THE VISCERAL NUCLEI OF THEOCULOMOTOR COMPLEX

BY Ronald M. Burde, MD

THE EXISTENCE OF THE VISCERAL NUCLEI OF THE OCULOMOTOR COMPLEX WAS

first reported by Edinger in 1885.1 In 1887 Westphal2 associated thisnucleus, Edinger-Westphal nucleus (EWN), with pupillary function in acase report of a patient who had lost his light reflex but not accommoda-tion. Interestingly, in this patient the EWN was relatively preserved.Westphal cautiously ended the report by stating that the exact localizationof the pupilloconstrictor center remained unknown. Although the pupil-lary (and) accommodative systems have been under investigation in manand animals for more than two centuries,3-7 until recently there has beensubstantial uncertainty with respect to the afferent and efferent pathwayssubserving even the pupillary light reflex.3'8'9 This uncertainty has beencompounded by the contradictory results obtained in studies of bothexperimental and pathologic material. In spite of the paucity of knowl-edge of the underlying neuroanatomical pathways, investigators haveattempted to draw universal "truisms" about pupillary pathways andphysiology as they relate to man based on experimental studies per-formed in other species, eg, the cat, 10-13 further confusing the subject.

Bernheimer'4 has reported retrograde degeneration in the EWN of therabbit after damaging the oculomotor nerve. This work was not substanti-ated by the subsequent studies of van Biervliet"5 or Levinsohn.'6 Remov-al of the ciliary ganglion in the cat has revealed minimal to no changes inthe EWN,'7"18 blut Crouch'7 was able to conclude that fibers from theEWN entered the oculomotor nerve based on data derived from cats withlesions of the third nerve. Conversely, chromolytic changes have beenseen consistently in the dog'" following ciliary ganglionectomy. In 1954 ina classic series of experiments on the primate, Warwick3 performed thefollowing procedures: extirpation of the ciliary ganglion (three animals),division of the nerve to the inferior oblique (two animals), division of theinferior ramus of the oculomotor nerve (one animal), and division of theoculomotor nerve itself (five animals), and he demonstrated that the

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EWN and its rostral extension, the anteromedian nucleus,20 were thecentral substrates subserving the ciliary ganglion.

Although Cajal,2' Hogg,'8 and Pearson,22 using silver stained prepara-tions, failed to demonstrate that axons arising from the EWN enter theoculomotor nerve, Brouwer23 and Lenz24'25 have shown that the EWNwas the source of parasympathetic outflow to the eye in man based ontheir clinicopathologic investigations.

Subsequent experiments utilizing the axonal tracer substance, horse-radish peroxidase (HRP), in a retrograde fashion have revealed that thereare distinct differences in the mesencephalic substrates subserving theparasympathetic outflow in the cat26-28 and the monkey.29-3' In the cat,label has been demonstrated in the EWN, in the periaqueductal gray,and more interestingly in the ventral tegmental area. In the monkey,labeled cells have been found in the anteromedian nucleus (AM),29 thedorsal visceral column (DVC),29'3() and the nucleus of Perlia (NP).29 Nolabeling has been found in the lateral visceral column (LVC).29,3(' Fromthese experiments it was evident that data could not be extrapolatedreadily from nonprimates to man. The similarity between higher primatesand man, on the other hand, has been well accepted.

