Clinico-Radiological Correlation of Weber's Syndrome.

Weber's syndrome, named after Hermann Weber, is characterized by midbrain lesions often caused by strokes, resulting in ipsilateral third nerve palsy, including ptosis and pupillary abnormalities, and contralateral hemiplegia. We discuss a case of a 35-year-old lady with cognitive impairment, right hemiparesis, diplopia, left eye ptosis, and lateral eye deviation. MRI of the brain with contrast suggested an acute infarct in the left-sided paramedian region of the midbrain. The oculomotor nucleus and cerebral peduncle were both affected by an abrupt left-sided paramedian midbrain stroke. The participation of particular midbrain nuclei together with symptoms including drooping eyelids, diplopia, and limb paralysis suggested Weber's syndrome. An MRI study of the brain is the modality of choice in suspected stroke cases and is more sensitive when it comes to the brainstem lesions. A comprehensive neurological examination with a clinical diagnosis of Weber's syndrome before radiological investigations is of great help for localizing brain stem lesions and thus aids in early diagnosis and treatment.

Reduced activity of vertically acting motoneurons during convergence.

Previous studies have revealed unexpected relationships between the firing rates of horizontally acting motoneurons and vergence. During a vergence task, for example, antidromically identified abducens internuclear neurons show a negative correlation between vergence angle and firing rate, which is the opposite of the modulation displayed by the medial rectus motoneurons to which they project. For a given horizontal eye position, medial rectus motoneurons discharge at a higher rate if the eyes are converged than if the same eye position is reached during a task that requires version; paradoxically, however, the horizontal rectus eye muscles show corelaxation during vergence. These complex and unexpected relationships inspired the present author to investigate whether the tonic firing rates of vertically acting motoneurons in oculomotor nucleus are correlated with vergence angle. Monkeys were trained to fixate a single, randomly selected, visual target among an array of 60 red plus-shaped LEDs, arranged at 12 different distances in three-dimensional space. The targets were arranged to permit dissociation of vertical eye position and vergence angle. Here I report, for the first time, that most vertically acting motoneurons in oculomotor nucleus show a significant negative correlation between tonic firing rate and vergence angle. This suggests the possibility that there may be a general corelaxation of extraocular muscles during vergence.NEW & NOTEWORTHY An array of 60 plus-shaped LEDs, positioned at various locations in three-dimensional space, was used to elicit conjugate and disjunctive saccades while single neurons in oculomotor nucleus were recorded from rhesus monkeys. This study demonstrates that most vertically acting motoneurons in oculomotor nucleus discharge at a lower rate when the eyes are converged.

Paramedian Midbrain Infarction Presenting with Bilateral Ptosis and Unilateral Median Longitudinal Fasciculus Syndrome: A Peculiar Midbrain Syndrome.

We report a case of bilateral ptosis due to paramedian midbrain infarction, which was associated with ipsilateral impaired adduction of the eye and contralateral ataxia. T2-weighted magnetic resonance imaging of the brain revealed a right paramedian midbrain infarction. The ptosis rapidly improved without a difference between the left and right sides, while the other symptoms mostly resolved within a month following treatment with antiplatelet agents and rehabilitation. An infarction of the paramedian dorsocaudal portion of the midbrain can involve both the central caudal nucleus and the median longitudinal fasciculus (MLF), causing a peculiar combination of symptoms, bilateral ptosis, and unilateral MLF syndrome.

Functional Organization of Extraocular Motoneurons and Eye Muscles.

Eye movements are indispensable for visual image stabilization during self-generated and passive head and body motion and for visual orientation. Eye muscles and neuronal control elements are evolutionarily conserved, with novel behavioral repertoires emerging during the evolution of frontal eyes and foveae. The precise execution of eye movements with different dynamics is ensured by morphologically diverse yet complementary sets of extraocular muscle fibers and associated motoneurons. Singly and multiply innervated muscle fibers are controlled by motoneuronal subpopulations with largely selective premotor inputs from task-specific ocular motor control centers. The morphological duality of the neuromuscular interface is matched by complementary biochemical and molecular features that collectively assign different physiological properties to the motor entities. In contrast, the functionality represents a continuum where most motor elements contribute to any type of eye movement, although within preferential dynamic ranges, suggesting that signal transmission and muscle contractions occur within bands of frequency-selective pathways.

