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The parasympathetic pathways to
internal eye muscles
Gerald Westheimer and Sidney M. Blair
The sphincter iridae and ciliary muscles of the alert monkey differ in their frequency response
to intracranial electrical stimulation of the third nerve. Unilateral pupil constriction falls off
when stimulation frequencies exceed 100 Hz., but brisk accommodation responses are obtained
up to at least 1,000 Hz. Electrical stimulation of the short ciliary nerves in the anesthetized
monkey produces good responses in both sphincter iridae and ciliary muscles to frequencies of
at least 1,000 Hz. Local application of nicotine to the ciliary ganglion abolishes pupil constriction, but not accommodation, on electrical stimulation of the third cranial nerve proximal
to the ciliary ganglion. It is concluded that the motor pathway for accommodation does not
have a synapse in the ciliary ganglion while that for pupil constriction does.
I
voluntary function, but sharing with other
parasympathetically controlled motor responses the characteristics of being subserved by a smooth muscle and the usual
preganglionic and postganglionic neurons.
Bernheimer,1 however, stoutly maintained
that exenteration of the eyeball causes
retrograde degeneration in the third nerve
nucleus, a finding which would suggest
that some fibers go directly from midbrain
motor regions into the eyeball without
synapse. Bernheimer's view was opposed
by Marina,^ but even the latter admitted
there were some chromatolytic cells in or
near the third nerve nucleus complex after
exenteration of the eyeball in several
species, including the monkey.
Warwick3 claimed that iridectomy leads
to degeneration of only 3 per cent of the
cells in the ciliary ganglion, while total
exenteration of the bulb produces virtually
total degeneration in the ciliary ganglion.
He found no degeneration in the third
nerve nucleus following either procedure.
In an experimental study in the monkey,
Jampel and Mindel4 determined that stim-
n mammalian neurophysiology, the distinction between the voluntary control of
skeletal muscle and the autonomic (i.e.,
involuntary) function of smooth muscle
is so fundamental that many writers have
remarked on the singularity of ocular accommodation, which is a voluntary function, being subserved by a smooth muscle.
Around the turn of the twentieth century there was heated argument over the
role of the ciliary ganglion, but in the
unanimous view of textbooks this was
settled in favor of a synapse in the ciliary
ganglion for both accommodation and pupil
constriction. This seemed to affirm the
anomalous position of accommodation: a
From the Department of Physiology-Anatomy,
University of California, Berkeley, Calif. 94720.
This research was supported in part by Grant
EY-00592 from the National Eye Institute,
United States Public Health Service.
Manuscript submitted for publication Nov. 27,
1972; manuscript accepted for publication Jan.
12, 1973.
193
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Investigative Ophthalmology
March 1973
194 Westheimer and Blair
ulation of various portions of the third
nerve nucleus causes unilateral accommodation or pupil constriction and that the
two functions could be elicited from regions
which partially overlapped.
Against this background we offer the
following experimental findings which
mark an important distinction between the
innervation of the ciliary muscle and that
of the sphincter pupillae.
Method
Experiments of two kinds were conducted on
young adult male monkeys, either Macaca speciosa
or Cercopithecus atheiops.
In the first set of experiments, 0.9 per cent
NaCl-filled micropipettes with an impedance of 1
to 3 M^ were stereotaxically directed through a
trephine hole in the skull to stimulate midbrain
structures. The monkey had an implanted headgear which immobilized his head; otherwise, he
was at liberty to move. In these particular experiments the monkey was unanesthetized and unmedicated. Stimulation was by trains of 0.5 msec,
pulses at controlled frequencies and voltage; the
current never exceeded 150 juamps, was usually
50 /tamps, and occasionally was as low as 10
/"amps. The monkey's accommodative state was
determined by retinoscopy. Using a streak retinoscope it is easy to determine whether accommodation responses are binocular or uniocular. Since a
monkey's interpupillary distance is 25 mm., the
streak may be placed horizontally to cover both
pupils and the reflex may be seen simultaneously
in both eyes; when only one eye accommodates,
a very striking "see-saw" effect is seen. Pupil
constriction was monitored by inspection.
The second set of experiments was performed
on the same monkeys at a later stage in their
laboratory careers. They had experienced various
neurologic interventions in the interim, but none
had any demonstrable defect in the peripheral
pathways to the eye. Under deep nembutal anesthesia the ciliary ganglion was approached via an
extensive frontotemporal opening in the skull,
removal of the frontal lobe, and excision of the
roof and lateral wall of the orbit. The levator
palpebrae. the superior and lateral recti, and a
slip of the retractor bulbi were detached from
the globe and retracted. Sufficient orbital fat was
removed to expose the ciliary ganglion with its
various roots. (In the monkey, the ciliary ganglion
is intimately connected to the third nerve branch
from the inferior oblique muscle, and does not
exhibit a distinct motor root.) Bipolar electrodes
were used to stimulate either the short ciliary
nerves or the third nerve proximal to its connec-
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tion to the ciliary ganglion. Accommodation was
evaluated by retinoscopy and pupil constriction by
inspection.
