Journal of Cerebral Blood Flow & Metabolism (2014) 34, 578–584

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OPINION ARTICLE
Function of circle of Willis
Zvonimir Vrselja1,2, Hrvoje Brkic3, Stefan Mrdenovic4, Radivoje Radic1 and Goran Curic5,6

Nearly 400 years ago, Thomas Willis described the arterial ring at the base of the brain (the circle of Willis, CW) and recognized it as a
compensatory system in the case of arterial occlusion. This theory is still accepted. We present several arguments that via negativa
should discard the compensatory theory. (1) Current theory is anthropocentric; it ignores other species and their analog structures.
(2) Arterial pathologies are diseases of old age, appearing after gene propagation. (3) According to the current theory, evolution has
foresight. (4) Its commonness among animals indicates that it is probably a convergent evolutionary structure. (5) It was observed
that communicating arteries are too small for effective blood flow, and (6) missing or hypoplastic in the majority of the population.
We infer that CW, under physiologic conditions, serves as a passive pressure dissipating system; without considerable blood flow,
pressure is transferred from the high to low pressure end, the latter being another arterial component of CW. Pressure gradient exists
because pulse wave and blood flow arrive into the skull through different cerebral arteries asynchronously, due to arterial tree
asymmetry. Therefore, CW and its communicating arteries protect cerebral artery and blood–brain barrier from hemodynamic stress.

Journal of Cerebral Blood Flow & Metabolism (2014) 34, 578–584; doi:10.1038/jcbfm.2014.7; published online 29 January 2014
Keywords: atherosclerosis; cerebrovascular disease; comparative anatomy; evolution; pulse wave analysis; redundancy

INTRODUCTION
Nearly 400 years ago, Thomas Willis gave the most detailed
anatomic description of the arterial anastomosis at the base of the
brain, surrounded by cerebrospinal fluid. The arterial anastomotic
ring that connects the left internal carotid artery (ICA), right ICA,
and vertebrobasilar circulation by communicating arteries is called
the circle of Willis (CW) (Figure 1). This arterial circle was well
known before Thomas Willis, but it is said that with his detailed
description he also recognized its function.1 In his work,1 Thomas
Willis states that CW functions as a compensatory mechanism in
the case of occlusion or stenosis of ICA or vertebral artery.2,3
The compensatory function stated by Thomas Willis is still
considered valid. When Thomas Willis introduced his theory, he
did not consider the function of CW from the evolutionary point of
view. After the introduction of the theory of evolution, that came
200 years later, a lot has changed in the scientific view of Life.
Since ‘nothing in biology makes sense except in the light of
evolution’,4 Thomas Willis could not have made a proper biologic
analysis of the function of CW. Therefore, we hypothesize that the
primary function of CW is not the redistribution of blood flow in
the case of occlusion event.
ANALYSIS OF FUNCTION IN BIOLOGY
When studying the specific design of an organism, or its part, one
has to take into account; (1) structural, (2) functional, and (3)
environmental point of view, along with (4) the change in time. The
structural shape of a specific part or entire organism dictates
function. The environment in which structure appears and
develops has to be accounted. Proper evolutionary analysis can
be done only when dimension of time is considered too.5 After all
four aspects have been accounted for, conclusions about an
organism or its specific part can be made. Thus, conclusions about
function can be wrong, if the environment and the time are not
considered.
According to compensatory theory, CW maintains cerebral blood
flow in the case of ICA or basilar artery occlusion or stenosis.6–9 It is
important to stress that in case of slowly progressing stenosis of
large cerebral artery anatomically complete communicating
arteries will have time to adapt and enlarge to maintain
perfusion. After observation of enlarged communicating arteries
during the study of a few pathologic processes, it was accepted
that ensuring collateral blood flow is the function of CW, implying
that CW has no function under physiologic conditions. It is unlikely
that pathologic process, such as vascular occlusion, could steer
evolutionary process. Evolution produces organisms with structural
specificities that are adaptations to specific environments.
Evolution results in a specific anatomic structure that in turn will
result in specific pathologies, and not the other way around.
Therefore, pathologic process would not force species to adapt;
rather it would lead to its extinction. It is more likely that physical
constraints and physical loads act as a selective pressure in a
specific circumstance (i.e., running distance limitation in cheetahs
due to overheating). The current theory of function of CW does not
make sense due to several considerations.
First, an explanation of the function of CW is drawn from very
specific environment. Cardiovascular events are leading cause of
death today, since several epidemiologic transitions have allowed
humans to live longer. Before the rise of modern medicine in the
last two centuries, it was very unlikely that people would succumb
to cerebrovascular disease. Global human life span at the
beginning of the 19th century was 28.5 years,10 and at this age,
cardiovascular disease is extremely rare. The occlusion event is
more likely to occur in the older population of the higher social

1
Department of Anatomy and Neuroscience, Medical School of J. J. Strossmayer University in Osijek, Osijek, Croatia; 2Department of Radiology, Osijek University Medical Center,
Osijek, Croatia; 3Department of Biophysics, Medical Statistics and Medical Informatics, Medical School of J. J. Strossmayer University in Osijek, Osijek, Croatia; 4Department of
Hematology, Osijek University Medical Center, Osijek, Croatia; 5Department of Chemistry and Biochemistry, Laboratory for DNA Analysis, Medical School of J. J. Strossmayer
University in Osijek, Osijek, Croatia and 6Department of Pathology and Legal Medicine, Osijek University Medical Center, Osijek, Croatia. Correspondence: Assistant Professor,
G Curic, Medical School of J. J. Strossmayer University in Osijek, J Huttlera 4, Osijek 31000, Croatia.
E-mail: gcuric@mefos.hr
Received 10 September 2013; revised 31 December 2013; accepted 6 January 2014; published online 29 January 2014

Figure 1. The anatomy and embryology of brain arterial circulation.