Pierson and Carpenter8 and Benevento and associates9 have demon-strated that the retinorecipient structures in the pretectum of the primatewere the olivary nucleus (ON),8'9 sublentiform nucleus (SL)8 9 and thenucleus of the optic tract. 8,32 The retinorecipient nuclei have been shownto project in turn to the visceral nuclei of the oculomotor complex.8'9'32'33In addition, it has been demonstrated that the pretectal ON projectsmainly to the contralateral LVC,9 32'33 although in one study projectionsto the AM were reported.32 The SL has been shown to project bilaterallyto the AM and the EWN with fibers decussating above and below theaqueduct using tritiated amino acids.9 These neuronal projections fromthe SL pass through the nucleus of the posterior commissure (NPC).Carpenter and Pierson32 have postulated that there were major projec-tions from the nucleus of the optic tract and the SL to the NPC, and inturn the NPC sent fibers which terminated bilaterally on the medialvisceral volumns (MVC). They believed these fibers partially decussatedbelow the aqueduct as well as in the posterior commissure. Beneventoand associates9 have postulated that these tracts from the SL were de-stroyed in the ablative experiments of Carpenter and Pierson.32 Thus, theprojections Carpenter and Pierson32 believed to arise in the NPC reallyoriginated in the SL.

As mentioned previously, recent studies utilizing the tracer substance,HRP, have established that there were axonal connections between the

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ciliary ganglion and all the subdivisions of the visceral nuclei (AM, DVC,MVC) with the exception of the lateral visceral subdivision.29'30 Theabsence of labeling in the lateral subdivision of the visceral columnsseemed paradoxical as these columns received input from the retinorecip-ient nuclei or their subservient areas.8 9'32'33 A number of investigatorshave demonstrated that the connections of the visceral nuclei in both thecat26 2734'36 and the monkey29 were more complex than originallythought. Retrograde label has been found in neurons of the visceral nucleiusing HRP following injections in the lower brain stem, cervical spinalcord, cerebellum, and in the ciliary ganglion. Burde and Loewy29 haveshown that the LVCs as well as the AM, DVC, MVC, and NP werelabeled by injections of HRP into the cervical spinal cord of monkeys.Pierson and Carpenter8 have produced lesions in the LVC and found nochange in pupillary size or pupillary reactivity to light. In addition, theyhave not found degeneration accompanying these lesions in the oculo-motor fascicles.For the remainder of this work, the visceral nuclei were considered to

consist of the paired anteromedian nuclei,20'29'37 the pairedDVCs3'29'30'37 and their caudal extensions, the MVC and the LVC, andthe central NP. 4,20,29,37 The eponym, EWN, was reserved for the paireddorsal columns and their caudal extensions, the MVC and LVC. In anattempt to determine the role of the LVC, it was decided to reinvestigatethe mesencephalic substrates subserving the ciliary ganglion using thenewer fluorescent retrograde tracers, fast blue (FB) and nuclear yellow(NY), ,-41 a more sensitive method in some systems than HRP tech-niques.42 The definition of the mesencephalic substrates subserving theciliary ganglion would provide the necessary background data for the lateruse of double-labeling techniques38-41 to determine the unity or lack ofunity of the cells of the visceral nuclei projecting to the ciliary ganglionand cervical spinal cord.

MATERIALS AND METHODS

Six cynomolgus monkeys (Macaca fascicularis) were used in this study.All experimental procedures utilized ketamine hydrochloride anesthesiasupplemented with sodium pentobarbital. The ciliary ganglion was isolat-ed either unilaterally (four animals) or bilaterally (two animals) by micro-surgical orbitotomy (Fig 1). The ciliary ganglion was injected with 0.5 to1.0 ,ul of either 3% NY (dissolved in distilled water) or 5% FB (dissolvedin distilled water) through a glass micropipette connected to a 10-pllHamilton syringe (Fig 1B). The injection schedule is outlined in Table.

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Oculomotor Nuclei

FIGURE 1

A: Photomicrograph taken through a Zeiss OPMI I of ciliary ganglion (arrow) exposed bymicrosurgical orbitotomy. B: Photomicrograph of micropipette filled with fast blue (FB)conniected to bore of a Hamilton syringe. C: Photomicrograph of micropipette impaled intothe ciliary ganglion at time of injection of FB. D: Photomicrograph of ciliary ganiglion

following injection of FB. Arrow designates puncture site.