After preganglionic and postganglionic pupillary
and accommodation responses to stimulation were
recorded, a few drops of 10 per cent nicotine
sulfate were applied to the ganglion and the responses to preganglionic and postganglionic stimulation again recorded. Now, stimuli were trains
of 0.5 msec, pulses at 3 to 8 volts, at controlled
frequency. The bipolar electrodes had in situ
resistance in the 5 to 10 Kfi range.
On completion of the experimental procedures,
the monkeys were killed by injections of nembutal
and perfused with 10 per cent formalin. The
ciliary ganglia on the side opposite that used for
the experiment were dissected out and stained by
overnight immersion in 2 per cent osmic acid. The
stained ganglia were embedded in paraffin. Serial
sections at 15/u were mounted, cleared, and covered, then examined for fibers passing through
the ganglion without synapse.
Results
Stimulation of the mesencephalon in the
alert monkey. It is possible, consistently, to
induce binocular accommodation by trains
of stimuli delivered to a midline region
just dorsal and rostral to the third nerve
nucleus, but this is by no means the only
site yielding accommodation responses.
Frequencies of 400 to 500 Hz. are most
effective and frequencies below 200 Hz.
progressively less so. In the site mentioned,
stimulation results in the full near triad,
with symmetrical convergence and pupil
constriction accompanying accommodation.
Depending on exact electrode placement,
there may also be a concomitant infraversion or, rarely, supraversion with lid
retraction. This full near triad response
should be contrasted with the response
seen when one stimulates among the third
nerve roots after they have left the third
nerve nucleus. Here stimulation causes unilateral accommodation when a frequency
of 400 to 500 Hz. is used; oculomotor responses are seen but there is little accompanying pupil constriction. If the frequency
of the stimulus train is lowered, the picture changes radically. Brisk pupil constriction confined to the ipsilateral eye occurs in a frequency range of 60 to 150 Hz.;
Parasympathetic pathways 195
Volume 12
Number 3
MIOSIS
TRIAD
QCCOMMOOQTION
I
ig
too
»oo
I
10
100
1000
Fig. 1. Range of effective stimulation frequencies at various sites involved in accommodation
and pupil constriction, a. Dorso-rostral to the III nerve nucleus, b. Ill Nerve trunk central to
ciliary ganglion, c. Short ciliary nerves.
at frequencies above 250 Hz. only a transient flick of pupil constriction is seen, usually followed by slight pupil dilatation. At
the frequencies where the pupil responds
best to stimulation in the third nerve
roots, accommodation response is sluggish.
As stimulating frequency increases, accommodation responds more briskly and
continues to do so up to 1,000 Hz. The differing frequency optima for accommodation
and pupil constriction are shown in Fig. 1.
Does the large difference between the
frequency optima for stimulating accommodation and pupil constriction imply a
difference in physiology of the ciliary and
sphincter iridae muscles, or is it rather
a result of different neural pathways to
the eye? To decide this, the ciliary ganglion and its roots were stimulated directly
in anesthetized monkeys.
Intraorbital stimulation. Stimulation of
the short posterior ciliary nerves causes
both pupil constriction and accommodation. In contrast to the finding when stimulating the third nerve roots intracranially,
both the sphincter and the ciliary muscle
show good contractions throughout the
frequency range up to 1,000 Hz. Thus, the
poor response of the sphincter muscle seen
when the third nerve roots are stimulated
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at frequencies above 150 Hz. is not a consequence of the inability of the sphincter
muscle to follow high frequency stimuli
and may be the result of synapse in the
ciliary ganglion. Previous work on cervical
sympathetic ganglia in the rabbit5- ° has
shown that autonomic ganglia begin to
fail in the transmission of stimuli when
rates of 100 Hz. are approached. To prove
that it is indeed the synapse in the ciliary
ganglion that limits the frequency response
of pupil constriction, the ciliary ganglion
was painted with nicotine as described by
Langley and Anderson.7 We find that stimulation of preganglionic fibers to the ciliary
ganglion causes pupil constriction up to a
frequency of 150 Hz. before the application of nicotine, but stimulation is ineffective at any frequency after application of
nicotine.
Accommodation responses to intraorbital
stimulation of the third nerve, although
perceptibly diminished, are still clearly
seen after application of nicotine to the
ciliary ganglion.
Thus the pathway for accommodation,
as distinct from that for pupil constriction,
either does not synapse (at least entirely)
in the ciliary ganglion or if it does synapse
entirely, the synaptic transmission is of
196 Westheimer and Blair
Investigative Ophthalmology
March 1973
C6MT6R FOR
OTHGft. INPUTS
PUPIL CONSTRICTION
1/
OTHCR. INPUTS POR.
ACCOM HOD*VTIOM
SPHINCT6R.
PUPlLLRe
Fig. 2. Outline of the motor pathways subserving accommodation, pupil constriction, and
convergence.
radically different character than in the
pupil constrictor pathway.
Anatomic study of the ciliary ganglion.
In serial sections of the ciliary ganglion,
large numbers of myelinated fibers are
seen to course together from the third nerve
through the ganglion to the short ciliary
nerves, but the tortuous path of fibers precludes tracing them individually from entry
to exit. In lightly stained specimens the
bundle is sufficiently prominent to be seen
running across the surface of the ganglion.
