Core Body Temperature Effects on the Mouse Vestibulo-ocular Reflex.

Core body temperature has been shown to affect vestibular end-organ and nerve afferents so that their resting discharge rate and sensitivity increase with temperature. Our aim was to determine whether these changes observed in extracellular nerve recordings of anaesthetized C57BL/6 mice corresponded to changes in the behavioural vestibulo-ocular reflex (VOR) of alert mice. The VOR drives eye rotations to keep images stable on the retina during head movements. We measured the VOR gain (eye velocity/head velocity) and phase (delay between vestibular stimulus and response) during whole-body sinusoidal rotations ranging 0.5-12 Hz with peak velocity 50 or 100 °/s in nine adult C57BL/6 mice. We also measured the VOR during whole-body transient rotations with acceleration 3000 or 6000 °/s2 reaching a plateau of 150 or 300 °/s. These measures were obtained while the mouse's core body temperature was held at either 32 or 37 °C for at least 35 min before recording. The temperature presentation order and timing were pseudo-randomized. We found that a temperature increase from 32 to 37 °C caused a significant increase in sinusoidal VOR gain of 17 % (P < 0.001). Temperature had no other effects on the behavioural VOR. Our data suggest that temperature effects on regularly firing afferents best correspond to the changes that we observed in the VOR gain.

Cold Thermal Irrigation Decreases the Ipsilateral Gain of the Vestibulo-Ocular Reflex.

OBJECTIVES: During head rotations, neuronal firing rates increase in ipsilateral and decrease in contralateral vestibular afferents. At low accelerations, this "push-pull mechanism" is linear. At high accelerations, however, the change of firing rates is nonlinear in that the ipsilateral increase of firing rate is larger than the contralateral decrease. This mechanism of stronger ipsilateral excitation than contralateral inhibition during high-acceleration head rotation, known as Ewald's second law, is implemented within the nonlinear pathways. The authors asked whether caloric stimulation could provide an acceleration signal high enough to influence the contribution of the nonlinear pathway to the rotational vestibulo-ocular reflex gain (rVOR gain) during head impulses. DESIGN: Caloric warm (44°C) and cold (24, 27, and 30°C) water irrigations of the left ear were performed in 7 healthy human subjects with the lateral semicircular canals oriented approximately earth-vertical (head inclined 30° from supine) and earth-horizontal (head inclined 30° from upright). RESULTS: With the lateral semicircular canal oriented earth-vertical, the strongest cold caloric stimulus (24°C) significantly decreased the rVOR gain during ipsilateral head impulses, while all other irrigations, irrespective of head position, had no significant effect on rVOR gains during head impulses to either side. CONCLUSIONS: Strong caloric irrigation, which can only be achieved with cold water, reduces the rVOR gain during ipsilateral head impulses and thus demonstrates Ewald's second law in healthy subjects. This unilateral gain reduction suggests that cold-water caloric irritation shifts the set point of the nonlinear relation between head acceleration and the vestibular firing rate toward a less acceleration-sensitive zone.

Visual contribution to the high-frequency human angular vestibulo-ocular reflex.

The vestibulo-ocular reflex (VOR) acts to maintain images stable on the retina by rotating the eyes in exactly the opposite direction, but with equal magnitude, to head velocity. When viewing a near target, this reflex has an increased response to compensate for the translation of the eyes relative to the target that acts to reduce retinal image slip. Previous studies have shown that retinal velocity error provides an important visual feedback signal to increase the low-frequency (<1 Hz) VOR response during near viewing. We sought to determine whether initial eye position and retinal image position error could provide enough information to substantially increase the high-frequency VOR gain (eye velocity/head velocity) during near viewing. Ten human subjects were tested using the scleral search coil technique during horizontal head impulses under different lighting conditions (constant dark, strobe light at 0.5, 1, 2, 4, 10, 15 Hz, constant light) while viewing near (9.5 ± 1.3 cm) and far (104 cm) targets. Our results showed that the VOR gain increased during near viewing compared to far viewing, even during constant dark. For the near target, there was an increase in VOR gain with increasing strobe frequency from 1.17 ± 0.17 in constant dark to 1.36 ± 0.27 in constant light, a 21 ± 9 % increase. For the far target, strobe frequency had no effect. Presentation order of strobe frequency (i.e. 0.5-15 vs. 15-0.5 Hz) did not affect the gain, but it did affect the vergence angle (angle between the two eye's lines of sight). The VOR gain and vergence angles were constant during each trial. Our findings show that a retinal position error signal helps increase the vergence angle and could be invoking vestibular adaptation mechanisms to increase the high-frequency VOR response during near viewing. This is in contrast to the low-frequency VOR that depends more on retinal velocity error and predictive adaptation mechanisms.

