The vestibulo-ocular reflex and velocity storage in spinocerebellar ataxia 8

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases characterized by progressive instability of posture and gait, incoordination, ocular motor dysfunction, and dysarthria due to degeneration of cerebellar and brainstem neurons. Among the more than 20 genetically distinct subtypes, SCA8 is one of several wherein clinical observations indicate that cerebellar dysfunction is primary, and there is little evidence for other CNS involvement. The aim of the present work was to study the decay of the horizontal vestibulo-ocular reflex (VOR) after a short period of constant acceleration to understand the pathophysiology of the VOR due to cerebellar Purkinje cell degeneration in SCA8. The VOR was recorded in patients with genetically defined SCA8 during rotation in the dark. Moderate to severely affected patients had a qualitatively intact VOR, but there were quantitative differences in the gain and dynamics compared to normal controls. During angular velocity ramp rotations, there was a reversal in the direction of the VOR that was more pronounced in SCA8 compared to controls. Modeling studies indicate that there are significant changes in the velocity storage network, including abnormal feedback of an eye position signal into the network that contributes to this reversal. These and other results will help to identify features that are diagnostic for SCA subtypes and provide new information about selective vulnerability of neurons controlling vestibular reflexes.     

A vestibulo-ocular reflex with no head movement

Eye movements were produced in an elasmobranch preparation by electrical stimulation of the horizontal canal ampullary nerves. A pseudorandom binary sequence of stimulus pulse trains was delivered bilaterally. Eye position during this stimulus was cross-correlated with the stimulus pattern to obtain a linear model of the response. Sums of exponential functions were fitted to the crosscorrelogram data to estimate time-constants and transfer functions. The data was examined in the frequency domain by using Fourier transformation.The response is accurately described by a second order linear filter, which is essentially a low pass filter with a cutoff at 0.22 Hz. This nearly two octaves below the cutoff frequency of the eye motor plant, which has been estimated by the same method. Our data shows that there is no central phase compensation or prediction which might offset the substantial delay in eye motor plant response. We hypothesise that the necessary phase compensation may be achieved by driving the vestibulo-ocular reflex with sensory neurons having a phase advance at high frequency.     

Simulation of adaptive mechanisms in the vestibulo-ocular reflex

The vestibulo-ocular reflex (VOR), which stabilizes the eyes in space during head movements, can undergo adaptive modification to maintain retinal stability in response to natural or experimental challenges. A number of models and neural sites have been proposed to account for this adaptation but these do not fully explain how the nervous system can detect and correct errors in both gain and phase of the VOR. This paper presents a general error correction algorithm based on the multiplicative combination of three signals (retinal slip velocity, head position, head velocity) directly relevant to processing of the VOR. The algorithm is highly specific, requiring the combination of particular sets of signals to achieve compensation. It is robust, with essentially perfect compensation observed for all gain (0.25X–4.0X) and phase (-180°–+180°) errors tested. Output of the model closely resembles behavioral data from both gain and phase adaptation experiments in a variety of species. Imposing physiological constraints (no negative activation levels or changes in the sign of unit weights) does not alter the effectiveness of the algorithm. These results suggest that the mechanisms implemented in our model correspond to those implemented in the brain of the behaving organism. Predictions concerning the nature of the adaptive process are specific enough to permit experimental verification using electrophysiological techniques. In addition, the model provides a strategy for adaptive control of any first order mechanical system.     

Plasticity in the adult vestibulo-ocular reflex arc.

Human subjects with maintained reversal of their horizontal field of vision exhibit very substantial adaptive changes in their 'horizontal' vestibulo-ocular reflex (v.o.r.). Short durations (8 min) of vision reversal during natural head movement led to 20% v.o.r. attenuation while long periods (4 weeks) eventually led to approximate reversal of the reflex. The reversed condition is approached by a complex, but highly systematic, series of changes in gain and phase of the reflex response relative to normal. Recovery after return to normal vision exhibits a similar duration, but different pattern, to that of the original adaptation. A chronic cat preparation with long-term optical reversal of vision has now been developed and shows similar adaptive and recovery changes at low test stimulus amplitudes, but different patterns of adaptive response at high amplitudes. An adaptive neural model employing known vestibulo-ocular pathways is proposed to account for these experimentally observed plastic changes. The model is used to predict the adapted response to patterns of stimulation extending beyond the range of experimental investigation.     

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.     

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.     