Internal carotid artery (ICA) during its course toward the carotid
canal in the temporal bone has only small branches. Short
intracranial part of the ICA is located in the subarachnoid space,
surrounded by cerebrospinal fluid, giving rise to relatively small
ophthalmic artery and then it abruptly branches into terminal
arteries: the middle cerebral artery and anterior cerebral artery
(ACA). The ACA is through the anterior communicating artery
connected to the counterpart ACA. Two vertebral arteries on the
anterior part of the brainstem form basilar artery, which branches
terminally into the. Posterior communicating artery connects
posterior cerebral artery to the terminal part of the same-side ICA.
In human embryonic development among cerebral arteries, ICAs
develop first, followed by posterior communicating artery (as caudal
branch of ICA), vertebral and basilar artery. Main cerebral arteries
(ACA, MCA, and PCA) are formed later, while the anterior
communicating artery is formed last, thereby completing the circle
of Willis at about the sixth or seventh gestation week.66–68 (Figure
adapted from file freely available through public domain (the
Wikimedia Commons)).
status, which represents extremely small portion of the entire
human population that ever lived. If CW has a compensatory
function, then hypoplastic or missing communicating arteries
would be undesirable trait, but evident probably after a carrier
was more than a decade sexually mature and probably have had
propagated his/her genes. Since the majority of human beings
that ever lived died before the age when a stenosis is expected to
develop, such pathologic process cannot act as a selective force
(i.e., trait not under evolutionary pressure, similar to Huntington’s
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Function of circle of Willis
Z Vrselja et al
579
disease). Even today, the prevalence of carotid artery stenosis in
the general population is around 1% or less,11 and carotid arteries
deliver B80% of the blood to the brain.12,13 Therefore, the
diseases of older age that became prevalent with Western
civilization cannot explain the existence and the function of CW.
The current interpretation of the function of CW has even less
sense if the other species are taken into account, since it is unlikely
for an animal to experience the cerebrovascular disease.
Second, the current view of the function of CW is anthropo-
centric, as it ignores other species’ CW and analog structures.
Circle of Willis-like structures are found in a large number of
animals that vary in brain size, body size, and type of circulation
(i.e., contribution of carotid and vertebrobasilar flow to overall
blood supply).14,15 Birds and mammals have structures similar to
CW, although their common ancestor lived in the Permian
period.16 Birds have a well-developed arterial communication
between ICAs (cerebral intercarotid anastomosis; ‘H’, ‘X’, or
‘I’ type).14,15 The commonness of CW and analog structures
indicates that its function is not compensatory in the case of
occlusion event, since the majority of birds and other animals do
not die from cerebrovascular events. It is more likely that CW is a
convergent evolutionary structure that has a function under
physiologic conditions. The colonization of the land and the air
coincides with the development of complex circulatory systems
with high arterial pressures, which expose brain enclosed in the
cranial cavity to high pulsatile stress. The development of CW is
probably a forced move, the evolutionary selected solution in the
constraints of previous evolutionary moves in Life’s adjustment to
the environment outside the water.
Third, the compensatory theory of CW implies that
evolution has a foresight. Evolution has no foresight; it is a
process, a force that acts in the present time in the constraints of
previously made evolutionary steps and physical abilities.
New structures appear and are evolutionary preserved if they
increase survival, i.e., give an evolutionary advantage to the
carrier. Some structures may be preadaptive; might serve some
purpose in the future, but such occurrence is a result of
randomness, not of foresight.
Fourth, the most common location for the arterial stenosis or
occlusion (thrombotic or embolic) is proximal part of the ICA and
the distal part of middle cerebral artery (MCA).17 It was observed
that the compensatory function is only possible in the vicinity of
CW.6 If CW has a compensatory function then it is odd that the
redundancy is only partially effective for distal parts of the MCA,
thus leaving a large part of each hemisphere unprotected. (Pial
arterial anastomoses between the terminal arteries of anterior and
posterior cerebral artery with the MCA terminal distribution
arteries provide enough collateral blood flow into the edge of
the MCA distribution region.)
Fifth, it was shown that under physiologic conditions blood
does not cross the midline of the brain.18 The absence of effective
contralateral blood flow was observed even within anatomically
and functionally complete CW.6,18 Anatomic and physiologic
textbooks6,18 state that communicating arteries are too small for
effective blood flow, since their radius is too small. According to
the Poisseuille law, flow of the viscous fluid through the vessel is
dependent of the fourth exponent of radius (Equation 1); V—
volume, t—time, R—radius, P—pressure, Z—viscosity of the blood,
and L—length of vessel segment.
V R4 pDp
¼ ð1Þ
t 8ZL
Sixth, it was found that 50% of the population had a CW with at
least one communicating artery missing, very small or incomple-
tely developed and complete CW is present in only 21% of
persons.19 Anatomically complete CW is present in most
individuals, although functional completeness was identified in
less than a half of the population, since one of the communicating
Journal of Cerebral Blood Flow & Metabolism (2014), 578 – 584
 Function of circle of Willis
Z Vrselja et al
580
Table 1. The completeness of the circle of Willis
Population Method Sample size (N) Incompletea (%)
China Autopsy 170 73.0
Egypt CT 250 53.3
Sri Lanka MRA 225 85.8
Brazil Autopsy 50 54.0
USA Autopsy 994 80.7
Iran Autopsy 102 68.5
CT, computed tomography; MRA, magnetic resonance angiography.
a
Anatomical or functional incompleteness, as concluded in the original
study, according to the criterion of at least one artery missing, or
hypoplastic (diameter o0.3 mm).
