Investigative Ophthalmology & Visual Science, Vol. 31, No.

9, September 1990
Copyright © Association for Research in Vision and Ophthalmology

Pepfidergic Innervafion of the Retinal Vasculature

and Optic Nerve Head
Xioodan Ye, Alon M. Lories, and Richard A. Srone

Using immunocytochemistry, the authors studied the peptidergic innervation to the vasculature of the
optic nerve and retina in the rhesus monkey and rat. In the monkey, beaded nerve fibers immunoreac-
tive to the vasoactive peptides, calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), sub-
stance P (SP), and vasoactive intestinal peptide (VIP), are present in the adventitia and perivascular
space along the course of the central retinal artery within the optic nerve. The CGRP and SP
immunoreactivities fully co-localize. Perivascular peptidergic nerve fibers terminate as the blood
vessel enters the globe and do not follow the branches of the central retinal artery inside the eye.
Within the substance of the optic nerve behind the lamina cribrosa, small blood vessels occasionally
are supplied with CGRP-, SP-, and sometimes NPY- or VIP-immunoreactive nerve fibers. Of special
note, fine nerve fibers not clearly related to blood vessels are seen within the lamina cribrosa; their
simultaneous immunoreactivity to CGRP and SP suggests a sensory function. In the rat as in the
monkey, the retinal arterioles beyond the surface of the optic disc lack evident peptidergic innervation.
Perhaps an explanation for the known physiologic reactivity of the retinal circulation to neurohumors
in the absence of recognizable peripheral innervation can be based on comparison to the brain where
intraparenchymai blood vessels may be regulated by local neurons. Since the inner piexiform layer has
abundant amacrine-derived nerve processes containing classical neurotransmitters and/or neuropep-
tides, a local mechanism coupled to intrinsic retinal activity might contribute to the regulation of the
circulation. Invest Ophthalmol Vis Sci 31:1731-1737,1990

Whether or not peripheral nerve fibers innervate
the intraocular branches of the central retinal artery
(CRA) remains controversial. Claims for such inner-
vation originally made on the basis of silver stains'
have not been supported by electron microscopic2"4
or histochemical studies,5"7 except in the rabbit.8"10
As a result, the retinal vascular tree in most species is
now considered devoid of extrinsic nerve fibers. Yet a
paradox exists: evidence is mounting that the retinal
blood vessels have receptors for and sensitivity to
neurotransmitters and neurohormones, including bi-
ologically active peptides.""13 In an attempt to clarify
matters, we extended recent work on peripheral
neuropeptidergic innervation, examining the inner-
vation of the CRA and its intraocular branches in the
monkey and rat for four neuropeptides, calcitonin
gene-related peptide (CGRP), neuropeptide Y
(NPY), substance P (SP), and vasoactive intestinal
peptide (VIP). All four peptides are vasoactive and
From the Department of Ophthalmology, University of Penn-
sylvania School of Medicine, Scheie Eye Institute, Philadelphia,
Pennsylvania.
Supported by NIH grant EY05454 and the Harry and Edith H.
Hubschman Research Fund of the Scheie Eye Institute.
Reprint requests: Dr. Richard A. Stone, D-603 Richards Build-
ing, University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania 19104-6075.
occur in peripheral nerves supplying both the eye14
and blood vessels to the brain.15 In peripheral ocular
nerves, CGRP and SP nerve fibers are sensory, and
VIP nerve fibers are parasympathetic. Generally as-
sociated with the sympathetics, the assignment of
NPY is problematic; it also is found in some para-
sympathetic neurons supplying the eye, indicating a
mixed autonomic derivation.14
Materials and Methods
Eight rhesus monkey eyes were obtained immedi-
ately after death from animals killed under deep pen-
tobarbital anesthesia as part of the polio-vaccine test-
ing program of the Bureau of Biologies of the Food
and Drug Administration; the eyes were fixed by im-
mersion in Zamboni's solution16 at 4°C for 48 hr.
Twelve male Wistar rats also under deep pentobarbi-
tal anesthesia were perfused through the left ventricle
first with 0.85% NaCl and then with Zamboni's solu-
tion. The enucleated eyes were postfixed at 4°C for
48 hr. All tissues were washed overnight at 4°C in 0.1
M phosphate-buffered saline (PBS), pH 7.4, with 30%
sucrose. Then 16-20 /im thick cryostat tissue sections
were cut in a horizontal plane to include the optic
nerve head. Tissue sections were thaw mounted on
gelatin-coated slides, dried at room temperature, and

