Consensus Paper: Neurophysiological Assessments of Ataxias in Daily Practice.

The purpose of this consensus paper is to review electrophysiological abnormalities and to provide a guideline of neurophysiological assessments in cerebellar ataxias. All authors agree that standard electrophysiological methods should be systematically applied in all cases of ataxia to reveal accompanying peripheral neuropathy, the involvement of the dorsal columns, pyramidal tracts and the brainstem. Electroencephalography should also be considered, although findings are frequently non-specific. Electrophysiology helps define the neuronal systems affected by the disease in an individual patient and to understand the phenotypes of the different types of ataxia on a more general level. As yet, there is no established electrophysiological measure which is sensitive and specific of cerebellar dysfunction in ataxias. The authors agree that cerebellar brain inhibition (CBI), which is based on a paired-pulse transcranial magnetic stimulation (TMS) paradigm assessing cerebellar-cortical connectivity, is likely a useful measure of cerebellar function. Although its role in the investigation and diagnoses of different types of ataxias is unclear, it will be of interest to study its utility in this type of conditions. The authors agree that detailed clinical examination reveals core features of ataxia (i.e., dysarthria, truncal, gait and limb ataxia, oculomotor dysfunction) and is sufficient for formulating a differential diagnosis. Clinical assessment of oculomotor function, especially saccades and the vestibulo-ocular reflex (VOR) which are most easily examined both at the bedside and with quantitative testing techniques, is of particular help for differential diagnosis in many cases. Pure clinical measures, however, are not sensitive enough to reveal minute fluctuations or early treatment response as most relevant for pre-clinical stages of disease which might be amenable to study in future intervention trials. The authors agree that quantitative measures of ataxia are desirable as biomarkers. Methods are discussed that allow quantification of ataxia in laboratory as well as in clinical and real-life settings, for instance at the patients' home. Future studies are needed to demonstrate their usefulness as biomarkers in pharmaceutical or rehabilitation trials.

Ocular stability and set-point adaptation.

A fundamental challenge to the brain is how to prevent intrusive movements when quiet is needed. Unwanted limb movements such as tremor impair fine motor control and unwanted eye drifts such as nystagmus impair vision. A stable platform is also necessary to launch accurate movements. Accordingly, nature has designed control systems with agonist (excitation) and antagonist (inhibition) muscle pairs functioning in push-pull, around a steady level of balanced tonic activity, the set-point Sensory information can be organized similarly, as in the vestibulo-ocular reflex, which generates eye movements that compensate for head movements. The semicircular canals, working in coplanar pairs, one in each labyrinth, are reciprocally excited and inhibited as they transduce head rotations. The relative change in activity is relayed to the vestibular nuclei, which operate around a set-point of stable balanced activity. When a pathological imbalance occurs, producing unwanted nystagmus without head movement, an adaptive mechanism restores the proper set-point and eliminates the nystagmus. Here we used 90 min of continuous 7 T magnetic field labyrinthine stimulation (MVS) in normal humans to produce sustained nystagmus simulating vestibular imbalance. We identified multiple time-scale processes towards a new zero set-point showing that MVS is an excellent paradigm to investigate the neurobiology of set-point adaptation.This article is part of the themed issue 'Movement suppression: brain mechanisms for stopping and stillness'.

Eye movements in vestibular disorders.

The differential diagnosis of patients with vestibular symptoms usually begins with the question: is the lesion central or is it peripheral? The answer commonly emerges from a careful examination of eye movements, especially when the lesion is located in otherwise clinically silent areas of the brain such as the vestibular portions of the cerebellum (flocculus, paraflocculus which is called the tonsils in humans, nodulus, and uvula) and the vestibular nuclei as well as immediately adjacent areas (the perihypoglossal nuclei and the paramedian nuclei and tracts). The neural circuitry that controls vestibular eye movements is intertwined with a larger network within the brainstem and cerebellum that also controls other types of conjugate eye movements. These include saccades and pursuit as well as the mechanisms that enable steady fixation, both straight ahead and in eccentric gaze positions. Navigating through this complex network requires a thorough knowledge about all classes of eye movements to help localize lesions causing a vestibular disorder. Here we review the different classes of eye movements and how to examine them, and then describe common ocular motor findings associated with central vestibular lesions from both a topographic and functional perspective.