Unidirectional rotations produce asymmetric changes in horizontal VOR gain before and after unilateral labyrinthectomy in macaques.

Unilateral vestibular lesions cause marked asymmetry in the horizontal vestibulo-ocular reflex (VOR) during rapid head rotations, with VOR gain being lower for head rotations toward the lesion than for rotations in the opposite direction. Reducing this gain asymmetry by enhancing ipsilesional responses would be an important step toward improving gaze stability following vestibular lesions. To that end, there were two goals in this study. First, we wanted to determine whether we could selectively increase VOR gain in only one rotational direction in normal monkeys by exposing them to a training session comprised of a 3-h series of rotations in only one direction (1,000°/s² acceleration to a plateau of 150°/s for 1 s) while they wore 1.7 × magnifying spectacles. Second, in monkeys with unilateral vestibular lesions, we designed a paradigm intended to reduce the gain asymmetry by rotating the monkeys toward the side of the lesion in the same way as above but without spectacles. There were three main findings (1) unidirectional rotations with magnifying spectacles result in gain asymmetry in normal monkeys, (2) gain asymmetry is reduced when animals are rotated towards the side of the labyrinthectomy via the ipsilesional rotation paradigm, and (3) repeated training causes lasting reduction in VOR gain asymmetry.

Variation in response dynamics of regular and irregular vestibular-nerve afferents during sinusoidal head rotations and currents in the chinchilla.

In mammals, vestibular-nerve afferents that innervate only type I hair cells (calyx-only afferents) respond nearly in phase with head acceleration for high-frequency motion, whereas afferents that innervate both type I and type II (dimorphic) or only type II (bouton-only) hair cells respond more in phase with head velocity. Afferents that exhibit irregular background discharge rates have a larger phase lead re-head velocity than those that fire more regularly. The goal of this study was to investigate the cause of the variation in phase lead between regular and irregular afferents at high-frequency head rotations. Under the assumption that externally applied galvanic currents act directly on the nerve, we derived a transfer function describing the dynamics of a semicircular canal and its hair cells through comparison of responses to sinusoidally modulated head velocity and currents. Responses of all afferents were fit well with a transfer function with one zero (lead term). Best-fit lead terms describing responses to current for each group of afferents were similar to the lead term describing responses to head velocity for regular afferents (0.006 s + 1). This finding indicated that the pre-synaptic and synaptic inputs to regular afferents were likely to be pure velocity transducers. However, the variation in phase lead between regular and irregular afferents could not be explained solely by the ratio of type I to II hair cells (Baird et al 1988), suggesting that the variation was caused by a combination of pre- (type of hair cell) and post-synaptic properties.

Static and dynamic discharge properties of vestibular-nerve afferents in the mouse are affected by core body temperature.

The goal of this study was to determine the effect of changes in core body temperature on the resting discharge rate and sensitivity of vestibular-nerve afferents. Extracellular recordings were made from vestibular-nerve afferents innervating the semicircular canals in anesthetized C57BL/6 mice maintained at a core body temperature of either 30-32 degrees C (T (31)) or 35-37 degrees C (T (36)). The resting rates of regular (CV* < 0.1) and irregular afferents (CV* > 0.1) were lower at T (31) than at T (36). Sensitivity and phase were compared for rotations ranging from 0.1 to 12 Hz by calculating coefficients of a transfer function, g . t(c)S . (t(z)S +1)/(t(c)S + 1), for each afferent. The sensitivity (g) increased with CV* and with higher core body temperature. The value of the coefficient representing the low-frequency dynamics (t (c)) varied inversely with CV* but did not change with core body temperature. The high-frequency dynamics represented by t (z) increased with CV* and decreased with higher core body temperature. These findings indicate that changes in temperature have effects on the static and dynamic properties of vestibular-nerve afferents.

Tonic and phasic contributions to the pathways mediating compensation and adaptation of the vestibulo-ocular reflex.