Thirty-six to 48 hours following the ciliary ganglion injections, themonkeys were perfused with 0.1 M phosphate buffer followed by 10%formalin in 0.1 M phosphate buffer plus 7% sucrose. The brain was

removed, blocked and stored in 0.1 M phosphate buffer containing 30%sucrose prior to sectioning. Transverse serial frozen sections (50 urm) weremounted without cover slips as soon as they were cut and then air dried.30

TABLE I: EXPERINIENTAL PROTOCOL

1 Bilateral ciliary ganglion inijectioni NY2 Bilateral ciliarv ganglioni inijection FB3 Unilateral ciliary ganglioni inijectioni NY4 Uniilateral ciliarv ganiglion injectioni NY5 Unilateral ciliarv ganglioni inijectioni FB6 Uniilateral ciliary ganglioni inijectioni FB

FB - Fast blue.NY - Nuclear vellow.

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The 0.1 M phosphate buffer was changed every 25 sections. The sectionswere examined either immediately or were stored in the dark at - 4°Cand then examined utilizing a fluorescence microscope with an excitingwavelength of 360 jm with Zeiss Neofluor objective lenses. Cameralucida drawings were made of every third section. Cell counts wereestimated roughly on every section in three animals. Photomicrographswere taken utilizing either Ektachrome 400 or PAN X 200.The sections were then counterstained with 0.6% thionin and cover-

slipped (three animals). The slides were then studied with conventionallight microscopy in order to clearly identify neuroanatomical landmarks.Low power photomicrographs were taken of every third section utilizingeither color (Polacolor 2, type 58) or black and white (Polaroid, type 55)film.

RESULTS

Neuronal labeling with NY was noted as a golden yellow fluorescence ofthe nucleus (Fig 2). Neuronal labeling with FB was seen as a blue cyto-plasmic fluorescence with a clear void in the region of the nucleus (Fig 2).These experiments clearly demonstrated labeling in the AM, the DVC,

FIGURE 2Labeled nuclei with NY. Note relative intensitv of ntuclear staining versus glial staining fromNY (small arrow). Celluilar cvtoplasmic staininlg with FB. Note unistained nuclear areas (large

arrow) of overlapping cells anid axonial streaminig. Scale = 50 ,.m.

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Oculomotor Nuclei

the MVC, and the LVC as well as identifying an additional subdivision ofthe LVCs caudally (Figs 3 to 6). Thus, caudally the visceral complexdivided into three separate columns on either side of the midline (Fig 6Cand D). There was relatively sparse labeling in the region of Perlia'snucleus compared to the labeling found either in the AM or EWN, butsimilar in extent to that found in the LVC and its subdivision (Fig 6A).The anteromedian nuclei as originally described by Perlia20 and more

recently by Olszewski and Baxter37 lay rostra] and ventral to the oculo-motor complex (Figs 3 and 4). It had a rostral caudal extent of approxi-mately 1000 ,um and consisted of a paired slender sheet of cells. Thenumber of labeled cells on each side in the AM were estimated to begreater than 200. The DVC3'4 (Fig 5A and B) of the EWN blends with theAM rostrally and then extends over the anterior end of the somaticoculomotor complex. Each side was found to contain approximately 100

FIGURE 3A: Photomicrograph of frontal sectioni of pretectnm and mesenicephalon. Section is approxi-mately 400 p.im catndal to rostral tip of the aniteromilediain itclenes (ANI). Nlost rostral faisciclesof developing oculomiiotor nerve (arrowv) are seen ventrallv. Rectanigle delinieates extenit ofANI (x 20). RN. redl niclents. B: FB-labeled cells fromi l)ilateral inijectioins of the ciliarvganiglions deemonstratinig slenider paired sheets of ANI oni eithier side of midlinie. ( x 80).