The cerebellum in eye movement control: nystagmus, coordinate frames and disconjugacy.

In this review we discuss several aspects of eye movement control in which the cerebellum is thought to have a key role, but have been relatively ignored. We will focus on the mechanisms underlying certain forms of cerebellar nystagmus, as well as the contributions of the cerebellum to binocular alignment in healthy and diseased states. A contemporary review of our understanding provides a basis for directions of further inquiry to address some of the uncertainties regarding the contributions of the cerebellum to ocular motor control.

Continuous theta-burst stimulation of the right superior temporal gyrus impairs self-motion perception.

Sensory input from the semicircular canals (SCC) and otolith organs is centrally combined with signals from other sensory modalities to continuously update the internal estimate of self-motion. Constant velocity vertical on-axis rotation leads to decay of the nystagmus response from the horizontal SCC and of perceived angular velocity (PAV), and when the rotation stops, a similar oppositely directed post-rotatory response occurs. Case reports and electrical stimulation studies suggest an involvement of the temporo-peri-Sylvian vestibular cortex in generating the PAV. Here, we transiently inhibited the right superior temporal gyrus (STG) by use of continuous theta-burst stimulation (cTBS) and predicted an accelerated decay of PAV compared to controls (n = 5 control session first, n = 1 cTBS session first). Constant velocity (100°/s) vertical on-axis rotations were applied over 75 s before (1 block) and after (3 blocks) cTBS over the right STG in six subjects. Breaks between the rotations (75 s) were initiated by abrupt stops. By use of a rotating potentiometer, subjects indicated the PAV during and after the chair rotations. Simultaneously eye positions were recorded using a scleral search coil. One subject was excluded for per-rotary analysis. Early after cTBS, the post-rotary PAV decay time constant (DTC) was significantly (9.4 ± 5.7 vs. 13.6 ± 5.9 s; p = 0.049) reduced (no directionality to this effect observed). Overall, post-rotary PAV showed a trend toward shortened DTC compared to the control trials (p = 0.086) in the first 25 min after cTBS, while per-rotary PAV was not significantly changed. Per-rotary and post-rotary aVOR DTC were not significantly changed after cTBS (p > 0.05). These findings support the hypothesis that the right STG is involved in mediating self-motion perception and can be modulated by cTBS.

How stable is perceived direction of gravity over extended periods in darkness?

Previous studies reported linear drift of perceived vertical for brief (≤10 min) observation periods. Here, we repeated estimates of direction of gravity up to 60 min to evaluate whether the drift is sustained, shows saturation or even reverses over time. Fifteen healthy human subjects repetitively adjusted a luminous line along subjective visual vertical (SVV) and horizontal (SVH) over periods of 5 min (constituting one block). We obtained seven blocks within 60 min in each subject for SVV and SVH. In between the first six blocks, subjects remained in darkness for 5 min each, whereas the lights were briefly turned on before block 7. We noted significantly (p < 0.05) increased errors in perceived direction of gravity by block 2 (SVV) and 3 (SVH). These increases disappeared after turning on the lights before block 7. Focusing on blocks 2-6, significant drift started from similar offset positions and pointed to the same direction in a majority of runs in 9/15 (SVV) and 11/15 (SVH) subjects. When pooling data from all blocks, orthogonality of errors was lost in all subjects. Trial-to-trial variability remained stable over the seven runs for SVV and SVH. Only when pooling all runs, precision was significantly (p < 0.05) higher for the SVH. Our findings suggest that perceived direction of gravity continues to fluctuate over extended recording periods with individuals showing unique patterns of direction-specific drift while variability remains stable. As subjects were upright during the entire experiment and as drift persisted over several blocks, sensory adaptation seems unlikely. We therefore favor a central origin of this kind of drift.

The bedside examination of the vestibulo-ocular reflex (VOR): an update.

Diagnosing dizzy patients remains a daunting challenge to the clinician in spite of modern imaging and increasingly sophisticated electrophysiological testing. Here we review the major bedside tests of the vestibulo-ocular reflex and how, when combined with a proper examination of the other eye movement systems, one can arrive at an accurate vestibular diagnosis.

