SPECIAL ARTICLE The Accessory Optic System The Fugitive Visual Control System in Infantile Strabismus

Michael C. Brodsky, MD

nfantile strabismus inaugurates a constellation of dissociated eye movements that corre- spond to visuovestibular reflexes in lateral-eyed animals. These visual reflexes are gener- ated by subcortical visual pathways that use binocular visual input to modulate central ves- tibular tone. In this article, I present evidence that the accessory optic system is uniquely Isuited to provide an innervational substrate for visuovestibular eye movements in with infantile strabismus. Arch Ophthalmol. 2012;130(8):1055-1059

Infantile strabismus is characterized by dis- subcortical visual motion detection sys- sociated binocular vision, which is the nor- tem, could generate the dissociated and non- mal condition in lateral-eyed animals.1,2 dissociated torsional eye movements that ac- Early binocular misalignment gives rise to company infantile strabismus. dissociated eye movements (changes in eye position evoked by unequal visual input WHAT IS THE AOS? to the 2 eyes).3 These include latent nys- tagmus, dissociated vertical divergence, The AOS consists of 3 nuclei at the me- and dissociated horizontal deviation,1-3 all sodiencephalic border that receive direct of which have a prominent torsional com- retinal input from the accessory optic tract ponent. Primary oblique muscle overac- (AOT)6-9 (Figure 1). The AOT com- tion, which accompanies infantile strabis- prises an inferior and a superior fascicu- mus but is not dissociated in nature, is also lus, with its superior fasciculus divided characterized by a torsional misalign- into a posterior branch, a middle branch, ment of the eyes.4 and an anterior branch that is identical to the original transpeduncular tract (trac- tus peduncularis transversus) discovered For editorial comment in 1870 by Gudden.10,11 The number of see page 1060 accessory optic fibers is small.7 In almost all mammalian species, most optic fibers reach the accessory optic nuclei via the These binocular deviations all corre- transpeduncular tract, which is visible as spond to normal visuovestibular reflexes it courses over the brachium of the supe- that are operative in lateral-eyed ani- rior colliculus.12 1-4 mals. Evolutionarily, these visual re- In most mammalian species, the AOS flexes antedate development of the visual is composed of 3 paired terminal nuclei, cortex, which does not generate torsional namely, the dorsoterminal nucleus (DTN), 5 eye movements in humans. Therefore, any the lateroterminal nucleus (LTN), and the attempt to anatomize infantile strabismus medioterminal nucleus (MTN), which re- must explain the reemergence of these ata- ceive innervation from primary optic fi- vistic reflexes, as well as their prominent tor- bers.7-9 Input to these 3 accessory optic ter- sional components. I propose that the ac- minal nuclei is predominantly from the cessory optic system (AOS), an atavistic contralateral eye.7-9,11,12 Along with the nucleus of the optic tract (NOT), these 3 Author Affiliation: Departments of Ophthalmology and Neurology, Mayo Clinic terminal nuclei project differentially to the and Mayo Foundation, Rochester, Minnesota. dorsal cap of the inferior olive,13-16 which

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Corrected on August 21, 2012 rective eye movements to stabilize 7-9 Rostral the retinal image. As an analyzer NOT of self-motion, the AOS subserves vi- sual in the afoveate CP animal.7-9 DTN The AOS is a that

ML RN is organized in vestibular coordi- D EW 7-9 VTRZ LTN nates. According to results of ex- INC MTN 3n MTN perimental studies by Simpson and PAGm 4n colleagues, visual and vestibular sig- inSFp nals that produce compensatory eye movements are organized about a DMNm common set of axes derived from the orientation of the semicircular ca- MLF nals (Figure 2).7,9,12,16,17 Because the rpo AOS is directionally sensitive to low- velocity movements while the ves- PVG rpc tibular system typically responds to

