Vertical Gaze Control Research Articles

An Indirect Pathway from the Rat Interstitial Nucleus of Cajal to the Vestibulocerebellum Involved in Vertical Gaze Holding.

The neural network, including the interstitial nucleus of Cajal (INC), functions as an oculomotor neural integrator involved in the control of vertical gaze holding. Impairment of the vestibulocerebellum (VC), including the flocculus (FL), has been shown to affect vertical gaze holding, indicating that the INC cooperates with the VC in controlling this function. However, a network between the INC and VC has not been identified. In this study, we aimed to obtain anatomical evidence of a neural pathway from the INC to the VC (the INC-VC pathway) in rats. Injection of dextran-conjugated Alexa Fluor 488 or adeno-associated virus 2-retro (AAV2retro) expressing GFP into the FL or another VC region (uvula/nodulus) did not reveal any retrogradely labeled neurons in the INC, suggesting that INC neurons do not project directly to the VC. Rabies virus-based transsynaptic tracing experiments revealed that the INC-VC pathway is mediated via synaptic connections with the prepositus hypoglossi nucleus (PHN) and medial vestibular nucleus (MVN). The INC neurons in the INC-VC pathway were mainly localized bilaterally within the rostral region of the INC. Transsynaptic tracing experiments involving the INC-FL pathway revealed that INC neurons connected to the FL via the bilateral PHN and MVN. These results indicate that the INC-VC pathway is not a direct pathway but is mediated via the PHN and MVN. These findings can provide clues for understanding the network mechanisms responsible for vertical gaze holding.

Serotonergic current responses of neurons in rat oculomotor neural integrators.

The prepositus hypoglossi nucleus (PHN) and the interstitial nucleus of Cajal (INC) are involved in controlling horizontal and vertical gaze, respectively. Previous studies have shown that PHN neurons exhibit depolarized or hyperpolarized responses to serotonin (5-hydroxytryptamine, 5-HT). However, serotonergic modulation of INC neurons has not been examined. Furthermore, the relationship between 5-HT-induced responses and neuron types based on neurotransmitter phenotypes has not been clarified. In this study, we investigated 5-HT-induced current responses in PHN and INC neurons and the distributions of distinct current responses in different neuron types, using whole cell recordings of wild-type and transgenic rat brain stem slices. Local application of 5-HT to the cell soma confirmed that slow inward (SI) and slow outward (SO) currents were mediated by 5-HT2 and 5-HT1A receptors, respectively. Furthermore, fast inward (FI) currents that were mediated by 5-HT3 receptors were observed. These three current responses were observed in both PHN and INC neurons. Analyses of the distributions of the three current responses revealed that fluorescently identified glutamatergic and inhibitory neurons in the PHN showed high proportions of SI and SO currents, respectively, whereas glutamatergic and inhibitory neurons in the INC showed mainly SO currents. When PHN and INC neurons were characterized on the basis of firing patterns, the proportions of the currents depended on the firing patterns. The different distributions of 5-HT-induced currents suggest distinct serotonergic modulation modes specific to horizontal and vertical gaze control.NEW & NOTEWORTHY Serotonergic modulation of vertical gaze control (interstitial nucleus of Cajal, INC) is less understood than that of horizontal gaze control (prepositus hypoglossal nucleus, PHN). Here, we report 5-HT-induced fast inward currents in addition to the previously reported slow inward and outward currents. The distributions of these currents in INC neurons based on neurotransmitter phenotypes differ from those in PHN neurons. These results suggest distinct serotonergic modulation modes in horizontal and vertical gaze control centers.

Distinct purinergic receptor-mediated currents of rat oculomotor integrator neurons characterized by different firing patterns.

