Edited by: Herman Kingma, Eindhoven University of Technology, Netherlands
Reviewed by: Bernhard Baier, University Hospital of Mainz, Germany; Barry M. Seemungal, Imperial College London, UK
*Correspondence: Alexander A. Tarnutzer, Vestibulo-Ocularmotor Lab, Department of Neurology, University Hospital Zurich, Frauenklinikstr. 26, 8091 Zurich, Switzerland. e-mail:
This article was submitted to Frontiers in Neuro-otology, a specialty of Frontiers in Neurology.
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Transformation of head-fixed otolith signals into a space-fixed frame of reference is essential for perception of self-orientation and ocular motor control. In monkeys the nodulus and ventral uvula of the vestibulo-cerebellum facilitate this transformation by computing an internal estimate of direction of gravity. These experimental findings motivated the hypothesis that degeneration of the vestibulo-cerebellum in humans alter perceptual and ocular motor functions that rely on accurate estimates of gravity, such as subjective visual vertical (SVV), static ocular counterroll (OCR), and gravity-dependent modulation of vertical ocular drifts. We assessed the SVV, OCR, and spontaneous vertical ocular drifts in 12 patients with chronic vestibulo-cerebellar disease and in 10 controls. Substantially increased variability in estimated SVV was noted in the patients. Furthermore, gravity-dependent modulation of spontaneous vertical ocular drifts along the pitch plane was significantly (
The otolith organs sense self-motion in head-fixed coordinates, and therefore cannot discriminate relatively equivalent linear acceleration and gravity. However, accurate perception of self-orientation in space as well as optimal ocular motor and postural control require an estimate of motion in a space-fixed frame of reference. Self-motion is centrally transformed from head-fixed to space-fixed coordinates (Angelaki et al.,
Acute unilateral damage of vestibulo-cerebellar structures, e.g., due to ischemia or hemorrhage, leads to typical signs of imbalance in otolith-mediated pathways, i.e., partial or complete ocular tilt reaction [OTR, i.e., a triad of head tilt, vertical ocular misalignment (also termed skew deviation), and ocular torsion; Westheimer and Blair,
We hypothesize that due to the more balanced pattern of degeneration (Klockgether,
Twelve patients with chronic degeneration of the vestibulo-cerebellum due to hereditary or sporadic disease (Table
Patient | Onset | Diagnosis | Main clinical findings | Findings on brain MRI |
---|---|---|---|---|
A.M., f, 67 | 62 | SAOA | DBN, GEN, saccadic SPEM, (GA) | Slight atrophy of V |
H.H., m, 81 | 62 | SAOA | DBN, GEN, saccadic SPEM, GA | Severe atrophy of VestCb |
E.Z., m, 51 | 30 | SAOA | (DBN), GEN, saccadic SPEM, GA, (LA) | Slight atrophy of V and cerebellar hemispheres |
E.S., f, 54 | 35 | Probable EA II | (DBN), saccadic SPEM, (GA) | Normal |
E.Sch., f, 66 | 64 | SAOA | (DBN), GEN, saccadic SPEM, ocular flutter, (GA) | Slight atrophy of VestCb, Hemispheres, Colliculus superior |
C.E., m, 51 | 45 | SAOA | (DBN), GEN, saccadic SPEM, GA, (LA) | Atrophy of V |
W.T., m, 70 | 68 | SAOA | DBN, GEN, saccadic SPEM, GA | Atrophy of V |
B.U., m, 66 | 64 | SAOA | DBN, GEN, saccadic SPEM, GA | Slight atrophy of VestCb |
B.G., f, 46 | 40 | SAOA | DBN, GEN, saccadic SPEM, GA | Atrophy of VestCb |
L.M., f, 65 | 42 | SAOA | DBN, GEN, saccadic SPEM, GA | Slight atrophy of Fl |
G.M., m, 33 | 17 | A–T | GEN, saccadic SPEM, GA | Severe atrophy of V, moderate atrophy of Hemispheres |
B.M., m, 32 | 22 | A–T | GEN, saccadic SPEM, GA | No imaging studies available |
Subjects were seated upright on a motor-driven three axes turntable (Acutronic, Jona, Switzerland) with their head restrained looking straight-ahead for all paradigms. Subjects were positioned so that the roll axis of the turntable intersected the center of the inter-aural line. Pillows and safety belts minimized body movements.
