Blood Capillary Distribution Correlates
with Hemodynamic-based Functional
Imaging in Cerebral Cortex
Our study concerns the mechanisms that underlie functional imaging
of sensory areas of cortex using hemodynamic-based methods
such as optical imaging of intrinsic signals, functional magnetic
resonance imaging and positron emission tomography. In temporal
cortex of chinchilla, we have used optical imaging of intrinsic signals
evoked by acoustic stimulation to define the functionally responsive
area and then made (scanning electron microscopy) observations of
the corresponding capillary networks prepared by corrosion cast
methods. We report that intrinsic signals associated with auditory
cortex correlate directly with discrete capillary beds. These capillary
beds, within the cortical surface layers, are distributed across the
cortex in a non-uniform fashion. Within cortex both the arterial
supply and the capillary network contain various flow control
structures. Our study suggests a causal relationship between the
metabolic demands of local neuronal activity and both the density of
the capillary network and the placement of the control structures.
Such relationships will affect the ultimate spatial resolution
obtainable by hemodynamic-based functional brain imaging studies.
These relationships will also affect quantitative comparisons of
activity levels in different areas of cortex.
Introduction
Functional brain imaging techniques such as functional magnetic resonance imaging (fMRI), positron emission tomography
(PET) and optical imaging of intrinsic signals rely on the
apparently close coupling between metabolic demand of
activated neurons and local changes (typically increases) in
blood supply (Roy and Sherrington, 1890; Lou et al., 1987).
Numerous studies have focused on the exact relationships
between nerve-cell activity and the mechanisms of local blood
f low modulation (Lazorthes et al., 1968; Black et al., 1987; Toga,
1987; Sirevaag et al., 1988; Edelman and Gally, 1992; Iadecola,
1993; Argandoña and Lafuente, 1996, 2000; Estrada and
DeFelipe, 1998). Investigations concerned with improving
functional imaging methods (particularly fMRI) have explored
the possibility of capturing the earliest (and most local) hemodynamic/metabolic events associated with neural activity, thus
achieving an improved spatial resolution (Malonek and Grinvald,
1996; Logothetis et al., 1999; Kim et al., 2000). In any case, all
these imaging techniques have a limiting factor which is defined
by the physical relationship between blood capillaries and the
neurons of interest. Essentially all techniques that rely on
changing hemodynamics, or blood oxygen level dependent
(BOLD) mechanisms, are bound in their functional (spatial)
resolution by the density of blood capillary vasculature and the
fineness of hemodynamic control within those vascular beds.
In the present study we have explored these relationships in
detail. We have optically imaged intrinsic signals (Grinvald et al.,
1986; Frostig et al., 1990; Bonhoeffer and Grinvald, 1996)
evoked by acoustic stimulation in auditory areas of temporal
cerebral cortex (Harrison et al., 1998; Harel et al., 2000). We
have then made corrosion casts of the vascular anatomy in the
© Oxford University Press 2002. All rights reserved.
Robert V. Harrison, Noam Harel1, Jaswinder Panesar and
Richard J. Mount
Auditory Science Laboratory, Department of Otolaryngology
and Brain and Behaviour Division, The Hospital for Sick
Children, University of Toronto, Toronto, Ontario, Canada
1
Present address: Center for Magnetic Resonance Research,
University of Minnesota Medical School, Minneapolis,
MN 55455, USA
same areas for viewing by scanning electron microscopy (SEM).
We find that for core areas of auditory cortex, the spatial pattern
of intrinsic signals (relating to hemodynamic change) relates
directly to the physical position and density of capillary beds,
and to the distribution of the myogenic valves that control blood
f low to these capillar y beds. Our findings have important
implications for a wide range of medical imaging techniques
which aim to imply neuronal function from hemodynamic
change.
Materials and Methods
Functional imaging and subsequent corrosion cast preparation was
performed on five adult chinchillas (Chinchilla laniger). In the
ketamine-anesthetized subject, intrinsic signal imaging of temporal
cortex was used to define active regions of auditory cortex. This was
immediately followed by plastic injection of cerebral blood vessels (via
aortic perfusion). Following plastic polymerization, and digestion of
tissue, these (whole brain) corrosion casts were studied using SEM. All
procedures were carried out following the guidelines of the Canadian
Council on Animal Care, and with the approval of the local animal care
committee. Experimental details are as follows.
