Biomedical subjects
Publications and source records attributed to J A Büttner-Ennever.
This chapter gives an introduction to the oculomotor system, thus providing a framework for the subsequent chapters. This chapter describes the characteristics, and outlines the structures involved, of the five basic types of eye movements, for gaze holding ("neural integrator") and eye movements in three dimensions (Listing's law, pulleys).
The role of sensory receptors in eye muscles is not well understood, but there is physiological and clinical evidence for the presence of proprioceptive signals in many areas of the central nervous system. It is unclear which structures generate these sensory signals, and which central neural pathways are involved. Three different types of receptors are associated with eye muscles: (1) muscle spindles, (2) palisade endings, and (3) Golgi tendon organs, but their occurrence varies wildly between species. A review of their organization shows that each receptor is mainly confined to a morphologically separate layer of the eye muscle. The palisade endings - which are unique to eye muscles, are associated with the global layer; and they have been found in all mammals studied so far. Their function is unknown. The muscle spindles, if they are present in a species, lie in the orbital layer, or at its junction to the global layer. Golgi tendon organs appear to be unique to artiodactyls (i.e., sheep and goats, etc.); they lie in an outer distal marginal layer of the eye muscle, called the "peripheral patch layer" in sheep. The specific association between palisade endings and the multiply innervated type of muscle fibers of the global layer has led to the hypothesis that together they may act as a sensory receptor, and provide a source of central proprioceptive signals. But other interpretations of the morphological evidence do not support this role.
The organization of the motoneuron subgroups in the brainstem controlling each extraocular eye muscle is highly stable through the vertebrate species. The subgroups are topographically organized in the oculomotor nucleus (III) and are usually considered to form the final common pathway for eye muscle control. Eye muscles contain a unique type of slow non-twitch, fatigue-resistant muscle fiber, the multiply innervated muscle fibers (MIFs). The recent identification the MIF motoneurons shows that they too have topographic organization, but very different from the classical singly innervated muscle fiber (SIF) motoneurons. The MIF motoneurons lie around the periphery of the oculomotor nucleus (III), trochlear nucleus (IV), and abducens nucleus (VI), slightly separated from the SIF subgroups. The location of four different types of neurons in VI are described and illustrated: (1) SIF motoneurons, (2) MIF motoneurons, (3) internuclear neurons, and (4) the paramedian tract neurons which project to the flocculus. Afferents to the motoneurons arise from the vestibular nuclei, the oculomotor and abducens internuclear neurons, the mesencephalic and pontine burst neurons, the interstitial nucleus of Cajal, nucleus prepositus hypoglossi, the supraoculomotor area and the central mesencephalic reticular formation and the pretectum. The MIF and SIF motoneurons have different histochemical properties and different afferent inputs. The hypothesis that SIFs participate in moving the eye and MIFs determine the alignment seems possible but is not compatible with the concept of a final common pathway.
In mammals, the extraocular muscle fibers can be categorized in singly-innervated and multiply-innervated muscle fibers. In the monkey oculomotor, trochlear and abducens nucleus the motoneurons of multiply-innervated muscle fibers lie separated from those innervating singly-innervated muscle fibers and show different histochemical properties. In order to discover, if this organization is a general feature of the oculomotor system, we investigated the location of singly-innervated muscle fiber and multiply-innervated muscle fiber motoneurons in the rat using combined tract-tracing and immunohistochemical techniques. The singly-innervated muscle fiber and multiply-innervated muscle fiber motoneurons of the medial and lateral rectus muscle were identified by retrograde tracer injections into the muscle belly or the distal myotendinous junction. The belly injections labeled the medial rectus muscle subgroup of the oculomotor nucleus or the greatest part of abducens nucleus, including some cells outside the medial border of abducens nucleus. In contrast, the distal injections labeled only a subset of the medial rectus muscle motoneurons and exclusively cells outside the medial border of abducens nucleus. The tracer detection was combined with immunolabeling using antibodies for perineuronal nets (chondroitin sulfate proteoglycan) and non-phosphorylated neurofilaments. In monkeys both antibodies permit a distinction between singly-innervated muscle fiber and multiply-innervated muscle fiber motoneurons. The experiments revealed that neurons labeled from a distal injection lack both markers and are assumed to represent multiply-innervated muscle fiber motoneurons, whereas those labeled from a belly injection are chondroitin sulfate proteoglycan- and non-phosphorylated neurofilament-immunopositive and assumed to represent singly-innervated muscle fiber motoneurons. The overall identification of multiply-innervated muscle fiber and singly-innervated muscle fiber motoneurons within the rat oculomotor nucleus, trochlear nucleus, and abducens nucleus revealed that the smaller multiply-innervated muscle fiber motoneurons tend to lie separate from the larger diameter singly-innervated muscle fiber motoneurons. Our data provide evidence that rat extraocular muscles are innervated by two sets of motoneurons that differ in their molecular, morphological, and anatomical properties.