Temporal constancy of perceived direction of gravity assessed by visual line adjustments.

Here we investigated how well internal estimates of direction of gravity are preserved over time and if the subjective visual vertical (SVV) and horizontal (SVH) can be used inter-changeably. Fourteen human subjects repetitively aligned a luminous line to SVV, SVH or subjective visual oblique (± 45°) over 5 min in otherwise complete darkness and also in dim light. Both accuracy (i.e., the degree of veracity as reflected by the median adjustment error) and precision (i.e., the degree of reproducability as reflected by the trial-to-trial variability) of adjustments along the principle axes were significantly higher than along the oblique axes. Orthogonality was only preserved in a minority of subjects. Adjustments were significantly different between SVV vs. SVH (7/14 subjects) and between ±45° vs. -45° (12/14) in darkness and in 6/14 and 14/14 subjects, respectively, in dim light. In darkness, significant drifts over 5min were observed in a majority of trials (33/56). Both accuracy and precision were higher if more time was taken to make the adjustment. These results introduce important caveats when interpreting studies related to graviception. The test re-test reliability of SVV and SVH can be influenced by drift of the internal estimate of gravity. Based on spectral density analysis we found a noise pattern consistent with 1/fß noise, indicating that at least part of the trial-to-trial dynamics observed in our experiments is due to the dependence of the serial adjustments over time. Furthermore, using results from the SVV and SVH inter-changeably may be misleading as many subjects do not show orthogonality. The poor fidelity of perceived ± 45° indicates that the brain has limited ability to estimate oblique angles.

Penlight-cover test: a new bedside method to unmask nystagmus.

BACKGROUND: Most patients with acute vestibular syndrome have vestibular neuritis or labyrinthitis. Some harbour strokes that can only be differentiated on the basis of subtle eye movement findings, including nystagmus. Peripheral nystagmus should be enhanced by removal of visual fixation. Current bedside methods for removing fixation require expensive equipment or technical skill not routinely available. We sought to test a new method for blocking fixation. METHODS: Proof-of-concept study for a new bedside oculomotor diagnostic test using an established physiological measurement of eye movements (electro-oculography (EOG)) as the reference standard. We sampled unselected patients undergoing caloric testing (surrogate model for neuritis) in an academic vestibular clinic. During the brief (30-60 s) decay phase of caloric-induced peripheral vestibular nystagmus, we shone a penlight in the left eye while intermittently occluding the right. We assessed nystagmus intensity (slow-phase velocity) clinically in all subjects and quantified change in two exemplar cases. RESULTS: Caloric responses frequently decayed before the test was complete, and artefacts rendered many EOGs uninterpretable during the short decay period. A clinically evident increase in nystagmus was seen 18 times in 10 patients and corroborated by EOG in 15. In quantified cases, slow-phase velocity increased as expected (mean change +42%) with fixation blocked. CONCLUSION: The penlight-cover test could offer a low-cost, simple means of disrupting visual fixation in clinical settings where differentiating peripheral from central vestibular disorders is crucial, such as the emergency department. Prospective studies are needed to determine the test's utility for excluding dangerous central causes among patients with suspected peripheral lesions.

Gaze fixation deficits and their implication in ataxia-telangiectasia.

BACKGROUND AND AIMS: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterised by progressive neurological deficits, including prominent ocular motor dysfunction. Unstable fixation often leads to difficulty reading and blurred vision. Here we characterise the disturbance of visual fixation in A-T. METHODS: Eye movements were recorded from 13 A-T patients (with dual search coils in five patients and video oculography in seven) during attempted fixation. RESULTS: Two abnormalities--nystagmus and saccadic intrusions--were common. Horizontal, vertical and torsional nystagmus was present in straight ahead (spontaneous nystagmus) and eccentric gaze (gaze evoked nystagmus). In eight patients the horizontal nystagmus changed directions--periodic alternating nystagmus (PAN). Two types of saccadic intrusions were seen--micro-saccadic oscillations (SO) and square wave saccadic intrusions (SWSI). SO were small amplitude (0.1-0.9 degrees) and high frequency (14-33 Hz) back to back horizontal saccades. SWSI ranged between 1 degree and 18 degrees (median 3 degrees) with an intersaccadic interval ranging between 50 and 800 ms (median 300 ms). The potential impact of abnormal gaze stabilisation on vision was quantified. DISCUSSION: Degeneration of cerebellar Purkinje neurons disinhibit the caudal fastigial oculomotor region (FOR) and vestibular nuclei (VN). Disinhibition of VN can cause nystagmus, including PAN, while disinhibition of FOR can affect saccade generating mechanisms, leading to SWSI and SO.