The prepositus hypoglossi nucleus (PHN) and the interstitial nucleus of Cajal (INC) are oculomotor neural integrators involved in the control of horizontal and vertical gaze, respectively. We previously reported that local application of adenosine 5'-trisphosphate (ATP) to PHN neurons induced P2X receptor-mediated fast inward currents, P2Y receptor-mediated slow inward currents, and/or adenosine P1 receptor-mediated slow outward currents. In contrast to the findings on PHN neurons, the expression of functional purinergic receptors in INC neurons has not been examined. In this study, we investigated ATP-induced current responses in INC neurons and the distributions of the three current types across distinct firing patterns in PHN and INC neurons using whole cell recordings of rat brainstem slices. The application of ATP induced all three current types in INC neurons. Pharmacological analyses indicated that the fast inward and slow outward currents were mainly mediated by the P2X and P1 subtypes, respectively, corresponding to the receptor subtypes in PHN neurons. However, agonists of the P2Y subtype did not induce the slow inward current in INC neurons, suggesting that other subtypes or mechanisms are responsible for this current. Analysis of the distribution of the three current types in PHN and INC neurons revealed that the proportions of the currents were distinctly dependent on the firing patterns of PHN neurons whereas the proportion of the fast inward current was higher during all firing patterns of INC neurons. The different distributions of ATP-induced currents suggest distinct modes of purinergic modulation specific to horizontal and vertical integrators.NEW & NOTEWORTHY The roles of purinergic signaling on vertical (mediated by the interstitial nucleus of Cajal; INC) and horizontal (prepositus hypoglossal nucleus; PHN) gaze control are not understood. Here, we report three current types induced by ATP in INC neurons; the distribution of these current types across different types of INC neurons is different from that in PHN neurons. These results suggest distinct modes of purinergic modulation in horizontal and vertical gaze control centers.

Role of neural integrators in oculomotor systems: asystematic narrative literature review.

To evaluate the role of neural integrators (NI) in the oculomotor system. A literature search was carried out using several electronic databases during the months of June 2014 to March 2015. The following keywords were used to generate focused results: 'neural integrators', 'gaze-holding', 'oculomotor integration', 'impaired gaze-holding', 'gaze evoked nystagmus' and 'gaze dysfunction'. Further materials were found through searching relevant articles within reference lists. Seventy-one articles were sourced for this review which analysed animal and human subjects and network models; 45 were studies of humans, 16 studies of primates, three studies of felines and one study from rats and network models. The remaining articles were literature reviews. The horizontal and vertical, including torsional, NI are located logically in the brainstem, nearby their appropriate target extraocular motoneuron nuclei for stable eye position in eccentric position. The nucleus prepositus hypoglossi (NPH) and medial vestibular nuclei (MVN) are closely linked at the caudal pons and dorsal rostral medulla, integrating horizontal conjugate eye movement. The interstitial nucleus of Cajal (INC) integrates vertical and torsional eye movement at the upper midbrain. The integrator time constant is averaged to 25seconds in human horizontal and animal vertical NI to perform its function. Case reports revealed that dysfunction of horizontal NI also resulted in vertical ocular deviations, indicating some overlap of horizontal and vertical gaze control. Furthermore, pharmacological inactivation of NI exposed a population of inhibitory neurotransmitters that permits its mechanism of action; allowing for smooth conjugate movement. Neural integrators operate to integrate eye velocity and eye position information to provide signals to extraocular motoneurons to attain and maintain a new position. Therefore, NI allow image stabilization during horizontal and vertical eye movements at eccentric positions for comfortable single vision.

EP 38. Voxel-based morphometry reveals increased gray matter density in the uvula in physiological upbeat nystagmus

