4-Aminopyridine Does Not Enhance Flocculus Function in Tottering,a Mouse Model of Vestibulocerebellar Dysfunction and Ataxia

The potassium channel antagonist 4-aminopyridine (4-AP) improves a variety of motor abnormalities associated with disorders of the cerebellum. The most rigorous quantitative data relate to 4-AP''s ability to improve eye movement deficits in humans referable to dysfunction of the cerebellar flocculus. Largely based on work in the ataxic mouse mutant tottering (which carries a mutation of the Cacna1a gene of the P/Q voltage-activated calcium channel), 4-AP is hypothesized to function by enhancing excitability or rhythmicity of floccular Purkinje cells. We tested this hypothesis by determining whether systemic or intrafloccular administration of 4-AP would ameliorate the eye movement deficits in tottering that are attributable to flocculus dysfunction, including the reductions in amplitude of the yaw-axis vestibulo-ocular reflex (VOR) and vision-enhanced vestibulo-ocular reflex (VVOR), and the optokinetic reflex (OKR) about yaw and roll axes. Because tottering''s deficits increase with age, both young and elderly mutants were tested to detect any age-dependent 4-AP effects. 4-AP failed to improve VOR, VVOR, and OKR gains during sinusoidal stimuli, although it may have reduced the tendency of the mutants'' responses to VOR and VVOR to decline over the course of a one-hour recording session. For constant-velocity optokinetic stimuli, 4-AP generated some enhancement of yaw OKR and upward-directed roll OKR, but the effects were also seen in normal C57BL/6 controls, and thus do not represent a specific reversal of the electrophysiological consequences of the tottering mutation. Data support a possible extra-floccular locus for the effects of 4-AP on habituation and roll OKR. Unilateral intrafloccular 4-AP injections did not affect ocular motility, except to generate mild eye elevations, consistent with reduced floccular output. Because 4-AP did not produce the effects expected if it normalized outputs of floccular Purkinje cells, there is a need for further studies to elucidate the drug''s mechanism of action on cerebellar motor dysfunction.     

Eye movements and brainstem neuronal responses evoked by cerebellar and vestibular stimulation in chicks

Summary The vestibulo-ocular reflex undergoes adaptive changes that require inputs from the cerebellar flocculus onto brainstem vestibular neurons. As a step toward developing an in vitro preparation in chicks for studying the synaptic basis of those changes, we have elucidated the organization of the pathways through which the flocculus influences vestibulo-ocular movements. Electrical stimulation of the vestibular ampulla evoked brief, contralaterally directed movements in both eyes. Although single current pulses to the flocculus elicited no response, conjunctive stimulation of the flocculus and the vestibular apparatus significantly reduced the vestibularly-evoked movement. Trains of current pulses applied to the flocculus and ampulla evoked eye movements directed toward and away from the side of stimulation, respectively. Recordings from the brainstem revealed neurons that were activated by ipsilateral vestibular stimulation and inhibited by ipsilateral floccular stimulation. Our sample included neurons in the lateral vestibular nucleus, the ventrolateral portion of the medial vestibular nucleus, and the superior vestibular nucleus. Similarities between these findings and those of similar studies in mammals indicate that the chick will provide a good model system for cellular studies of adaptive changes in the vestibulo-ocular reflex.Abbreviations FTN flocculus target neuron - VOR vestibuloocular reflex     

Afferent signals from the extraocular muscles of the pigeon modify the electromyogram of these muscles during the vestibulo-ocular reflex.

There is no general agreement on whether afferent signals from the extraocular muscles play any part in oculomotor control. However, we have previously shown that they modify the responses of cells in the oculomotor control system during the vestibulo-ocular reflex (VOR). If, as we suspect, these signals have an important role in the control of the VOR from moment-to-moment, we should be able to demonstrate similar, functionally significant, modifications at the output of the reflex. We have recorded the electromyographic activity of several extraocular muscles of the right eye during the VOR and while imposing movements on the left eye. We describe how the activity of the muscles, reflected in the electromyogram, is modified in specific ways depending on the parameters of the imposed eye movements. The effects of the extraocular afferent signals on the eye-muscle responses to vestibular drive during the slow phase of the VOR appear to be corrective. Thus the present results provide strong evidence that afferent signals from the extraocular muscles are concerned in the control of the reflex from moment-to-moment, and suggest that the wider question of their role in oculomotor control merits further consideration.     