Applying saccade models to account for oscillations.

Saccadic oscillations are unwanted back-to-back saccades occurring one upon the other that produce a high-frequency oscillation of the eyes (usually 15-30 Hz). These may occur transiently in normal subjects, for example, around the orthogonal axis of a purely horizontal or vertical saccade, during combined saccade-vergence gaze shifts or during blinks. Some subjects may produce saccadic oscillations at will, usually with convergence. Pathological, involuntary saccadic oscillations such as flutter and opsoclonus are prominent in certain diseases. Our recent mathematical model of the premotor circuit for generating saccades includes brainstem burst neurons in the paramedian pontine reticular formation (PPRF), which show the physiological phenomenon of post-inhibitory rebound (PIR). This model makes saccadic oscillations because of the positive feedback among excitatory and inhibitory burst neurons. Here we review our recent findings and hypotheses and show how they may be reproduced using our lumped model of the saccadic premotor circuitry by reducing the inhibitory efficacy of omnipause neurons.

Do humans show velocity-storage in the vertical rVOR?

To investigate the contribution of the vestibular velocity-storage mechanism (VSM) to the vertical rotational vestibulo-ocular reflex (rVOR) we recorded eye movements evoked by off-vertical axis rotation (OVAR) using whole-body constant-velocity pitch rotations about an earth-horizontal, interaural axis in four healthy human subjects. Subjects were tumbled forward, and backward, at 60 deg/s for over 1 min using a 3D turntable. Slow-phase velocity (SPV) responses were similar to the horizontal responses elicited by OVAR along the body longitudinal axis, ('barbecue' rotation), with exponentially decaying amplitudes and a residual, otolith-driven sinusoidal response with a bias. The time constants of the vertical SPV ranged from 6 to 9 s. These values are closer to those that reflect the dynamic properties of vestibular afferents than the typical 20 s produced by the VSM in the horizontal plane, confirming the relatively smaller contribution of the VSM to these vertical responses. Our preliminary results also agree with the idea that the VSM velocity response aligns with the direction of gravity. The horizontal and torsional eye velocity traces were also sinusoidally modulated by the change in gravity, but showed no exponential decay.

Perception of self motion during and after passive rotation of the body around an earth-vertical axis.

We investigated the perception of self-rotation using constant-velocity chair rotations. Subjects signalled self motion during three independent tasks (1) by pushing a button when rotation was first sensed, when velocity reached a peak, when velocity began to decrease, and when velocity reached zero, (2) by rotating a disc to match the perceived motion of the body, or (3) by changing the static position of the dial such that a bigger change in its position correlated with a larger perceived velocity. All three tasks gave a consistent quantitative measure of perceived angular velocity. We found a delay in the time at which peak velocity of self-rotation was perceived (2-5 s) relative to the beginning or to the end of chair rotation. In addition the decay of the perception of self-rotation was preceded by a sensed constant-velocity interval or plateau (9-14 s). This delay in the rise of self-motion perception, and the plateau for the maximum perceived velocity, contrasts with the rapid rise and the immediate decay of the angular vestibuloocular reflex (aVOR). This difference suggests that the sensory signal from the semicircular canals undergoes additional neural processing, beyond the contribution of the velocity-storage mechanism of the aVOR, to compute the percept of self-motion.

Cyclovergence evoked by up-down acceleration along longitudinal axis in humans.

We present results of a study of torsional eye movements evoked by earth-vertical accelerations along the subject's longitudinal axis. The earth-vertical stimulus leads to a gravito-inertial acceleration vector that changes magnitude but not direction. It can therefore be viewed as a dynamic change of the gravity level. Up-down oscillations induced relatively symmetric cyclovergence (0.6-2.2 degrees peak-to-peak). Eyes intorted/extorted for higher/lower effective gravity. The phase of this modulation was small relative to chair acceleration. We contrast this behaviour to the dynamics of cycloversion in response to interaural acceleration, which shows a considerably larger phase lag. This strikingly different dynamics suggest a different processing of otolith signals during interaural and longitudinal stimulation.