pdl pm movements of higher velocity, the pv AOS and vestibular labyrinths form vs 2 complementary systems to detect 6n vl self-motion and promote image sta- vm bilization so that objects in the vi- vsp sual world can be quickly and ac- curately analyzed.7,8,12,13 The AOS exists in all vertebrate DC,VLO classes,6,7,18,19 including humans,20 β but it has been studied most exten- Contralateral Ipsilateral sively in the rabbit. The 3 preferred IOp MAO directions for cells in the accessory optic terminal nuclei define 3 direc- Caudal tions in visual space, namely, hori- zontally from posterior to anterior Figure 1. Neuroanatomical connections of the accessory optic system. The brainstem is depicted from for the DTN, vertically up and down the front (with the left-hand side of the animal on the right-hand side of the drawing). Accessory terminal for the MTN, and vertically down for nuclei include the dorsoterminal nucleus (DTN), which lies adjacent to the nucleus of the optic tract the LTN.7-9,11-14,21 Its 3 pretectal ac- (NOT); medial terminal nucleus (MTN); lateral terminal nucleus (LTN); and principal part of the inferior olive (IOp). Optokinetic input from the right crosses to the left accessory optic nuclei (depicted), cessory optic nuclei are closely re- which send ipsilateral projections to the left dorsal cap (DC) of the inferior olive and then back to the right lated to the NOT and receive input flocculus (not shown), resulting in a double decussation of motion pathways from each eye. Adapted with predominantly from the contralat- 12 permission from Simpson et al. CP indicates posterior commissure; D, nucleus of Darkschewitsch; 7-9,12,13 DMNm, deep mesencephalic nucleus, pars medialis; EW, nucleus of Edinger-Westphal; INC, interstitial eral eye. Direction-sensitive nucleus of Cajal; inSFp, intersitial nucleus of the superior fasciculus, posterior fibers; MAO, medial ON–type retinal ganglion cells en- accessory nucleus, inferior olivary complex; ML, medial lemniscus; MLF, medial longitudinal fasciculus; code retinal image slip22,23 and trans- PAGm, periaqueductal gray, medial part; pdl, dorsolateral division, basal pontine complex; pm, medial mit this information to the AOS, in- division, basal pontine complex; pv, ventral division, basal pontine complex; PVG, periventricular gray; 24 RN, red nucleus; rpc, pontine reticular nucleus, pars caudalis; rpo, pontine reticular nucleus, pars oralis; ferior olive floccular climbing vl, lateral vestibular nucleus; VLO, ventrolateral outgrowth, inferior olivary complex; vm, medial vestibular fibers,25 and floccular Purkinje nucleus; vs, superior vestibular nucleus; vsp, spinal vestibular nucleus; VTRZ, visual tegmental relay cells.26 These 3 pairs of channels re- zone; ␤, nucleus ␤ of the inferior olive; 3n, oculomotor ; 4n, ; and 6n, . main anatomically distinguishable within the AOS, inferior olive, and floccular zones, which (when stimu- provides the only source of climb- type direction-sensitive ganglion lated) elicit eye movements orga- ing fibers to the flocculonodular lobe cells. The AOS neurons have large nized in a canal-like coordinate sys- of the cerebellum.7-9,13-17 In this way, receptive fields (averaging about tem.18,27-29 Each pair conveys signals cells of the AOS converge with those 40° vertically and 60° horizon- about flow of the visual surround of the in the ves- tally), are direction selective, and about 1 of 3 rotation axes, which are tibulocerebellum.7-9 have a preference for slow-moving approximately collinear with the Despite its name, the AOS is a pri- stimuli.7-9,12,13 The AOS processes in- best-response axes of the semicir- mary visual system receiving direct formation about the speed and di- cular canals and the rotation axes of visual information from the retina rection of movement of large tex- the extraocular muscles.28 via 1 or more AOTs13 that are re- tured parts of the visual world.7-9 The The rabbit flocculus ipsilateral to sponsible for visuovestibular inter- AOS signals self-motion as a func- the seeing eye is optimally sensi- action in afoveate animals.7,16,17 Its tion of slip of the visual world over tive to optokinetic stimulation about retinal input is derived from ON– the retinal surface and generates cor- a 135° axis, while the flocculus con-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Corrected on August 21, 2012 tralateral to the seeing eye is opti- mally sensitive to optokinetic stimu- Rotation Axes Visual Climbing Fibers lation around a horizontal 45° axis (Left Flocculus of Dominant Eye) (Figure 3).26-29 For horizontal VA stimulation, the DTN and its adja- cent NOT are selectively sensitive to Paired vertical recti nasally directed optokinetic stimu- 148° lation presented to the contralat- 7,8,12,13 Paired eral eye. Conversely, electri- obliques cal microstimulation in the alert 43° ∗ ∗ rabbit’s flocculus produces abduc- ∗ 143° tion of the ipsilateral eye27,29,30 or dis-