The use of matrices in analyzing the three-dimensional behavior of the vestibulo-ocular reflex

The vestibulo-ocular reflex rotates the eye about the axis of a head rotation at the same speed but in the opposite direction to make the visual axes in space independent of head motion. This reflex works in all three degrees of freedom: roll, pitch, and yaw. The rotations may be described by vectors and the reflex by a transformation in the form of a matrix. The reflex consists of three parts: sensory, central, and motor. The transduction of head rotation into three neural signals, which may also be described by a vector, is described by a canal matrix. The neural, motorcommand vector is transformed to an eye rotation by a muscle matrix. Since these two matrices are known, one can solve for the central matrix which gives the strength of the connections between all the vestibular neurons and all the eye-muscle motoneurons. The role of the metric tensor in these transformations is described. This method of analysis is used in three applications. A lesion may be simulated by altering the elements in any or all of the three component matrices. By matrix multiplication, the resulting abnormal behavior of the reflex can be described quantitatively in all degrees of freedom. The method is also used to directly compare the differences in brain-stem connections between humans and rabbits that accommodate the altered actions of the muscles of the two species. Finally the method allows a quantitative assessment of the changes that take place in the brainstem connections when plastic changes are induced by artificially dissociating head movements from apparent motion of the visual environment.     

The cerebellar nodulus/uvula integrates otolith signals for the translational vestibulo-ocular reflex

BACKGROUND: The otolith-driven translational vestibulo-ocular reflex (tVOR) generates compensatory eye movements to linear head accelerations. Studies in humans indicate that the cerebellum plays a critical role in the neural control of the tVOR, but little is known about mechanisms of this control or the functions of specific cerebellar structures. Here, we chose to investigate the contribution of the nodulus and uvula, which have been shown by prior studies to be involved in the processing of otolith signals in other contexts. METHODOLOGY/PRINCIPAL FINDINGS: We recorded eye movements in two rhesus monkeys during steps of linear motion along the interaural axis before and after surgical lesions of the cerebellar uvula and nodulus. The lesions strikingly reduced eye velocity during constant-velocity motion but had only a small effect on the response to initial head acceleration. We fit eye velocity to a linear combination of head acceleration and velocity and to a dynamic mathematical model of the tVOR that incorporated a specific integrator of head acceleration. Based on parameter optimization, the lesion decreased the gain of the pathway containing this new integrator by 62%. The component of eye velocity that depended directly on head acceleration changed little (gain decrease of 13%). In a final set of simulations, we compared our data to the predictions of previous models of the tVOR, none of which could account for our experimental findings. CONCLUSIONS/ SIGNIFICANCE: Our results provide new and important information regarding the neural control of the tVOR. Specifically, they point to a key role for the cerebellar nodulus and uvula in the mathematical integration of afferent linear head acceleration signals. This function is likely to be critical not only for the tVOR but also for the otolith-mediated reflexes that control posture and balance.     

An adaptive gaze stabilization controller inspired by the vestibulo-ocular reflex

The vestibulo-ocular reflex stabilizes vision in many vertebrates. It integrates inertial and visual information to drive the eyes in the opposite direction to head movement and thereby stabilizes the image on the retina. Its adaptive nature guarantees stable vision even when the biological system undergoes dynamic changes (due to disease, growth or fatigue etc), a characteristic especially desirable in autonomous robotic systems. Based on novel, biologically plausible neurological models, we have developed a robotic testbed to qualitatively evaluate the performance of these algorithms. We show how the adaptive controller can adapt to a time varying plant and elaborate how this biologically inspired control architecture can be employed in general engineering applications where sensory feedback is very noisy and/or delayed.     

Neural network models of velocity storage in the horizontal vestibulo-ocular reflex

The vestibulo-ocular reflex (VOR) produces compensatory eye movements by utilizing head rotational velocity signals from the semicircular canals to control contractions of the extraocular muscles. In mammals, the time course of horizontal VOR is longer than that of the canal signals driving it, revealing the presence of a central integrator known as velocity storage. Although the neurons mediating VOR have been described neurophysiologically, their properties, and the mechanism of velocity storage itself, remain unexplained. Recent models of integration in VOR are based on systems of linear elements, interconnected in arbitrary ways. The present study extends this work by modeling horizontal VOR as a learning network composed of nonlinear model neurons. Network architectures are based on the VOR arc (canal afferents, vestibular nucleus (VN) neurons and extraocular motoneurons) and have both forward and lateral connections. The networks learn to produce velocity storage integration by forming lateral (commissural) inhibitory feedback loops between VN neurons. These loops overlap and interact in a complex way, forming both fast and slow VN pathways. The networks exhibit some of the nonlinear properties of the actual VOR, such as dependency of decay rate and phase lag upon input magnitude, and skewing of the response to higher magnitude sinusoidal inputs. Model VN neurons resemble their real counterparts. Both have increased time constant and gain, and decreased spontaneous rate as compared to canal afferents. Also, both model and real VN neurons exhibit rectification and skew. The results suggest that lateral inhibitory interactions produce velocity storage and also determine the properties of neurons mediating VOR. The neural network models demonstrate how commissural inhibition may be organized along the VOR pathway.     