Estimating the time constant of pitch rVOR by separation of otoliths and semicircular canals contributions.

The rotational vestibulo-ocular reflex (rVOR) contributes to gaze stabilitization by compensating head rotational movements sensed by the semicircular canals (SCC). The CNS improves the performance of the horizontal rVOR through the so called velocity storage mechanism (VSM). However the properties of the VSM in response to pitch rotations are less well known. We recorded eye movements evoked by whole-body constant-velocity pitch rotations about an earth-horizontal, interaural axis in four healthy human subjects. Subjects were tumbled forward, and backward, at 60 deg/s for over one minute using a 3D turntable. In these conditions also the otoliths contribute to the perception of head rotation because they sense the changes in direction of the gravity vector. The vertical slow phase velocity (SPV) responses show the typical exponential decay of the rVOR and a residual, otolith-driven sinusoidal modulation with a bias. Here the estimates of the contributions coming from the otoliths and from the canals are based on a linear summation hypothesis. The time constants of the canal-driven vertical component of the SPV ranged from 6 to 9 seconds. These values are closer to those produced by the SCC alone than the typical 20 s produced by the VSM in the horizontal plane, confirming the relatively small contribution of the VSM to these vertical responses. We also show that the estimation method, while it may be not physiologically accurate, is easy to implement and leads to reliable results.

Irregularity distinguishes limb tremor in cervical dystonia from essential tremor.

INTRODUCTION: Patients with cervical dystonia (CD) often have limb tremor that is clinically indistinguishable from essential tremor (ET). Whether a common central mechanism underlies the tremor in these conditions is unknown. We addressed this issue by quantifying limb tremor in 19 patients with CD and 35 patients with ET. METHOD: Postural, resting and kinetic tremors were quantified (amplitude, mean frequency and regularity) using a three-axis accelerometer. RESULTS: The amplitude of limb tremor in ET was significantly higher than in CD, but the mean frequency was not significantly different between the groups. The cycle-to-cycle variability of the frequency (ie the tremor irregularity), however, was significantly greater (approximately 50%) in CD. Analysis of covariance excluded the possibility that the increased irregularity was related to the smaller amplitude of tremor in CD (ANCOVA: p = 0.007, F = 5.31). DISCUSSION: We propose that tremor in CD arises from oscillators with different dynamic characteristics, producing a more irregular output, whereas the tremor in ET arises from oscillators with similar dynamic characteristics, producing a more regular output. We suggest that variability of tremor is an important parameter for distinguishing tremor mechanisms. It is possible that changes in membrane kinetics based on the pattern of ion channel expression underlie the differences in tremor in some diseases.

Pursuit responses to target steps during ongoing tracking.

Brief smooth eye-velocity responses to target position steps have been reported during smooth pursuit. We investigated position-error responses in eight healthy human subjects, comparing the effects of a step-ramp change in target position when imposed on steady-state smooth pursuit, vestibuloocular reflex (VOR) slow phases, or fixation. During steady-state pursuit or VOR, the target performed a step-ramp movement in the same or in the opposite direction relative to ongoing eye movements. When the step was directed backward relative to steady-state smooth pursuit, eye velocity transiently decreased (1.3 +/- 0.4 degrees /s; average peak change in amplitude +/- SD), beginning about 100 ms after the step. The amplitude of position-error responses varied inversely with the step size. In contrast, there was little or no response in trials with forward steps during steady-state smooth pursuit, when step-ramps were imposed on VOR or when smooth pursuit began from fixation. We hypothesize that during ongoing smooth tracking when a sudden shift in target position is detected the pursuit system compares the direction of ongoing eye velocity with the relative positional error on the retina. In the case of different relative directions between ongoing tracking and a new target eccentricity, a position-error response toward the new target is initiated. Such a mechanism might help the smooth pursuit system to respond better to changes in target direction. These experimental findings were simulated by a mathematical model of smooth pursuit by implementing direction-dependent behavior with a position-error gating mechanism.