John S. Stahl

A comparison of video and magnetic search coil recordings of mouse eye movements.

Interest in connecting molecular biology and behavior is motivating research into the eye movements of mice. Unfortunately, recording eye movements in this diminutive animal is technically difficult. We present the first method for obtaining calibrated video oculography, and contrast the results with simultaneously obtained scleral search coil recordings in C57BL/6 pigmented mice. We determined the distance of the pupil from the center of corneal curvature, based upon relative motions of the pupil and corneal reflections during camera movements, and used the distance to convert subsequent video measurements of pupil motion to eye rotation. We recorded responses during sinusoidal rotation (0.1-1.6 Hz) in the light, by video prior to search coil implantation, and by video and search coil simultaneously following implantation. Pre-implantation, video-derived gains ranged from 0.86+/-0.03 (mean+/-SD) at 0.1 Hz to 0.95+/-0.03 at 0.8 Hz. Phase progressed monotonically from -3.1+/-2. 6 degrees (eye leads head) at 0.1 Hz to +5.9+/-1.1 degrees at 1.6 Hz. Coil implantation reduced the range of video-derived gains to 0. 64-0.79. This reduction reflects disruption of normal behavior by the coil. Coil data confirmed the video results. Video and search coil techniques each have advantages. Specific precautions are required when designing and interpreting experiments using the coil technique.

Amplitude of human head movements associated with horizontal saccades

Abstract Human saccades may or may not be associated with head movements. To date, little attention has been devoted to the mechanisms determining head movement recruitment and scaling. Normal human subjects made horizontal, centrifugal saccades along an encircling array of light-emitting diodes. Measurements of gaze, head, and eye-in-head angle were made at the conclusion of the head movement (or at the end of the eye movement in eye-only saccades). We found that head movement amplitude (ΔH) related in a simple fashion to the eye eccentricity that would have resulted if the gaze shift had been performed without a head movement. Plots of ΔH vs this predicted eye eccentricity (EPRED) had a central flat region in which gaze shifts were unaccompanied by head movements (the eye-only range) and two flanking lobes in which ΔH was a linear function of EPRED (the eye-head ranges). ΔH correlated with EPRED better than with gaze shift amplitude, as would be expected if head movements were controlled so as to keep eye eccentricity within a particular range. Head movement tendencies were quantified by the width of the eye-only range, the slope of the eye-head range, and the width of the region within which the eye was likely to be found at the conclusion of the completed gaze-shifting behavior (the customary ocular motor range). The measures ranged widely in these normal subjects: 35.8±31.9° for the eye-only range (mean±SD), 0.77±0.16 for the slope of the eye-head range, and 44.0±23.8° for the customary ocular motor range. Yet for a given subject, the measurements were reproducible across experimental sessions, with the customary ocular motor range being the most consistent measure of the three. The form of the ΔH vs EPRED plots suggests that the neural circuitry underlying eye-head coordination carries out two distinct functions – gating the head movement and scaling the head movement. The reason for the large intersubject variability of head movement tendencies is unknown. It does not parallel intersubject differences in full-scale eye (in orbit) range or full-scale neck range.

Increased noise level of purkinje cell activities minimizes impact of their modulation during sensorimotor control

While firing rate is well established as a relevant parameter for encoding information exchanged between neurons, the significance of other parameters is more conjectural. Here, we show that regularity of neuronal spike activities affects sensorimotor processing in tottering mutants, which suffer from a mutation in P/Q-type voltage-gated calcium channels. While the modulation amplitude of the simple spike firing rate of their floccular Purkinje cells during optokinetic stimulation is indistinguishable from that of wild-types, the regularity of their firing is markedly disrupted. The gain and phase values of totterings compensatory eye movements are indistinguishable from those of flocculectomized wild-types or from totterings with the flocculus treated with P/Q-type calcium channel blockers. Moreover, normal eye movements can be evoked in tottering when the flocculus is electrically stimulated with regular spike trains mimicking the firing pattern of normal simple spikes. This study demonstrates the importance of regularity of firing in Purkinje cells for neuronal information processing.

The dynamic characteristics of the mouse horizontal vestibulo-ocular and optokinetic response.

