Brain, Vol. 124, No. 12, 2407-2416,
December 2001
© 2001 Oxford University Press
Otolith function in cerebellar ataxia due to mutations in the calcium channel gene CACNA1A
1 Reed Neurological Research Center, Department of Neurology, 2 Jules Stein Eye Institute, Department of Ophthalmology and 3 Department of Surgery, UCLA School of Medicine, Los Angeles, California, USA
Correspondence to:
Joseph L. Demer, MD, Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Los Angeles, CA 90095-7002, USA E-mail: jld{at}ucla.edu
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Abstract |
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The vestibulo-ocular reflexes stabilize retinal images during head movements. While there is a wealth of information about the interaction between the cerebellum and vestibulo-ocular reflexes mediated by the semicircular canals, little is known about the role of the cerebellum in the generation of the otolith-mediated linear vestibulo-ocular reflex (LVOR). By means of transient linear acceleration of the whole body along the interaural axis, we examined the LVOR in six patients with hereditary cerebellar ataxia due to mutations of the calcium channel gene CACNA1A, five with spinocerebellar ataxia type 6 (SCA6) and one with episodic ataxia type 2 (EA-2). Six age-matched normal subjects served as controls. Using a peak acceleration of 0.5 g in combination with recording by the binocular scleral magnetic search coil method, it was possible to study the latency and sensitivity of the LVOR in the first 150 ms after motion onset. The normal LVOR showed a significant dependence on viewing distance and covaried with vergence angle, and could be enhanced by the presence of a visible target. In contrast, the LVOR of ataxic patients had normal latency but significantly decreased sensitivity that was not enhanced with visible or nearer targets despite normal vergence. Substituting for the normal smooth LVOR slow phase, ataxic patients employed catch-up saccades 150–250 ms after motion onset. These findings suggest a critical role of the cerebellum in the modulation of otolith-ocular signals that is independent of motor vergence.
CACNA1A; otolith-ocular reflex; linear vestibulo-ocular reflex; cerebellar ataxia; eye movements
EA-2 = episodic ataxia type 2; (L)VOR = (linear) vestibulo-ocular reflex; SCA6 = spinocerebellar ataxia type 6
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Introduction |
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TopAbstractIntroductionPatients and methodsResultsDiscussionAcknowledgementsReferences |
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Spinocerebellar ataxia type 6 (SCA6) and episodic ataxia type 2 (EA-2) are genetically distinct subtypes of the autosomal dominant spinocerebellar ataxias (SCAs) (Klockgether and Evert, 1998
; Baloh and Jen, 2000). Both SCA6 and EA-2 result from mutations in the calcium channel gene CACNA1A, which codes for the main transmembrane component of a calcium channel expressed most heavily in the cerebellum (Volsen et al., 1995; Ludwig et al., 1997). Radiological and neuropathological studies in patients with SCA6 show selective atrophy of the cerebellum and extensive loss of Purkinje cells in the cerebellar cortex (Gomez et al., 1997). Whereas several previous reports focused on abnormalities of the oculomotor system and the angular vestibulo-ocular reflex, showing normal saccade velocities and vestibulo-ocular reflex (VOR) gain but impaired smooth pursuit in these entities (Baloh et al., 1997; Gomez et al., 1997; Buttner et al., 1998), the linear VOR (LVOR), mediated by the otoliths, has not yet been evaluated. The LVOR response is normally small for remote targets and increases with target proximity as binocular convergence increases. A direct relationship between LVOR sensitivity and convergence has been postulated (Paige and Tomko, 1991a, 1991b; Paige et al., 1998).
In the present study, we examined the LVOR in patients with CACNA1A mutations by means of transient linear high acceleration delivered along the interaural axis. Since SCA6 and EA-2 are not associated with primary vestibular pathology or deficient convergence (Buttner et al., 1998), they represent ideal conditions to study the function of the cerebellum in the LVOR.