Turntable acceleration/deceleration during changes of body roll position was set to ±10°/s2. An arrow that extended over the central 9.5° of the visual field and that was projected onto a screen (distance to subject: 1.5 m) was used to indicate perceived vertical. Experiments were performed in otherwise complete darkness.
Recording of eye movements were obtained monocularly (in 6/12 patients) or binocularly (in 6/12 patients and 10/10 controls) in three dimensions with a frequency of 1000 Hz using magnetic search coils (Skalar Instruments, Delft, The Netherlands). The search coil setup and the procedure was identical to the one described in Straumann et al.,
Subjects were asked to rapidly (<6 s) adjust the orientation of the arrow to perceived vertical with the arrow-head pointing up. Whenever completion was not confirmed within the time limit, the trial was repeated later. The presentation of the arrow started 10 s after the turntable came to a full stop and was offset clockwise (CW) or counter-clockwise (CCW) relative to vertical pseudo-randomly between 28° and 72°. Twenty-four adjustments were collected in each orientation (0° = upright; 75° = right-ear-down; -75° = left-ear-down) in pseudo-random order, resulting in a total of 72 trials, recorded in a single session. The direction of arrow rotation (CW vs. CCW) did not significantly affect its final orientation and its variability (
Subjects were instructed to keep gaze steady upon a laser dot presented at 1.5 m distance straight-ahead in otherwise complete darkness. They were subsequently moved to 75°, 45°, 30°, 20°, and 10° left-ear-down (LED) roll positions and afterward back to upright position, then to 75°, 45°, 30°, 20°, and 10° right-ear-down (RED) roll positions and again back to upright position; every position was held for 30 s.
For measurements of spontaneous vertical ocular drift subjects were asked to keep their eyes steady on a flashing laser dot (duration: 20 ms, interval: 2 s) projected straight-ahead on a turntable-fixed screen (distance: 0.59 m) in otherwise complete darkness. We used a flashing dot to ensure that visual following mechanisms could not aid fixation of the visual target. For the assessment of the gravity-dependent modulation of DBN, the paradigm of Marti was used (Marti et al.,
Outliers >3 SDs from the mean were discarded, resulting in the removal of <0.1% of all trials. In the following, we will use the term “intra-individual variability” whenever we report trial-to-trial SD. If not stated otherwise, statistical analysis was done using ANOVA (Minitab, Minitab Inc., State College). Tukey’s correction was used to compensate for multiple comparisons. To assess for correlations between the distinct otolith – tests, generalized estimated equations (GEE) were used (SPSS 16, SPSS Inc., Chicago). Whenever
Figure
In the cerebellar patients, although SVV in upright orientation was accurate (0.1 ± 2.2°), the adjustments deviated significantly from zero (
These results suggest that patients with chronic vestibulo-cerebellar disease are relatively more uncertain and tend to make more errors in perception of verticality.
Figure
The values of spontaneous vertical ocular drift in the left versus right eye data did not significantly differ in either patients or controls (
In the 10 patients, who had cerebellar degeneration due to the cause other than ataxia–telangiectasia (A–T), SVD exhibited the typical pattern of sinusoidal gravity-dependent modulation along the pitch plane: upward ocular drift increased in sustained prone positions and decreased in sustained supine positions as previously reported (Marti et al.,
Precise computation of internal estimates of direction of gravity is needed for accurate spatial perception, ocular motor, and postural control and relies on various sensory signals, e.g., vestibular, proprioceptive, and visual inputs. The cerebellum is critically involved in the central processing of vestibular signals. Our results demonstrate that patients with diffuse vestibulo-cerebellar degeneration exhibit increased variability in internal estimates of verticality of modest but significant size with respect to self-orientation both on the perceptual and on the ocular motor levels. However, besides the increased variability of SVV noted, the patients did surprisingly well in these tasks with normal accuracy of SVV, preserved OCR gains reflecting an intact rotational VOR (rVOR) and no increased drift of torsional eye position over time. Our findings underline the robustness of the static otolith-mediated functions.
