Disturbed vestibular-neck interaction in cerebellar disease.

Cerebellar dysfunction results in ataxia including postural deficits. Evidence from animal experiments suggests convergence of vestibular and neck-position related inputs in cerebellar midline structures. We investigated 20 ambulatory patients with cerebellar disease for disturbed postural control using posturography during static lateral head turns. Binaural bipolar sine-wave galvanic vestibular stimulation (GVS) was used to evoke specific body movements. The Klockgether clinical score was used to assess the severity of cerebellar dysfunction (4-17 of maximal 35 points). In 12 healthy controls and seven lightly affected patients (score <8), GVS elicited physiologic alternating body sway in the head-frontal plane in seven head-on-trunk positions (0°; 30°, 45° and 60° left and right). Body sway turning with head excursion was progressively attenuated or abolished in more severely affected patients (scores 9-17; r = 0.57, p = 0.008). With most severe impairment, body sway was always in the body-frontal plane irrespective of head turn. A simple clinical test with walking under maximal head turn and closed eyes correlated with posturography data (r = 0.87, p < 0.001) and with Klockgether scores (r = 0.71, p < 0.001). Thus in cerebellar disease, head on trunk position can have a pronounced effect on postural control.

MSTd neurons during ocular following and smooth pursuit perturbation.

MSTd neurons in the behaving monkey were investigated during step-ramp smooth pursuit eye movements (SPEM), short perturbations of the small visual target during ongoing pursuit, and large-field visual stimulation inducing ocular following responses (OFR). Neurons responded with short latencies to visual motion during OFR. In contrast the non-retinal responses during SPEM and perturbations followed the eye movements by 100-150 ms and were in the opposite direction to the OFR response. Often neurons were not modulated by the perturbation. Although, both the OFR and the perturbation response are involuntary eye movements due to visual motion, it seems very unlikely that these MSTd neurons with non-retinal responses are involved in their direct control. Based on these responses, we suggest that our MSTd neurons may code for gaze direction in space based on visual estimates of self-motion and extraretinal estimates of eye-in-head motion.

Eye and head torsion is affected in patients with midbrain lesions.

The midbrain has been shown to contain crucial nuclei for the control of vertical and torsional eye movements. Recent studies in monkeys demonstrated that midbrain lesions also affect head movements during gaze saccades, but so far clinical reports on the matter have been missing. We measured 3D eye and head movements in two patients with oculomotor deficits due to unilateral midbrain lesions and in healthy control subjects. Subjects had (1) to perform head-free target directed gaze saccades (head-free task), and (2) to point to the target with a head-laser (head-only task). The patients had vertical eye movement deficits, which were not compensated by the head. Three-dimensional analysis revealed torsional deviations from the normal range of movements for both, the eye and the head movements.

Nanoplough-constrictions on thin YBCO films made with atomic force microscopy.

Utilizing atomic force microscope (AFM) with a diamond tip, we were able to successfully plough nano-constrictions on epitaxially grown YBa2Cu3O(7-x) thin films deposited on MgO substrates. The thickness, width, and length of the obtained constrictions were in the range of a few 100 nm. Furthermore, we managed to produce a new S-type constriction, of which the dimensions are easier to control than for conventional constrictions.

Present concepts of oculomotor organization.

This chapter gives an introduction to the oculomotor system, thus providing a framework for the subsequent chapters. This chapter describes the characteristics, and outlines the structures involved, of the five basic types of eye movements, for gaze holding ("neural integrator") and eye movements in three dimensions (Listing's law, pulleys).

Saccades to moving targets.

The metrics and dynamics of saccades to stationary and moving targets were observed in monkeys (Macaca mulatta). To isolate the effects of target speed on the saccade from contributions of smooth pursuit, saccade velocity was corrected for intrasaccadic pursuit velocity on a trial-by-trial basis prior to analysis. The effects of presaccadic retinal error and target speed on the saccadic velocity profile were determined by analyzing the partial correlations computed as a function of time after saccade onset. The main results are: (1) Saccade amplitude is determined not only by the retinal error sampled before the saccade, but also by the speed of the target during the latency period. (2) The dynamics of saccades, even if compensated for smooth-pursuit components, differ between forward- and backward-moving targets. (3) Whereas the presaccadic retinal error affects the eye velocity throughout the saccade, target speed has no effect before peak velocity. These results are discussed in the context of current models of saccade generation and their physiological substrates, in particular the role of the cerebellum in the local feedback loop.

4-aminopyridine restores visual ocular motor function in upbeat nystagmus.