A linear canal-otolith interaction model to describe the human vestibulo-ocular reflex

A control systems model of the vestibulo-ocular reflex (VOR) originally derived for yaw rotation about an eccentric axis (Crane et al. 1997) was applied to data collected during ambulation and dynamic posturography. The model incorporates a linear summation of an otolith response due to head translation scaled by target distance, adding to a semi-circular canal response that depends only on angular head rotation. The results of the model were compared with human experimental data by supplying head angular velocity as determined by magnetic search coil recording as the input for the canal branch of the model and supplying linear acceleration as determined by flux gate magnetometer measurements of otolith position. The model was fit to data by determining otolith weighting that enabled the model to best fit the data. We fit to the model experimental data from normal subjects who were: standing quietly, walking, running, or making active sinusoidal head movements. We also fit data obtained during dynamic posturography tasks of: standing on a platform sliding in a horizontal plane at 0.2 Hz, standing directly on a platform tilting at 0.1 Hz, and standing on the tilting platform buffered by a 5-cm thick foam rubber cushion. Each task was done with the subject attending a target approximately 500, 100, or 50 cm distant, both in light and darkness. The model accurately predicted the observed VOR response during each test. Greater otolith weighting was required for near targets for nearly all activities, consistent with weights for the otolith component found in previous studies employing imposed rotations. The only exceptions were for vertical axis motion during standing, sliding, and tilting when the platform was buffered with foam rubber. In the horizontal axis, the model always fit near target data better with a higher otolith component. Otolith weights were similar with the target visible and in darkness. The model predicts eye movement during both passive whole-body rotation and free head movement in space implying that the VOR is controlled by a similar mechanism during both situations. Factors such as vision, proprioception, and efference copy that are available during head free motion but not during whole-body rotation are probably not important to gaze stabilization during ambulation and postural stabilizing movement. The linearity of the canal-otolith interaction was tested by re-analysis of the whole body rotation data on which the model is based (Crane et al. 1997). Normalized otolith-mediated gain enhancement was determined for each axis of rotation. This analysis uncovered minor non-linearities in the canal-otolith interaction at frequencies above 1.6 Hz and when the axis of rotation was posterior to the head. Received: 11 March 1998 / Received in revised form: 1 March 1999     

The development of the static vestibulo-ocular reflex in the Southern Clawed Toad,Xenopus laevis

In the clawed toad, Xenopus laevis, the static vestibulo-ocular reflex appears in 3 days old tadpoles (developmental stage 42) (Fig. 2). The amplitude and gain of this reflex increase up to stage 52, and then decrease to an almost constant value at stage 60 and older tadpoles (Fig. 3). The most effective roll angle gradually increases during development (Fig. 4). The size of the sensory epithelia reaches the final value at the end of the premetamorphic period (stage 56) (Fig. 5). The small-cellular medial ventral vestibular nucleus (VVN) reaches its maximal number of neurons before the large-cellular lateral VVN. Cell death is more pronounced in the medial than in the lateral part of the VVN. In the dorsal vestibular nucleus (DVN), the numerical development of the small and large neurons is similar to that in the small-cellular medial and large-cellular lateral portion of the VVN (Fig. 7). The results demonstrate that labyrinth and oculomotor centres are anatomically connected before the labyrinth and the vestibular nuclei are fully developed. We discuss the possibility that the ciliary polarity pattern of the sensory epithelium is radial during the first period of life, and changes to the vertebrate fan-type pattern during the second week of life. According to the increase of gain during the first three weeks of life, an increase of the spontaneous activity of vestibular neurons may occur during this period.     

The development of the static vestibulo-ocular reflex in the Southern Clawed Toad,Xenopus laevis

The static vestibulo-ocular reflex was investigated in tadpoles at different times following unilateral destruction of the labyrinth during the period of early organogenesis and premetamorphosis. Balance compensation is completed after a few weeks, while gain compensation only occurs partially (Figs. 2-4). Tadpoles hemilabyrinthectomized in the age of 2.5 days (stage 38) develop no vestibular nuclei on their lesioned side, while tadpoles operated later in their life, possess these nuclei (Figs. 5, 6) even if they were not detectable at the operation day (Fig. 7). For their dorsal vestibular nucleus (DVN), the number of neurons is usually larger on the intact than on the lesioned side; while for the ventral vestibular nucleus (VVN), there is either numerical symmetry or a transient decrease of cell number on the intact side (Fig. 5). The results demonstrate that vestibular compensation occurs even if vestibular nuclei have developed only on one side, i.e. the vestibular commissure is not a prerequisite for a successful compensation process. It is discussed whether the use of extra-vestibular error signals for balance but not for gain compensation may cause the differences in time courses of both compensation processes.     