arteries is usually too narrow (diameter o0.3 mm) to enable
effective blood flow.20 The most common variation is hypoplastic
posterior communicating artery, while other structural variations
include duplicated or missing communicating arteries.6 Studies
investigating the anatomy of CW in random populations found
the presence of at least one communicating artery and
considerable anatomic variations in the number and diameter of
the arteries of CW (Table 1).19,21–27 In all studied individuals, ICA
was always connected through at least one communicating
artery to other parts of CW. Previous studies suggest that ‘a
diameter range in which a communicating artery may be
either functional or not [y] spread from 0.5 mm to 1.0 mm’.28 If
CW has a compensatory function then hypoplastic or missing
communicating arteries would not be frequent in the population;
one would expect to find relatively larger communicating arteries
that would allow an effective blood flow. Since anatomically
complete CW is present in the large proportion of the population,
the development of arterial stenosis near CW in an individual
would allow gradual widening of the communicant arteries to
maintain cerebral perfusion. Incomplete CW is more common in
patients with classic migraine (migraine with aura),29 while the
absence of all three communicant arteries was described
in a single case report of a 33-year-old woman, whose brain
perfusion was preserved, but had severe headache attacks.30 It
was suggested that a headache in this case might be caused by
hemodynamic stress.30
CIRCULATION AND PULSE WAVE
Everything in the skull pulsates in synchrony with heartbeat.31,32
With every heartbeat, energy in the form of blood flow (flow
pulsation) and a traveling pulse wave (pressure pulsation) is
inserted into the arterial system. The cardiovascular system is
considered to be in a steady-state oscillation; characterized by a
periodic rise and fall of the arterial pressure under physiologic
conditions. It has been proposed that every heart beat should be
considered as an isolated event.33 Because the aorta is compliant,
the vessel wall expands as blood is ejected into the aorta. That
expansion of the vessel wall is essential for the accommodation to
the increased volume of blood, since already present blood is inert
and cannot be instantly moved distally. Thus, blood inflow to the
aorta is higher than the blood outflow during systole (Equation 2);
Q—flow.
Qinflow 4Qoutflow
The aorta has the highest compliance among all arteries, but its
branches also add to overall compliance of the arterial system. If it
was not for the compliance, all new blood would have to go
through the peripheral vessels between systoles and no blood
flow would occur during diastole.34 Aortic pressure rises as new
blood accumulates in the aorta, (Equation 3); P—arterial pressure,
Journal of Cerebral Blood Flow & Metabolism (2014), 578 – 584
C—arterial compliance, and t—time.
dP=dt ¼ 1=CðQinflow  Qoutflow Þ ð3Þ
Pressure rise depends on the ability of the arterial wall to
expand. At one point pressure overcomes inertia and starts to
propagate through the arterial system in the form of pressure
pulse—this is called transmission of the pressure pulse. This
pressure pulse is a traveling wave of pressure or simple, pulse
wave that equals the difference between systolic and diastolic
arterial pressure. Every heart beat creates a separate pulse wave;
with its speed c. Pulse wave is a wavefront that represents the
change in specific property (pressure) during the observed time.33
Newly introduced perturbations in arterial system will propagate
as a wave; in forward with the speed U þ c, and in the backward
direction with the speed U—c; U—velocity of the blood, c—wave
speed dependent on elastic properties of arteries.33 Traveling
pulse wave expands arteries, which, in turn compress the
surrounding tissue. This arterial expansion under the skin
can be observed as a pulse. Strong pressure pulse under
physiologic conditions is found during physical exercise and
pregnancy, reaching up to 100 mm Hg in contrast to resting
40 mm Hg. Also, it can be found under some pathologic
conditions, such as aortic insufficiency, anemia, fever, and
beriberi disease.18 Pressure pulse can be extremely strong and
cause hearable sounds or even head nodding in synchrony with
the heart beat.18 Pulse wave propagates mostly independent of
blood flow; pulse wave travels 4 m/s in aorta and speeds up to
30 m/s in distal arteries, while blood flows 10 to 15 times slower.18
Although velocity of the blood flow is mostly independent
of the velocity of the pulse wave, peak systolic velocity of the
blood flow increases 0.0021 m/s for every 1 mm Hg increase in
pressure pulse.35
PULSE WAVE INTENSITY
Pulse wave represents traveling energy that can be described with
wave intensity. The wave intensity (I) is defined as a change in
pressure (P) times the change in speed (V), during the period of
time (t) (Equation 4). The wave intensity represents a newly arrived
energy per unit area; and has unit W/m2.
dI ¼ dPdV=dtdt ð4Þ
Because of the arterial damping, dissipation of the energy of the
pulse wave equals to resistance (R) times compliance (C)
(Equation 5).
Damping ¼ RC ð5Þ
The compliance of elastic arteries, mainly aorta and its branches
(also called conducting arteries), has an important function of
dampening of the pulsatile output of the heart, thereby reducing
the intensity of the pulse wave.34 Therefore, elastic reservoir of the
arterial system dissipates newly entered energy and evens out the
blood flow at the capillary level. If it was not for the compliance,
arteries would behave similar to rigid tubes; blood would flow
only during the systole. Elastic properties of the large arteries are
essential for their compliance. These properties are in part due to
their relatively greater proportion of elastin fibers to smooth
muscle and collagen fibers. Together, elastin fibers and vascular
smooth muscle cells provide flexibility and resilience to the elastic
arteries. Hence, reduced compliance will result in a higher
ð2Þ intensity of the pulse wave (Equation 5).34
PULSE WAVE REFLECTION
As the pulse wave travels forward through a conductive medium
(blood), its energy decreases toward the periphery, due to the
elastic properties of arterial reservoir. When forward traveling
pulse wave reaches the distal end of the arterial system (physically
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described as the discontinuity of conditions) it is transmitted and
reflected.33 The magnitudes of transmitted and reflected pulse
waves are dependent on the reflection coefficient; reflecting wave
arises because boundary conditions have to be satisfied.33 Arterial
bifurcations give rise to small but constant amount of the
reflecting pulse waves, while the peripheral arterioles contribution
varies depending on arteriole constriction.36 Increased peripheral
resistance will result with the reflected pulse wave of high
intensity.36 Wave intensity at a given point is a sum of forward and
backward traveling pulse wave intensities (Equation 6); I—wave
intensity.