sociated torsional and vertical rota- 47° 90° tions of the 2 eyes, corresponding to 0° Paired 45° Paired the plane of 1 semicircular ca- vertical canals vertical canals nal.26-30 Because floccular motion de- 41° 139° tection for each eye is not fully rep- resented on its own side of the body, monocular optokinetic responses must be derived from the synthesis of bilateral floccular representa- 28 tions. Therefore, the flocculus pro- Figure 2. Spatial orientation of preferred axes of 3-dimensional rotation for dorsal cap neurons in the vides a subcortical binocular visual right inferior olive recorded during optokinetic stimulation in a spherical enclosure. Adapted with system that generates asymmetri- permission from Van der Steen et al.27 VA indicates vertical axis. cal torsional eye movements under dissociated conditions of optoki- netic stimulation.28 strate whereby vertical monocular put that modulates the dorsal light Studies using decortication have subcortical motion biases could reflex in fish (which corresponds revealed contributions from the vi- generate the canal-based torsional to dissociated vertical divergence sual cortex to the AOS. Disruption eye movements that characterize and primary oblique muscle over- of contributions from the visual cor- primary oblique muscle overaction action in humans with infantile tex to the AOS by strabismus may and dissociated vertical diver- strabismus)1,2 is transmitted to the alter the inherent biases of the ac- gence.2,4 Although we observe and central pretectal nucleus in the con- cessory optic nuclei.31-33 The ipsilat- analyze these eye movements in tralateral midbrain and then down eral is necessary for yaw, pitch, and roll,2 they are en- to the vestibulocerebellum, which several response properties that dis- coded in a canal-oriented push- integrates visual and vestibular in- tinguish DTN and LTN neurons in pull bilateral coordinate system put.39 These luminance and mo- the cat from those in the rabbit. Fol- that detects optokinetic flow in ev- tion pathways may constitute the lowing decortication, cat DTN and ery direction.36 subcortical equivalents of the “what” LTN neurons lose their binocular- Photic stimulation can activate and “where” visual streams within ity and become almost totally domi- the AOT in the rabbit.4,37 The AOS the association visual cortex. How nated by the contralateral eye.33 For neurons show the same responses to these subcortical visual streams in- example, LTN neurons excited by retinal illumination as ON–type di- tercommunicate to consolidate spa- upward movement, which in the cat rection-sensitive retinal ganglion tial and temporal summation of vi- are equal in number to those ex- cells, being excited only at the on- sual information at the subcortical cited by downward movement, be- set of retinal stimulation,23 and gen- levels remains a mystery. But the come less numerous so that the cat erate a firing response that is re- likelihood that they provide the in- LTN becomes like that of the rab- lated to light intensity.32 In this way, nervational substrate for the atavis- bit, consisting of neurons excited by the AOS may implement the vi- tic eye movements that character- slow downward movements to the suovestibular reflexes that charac- ize infantile strabismus should not contralateral eye.33 Unlike the LTN terize infantile strabismus.1,2 How- be ignored. and DTN, neurons in the cat MTN ever, because the AOS is primarily are largely monocular and similar to a motion detector, central modula- CONCLUSIONS those in the rabbit.12 The monocu- tion of the primitive luminance re- lar nasotemporal optokinetic asym- flexes that characterize infantile stra- The AOS provides a critical piece of metry that characterizes infantile bismus may require input from the puzzle for infantile strabismus by strabismus is known to result from additional subcortical visual path- serving as a neuroanatomic sub- monocular cortical input to the NOT ways. It is possible that other primi- strate for visuovestibular eye move- and DTN,34 unmasking a subcorti- tive luminance pathways may pro- ments. The AOS is atavistic, present cal visuovestibular bias that gener- vide parallel subcortical luminance in humans, subcortical, crossed, and ates latent nystagmus.35 The AOS input to the visuovestibular sys- sensitive to optokinetic motion. It op- provides a neuroanatomical sub- tem.38 Like the AOS, luminance in- erates in a canal-based coordinate sys-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Corrected on August 21, 2012 Correspondence: Michael C. Brod- sky, MD, Department of Ophthal- A Monocular viewing Posterior (135°) Axis Type CCW Ipsilateral Spontaneous activity mology, Mayo Clinic and Mayo CW 2.5 Foundation, 200 First St SW, Roch- ester, MN 55905 (Brodsky.michael 0° @mayo.edu). 2.0 Financial Disclosure: None re-