1731

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 1732 INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / September 1990
stored at -20°C until stained with the indirect im-
munohistochemical technique.
For primary antisera, we used polyclonal antisera
generated in rabbits against CGRP (Lot #
V054/5517; Cambridge Research Biochemical, Val-
ley Stream, NY), NPY (Lot # 00317/1098; Cam-
bridge), SP (Lot # 8706025; INCStar, Stillwater,
MN), VIP (Lot # 8726017; INCStar), and monoclo-
nal antibodies raised in the rat against SP (Lot #
B3K35; Pel-Freez, Rogers, AR). All primary and sec-
ondary antisera were diluted in 0.05 M PBS, pH 7.2,
containing 0.3% Triton X-100, and all rinses were
done with 0.05 M PBS, pH 7.2, containing 0.2% Tri-
ton X-100.
Tissue sections from both species were incubated
overnight at room temperature with the primary an-
tibody (anti-VIP diluted 1:500; anti-SP, 1:500; anti-
NPY, 1:800; and anti-CGRP, 1:800). After rinsing,
the tissue sections were incubated for 1 hr at 37°C
with the biotinylated F(ab')2 fragment of donkey
anti-rabbit IgG diluted 1:300, followed by a 15-min
incubation at 37°C with fluorescein-labeled avidin
diluted 1:300 (Amersham International, Arlington
Heights, IL). The stained tissue sections were
mounted in a TRIS-glycerin mixture and were exam-
ined with an epi-illumination system.
For the co-localization of CGRP and SP in the
monkey eye, tissue sections were incubated overnight
at room temperature with a mixture of rabbit CGRP
antiserum and rat SP monoclonal antibodies, each
diluted 1:300, and then for 1 hr at 37°C with a mix-
ture of goat anti-rabbit IgG conjugated to rhodamine
isothiocyanate (RITC; Cappel Laboratories, West
Chester, PA) and goat anti-rat IgG conjugated to fluo-
rescein isothiocyanate (FITC; Cappel), respectively
diluted 1:400 and 1:300. The microscope illumina-
tion system allowed for rapid alteration of optimum
filter combinations for visualization of RITC
(510-560 nm exciter; 580 nm dichromatic beam
splitter; 590 nm barrier filter) or FITC (450-490 nm
exciter; 510 nm dichromatic beam splitter; 520 nm
barrier filter) fluorescence.
For controls, the primary antisera were preab-
sorbed by overnight incubation at 4°C of each diluted
primary antiserum with 1.0 /xM of the respective
peptide (Peninsula Laboratories, San Carlos, CA); the
preabsorbed antisera then were substituted in the im-
munohistochemical procedure. As another control,
the primary antiserum was omitted entirely. To eval-
uate specificity for the co-localization studies, the
primary antibody mixture was preabsorbed with 1.0
nM CGRP or SP. For additional specificity controls,
tissue sections stained with rabbit primary antiserum
were reacted with the anti-rat secondary antiserum;
those stained with the rat monoclonal antibodies
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Vol. 31
were reacted with the anti-rabbit secondary anti-
serum. All control studies demonstrated appropriate
immunohistochemical specificities.
For the histologic sections of rat CRA, enucleated
rat eyes were dehydrated and embedded in Historesin
(Microscopic Optical Consulting, Valley Cottage,
NY). Then 4-ixm tissue sections were stained with a
0.5% azure II, 0.5% methylene blue, 1% sodium bo-
rate solution. All studies conformed with the ARVO
Resolution on the Use of Animals in Research.
Results
Peptidergic Innervation of Central Retinal Artery
and Optic Disc
In the monkey orbit, the CRA and central retinal
vein together enter the optic nerve some 3-8 mm
behind the lamina cribrosa, surrounded by a sheath
of glia and connective tissue. They rapidly gain a
central position, travel forward, and finally pass
through the lamina cribrosa to divide at the face of
the optic nerve head. Immunoreactive nervefibersof
beaded appearance and meandering course, typical of
peripheral nerve fibers, were seen in the vascular ad-
ventitia of the artery during its intraorbital course.
Frequently they extended inwards to the adventitia-
media border. In separate preparations, nerve fibers
immunoreactive for each of the four neuropeptides
under study were visualized (Fig. 1). The NPY-like
immunoreactive (-LI) nerve fibers were consistently
more numerous than those of CGRP, SP, or VIP. As
nervefiberstraveled forward with the blood vessels in
the optic nerve, no significant change of innervation
density was detectable behind the lamina cribrosa.
Between the lamina cribrosa and the optic disc sur-
face, a rapid and profound attenuation occurred: no
CRA branches emanating from the optic disc had an
observable peptidergic nerve supply (Fig. 2). When
specifically studied, CGRP and SP fully co-localized
(Fig. 1). In comparison with the artery, the nerve
supply to the central retinal vein was consistently far
lower in density and less predictable; in many in-
stances, it was absent.
In the intracanalicular segment of the monkey
optic nerve, individual fine CGRP- and SP-LI nerve
fibers also were seen in the posterior part of lamina
cribrosa (Fig. 3). They were immediately adjacent to
laminar beams oriented perpendicular to the optic
nerve axons. CGRP and SP co-localized fully in these
nerve fibers as in other locations. Even though small
intrascleral blood vessels adjacent to the optic nerve
head in the circle of Zinn-Haller and others passing
between the sclera and lamina cribrosa were occa-
sionally surrounded by nerve fibers similarly immu-
noreactive to CGRP and SP, we could not identify
 No. 9 PEPTI.DERGIC INNERVATION / Ye er ol 1733