Processes of vestibular compensation mediate recovery of many aspects of vestibular dysfunction following unilateral vestibular injury. The VOR in response to high-frequency, high-acceleration head movements, however, retains an enduring asymmetry. Head movements that are inhibitory with respect to semicircular canals on the intact side lead to a diminished VOR whereas head movements that are excitatory for semicircular canals on the intact side lead to a VOR that returns close to normal. We review our work directed toward understanding the processes of VOR compensation to high-frequency, high-acceleration head movements and the related topic of adaptation to changes in the visual requirements for a compensatory VOR. Our work has shown that the processes of both compensation and adaptation to these stimuli can be described by a mathematical model with inputs from tonic and phasic components. We have further shown that the dynamics of regular afferents have close resemblance to the tonic pathway whereas the dynamics of irregular afferents match those of the phasic pathway.

Rotational responses of vestibular-nerve afferents innervating the semicircular canals in the C57BL/6 mouse.

Extracellular recordings were made from vestibular-nerve afferents innervating the semicircular canals in anesthetized C57BL/6 mice ranging in age from 4-24 weeks. A normalized coefficient of variation was used to divide afferents into regular (CV*<0.1) and irregular (CV*>0.1) groups. There were three overall conclusions from this study. First, mouse afferents resemble those of other mammals in properties such as resting discharge rate and dependence of response dynamics on discharge regularity. Second, there are differences in mouse afferents relative to other mammals that are likely related to the smaller size of the semicircular canals. The rotational sensitivity of mouse afferents is approximately threefold lower than that reported for afferents in other mammals. One consequence of the lower sensitivity is that mouse afferents have a larger linear range for encoding head velocity. The long time constant of afferent discharge, which is a measure of low-frequency response dynamics, is shorter in mouse afferents than in other species. Third, juvenile mice (age 4-7 weeks) appear to lack a class of low-sensitivity, highly irregular afferents that are present in adult animals (age 10-24 weeks). By analogy to studies in the chinchilla, these irregular afferents with low sensitivities for lower rotational frequencies correspond to calyx-only afferents. These findings suggest that, although the calyx ending on to type I hair cells is morphologically complete in mice by the age of about 1 month, the physiological response properties in these juvenile animals are not equivalent to those in adults.

Responses of irregularly discharging chinchilla semicircular canal vestibular-nerve afferents during high-frequency head rotations.

Mammalian vestibular-nerve afferents innervating the semicircular canals have been divided into groups according to their discharge regularity, gain at 2-Hz rotational stimulation, and morphology. Low-gain irregular afferents terminate in calyx endings in the central crista, high-gain irregular afferents synapse more peripherally in dimorphic (bouton and calyx) endings, and regular afferents terminate in the peripheral zone as bouton-only and dimorphic endings. The response dynamics of these three groups have been described only up to 4 Hz in previous studies. Reported here are responses of chinchilla semicircular canal vestibular-nerve afferents to rotational stimuli at frequencies up to 16 Hz. The sensitivity of all afferents increased with increasing frequency with the sensitivity of low-gain irregular afferents increasing the most and matching the high-gain irregular afferents at 16 Hz. All afferents increased their phase lead with respect to stimulus velocity at higher frequencies with the highest leads in low-gain irregular afferents and the lowest in regular afferents. No attenuation of sensitivity or shift in phase consistent with the presence of a high-frequency pole over the range tested was noted. Responses were best fit with a torsion-pendulum model combined with a lead operator (tau(HF1)s + 1)(tau(HF2)s + 1). The discharge regularity of individual afferents was correlated to the value of each afferent's lead operator time constants. These findings suggest that low-gain irregular afferents are well suited for encoding the onset of rapid head movements, a property that would be advantageous for initiation of reflexes with short latency such as the vestibulo-ocular reflex.

The three-dimensional vestibulo-ocular reflex evoked by high-acceleration rotations in the squirrel monkey.