Eye muscles are unusual in several ways; one is that they have up to three different layers-the inner global layer, the outer orbital layer, and in some species an external marginal layer has been described. In sheep this is called the "peripheral patch layer." Three different types of proprioceptors are found in eye muscles-muscle spindles, Golgi tendon organs, and palisade endings. A survey of the organization of their location leads us to the hypothesis that each receptor is confined to a separate layer of the eye muscle. The palisade endings are associated with the global layer, the muscle spindles lie predominantly in the orbital layer, and the Golgi tendon organs are found only in the peripheral patch layer. This well-organized scheme may help us to understand the proprioceptive system in eye muscles.
BACKGROUND: The topodiagnostic value and specificity of nystagmus in patients with mesencephalic lesions and its relation to tonic torsional deficits and vertical saccade deficits is controversial and anecdotal. METHODS: The authors examined 11 patients with vascular MRI-identified mesencephalic lesions and clinical evidence of vertical-torsional nystagmus on gaze straight ahead, focusing on the three-dimensional nystagmus components recorded with the three-dimensional search coil technique. RESULTS: Combined lesions of the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) and the interstitial nucleus of Cajal (iC) are much more frequent than riMLF and, in particular, iC lesions alone. Eight patients showed contralesional torsional nystagmus with a conjugate vertical component on gaze straight ahead and had anatomic (MRI) and clinical evidence (slowing of vertical saccades) for riMLF involvement. Tonic ocular torsion and the subjective visual vertical were shifted to the contralesional side (n = 7). Torsional nystagmus to the ipsilesional side was uncommon (n = 3) and found in patients with midbrain lesions involving the iC, all of whom also had decreased time constants of the slow phases of gaze-evoked nystagmus. CONCLUSIONS: Contrary to previous proposals, contralesional torsional nystagmus was the most frequent direction and is probably not compensatory for contralesional tonic ocular torsion. Small amplitude vertical saccades with normal velocities in association with ipsilesional torsional nystagmus may indicate isolated iC lesions. Torsional nystagmus following mesencephalic lesions may last for years and may help to distinguish rostral (riMLF) from caudal (iC) midbrain lesions.
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OBJECTIVES: To investigate the relative roles of burst neurons (which generate the saccadic command) and omnipause neurons (which gate the activity of burst neurons) in the pathogenesis of slow saccades in progressive supranuclear palsy (PSP). BACKGROUND: Experimental inactivation of mesencephalic burst neurons impairs vertical but not horizontal saccades. Experimental inactivation of omnipause neurons causes slowing of both horizontal and vertical saccades. Combining saccadic with vergence movements in healthy subjects induces small, high-frequency, conjugate oscillations, which indicate that omnipause neurons are inhibited. METHODS: The authors studied seven patients with PSP, six patients with other parkinsonian syndromes, and seven age-matched control subjects. They compared vertical saccades of similar sizes made with or without associated vergence movements. They compared the speed of vertical and horizontal saccades. RESULTS: Five patients with PSP and the six patients with other parkinsonian made vertical saccades in combination with horizontal vergence; all showed conjugate horizontal oscillations (29 to 41 Hz) during 27% to 93% of saccade-vergence trials. Vertical saccades made in conjunction with vergence movements were not speeded up or increased in size compared with saccades made between equidistant targets for the PSP or parkinsonian groups. Vertical saccades were slowed more than horizontal saccades in the PSP group (p < 0.005) but not in the parkinsonian group. CONCLUSIONS: Dysfunction of omnipause neurons ("gate dysfunction") is unlikely to be the primary cause of slow vertical saccades in progressive supranuclear palsy. Deficient generation of the motor command by midbrain burst neurons is the more likely cause.