dI¼ dIforward þ dIbackward ð6Þ
PRESSURES IN ARTERIAL SYSTEM
Arterial compliance enables blood flow through the entire cardiac
cycle and it also creates reservoir pressure. Traveling pulse wave
causes an increase in pressure in observed arterial segment. Thus,
intraarterial pressure is a sum of pulse wave pressure (Pwave) and
reservoir pressure (Preservoir) (Equation 7).37,38
Ptotal ¼Pwave þ Preservoir ð7Þ
If reservoir pressure is ignored (as in the system that lacks
compliance), forward pulse wave accounts for 70% and backward
pulse wave for 30% of the total pressure.38 When reservoir
pressure is accounted for, it contributes to total arterial pressure
with B50%, forward pulse wave with 44% and backward pulse
wave with 6%.38
Arterial flow in cerebral arteries changes during exercise;39
systolic velocity increases while diastolic velocity is unchanged—
similar to the behavior of the fluid in a conducting system with
low compliance, indicating that pulse wave pressure (forward and
backward) might be the major contributor to the total cerebral
arterial pressure. If it was not for dampening and gradual
dissipation of energy of the pulse wave, a sudden transfer of
energy at the end of arterial system would cause structural
damage.31 Such sudden transfer of energy can be compared with
an effect of closing a downstream valve in the rigid tube system
that, in turn, will cause a loud bang produced by a sudden stop of
incompressible fluid and subsequent transfer of energy to the
system of tubes. A sharp increase in pressure caused by the stop
of fluid in a system of tubes is called hydraulic shock, or water
hammer, and in the arterial system it is described by an
equation (8); P—pressure, r—density of the blood, c—pulse wave
velocity, U—blood flow velocity,±—negative sign denotes back-
ward, and positive forward traveling wave.
dP  ¼  rcdU  ð8Þ
40
Since the brain is exposed to high pulsatile stress and due to
several specificities of cerebral circulation (when compared with
the systemic circulation), avoidance of hemodynamic stress in the
brain is of great importance.
CEREBRAL BLOOD FLOW AND CEREBRAL AUTOREGULATION
Cerebral blood flow is constant when arterial pressure is between
70 and 140 mm Hg.18 Cerebral autoregulation is controlled by
myogenic, metabolic, and neurogenic mechanisms,13,41–43 which
ensure perfusion and protect the blood–brain barrier (BBB) and
fragile neural tissue from sudden changes in arterial pressure.44
Stable flow is maintained with adjustment of vascular resistance,
since the BBB can be easily disrupted with a sudden marked
increase in blood pressure.18 The response time for cerebral
autoregulation is B3 to 5 seconds, therefore blood velocity
fluctuates in large cerebral arteries,45 indicating that cerebral
arteries are exposed to high physical stress.
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STRUCTURAL AND FUNCTIONAL PROPERTIES OF CEREBRAL
ARTERIES
The cerebral arterial circulation consists of cerebral macrocircula-
tion and microcirculation, connected with penetrating arterioles.
Cerebral macrocirculation consists of the four delivering arteries,
its large branches and small pial that continue into penetrating
arteries, found in the Virchow–Robinson space in the brain
parenchyma. Microcirculation is composed of small arterioles,
capillaries, and venules.
Previous studies indicate that cerebral arteries (especially
lenticular arteries) are prone to structural damage (bursting),
compared with other systemic arteries in humans.46 The cerebral
arteries of different animal models have 3 to 4 times larger
diameter for a given arterial pressure than arteries of other
systems,47 and according to the law of Laplace for cylindrical
structures, arterial wall tension for a given amount of arterial
pressure is larger in cerebral arteries. Cerebral arteries structurally
differ from the other systemic arteries; have scarce elastin fibers in
medial layer and thin adventitia, lack external elastic lamina
(between medial layer and adventitia), and have well-developed
internal elastic lamina instead (between intimal and medial layer).48
Smooth muscle fibers of the cerebral arteries are arranged
circularly, perpendicularly oriented to the blood flow, while other
systemic arteries have smooth muscle fibers arranged spirally
around the long axis of the vessel.43 Perpendicular orientation of
smooth muscles may be an adaptation to the high wall tension
present in cerebral arteries, where such structural property might
have a preventive role against the arterial wall bursting.
Bifurcations of cerebral arteries, in comparison with other
systemic arteries of similar size, tend to be more perpendicular
than parallel, while penetrating arteries have right angle bifurca-
tions with pial arteries.43 Such bifurcations ensure a significant
decrease in blood velocity, larger transfer of kinetic energy and
larger increase in hydrostatic pressure (through mechanisms
called hydraulic shock). Another anatomic specificity of cerebral
arteries is that they branch more progressively into smaller arteries
and arterioles than other peripheral arteries.43 Therefore, as the
contact surface between blood and vessels increases, resistance in
the arterial system rises sharply. To protect the microcirculation
from the sharp pressure rise, large cerebral arteries receive a large
portion of pressure burden.
It was previously reported that cerebrovascular resistance under
resting conditions lies downstream of MCA, at the arteriolar level,
and with the increase in systolic pressure (i.e., during exercise)
resistance shifts toward large cerebral arteries,44,49 toward CW.
Anatomically, energy dissipation is shifted toward CW when the
input of the energy into the cerebral circulation (in the form of
higher pulse wave intensity and velocity) is increased.
After a craniotomy in anesthetized patients, moderate changes
in diameter occurred in distal cerebral arteries in response to
changes in arterial pressure and CO2, whereas changes in
diameter of the major cerebral arteries were o4%.50 Early
studies of proximal MCA diameter without craniotomy also
could not detect significant changes with CO2 alterations or
lower body negative pressure.51,52 However, more recent work
does indicate a small but significant inverse correlation of the
extracranial ICA diameter with arterial pressure and concordant
differences in the slope of the relationship of ICA volumetric flow
versus ICA velocity with pharmacologically induced changes in
arterial pressure.53 Because the percent changes in MCA velocity
matched the percent changes in ICA velocity, MCA diameter may
also have an inverse relationship with arterial pressure and
thereby contribute to autoregulation. Thus, some uncertainty
remains about the magnitude of diameter changes that occur in
the proximal MCA. Recently, Koller and Toth54 reported that an
increase in the intraluminal pressure and blood flow may cause an
increase in vascular tone of large cerebral arteries. Nevertheless,
Journal of Cerebral Blood Flow & Metabolism (2014), 578 – 584
 Function of circle of Willis
Z Vrselja et al
582
the relatively small magnitude of diameter changes in the
proximal MCA suggests a relatively small reservoir pressure
component in large cerebral arteries.