For optical imaging of intrinsic signals, a craniotomy was made over
the temporal region of the brain extending ventrally to zygoma and
dorsally to the parietal frontal bones. Body temperature was maintained at
36°C; animals are maintained under light ketamine anesthesia (15 mg/kg;
i.m.). Our animals are respiring spontaneously. Positive pressure
pumping causes considerable mechanical movements of the brain which
are a problem in optical imaging. Other groups imaging visual cortex in
the cat (Bonhoeffer and Grinvald, 1996) have time-locked image capture
to respiratory pumping cycle, but this has not proved useful in our
experience with the chinchilla. Without pumping we have, theoretically,
less control over the physiological condition of our subjects; however, our
experience has been that there is no evidence of hypoxia for 6–8 h light
ketamine anesthesia. The dura was excised, the cortical surface was
covered with silicone oil and a glass coverslip placed over the area to
produce an optically f lat interface. The cortical surface was evenly
illuminated with 540 nm wavelength light. Images of the cortex were
acquired with a CCD camera and macro lens assembly (Imager 2001,
Optical Imaging Inc. Germantown, NY). Activity in auditory cortex was
evoked by a 3 s duration broadband noise at 80 dB SPL presented to the
ear contralateral to the imaged cortex. Imaging was carried out during
and after acoustic stimulation for a period of up to 10 s (Harrison et al.,
1998; Harel et al., 2000).
To prepare corrosion casts of the cerebral vasculature, the ascending
aorta was perfused with 50 ml heparinized phosphate buffered saline
(PBS) followed by 20 ml of Batson’s #17 resin. Complete polymerization
of the resin took ∼12 h, after which the brain was dissected from the
cranium. Tissue was macerated in 40% KOH at 50°C for 24 h with
intermittent distilled water rinses. The plastic cast was air dried, mounted
onto a stub with colloidal silver paste and sputter coated with gold. The
cast was examined in an Hitachi S570 SEM at 10 keV.
Results
Definition of Functional Area
Figure 1 shows the time course and spatial position of the
Cerebral Cortex Mar 2002;12:225–233; 1047–3211/02/$4.00
Figure 1. Optical imaging of intrinsic signal in auditory cortex. The upper panels show signals imaged from temporal cortex in response to a 3 s, 80 dB SPL noise stimulus. Each image
represents a 0.5 s time window. The signal reaches a maximum at 1–1.5 s (third image), and this response area has been superimposed on an image of the cortical surface (upper
right). The lower panels demonstrate the lack of signal during a no-stimulus control trial.
intrinsic signal in response to a broadband sound stimulus. The
figure shows thresholded images from one experimental subject
recorded at 0.5 s intervals during acoustic stimulation (upper
data series) and in a no-stimulus condition (lower data series).
The outline of the maximum intrinsic signal, captured at 1–1.5 s
after stimulus onset (third image of the stimulus trial), is
superimposed on the grayscale image of the cortical surface in
the upper right-hand panel. The response is typical of that
previously reported (Harrison et al., 1998; Harel et al., 2000).
The intrinsic signal area corresponds with regions of ‘core’
auditory cortex (A I, A II and anterior auditory field) within
which single units respond very actively to acoustic stimulation.
Figure 2 shows this relationship for one subject in which we
have made concurrent intrinsic signal imaging (1 kHz, 80 dB)
and single unit electrophysiological recordings. Point symbols
are at sites where neurons are acoustically driven; × symbols
show no-response sites.
The relationship between cortical surface and the intrinsic
signal boundary from Figure 1 is reproduced in the left panel of
Figure 3. The right panel shows an SEM image of the same area
after corrosion cast preparation, and again the boundary of the
intrinsic signal area is indicated. Note that both images are f lat
representations of cur ved structures at slightly different
226 Capillary Distribution and Functional Imaging in Cortex • Harrison et al.
Figure 2. Correlation between optically imaged intrinsic signal area from auditory
cortex (1 kHz, 80 dB) and the sites of acoustically driven neurons (point symbols) and
recording positions at which there is no-response (× symbols). Bar = 1 mm.
Figure 3. Correlation of intrinsic signal area and cortical vasculature. The left panel shows the cortical surface within the craniotomy as seen during intrinsic signal imaging; the
maximum area of intrinsic signals (from Fig. 1) has been superimposed. The right panel is a scanning electron micrograph of the same area after corrosion casting, again the maximum
area of intrinsic signals (from Fig. 1) has been superimposed. Bar = 1 mm (both images).
orientations, thus the intrinsic signal outlines have similar but
not identical shapes.