In the present study the optokinetic reflex, vestibulo-ocular reflex and their interaction were investigated in the mouse, using a modified subconjunctival search coil technique. Gain of the ocular response to sinusoidal optokinetic stimulation was relatively constant for peak velocities lower than 8 degrees /s, ranging from 0.7 to 0.8. Gain decreased proportionally to velocity for faster stimuli. The vestibulo-ocular reflex acted to produce a sinusoidal compensatory eye movement in response to sinusoidal stimuli. The phase of the eye movement with respect to head movement advanced as stimulus frequency decreased, the familiar signature of the torsion pendulum behavior of the semicircular canals. The first-order time constant of the vestibulo-ocular reflex, as measured from the eye velocity decay after a vestibular velocity step, was 660 ms. The response of the vestibulo-ocular reflex changed with stimulus amplitude, having a higher gain and smaller phase lead when stimulus amplitude was increased. As a result of this nonlinear behavior, reflex gain correlated strongly with stimulus acceleration over the 0.1-1.6 Hz frequency range. When whole body rotation was performed in the light the optokinetic and vestibular system combined to generate nearly constant response gain (approximately 0.8) and phase (approximately 0 degrees ) over the tested frequency range of 0.1-1.6 Hz. We conclude that the compensatory eye movements of the mouse are similar to those found in other afoveate mammals, but there are also significant differences, namely shorter apparent time constants of the angular VOR and stronger nonlinearities.

Using eye movements to assess brain function in mice

Examining eye movements is an important part of the neurological evaluation of humans; the distribution of the neural circuits that control these movements is such that they are disrupted--often in highly characteristic fashions--by many disease processes. Technical advances have made it possible to measure accurately the eye movements of mice, so it is now possible to use the detective power of eye movement recording to characterize neurological dysfunction in genetically altered strains. Here we introduce analytical tools used in ocular motor research and demonstrate their ability to reveal disorders of the visual pathways, inner ear, and cerebellum.

Crossover trial of gabapentin and memantine as treatment for acquired nystagmus

We conducted a masked, crossover, therapeutic trial of gabapentin (1,200mg/day) versus memantine (40mg/day) for acquired nystagmus in 10 patients (aged 28–61 years; 7 female; 3 multiple sclerosis [MS]; 6 post‐stroke; 1 post‐traumatic). Nystagmus was pendular in 6 patients (4 oculopalatal tremor; 2 MS) and jerk upbeat, hemi‐seesaw, torsional, or upbeat‐diagonal in each of the others. For the group, both drugs reduced median eye speed (p < 0.001), gabapentin by 32.8% and memantine by 27.8%, and improved visual acuity (p < 0.05). Each patient improved with 1 or both drugs. Side effects included unsteadiness with gabapentin and lethargy with memantine. Both drugs should be considered as treatment for acquired forms of nystagmus. ANN NEUROL 2010;67:676–680

Simple spike and complex spike activity of floccular Purkinje cells during the optokinetic reflex in mice lacking cerebellar long-term depression

Cerebellar long‐term depression (LTD) at parallel fibre–Purkinje cell (P‐cell) synapses is thought to embody neuronal information storage for motor learning. Transgenic L7‐protein kinase C inhibitor (PKCI) mice in which cerebellar LTD is selectively blocked do indeed exhibit impaired adaptation in the vestibulo‐ocular reflex (VOR) while their default oculomotor performance is unaffected. Although supportive, these data do not definitively establish a causal link between memory storage required for motor learning and cerebellar LTD. As the L7‐PKCI transgene is probably activated from the early stages of P‐cell development, an alternative could be that P‐cells develop abnormal signals in L7‐PKCI mutants, disturbing mechanisms of motor learning that rely on proper P‐cell outputs. To test this alternative hypothesis, we studied simple spike (SS) and complex spike (CS) activity of vertical axis P‐cells in the flocculus of L7‐PKCI mice and their wild‐type littermates during sinusoidal optokinetic stimulation. Both SS and CS discharge dynamics appeared to be very similar in wild‐type and transgenic P‐cells at all stimulus frequencies (0.05–0.8 Hz). The CS activity of all vertical axis cells increased with contralateral stimulus rotation and lagged ipsiversive eye velocity by 165–180°. The SS modulation was roughly reciprocal to the CS modulation and lagged ipsiversive eye velocity by ∼ 15°. The baseline SS and CS discharge characteristics were indistinguishable between the two genotypes. We conclude that the impaired VOR learning in L7‐PKCI mutants does not reflect fundamental aberrations of the cerebellar circuitry. The data thus strengthen the evidence that cerebellar LTD is implicated in rapid VOR learning but not in the development of normal default response patterns.