Control and modulation of canal driven vestibulo-ocular reflex.

It has been well known that the canal driven vestibulo-ocular reflex (VOR) is controlled and modulated through the central nervous system by external sensory information (e.g. visual, otolithic and somatosensory inputs) and by mental conditions. Because the origin of retinal image motion exists both in the subjects (eye, head and body motions) and in the external world (object motion), the head motion should be canceled and/or the object should be followed by smooth eye movements. Human has developed a lot of central nervous mechanisms for smooth eye movements (e.g. VOR, optokinetic reflex and smooth pursuit eye movements). These mechanisms are thought to work for the purpose of better seeing. Distinct mechanism will work in appropriate self motion and/or object motion. As the results, whole mechanisms are controlled in a purpose-directed manner. This can be achieved by a self-organizing holistic system. Holistic system is very useful for understanding human oculomotor behavior.     

Central adaptation models of the vestibulo-ocular and optokinetic systems

A theoretical analysis of two models of the vestibulo-ocular and optokinetic systems was performed. Each model contains a filter element in the vestibular periphery to account for peripheral adaptation, and a filter element in the central vestibulooptokinetic circuit to account for central adaptation. Both models account for1 adaptation, i.e. a response decay to a constant angular acceleration input, in both peripheral vestibular afferent and vestibulo-ocular reflex (VOR) responses and2 the reversal phases of optokinetic after-nystagmus (OKAN) and the VOR and3 oscillatory behavior such as periodic alternating nystagmus. The two models differ regarding the order of their VOR transfer function. Also, they predict different OKAN patterns following a prolonged optokinetic stimulus. These models have behavioral implications and suggest future experiments.     

The fractional-order dynamics of brainstem vestibulo-oculomotor neurons

The vestibulo-ocular reflex (VOR) and other oculomotor subsystems such as pursuit and saccades are ultimately mediated in the brainstem by premotor neurons in the vestibular and prepositus nuclei that relay eye movement commands to extraocular motoneurons. The premotor neurons receive vestibular signals from canal afferents. Canal afferent frequency responses have a component that can be characterized as a fractional-order differentiation (d ^k x/dt _k where k is a nonnegative real number). This article extends the use of fractional calculus to describe the dynamics of motor and premotor neurons. It suggests that the oculomotor integrator, which converts eye velocity into eye position commands, may be of fractional order. This order is less than one, and the velocity commands have order one or greater, so the resulting net output of motor and premotor neurons can be described as fractional differentiation relative to eye position. The fractional derivative dynamics of motor and premotor neurons may serve to compensate fractional integral dynamics of the eye. Fractional differentiation can be used to account for the constant phase shift across frequencies, and the apparent decrease in time constant as VOR and pursuit frequency increases, that are observed for motor and premotor neurons. Fractional integration can reproduce the time course of motor and premotor neuron saccade-related activity, and the complex dynamics of the eye. Insight into the nature of fractional dynamics can be gained through simulations in which fractional-order differentiators and integrators are approximated by sums of integer-order high-pass and low-pass filters, respectively. Fractional dynamics may be applicable not only to the oculomotor system, but to motor control systems in general.     

Automatic detection and removal of fast phases from nystagmographic recordings by optimal thresholding

Recording of ocular nystagmus during vestibular tests does not measure the true response of the vestibulo-ocular reflex (VOR), because the VOR response (so-called slow phase of nystagmus) is interrupted by resetting saccades (so-called fast phase of nystagmus). In order to extract the real VOR contribution, saccades must be removed. In most of the nystagmus processing algorithms, saccade removal requires a human operator to choose a suitable eye velocity threshold able to separate fast from slow nystagmus phases. In the present report a fully automatic removal system is presented which selects an optimal velocity threshold by computing the VOR frequency response and maximizing its coherence function.     