Fig. 1. Calcitonin gene-

related peptide and sub-
stance P-like immunoreac-
tive nerves associated with
the centra) retinal artery
of the rhesus monkey.
In a longitudinal section
through the optic nerve al-
ternatively viewed for
CGRPin(A)andSPin(B),
fibers immunoreactive to
each peptide innervate the
central retinal artery {CRA)
throughout most of its
length. Arrows point out the
precise registration of the
immunoreactivity to each
peptide, indicating co-local-
ization. An arrowhead indi-
cates the vitreal surface of
the optic nerve head. Mag-
nification bar, 50 jiiti.

clear vascular associations of the fine nerve fibers in
the lamina cribrosa. No NPY- or VIP-LI nerve fibers
of similar distribution were observed within the lami-
nar region.
In contrast to its course in the monkey, the CRA in
the rat passes inferolaterally to the optic nerve and
enters the optic nerve head obliquely between the
sclera and optic nerve. CGRP-, NPY-, SP-, and VIP-
LI nerve fibers were present in the adventitia of the
CRA. The CGRP-LI fibers terminated just before the
CRA entered the globe. The other three types of pep-
tidergic nerve fibers underwent a small decrease in

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 1734 INVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIENCE / September 1990
density as the blood vessel passed forward to the optic
disc and then also ended abruptly (Figs. 4, 5). As in
the monkey, very few peptidergic nerve fibers were
observed around the central retinal vein.
Neurovascular Relationships Within the Retina
The arteriolar branches of the CRA repeatedly bi-
furcate in the superficial nervefiberlayer to distribute
into layered capillary beds, the deepest of which reach
the outer plexiform layer. As capillaries penetrate the
inner plexiform layer, they are in immediate proxim-
ity to amacrine cell processes. The monkey and rat
retina contained VIP- and SP-LI amacrine cell bodies
with inner plexiform layer processes.17 In both spe-
cies, alternating-phase and fluorescence microscopy
clearly demonstrated that capillaries penetrate the
inner plexiform layer in close proximity to peptider-
gic nerve fibers (Fig. 6).
Discussion
The existence of a rich and complex nerve fiber
plexus to the CRA in its course through the optic
nerve has been well known for many years. In fact,
the sympathetic contribution was described by Tie-
demann and others in the early 19th century.18 As
specific histochemical methods for the identification
of neurotransmitters and/or their enzyme systems
supplemented nonspecific silver staining, a choliner-
gic component was ascribed to parasympathetic
sources. In the rat and monkey, the two species we
studied, only a few adrenergic or cholinergic fibers
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Vol. 31
Fig. 2. Absence of peptid-
ergic innervation to the su-
perficial retinal blood ves-
sels. Near the monkey optic
disc, a superficial retinal
blood vessel (asterisk) is de-
void of innervation. Va-
soactive intestinal peptide-
like immunoreactive nerve
fibers are visible within the
inner plexiform layer
(arrows) of the retina and
surround choroidal blood
vessels of differing sizes (ar-
rowheads). Magnification
bar, 50 fim.
were observed to surround the branch retinal blood
vessels at the optic nerve head, and none served the
retinal blood vessels.6'7'9
In this report, we extended prior histochemical re-
sults on adrenergic and cholinergic innervation to