The effect of the potassium channel blocker 4-aminopyridine (4-AP) on spontaneous upbeat nystagmus (UBN) was investigated with the search coil technique during fixation in different gaze positions and smooth pursuit in a patient before and after ingestion of 10 mg 4-AP. UBN was reduced from 8.6 deg/s to 2.0 deg/s by 4-AP causing subjective relief from distressing oscillopsia, and impaired upward smooth pursuit was restored (gains: before medication 0.38; after medication 0.86). In the dark, UBN was slightly stronger and not affected by 4-AP. We propose that 4-AP improved the function of cerebellar pathways that mediate gaze holding and smooth pursuit by intensifying the excitability of cerebellar Purkinje cells.

Trunk position influences vestibular responses of fastigial nucleus neurons in the alert monkey.

Vestibulospinal reflexes play an important role for body stabilization during locomotion and for postural control. For an appropriate distribution of vestibular signals to spinal motoneurons, the orientation of the body relative to the head needs to be taken into account. For different trunk positions, identical vestibular stimuli must activate different sets of muscles to ensure body stabilization. Because the cerebellar vermis and the underlying fastigial nucleus (FN) might be involved in this task, vestibular neurons in the rostral FN of alert rhesus monkeys were recorded during sinusoidal vestibular stimulation (0.1-1.0 Hz) in the roll and pitch planes at different trunk-re-head positions (center and +/-45 degrees ). From the sensitivity and phase values measured in these planes, the response properties in the intermediate planes and the stimulus orientation eliciting the optimal response [response vector orientation (RVO)] were calculated. In most neurons, the RVOs rotated systematically with respect to the head, when trunk-re-head position was altered, so that they tended to maintain their orientation with respect to the trunk. Sensitivity and phase at the RVO were not affected. This pattern was the same for neurons in the right and left FN and independent of stimulus frequency. The average sensitivity of this partially compensatory RVO shift in response to trunk-re-head displacements, evaluated by linear regression analyses, was 0.59 degrees / degrees (n = 73 neurons). These data show that FN neurons may encode vestibular information in a coordinate system that is closer to a trunk-centered than to a head-centered reference frame. They indicate an important role of this nucleus in motor programs related to posture and gait control.

Multimodal signal integration in vestibular neurons of the primate fastigial nucleus.

The rostral fastigial nucleus contains vestibular neurons, which presumably are involved in spinal mechanisms (neck, gait, posture) and which are not modulated with individual eye movements. Single-unit recordings in the alert behaving monkey during natural stimulus conditions reveal that virtually all neurons demonstrate integration of several sensory inputs. This applies not only for canal-canal and canal-otolith interaction, but also for otolith-otolith interaction. There is also some evidence that most neurons receive not only an utriculus but also a sacculus input. Furthermore, most neurons also respond to large-field optokinetic stimulation, reflecting visual-vestibular interaction. Neurons are also affected by the head on trunk position, which would allow these neurons to operate in a body-centered rather than a head-centered reference frame. These complex, multisensory features could permit fastigial nucleus neurons to rather specifically affect spinal motor functions.

Discharge properties of saccade-related neurons in the primate fastigial oculomotor region.

To clarify the mechanisms by which the cerebellar fastigial oculomotor region (FOR) contributes to the control of saccadic eye movements, we recorded saccade-related FOR units in alert monkeys that made horizontal saccades between neighboring points of a three-by-three grid of target positions (16 degrees amplitude). As in previous studies, FOR units exhibited saccade-related bursts that occurred earlier for contralateral than for ipsilateral saccades. In addition, many FOR units reflected variations in the kinematic profiles of the saccades by exhibiting bursts with earlier onset and shorter peak latencies and higher peak discharge rates for fast as compared with slow saccades of the same amplitude. Moreover, reflecting systematic differences in saccade velocity rather than an influence of eye position itself, FOR bursts showed subtle but recurrent and, at the population level, statistically significant differences between centripetal and centrifugal saccades that closely paralleled the eye position dependency of saccadic dysmetria seen after FOR lesions. We conclude that the FOR output signal is not, as previously proposed, specifically related to the temporal properties of the saccade, but also contains information about saccade velocity. Moreover, the FOR output signal appears to change systematically depending on the actual kinematic properties of the saccade, in a way that would help to maintain saccadic accuracy.

Treatment of downbeat nystagmus with 3,4-diaminopyridine: a placebo-controlled study.