Differential Vulnerability of Oculomotor Versus Hypoglossal Nucleus During ALS: Involvement of PACAP.

Amyotrophic lateral sclerosis (ALS) is a progressive multifactorial disease characterized by the loss of motor neurons (MNs). Not all MNs undergo degeneration: neurons of the oculomotor nucleus, which regulate eye movements, are less vulnerable compared to hypoglossal nucleus MNs. Several molecular studies have been performed to understand the different vulnerability of these MNs. By analyzing postmortem samples from ALS patients to other unrelated decedents, the differential genomic pattern between the two nuclei has been profiled. Among identified genes, adenylate cyclase activating polypeptide 1 (ADCYAP1) gene, encoding for pituitary adenylate cyclase-activating polypeptide (PACAP), was found significantly up-regulated in the oculomotor versus hypoglossal nucleus suggesting that it could play a trophic effect on MNs in ALS. In the present review, some aspects regarding the different vulnerability of oculomotor and hypoglossal nucleus to degeneration will be summarized. The distribution and potential role of PACAP on these MNs as studied largely in an animal model of ALS compared to controls, will be discussed.

Is there a primitive reflex residue underlying Marcus Gunn Syndrome? Rat electrophysiology.

AIM: To make an electrophysiological demonstration of a possible jaw muscle afferents-oculomotor neural pathway that was proposed by our previous works on rats, which substantiates an early "release hypothesis" on pathogenesis of human Marcus Gunn Syndrome (MGS). METHODS: Extracellular unit discharge recording was applied and both orthodromic and spontaneous unitary firing were recorded in the oculomotor nucleus (III), and the complex of pre-oculomotor interstitial nucleus of Cajal and Darkschewitsch nucleus (INC/DN), following electric stimulation of the ipsilateral masseter nerve (MN) in rats. RESULTS: Extracellular orthodromic unit discharges, with latencies of 3.7±1.3 and 4.7±2.9ms, were recorded unilaterally in the III, and the INC/DN neurons, respectively. Spontaneous unit discharges were also recorded mostly in the INC/DN and less frequently in the III. Train stimulation could prompt either facilitation or inhibition on those spontaneous unit discharges. The inhibition pattern of train stimulation on the spontaneous discharging was rather different in the III and INC/DN. A slow inhibitory pattern in which spontaneous firing rate decreased further and further following repeated train stimulation was observed in the III. While, some high spontaneous firing rate units, responding promptly to the train stimuli with a short-term inhibition and recovered quickly when stimuli are off, were recorded in the INC/DN. However, orthodromic unit discharge was not recorded in the III and INC/DN in a considerable number of experiment animals. CONCLUSION: A residual neuronal circuit might exist in mammals for the primitive jaw-eyelid reflex observed in amphibians, which might not be well-developed in all experimental mammals in current study. Nonetheless, this pathway can be still considered as a neuroanatomic substrate for development of MGS in some cases among all MGS with different kind of etiology.

Apoptotic Markers in the Midbrain of the Human Neonate After Perinatal Hypoxic/Ischemic Injury.

Our previous postmortem studies on neonates with neuropathological injury of perinatal hypoxia/ischemia (PHI) showed a dramatic reduction of tyrosine hydroxylase expression (dopamine synthesis enzyme) in substantia nigra (SN) neurons, with reduction of their cellular size. In order to investigate if the above observations represent an early stage of SN degeneration, we immunohistochemically studied the expression of cleaved caspase-3 (CCP3), apoptosis inducing factor (AIF), and DNA fragmentation by using terminal deoxynucleotidyltransferase-mediated dUTP-biotin 3'-end-labeling (TUNEL) technique in the SN of 22 autopsied neonates (corrected age ranging from 34 to 46.5 gestational weeks), in relation to the severity/duration of PHI injury, as estimated by neuropathological criteria. No CCP3-immunoreactive neurons and a limited number of apoptotic TUNEL-positive neurons with pyknotic characteristics were found in the SN. Nuclear AIF staining was revealed only in few SN neurons, indicating the presence of early signs of AIF-mediated degeneration. By contrast, motor neurons of the oculomotor nucleus showed higher cytoplasmic AIF expression and nuclear translocation, possibly attributed to the combined effect of developmental processes and increased oxidative stress induced by antemortem and postmortem factors. Our study indicates the activation of AIF, but not CCP3, in the SN and oculomotor nucleus of the human neonate in the developmentally critical perinatal period.