Aim Some videooculography (VOG) studies have reported a spontaneous upbeat nystagmus (UBN) in the absence of fixation in a number of healthy subjects ( Bisdorff et al., 2000 ). These oscillations of the vertical gaze system are thought to be under the influence of the gravitational force vector, termed vestibular nystagmus. The neural basis of this UBN and whether structural differences can be attributed to it, however, remain unclear. Aim of our combined voxel-based morphometry (VBM) and VOG approach within the context of a larger vestibular stimulation study was to investigate the anatomical substrate of this UBN in healthy subjects. Methods 44 right-handed healthy subjects (21 F; mean age 28 years) were examined in supine position by means of VOG (EyeSeeCam©) without fixation before and after bimastoidal galvanic vestibular stimulation (GVS). Then structural and functional images were obtained in a clinical 3T scanner (Siemens Magnetom Verio, Erlangen, Germany) with a 32-channel head coil. The protocol included an isotropic (1 × 1 × 1 m) MPRAGE sequence and a resting-state session with 165 volumes, each consisting of 36 slices of a T2 ∗ -weighted ascending EPI sequence (TR 2.31s). Data analysis was performed using the VBM12 toolbox within SPM 12 (Version 6407 Wellcome Department of Imaging Neuroscience, London, UK) in Matlab 2015b (The MathWorks, Natick, Massachusetts, USA) after standard preprocessing. T-contrasts were calculated with respect to the rest condition and were considered significant at p Results In the VOG experiment, a spontaneous UBN occurred in 20 of 44 subjects (9 F) with a mean slow phase velocity (SPV) of 2,3°/s (SD = 1.1). After GVS, SPV decreased significantly by 52% (mean reduction of SPV = 1.06 °/s, SD = 1.0; paired t(19) = 0.03, p Conclusion Individual structural differences in the uvula could account for the physiological UBN in the absence of fixation in supine position. The uvula contributes to the processing of otolith information and responds both to translation and changes in orientation relative to gravity ( Angelaki et al., 2004 ). The tonsil on the other hand seems to be crucial for gaze-holding. Our results point to the importance of a balanced interplay of uvula and tonsil in vertical gaze control. The combination of a minimized influence of gravity on vertical eye movements in supine position and the absence of visual information might demask central oscillatory signals within the vertical gaze system. High frequency dampening via GVS might in return result in an artificial external stabilization of this system, reflected in a decrease of UBN. Supported by the German Foundation for Neurology (DSN) and the German Research Foundation.

Unilateral thalamic infarction presenting as vertical gaze palsy: a case report

IntroductionVertical gaze palsy is a recognized manifestation of midbrain lesions. It rarely is a consequence of unilateral thalamic infarction.Case presentationWe report the case of a 48-year-old African-American woman who presented to our facility with vertical gaze palsy and evidence of left medial thalamic infarct on diffusion-weighted imaging without coexisting midbrain ischemia. The etiology of infarct was determined to be small vessel disease after extensive investigation.ConclusionsThis report suggests a possible role of the thalamus as a vertical gaze control center. Clinicoradiological studies are needed to further define the role of the thalamus in vertical gaze control.

Revisión del modelo del control de la mirada vertical

The main structures involved in the control of vertical gaze, both saccades, smooth pursuit and oculovestibular reflexes, are the rostral interstitial nucleus of medial longitudinal fasciculus, posterior commissure, interstitial nucleus of Cajal, oculomotor complex and trochlear nerve nucleus. Despite knowing the functions of these nuclei, and their main interconnections, afferents and efferents, there is no definitive and contrasted model of vertical gaze control in humans.Through the description of three cases, and as described in scientific literature, our aim is to review the models described to date.The control of vertical saccades generates in the rostral interstitial nucleus of medial longitudinal fasciculus, projecting to the pertinent oculomotor nuclei ipsilaterally for the inferior gaze, and bilaterally for the superior gaze.The double cross-innervation of the nuclei responsible for superior gaze, implies that unilateral lesions predominantly affect the inferior gaze.

Niemann‐Pick Type C Disease in Two Affected Sisters: Ocular Motor Recordings and Brain‐Stem Neuropathology

Two sisters with Niemann-Pick disease type C were examined: the brain in one sister, who had died, was examined, and eye movements in the other, surviving sister were recorded. Ocular motor recordings showed marked slowing of vertical saccades with relative sparing of horizontal saccades, pursuit, and the vestibulo-ocular reflex. Neuropathological findings included glial fibrillary lesions in the area of the posterior commissure and neuronal loss in the rostral interstitial nucleus of the MLF with preservation of the interstitial nucleus of Cajal and ocular motor complex. These neuropathologic findings correlate well with our current understanding of the anatomy and physiology of the supranuclear control of vertical gaze.