BACKGROUND: Several drugs that primarily act on gamma-aminobutyrate or muscarinic receptors have been used to treat downbeat nystagmus (DBN) syndrome despite their having only moderate success and causing several side effects that limit their effectiveness. These drugs were tested under the assumption that DBN was caused by a disinhibition of a physiologic inhibitory cerebellar input on vestibular nuclei. OBJECTIVE: To evaluate the effects of a single dose of the potassium channel blocker 3,4-diaminopyridine (3,4-DAP), which is known to increase the excitability of Purkinje cells, on DBN in a prospective, placebo-controlled, double-blind study with a crossover design. METHODS: Seventeen patients with DBN due to cerebellar atrophy (5), infarction (3), Arnold-Chiari malformation (1), or unknown etiology (8) were included in the study (1 of 18 patients had to be excluded). Mean peak slow-phase velocity (PSPV) was measured before and 30 minutes after randomized ingestion of 20 mg of 3,4-DAP or placebo orally; at least 1 week later, the treatments were switched. RESULTS: 3,4-DAP reduced mean PSPV of DBN from 7.2 +/- 4.2 degrees /s (mean +/- SD) before treatment to 3.1 +/- 2.5 degrees/s 30 minutes after ingestion of the 3,4-DAP (p < 0.001, two-way analysis of variance). Placebo had no measurable effect. In 10 of 17 subjects, the mean PSPV decreased by >50% and in 12 of 17 by >40%. In parallel, the subjects had less oscillopsia and felt more stable while standing and walking. Nine of the subjects continued to take the drug with success. Except for transient minor perioral or digital paresthesia reported by three subjects and nausea and headache reported by one, no other side effects were observed. CONCLUSIONS: In this study, the authors demonstrated that a single dose of 3,4-DAP significantly improved DBN. In view of animal studies reporting that micromolar concentrations of 4-aminopyridine increased the excitability of Purkinje cells, it is suggested that the efficacy of 3,4-DAP may be due to an increase of the physiologic inhibitory influence of the vestibulocerebellum on the vestibular nuclei.

Saccade-related neurons in the primate fastigial nucleus: what do they encode?

The cerebellar fastigial oculomotor region (FOR) and the overlying oculomotor vermis (OV) are involved in the control of saccadic eye movements, but nature and function of their saccade-related neuronal signals are not fully understood. There is controversy in at least two major aspects: first, lesion studies in OV/FOR reported eye-position-dependent dysmetria-with FOR lesions, centripetal saccades became more hypermetric than centrifugal saccades-suggesting that the cerebellum may compensate for orbital mechanics. However, single-unit studies failed to reveal corresponding eye-position dependencies in FOR saccade-related discharge patterns. Second, some single-unit studies reported precise correlation between burst and saccade duration in the FOR. However, others stated that FOR bursts were only weakly related to saccade properties. In an attempt to resolve these discrepancies, we recorded single FOR units in monkeys that made horizontal saccades (16 degrees ) from different starting positions. Sampling saccades of one fixed amplitude and application of an objective, computer-based burst-detection-routine allowed us to correlate burst parameters (onset latency, peak latency, peak amplitude, number of spikes, duration) and kinematic properties of individual saccades. FOR bursts were found to start and peak earlier and exhibit higher peak burst amplitudes for faster than for slower saccades of the same amplitude. While these correlations between FOR bursts and saccade properties were statistically significant for a minority of approximately 20-25% of individual units, the same effects were also predominant in the remainder of the neuronal sample and statistically significant on the population level. Neuronal activity was not significantly modulated by eye position itself. However, reflecting differences in saccade velocities but not an actual influence of eye position per se, FOR bursts for centripetal and centrifugal saccades exhibited subtle but systematic differences, which closely paralleled, and hence probably explain, the eye-position dependency of deficits observed after FOR inactivation. Our findings indicate that FOR signals reflect much of the kinematic properties of the saccade. Moreover, they are consistent with the idea that the FOR output is purposefully modified according to these kinematic properties to maintain saccadic accuracy.

Three-dimensional eye position and slow phase velocity in humans with downbeat nystagmus.

Downbeat nystagmus (DN), a fixation nystagmus with the fast phases directed downward, is usually caused by cerebellar lesions, but the precise etiology is not known. A disorder of the smooth-pursuit system or of central vestibular pathways has been proposed. However, both hypotheses fail to explain why DN is usually accompanied by gaze-holding nystagmus, which implies a leaky neural velocity-to-position integrator. Because three-dimensional (3-D) analysis of nystagmus slow phases provides an excellent means for testing both hypotheses, we examined 19 patients with DN during a fixation task and compared them with healthy subjects. We show that the presentation of DN patients is not uniform; they can be grouped according to their deficits: DN with vertical integrator leakage, DN with vertical and horizontal integrator leakage, and DN without integrator leakage. The 3-D analysis of the slow phases of DN patients revealed that DN is most likely neither caused by damage to central vestibular pathways carrying semicircular canal information nor by a smooth pursuit imbalance. We propose that the observed effects can be explained by partial damage of a brain stem-cerebellar loop that augments the time constant of the neural velocity to position integrators in the brain stem and neurally adjusts the orientation of Listing's plane.

Localizing value of torsional nystagmus in small midbrain lesions.