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Patients and methods |
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Patients
Five patients with SCA6 and one with EA-2 were tested. The clinical characteristics of all patients are listed in Table 1
. Age ranged from 41 to 79 years and the duration of symptoms from 9 to 20 years. All patients had saccadic pursuit tracking with gaze-evoked and/or downbeat nystagmus. Angular VOR gain, tested by digitally sampled electrooculography during sinusoidal, whole-body rotation in darkness at 0.05 and 0.4 Hz, was in the high normal range (Baloh et al., 1984) in the five patients in whom it was tested. The LVOR responses of patients (mean ± standard deviation age 59 ± 14 years, range 41–79 years) were compared with those of six age-matched controls (mean age 48 ± 16 years, range 31–67 years). All patients and subjects could converge for binocular fixation of targets 
15 cm. The near point of convergence was the tip of the nose in five control subjects and 8 cm for the sixth. For patients, the near point of convergence was the tip of the nose in three subjects and 8, 12 and 15 cm in the remaining three. All patients and control subjects gave written informed consent to participation in this study.
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Measurements
Linear acceleration was generated by means of a pneumatically driven, servo-controlled chair moving along the interaural axis. Peak acceleration was 0.5 g over a distance of ± 25 cm. Each subject was seated upright in the chair, which was fitted with dense foam cushions, and the body was secured by a lap belt. The subject's head was held by a seven-point restraint. Interaural head acceleration was measured with a linear accelerometer mounted on a dental appliance moulded to the upper teeth. A magnetic search coil was also mounted on the bite appliance to verify the absence of significant head rotation. For each condition, 10 acceleration steps were applied in random sequence in each direction. Subjects were instructed to fixate a target whenever it was visible. The target consisted of a small red laser spot projected on a screen that was either 200 or 25 cm in front of the subject. In the LVOR condition, subjects were instructed to maintain gaze on the earth-fixed target, but the target was extinguished at a random interval of 30–60 ms before the chair motion. In the visually enhanced LVOR condition, the earth-fixed target remained visible throughout the chair movement. In the LVOR cancellation condition, the target moved with the chair, requiring suppression of eye movement during chair motion. Eye movements were recorded with the magnetic search coil method (Robinson, 1963
; Collewijn et al., 1975), with simultaneous recording of both eyes to indicate vergence. Reference magnetic fields were generated by horizontal and vertical coil pairs that were mounted on the chair. Angular eye and head positions were low-pass-filtered at 300 Hz before 16-bit digital sampling at 1200 Hz by a Power Macintosh computer running the MacEyeball (Regents of The University of California, Los Angeles, Calif., USA) software package under LabView (National Instruments, Austin, Tex., USA). The same computer provided synchronous control of chair acceleration, target illumination and room illumination.
Data analysis
The onset of head motion was determined from the accelerometer on the upper teeth (Fig. 1). The onset of eye motion was determined from the search coil measure of angular eye position in the following manner. To obtain a measure of baseline eye position noise, the standard deviation of eye position was calculated for 83 ms (100 data points) starting 100 ms before chair motion. For all subjects, the mean position standard deviation was <0.4°. The mean position standard deviation before chair motion for control subjects was 0.16° and the corresponding value for patients was 0.15°. The time when the first eye position exceeded baseline by 3 SD was identified as eye motion onset. It is more complicated to determine the latency of the LVOR than that of the angular VOR because of the different dynamic characteristics of the transducers used to measure angular eye movement and linear head motion. Data were corrected for time delay in the angular position and linear acceleration transducers on the basis of measurements made using an armature to convert linear chair motion to the rotation of a reference search coil with zero time difference. The sensitivity of the LVOR was calculated in the position domain 150 ms after motion onset by comparing the magnitude of the response with the ideal response required to maintain gaze on the target (Fig. 1).
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The LVOR responses were analysed using two-sample t-tests for comparison between responses in normal subjects and patients and paired t-tests for within-subject differences. A 0.05 significance level was employed.
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Results |
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As we did not find a significant effect of motion direction in any of the tasks when the responses to the right and left were compared, we pooled the responses from the two sides for statistical analysis.
Angular head position
Recording of head yaw position showed no significant rotations in any subject in the first 150 ms after onset of head translation and no more than 1° at any time in the first 300 ms (Fig. 2). This meant that recorded eye movements are not attributable to the angular VOR.
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Vergence performance
All normal subjects and patients with CACNA1A mutations maintained stable vergence appropriate to the 200 and 25 cm target distances throughout every trial (Fig. 3
). The vergence performances of control subjects and patients were indistinguishable. At the 25 cm target distance, individual vergence angles varied predictably with interpupillary distance and diminished towards the end of chair motion, which was roughly consistent with geometric requirements.