45° ported. 1.5 Funding/Support: This study was supported in part by an unre-

90° stricted grant from Research to Pre- 1.0 vent Blindness to the Department of Ophthalmology, Mayo Clinic.

135° Spikes/s Mean Firing Frequency, 0.5 Additional Contributions: John Top view Simpson, PhD, and Alfredo Sadun, MD, PhD, provided invaluable ad- 0.0 vice and guidance in developing the 0.6°/s 0 45 90 135 180 5.3 Planetarium Axis Angle, ° translational proposal of a role for 2.6 CW CCW 15 Repetitions Spikes/s Spontaneous 5 s 100 ms Bin width the accessory optic system in infan- activity tile strabismus.

B Monocular viewing Anterior (45°) Axis Type Contralateral REFERENCES

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Corrected on August 21, 2012 In: Baker R, Berthoz A, eds. Control of Gaze by Brain rons of the dorsal cap of Kooy. J Neurophysiol. 32. Grasse KL, Cynader MS. The accessory optic sys- Stem Neurons: Developments in Neuroscience. Am- 1988;60(6):2073-2090. tem of the monocularly deprived cat. Brain Res. sterdam, the Netherlands: Elsevier/North-Holland 25. Simpson JI,Graf W, Leonard CS. Three-dimensional 1987;428(2):229-241. Biomed; 1977:187-195. representation of retinal image movement by climb- 33. Grasse KL, Cynader MS, Douglas RM. Altera- 16. Maekawa K, Simpson JI. Climbing fiber activa- ing fiber activity. In: Strata P, ed. The Olivocerebel- tions in response properties in the lateral and dor- tion of Purkinje cells in the flocculus by impulses larSysteminMotorControl.Berlin,Germany:Springer sal terminal nuclei of the cat accessory optic sys- transferred through the visual pathway. Brain Res. Verlag; 1989:323-337. Experimental Brain Research tem following visual cortex lesions. Exp Brain Res. 1972;39(1):245-251. Series 17. 1984;55(1):69-80. 17. Maekawa K, Simpson JI. Climbing fiber re- 26. Graf W, Simpson JI, Leonard CS. Spatial organi- 34. Hoffmann KP. Cortical vs subcortical contribu- sponses evoked in vestibulocerebellum of rabbit zation of visual messages of the rabbit’s cerebel- tions to the optokinetic reflex in the cat. In: Lenne- from visual system. J Neurophysiol. 1973;36 lar flocculus. II. Complex and simple spike re- rstrand G, Zee DS, Keller EL, eds. Functional Ba- (4):649-666. sponses of Purkinje cells. J Neurophysiol. 1988; sis of Ocular Motility Disorders. Oxford, England: 18. Ebbesson SO. On the organization of central vi- 60(6):2091-2121. Pergamon; 1982:303-310. sual pathways in vertebrates. Brain Behav Evol. 27. Van der Steen J, Simpson JI, Tan J. Representa- 35. Brodsky MC, Tusa RJ. Latent nystagmus: ves- 1970;3(1):178-194. tion of three-dimensional eye movements in the tibular nystagmus with a twist. Arch Ophthalmol. 