BACKGROUND: The topodiagnostic value and specificity of nystagmus in patients with mesencephalic lesions and its relation to tonic torsional deficits and vertical saccade deficits is controversial and anecdotal. METHODS: The authors examined 11 patients with vascular MRI-identified mesencephalic lesions and clinical evidence of vertical-torsional nystagmus on gaze straight ahead, focusing on the three-dimensional nystagmus components recorded with the three-dimensional search coil technique. RESULTS: Combined lesions of the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) and the interstitial nucleus of Cajal (iC) are much more frequent than riMLF and, in particular, iC lesions alone. Eight patients showed contralesional torsional nystagmus with a conjugate vertical component on gaze straight ahead and had anatomic (MRI) and clinical evidence (slowing of vertical saccades) for riMLF involvement. Tonic ocular torsion and the subjective visual vertical were shifted to the contralesional side (n = 7). Torsional nystagmus to the ipsilesional side was uncommon (n = 3) and found in patients with midbrain lesions involving the iC, all of whom also had decreased time constants of the slow phases of gaze-evoked nystagmus. CONCLUSIONS: Contrary to previous proposals, contralesional torsional nystagmus was the most frequent direction and is probably not compensatory for contralesional tonic ocular torsion. Small amplitude vertical saccades with normal velocities in association with ipsilesional torsional nystagmus may indicate isolated iC lesions. Torsional nystagmus following mesencephalic lesions may last for years and may help to distinguish rostral (riMLF) from caudal (iC) midbrain lesions.

Non-linear interaction of angular and translational vestibulo-ocular reflex during eccentric rotation in the monkey.

Eccentric sinusoidal rotation with the nose facing out or in leads to gain modulation of the vestibulo-ocular reflex (VOR), which is a result of an interaction between angular and translational VOR. There are conflicting reports with regard to the type of interaction. Combined angular and translational VOR during eccentric sinusoidal rotations over a wide range of target distances (12-180 cm), eccentricities (centric, 30 and 50 cm nose-out and nose-in eccentric) and frequencies (0.1-4 Hz) were studied in macaque monkeys trained to fixate earth-stationary light-emitting diode (LED) targets while binocular eye positions were measured using magnetic search coils. The monkeys were also exposed to sudden unpredictable position steps with peak accelerations of 500 degrees/s(2) using similar eccentricities and target distances. VOR gain enhancement during nose-out eccentric sinusoidal rotation was almost compensatory when the target was visible and was independent of stimulus frequency. Mean responses were still close to ideal when the target was extinguished; however, individual data showed increased variability. Sensitivities of the translational portion of the combined VOR were compensatory. These sensitivities were clearly reduced during nose-in eccentric sinusoidal rotation. Thus, especially for close targets at 4 Hz combined VOR was not compensatory, independent of target visibility. VOR elicited by sudden position steps showed a sequential response: (1) purely angular VOR (up to 40-45 ms); (2) additional translational VOR that was not modulated by target distance (45-65 ms); and (3) translational VOR weighted for target location (>65 ms). We conclude that angular and translational VOR have different latencies during transient accelerations and interact differently during agonistic (nose-out) and antagonistic stimulation (nose-in).

Absence of nystagmus during REM sleep in patients with vestibular neuritis.

Saccades, including fast phases of nystagmus, disappear during drowsiness and non-rapid eye movement (NREM) sleep, but are present during the alert state and REM sleep. The purpose of this study was to determine whether spontaneous nystagmus is present in patients with vestibular neuritis during REM sleep. Eight patients with spontaneous nystagmus due to vestibular neuritis and eight control patients without any nystagmus underwent at least one night of polysomnography. Fast phases of nystagmus were analyzed. The number of right and left horizontal saccades were counted, first during 3-5 minute samples of the awake state before sleep onset, then during the first REM episode and the last REM episode of nocturnal sleep, and finally during the alert state in the morning after nocturnal sleep. All patients with vestibular neuritis showed significantly more saccades (fast phases) towards the side contralateral to their vestibular lesion in the awake state before and after the polysomnography. This reflects their spontaneous nystagmus. By contrast, during REM sleep the patients with vestibular neuritis showed no preponderance in saccade direction. The eye movement pattern in REM was the same for patients and controls. In conclusion, peripheral vestibular imbalance producing nystagmus in vestibular neuritis in the awake state is not active at the brain stem level during REM sleep.

Contraversive eye deviation during deep brain stimulation of the globus pallidus internus.

Clinical signs help determine correct electrode positioning during stereotactic implantation for chronic high-frequency pallidal stimulation in Parkinson's diease (PD). The authors describe a patient who had marked, sustained, contraversive eye deviation caused by stimulation during pallidal surgery. The underlying mechanism is probably an excitation of fibers in the internal capsule by volume-conducted current spread. Such conjugate eye deviation is thus not necessarily an indication of incorrect electrode placement.