The increased SVV variability in the patient group may be best explained by a disturbance in the generation of a central estimate of direction of gravity, and thus the transformation of otolith-input from a head-fixed to a space-fixed reference frame (Angelaki et al.,
Theoretically, visual blurring due to vertical ocular drift may result in a more variable visual feedback of SVV adjustments and explain the patients’ impaired ability to perform precise line adjustments. However, no correlation between the amount of spontaneous vertical ocular drift and SVV variability was seen in upright position. Moreover, the patients’ ability to hold a certain torsional eye position over a 10-s period of time while roll-tilted was not impaired. Given the unchanged within-trial variability of OCR, we think that the decreased SVV precision in the patients cannot be attributed to less stable visual fixation while setting the SVV. Finally, the increased SVV variability could also be caused by limb ataxia, but only two patients showed mild limb ataxia and variability values observed in these two patients were either close to (EZ) or below (CE) the mean values observed for the patient population; therefore, limb ataxia is unlikely to play a major role in this context.
The preserved SVV accuracy and static OCR gains in our patients with diffuse vestibulo-cerebellar degeneration reflect an intact static rVOR in slowly progressive cerebellar disease and markedly contrasts to the pattern observed in patients with acute lateralized cerebellar lesions, where the nodulus (Mossman and Halmagyi,
With regard to the clinical presentation of our patients, it seems reasonable to assume that the degenerative process has involved the nodulus, uvula, and the deep cerebellar nuclei on both sides to a similar extent. Thus, our data supports earlier reports that SVV tilts and ocular tilt reaction in cerebellar disease are suggestive of focal lesions disrupting otolith-input asymmetrically, while at least bilateral lesions of the nodulus seem not to give rise to ocular tilt reaction (Kim et al.,
In our patients, static rVOR was preserved, indicated by static OCR values not being significantly impaired both in terms of gain and in terms of torsional gaze holding over time in comparison to age-matched controls. Wong and Sharpe,
In contrast to preserved static OCR in degenerative cerebellar disease, the tVOR has been found to be severely impaired (Wiest et al.,
Furthermore, binocular control of torsional eye position, i.e., cycloversion, in the cerebellar patients was preserved, suggesting no major involvement of the cerebellum in the control of cycloversion under static conditions. However, due to the small number of cerebellar patients where binocular torsional eye movements had been obtained (
Our data confirm that DBN, which is typical for chronic vestibulo-cerebellar disease (Leigh and Zee,
The increase in trial-to-trial variability for the SVV task found in the patient group at a single roll angle (±75° ear-down) – although being statistically significant – was of small size, prompting interpretation of this finding with caution and demanding further studies with a larger and ideally more homogeneous sample size and additional roll-angles. Furthermore, the patients included clinically all demonstrated typical vestibulo-cerebellar disease, while magnetic resonance (MR) findings varied considerably and no volumetric analyses were performed. Therefore, structure-specific correlations of our findings remain limited. The patients with A–T demonstrated an atypical pattern of gravity-dependent modulation of vertical ocular drift. As we studied only two A–T patients, it remains unclear whether this pattern is generally found in A–T or not. Further studies in a larger number of A–T patients are needed to clarify on this point. Marked cerebellar atrophy – being most profound in the vermis – is considered a hallmark sign in A–T (Farina et al.,
Despite these limitations, we see important implications of this study both with regards to a better understanding of self-orientation relative to gravity in degenerative cerebellar disease and to the clinical evaluation of patients with vestibulo-cerebellar disease. Compared to patients with acute unilateral cerebellar lesions, patients with slowly progressive diffuse degenerative vestibulo-cerebellar disease do not present with offsets of their internal estimates of direction of gravity, however, as a surrogate of impaired cerebellar function, their ability to control for variability of motor commands and otolith-based internal estimates is impaired. Considering the relatively intact performance in various paradigms tested here and the slowly progressive nature of the patients underlying cerebellar diseases, central adaptation, and reweighting (Angelaki et al.,
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We thank David S. Zee for critically reading the manuscript and Albert Züger for technical assistance. This work was supported by the Swiss National Science Foundation (3200B0-105434); the Betty and David Koetser Foundation for Brain Research, Zurich, Switzerland; the Boehringer Ingelheim Fonds Foundation; the Human Frontier’s Science Program; the Ataxia–Telangiectasia Society (UK); the Ataxia–Telangiectasia Children’s Project; the Bonizzi-Theler Foundation; and the Center of Integrative Human Physiology, University of Zurich, Switzerland. None of these sponsors was involved in the study design; in the collection, analysis, and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.