A hypothetical scheme for the brainstem control of vertical gaze

Although the brainstem control for horizontal gaze is fairly well delineated, the exact pathways for vertical gaze are less clear. Modern experimental techniques have clarified the anatomic connections that serve vertical gaze, defined neuronal populations with similar electrophysiologic properties, and delineated behavioral changes caused by inactivation of such populations. In this review, the authors summarize these new anatomic and behavioral studies and use them to develop a hypothetical scheme for vertical gaze to account for clinical disorders. Vertical saccades are generated by burst neurons lying in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). Each burst neuron projects to motoneurons in a manner such that the eyes are tightly coordinated during vertical saccades. Saccadic innervation from the riMLF is unilateral to depressor muscles but bilateral to elevtor muscles, with axons crossing within the oculomotor nucleus. Thus, riMLF lesions cause conjugate saccadic palsies that are usually either complete or selectively downward. Each riMLF contains burst neurons for both up and down saccades, but only for ipsilateral torsional saccades. Therefore, unilateral riMLF lesions can be detected at the bedside if torsional quick phases are absent during ipsidirectional head rotations in roll. The interstitial nucleus of Cajal (INC) is important for holding the eye in eccentric gaze after a vertical saccade and coordinating eye-head movements in roll. Bilateral INC lesions limit the range of vertical gaze. The posterior commissure (PC) is the route by which the INC projects to ocular motoneurons. Inactivation of the PC causes vertical gaze-evoked nystagmus, but destructive lesions cause a more profound defect of vertical gaze, probably due to involvement of the nucleus of the PC. Vestibular signals originating from each of the vertical labyrinthine canals ascend to the midbrain through several distinct pathways. Normal vestibular function is best tested by rotating the patient’s head in the planes of these canals. These predictions of a scheme to account for vertical gaze palsies should be testable at the bedside with systematic examination of each functional class of eye movements.—Nancy J. Newman

A hypothetical scheme for the brainstem control of vertical gaze.

To develop a hypothetical scheme to account for clinical disorders of vertical gaze based on recent insights gained from experimental studies. The authors critically reviewed reports of anatomy, physiology, and effects of pharmacologic inactivation of midbrain nuclei. Vertical saccades are generated by burst neurons lying in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). Each burst neuron projects to motoneurons in a manner such that the eyes are tightly coordinated (yoked) during vertical saccades. Saccadic innervation from riMLF is unilateral to depressor muscles but bilateral to elevator muscles, with axons crossing within the oculomotor nucleus. Thus, riMLF lesions cause conjugate saccadic palsies that are usually either complete or selectively downward. Each riMLF contains burst neurons for both up and down saccades, but only for ipsilateral torsional saccades. Therefore, unilateral riMLF lesions can be detected at the bedside if torsional quick phases are absent during ipsidirectional head rotations in roll. The interstitial nucleus of Cajal (INC) is important for holding the eye in eccentric gaze after a vertical saccade and coordinating eye-head movements in roll. Bilateral INC lesions limit the range of vertical gaze. The posterior commissure (PC) is the route by which INC projects to ocular motoneurons. Inactivation of PC causes vertical gaze-evoked nystagmus, but destructive lesions cause a more profound defect of vertical gaze, probably due to involvement of the nucleus of the PC. Vestibular signals originating from each of the vertical labyrinthine canals ascend to the midbrain through several distinct pathways; normal vestibular function is best tested by rotating the patient's head in the planes of these canals. Predictions of a current scheme to account for vertical gaze palsy can be tested at the bedside with systematic examination of each functional class of eye movements.

Synkinesis between facial nerve and oculomotor nerve. A case report

We present a case history of a young man suffering from a facial-oculomotor synkinesis. The findings speak in favour of an acquired synkinesis due to trauma. Most probably the injury occurred in the midbrain, in the area of the vertical gaze control center and/or the area of the levator palpebrae motoneurons. A congenital synkinesis due to embryonic malformation seems to be unlikely, because at birth no restriction of the eye-ball motility was present.