Extraocular muscles involved in convergence are innervated by an additional set of palisade endings that may differ in their excitability: A human study.

Palisade endings are located at the myotendinous junction of extraocular muscles in most mammals. Irrespective of their unclarified function as motor or sensory nerve endings, a specialized role in convergence is proposed, based on their high number in the medial rectus muscle (MR). Further support comes from a study in monkey demonstrating that only the MR and inferior rectus muscle (IR) contain an additional population of palisade endings that express the calcium-binding protein calretinin (CR) in addition to choline acetyltransferase (ChAT). Here we studied, whether CR-positive palisade endings are present in human as well and confined to extraocular muscles most active during convergence. The systematic analysis of all eye muscles of 17 human specimen revealed that only the MR and IR contain an additional population of CR-positive palisade endings and multiple en-grappe endings, which target non-twitch muscle fibers along their whole length. Approximately 80% of all palisade endings in the MR expressed CR. Furthermore, the intrafusal muscle fibers of some muscle spindles in the MR were innervated by CR-positive annulospiral nerve endings that transmit the signals of muscle length changes to the brain. All extraocular muscles contained few thin CR-positive, but ChAT-negative nerve fibers, possibly representing free sensory or autonomic endings arising from the trigeminal ganglion. As in monkey, in the medial periphery of the human oculomotor nucleus ChAT-positive neurons were found to co-express CR. Therefore these neurons most likely represent the cell bodies of CR-positive palisade endings in the MR. Unlike in monkey, these neurons do not lie within a compact cell group, but are more scattered. In conclusion, the MR and IR in human contain two histochemically different populations of palisade and multiple endings that may contribute to ocular alignment and convergence in a different way.

The Amniote Oculomotor Complex.

The oculomotor (OM) complex is a combination of somatic and parasympatethic neurons. The correct development and wiring of this cranial pair is essential to perform basic functions: eyeball and eyelid movements, pupillary constriction, and lens accommodation. The improper formation or function of this nucleus leads pathologies such as strabismus. We describe the OM organization and function in different vertebrate brains, including chick, mouse, and human. The morphological localization is detailed, as well as the spatial relation with the trochlear nucleus in order to adjust some misleading anatomical topographic descriptions. We detailed the signaling processes needed for the specification of the OM neurons. The transcriptional programs driven the specification and differentiation of these neurons are partially determined. We summarized recent genetic studies that have led to the identification of guidance mechanisms involved in the migration, axon pathfinding, and targeting of the OM neurons. Finally, we overviewed the pathology associated to genetic malformations in the OM development and related clinical alterations. Anat Rec, 302:446-451, 2019. © 2018 Wiley Periodicals, Inc.

The Eye Opener: Finding and Targeting the Midbrain Lesion.

Lesions of the central nucleus of the third cranial nerve in midbrain leads to bilateral ptosis. We present a case of a 14 year old boy, who was found to have B/L non-correctable ptosis and medial rectus palsy. There was a ring enhancing lesion in the midbrain in contrast MRI which resolved with treatment. The case exemplifies that bilateral ptosis results from the central nucleus involvement of third nerve which has bilateral innervation.

Structural neural connectivity of the vestibular nuclei in the human brain: a diffusion tensor imagingS study.