Eye muscle fibers can be divided into two categories: nontwitch, multiply innervated muscle fibers (MIFs), and twitch, singly innervated muscle fibers (SIFs). We investigated the location of motoneurons supplying SIFs and MIFs in the six extraocular muscles of monkeys. Injections of retrograde tracers into eye muscles were placed either centrally, within the central SIF endplate zone; in an intermediate zone, outside the SIF endplate zone, targeting MIF endplates along the length of muscle fiber; or distally, into the myotendinous junction containing palisade endings. Central injections labeled large motoneurons within the abducens, trochlear or oculomotor nucleus, and smaller motoneurons lying mainly around the periphery of the motor nuclei. Intermediate injections labeled some large motoneurons within the motor nuclei but also labeled many peripheral motoneurons. Distal injections labeled small and medium-large peripheral neurons strongly and almost exclusively. The peripheral neurons labeled from the lateral rectus muscle surround the medial half of the abducens nucleus: from superior oblique, they form a cap over the dorsal trochlear nucleus; from inferior oblique and superior rectus, they are scattered bilaterally around the midline, between the oculomotor nucleus; from both medial and inferior rectus, they lie mainly in the C-group, on the dorsomedial border of oculomotor nucleus. In the medial rectus distal injections, a "C-group extension" extended up to the Edinger-Westphal nucleus and labeled dendrites within the supraoculomotor area. We conclude that large motoneurons within the motor nuclei innervate twitch fibers, whereas smaller motoneurons around the periphery innervate nontwitch, MIF fibers. The peripheral subgroups also contain medium-large neurons which may be associated with the palisade endings of global MIFs. The role of MIFs in eye movements is unclear, but the concept of a final common pathway must now be reconsidered.
The rostral interstitial nucleus of the medial longitudinal fascicle (riMLF) contains premotor neurons essential for the generation of rapid vertical eye movements. The Alzheimer's disease (AD)-related cytoskeletal changes and beta-amyloid deposits in this nucleus were examined in 30 autopsy cases and compared to the involvement of three associated nuclei - Edinger-Westphal nucleus, nucleus of Darkschewitsch and interstitial nucleus of Cajal. The riMLF displays slight cytoskeletal alterations already in the early stages in the development of the cortical cytoskeletal pathology (cortical NFT/NT-stages I-II, representing the preclinical phase of AD). In the cortical NFT/NT-stages III-IV (i.e. incipient phase of AD), the cytoskeletal pathology in the riMLF is pronounced and in stages V-VI (i.e. clinical phase of AD) it is severe. The progression of the cytoskeletal pathology in the riMLF correlates significantly with the cortical NFT/NT-stages I-VI that reflect the clinical course of AD. Isolated beta-amyloid deposits appear in the riMLF for the first time in the final beta-amyloid stage. In the Edinger-Westphal nucleus, in the nucleus of Darkschewitsch and most markedly in the interstitial nucleus of Cajal, the pathological changes were significantly less severe than those in the riMLF. In the event that the cytoskeletal pathology impairs the function of the premotor neurons of the riMLF, one would predict a progressive slowing of vertical saccades corresponding to the advancing cortical NFT/NT-stages.