CEREBRAL BLOOD FLOW DURING PHYSICAL EXERCISE
In different physiologic and pathophysiologic circumstances,
arterial blood pressure rises well above the resting values.18
During heavy exercise in healthy subjects, with heart rate around
150 per minute, pressure pulse increases up to 100 mm Hg and
mean arterial pressure up to 100 mm Hg.39 The same study
established that the mean blood velocity through MCA increased
from 0.61 m/s to 0.71 m/s, more specifically, systolic blood velocity
and mean blood velocity increased while diastolic blood velocity
decreased.39 Ogoh et al39 also showed that the arterial blood
pressure in MCA reaches 180 to 190 mm Hg during heavy exercise,
while maximal systolic blood velocity in MCA reaches 1.9 m/s
(resting value was up to 0.9 m/s). Strenuous physical exercise
causes an increase in intraabdominal and intrathoracic pressures,
with subsequent obstruction of cerebral blood outflow via the
internal jugular vein, thus leading to the increase in intracranial
pressure.55,56 Therefore, physical exercise, as well as other physio-
logic and pathophysiologic conditions (coughing, defecating,
emesis, and obesity57), increases intracranial pressure. As intra-
cranial pressure increases, intracranial compliance decreases.31
(Intracranial compliance is ‘comprised of four main components:
actual brain tissue compliance (which is small), arterial compliance,
venous compliance (veins have highly compliant walls), and
compliance of the spinal thecal sac (which communicates with the
brain via the cerebrospinal fluid spaces) which is made out of four
components.31) Intracranial pressure and volume have an
exponential relationship; increased pressure will cause the
system to become more rigid (less compliant) and prone to a
large increase in pulsatility after a minor increase in volume.31
Therefore, physical exercise represents a challenge to cerebral
autoregulation; a large and sharp increase in pressure pulse and
systolic blood velocity has to be surmounted to ensure protection
of the sensitive BBB and neural tissue.
SUMMARY OF CEREBRAL BLOOD FLOW
Cerebral blood flow is maintained constant under physiologic
conditions. The cerebral circulation consists of cerebral macro-
circulation and microcirculation, connected with penetrating
arterioles. As cerebral arteries branch progressively, contact
surface increases sharply, causing a sharp increase in resistance.
This marked increase in resistance protects microcirculation and
the BBB from high systolic pressure. The basal cerebral vessel tone
is set by intraluminal pressure and flow, and can be modulated by
metabolism, neural signals, and astrocyte–glia interactions.54
Cerebral circulation is exposed to cardiac-generated pulsatility:
arterial pressure pulsation and flow pulsation. These circulation
components input energy into the skull which has to be
dissipated to protect microcirculation and BBB from damage. It
was reported that cerebrovascular resistance lies downstream
from large cerebral arteries, but with the increase in systolic
pressure, resistance (energy dissipation) shifts toward larger
arteries, toward CW. Relative small magnitude of diameter
changes observed in large cerebral arteries indicates that these
arteries might be less compliant and less capable in dampening
pulse wave intensity (through compliance-based dampening
mechanism).
In extracranial tissues, tissue compliance dissipates pulse
energy. Due to structural and physical constraints, cranial tissues
have complex cranial compliance composed of four different
components (brain parenchyma compliance, arterial compliance,
venous and spinal thecal sac compliance) that should dampen the
arterial pulsations and ensure protection of the sensitive BBB and
Journal of Cerebral Blood Flow & Metabolism (2014), 578 – 584
neural tissue, but not entirely, since some pulsation is essential for
proper function of microcirculation.
Intracranial compliance decreases with increased intracranial
pressure. Intracranial pressure and volume have an exponential
relationship; increased pressure will cause a system to become
less compliant and prone to a large increase in pulsatility after a
minor increase in volume.
According to system analysis, flow and pressure energy (input
signals) that is being inputted into the cranium (system) has to be
converted (absorbed) to an acceptable level (output signal) that
will not damage the intracranial structures. Modulation of
absorption of energy inputted into the system is complex and
dependent on cardiac frequency.31,58,59
FUNCTION OF THE CIRCLE OF WILLIS—HYPOTHESIS
We hypothesize that CW functions as a pressure absorber
mechanism that prevents damage of the cranial microvasculature
and BBB.
CEREBRAL ARTERIES AND HYDRAULIC SHOCK
Hydraulic shock is a transitory pressure increase, occurring due to
a sudden change in a direction or velocity of the fluid. Sudden
deceleration of the fluid in closed tubes causes pressure build up
and transfer of energy to the walls, resulting in the propagating
shock wave. If the shock wave would not be controlled, wall
damage would occur, because incompressible fluid and wall
cannot absorb the shock. Similarly, a sudden change in blood flow
direction and velocity causes the pressure rise. Every waveform of
the blood velocity has a specific momentum per unit of volume
flow.60 The waveform of blood velocity converts its energy to
pressure when it decelerates or stops, and that occurs near
bifurcations from which communicating arteries branch-out.60
Momentum is converted into pressure that is transmitted to the
arterial wall and surrounding structures. Pulsatile impulse (I) is a
change in the momentum (p) with respect to time t (Equation 9).
During physical exercise, when the time t between the systolic
flows is decreased, increased blood velocity will cause transmis-
sion of the higher force to the arterial wall and surrounding tissue
(Equation 10); F—force, t—time, and p—pressure. Thus, total
pressure exerted to the arterial wall is a sum of the impulse energy
and pulse wave intensities.60
Zt2
! !
I ¼ F dt ð9Þ
t1
!
! Dp
F ¼ ð10Þ
Dt
When the pressure exerted to the arterial wall exceeds vessel
‘strength’, an artery can burst or become aneurysmally dilated,
hence aneurismal dilatations of the arterial wall are most often
found in CW, with exception of the aorta.61 Cerebral aneurysms
are berry-shaped arterial wall dilatations caused by weakening of
the vessel wall. It is considered that they appear due to changes in
intrinsic factors of the arterial wall and possibly due to exposure to
hydraulic stress.61 It has been shown that the location of the berry
aneurisms does not correspond to structural defects in cerebral
arteries, but rather to the anatomic location, where a significant
amount of blood momentum is preserved.60 Aneurisms are mostly
located at the communicating arteries; in anterior cerebral artery
(around anterior communicating artery), in proximal MCA (around
posterior communicating artery), and in distal MCA.62 Berry
aneurysms are often found in patients with aortic coarctation.61
Coarctation is a localized narrowing of the aorta and it is most
often seen in the proximal portion of the aorta, near left
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subclavian artery. Aortic coarctation causes high arterial pressures
in cerebral circulation and exposes CW to high hemodynamic
stress. Thus, high hemodynamic stress is associated with higher
risk of developing berry aneurisms in the vicinity of CW.