Many animal studies have reported on the neural connectivity of the vestibular nuclei (VN). However, little is reported on the structural neural connectivity of the VN in the human brain. In this study, we attempted to investigate the structural neural connectivity of the VN in 37 healthy subjects using diffusion tensor tractography. A seed region of interest was placed on the isolated VN using probabilistic diffusion tensor tractography. Connectivity was defined as the incidence of connection between the VN and each brain region. The VN showed 100% connectivity with the cerebellum, thalamus, oculomotor nucleus, trochlear nucleus, abducens nucleus, and reticular formation, irrespective of thresholds. At the threshold of 5 streamlines, the VN showed connectivity with the primary motor cortex (95.9%), primary somatosensory cortex (90.5%), premotor cortex (87.8%), hypothalamus (86.5%), posterior parietal cortex (75.7%), lateral prefrontal cortex (70.3%), ventromedial prefrontal cortex (51.4%), and orbitofrontal cortex (40.5%), respectively. These results suggest that the VN showed high connectivity with the cerebellum, thalamus, oculomotor nucleus, trochlear nucleus, abducens nucleus, and reticular formation, which are the brain regions related to the functions of the VN, including equilibrium, control of eye movements, conscious perception of movement, and spatial orientation.

Sporadic amyotrophic lateral sclerosis: is SMN-Gemins protein complex of importance for the relative resistance of oculomotor nucleus motoneurons to degeneration?

Lower motoneurons (MNs) show varied vulnerability in amyotrophic lateral sclerosis (ALS): those of non-ocular brainstem nuclei and most of those of the spinal cord are highly vulnerable, while those of extraocular brainstem nuclei are quite resistant. Results of our former study on the immunoexpression of the survival of motor neuron protein (SMN) and Gemins 2-4 in cervical spinal cord anterior horn -MNs of sporadic ALS patients suggested that a relative deficit in Gemin2 may play some role in the pathomechanism of the disease. Here, we tested this idea further by comparing immunoexpression patterns of SMN and Gemins 2-8 between MNs of the oculomotor nucleus and -MNs of the cervical spinal cord anterior horns in autopsy material from sALS patients and controls. In the latter, no considerable difference in any studied protein was found between these structures except that SMN expression was slightly but significantly lower (p < 0.01) in the oculomotor MNs. In the sporadic ALS patients, the expression of SMN, Gemin4 and Gemin7 was significantly weaker (p < 0.05, p < 0.05 and p < 0.01, respectively), while that of Gemin8 was stronger (p < 0.001) in the MNs of the oculomotor nucleus than in the examined cervical spinal cord anterior horn -MNs. The immunoexpression of Gemin3 and Gemin6 in the spinal cord correlated strongly negatively with ALS duration (Spearman's correlation coefficient: RS = -0.84, p < 0.001, and RS = -0.86, p = 0.002, respectively). In the oculomotor nucleus MNs, no studied protein immunoexpression correlated significantly with ALS duration, but there was a tendency for such negative correlation for Gemin2 (RS = -0.56, p = 0.07). There was an apparent relative deficit of Gemin2 and Gemin8 in the spinal cord -MNs and of Gemins 2, 4 and 7 in the oculomotor nucleus MNs. These data do not support the hypothesis that the diverse ALS vulnerability of the two MN subsets is related to their disparate expression patterns of SMN and Gemins 2-8. The differences in these patterns may result from ALS-related epiphenomena, or from intrinsic differences in the structure and function between the MN subsets, or both.

Cholinergic Oculomotor Nucleus Activity Is Induced by REM Sleep Deprivation Negatively Impacting on Cognition.

Several efforts have been made to understand the involvement of rapid eye movement (REM) sleep for cognitive processes. Consolidation or retention of recognition memories is severely disrupted by REM sleep deprivation (REMSD). In this regard, pedunculopontine tegmental nucleus (PPT) and other brainstem nuclei, such as pontine nucleus (Pn) and oculomotor nucleus (OCM), appear to be candidates to take part in this REM sleep circuitry with potential involvement in cognition. Therefore, the objective of this study was to investigate a possible association between the performance of Wistar rats in a declarative memory and PPT, Pn, and OCM activities after different periods of REMSD. We examined c-Fos and choline acetyltransferase (ChaT) expressions as indicators of neuronal activity as well as a familiarity-based memory test. The animals were distributed in groups: control, REMSD, and sleep rebound (REB). At the end of the different REMSD (24, 48, 72, and 96 h) and REB (24 h) time points, the rats were immediately tested in the object recognition test and then the brains were collected. Results indicated that OCM neurons presented an increased activity, due to ChaT-labeling associated with REMSD that negatively correlated (r = -0.32) with the cognitive performance. This suggests the existence of a cholinergic compensatory mechanism within the OCM during REMSD. We also showed that 24 h of REMSD impacted similarly in memory, compared to longer periods of REMSD. These data extend the notion that REM sleep is influenced by areas other than PPT, i.e., Pn and OCM, which could be key players in both sleep processes and cognition.