Square-wave jerks induced by pallidotomy in parkinsonian patients

Article abstract Square-wave jerks (SWJs) are small, inappropriate saccades that intrude on steady fixation by taking the eye away from the target and then returning it after approximately 200 msec. The pathophysiology of SWJs is unknown; they have not been attributed to any specific lesion. We found that unilateral pallidotomy substantially increased the frequency of SWJs in three patients with Parkinson’s disease. This effect is likely due to imbalance in the fixation system caused by asymmetric reactivation of prefrontal cortex via ascending thalamocortical projections. Alternatively, disruption of nigral projections to the superior colliculus might be responsible.

Calcium Channelopathy Mutants and Their Role in Ocular Motor Research

Abstract: Thanks to technical advances in eye movement recording, the mouse is destined to become increasingly important in ocular motor research. An advantage of this species is the wide range of existing mutant strains and techniques to generate new mutations affecting specific cell types. Mutations of ion channels may be used to modulate the intrinsic properties of neurons, and this approach may generate insight into the degree to which neuronal computations depend upon those intrinsic properties as opposed to the properties of circuits of neurons. Dendritic calcium currents carried by P‐type voltage‐activated calcium channels have been widely postulated to perform important computational functions in cerebellar Purkinje cells. Mutations of this channel lead to human diseases, and several ataxic strains of mice are now known to harbor mutations of this calcium channel. Murine P‐channel mutants such as rocker are ataxic, but have normal or near‐normal numbers of cerebellar Purkinje cells and thus offer the opportunity to study the effects of biophysical perturbations as opposed to outright cell destruction or inactivation. Initial studies of rocker mice reveal an array of ocular motor abnormalities, including static hyperdeviation of the eyes and an attenuation of vestibulo‐ocular reflex gains at high stimulus frequencies. The pattern of gain and phase abnormalities is entirely different in lurcher, an ataxic mutant in which Purkinje cells degenerate. The ocular motor abnormalities of rocker progress with animal age, underscoring the importance of careful attention to animal age when performing ocular motor studies in this short‐lived species.

Saccadic and Vestibular Abnormalities in Multiple Sclerosis

Determining the effectiveness of treatments for multiple sclerosis (MS) is complicated because of two factors: (1) the clinical course is unpredictable; and (2) the disease may remain active, as evident on MRI, even though neither the patient nor the physician can detect progression.1 Thus, there is a need to improve clinical methods for evaluating patients with MS that extend the system introduced by Kurtzke 40 years ago.2,3 The goal of our study was to determine whether an examination that specifically tests saccades and vestibular eye movements is more sensitive than conventional clinical examinations in identifying brainstem and cerebellar dysfunction in MS.3,4 We examined 50 patients (8 female) with MS seen consecutively in our VA outpatient Neurology Clinic between August 1999 and April 2000. The study was approved by our Institutional Review Board. Kurtzke Functional Neurological Status (FSS) and Expanded Disability Status Scale (EDSS) scores in each patient were based on agreement between two examiners.2,5 We assessed corrected, near visual acuity (Rosenbaum card, expressed as a decimal); visual fields by confrontation; color vision using Ishihara plates (correct responses expressed as decimal of total); pupillary size and reactions; and the presence of optic disc pallor by direct ophthalmoscopy. The eye movements examination consisted of: (1) observing range of movement and covering each eye in turn to test for static ocular alignment; (2) observation of fixation stability in central gaze, and eccentric horizontal, and eccentric vertical gaze; (3) observation of the speed, accuracy, and conjugacy of horizontal and vertical saccades (rapid eye movements) made between two stationary targets (a pencil tip and the examiner’s nose); (4) observation of horizontal and vertical smooth