ASYNCHRONOUS ARRIVAL OF THE PULSE WAVES TO THE
CRANIAL CAVITY
Four different pulse waves from the four large arteries that supply
the brain arrive at different times to CW. The asynchronous arrival
of pulse waves is a result of the anatomic configuration of the
arterial system. First aortal branch is brachiocephalic trunk that
branches into the right subclavian artery and right common
carotid artery, the latter terminating with ICA and external carotid
artery. The second branch is left common carotid artery that has
the same branches as the right-sided artery. Third artery that
arises from the arch of the aorta is the left subclavian artery. The
branching is similar in both subclavian arteries, and the first major
branch is vertebral artery. Such anatomic configuration results
with longer left-side cerebral arteries (distance from the heart to
CW). Due to left-right asymmetry of the arterial system, pulse
waves and blood flow reach CW at different times.63 A small
increase in volume can lead to a significant pressure rise in the low
compliance system, such as cranial cavity can be, indicating that
asymmetry of the cerebral arterial tree might be important for the
physiology of the cerebral circulation. Moreover, the asynchronous
arrival of forward pulse waves leads to asynchrony of backward
pulse waves too. It was observed in arterial circulation models that
the symmetry of the arterial tree ‘resulted in simultaneous
reflections from each of the legs which resulted in unwanted
interactions between reflected waves’.63
ROLE OF THE COMMUNICATING ARTERIES
Due to a progressive branching of cerebral arteries after CW,
peripheral resistance sharply increases. As blood slows down, its
kinetic energy is transferred to arterial walls, locally increasing the
hydrostatic pressure. Perpendicular bifurcations of the large
cerebral arteries ensure transfer of a significant amount of the
kinetic energy to the arterial wall, causing the large increase in
hydrostatic pressure.
As the pulse wave travels independently of blood to the end of
the arterial system in the brain, it speeds up due to the low
compliance. When forward traveling pulse wave reaches small,
resistant arteries and arterioles, it reflects and goes backwards, as
backward traveling pulse wave. Forward and backward traveling
pulse waves may pass through the arterial segment at the same
time, further increasing local hydrostatic pressure. Positive
interference of forward and backward traveling pulse waves is a
stochastic event, but it can occur, and when it occurs, it is
necessary that the sum of the pressures is lower than what
cerebral artery can withstand.
As previously shown, diameter of large cerebral arteries is
constant, or of small magnitude of diameter change under various
physiologic conditions, indicating diminished reservoir pressures
(compliance). The properties of large cerebral arteries found
in vivo are similar to conducting system with low compliance and
reduced energy dissipation ability. Structural specificities of
cerebral arteries might compensate for decreased compliance
(i.e., perpendicularly oriented smooth muscle fibers exert more
force compared with oblique oriented smooth muscle fibers).
Since large cerebral arteries have diminished active energy
dissipation system (compliance), we infer that communicating
arteries function as a passive energy dissipation system. As the
blood flow through communicating arteries is almost nonexistent
under physiologic conditions, we infer that the blood in the
communicating arteries acts as an analog of rubber diaphragm
found in the rigid tube system. Rubber diaphragm absorbs the
& 2014 ISCBFM
Function of circle of Willis
Z Vrselja et al
583
energy of moving fluid and pressure rise at the high pressure end
by stretching into the low pressure area, thus transferring the
pressure to low pressure end. Blood already present in the
communicating arteries serves as a medium in which elastic wave
(pressure) propagates and allows dissipation of the pressure to the
low pressure end, namely, the arterial tree of other artery that
comprises CW, without a significant blood flow. Pressure
dissipation is possible because pulse waves and blood flow
through main conducting arteries to the cranial cavity arrive
asynchronously. Therefore, lack of communicating arteries (or
other arterial components of CW that resemble communicating
arteries, depending on CW variations) would expose cerebral
microcirculation to high stress that might cause arterial wall and
BBB damage, especially during strenuous physical activity. In this
context, a rare anatomic variation, such as embryological
remnants (persistent primitive trigeminal artery, carotid–basilar
anastomosis that is associated with numerous vascular abnorm-
alities64,65), would represent a valuable hemodynamic model for
testing the function of the communicating arteries.
CONCLUSIONS
From the evolutionary point of view, the compensatory function
of the CW is incorrect, since pathologic conditions of the older age
are unlikely to steer evolution. Moreover, the communicating
arteries are too small or hypoplastic in majority of the population,
hence ineffective for blood transfer. The communicating arteries
of CW probably serve as a passive energy (pressure) dissipating
system: they transfer pressure without considerable blood flow
from the high pressure end to the low pressure end, the latter
being other arterial components of CW, where pulse wave and
blood flow arrive asynchronously.
DISCLOSURE/CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGMENTS
The authors would like to acknowledge the anonymous reviewers and Professor Sven
Kurbel whose suggestions were helpful in preparing this manuscript.
REFERENCES
1 Lo WB, Ellis H. The circle before Willis: a historical account of the intracranial
anastomosis. Neurosurgery 2010; 66: 7–18.
2 Willis T, Feindel W. The Anatomy of the Brain and Nerves. Classics of Medicine
Library: Birmingham, AL, 1978.
3 Symonds C. The circle of Willis. Br Med J 1955; 1: 119.
4 Dobzhansky T. Nothing in biology makes sense except in the light of evolution.
Am Biol Teach 1973; 35: 125–129.
5 Kardong KV. Vertebrates: Comparative Anatomy, Function, Evolution. McGraw-Hill:
Boston, 2006.
6 Standring S, Ellis H, Healy J, Johnson D, Williams A, Collins P et al. (eds). Gray’s
anatomy: the anatomical basis of clinical practice. Am J Neuroradiol 2005; 26:
2703.