Vascular Organization
The general organization of the cortical layer vasculature is that
both major arterial supply and venous drainage is at the surface
of cortex, and can be directly visualized as seen in the left image
of Figure 3. The pial arteries give rise to arterioles which course
down perpendicular to the surface; some vessels pass directly
down to deeper cortical areas with little or no branching, and
others feed a subsurface capillary system. There is venous return
from such capillary beds back to the cortical surface.
Our first important observation is that the capillary bed
distribution across (temporal) cortex is not uniform. Figure 4
shows areas with a very dense capillary network separated by
regions with few or no capillaries from four different subjects.
Our second observation is that certain of these dense capillary
beds closely fit the boundary of the intrinsic signal area. In the
example shown (Figure 3, left) this is particularly evident on the
posterior (caudal) boundary of the intrinsic signal region. Figure
5 shows a higher magnification image of this area. The upper
inset shows the cortical surface view of the identical region with
the intrinsic signal boundary superimposed. The major vein and
artery are labeled (A and B respectively) on both images. The
capillary bed on the left side of the SEM image is clearly
associated with the measured intrinsic signal from primar y
auditory cortex; indeed it is difficult not to conclude that the
intrinsic signal results from hemodynamic changes in that
capillary bed. The dense capillary mesh to the right in this SEM
image produced no acoustically evoked intrinsic signal. Between
these two high-density capillary areas is a region with no
capillary bed. We do not believe that this uneven distribution is
a preparation artifact for a number of reasons. First, we know
that capillary beds are well perfused when the resin is seen to fill
the venous side of the system. Secondly, close inspection of the
arterioles adjacent to this gap does not reveal evidence of
incomplete plastic infiltration of side branching vessels. In
addition, similar patterns of heterogeneous capillary bed
distribution were observed in all subjects.
Vascular Control System
Figure 6 shows the dense capillar y mesh associated with
auditory cortex. This is an area within that corresponding to the
maximum intrinsic signal response to the noise stimulus.
Arteries and their branches (A) can be recognized by their round
profile and the elongated imprints of vessel wall epithelial cells
(Hodde et al., 1997); resin casts of veins (V) tend to be f lattened
and with a smoother surface. The rich vascular network has clear
properties that indicate that it is not passively gorged with
blood, but rather has a number of controlling sites. Most obvious
in the corrosion cast preparations is evidence of the position of
smooth muscle bands, strategically placed along arteriole trunks
and at branching points (asterisks), to control blood f low to the
capillary networks. In these corrosion casts we do not observe
directly the smooth muscles but rather the cast of the endothelial
spaces that surround the muscle, sometimes referred to as plastic
strips (Anderson and Anderson, 1978; Castenholz, 1983a, b;
Reina-De La Torre et al., 1998). The larger arteries show
evidence of patchy muscle banding. It is likely that this
incomplete pattern is due to the limitations of the corrosion
casting technique, which can only show spaces that have a
continuum with the inside of blood vessels.
The main artery (A) gives off three types of collateral vessel.
The first type (labeled 1) courses over the cortical surface for
some distance, giving rise to other collateral vessels before either
penetrating the cortical surface itself or dividing into terminal
branches which eventually penetrate the surface. The second
type (2) arises from the side or undersurface of the artery and
branches out both collaterally and terminally, giving rise to many
pre-capillar y arterioles. The third type (3) is an intracortical
artery which penetrates deep within cortex without
contributing to the superficial capillary network. Most arterioles
(e.g. all those shown in Fig. 6) show some evidence of myogenic
banding, and we have an impression that those vessels feeding
capillary beds have more such structures (compare arteriole 2 to
arteriole 3); further quantitative analysis is needed. We have
noted that these smooth muscle zones are often associated with
arteriole branch points and can serve either to constrict
downstream vessel walls or to distort areas next to side branches
so as to alter blood f low down them.
Pre-capillary arterioles frequently possess a distinct form of
smooth muscle banding as seen in the upper panels of Figure 7.