neuropeptides and found that peptidergic nerve fibers
disappear as the CRA passes forward into the globe.
The attenuation is such that, although a few peptid-
ergic nerve fibers can be traced as far forward as the
vitreal surface of the optic nerve head, none follow
the blood vessels in their course over the retina. The
entire series of histochemical and immunocytochem-
ical observations is supported by electron micro-
scopic findings which also demonstrate no nerve ter-
minals on branch retinal blood vessels in rats, mon-
keys, and humans.2"4 The rabbit is a limited
exception to this generalization. Although SP-LI
nerve fibers surrounding its CRA do not extend into
the globe,19 a definite adrenergic innervation to reti-
nal blood vessels has been observed on several occa-
sions.8"10 In this respect, however, the rabbit and hare
are distinct among mammals: their retinal blood ves-
sels are restricted in distribution to the horizontal
region of the vascular stripe, an area more or less
coextensive with myelinated ganglion cell axons.20
An observation that retinal blood vessels in the dog
and in pathologic human eyes are innervated has not
been replicated.21
Based on these considerations, the regulatory po-
tential for the vascular innervation would seem to
depend on the location of blood vessels in relation to
the optic nerve head. Regarding the extraocular com-
 No. 9 PEPTIDERGIC INNEfWATION / Ye er ol
Fig. 3. Presumed sensory nerve fibers at the lamina cribrosa of
the monkey. (A, B) A small nerve fiber (arrow) at the lamina
cribrosa stains simultaneously for CGRP in (A) and SP in (B)
evidence for a sensory origin. (C) The location of this nervefiberis
indicated on the phase micrograph of the identical field (arrow)
seen in (A) and (B), Magnification bar, 50 nm.
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1735
Fig. 4. Vasoactive intestinal peptide and innervation of the rat
central retinal artery. (A) The central retinal artery (CRA) enters
the eye inferior to the optic nerve. Its course through the optic
nerve is oblique and short. (B) Vasoactive intestinal peptide-likc
immunoreactive (VIP-LI) nerve fibers (arrow) accompany the ar-
tery as it enters the eye. Note that branch blood vessels (asterisks)
within eye are devoid of VIP nerves. A few VIP-LI nervefibersare
visible in the inner plexiform layer (arrowhead). Magnification bar,
50jum.
 1736 INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / September 1990
Fig. 5. Neuropeptide Y and the innervation of the rat central
retinal artery. Neuropeptide Y-like immunoreactive (NPY-LI)
nerve fibers (arrow) supply the central retinal artery (CRA) as it
travels to the surface of the optic nerve (ON). Note also the NPY-LI
nerve fibers in the choroid (arrowheads). R = retina; magnification
bar, 50 ^m.
ponent, an active innervation probably influences the
head of pressure reaching the retina at the optic disc.
Evidence for this comes from several sources. For
example, superior cervical ganglion stimulation in
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Vol. 01
the cat is followed by a widespread drop in retinal
oxygen tension independent of the choroidal circula-
tion.22 More directly, the isolated perfused ophthal-
mic artery of the Japanese monkey demonstrates
graded reactivity to vasoactive amines, such as nor-
epinephrine and tyramine.23
Less certain is what occurs to the blood vessels in