7 Nornes H. The role of the circle of Willis in graded occlusion of the internal carotid
artery in man. Acta Neurochir (Wien) 1973; 28: 165–177.
8 Edelman R, Mattle H, O’Reilly G, Wentz K, Liu C, Zhao B. Magnetic resonance
imaging of flow dynamics in the circle of Willis. Stroke 1990; 21: 56–65.
9 Hoksbergen A, Fülesdi B, Legemate D, Csiba L. Collateral configuration of the
circle of Willis transcranial color-coded duplex ultrasonography and comparison
with postmortem anatomy. Stroke 2000; 31: 1346–1351.
10 Ferguson N. Civilization: the West and the Rest. Penguin Books: New York, NY,
2011.
11 Wolff T, Guirguis-Blake J, Miller T, Gillespie M, Harris R. Screening for carotid artery
stenosis: an update of the evidence for the US Preventive Services Task Force. Ann
Intern Med 2007; 147: 860–870.
12 Purves J. The Physiology of the Cerebral Circulation. University Press: London, UK,
1972.
Journal of Cerebral Blood Flow & Metabolism (2014), 578 – 584
 Function of circle of Willis
Z Vrselja et al
584
13 Kulik T, Kusano Y, Aronhime S, Sandler AL, Winn HR. Regulation of cerebral
vasculature in normal and ischemic brain. Neuropharmacology 2008; 55:
281–288.
14 Baumel JJ. Handbook of Avian Anatomy: Nomina Anatomica Avium. Publications of
the Nuttall Ornithological Club: Cambridge, MA, 1993.
15 Aslan K, Atalgin H, Kurtul I, Bozkurt E. Patterns of the internal and cerebral carotid
arteries in various avian species: a comparative study. Rev Med Vet (Toulouse)
2006; 157: 619.
16 Lane N. Life Ascending: The Ten Great Inventions of Evolution. Profile Books:
London, UK, 2010.
17 Aminoff MJ, Greenberg DA, Simon RP. Clinical Neurology. Lange Medical
Books/McGraw-Hill, Medical Pub Division: New York, NY, 2005.
18 Ganong WF, Barrett KE. Review of Medical Physiology vol. 21. McGraw-Hill Medical:
New York, 2005.
19 Lippert H, Pabst R. Arterial Variations in Man: Classification and Frequency.
Springer: München, Germany, 1985.
20 Krabbe-Hartkamp MJ, Van der Grond J, De Leeuw F, De Groot J, Algra A, Hillen B
et al. Circle of Willis: morphologic variation on three-dimensional time-of-flight
MR angiograms. Radiology 1998; 207: 103–111.
21 Li Q, Li J, Lv F, Li K, Luo T, Xie P. A multidetector CT angiography study of
variations in the circle of Willis in a Chinese population. J Clin Neurosci 2011; 18:
379–383.
22 Maaly MA, Ismail AA. Three dimensional magnetic resonance angiography
of the circle of Willis: anatomical variations in general Egyptian population. Egypt J
Radiol Nucl Med 2011; 42: 405–412.
23 De Silva KRD, Silva R, Gunasekera WL, Jayesekera R. Prevalence of typical circle of
Willis and the variation in the anterior communicating artery: a study of a Sri
Lankan population. Ann Indian Acad Neurol 2009; 12: 157.
24 Nordon David G, Rodrigues Junior OF. Variations in the brain circulation: the circle
of Willis. Braz J Morphol Sci 2012; 29: 243–247.
25 Riggs HE, Rupp C. Variation in form of circle of Willis: the relation of the variations
to collateral circulation: anatomic analysis. Arch Neurol 1963; 8: 8.
26 Kapoor K, Singh B, Dewan LIJ. Variations in the configuration of the circle of Willis.
Anat Sci Int 2008; 83: 96–106.
27 Eftekhar B, Dadmehr M, Ansari S, Ghodsi M, Nazparvar B, Ketabchi E. Are the
distributions of variations of circle of Willis different in different populations?–
Results of an anatomical study and review of literature. BMC Neurol 2006; 6: 22.
28 Orosz L, Hoksbergen AW, Molnár C, Siró P, Cassot F, Marc-Vergnes J-P et al. Clinical
applicability of a mathematical model in assessing the functional ability of the
communicating arteries of the circle of Willis. J Neurol Sci 2009; 287: 94–99.
29 Cucchiara B, Wolf RL, Nagae L, Zhang Q, Kasner S, Datta R et al. Migraine with Aura
is associated with an incomplete circle of Willis: results of a prospective obser-
vational study. PLoS ONE 2013; 8: e71007.
30 Sakellaropoulos A, Mourgela S, Kyrlesi A, Warnke J-P. Hypoplasia of
multiple cerebral arteries: report of an unusual case. J Stroke Cerebrovasc Dis 2008;
17: 161–163.
31 Wagshul ME, Eide PK, Madsen JR. The pulsating brain: a review of experimental
and clinical studies of intracranial pulsatility. Fluids Barriers CNS 2011; 8: 5.
32 Orešković D, Klarica M. Development of hydrocephalus and classical hypothesis of
cerebrospinal fluid hydrodynamics: facts and illusions. Prog Neurobiol 2011; 94:
238–258.
33 Parker KH. An introduction to wave intensity analysis. Med Biol Eng Comput 2009;
47: 175–188.
34 Hall JE. Guyton and Hall Textbook of Medical Physiology: Enhanced E-book. Elsevier
Health Sciences: Philadelphia, PA, 2010.
35 Spencer EB, Sheafor DH, Hertzberg BS, Bowie JD, Nelson RC, Carroll BA et al.
Nonstenotic Internal carotid arteries: effects of age and blood pressure at
the time of scanning on Doppler US velocity measurements. Radiology 2001; 220:
174–178.
36 Westerhof N, Sipkema P, Van Den Bos G, Elzinga G. Forward and backward waves
in the arterial system. Cardiovasc Res 1972; 6: 648–656.
37 Tyberg JV, Davies JE, Wang Z, Whitelaw WA, Flewitt JA, Shrive NG et al. Wave
intensity analysis and the development of the reservoir–wave approach. Med Biol
Eng Comput 2009; 47: 221–232.