The aim of this study was to determine if the angular vestibulo-ocular reflex (VOR) in response to pitch, roll, left anterior-right posterior (LARP), and right anterior-left posterior (RALP) head rotations exhibited the same linear and nonlinear characteristics as those found in the horizontal VOR. Three-dimensional eye movements were recorded with the scleral search coil technique. The VOR in response to rotations in five planes (horizontal, vertical, torsional, LARP, and RALP) was studied in three squirrel monkeys. The latency of the VOR evoked by steps of acceleration in darkness (3,000 degrees /s(2) reaching a velocity of 150 degrees /s) was 5.8+/-1.7 ms and was the same in response to head rotations in all five planes of rotation. The gain of the reflex during the acceleration was 36.7+/-15.4% greater than that measured at the plateau of head velocity. Polynomial fits to the trajectory of the response show that eye velocity is proportional to the cube of head velocity in all five planes of rotation. For sinusoidal rotations of 0.5-15 Hz with a peak velocity of 20 degrees /s, the VOR gain did not change with frequency (0.74+/-0.06, 0.74+/-0.07, 0.37+/-0.05, 0.69+/-0.06, and 0.64+/-0.06, for yaw, pitch, roll, LARP, and RALP respectively). The VOR gain increased with head velocity for sinusoidal rotations at frequencies > or =4 Hz. For rotational frequencies > or =4 Hz, we show that the vertical, torsional, LARP, and RALP VORs have the same linear and nonlinear characteristics as the horizontal VOR. In addition, we show that the gain, phase and axis of eye rotation during LARP and RALP head rotations can be predicted once the pitch and roll responses are characterized.

Differential adaptation of the linear and nonlinear components of the horizontal vestibuloocular reflex in squirrel monkeys.

Previous work in squirrel monkeys has demonstrated the presence of linear and nonlinear components to the horizontal vestibuloocular reflex (VOR) evoked by high-acceleration rotations. The nonlinear component is seen as a rise in gain with increasing velocity of rotation at frequencies more than 2 Hz (a velocity-dependent gain enhancement). We have shown that there are greater changes in the nonlinear than linear component of the response after spectacle-induced adaptation. The present study was conducted to determine if the two components of the response share a common adaptive process. The gain of the VOR, in the dark, to sinusoidal stimuli at 4 Hz (peak velocities: 20-150 degrees /s) and 10 Hz (peak velocities: 20 and 100 degrees /s) was measured pre- and postadaptation. Adaptation was induced over 4 h with x0.45 minimizing spectacles. Sum-of-sines stimuli were used to induce adaptation, and the parameters of the stimuli were adjusted to invoke only the linear or both linear and nonlinear components of the response. Preadaptation, there was a velocity-dependent gain enhancement at 4 and 10 Hz. In postadaptation with the paradigms that only recruited the linear component, there was a decrease in gain and a persistent velocity-dependent gain enhancement (indicating adaptation of only the linear component). After adaptation with the paradigm designed to recruit both the linear and nonlinear components, there was a decrease in gain and no velocity-dependent gain enhancement (indicating adaptation of both components). There were comparable changes in the response to steps of acceleration. We interpret these results to indicate that separate processes drive the adaptation of the linear and nonlinear components of the response.

Vergence-mediated modulation of the human horizontal angular VOR provides evidence of pathway-specific changes in VOR dynamics.

The horizontal vestibulo-ocular reflex (VOR) evoked by passive, high-acceleration, head-on-body rotations (head thrusts) while viewing a far (124-cm) or near (15-cm) target was recorded (scleral search coil) in four subjects with normal vestibular function and in one subject with unilateral vestibular hypofunction. For responses in the subjects with normal vestibular function, the latency of responses relative to the onset of head movement was 7.5 +/- 1.5 ms for the VOR and 21.6 +/- 1.2 ms for the vergence-mediated increase in VOR gain. The gain of the VOR at the peak of the velocity response while viewing a far target was 1.01 +/- 0.06; while viewing a near target, it was 1.25 +/- 0.08 (p <0.003). The responses were modeled with two pathways based on the different latencies. The "far-viewing" pathway was represented by a constant gain term. The "near-viewing" pathway was represented by a first-order lead term, a gain that was dependent on viewing distance, and a delay. Analysis of the responses revealed that the lead term was greater for the adducting than the abducting eye. In the subject with unilateral vestibular hypofunction, ipsilesional responses showed no change in VOR gain with respect to viewing distance. Contralesional responses retained the vergence-dependent increase in gain. A bilateral model was developed based on the data from the subjects with normal vestibular function. Simulations of this model when inputs were eliminated from one side predict the changes observed in the subject with unilateral vestibular hypofunction. The response asymmetries arise because the near-viewing pathway is more susceptible to inhibitory cutoff than is the far-viewing pathway.