Tests of a linear model of visual-vestibular interaction using the technique of parameter estimation.

The goal of this study was to test whether a superposition model of smooth-pursuit and vestibuloocular reflex (VOR) eye movements could account for the stability of gaze that subjects show as they view a stationary target, during head rotations at frequencies that correspond to natural movements. Horizontal smooth-pursuit and the VOR were tested using sinusoidal stimuli with frequencies in the range 1.0-3.5 Hz. During head rotation, subjects viewed a stationary target either directly or through an optical device that required eye movements to be approximately twice the amplitude of head movements in order to maintain foveal vision of the target. The gain of compensatory eye movements during viewing through the optical device was generally greater than during direct viewing or during attempted fixation of the remembered target location in darkness. This suggests that visual factors influence the response, even at high frequencies of head rotation. During viewing through the optical device, the gain of compensatory eye movements declined as a function of the frequency of head rotation (P < 0.001) but, at any particular frequency, there was no correlation with peak head velocity 9P > 0.23), peak head acceleration (P > 0.22) or retinal slip speed (P > 0.22). The optimal values of parameters of smooth-pursuit and VOR components of a simple superposition model were estimated in the frequency domain, using the measured responses during head rotation, as each subject viewed the stationary target through the optical device. We then compared the model's prediction of smooth-pursuit gain and phase, at each frequency, with values obtained experimentally. Each subject's pursuit showed lower gain and greater phase lag than the model predicted. Smooth-pursuit performance did not improve significantly if the moving target was a 10 deg x 10 deg Amsler grid, or if sinusoidal oscillation of the target was superimposed on ramp motion. Further, subjects were still able to modulate the gain of compensatory eye movements during pseudo-random head perturbations, making improved predictor performance during visual-vestibular interactions unlikely. We conclude that the increase in gain of eye movements that compensate for head rotations when subjects view, rather than imagine, a stationary target cannot be adequately explained by superposition of VOR and smooth-pursuit signals. Instead, vision may affect VOR performance by determining the context of the behavior.

Evidence for independent feedback control of horizontal and vertical saccades from Niemann-Pick type C disease.

We measured the eye movements of three sisters with Niemann-Pick type C disease who had a selective defect of vertical saccades, which were slow and hypometric. Horizontal saccades, and horizontal and vertical pursuit and vestibular eye movements were similar to control subjects. The initial movement of oblique saccades was mainly horizontal and most of the vertical component occurred after the horizontal component ended; this resulted in strongly curved trajectories. After completion of the horizontal component of an oblique saccade, the eyes oscillated horizontally at 10-20 Hz until the vertical component ended. These findings are best explained by models that incorporate separate feedback loops for horizontal and vertical burst neurons, and in which the disease selectively affects vertical burst neurons.

Quantitative measurements of eye movements in a patient with Tullio phenomenon.

The Tullio phenomenon consists of vestibular symptoms on exposure to high-intensity acoustic stimuli, reflecting pathological stimulation of semicircular canals or otoliths. We report a patient with posttraumatic Tullio phenomenon to illustrate how precise measurement of eye movements during auditory stimulation, using the magnetic search coil technique, may characterize movements that are not clinically apparent or easily measured by other means. Such measurements in patients with surgically verified lesions may further elucidate the mechanisms responsible for this phenomenon.

Comparison of horizontal, vertical and diagonal smooth pursuit eye movements in normal human subjects.

We compared horizontal and vertical smooth pursuit eye movements in five healthy human subjects. When maintenance of pursuit was tested using predictable waveforms (sinusoidal or triangular target motion), the gain of horizontal pursuit was greater, in all subjects, than that of vertical pursuit; this was also the case for the horizontal and vertical components of diagonal and circular tracking. When initiation of pursuit was tested, four subjects tended to show larger eye accelerations for vertical as opposed to horizontal pursuit; this trend became a consistent finding during diagonal tracking. These findings support the view that different mechanisms govern the onset of smooth pursuit, and its subsequent maintenance when the target moves in a predictable waveform. Since the properties of these two aspects of pursuit differ for horizontal and vertical movements, our findings also point to separate control of horizontal and vertical pursuit.