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LVOR responses
Normal subjects exhibited a robust LVOR at 200 cm target distance, although the reflex was less than would be geometrically ideal for stabilization of the target on the fovea. Since the acceleration stimulus was highly reproducible, LVOR sensitivity was reflected by the compensatory eye displacement 150 ms after motion onset. The ideal sensitivity at that time was computed trigonometrically on the basis of initial placement of the target in front of the right eye, target distance and the measured chair displacement at 150 ms. Mean sensitivity of normal subjects was 0.52 ± 0.12°, representing 44 ± 12% of the ideal (Fig. 4A
). LVOR sensitivity markedly increased in controls as they increased vergence for the 25 cm target, to 2.2 ± 0.7°, representing 21 ± 6% of ideal (P < 0.0001) (Fig. 4A).
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Patients with CACNA1A mutations showed decreased sensitivity at 200 cm target distance of 0.14 ± 0.08°, representing 15 ± 10% of the ideal (Fig. 4B
), in comparison with normal subjects (P < 0.0001). Vergence at 25 cm targets had almost no effect on LVOR sensitivity in patients (0.27 ± 0.14° representing 3.6 ± 2.0% of ideal) (Fig. 4B), being significantly reduced in comparison with the responses in normal subjects at 25 cm (P < 0.0001). All patients with CACNA1A mutations generated catch-up saccades towards the target 150–250 ms after motion onset.
Visually enhanced LVOR responses
In comparison with the LVOR responses in darkness at 200 cm target distance, normal subjects showed significant improvement in the sensitivity of the visually enhanced LVOR with the visible target of 0.69 ± 0.16°, representing 53 ± 9% of ideal (P = 0.005, Fig. 5A). Patients with CACNA1A mutations showed only a slight increase in sensitivity for the visually enhanced LVOR, to 0.20 ± 0.10°, representing 21 ± 9% of ideal, in comparison with their LVOR responses (P = 0.07) (Fig. 5B).
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In the visible target condition, normal subjects also showed a highly significant increase of sensitivity at 25 cm target distance, to 3.1 ± 0.8°, representing 29 ± 7% of ideal (P < 0.0001, Fig. 5A
). The patients' visually enhanced LVOR sensitivity for the 25 cm target distance remained almost unchanged from the distant target condition at 0.29 ± 0.15°, representing only 3.9 ± 2.0% of ideal (P = 0.25, Fig. 5B). At 25 cm target distance, all patients again generated catch-up saccades 150–250 ms after motion onset.
Cancellation of the LVOR
Ideal cancellation would result in zero eye movement in response to translation. Normal subjects were able to suppress almost completely the initial LVOR while fixating a target moving with the chair at a distance of 200 cm (Fig. 6A). The mean deviation of the eyes, which was in a direction opposite to that of the direction of motion and measured 200 ms after motion onset, was 0.18 ± 0.12°. In contrast, LVOR cancellation was less complete in normal subjects when viewing a target that moved with the chair at a distance of 25 cm (Fig. 6A). In this condition, the mean eye deviation, measured 200 cm after motion onset, was 0.87 ± 0.34° (P = 0.0001). The patient's cancellation performance for the 200 cm target was almost the same as in controls (0.16 ± 0.14°) but was essentially unchanged for the 25 cm target (0.2 ± 0.17, P = 0.28) (Fig. 6B).
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Latency of the LVOR
The latency of the LVOR was difficult to determine even in normal subjects for the 200 cm target since the response amplitude was low. Mean LVOR latency for the 25 cm target in normal subjects was 65 ± 14 ms, being almost identical for the visually enhanced LVOR (67 ± 17 ms; P > 0.1). In two patients with CACNA1A mutations who had relatively high sensitivities, mean LVOR latency (72 ± 25 ms) was not significantly different from normal; in four patients it was indeterminate because of low sensitivity (i.e. latency >250 ms). Visually enhanced LVOR latency was 91 ± 30 ms in four patients with CACNA1A mutations and was indeterminate in two patients. Latency of the LVOR and visually enhanced LVOR was thus not significantly prolonged in those patients in whom it could be determined.
