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Show STATE OF THE ART The Near Response: The Contributions of Kenji Ohtsuka, MD Yasuo Suzuki, MD Abstract: Kenji Ohtsuka, MD and his colleagues at the Sapporo Medical University have investigated the central organization of the near response with anatomical and neurophysiologic studies in cats. Based on their data and clinical observations, they proposed that the rostral pole of the superior colliculus has a critical role in the control of accommodation, vergence, and fixation. Although the central pathways have yet to be fully worked out, the contributions of Dr. Ohtsuka, who died in 2005, have laid an important foundation in the understanding of these functions. (/ Neuro- Ophthalmol 2007; 27: 138- 142) The near response is a reflexive reaction of the visual system during a gaze shift in the near- far plane that occurs in frontal- eyed animals such as humans, monkeys, and cats. The combination of convergence, accommodation, and pupil constriction, called " the near triad" or " the near response," is controlled, synchronized, and associated by supranuclear connections. Although the central neural organization of this response has been not yet been well worked out, major contributions have come from the laboratory of Kenji Ohtsuka, MD in the ophthalmology department of Sapporo Medical University, Sapporo, Japan. Professor Ohtsuka died at the age of 51 in 2005. He and his colleagues have proposed that the rostral pole of the superior colliculus ( rSC) in cats is critical in the control of accommodation, vergence, and fixation. I will review their work. DISCOVERIES The Near Response is Evoked by Electrical Stimulation of the Lateral Suprasylvian Area The lateral suprasylvian ( LS) area is a visual cortical area located in the posterolateral cerebral cortex in cats Orbital Disease and Neuro- Ophthalmology Center, Teine Keijinkai Hospital, Teine- ku, Sapporo, Japan; E- mail: yasuzuki. tdr@ keijinkai. or. jp ( Fig. 1). Area 7a of the posterior parietal cortex of monkeys is thought to be analogous to the LS area of cats ( 1). The LS area receives visual inputs from visual cortex ( areas 17, 18, and 19), the lateral geniculate body ( LGB), and the lateral posterior nucleus of the thalamus ( LP). Some neurons in the LS area were selectively responsive to motion disparity ( 2). In 1981, lens accommodation- related neurons were found in the area surrounding the middle suprasylvian sulcus in cats by Bando et al ( 3). They reported that 67% of lens accommodation- related neurons were antidromically activated from the SC) and/ or pretectal ( 4). They also induced lens accommodation ( 4), pupillary constriction ( 5), and convergence ( 6) by electrical micro stimulation ( EMS) of the LS area in cats. Ohtsuka et al ( 7) reported a single case of accommodation and convergence insufficiency with left middle cerebral artery occlusion in 1988. Shortly after this report, they started investigation of the near response. The Center of the Near Response in Cats In 1992, Ohtsuka and colleagues ( 8) evoked lens accommodation by EMS of the LS area in anesthetized cats ( Figs. 1 and 2). Afferent and efferent connections of the lens accommodation- related LS area were investigated anatomically with microinjections of wheat germ aggluti-nin- horseradish peroxidase ( WGA- HRP) ( 9). Retrogradely labeled cells were found mainly in the ipsilateral visual cortex ( areas 17, 18, and 19), the pulvinar, the LP, and the contralateral LS area. Anterogradely labeled terminals were located mainly in the ipsilateral LP, the rostral portion of the pontine nucleus, and the superficial layer of the ipsilateral rSC corresponding to the representation of the central visual field. Later, they confirmed ascending projection from -/- cells in the area centralis of the retina to the accommodation- related area in the rSC with WGA- HRP ( 10). Based on their findings and the reports from Bando's laboratory, Ohtsuka speculated that the rSC and the pretecrum had an important role in the near response. In 1994, Sawa and Ohtsuka ( 11) evoked lens accommodation by EMS of the rSC in anesthetized cats. They also evoked lens accommodation by EMS of the posterolateral part of the pretecrum corresponding to the nucleus of the optic tract ( NOT), the posterior pretectal 138 J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 The Near Response J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 CG EW 1 ^ ij III O/ i Vergenoe signal Accommodation signal Pupil constriction signal FIG. 1. Electrical microstimulation of the lateral suprasylvian ( LS) area in the cat. It induces the near triad via the Edinger- Westphal nucleus ( EW), cranial nerve III ( III), and the ciliary ganglion ( CG). The effectors are the medial rectus, ciliary, and iris sphincter muscles. DTN, dorsal terminal nucleus; FEF, frontal eye field; LGB, lateral geniculate body; LP, lateral posterior nucleus of the thalamus; MRF, mesencephalic reticular formation, NOT, nucleus of the optic tract, NPC, nucleus of the posterior commissure, NRTP, nucleus reticularis tegmenti pontis; OPN, olivary pretectal nucleus; PPN, posterior pretectal nucleus; PPRF, paramedian pontine reticular formation; PT, pretectum; RIP, nucleus raphe interpositus; rSC, rostral pole of the superior colliculus; SC, superior colliculus; SEF, supplementary eye field; WGA- HRP, wheat germ agglutinin- horseradish peroxidase. nucleus ( PPN), and the nucleus of the posterior commissure ( NPC) ( 12). Parallel descending projections from the LS area were shown anatomically with WGA- HRP. They found that neurons in the lens accommodation-related area of the LS area ( lower part of the medial bank of the middle suprasylvian sulcus) projected to the rSC but those in the upper part of the medial bank of the middle suprasylvian sulcus ( an accommodation- unrelated but pupillary constriction- related area of