19. Cooper HM, Magnin M. A common mammalian plan cerebellar flocculus of the rabbit. In: Schmid R, 2004;122(2):202-209. of accessory optic system organization revealed in Zambarbieri D, eds. Oculomotor Control and Cog- 36. Simpson JI, Graf W. The selection of reference all primates. Nature. 1986;324(6096):457-459. nitive Processes. Amsterdam, the Netherlands: El- frames by nature and its investigators. Rev Ocu- 20. Fredericks CA, Giolli RA, Blanks RH, Sadun AA. sevier; 1991:63-77. lomot Res. 1985;1:3-16. The human accessory optic system. Brain Res. 28. Tan HS, van der Steen J, Simpson JI, Collewijn H. 1988;454(1-2):116-122. Three-dimensional organization of optokinetic re- 37. Hamasaki D, Marg E. Microelectrode study of ac- 21. Simpson JI, Leonard CS, Soodak RE. The acces- sponses in the rabbit. J Neurophysiol. 1993;69 cessory optic tract in the rabbit. Am J Physiol. sory optic system of rabbit. II. Spatial organiza- (2):303-317. 1962;202:480-486. tion of direction selectivity. J Neurophysiol. 1988; 29. Simpson JI, Van der Steen J, Tan J, Graf W, Leon- 38. Schiller PH. Parallel information processing chan- 60(6):2055-2072. ard CS. Representations of ocular rotations in the nels created in the retina. Proc Natl Acad Sci U S A. 22. Oyster CW. The analysis of image motion by cerebellar flocculus of the rabbit. Prog Brain Res. 2010;107(40):17087-17094. the rabbit retina. J Physiol. 1968;199(3):613- 1989;80:213-223. 39. Yanagihara D, Watanabe S, Takagi S, Mitarai G. 635. 30. Ito M, Nisimaru N, Yamamoto M. Specific patterns Neuroanatomical substrate for the dorsal light re- 23. Soodak RE, Simpson JI. The accessory optic sys- of neuronal connexions involved in the control of the sponse. II. Effects of kainic acid-induced lesions tem of rabbit. I. Basic visual response properties. rabbit’s vestibulo-ocular reflexes by the cerebellar of the valvula cerebelli on the goldfish dorsal light J Neurophysiol. 1988;60(6):2037-2054. flocculus. J Physiol. 1977;265(3):833-854. response. Neurosci Res. 1993;16(1):33-37. 24. Leonard CS, Simpson JI, Graf W. Spatial organi- 31. GrasseKL,CynaderMS.Responsepropertiesofsingle 40. Chavesse FB, Worth CA, Lyle TK. The Binocular zation of visual messages of the rabbit’s cerebel- unitsintheaccessoryopticsystemofthedark-reared Reflexes and Treatment of Strabismus. Philadel- lar flocculus. I. Typology of inferior olive neu- cat. Brain Res. 1986;392(1-2):199-210. phia, PA: Blakeston; 1950.

Correction

Error in Figure 4F. In the Clinical Sciences article titled “Spectral-Domain Optical Coherence Tomographic As- sessment of Severity of Cystoid Macular Edema in Reti- nopathy of Prematurity,” by Maldonado et al, pub- lished in the May issue of the Archives (2012;130[5]: 569-578), an error occurred in the y-axis of Figure 4F on page 573. The axis range should not be from 0 to 500 µm but from 0.00 to 2.00, as in Figure 4D and E. This article was corrected online.

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