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Discussion |
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While the AVOR compensates for angular head movements, the LVOR compensates for translational head motion. Unlike the angular VOR, the LVOR transforms linear head acceleration into angular eye rotation. The normal LVOR response varies strongly with proximity of the object of regard (Schwarz et al., 1989
; Paige and Tomko, 1991a, 1991b; Telford et al., 1997). As both the angular VOR and LVOR operate best at high frequencies (Paige, 1996), transient linear high acceleration is the most appropriate stimulus for the examination of LVOR (Bronstein and Gresty, 1988). It is advantageous to assess the initial 150 ms of the LVOR to preclude any contamination of the otolithic responses by longer-latency visual pursuit eye movements. Experiments in normal human subjects showed that pursuit usually has latency >150 ms (Bronstein and Gresty, 1988). The present experiment prevented all visual tracking effects by evoking the LVOR in darkness very shortly after target viewing.
The finding that LVOR sensitivity in normal subjects was inversely proportional to fixation distance is consistent with previous experiments both in animals (Schwarz et al., 1989; Schwarz and Miles, 1991; Oas et al., 1992; Telford et al., 1997; Angelaki, 1998; Paige et al., 1998; Angelaki et al., 2000) and humans (Skipper and Barnes, 1989; Gianna et al., 1997). Our data also provide evidence that the presence of visual context enhances LVOR sensitivity, since in normal subjects the continuously visible target present for the visually enhanced LVOR increased sensitivity.
Latency of the LVOR in humans was determined recently at around 30–40 ms using the magnetic search coil technique (Crane et al., 2000). This range is similar to that in previous electrooculographic recordings (Bronstein and Gresty, 1988). Latencies in our normal subjects were prolonged (65 ± 14 ms) in comparison with those reported by Crane and colleagues (Crane et al., 2000), which is perhaps attributable to the greater age of the controls in the present study. A significant prolongation of angular VOR latency with ageing is now recognized (Tian et al., 2001). Although low sensitivity precluded determination of LVOR latency in most patients with CACNA1A mutations, latencies were not significantly abnormal where they could be determined. This normality further argues for the intactness of otolith afferents in the patients with CACNA1A mutations.
Our experiments demonstrated significantly reduced otolithic sensitivity and almost absent modulation of the LVOR by vergence angle in patients with CACNA1A mutations. These effects were unlikely to have resulted from dysfunction of the vestibular or ocular motor periphery, since angular VOR performance during standard rotational testing by electrooculography was normal in all patients examined (Table 1). The results of the cancellation task in our normal controls suggest that we recorded true otolith-mediated reflexive eye movements in our experiments. Like the normal subjects, who were unable to suppress the angular VOR at very high frequencies of rotation, the normal subjects were unable to cancel the LVOR during target fixation.
Previous studies in humans have used off-vertical axis rotation to assess otolith-ocular function in cerebellar ataxia (Furman, 1997; Anastasopoulos et al., 1998). Off-vertical axis rotation stimulates the otolith organs by constantly changing a subject's orientation with respect to gravity, producing a continuous nystagmus whose slow-component velocity contains a periodic or modulation component superimposed on a bias component. The modulation component, which presumably depends on the stimulation of the otolith organs (Goldberg and Fernandez, 1981), was normal (Furman, 1997) or increased (Anastasopoulos et al., 1998) in cerebellar patients. Anastasopoulos and colleagues suggested that the enhanced modulation in off-vertical axis rotation responses in cerebellar patients was due to the loss of cerebellar inhibition, and that smooth-pursuit eye movements and otolith–ocular responses were impaired differently in cerebellar ataxia (Anastasopoulos et al., 1998). However, Angelaki showed that the modulation component during off-vertical axis rotation reflects the low-frequency orienting behaviour of the LVOR and thus cannot be compared directly with the high-frequency compensatory movements in our study (Angelaki, 1998). The assumption that the responses in our experiments represent pure otolithic signals is supported by the observation that the LVOR operates with high-pass characteristics and performs well at high frequencies that exceed the capabilities of visual following mechanisms (Paige et al., 1998).