Dynamic properties of horizontal and vertical eye movements in parkinsonian syndromes.

We studied dynamic properties of horizontal, vertical, and oblique eye movements in 23 patients with the following parkinsonian syndromes: idiopathic parkinsonism (PD), multiple system atrophy (MSA), pure akinesia (PA), progressive supranuclear palsy (PSP), and cortical-basal ganglionic degeneration (CBGD). Compared with age-matched controls, only PSP patients showed slowing of saccades. Patients in all groups showed saccadic hypometria that was most marked vertically. The trajectories of saccades made to diagonal target jumps were deviated toward the horizontal plane, due to the vertical hypometria; this was most marked in PA and PSP groups. Saccade latency was only increased in the CBGD group. Sinusoidal smooth pursuit did not differentiate between controls and patients; however, with step-ramp stimuli, pursuit eye acceleration was impaired in all patient groups compared with controls. The vestibulo-ocular reflex, with or without visual enhancement, was similar in patients and controls. These findings indicate that (1) in parkinsonian syndromes apart from PSP, the saccade-generating brainstem burst neurons are probably spared, but the signals that they receive, specifying the size and direction of saccades, are flawed; and (2) measurements of the gain and trajectory of oblique saccades, and initiation of smooth pursuit, may aid in diagnosing these different types of parkinsonism.

Tracking of illusory target motion: differences between gaze and head responses.

We compared ocular and eye-head tracking responses to an illusion of diagonal motion produced when vertical movement of a small visual target was synchronized to horizontal movement of a background display. In response to sinusoidal movement, smooth ocular pursuit followed vertical target motion, with only a small horizontal component. In response to regular stepping movement, all anticipatory saccades were in the direction of the illusion; these erroneous oblique movements were followed by corrective horizontal saccades. When the head was free to move, it usually showed a diagonal trajectory that, for both sinusoidal and stepping target motion, was always in the direction of the illusion; no corrective movements were present. Thus, for our illusory stimuli, eye and head tracking showed qualitative differences that imply that ocular tracking was ultimately controlled by actual target motion but head tracking was controlled by illusory target motion.

Head perturbations during walking while viewing a head-fixed target.

BACKGROUND: Inexpensive, head-fixed computer displays are now available that subjects can wear during locomotion. HYPOTHESIS: Viewing a head-fixed visual display will change the characteristics of rotational head perturbations during natural walking. METHODS: Using a 3-axis angular rate sensor, we measured head rotations during natural or treadmill walking, in 10 normal subjects and 2 patients with deficient vestibular function, as they attempted to view (A) a stationary target at optical infinity; and (B) a target at a distance of 20 cm rigidly attached to the head. RESULTS: Normal subjects and patients showed no significant change in the predominant frequency of head rotations in any plane (ranging 0.7-5.7 Hz) during the two different viewing tasks (p > 0.1). Mean peak head velocities (ranging 6-36 degrees.s-1) also showed no difference during the two viewing conditions except in the yaw plane, in which values were greater while viewing the near target (p < 0.005). Predominant frequencies of head rotations were similar in the pitch plane during natural or treadmill walking; however, peak velocities of pitch head rotations were substantially greater during natural walking (p < 0.05). One vestibular patient showed modest increases of head velocity during natural walking compared with normal subjects. CONCLUSIONS: Rotational head perturbations that occur during natural walking are largely unaffected when subjects view a head-fixed target. There is need to study how such perturbations, which induce vestibular eye movements, affect vision of head-fixed displays.

Modulation of high-frequency vestibuloocular reflex during visual tracking in humans.