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Burde

FIGURE 4A: Photomicrograph of frontal sectioni of pretecttiom and( mesencephalon. Section is approxi-mately 150 p.im caudal to Fig 3 and demonistrates dlorsal migration of ANM as it aipproaclhessomatic oculomotor coomplex ( x 20). B: FB-labeled cells from l)ilateral inijectionis of ciliary

ganglionis demono.stratinig slencder paired sheets of ANI oni either side of midllinie ( x 80).

labeled cells. As described by Warwick,3 4 the DVC divided caudally intoa medial and lateral column. Each column contained a lower density ofsmaller cells. The medial and LVC were found to contain approximately40 labeled cells on each side.At the junction of the anterior two-thirds and posterior one-third of the

somatic nucleus (Fig 6C), three visceral columns could be identified oneach side of the midline. The most lateral column was found to containabout 15 labeled cells, the intermediate and medial columns about 40labeled cells on each side of the midline. The caudal extent of the visceralnuclei extended at least to the level of the junction of the anterior one-third of the central caudal nucleus (CCN) (Fig 6D). The visceral nuclei

538

Oculomotor Nuclei 539

; L,7P,>. : ' - '

uie

p:~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..@W';^'., ..,. . ... .-.......^~~~~~~~~~~~~~~~~~T''

...' ...'..'....

FIGURE 5A: Photomicrograph of frontal section of pretectum and mesencephalon. Section is approxi-mately 450 ,m to Fig 4 and 1000 ,u-m from Inost rostral tip of AM. It is at anterior end ofsomatic oculomotor complex (III). At this level only dorsal somatic column (DCC) subservi-ng inferior rectus muscle is present. Rectangle surrounds blending of caudal end of AM androstral end of DVC ofEWN (x 20). INSET: FB-labeled cells demonstrating development ofDVC as sections move caudally ( x 80). B: Photograph of frontal section of pretectum andmesencephalon. Section is at level of somatic complex where DCC and ventral somaticcomplex (VCC) are identifiable (x 20). INSET: FB-labeled cells demonstrating develop-

ment of DVC as sections move caudally (x 80).

were displaced around the CCN. As described by Warwick, 4 the caudalextent of the visceral columns stopped short of the CCN, but this findingwas similar to that described by Olszewski and Baxter.37The central NP as defined by Olszewski and Baxter37 was found to have

about 40 labeled cells unilaterally. All of the visceral nuclei projected onlyto the ipsilateral ciliary ganglion. The pattern of labeling and the numberof cells labeled was independent of whether FB or NY was injected intothe ciliary ganglion or whether the injection was unilateral or bilateral.

DISCUSSION

From these experiments in which the fluorescent tracer substances, FBor NY, are injected into the ciliary ganglion, it is evident that there arethree distinct regions in the mesencephalon in the monkey that project to(or through) the ciliary ganglion: (1) the AM, (2) the NP, and (3) theEWN. It is now clear that the LVC projects to the ciliary ganglion and

Burde

that caudally the LVC subdivides into a major column and an accessorycolumn. The functional significance, if any, of this division remains ob-scure.

At first it appears difficult to explain the differences in the findingsreported here, ie, labeling of the LVC with the distinct lack of labelingreported by others. 29'30) A look at the methodology associated with the useofHRP reveals a continual evolution of the experimental protocol since itsintroduction as a central nervous system tracer by LaVail and LaVail43utilizing diaminobenzidine as the chromogen. Mesulam44 discusses in

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Oculomotor Nuclei

detail the variables involved in the successful application of HRP method-ology and emphasizes the increased sensitivity of using the chromogentetramethylbenzidine rather than diaminobenzidine to produce the reac-tion product. He demonstrates that when optimal histochemical parame-ters are used, neural connections which previously eluded detectionbecame readily visible. In spite of using tetramethylbenzidine and wheatgerm agglutinin (WGA) as the chromogens in a similar experimentalmodel, Akert and associates30 fail to find labeling in the AM as reportedby Burde and Loewy29 and confirmed in the work reported here.