Síndrome del uno y medio vertical como única manifestación de un infarto talamosubtalámico bilateral

The one and a half vertical syndrome consists of paralysis of upward vertical conjugated gaze and monocular paralysis of downward gaze or vice-versa. It occurs as a consequence of a mesencephalodiencephalic lesion, either unilaterally or bilaterally, due to effects on structures such as the interstitial nucleus of Cajal, posterior commissure and rostral interstitial nucleus of the medial longitudinal bundle. The arterial supply of the structures involved in the supranuclear control of vertical gaze depends on the paramedian thalamic arteries (or posterior thalamo-subthalamic arteries) and the paramedian peduncular arteries. We present the case of a 58 year old woman with non-insulin dependent diabetes mellitus who presented with sudden onset of diplopia of vertical gaze. On examination there was paralysis of superior vertical conjugated gaze and monocular paralysis of ocular infraversion (one and a half syndrome) with no other pathological findings. Cerebral angioresonance and Doppler studies of the territory supplied by the posterior cerebral artery were normal. Both unilateral and bilateral mesencephalodiencephalic infarcts usually present clinically as disorders of consciousness and of conduct (the almost universal form of presentation), involvement of the pyramidal tract, the third cranial nerves and a supranuclear disorder of vertical gaze. The unusual feature of the case we present is a bilateral thalamo-subthalamic infarct which presented solely as a one and a half vertical syndrome with no clinically apparent effect on anatomically adjacent structures. We have not found any similar cases in the literature.

The ocular motor system.

AbstractRecent advances in ocular motor neurophysiology are reviewed with emphasis on brainstem control of horizontal saccadic and pursuit eye movements. Certain aspects of the control of vertical gaze and the role of the cerebellum and medial longitudinal fasciculus in normal and pathological states are also discussed. Current nomenclature and concepts are clarified so that they may be applied to the understanding of clinical ocular motor phenomenology.

Conjugate Downward Gaze Palsy Following Mumps Encephalomyelitis

The occurrence of isolated and complex patterns of extraocular muscle palsy in various postinfectious disease syndromes has been well documented. The supranuclear gaze palsies are of special interest to neurology and neuro-ophthalmology because of the implied diagnostic differential with respect of tumors, vascular lesions, a variety of specific and nonspecific inflammatory disorders (virus infections, lupus erythematosus, periarteritis, etc.), and the various demyelinating diseases. 1 It seems worthwhile, therefore, to report a case of downward gaze palsy following an apparent mumps encephalomyelitis and to discuss some of the modern concepts of vertical gaze control. Report of Case The patient is a 5-year-old boy with a history of normal growth and development. At age 1½ years a diagnosis of mumps was made on the basis of unilateral parotid swelling and febrile illness lasting about one week. A few days afterwards it was noted that he walked with his head tilted down and

National Maternity Report: Correction

<h3>Objective</h3> To explain (1) why an initial upbeat nystagmus (UBN) converts to a permanent downbeat nystagmus (DBN) in Wernicke encephalopathy (WE) and (2) why convergence and certain vestibular provocative maneuvers may transiently switch UBN to DBN. <h3>Methods</h3> Following a literature review and study of our 2 patients, we develop hypotheses for the unusual patterns of vertical nystagmus in WE. <h3>Results</h3> Our overarching hypothesis is that there is a selective vulnerability and a selective recovery from thiamine deficiency of neurons within brainstem gaze-holding networks. Furthermore, since the circuits affected in WE are commonly paraventricular, especially medially, just under the floor of the fourth ventricle where lie structures important for control of vertical gaze, we suggest the patterns of involvement in WE also reflect a breakdown in vulnerable areas of the blood–brain barrier. Many of the initial deficits of our patients improved over time, but their DBN did not. Irreversible changes in paramedian tract neurons, which project to the cerebellar flocculus, may be the cause. Here we suggest that conversion of UBN to permanent DBN points to thiamine deficiency and may argue for a chronic, nonprogressive DBN/truncal ataxia syndrome. Finally, we posit that the transient switch of UBN to DBN reflects abnormal processing of otolith information about linear acceleration, and often points to a diagnosis of WE. <h3>Conclusion</h3> Recognizing the unusual patterns of transient switching and then permanent conversion of UBN to DBN in WE is vital since long-term disability from WE may be prevented by timely, parenteral high-dose thiamine.