A single bifurcating structure encircles the arteriole. These
are often seen in close association with collateral capil-
Cerebral Cortex Mar 2002, V 12 N 3 227
Figure 4. Vasculature of temporal lobe from four chinchillas demonstrating the varying density of capillary distribution within cortex. Upper panels, bar = 500 µm; lower panels, bar
= 100 µm.
laries. Downstream from the arterioles we see evidence of a
second set of vascular control structures, the vascular
pericytes (Castenholz, 1980, 1983a; Sims, 1986; Tilton, 1991;
Rodriguez-Baeza et al., et al., 1998). Most often with corrosion
casting, pericytes do not become resin filled but rather leave
their signature depressions surrounding the capillary
(Kojimahara and Ooneda, 1980; Castenholz, 1983a; Motti et al.,
1986; Pannarale et al., 1996). Examples of these often
sphincter-like depressions are seen in the lower panels of Figure
7 (arrows). In capillary beds of auditory cortex these structures
are usually situated at or close to capillary branching points.
The capillary mesh itself is a complicated series of loops. In
228 Capillary Distribution and Functional Imaging in Cortex • Harrison et al.
Figure 8 we have traced two of these loops from the arterial
supply to the venous drain. Multiple stereo-pair micrographs
were used to follow the course of these capillaries. First we note
that most, if not all, capillaries in this micrograph are
interconnected. The path of only two capillary loops are
highlighted. A pre-capillar y arteriole (red) gives rise to a
collateral capillary (green) which divides into two terminal
capillaries, one short (orange) and the other longer (cyan). The
short (orange) capillar y connects with three other capillary
loops before entering a post-capillary venule (blue) as a collateral
vessel ∼35 µm above its origin. The longer capillary (cyan)
follows a more tortuous route circling the venule and connecting
Figure 5. Corrosion cast scanning electron micrograph image from caudal border area of the auditory intrinsic signal region. The inset shows the surface view of cortex with the
boundary of the intrinsic signal area superimposed. A and B are fiducial marks on a vein and artery respectively to aid in comparison of the two images. Bar = 250 µm.
with nine other capillar y loops before entering the same
post-capillary venule, also as a collateral vessel. Approximately
15 µm above this point the venule is joined by another
post-capillary venule these join with others to become the
venous branch shown in Figure 6.
Discussion
Corrosion Cast Technique
A number of studies have used corrosion casting to explore the
capillary networks of cerebral cortex (Motti et al., 1986;
Reina-De La Torre et al., 1998; Rodriguez-Baeza et al., 1998).
Many of the features that we obser ve in chinchilla auditory
cortex are similar to previous descriptions, including the
sphincter-like grooves caused by vascular pericytes (Kojimahara
and Ooneda, 1980). Rodriguez-Baeza and his group have
recently reported on corrosion cast SEM studies in human
cerebrum (Reina-De La Torre et al., 1998; Rodriguez-Baeza et al.,
1998), and the general arrangement of vasculature is similar to
that reported for other mammalian species. These authors draw
special attention to the variations in vascularity according to
depth, including a lack of capillarity in the superficial (pial) layer
which we also obser ve. An increase in capillary density
associated with cytoarchitectonic distinct whisker barrels has
been shown (Cox et al., 1993; Woolsey et al., 1996).
The clear evidence of smooth muscle banding on arteriole
walls and of capillary vascular pericytes has been described in
detail by other authors (Castenholz, 1983a; Motti et al., 1986;
Cerebral Cortex Mar 2002, V 12 N 3 229
Figure 6. Scanning electron micrograph revealing vasculature within the area corresponding to the maximum acoustically evoked intrinsic signal. The arteries (A) and vein (V) can be
clearly distinguished. 1, 2, 3: three types of arterial collateral vessels (see text). Note evidence of smooth muscle banding (asterisk symbols) on arteriole walls. Bar = 100 µm.
Reina-De La Torre et al., 1998; Rodriguez-Baeza et al., 1998),
although not directly in the context of functional imaging. In the
case of smooth muscle banding on arterioles, it is assumed that
the plastic cast is of endothelial space surrounding smooth
muscle cells which is connected to the vessel lumen. As for the
vascular pericytes, we occasionally obser ve casts of these
structures which are similar to those described by others
(Castenholz, 1983a; Rodriguez-Baeza et al., 1998); however,
most often in our preparations we see only the deep grooves that
they make in capillary walls. It should be noted that some of
these grooves have also been interpreted as evidence of
peristaltic vasomotion (Toribatake et al., 1997). In any case, the
function of these vaso-surrounding structures is now widely
assumed to be related to the fine control of blood f low in cortical
capillary beds. We have not yet made a quantitative analysis of
the distribution of ‘vascular control points’; we observe them
ubiquitously. However, we hypothesize that their density could
be different in cortical areas which require a refined
hemodynamic control.