The control of gaze (3). Neurological defects

Eye movements serve vision, which has two different aims: changing images using saccades, i.e. rapid eye movements, and stabilizing new images on the retina using slow eye movements. Eye movements are performed by ocular motor nuclei in the brainstem, on which supranuclear pathways--originating in the cerebral cortex, cerebellum and vestibular structures--converge. It is useful for the neurologist to know the clinical abnormalities of eye movements visible at the bedside since such signs are helpful for localization. Eye movement paralysis may be nuclear or infranuclear (nerves), involving all types of eye movements, i.e. saccades as well as the vestibulo-ocular reflex (VOR), or supranuclear, in which case the VOR is usually preserved. Lateral eye movements are organized in the pons, with paralysis of adduction (and preservation of convergence) when the lesion affects the medial longitudinal fasciculus (internuclear ophthalmoplegia), paralysis of conjugate lateral eye movements when the lesion affects the abducens nucleus (VI) and the "one-and-a-half" syndrome when both these structures are involved. Vertical eye movements are organized in the midbrain, with ipsilateral oculomotor (III) paralysis and contralateral paralysis of the superior rectus muscle when the third nerve nucleus is unilaterally damaged, supranuclear upward gaze paralysis when the posterior commissure is unilaterally damaged and supranuclear downward gaze paralysis (often coupled with upward gaze paralysis) when the mesencephalic reticular formations are bilaterally damaged. Numerous types of abnormal eye movements exist, of which nystagmus is the most frequent and usually due to damage to peripheral or central vestibular pathways. Cerebral hemispheric or cerebellar damage results in subtle eye movement abnormalities at the bedside, in general only detected using eye movement recordings, because of the multiplicity of eye movement pathways at these levels and their reciprocal compensation in the case of a lesion. Lastly, eye movements can also help the neuroscientist to understand the organization of the brain. They are a good model of motricity allowing us, using eye movement recordings, to study the afferent pathways of the cortical areas that trigger them, and thus to analyze relatively complex neuropsychological processes such as visuo-spatial integration, spatial memory, motivation and the preparation of motor programs.     

A non-linear model for visual-vestibular interaction during body rotation in man

A mathematical model for visual-vestibular interaction during body rotation in an illuminated visual surround is obtained by combining a previous model of the optokinetic reflex (OKR) with a simplified model of the vestibulo-ocular reflex (VOR). OKR is activated by the slip of the image of the external world on the retina, and represents a negative feedback loop around VOR. For large retinal slip velocities OKR behaves as a basically non-linear system. The validity of the model is proved via computer simulation by comparing predicted responses with the experimental results obtained in man by Koenig et al. (1978) in different situations of visual-vestibular interaction.Work supported by C.N.R. (Rome, Italy), Special Project on Piomedical Engineering, Grant No. 79.01255.86     

Model interpretation of visual-vestibular interaction in patients with labyrinthine and cerebellar pathologies

Oculomotor responses to combined optokinetic and vestibular stimulations in labyrinthine and cerebellar defective patients are discussed in terms of parametric changes in a model describing the interaction between the vestibulo-ocular reflex (VOR) and the optokinetic reflex (OKR). By making a few reasonable hypotheses about model parameter variations in relation to the type of pathology, the experimental results obtained by several authors can correctly be predicted and explained by the model. The model can therefore be used to define a set of parameters giving an estimate of the state of the system subserving VOR-OKR interaction in the examined patients. The model is also shown to be a powerful tool to assess the validity and the diagnostic significance of the procedures used to test VOR-OKR interaction.Work supported by CNR, Rome, Italy. Some results reported in this paper have been previously presented at the Eighth Extraordinary Meeting of the Bàràny Society, Basle, June 22th-25th, 1982.     

A mathematical model of the optokinetic reflex

The role of the optokinetic reflex (OKR) is that of cooperating with the vestibulo-ocular reflex (VOR) in the task of image stabilization on the retina during head rotations in a stationary visual surround. Since the dynamics of VOR was already well established, it has been possible to make a broad estimation of what the dynamics of OKR should be in order to obtain the performances observed in normal subjects. A mathematical model of OKR has been presented, and the experimental results obtained by Raphan et al. (1977) in the monkey and by Collins et al. (1970) in man were used to validate the model and to obtain a precise estimation of its parameters.Work supported by CNR, Special Project on Biomedical Engineering, grant No. 78.00512.86     

Stabilization of the gaze in chameleons: visual and vestibular reflexes

Some visual, vestibular and proprioceptive reflexes which contribute to gaze (head + eye) stabilization were quantified in the chameleon. All the reflexes were analysed in the horizontal plane, and the visual reflexes were also studied in the vertical plane. In restrained-head animals, both the optokinetic nystagmus (OKN) and the vestibulo-ocular reflex (VOR) had low gains. In free-head animals, the head (opto-collic or vestibulo-collic reflex) and eye (OKN or VOR) responses added their effects, thus improving gaze stabilization, especially during vestibular stimulation. Cervical stimulation provoked both a cervico-ocular reflex (COR) in the compensatory direction and a large number of saccades. The saccadic response was especially marked in the presence of patterned visual surroundings.     