Microsurgical Anatomy of the Oculomotor Nerve.

The oculomotor nerve supplies the extraocular muscles. It also supplies the ciliary and sphincter pupillae muscles through the ciliary ganglion. The nerve fibers leave the midbrain through the most medial part of the cerebral peduncle and enter the interpeduncular cistern. After the oculomotor nerve emerges from the interpeduncular fossa, it enters the cavernous sinus slightly lateral and anterior to the dorsum sellae. It enters the orbit through the superior orbital fissure, after exiting the cavernous sinus, to innervate the extraocular muscles. Therefore, knowledge of the detailed anatomy and pathway of the oculomotor nerve is critical for the management of lesions located in the middle cranial fossa and the clival, cavernous, and orbital regions. This review describes the microsurgical anatomy of the oculomotor nerve and presents pictures illustrating this nerve and its surrounding connective and neurovascular structures. Clin. Anat. 30:21-31, 2017. © 2016 Wiley Periodicals, Inc.

Calretinin as a Marker for Premotor Neurons Involved in Upgaze in Human Brainstem.

Eye movements are generated by different premotor pathways. Damage to them can cause specific deficits of eye movements, such as saccades. For correlative clinico-anatomical post-mortem studies of cases with eye movement disorders it is essential to identify the functional cell groups of the oculomotor system in the human brain by marker proteins. Based on monkey studies, the premotor neurons of the saccadic system can be identified by the histochemical markers parvalbumin (PAV) and perineuronal nets in humans. These areas involve the interstitial nucleus of Cajal (INC) and the rostral interstitial nucleus of the medial longitudinal fascicle (RIMLF), which both contain premotor neurons for upgaze and downgaze. Recent monkey and human studies revealed a selective excitatory calretinin (CR)-positive input to the motoneurons mediating upgaze, but not to those for downgaze. Three premotor regions were identified as sources of CR input in monkey: y-group, INC and RIMLF. These findings suggest that the expression pattern of parvalbumin and CR may help to identify premotor neurons involved in up- or downgaze. In a post-mortem study of five human cases without neurological diseases we investigated the y-group, INC and RIMLF for the presence of parvalbumin and CR positive neurons including their co-expression. Adjacent thin paraffin sections were stained for the aggrecan (ACAN) component of perineuronal nets, parvalbumin or CR and glutamate decarboxylase. The comparative analysis of scanned thin sections of INC and RIMLF revealed medium-sized parvalbumin positive neurons with and without CR coexpression, which were intermingled. The parvalbumin/CR positive neurons in both nuclei are considered as excitatory premotor upgaze neurons. Accordingly, the parvalbumin-positive neurons lacking CR are considered as premotor downgaze neurons in RIMLF, but may in addition include inhibitory premotor upgaze neurons in the INC as indicated by co-expression of glutamate decarboxylase in a subpopulation. CR-positive neurons ensheathed by perineuronal nets in the human y-group are considered as the homolog premotor neurons described in monkey, projecting to superior rectus (SR) and inferior oblique (IO) motoneurons. In conclusion, combined immunostaining for parvalbumin, perineuronal nets and CR may well be suited for the specific identification and subsequent analysis of premotor upgaze pathways in clinical cases of isolated up- or downgaze deficits.

Unraveling a masticatory - oculomotor neural pathway in rat: Implications for a pathophysiological neural circuit in human?