Except during blinks, movements of the upper eyelid are tightly coupled to vertical eye movements. The premotor source for the coordination of lid and eye movements is unknown. The present paper provides the anatomical identification of a new premotor cell group in the rostral mesencephalon of the monkey and human, which lies in close proximity to the premotor center for vertical saccades and is thought to participate in lid-eye coordination. After injections of a retrograde transsynaptic tracer (tetanus toxin fragment C or BII(b)) into the levator palpebrae (LP), the superior rectus (SR), or the inferior oblique (IO) muscle of macaque monkeys, a small circumscribed group of premotor neurons was labeled in the central gray of the rostral mesencephalon, but not after superior oblique or inferior rectus muscle injections. This group lies immediately rostral to the interstitial nucleus of Cajal and medial to the rostral interstitial nucleus of the medial longitudinal fasciculus, each of which contain premotor neurons for vertical saccades, and was termed the M-group. Injections of tritiated leucine into the M-group led to afferent labeling primarily over LP motoneurons. In addition, label was present over the SR- and IO-motoneuron subgroups in the oculomotor nucleus and frontalis muscle motoneurons in the facial nucleus. This projection pattern of the M-group suggests a role in the coordination of the upper eyelid and eyes during upgaze. Double-labeling experiments in macaque monkeys revealed that the M-group is strongly parvalbumin immunoreactive and contains high levels of cytochrome oxidase activity. With these two histochemical markers, the homologue of the M-group was identified in the human brain as well.
Descending projections from the superior colliculus (SC) motor map to the saccadic omnipause neurons (OPNs) were examined in monkeys by using anterograde transport of tritiated leucine. The SC was divided into three zones: the rostral pole of the motor map, a small horizontal saccade zone in central SC, and a large horizontal saccade zone in caudal SC. Tracer injections into the intermediate layers of the three zones led to different patterns of silver grain deposits in and around nucleus raphe interpositus (RIP), which contains the OPNs: 1) From the rostral pole of the motor map, coarse axon branches of the crossed predorsal bundle spread medially into the RIP, branched, and terminated predominantly unilaterally over cells on the same side. 2) From the small horizontal saccade zone, the axon branches were of a finer caliber and terminated diffusely in the RIP, mainly on the same side. 3) From the large horizontal saccade zone, no terminal labeling was found within the RIP. 4) From the rostral pole of the motor map and small horizontal saccade zone, fiber branches from the ipsilateral descending pathway terminated diffusely over RIP. 5) In addition, terminal labeling in reticulospinal areas of the pons and medulla increased in parallel with the size of the saccade according to the SC motor map. The results suggest that there are multiple projections directly onto OPNs from the rostral SC but not from the caudal SC associated with large gaze shifts. The efferents from the rostral pole of the motor map may subserve the suppression of saccades during visual fixation, and those from the small horizontal saccade zone could inhibit anatagonist premotor circuits.
Our knowledge of otolith pathways is developing rapidly, but is still far from complete. Primary afferents from the sacculus and utricle terminate mainly in the lateral, inferior and caudal superior vestibular nuclei, and the ventral cerebellum, in particular the nodulus. Otolith signals descend via reticulo- and vestibulospinal pathways in the spinal cord to influence neck motoneurons and ascending proprioceptive afferents. Utricular information can reach the extraocular eye muscles via mono-, di-, and multisynaptic pathways, but saccular afferents probably only by multisynaptic pathways. The otolith signals are relayed from the vestibular nuclei, medullary reticular formation, inferior olive, and lateral reticular nucleus to sagittal zones in the caudal cerebellar vermis (nodulus and uvula), and influence the deep cerebellar nuclei. The graviceptive information could be channeled by the cerebellar efferents back to the vestibular and inferior olive complex, or fed into ascending pathways that would innervate the mescencephalon, the thalamus, and cerebral cortex.