1. Humans may visually track a moving object either when they are stationary or in motion. To investigate visual-vestibular interaction during both conditions, we compared horizontal smooth pursuit (SP) and active combined eye-head tracking (CEHT) of a target moving sinusoidally at 0.4 Hz in four normal subjects while the subjects were either stationary or vibrated in yaw at 2.8 Hz. We also measured the visually enhanced vestibuloocular reflex (VVOR) during vibration in yaw at 2.8 Hz over a peak head velocity range of 5-40 degrees/s. 2. We found that the gain of the VVOR at 2.8 Hz increased in all four subjects as peak head velocity increased (P < 0.001), with minimal phase changes, such that mean retinal image slip was held below 5 degrees/s. However, no corresponding modulation in vestibuloocular reflex gain occurred with increasing peak head velocity during a control condition when subjects were rotated in darkness. 3. During both horizontal SP and CEHT, tracking gains were similar, and the mean slip speed of the target's image on the retina was held below 5.5 degrees/s whether subjects were stationary or being vibrated at 2.8 Hz. During both horizontal SP and CEHT of target motion at 0.4 Hz, while subjects were vibrated in yaw, VVOR gain for the 2.8-Hz head rotations was similar to or higher than that achieved during fixation of a stationary target. This is in contrast to the decrease of VVOR gain that is reported while stationary subjects perform CEHT.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of a video tracking device for measurement of horizontal and vertical eye rotations during locomotion.

We have evaluated a video-based method for measuring binocular horizontal and vertical eye movements of human subjects by comparing it with the magnetic search coil technique. This video tracking system (VTS) uses multiple infrared light sources and small video cameras to simultaneously measure the positions of reflected corneal images and the center of the pupil. The system has a linear range of approximately +/- 40 degrees horizontally and +/- 30 degrees vertically, a sampling rate of 120 Hz (180 Hz with the head fixed), and system noise with standard deviation of < 0.04 degree. The binocular eye-tracking system is light-weight (190 g), being mounted on goggles that, with the eyes in primary position, permit a field of view of 60 degrees horizontally and vertically. The VTS is insensitive to translations of the tracker relative to the eyes. By placing the video preprocessing unit on a cart, eye movements may be recorded while subjects walk through distances up to 100 feet. In comparison with the magnetic search coil technique, the VTS generally provides reliable measurements of horizontal and vertical eye position; eye velocity is noisier than corresponding coil signals, but superior to electro-oculography.

Investigations of the pathogenesis of acquired pendular nystagmus.

We investigated the pathogenesis of acquired pendular nystagmus (APN) in six patients, three of whom had multiple sclerosis. First, we tested the hypothesis that the oscillations of APN are due to a delay in visual feedback secondary, for example, to demyelination of the optic nerves. We manipulated the latency to onset of visually guided eye movements using an electronic technique that induces sinusoidal oscillations in normal subjects. This manipulation did not change the characteristics of the APN, but did superimpose lower-frequency oscillations similar to those induced in normal subjects. These results are consistent with current models for smooth (non-saccadic) eye movements, which predict that prolongation of visual feedback could not account for the high-frequency oscillations that often characterize APN. Secondly, we attempted to determine whether an increase in the gain of the visually-enhanced vestibulo-ocular reflex (VOR), produced by viewing a near target, was accompanied by a commensurate increase in the amplitude of APN. Increases in horizontal or vertical VOR gain during near viewing occurred in four patients, but only two of them showed a parallel increase in APN amplitude. On the other hand, APN amplitude decreased during viewing of the near target in the two patients who showed no change in VOR gain. Taken together, these data suggest that neither delayed visual feedback nor a disorder of central vestibular mechanisms is primarily responsible for APN. More likely, these ocular oscillations are produced by abnormalities of internal feedback circuits, such as the reciprocal connections between brainstem nuclei and cerebellum.

Experimental tests of a superposition hypothesis to explain the relationship between the vestibuloocular reflex and smooth pursuit during horizontal combined eye-head tracking in humans.