Anterograde tracers were injected into the mesencephalic trigeminal nucleus (Vme) in pons, labeled axons and terminals were observed in ipsilateral oculomotor (III) and trochlear (IV) nuclei, as well as in interstitial nucleus of Cajar and Darkschewitsch nucleus (INC/DN), the well-known premotor nuclei to the III/IV, but not in abducens nucleus and central mesencephalic and paramedian pontine reticular formation (CMRF/PPRF). Retrogradely labeled INC/DN neurons do ensue from injection of tracers into the III. Confocal microscopy revealed labeled Vme axonal terminals contact with labeled pre-oculomotor neurons in the INC/DN. In response to electrical stimulation of trigeminal nerve root (TR) jaw muscle branches, which contains peripheral processes of the jaw muscle spindle, extracellular unit discharges were recorded in the ipsilateral III/IV and INC/DN. Electromyography (EMG) was also recorded from superior rectus (SR) and levator palpebrae (LP) following electrical stimulation of the TR. Moreover, stimulation of the TR induced Fos expression in the INC/DN pre-oculomotor neurons, but not in CMRF/PPRF that harbors horizontal eye moving premotor neurons. By injection of retrograde tracers into the III combined with Fos immunostain, double labeled pre-oculomotor neurons were observed in the INC/DN. About 80% of retrogradely labeled III premotor neurons express Fos. These results suggest a neural pathway from the masticatory Vme neurons to the oculomotor system that is probably involved exclusively in vertical and torsional eye movement as well as eyelid retraction. The potential relationship between this pathway and Marcus Gunn Syndrome (MGS), a congenital jaw-winking syndrome, was discussed.

Electron Microscopic Examination of the Cat Oculomotor Nucleus Innervating the Medial Rectus Muscle

Oculoinotor nerve is a very important nerve in the ophthalornology, innervating the medial rectus, inferior rectus, inferior oblique, superior rectus, levator palpebrae superioris, and the presynaptic parasyrnpathetic outflow to the internal muscles of eye (the ciliary muscle and the sphincter muscle of the iris) . To examine the fine structure of neurons and synapses in the oculomotor nucleus projecting the rnedial rectus Hiuscle, 50% horseradish peroxidase (HRP) solution was injected into the rnedial rectus rnuscle of the cat, and serial sections of midbrain were studied with electron microscopes. Large motor neuron, small motor neuron and spindleshape motor neuron were examined. Cell body contained rich organells that. were nucleus, rough endoplasmic reticulum, HRP containing lysosorne, mitochondria and ribosome etc. Three kinds of synapses that are axosomatic synapse, axo-dendritic synapse and axo-axonic synapse were examed. Moreover, the nerve terminals had spherical-shaped synaptic vesicles. These results suggest that the function of inotorneurons related to the medial rectus muscle is not. defined by the shape and distribution of nerve terrninals but. depends on the shape of synaptic vesicles.

LOCALIZATION OF MOTOR NEURONS IN THE OCULOMOTOR NUCLEUS INNERVATING THE INFERIOR OBLIQUE MUSCLE AND THEIR DENDRITIC ARCHITECTURE IN THE RABBIT——A STUDY USING CT-HRP / 解剖学报

The localization of the neurons which control the inferior oblique muscle in the oculomotor nucleus and their dendritic architecture were studied by injecting the conjugated cholera toxin-horseradish peroxidase (CT-HRP) into the inferior oblique muscle of 7 rabbits.The oculomotor nucleus could be divided into oral, middle and caudal parts. The middle part was further divided into dorsomedial and ventrolateral parts, and the caudal part divided into dorsal and ventral parts. The labeled neurons innervating the inferior oblique muscle were mainly distributed ipsilaterally and occupying two thirds. of the rostrocaudal extent of the oculomotor nucleus, a few were scattered contralaterally.The labeled cells were found in the dorsomedial part of the nucleus orally, and shifted in successive caudal sections to the medial and then to the ventral part. No labeled cells in the oral and caudal ends of the nucleus could be identified.The dendritic branches of the labeled neurons covered the whole nucleus, but densest in its dorsomedial part. Many of them extended beyond the boundary of the nucleus into the central gray matter dorsally, some even approacheding the aqueduct, or through the medial longitudinal fasciculus into the reticular formation laterally and ventrally. A few dendrites crossed the midline into the contralateral nucleus. Therefore the receptive field of the oculomotor nucleus is presumably much larger than the area of the nucleus itself.