LS) projected to the lens accommodation- related area in the pretectum ( 13). Because lens accommodation evoked by EMS of the LS area could be abolished by the chemical inactivation of the rostral SC with muscimol ( 13), they speculated that accommodation- related signals in the LS area project mainly to the rSC. Thereafter, they re- investigated descending and ascending projections from the accommodation- related area in the rSC with biocytin. They showed ascending projections to the 1) pretectum [ caudal portion of the NOT, NPC, PPN, and olivary pretectal nucleus ( OPN)] and 2) mesencephalic reticular formation ( MRF) at the level of the oculomotor nucleus and 3) ipsilateral LP. They showed descending projections to the 1) paramedian pontine reticular formation ( PPRF), 2) nucleus raphe interpositus ( RIP), and 3) contralateral dorsomedial portion of the nucleus reticularis tegmenti pontis ( NRTP) ( 14). The finding of these projections suggested an accommodation area in the rSC- innervated, vergence-related MRF ( 15,16) and a fixation- related area with omni- pause neurons, the RIP ( 17- 21). Additionally, they speculated that the accommodation area in the rSC projected to the oculomotor nucleus through the ipsilateral pretectum area, including the pupil constriction area ( OPN and PPN) ( 22) because muscimol inactivation of the pretectum reduced ( by up to 33%) lens accommodation evoked by EMS of the rostral SC but did not abolish it ( 14). They also found accommodation- related neurons in the rSC that projected to the accommodation- related area in 139 J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 Suzuki LS( superficial part) •' illlljj'" Double projection signals ^ ^ = Fixation signal ^ ^ ™ Vergence signal Accommodation signal ^ ^- Pupil constriction signal FIG. 2. Hypothetical pathway for the supranuclear control of the near response and fixation in cats, as proposed by Ohtsuka. Double projection signals are shown by striped arrows. A broken line indicates a speculative projection. the pretectum and the omni- pause neuron area in the RIP ( 23). They speculated that these neurons have an important role in the interaction between accommodation and active fixation. Finally, they evoked small convergence by EMS of the rSC in alert cats. EMS of the same site interrupted spontaneous saccades. Chemical inactivation of the same site with muscimol reversibly abolished trained visually guided convergence ( 24). These observations suggested that the vergence area overlaps the fixation zone in the rSC. They speculated that the rSC is involved in the functional linkage between accommodation, convergence, and visual fixation. UNRESOLVED ISSUES Species Differences Between the Cat and the Monkey The role of rSC in the near response in cats seems discrepant with that in monkeys. EMS of the rostral SC evoked accommodation and convergence in cats ( 11,24,25) but not in alert monkeys ( 26). Furthermore, accommodation and convergence were relaxed by rSC stimulation when monkeys viewed a near target ( 26). Species differences were proposed as one explanation for the discrepancies. There are differences in the anatomical structure of the vergence- related area of the rSC in cats and monkeys ( 27). Guitton ( 27) speculated that EMS of the rSC in monkeys might activate convergence and divergence cells simultaneously. The net effect of the stimulation then became almost zero vergence. The role of the frontal eye field ( FEF) in the near response has been postulated in monkeys. Vergence and retinal disparity- related neurons have been found in the FEF ( 28- 30) and in the supplementary eye field ( SEF) ( 31) in monkeys. Development of the frontal cortex in primates may account for the discrepancies between cats and monkeys. However, the role of the rSC in the near response is important even in humans. Ohtsuka et al ( 32) reported a Japanese patient who showed paralysis of vergence and accommodation caused by demyelinating lesions affecting the bilateral rSC ( 32). A hypothetical pathway for the supranuclear control of the near response and fixation that incorporates Ohtsuka's contributions is shown in Figure 3. Fast ( Saccadic) Vergence and Slow ( Pursuit) Vergence Under natural conditions, gaze is shifted between targets at different distances and directions with saccades 140 © 2007 Lippincott Williams & Wilkins The Near Response J Neuro- Ophthalmol, Vol. 27, No. 2, 2007 FEF MT, MST CG ^ ^ = Fixation signal ^ ^ ™ Vergence signal Accommodation signal ^ ^ - Pupil constriction signal FIG. 3. Hypothetical pathway for the supranuclear control of the near response and fixation in primates incorporating the hypotheses of Ohtsuka. The pretectum ( PT) includes the olivary pretectal nucleus ( OPN), nucleus of the optic tract ( NOT), posterior pretectal nucleus ( PPN), and nucleus of the posterior commissure ( NPC). and vergence and is also moved slowly to follow a target moving between different distances and directions with pursuit and vergence. This means that there are two types of vergence: fast ( saccadic) and slow ( pursuit). Conceptual models of supranuclear control of vergence analogous to current models for the saccadic and pursuit systems have been proposed ( 33). The role of the neurons in the rSC may be different in these two control systems for vergence. Ohtsuka and colleagues ( 24) have speculated that the accommodation- related neurons in the rSC become inactive to allow release of saccadic and vergence burst generators during gaze shifts between targets at different distances and directions. However, the accommodation- related neurons in the rostral SC maintain activity to suppress saccades during slow ( ramp) vergence. The vergence evoked by EMS in cats has been classified as slow vergence because it is very small and slow ( less than 4° for a stimulation duration of 500 ms). 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