
fluid-attenuated inversion-recovery sequences can be used to velocities and collateral circulation (41, 128). Specifically, TCD
visualize “vascular hyperintensities” as an indirect method of has been used to measure flow diversion in the ipsilateral anterior
assessing collateral circulation in acute ischemic stroke (117). and posterior communicating arteries (i.e., >30% higher than
Single- and multi-phase CTA and/or MRA are often used to contralateral flow velocity) within 24 h of clinical angiography
identify the presence of large vessel occlusion, and can also in acute M1 MCA stenosis or occlusion, and has been associated
be used to assess collateral vessels (13, 100). In addition to with recruitment of leptomeningeal collaterals as seen on digital
providing invaluable information for the selection of patients subtraction angiography (38). TCD can also be used to measure
for thrombolytic and endovascular therapy (118–122), CTP collateral flow at the ophthalmic arteries (40, 41).
offers multiple opportunities for collateral circulation assessment
(100). With post-processing software, source images from CTP
(maximum intensity projections) can be used to reconstruct four MEASURING PRE-STROKE PHYSICAL
dimensional CTA to assess collateral circulation (123). Time- ACTIVITY LEVELS
to-maximum (Tmax) is a perfusion parameter derived from
deconvolution with an arterial input function, indicates the Measurement considerations for pre-stroke physical activity
severity of blood flow delay which, in the context of arterial are summarized in Table 2. Measuring pre-stroke physical
occlusion, reflects collateral blood flow quality (124). Regions activity is challenging with inherent limitations based on
of brain with perfusion delay defined as Tmax > 6 s provides study design (103, 129). Based on a recent systematic review
an estimate of the tissue at risk (ischemic core and penumbra) we conducted, along with other studies measuring pre-stroke
(101, 125). The hypoperfusion intensity ratio (HIR), defined as physical activity (23, 130–132), most studies were retrospective
the volumetric ratio of tissue with Tmax > 10 s to Tmax >6 s, and case-control designs and relied on self-reported physical
can serve as an indirect estimate of collateral circulation status activity questionnaires to recall pre-stroke activities (17, 18).
(101, 125). The HIR has been well correlated with collateral Questionnaires are relatively inexpensive, low resource burden,
grading in acute ischemic stroke patients as assessed by digital convenient to administer, and ideal for clinical settings
subtraction angiography by multiple investigators (8, 112, 126). (102). However, they are prone to risk of recall and social
Other CTP parameters have been correlated with collateral desirability bias, leading to questionable accuracy, especially
circulation, including cerebral blood volume (CBV) and cerebral for incidental, unstructured physical activity (102). Assessing
blood flow (CBF) (105, 127). Specifically, higher relative CBV pre-stroke physical activity soon after stroke incidence (i.e.,
(rCBV), defined as the ratio of mean CBV values within the during their acute hospital stay) may reduce potential recall bias
Tmax > 6 s regions to mean CBV values within the Tmax ≤ 4 s associated with memory. However, additional challenges may
regions (normal brain tissue), has been correlated with favorable present in acute stroke patients including impaired cognition
collateral grading in acute ischemic stroke patients (105). Using and memory, aphasia, and additional social desirability factors
CBF < 30% to estimate the ischemic core volume, slower associated with self-image after stroke (103). Prospective cohort
baseline ischemic core-growth rate, defined as the ischemic studies have the capacity to include objective measurements of
core volume divided by the time between stroke onset and physical activity, including accelerometers and pedometers, to
CTP imaging, has been correlated with favorable collateral reduce risk of bias and improve accuracy of physical activity