Analysis of the middle latency evoked potentials to angular acceleration impulses in man

The middle latency vestibular evoked potential (ML-VsEP) recorded with scalp electrodes in man in response to impulses of angular acceleration is dominated by a forehead positive peak at about 15 ms and a negative peak at about 20 ms; the peak amplitude of this component is about 30 μV. This is followed by slower, smaller amplitude activity. The latency of this initial peak is similar to the latency of the vestibulo-ocular reflex (VOR) in monkeys. The present study was undertaken to elucidate the possible relation between the ML-VsEPs and VOR. This included recordings from forehead-mastoid electrodes (sites used to record VsEP) and other scalp electrodes and the recording of potentials due to eye movement: the electro-oculogram. Direct recording of eye movements was also conducted using an infra-red reflection device in those experiments in which the head was not moved. The recordings were conducted in man during vestibular stimulation eliciting VsEPs, during voluntary eye movements and during caloric and optokinetic stimulation. These experiments indicated that the 15–20 ms component of the ML-VsEP was not due to movements of the eye (corneoretinal dipole). The large amplitude 15–20 ms component of the ML-VsEP was similar in general magnitude, waveform, polarity, duration and rise time to the highly synchronous pre-saccadic spike (neural and/or myogenic) which precedes nystagnys and voluntary saccades. It therefore probably represents vestibular-initiated electrical activity in motor units of the extra-ocular muscles which then produce anti-compensatory saccades.     

A matrix analysis for a conjugate vestibulo-ocular reflex

The technique of matrix analysis is used to compare the connectivity between vestibular neurons and oculomotor neurons of the two eyes that would generate a conjugate vestibulo-ocular reflex (VOR). The technique shows that the connectivity is normally anatomically symmetric. The technique is also used to determine the types and loci of adaptation within the VOR that will maintain conjugacy. Adaptation is divided into1) that evoked by changes in visual feedback, which requires VOR or system-specific changes and2) that produced by changes in the canals or muscles, which requires deficit-specific adaptation. In the former case, the adaptation could best be achieved by an additive alteration of the vestibularmotoneuron projections. In the latter case, the appropriate adaptations would be serial, multiplicative changes, applied at the level of the vestibular neurons when the canals are at fault or at the level of the motoneurons of the eye whose muscles are impaired. The analysis thus suggests multiple loci of plasticity within the VOR, specialized for adapting to different deficits.     

Anatomical substrates of oculomotor control

It is convenient to describe oculomotor neuroanatomy in terms in 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.     

Motor deficits in neurofibromatosis type 1 mice: the role of the cerebellum

Neurofibromatosis type 1 (NF1) is an autosomal dominantly inherited disease, characterized by various neurocutaneous symptoms, cognitive impairments and problems in fine and gross motor performance. Although cognitive deficits in NF1 have been attributed to increased release of the inhibitory neurotransmitter γ-amino butyric acid (GABA) in the hippocampus, the origin of the motor deficits is unknown. Cerebellar Purkinje cells, the sole output neurons of the cerebellar cortex, are GABAergic neurons and express neurofibromin at high levels, suggesting an important role for the cerebellum in the observed motor deficits in NF1. To test this, we determined the cerebellar contribution to motor problems in Nf1(+/-) mice, a validated mouse model for NF1. Using the Rotarod, a non-specific motor performance test, we confirmed that, like NF1 patients, Nf1(+/-) mice have motor deficits. Next, to evaluate the role of the cerebellum in these deficits, mice were subjected to cerebellum-specific motor performance and learning tests. Nf1(+/-) mice showed no impairment on the Erasmus ladder, as step time and number of missteps were not different. Furthermore, when compensatory eye movements were tested, no performance deficits were found in the optokinetic reflex and vestibulo-ocular reflex in the dark (VOR) or in the light (VVOR). Finally, Nf1(+/-) mice successfully completed short- and long-term VOR adaptation paradigms, tests that both depend on cerebellar function. Thus, despite the confirmed presence of motor performance problems in Nf1(+/-) mice, we found no indication of a cerebellar component. These results, combined with recent clinical data, suggest that cerebellar function is not overtly affected in NF1 patients.     