There is a previous report on the LVOR in patients with hereditary cerebellar ataxia (Baloh et al., 1995). This study used sinusoidal linear acceleration delivered by a parallel swing, and reported low LVOR responses with minimal change during earth-fixed or head-fixed targets, which is consistent with our results. However, it has been argued that, during sinusoidal acceleration at a frequency of 0.8 Hz, the responses do not depend exclusively on the otolith–ocular reflexes but also involve smooth-pursuit and other signals controlled by voluntary mechanisms (Anastasopoulos et al., 1998).
By using random high acceleration stimuli and recording the response in the initial 150 ms, we minimized these non-vestibular components of the response (Crane and Demer, 1998). Compared with the wealth of information available concerning the properties of synaptic actions from the semicircular canals to the extraocular motor neurones, there is limited knowledge about the pathways originating in the utricular maculae. Initial neurophysiological studies have shown that isolated electrical stimulation of otolith organs can induce short-latency eye movements and eye muscle contractions (Suzuki et al., 1969; Fluur and Mellstroem, 1971). The use of neuroanatomical tracing techniques in cats revealed that otolithic afferents project principally to the rostral part of the descending vestibular nucleus and the ventral part of the lateral vestibular nucleus (Imagawa et al., 1995). Furthermore, there is electrophysiological evidence of monosynaptic and disynaptic connections between utricular afferents and abducens motor neurones in cats (Uchino et al., 1994).
The abnormal otolith–ocular responses in our cerebellar patients imply that, besides this presumably weak direct otolithic pathway through the vestibular nuclei to the oculomotor nuclei, there must be a strong second, indirect pathway through the cerebellum. An electrophysiological study in cats recently established that vestibular neurones receiving inputs from the utriculus and/or sacculus project to the cerebellar cortex (Ono et al., 2000). The termination of this indirect otolithic pathway was found to be in the anterior cerebellar lobe and in the nodulus and uvula, which were also found to exhibit extensive Purkinje cell loss in patients with CACNA1A mutations (Gomez et al., 1997).
The profound LVOR deficits in our patients, in particular the absence of modulation of the responses with increased vergence angle, call into question the role of the cerebellum in the processing of otolithic signals. A recent study applied both angular and eccentric high-acceleration rotations in cerebellar patients to examine target distance modulation of the angular VOR. The findings suggested a role for the cerebellum in gain modulation of both the canal and otolith VOR in response to changes in distance, which supports our results for the LVOR (Crane et al., 2000). Patients with posterior fossa lesions showed impairments of the LVOR in response to lateral translation (Bronstein et al., 1991). However, it is unknown what signal conveys information about fixation distance and modulates LVOR sensitivity. Telford and colleagues speculated that the signal responsible for modulating the VOR is a central premotor or ‘motor command’ signal shared by the VOR and the vergence system (Telford et al., 1997). In this regard, it is of interest that the cerebellum is not only intimately related to the otolithic system (Buettner-Ennever, 1999) but is also thought to be involved in premotor vergence control (Versino et al., 1996). It should be noted that the ideal LVOR response is zero for an infinitely remote target. The reduced LVOR sensitivity observed in patients with CACNA1A mutations may represent a fixed or default sensitivity set for a remote target distance, and may be functionally disconnected from the modulatory effect of the vergence premotor target distance signal by the lesion. It seems probable that the functional lesion in CACNA1A mutations is cerebellar, but brainstem pathology cannot be excluded, particularly in those regions having extensive cerebellar connections.
In conclusion, this study has shown that CACNA1A mutations are characterized by reduced LVOR sensitivity, which may represent an essential part of the phenotype of these entities. Our findings imply that the cerebellum plays a critical role in the modulation of otolith–ocular signals. Future studies in patients with a variety of cerebellar lesions may provide a better understanding of the localization of otolithic processing within the cerebellum.
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Acknowledgements |
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We thank M. A. Amorim for help and N. DeSalles, F. Henriquez and L. Fleischman for technical assistance. This work was supported by NINCD DC02952. J.D. received a Research to Prevent Blindness Lew R. Wasserman merit award and is the David and Laraine Gerber Professor of Ophthalmology. G.W. was supported by the Austrian Science Fund.
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Received January 25, 2001. Revised May 30, 2001. Accepted July 10, 2001.
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