Our working hypothesis is that the capillary density of any
brain area develops in direct relationship to the metabolic
230 Capillary Distribution and Functional Imaging in Cortex • Harrison et al.
demand of local neurons. Thus while primary sensory areas will
have dense capillary nets, some non-sensory or association areas
may not. This notion has previously been put forward by a
number of authors who have explored the relationship between
neuronal activity and capillary density (Lazorthes et al., 1968;
Black et al., 1987; Toga, 1987; Sirevaag et al., 1988; Argandoña
and Lafuente, 1996).
Functional Brain Imaging
In many ways, the close relationship between the shape of the
intrinsic signal region and the distribution of the capillary
network should really not be much of a surprise. Intrinsic signals
arise from hemodynamic effects that have their origins in
capillary networks (Grinvald et al., 1986; Frostig et al., 1990).
However, this statement of the obvious has some important
implications for all those imaging techniques that capitalize on
function-related hemodynamic change (including fMRI, PET,
intrinsic signal imaging, Doppler blood f low measurement, etc.).
Importantly it means that there exist certain cortical areas in
which the density of blood vasculature is higher, and these areas
are more likely to light up in various functional tasks than less
Figure 7. Scanning electron micrograph images of corrosion cast specimens showing evidence of blood-flow control structures. Upper panels show resin-filled vascular pericytes
surrounding pre-capillary arterioles. The lower panels show examples of capillary constriction resulting from the perivascular structures (that are not filled by the resin). These are most
often observed near to capillary branching points. Bar = 10 µm (upper panels), 5 µm (lower panels).
vascularized regions. These areas are likely to include primary
sensory areas, motor cortex, and perhaps in humans,
speech-related regions such as Wernicke’s and Broca’s areas. The
corollary is that many areas, because of an insufficient blood
capillary network, may not produce a function related signal.
We postulate that, due to a variation in density of vascular
beds and their controlling points in different areas of cortex, the
spatial resolution of imaging methods will depend on which area
is under investigation. Thus functional imaging of a highly
vascularized area such as primary auditory cortex will reveal
local activity patterns at a considerably higher spatial resolution
than in less vascularized (less active) areas. In the chinchilla
auditory cortex, we have previously been able to demonstrate
(using optical imaging of intrinsic signals) tonotopic maps with
octave spaced frequency resolution (Harrison et al., 1998; Harel
et al., 2000). This represents a functional resolution of ∼400 µm.
On the basis of the present anatomical study, we might estimate the limit to this spatial resolution to be of the order of
100–150 µm based on the approximate distance between (pre)
capillary f low control valves and start of venous drainage (see
Fig. 6). There are intrinsic signal imaging and fMRI data from
striate cortex of the visual system which have revealed
orientation columns with a dimension in the 50–100 µm range
(Grinvald et al., 2000), and we therefore predict that the
capillary network in primar y visual cortex may be of finer
dimensions or have a greater abundance of controlling
sphincters to allow finer hemodynamic control.
The general notion that different areas of the cerebral cortex
have different densities of fine vasculature according to the
metabolic demands of neural activity, and/or that the fineness of
hemodynamic control differs from one region to the next, has a
significant implication for BOLD or other blood f low-based
imaging studies of neural function. Most obviously it means that
quantitative comparisons between signals coming from different
areas have to be made with caution. A worse-case scenario is that
perhaps only certain high-activity regions of cortex are endowed
with sufficient capillary network density/control to produce
signals for functional imaging, and that some areas of association
Cerebral Cortex Mar 2002, V 12 N 3 231
Figure 8. Corrosion cast scanning electron micrograph of a capillary plexus in auditory cortex. A pre-capillary arteriole (red) gives rise to a collateral capillary (green) which divides
into two terminal capillaries (orange and cyan). The short (orange) capillary connects with three other capillary loops before entering a post-capillary venule (blue). The long (cyan)
capillary connects with nine other capillaries before joining the same post-capillary venule. Bar = 50 µm.
cortex, for example, may never generate such a response.
Further detailed mapping studies of blood pathways and
associated control points in various cortical areas are needed to
estimate the ultimate spatial resolution of hemodynamic based
functional imaging methods such as fMRI and PET.
Notes
This research was supported by the Canadian Institutes of Health
Research (CIHR), and the Masonic Foundation of Ontario.
Address correspondence to Dr Robert V. Harrison, Department of
Otolaryngology, The Hospital for Sick Children, 555 University Avenue,
Toronto, Canada M5G 1X8. Email: [email protected].
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