Concomitantly, other investigators45 show that the conjugation of HRPwith WGA-HRP produces a tracer that is 40 times more sensitive thanfree HRP in tracing connections. As mentioned previously, the fluores-cent tracers are also demonstrated to be more sensitive than HRP in somesystems.45 Thus, the demonstrated labeling in the LVC and the furtheranatomical subdivision of the LVC into a major and accessory columnreflect the application of a more sensitive methodology.The anatomical pathways connecting the retinal receptor elements and

the ciliary ganglion (ultimately the pupil3'4) can be delineated (Figs 7 to9). Each retina projects bilaterally and equally to the sublentiform andpretectal ON.9 The SL projects bilaterally to all of the visceral nuclei withthe exception of the NP.9 The fibers decussate both in the posteriorcommissure and ventral to the aqueduct. The pretectal ON projectsmainly to the contralateral-lateral visceral column.8'32 There is some

FIGURE 6A: Photomicrograph of frontal section taken at level of oculomotor complex. Section isapproximately 600 pm caudal to rostral end of somatic complex. Dorsal somatic complex(DCC), intermediate somatic complex (ICC), and ventral somatic complex (VCC) are pres-ent. Dorsal rectangle (top) delineates extent of dorsal visceral column (DVC). Ventralrectangle (bottom) delineates nucleus of Perlia (NP). NP divides rostral two-thirds of somaticcomplex (x 20). TOP INSET: FB labeling of DVC. Bilateral injections demonstrate appar-ent fusion of nuclei as produced by FB-labeled cells. Unilateral injections demonstrate strictipsilateral projections (x 80). BOTTOM INSET: Higher power view of NP demonstratingpaired nature of nucleus with dorsoventral orientation of cells (x 80). B: Photomicrograph offrontal section taken at level ofoculomotor complex. Section is approximately 600 p.m caudalto Fig 6A. Rectangle delineates extent of EWN (x 20). III, somatic oculomotor complex.INSET: At this level DVC has divided into MVC, which appears fused, and LVC (x 80). C:Photomicrograph of frontal section taken at level of oculomotor complex. Section is approx-imately 300 p.m caudal to Fig 6B. Intermediate somatic complex and ventral somaticcomplex of somatic oculomotor complex (III) are present. Rectangle delineates extent of leftEWN (x 20). INSET: FB labeling ofneurons delineates EWN. At this level it is divided intothree columns: (1) MVC, (2) Major LVC, and (3) accessory LVC (x 80). D: Photomicrographof frontal section taken at level of oculomotor complex. Section is at caudal end of somaticcomplex. Rostral end of caudal central nucleus (CCN) is present (rectangle) as well as theICC (x 20). INSET: Left EWN. At this point it is still tripartite in nature, but density of

cells is decreased and displaced around CCN (x 80).

541

Burde

FIGURE 7Schematic drawing of a brain stem section rostral to most compact portion of posteriorcommissure (PC). At this level the pretectal olivary nucleus (ON), sublentiform nucleus(SL), anteromedian nucleus (AM), nuclei of the PC (NPCp, principalis; NPCm; medialis),and fascicles of the oculomotor nierve (IlIn) can be seen. The arrow (A) represents bilateralretinal input from divergent axons in optic tract. Fibers from SL pass through nucleus of thePC. Those destined for contralateral AM decussate both in PC and ventral to aqueduct inthe central gray. Those destined for ipsilateral AM pass through ipsilateral celntral gray.

evidence that the ON projects to the AM as well.32 As mentioned previ-ously, Carpenter and Pierson32 believe that the NPC projects bilaterallyto all of the visceral nuclei; whereas, Benevento and associates9 hold thatthis projection pathway represents an artifact of ablation; ie, the SLprojection passes through the NPC, and when the NPC is destroyed the

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Oculomotor Nuclei

A

ON

MVC ~~~~~0 LVCmvc~~~~~~~~~~lNP (RN

Fl(tTGRE 8Scheliatic drawving of' brain stem at approximately mi(Idle tihird of soma.ltic ocolomilotorcomi)plex (III). Diagrammatic represenitaitionis of rostral pretectal olivary nueleuis (ON) anids1I)blentiforminiucleuis (SL) are appended. Fibers projecting froimCON (hold lblack liles)dectnssate in PC anid ventral to a(lueduct to synapse in contralateral-LVC. There is soimequestion abolIt whetier ON projects to ANI. RN, red iucleuetis; NIVC, fuised me(diail visceral

coltiiminis; NP, nuLicleuis of Perlia.