Afferent signals from pigeon extraocular muscles modify the vestibular responses of units in the abducens nucleus.

Although the extraocular muscles contain stretch receptors it is generally believed that their afferents exert no influence on the control of eye movement. However, we have shown previously that these afferent signals reach various brainstem centres concerned with eye movement, notably the vestibular nuclei, and that the decerebrate pigeon is a favourable preparation in which to study their effects. If the extraocular muscle afferents do influence oculomotor control from moment-to-moment they should exert a demonstrable effect on the oculomotor nuclei. We now present evidence that extraocular muscle afferent signals do, indeed, alter the responses of units in an oculomotor nucleus (the abducens, VI nerve nucleus, which supplies the lateral rectus muscle) to horizontal, vestibular stimulation induced by sinusoidal oscillation of the bird. Such stimuli evoke a vestibulo-ocular reflex in the intact bird. The extraocular stretch receptors were activated by passive eye movement within the pigeon's saccadic range; such movements modified the vestibular responses of all 19 units studied which were all, histologically, in the abducens nucleus. The magnitude of the effects, purely inhibitory in 15 units, depended both on the amplitude and the velocity of the eye movement and most units showed selectivity for particular combinations of plane (e.g. horizontal versus vertical) and direction (e.g. rostral versus caudal) of eye movement. The results show that an afferent signal from the extraocular muscles influences vestibularly driven activity in the abducens nucleus to which it carries information related to amplitude, velocity, plane and direction of eye movement in the saccadic range. They thus strongly support the view that extraocular afferent signals are involved in the control of eye movement.     

Adaptive feedback control models of the vestibulocerebellum and spinocerebellum

We extend the cerebellar learning model proposed by Kawato and Gomi (1992) to the case where a specific region of the cerebellum executes adaptive feed-back control as well as feedforward control. The model is still based on the feedback-error-learning scheme. The proposed adaptive feedback control model is developed in detail as a specific neural circuit model for three different regions of the cerebellum and the learning of the corresponding representative movements: (i) the flocculus and adaptive modification of the vestibulo-ocular reflex and optokinetic eye-movement responses, (ii) the vermis and adaptive posture control, and (iii) the intermediate zones of the hemisphere and adaptive control of locomotion. As a representative example, simultaneous adaptation of the vestibulo-ocular reflex and the optokinetic eye-movement response was successfully simulated while the Purkinje cells receive copies of motor commands through recurrent neural connections as well as vestibular and retinal-slip parallel-fiber inputs.     

Twenty-four-hour variation of vestibular function in young and elderly adults

ABSTRACT

Animal and human studies demonstrate anatomical and functional links between the vestibular nuclei and the circadian timing system. This promotes the hypothesis of a circadian rhythm of vestibular function. The objective of this study was to evaluate the vestibular function through the vestibulo-ocular reflex using a rotatory chair at different times of the day to assess circadian rhythmicity of vestibular function. Two identical studies evaluating temporal variation of the vestibulo-ocular reflex (VOR) were performed, the first in young adults (age: 22.4 ± 1.5 y), and the second in older adults (70.7 ± 4.7 y). The slow phase velocity and time constant of the VOR were evaluated in six separate test sessions, i.e., 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00 h. In both studies, markers of circadian rhythmicity (temperature, fatigue, and sleepiness) displayed expected usual temporal variation. In young adults, the time constant of the VOR showed variation throughout the day (p < .005), being maximum 12:25 h (06:00 h test session) before the acrophase of temperature circadian rhythm. In older adults, the slow phase velocity and time constant also displayed temporal variation (p < .05). Maximum values were recorded at 10:35 h (06:00 h test session) before the acrophase of temperature circadian rhythm. The present study demonstrates that vestibular function is not constant throughout the day. The implication of the temporal variation in vestibular system in equilibrium potentially exposes the elderly, in particular, to differential risk during the 24 h of losing balance and falling.