1. We used a modeling approach to test the hypothesis that, in humans, the smooth pursuit (SP) system provides the primary signal for cancelling the vestibuloocular reflex (VOR) during combined eye-head tracking (CEHT) of a target moving smoothly in the horizontal plane. Separate models for SP and the VOR were developed. The optimal values of parameters of the two models were calculated using measured responses of four subjects to trials of SP and the visually enhanced VOR. After optimal parameter values were specified, each model generated waveforms that accurately reflected the subjects' responses to SP and vestibular stimuli. The models were then combined into a CEHT model wherein the final eye movement command signal was generated as the linear summation of the signals from the SP and VOR pathways. 2. The SP-VOR superposition hypothesis was tested using two types of CEHT stimuli, both of which involved passive rotation of subjects in a vestibular chair. The first stimulus consisted of a "chair brake" or sudden stop of the subject's head during CEHT; the visual target continued to move. The second stimulus consisted of a sudden change from the visually enhanced VOR to CEHT ("delayed target onset" paradigm); as the vestibular chair rotated past the angular position of the stationary visual stimulus, the latter started to move in synchrony with the chair. Data collected during experiments that employed these stimuli were compared quantitatively with predictions made by the CEHT model. 3. During CEHT, when the chair was suddenly and unexpectedly stopped, the eye promptly began to move in the orbit to track the moving target. Initially, gaze velocity did not completely match target velocity, however; this finally occurred approximately 100 ms after the brake onset. The model did predict the prompt onset of eye-in-orbit motion after the brake, but it did not predict that gaze velocity would initially be only approximately 70% of target velocity. One possible explanation for this discrepancy is that VOR gain can be dynamically modulated and, during sustained CEHT, it may assume a lower value. Consequently, during CEHT, a smaller-amplitude SP signal would be needed to cancel the lower-gain VOR. This reduction of the SP signal could account for the attenuated tracking response observed immediately after the brake. We found evidence for the dynamic modulation of VOR gain by noting differences in responses to the onset and offset of head rotation in trials of the visually enhanced VOR.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of eyelid closure and vocalization upon the vestibulo-ocular reflex during rotational testing.

During rotational testing of the vestibulo-ocular reflex (VOR), eyelid closure is known to reduce both VOR gain and nystagmus frequency. We tested the effect of vocalization, such as counting aloud, on the VOR in ten healthy normal subjects. Velocity-step and sinusoidal stimuli were applied in complete darkness under three test conditions: 1) eyes open, performing mental arithmetic; 2) eyes closed, performing mental arithmetic; and 3) eyes closed and vocalizing. With velocity-step stimuli, eyelid closure significantly reduced VOR gain (peak eye velocity/head velocity) and nystagmus duration, but vocalization reversed these effects and resulted in the highest gain values. Similar results were obtained for VOR gain during sinusoidal stimulation. This study demonstrates that when eyelid closure is necessary or unavoidable during VOR testing, continuous vocalization ensures responses that are comparable to or better than those with eyes open in darkness.

Maturation of the vestibulo-ocular reflex in normal infants during the first 2 months of life.

We measured the dynamic properties of the vestibulo-ocular reflex (VOR) in 20 healthy, newborn babies, using sinusoidal and velocity-step rotational stimuli. With sinusoidal stimuli, quick phases of nystagmus were uncommon and there was a large phase lead of eye position over head position that exceeded 20 degrees at frequencies below 0.5 Hz. With velocity-step stimuli, primary nystagmus lasted for a mean duration of 10 seconds and was followed by an early reversal phase of nystagmus. By 2 months of age, primary nystagmus induced by velocity-step stimuli was more prolonged (mean duration, 15 seconds) and the reversal phase occurred later. We postulate that these changes reflect maturation of visual pathways essential in calibrating the VOR so that vision remains clear during head perturbations.

Once-daily vs. continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin, and tobramycin.

The dosing frequency of aminoglycoside antibiotics may alter efficacy and toxicity independent of total daily dose. Once-daily tobramycin dosing was compared with continuous infusion in three models of efficacy. Acute pneumonia due to Pseudomonas aeruginosa in guinea pigs responded better to once-daily dosing, and chronic pneumonia in rats and endocarditis in rabbits responded equally to both regimens. Dogs given gentamicin, tobramycin, or netilmicin once daily, with maximum serum concentrations of greater than 100 mg/liter, had less nephrotoxicity than dogs given continuous infusions. Tobramycin was given once daily or continuously to 52 patients with cystic fibrosis who in 10 days had no change in creatinine clearance or hearing despite maximum serum tobramycin concentrations of 40 mg/liter. Intermittent dosing of aminoglycosides, causing infrequent large maximum serum concentrations, may be less toxic and equally efficacious as frequent dosing.