The development of the static vestibulo-ocular reflex in the Southern Clawed Toad,Xenopus laevis

Summary Acute hemilabyrinthectomized tadpoles of the Southern Clawed Toad (Xenopus laevis), younger than stage 47 (about 6 days old), perform no static vestibulo-ocular reflex (Fig. 1). Older acute lesioned animals respond with compensatory movements of both eyes during static roll. Their threshold roll angle, however, depends on the developmental stage. For lesioned stages 60 to 64, it is 75° while stage 52 to 56 tadpoles respond even during a lateral roll of 15° (Figs. 1 and 2). Selective destruction of single macula and crista organs revealed that the static vestibulo-ocular reflex is evoked by excitation of the macula utriculi (Figs. 3 and 4) even in young tadpoles.The results demonstrate that bilateral projections of the vestibular apparatus must have developed at the time of occurrence of the static VOR, that during the first week of life the excitation of a single labyrinth is subthreshold (Fig. 1). We discuss the possibility whether the loss of the static VOR during the prometamorphic period of life (Fig. 2) is caused by increasing formation of multimodal connections in the vestibular pathway.Abbreviations eye angle - roll angle - () response characteristic - A response amplitude - G response gain - VOR vestibulo-ocular reflex     

Ontogeny of mouse vestibulo-ocular reflex following genetic or environmental alteration of gravity sensing

The vestibular organs consist of complementary sensors: the semicircular canals detect rotations while the otoliths detect linear accelerations, including the constant pull of gravity. Several fundamental questions remain on how the vestibular system would develop and/or adapt to prolonged changes in gravity such as during long-term space journey. How do vestibular reflexes develop if the appropriate assembly of otoliths and semi-circular canals is perturbed? The aim of present work was to evaluate the role of gravity sensing during ontogeny of the vestibular system. In otoconia-deficient mice (ied), gravity cannot be sensed and therefore maculo-ocular reflexes (MOR) were absent. While canals-related reflexes were present, the ied deficit also led to the abnormal spatial tuning of the horizontal angular canal-related VOR. To identify putative otolith-related critical periods, normal C57Bl/6J mice were subjected to 2G hypergravity by chronic centrifugation during different periods of development or adulthood (Adult-HG) and compared to non-centrifuged (control) C57Bl/6J mice. Mice exposed to hypergravity during development had completely normal vestibulo-ocular reflexes 6 months after end of centrifugation. Adult-HG mice all displayed major abnormalities in maculo-ocular reflexe one month after return to normal gravity. During the next 5 months, adaptation to normal gravity occurred in half of the individuals. In summary, genetic suppression of gravity sensing indicated that otolith-related signals might be necessary to ensure proper functioning of canal-related vestibular reflexes. On the other hand, exposure to hypergravity during development was not sufficient to modify durably motor behaviour. Hence, 2G centrifugation during development revealed no otolith-specific critical period.     

Alterations in rat horizontal vestibulo-ocular reflex phase as a function of orientation in gravity

The effect of changes in static and dynamic gravity signals on the phase accuracy of the horizontal vestibulo-ocular reflex (HVOR) was studied in rats using chronically implanted scleral search coils to monitor eye movements. Rats were sinusoidally rotated using a range of different frequencies (0.035-2 Hz) in a plane which always activated the horizontal semicircular canals but in one of three different orientations with regard to gravity which differentially activated the otolith organs: 1) upright-normal static gravity signal, no dynamic otolith activation; 2) inverted-inverted static gravity signal, no dynamic otolith activation; 3) on-side-dynamic activation of the otolith organs. In the upright orientation, the HVOR shows a phase advance at 0.2 Hz and below but not at 0.5 Hz and above. Phase accuracy of the HVOR was further degraded in the inverted orientation with rats showing large phase leads at 0.2 Hz and below. In contrast, accuracy of the HVOR was significantly improved at 0.2 Hz and below in the on-side orientation with phase accurate eye movements down to the lowest frequency tested. The results further support the idea that otolith organs play an important role in VOR generation by supplementing the semicircular canals' response to angular head movements.