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In the monkey, premotor neurons for vertical gaze are located in the mesencephalic reticular formation: the rostral interstitial nucleus of the medial longitudinal fascicle (riMLF) contains medium-lead burst neurons, and the interstitial nucleus of Cajal (iC) acts as integrator for the eye-velocity signals to eye-position signals. Both nuclei lie adjacent to each other and are similar in appearance at the transition zone in Nissl-stained sections, which makes a delineation of the functionally different nuclei difficult in human. For a neuropathologic analysis of degenerative changes in saccadic disorders of patients, the histologic identification of the riMLF and the iC is important. The aim of this study is to identify both nuclei in human by using parvalbumin as a histologic marker. First, in monkeys the premotor neurons in riMLF and iC were identified by trans-synaptic labelling after injections of tetanus toxin fragment C into vertical-pulling eye muscles. Premotor neurons were found in the riMLF mainly ipsilateral to the corresponding eye muscle motoneurons and on both sides within the iC, but here the labelled cell populations differed: the contralateral side contained more medium-sized cells compared with the mainly small-sized cell population on the ipsilateral side. Double labelling showed that almost all premotor neurons in the iC and all premotor neurons in the riMLF were parvalbumin-immunoreactive. The immunocytochemical staining of human brainstem sections revealed the riMLF as a cluster of medium-sized, elongated parvalbumin-positive cells, with a similar appearance and at a similar location as that in monkey: a wing-shaped nucleus dorsomedial to the red nucleus, rostral to the traversing tractus retroflexus, dorsally bordered by the thalamo-subthalamic paramedian artery. The adjacent iC could be distinguished easily by its more densely packed, round parvalbumin-immunoreactive neurons. The exact identification of premotor neurons of the vertical system in the normal human brain provides a reference basis for the neuropathologic analysis of vertical gaze disorders at a cellular level.
It is convenient to describe oculomotor neuroanatomy in terms of five to six different eye movement types, each with relatively independent neural circuitry: saccades, vestibulo-ocular reflex, optokinetic response, smooth pursuit, vergence and, most recently added to the list, gaze-holding. Current research indicates that many structures participate in several eye movement types, such as the nucleus reticularis tegmenti pontis, frontal eye fields and pretectum. However, the circuits appear to run in parallel rather than being integrated.
To clarify the role of the pretectal nucleus of the optic tract (NOT) in ocular following, we traced NOT efferents with tritiated leucine in the monkey and identified the cell groups they targeted. Strong local projections from the NOT were demonstrated to the superior colliculus and the dorsal terminal nucleus bilaterally and to the contralateral NOT. The contralateral oculomotor complex, including motoneurons (C-group) and subdivisions of the Edinger-Westphal complex, including motoneurons (C-group) and subdivisions of the Edinger-Westphal complex, also received inputs. NOT efferents terminated in all accessory optic nuclei (AON) ipsilaterally; contralateral AON projections arose from the pretectal olivary nucleus embedded in the NOT. Descending pathways contacted precerebellar nuclei: the dorsolateral and dorsomedial pontine nuclei, the nucleus reticularis tegmenti pontis, and the inferior olive. Direct projections from NOT to the ipsilateral nucleus prepositus hypoglossi (ppH) appeared to be weak, but retrograde tracer injections into rostral ppH verified this projection; furthermore, the injections demonstrated that AON efferents also enter this area. Efferents from the NOT also targeted ascending reticular networks from the pedunculopontine tegmental nucleus and the locus coeruleus. Rostrally, NOT projections included the magnocellular layers of the lateral geniculate nucleus (lgn); the pregeniculate, peripeduncular, and thalamic reticular nuclei; and the pulvinar, the zona incerta, the mesencephalic reticular formation, the intralaminar thalamic nuclei, and the hypothalamus. The NOT could generate optokinetic nystagmus through projections to the AON, the ppH, and the precerebellar nuclei. However, NOT also projects to structures controlling saccades, ocular pursuit, the near response, lgn motion sensitivity, visual attention, vigilance, and gain modification of the vestibulo-ocular reflex. Any hypothesis on the function of NOT must take into account its connectivity to all of these visuomotor structures.
A group of cells lying along the midline of the mid-medulla, nucleus pararaphales, is shown to play a role in vertical eye movements. Its efferents project along the midline, then pass laterally to follow the ventral external arcuate fibers around the surface of the medulla into the restiform body. The fibers terminate in the flocculus and ventral paraflocculus. This nucleus is one of the "cell groups of the paramedian tracts," which, based on their connectivity, could provide a motor-feedback signal for eye-head position to the cerebellum. Lesions of these pathways could lead to gaze-evoked nystagmus.