38 Davies JE, Aguado-Sierra J, Francis DP, Hughes AD, Parker KH, Maye J. A unifying
explanation of the aortic pulse waveform in humans. J Am Coll Cardiol. Elsevier
Science Inc: New York, NY, USA, 2007.
39 Ogoh S, Fadel PJ, Zhang R, Selmer C, Jans Ø, Secher NH et al. Middle
cerebral artery flow velocity and pulse pressure during dynamic exercise in
humans. Am J Physiol Heart Circ Physiol 2005; 288: H1526–H1531.
Journal of Cerebral Blood Flow & Metabolism (2014), 578 – 584
40 O’Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular
disease in brain and kidney cause and logic of therapy. Hypertension 2005; 46:
200–204.
41 Meininger G, Davis M. Cellular mechanisms involved in the vascular myogenic
response. Am J Physiol 1992; 263: H647–H659.
42 Golding EM, Robertson CS, Bryan Jr RM. Comparison of the myogenic response in
rat cerebral arteries of different calibers. Brain Res 1998; 785: 293–298.
43 Cipolla MJ. The cerebral circulation. Integrated Systems Physiology: From Molecule
to Function 2009; 1: 1–59.
44 Kontos HA, Wei EP, Navari RM, Levasseur JE, Rosenblum W, Patterson J. Responses
of cerebral arteries and arterioles to acute hypotension and hypertension. Am J
Physiol 1978; 234: H371–H383.
45 Aaslid R, Lindegaard K-F, Sorteberg W, Nornes H. Cerebral autoregulation
dynamics in humans. Stroke 1989; 20: 45–52.
46 Fukasawa H. Hemodynamical studies of cerebral arteries by means of mathe-
matical analysis of arterial casts. Tohoku J Exp Med 1969; 99: 255–268.
47 Faraci FM, Heistad DD. Regulation of large cerebral arteries and cerebral micro-
vascular pressure. Circ Res 1990; 66: 8–17.
48 Lee RM. Morphology of cerebral arteries. Pharmacol Ther 1995; 66: 149–173.
49 Willie C, Ainslie P. Cool head, hot brain: cerebral blood flow distribution during
exercise. J Physiol 2011; 589: 2657–2658.
50 Giller CA, Bowman G, Dyer H, Mootz L, Krippner W. Cerebral arterial diameters
during changes in blood pressure and carbon dioxide during craniotomy. Neu-
rosurgery 1993; 32: 737–742.
51 Valdueza JM, Balzer JO, Villringer A, Vogl TJ, Kutter R, Einhäupl KM. Changes in
blood flow velocity and diameter of the middle cerebral artery during
hyperventilation: assessment with MR and transcranial Doppler sonography. AJNR
Am J Neuroradiol 1997; 18: 1929–1934.
52 Serrador JM, Picot PA, Rutt BK, Shoemaker JK, Bondar RL. MRI measures of
middle cerebral artery diameter in conscious humans during simulated orthos-
tasis. Stroke 2000; 31: 1672–1678.
53 Liu J, Zhu Y-S, Hill C, Armstrong K, Tarumi T, Hodics T et al. Cerebral auto-
regulation of blood velocity and volumetric flow during steady-state changes in
arterial pressure. Hypertension 2013; 62: 973–979.
54 Koller A, Toth P. Contribution of flow-dependent vasomotor mechanisms to the
autoregulation of cerebral blood flow. J Vasc Res 2012; 49: 375–389.
55 Bloomfield GL, Ridings PC, Blocher CR, Marmarou A, Sugerman HJ. A proposed
relationship between increased intra-abdominal, intrathoracic, and intracranial
pressure. Crit Care Med 1997; 25: 496–503.
56 Pott F, Van Lieshout JJ, Ide K, Madsen P, Secher NH. Middle cerebral artery blood
velocity during intense static exercise is dominated by a Valsalva maneuver.
J Appl Physiol (1985) 2003; 94: 1335–1344.
57 Sugerman H, Felton W, Salvant J, Sismanis A, Kellum J. Effects of surgically
induced weight loss on idiopathic intracranial hypertension in morbid obesity.
Neurology 1995; 45: 1655–1659.
58 Zou R, Park E-H, Kelly EM, Egnor M, Wagshul ME, Madsen JR. Intracranial pressure
waves: characterization of a pulsation absorber with notch filter properties using
systems analysis. J Neurosurg Pediatr 2008; 2: 83–94.
59 Wagshul ME, Kelly EJ, Yu HJ, Garlick B, Zimmerman T, Egnor MR. Resonant
and notch behavior in intracranial pressure dynamics: laboratory investigation.
J Neurosurg Pediatr 2009; 3: 354–364.
60 Ferguson GG. Physical factors in the initiation, growth, and rupture of human
intracranial saccular aneurysms. J Neurosurg 1972; 37: 666–677.
61 Goljan EF. Rapid Review Pathology: With Student Consult Online Access. WB
Saunders Company: Philadelphia, PA, 2013.
62 Kumar V, Abbas AK, Fausto N, Aster JC. Robbins & Cotran Pathologic Basis of
Disease. Elsevier Health Sciences: Philadelphia, PA, 2009.
63 Wang J, Parker K. Wave propagation in a model of the arterial circulation.
J Biomech 2004; 37: 457–470.
64 Arter PPT, Derleme B. Persistent primitive trigeminal artery: a review. Turk
Neurosurg 2012; 22: 399–406.
65 Alcalá-Cerra G, Tubbs RS, Niño-Hernández LM. Anatomical features and
clinical relevance of a persistent trigeminal artery. Surg Neurol Int 2012; 3: 111.
66 Padget DH. The development of the cranial arteries in the human embryo.
Contr Embryol 1948; 32: 205–261.
67 Van Overbeeke J, Hillen B, Tulleken C. A comparative study of the circle of Willis in
fetal and adult life. The configuration of the posterior bifurcation of the posterior
communicating artery. J Anat 1991; 176: 45.
68 Moffat D. The development of the posterior cerebral artery. J Anat 1961; 95
(Pt 4): 485.
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