measurement (104). However, prospective cohort designs are research settings. The HIR and rCBV may be solutions to
often expensive and time-consuming due to the long follow- this barrier, as perfusion maps that include Tmax and CBV
up and large samples required for disease incidence (103, parameters and associated HIR and rCBV values can be generated
133). As such, few prospective cohort studies have been by multiple automated software, such as the RApid Processing
conducted, including the Physician’s Health Study (132) and of Perfusion and Diffusion (RAPID) software, without extensive
Women’s Health Initiative cohorts (23), but neither studies and ongoing expert input (100, 101, 105). Clinically relevant
included objective measures of physical activity. Nevertheless, HIR threshold values have been established to reflect favorable
self-reported questionnaires remains a feasible, cost-effective and or unfavorable collateral status. Olivot et al. examined 99 acute
pragmatic method to measure pre-stroke physical activity in ischemic stroke patients, and reported that an HIR ≥ 0.4 was
acute or subacute settings, as demonstrated by many investigators associated with greater infarct growth and final infarct volume,
(17, 18). greater admission stroke severity, and unfavorable functional
Specific to acute clinical settings, assessing pre-stroke physical outcomes after stroke (8). Similar thresholds have been reported
activity can be challenging. The selection of measurement tools by other authors, where favorable HIR has been associated
need to consider the balance between burden of administering with less infarct growth, favorable functional outcomes, and
the questionnaire (i.e., time and attentional resources of patients even potentially eligibility for thrombectomy (112, 143–145).
and healthcare providers) and the level of detail on type Arenillas et al. examined 158 acute ischemic stroke patients,
and dose (i.e., intensity, frequency, and time) of pre-stroke and reported that higher rCBV was associated with favorable
physical activity (102). A variety of pre-stroke physical activity collateral circulation and slower infarct growth at 27-h follow-up
questionnaires have been used in the literature (17, 18). Authors (105), and favorable functional outcome in patients after acute
have used measures that are relatively less time consuming, ischemic stroke (105). Furthermore, Cortijo et al. invested 100
such as single-questionnaire measures to assess if they meet acute ischemic stroke patietns, and reported that lower rCBV was
minimum duration and frequency of leisure-time physical associated with poor colleateral circulation, and poor functional
activity (134–137) or standardized questionnaires [i.e., Saltin- outcome in the absence of recanalisation (146). Overall, both
Grimby Physical Activity Level Scales (138)]. However, the HIR and rCBV serve as accessible opportunities for a wider
brief nature of these questionnaires may provide limited detail group of health professions (i.e., physiotherapists and exercise
on physical activity type and dose and may preclude further physiologists) and research communities to indirectly assess
discussion on how to modify physical activity after stroke. collateral circulation status with relatively minimal on-going
Authors have also used relatively longer and more detailed expert input. However, in the absence of acute ischemic stroke
physical activity quesitonnaires (130, 139, 140), such as the and clinical imaging, in the case of potential clinical trials, follow-
International Physical Activity Questionnaire (141) and the up assessments to evaluate the change in collateral circulation
Physical Activity Scale for the Elderly (142). These standardized will require expert input, as HIR and rCBV has not been assessed
questionnaires provide more information of physical activity outside of the hyperacute phases of stroke. Advanced MRA may
type and dose, and may also be useful in continued assessment potentially be used to visualize collateral vessels (13), and TCD
and physical activity counseling post-stroke. Furthermore, the measurements at the MCA, ACA, or PCA in response to forced-
selection of questionnaires needs to be age-appropriate, where dilatory responses (i.e., hypercapnic breathing maneuvers) may
the types of physical activities assessed should be those commonly be used as surrogate measure of collateral recruitment (40–43).
engaged by older adults (17). However, further investigation is required regarding the clinical
relevance of cerebrovascular function assessments conducted
post-hyperacute stroke phase (13).
DISCUSSION
Potential Barriers and Solutions to Physical Activity, Collateral Circulation,
Measuring Collateral Circulation and Post-stroke Recovery
Given the well-documented benefits of physical activity and Physical activity is a widely accepted and important strategy
potential positive influence on cerebral vascular function for the prevention and management of stroke. Notably, physical
discussed above, we hypothesize that greater pre-stroke physical activity is currently recommended to improve physical function
activity is associated with better collateral circulation in and manage vascular risk factors for secondary prevention in
ischemic stroke. Assessing pre-stroke, and post-stroke, physical people who have had a stroke (94). However, to improve our
activity in acute and subacute clinical settings is feasible, understanding on the role of physical activity on key stroke
and the advent of advanced brain imaging integrated into recovery outcomes, generating new information on the possible
routine clinical care offers a cost-effective opportunity to assess link between physical activity and collateral circulation is a
of collateral circulation in acute ischemic stroke. However, worthwhile endeavor. The Stroke Recovery and Rehabilitation
collateral circulation grading using advanced imaging modalities Roundtable regard clinically acquired CT imaging, including
often requires expert input from experienced neurologists and perfusion, in the hyperacute phase of stroke as a potential
radiologists, and potential post-processing techniques by imaging biomarker for stroke recovery and a developmental priority for
scientists (100). This may be a barrier for collateral circulation future research (147). Exercise and physical activity interventions
grading where such expertise is limited within clinical and are effective and recommended for reducing disability, and