Discussion
We cannot as yet determine with definitive precision what central structures we
are stimulating to produce accommodation
and pupil effects and thus cannot take a
position concerning the exact localization
of accommodation, pupil, and convergence
functions in the various nuclear groups.
The simultaneous release of the complete
near triad by low threshold (10 /xamps)
electrical stimulation makes it likely that
a center for the near triad exists in the midline near the rostro-dorsal border of the
third nerve nucleus. From it, a presynaptic
input probably goes to different groups of
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cells on each side of the midline, cells
whose axons provide innervation, respectively, to the ipsilateral medial rectus, to
the ciliary muscle, and to the sphincter
pupillae (the last via a synapse in the
ciliary ganglion). The observation that
there is relaxation of the lateral rectus
during convergence8 demands, in addition,
an inhibitory pathway to the lateral recti
(Fig. 2). Whether additional integrative
paths to the eight vertical and oblique
external eye muscles should be added to
the schema is as yet an open matter. We
have found a participation of these muscles
in other purely horizontal conjugate movements9 and it seems likely that convergence
above or below the horizontal plane would
require some involvement of vertically acting muscles.
Although our demonstration of an uninterrupted motoneuron path to the ciliary
muscle comes after acceptance of the opposite view for nearly a century, it requires
surprisingly little reconciliation with conflicting evidence in the literature. Most
studies on the ciliary ganglion have lumped
accommodation and pupil constriction together. Usually only pupil constriction was
Volume 12
Number 3
measured and its pathway contrasted with
sympathetic and sensory pathways. Once
the presence of a synapse in the ciliary
ganglion was established, the clear findings of Bernheimer1 and Marina2 that there
is central neuronal degeneration following
exenteration of the eyeball came into disrepute. Lack of a synapse for the fibers to
the ciliary muscle would at once reconcile
these views: retrograde central degeneration after exenterio bulbi is due to the interruption of the nonsynapsing fibers for
accommodation.
Warwick's3 brief statement that he was
unable to find central degeneration after
exenteration conflicts with findings of several previous workers1-2 who had observed
such degeneration even in the monkey.
Warwick also saw almost complete cell
lysis in the ciliary ganglion after complete
exenteration, while 97 per cent of the cells
in the ciliary ganglion were spared after
iridectomy. He interpreted this as meaning
that 97 per cent of the ciliary ganglion
cells relate to the ciliary muscle and 3
per cent to the sphincter iridae. But it
may also mean simply that iridectomy as
carried out in his laboratory does not produce retrograde degeneration. Because the
extent of chromatolysis is proportional to
the amount of axon lost to the cell,10 it
may be that an iridectomy that disturbed
only the terminal ramifications of nerve
fibers to the iris would result in little or
no retrograde changes.
On the other hand, our results do not
exclude the possibility that some nerve
fibers reach the ciliary muscle after synapse in the ciliary ganglion. Yet the fibers
that do not synapse can produce maximum
accommodation by themselves; 440 Hz.
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Parasympathetic pathways 197
stimulation in the central end of the third
nerve, a stimulus that is not transmitted
by the ciliary ganglion, causes full accommodation responses.
Fig. 2 incorporates the best current outline of the motor pathways to the internal
eye muscles. The major difference in the
efferent pathway for accommodation and
pupil provides a welcome substrate for the
fact that the former is prominently a voluntary function while the latter is not.
REFERENCES
1. Bernheimer, S.: Die Wurzelgebiete der Augennerven, ihre Verbindungen und ihr Anschluss
an die Gehirnrinde, Graefe-Saemisch Handbuch der Gesamten Augenheilkunde Pt. 1,
Vol. 1, Ch. 6, p. 58, 1900.
2. Marina, A.: Das Neuron des Ganglion ciliare
und die Centra der Pupillenbewegungen,
Deutsche Zschr. Nervenh. 14: 356, 1899.
3. Warwick, R.: The ocular parasympathetic
nerve supply and its mesencephalic sources,
J. Anat. 88: 71, 1954.
4. Jampel, R. S., and Mindel, j . : The nucleus
for accommodation in the midbrain of the
macaque, INVEST. OPHTHALMOL. 6: 40, 1967.
5. Eccles, J. C : The nature of synaptic transmission in a sympathetic ganglion, J. Physiol.
103: 27, 1944.
6. Eccles, R. M.: Intracellular potentials recorded from a mammalian sympathetic ganglion, J. Physiol. 130: 572, 1955.
7. Langley, J. N., and Anderson, H. K.: The
action of nicotine on the ciliary ganglion and
on the endings of the third cranial nerves,
J. Physiol. 13: 460, 1892.
8. Breinin, G. M.: The Electrophysiology of
Extra-ocular Muscle. Toronto, 1962, University of Toronto Press, p. 54.
9. Westheimer, G., and Blair, S. M.: Concerning the supranuclear organization of eye
movements. Bibl. Ophthalmol. 82: 28, 1972.
10. Geist, F. D.: Chromatolysis of efferent neurons, Arch. Neurol. Psych. 29: 88, 1933.