the retina. Although such blood vessels lack extrinsic
innervation, autonomic receptors are present on their
walls.1213 Also altered vascular diameter and/or reti-
nal blood flow in response to change in the partial
pressure of blood gases indicates control of vessel cali-
ber.24 In most vascular beds such functions are attrib-
uted to precapillary arteriotes,25 but in the retina a site
for regulatory control remains uncertain. Although
precapillary endothelial specializations have been
observed in several species,26'27 there are none in
monkeys or humans, and thus there is no accepted
locus of control for circulation through the retinal
microvascular bed. In this respect, direct innervation
of capillaries by retinal neurons can be proposed as a
candidate mechanism for local circulatory control. In
anatomic support of this hypothesis, we repeatedly
visualized neuropeptide-containing amacrine pro-
cesses immediately adjacent to retinal capillaries in
the inner plexiform layer both in the monkey and rat
retina. Our observations complement the recent find-
ing in the same species of dopamine-containing ama-
crine processes to retinal capillaries.28 In fact, we
Fig. 6. Relation of retinal
blood vessels to peptidergic
nerve fibers in the inner
plexiform layer of the rat
retina. (A) A phase micro-
graph shows a small blood
vessel (arrow) passing
through the inner plexiform
layer (IPL). (B) A fluores-
cence micrograph of the
identical field illustrates va-
soactive intestinal peptide-
like immunoreactive ama-
crine cells (arrowheads) and
fluorescent dendrites in the
IPL. Dashed line indicates
position of the blood vessel
shown in (A). Magnification
bar,
 No. 9 PEPTIDERGIC INNEfWATION / Ye er ol
found dopamine-containing amacrine processes im-
mediately adjacent to capillaries as far sclerad as the
outer plexiform layer in the spider monkey retina
(data not shown). Support for local neural control
also comes by comparison with the brain, where neu-
ronal processes associated with intraparenchymal
blood vessels are suggested to regulate blood flow at
the capillary level.29 Unfortunately, confirmation of a
hypothesis of intrinsic neuronal regulation of retinal
blood flow requires a physiologic understanding of its
microcirculation that at present is lacking. Clearly for
retinal amacrine cell processes to alter retinal blood
flow, retinal capillaries would need to contract, a
function that remains to be established.
Regarding the fine nerve fibers in the lamina cri-
brosa, the coexistence of CGRP and SP immunor-
eactivities leads at once to speculation of a specialized
sensory function. Possibly relevant to intraocular
pressure regulation, this presumption is reinforced by
the lack of visceral motor fibers in the same location.
However, the difficulty of discriminating a free-run-
ning nerve fiber from one serving a small but unseen
blood vessel by light microscopy makes it impossible
to state firmly that these nerves truly serve the lamina
cribrosa and not the local circulation. Yet, the obser-
vation is sufficiently provocative to justify further in-
quiry by methods better suited to define local tissue
relationships, such as electron microscopy.
Key words: central retinal artery, innervation, neuropep-
tides, monkey, rat
Acknowledgment
The authors thank Dr. Patricia A. Grimes and Ms. Alice
McGlinn for valuable advice and assistance.
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