improving mobility and physical function in stroke survivors equipment and trained personal to conduct (153). While
(148, 149). If physical activity and collateral circulation are cardiorespiratory fitness is related to cerebrovascular
associated, collateral circulation status may emerge as a function (56), further investigation is needed to explore the
biomarker to stratify or identify patients for clinical trials, such association between cardiorespiratory fitness and cerebral
that we can target patients with poor collateral status and collateral circulation.
suspected poor functional outcomes who would most benefit
from enrolling in physical activity interventions. These physical CONCLUSION
activity interventions can potentially reduce the risk of poor
clinical outcomes in the event of first-ever strokes for high-risk Cerebral collateral circulation has physiological and clinical
populations or recurrent strokes for stroke survivors through prognostic value and may be an important therapeutic target
improvements in cerebral collateral circulation. Furthermore, for acute ischemic stroke survivors. While the effect of physical
physical activity interventions have the potential to improve activity on cerebrovascular function has been investigated, the
functional recovery after stroke. Limaye et al. conducted a association between physical activity and cerebral collateral
systematic review examining the effect of aerobic exercise circulation is unknown. Future studies can take advantage of
interventions on serum biomarkers of neuroplasticity in human routinely acquired medical imaging in primary stroke centers
stroke survivors (150). The authors included nine studies, and to assess collateral circulation status, its association with
found that aerobic interventions can increase brain-derived physical activity, and potential utility as a biomarker to identify
neurotrophic factors, insulin-like growth factor 1, and VEGF. patients who would benefit from physical activity and stroke
However, further investigation is needed to discern how these recovery interventions.
serum biomarkers of neuroplasticity are associated with collateral
circulation, the optimal exercise type and dose, most appropriate DATA AVAILABILITY STATEMENT
timing to commence physical activity interventions after stroke
(i.e., how early), and the effect on functional recovery across The original contributions presented in the study are included
different phases (i.e., acute, subacute and chronic) post-stroke in in the article/supplementary material, further inquiries can be
humans (148, 150). directed to the corresponding author/s.
The association between cerebral collateral circulation and
cardiorespiratory fitness has also not been examined. While AUTHOR CONTRIBUTIONS
physical activity is closely associated with cardiorespiratory
fitness (151), cardiorespiratory fitness is a direct physiological SH led the manuscript and designed, conceptualized,
measurement associated with endothelial function, and and drafted the manuscript. SK, EW, BC, and AB
potentially provides more accurate prediction cardiovascular played major roles in designing, conceptualizing, and
disease risk compared with physical activity alone (152). revising the manuscript for intellectual content. All
However, assessment of cardiorespiratory fitness is relatively authors contributed to the article and approved the
more burdensome for patients and requires specialized submitted version.
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HYPOTHESIS AND THEORY

published: 15 February 2022

Pre-stroke Physical Activity and

Favorable cerebral collateral circulation contributes to hindering penumbral tissue from

Received: 29 October 2021 INTRODUCTION

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Outcome Methodology Strengths Limitations

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