543

Burde

A

ONSL

mvc ~ a LVCMVC _____

NP RN

FI(;URE 9Schemaiiitic drawinig of l)rain stem at approximately middle third of somatic octilomotorcomnplex (111). l)iagramnmatic represenitationis of rostral pretectal olivary ntucleuis (ON) andsiel)letifornl titicletis (SL) are appended. Fibers I)rojecting from SL (bold black linles)destined for contralateral LVC and MVC, decussate in PC and ventral (not shown) toaqueduct. Fibers projecting from SL to same nuclei ipsilateral pass through NPC and

central gray (bold black lines). RN, red nucleus, NP, nucleus of Perlia.

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Oculomnotor Nuclei

neuronal projections of the SL are destroyed, thus producing parallelresults.The retinal axons decussate in the chiasm, and it appears to be estab-

lished that there is an almost equal ipsilateral and contralateral input tothe pretectal retinorecipient areas (ON and SL),9 in spite of some contro-versy in the past. 32,46-48 The SL sends fibers both ipsilaterally and contra-laterally to the visceral nuclei and the ON to the contralateral LVC. All ofthe visceral nuclei send fibers ipsilaterally to the ciliary ganglion as dem-onstrated in this report as well as others. 3,4,29 Thus, the existence of thesedouble decussating pathways offers a ready explanation of the nearlyequal, direct and consensual light reflexes.The need for further work is evident. Studies using electrical stimula-

tion of the visceral nuclei,495" some with histologic verification' 5 andthose utilizing destructive lesions of the various subdivisions of the vis-ceral nuclei' yield conflicting results in terms of determining the functionof individual subunits. Thus, at this time the exact role individual sub-units of the visceral nuclei play in mediating the pupillary light reflex,accommodation, and miosis to near stimulus remains unknown. In addi-tion, the brain stem connections of the NP and its function also remain tobe elucidated.The findings reported here define the extent of the visceral nuclei

subserving the ciliary ganglion, ie, the AM, EWN including DVC, MVC,LVC and subdivision, as well as the NP. The confirmed37 caudal extent ofthe visceral nuclei and the division of the LVC into a major and accessorybundle provides a clearer picture of the anatomy of the visceral nuclei ofthe oculomotor complex. This latter information provides a basis uponwhich to design future investigations such as whether the same neuronsproject to the ciliary ganglion and the spinal cord; that is, whether thereare divergent axon collaterals. The injection of FB or NY into the cord andthe other tracers into the ciliary ganglion, looking for double labeling,nucleus and cytoplasm, can answer this question.

SUMMARY

A series of experiments in monkeys utilizing the fluorescent tracer sub-stances, FB and NY, injected into the ciliary ganglion have demonstratedlabeling in three distinct regions in the mesencephalon: (1) the AM, (2)the NP, and (3) the EWN. Further, it was shown that the caudal exten-sionls of the EWN reached to the level of the CCN of the somatic complexand that the LVC divided into a major and accessory column at thejunction of the middle and posterior one-third of the somatic complex.

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546 Buirde

The latter finding, ie, projections from the LVC to the ciliary ganglion inconcert with the known connections of the retinorecipient areas in thepretectum with the visceral nuclei, allowed the formation of postulatesabout the reflex pupillarv light pathways.

ACKNOWLEDGMENTS

I would like to acknowledge the technical help of Fred Williams.This work was supported in part by an unrestricted grant from Re-

search to Prevent Blindness, New York, New York, and an unrestrictedgrant froIn Mrs Beatrice Edison.

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