Directional plasticity rapidly improves 3D vestibulo-ocular reflex alignment in monkeys using a multichannel vestibular prosthesis

Abstract

Bilateral loss of vestibular sensation can be disabling. We have shown that a multichannel vestibular prosthesis (MVP) can partly restore vestibular sensation as evidenced by improvements in the 3-dimensional angular vestibulo-ocular reflex (3D VOR). However, a key challenge is to minimize misalignment between the axes of eye and head rotation, which is apparently caused by current spread beyond each electrode's targeted nerve branch. We recently reported that rodents wearing a MVP markedly improve 3D VOR alignment during the first week after MVP activation, probably through the same central nervous system adaptive mechanisms that mediate cross-axis adaptation over time in normal individuals wearing prisms that cause visual scene movement about an axis different than the axis of head rotation. We hypothesized that rhesus monkeys would exhibit similar improvements with continuous prosthetic stimulation over time. We created bilateral vestibular deficiency in four rhesus monkeys via intratympanic injection of gentamicin. A MVP was mounted to the cranium, and eye movements in response to whole-body passive rotation in darkness were measured repeatedly over 1 week of continuous head motion-modulated prosthetic electrical stimulation. 3D VOR responses to whole-body rotations about each semicircular canal axis were measured on days 1, 3, and 7 of chronic stimulation. Horizontal VOR gain during 1 Hz, 50 °/s peak whole-body rotations before the prosthesis was turned on was <0.1, which is profoundly below normal (0.94 ± 0.12). On stimulation day 1, VOR gain was 0.4-0.8, but the axis of observed eye movements aligned poorly with head rotation (misalignment range ∼30-40 °). Substantial improvement of axis misalignment was observed after 7 days of continuous motion-modulated prosthetic stimulation under normal diurnal lighting. Similar improvements were noted for all animals, all three axes of rotation tested, for all sinusoidal frequencies tested (0.05-5 Hz), and for high-acceleration transient rotations. VOR asymmetry changes did not reach statistical significance, although they did trend toward slight improvement over time. Prior studies had already shown that directional plasticity reduces misalignment when a subject with normal labyrinths views abnormal visual scene movement. Our results show that the converse is also true: individuals receiving misoriented vestibular sensation under normal viewing conditions rapidly adapt to restore a well-aligned 3D VOR. Considering the similarity of VOR physiology across primate species, similar effects are likely to occur in humans using a MVP to treat bilateral vestibular deficiency.

FIG. 1

Semicircular canal (SCC) coordinate system used for the description of head rotation and three-dimensional vestibulo-ocular reflex (3D VOR) eye rotation responses. Skull coordinates +X, +Y, and +Z are mutually orthogonal stereotaxic axes perpendicular to the stereotactic coronal, sagittal, and horizontal planes, respectively. +X is nasal, +Y is out the left ear canal along the interaural axis, the plane containing +X and +Y passes through the inferior-most point of the cephalic edge of each orbital rim, and +Z is superior. SCC coordinate system axes +LARP, +RALP, and +H used in this study approximate the mean SCC axes measured from CT reconstructions of the animals used in this study. They are mutually orthogonal and centered on the XYZ stereotaxic origin. The mean +H axis is close to +Z but pitched back from the stereotaxic +Z axis by 15 ° toward the occiput. The +LARP and +RALP axes are each 45 ° off the midsagittal plane, and 45 ° off the +Y axis, but pitched 15 ° up from the [X, Y, Z] = [−1, 1, 0] and [1, 1, 0], respectively. Eye rotation velocity polarities are expressed in this canal-based reference frame using a right-hand rule convention, so that positive eye rotations about +LARP pitch the eye upward while rolling it clockwise (as viewed from behind the head); positive RALP eye rotations pitch the eye downward while rolling it clockwise, and positive H eye rotations yaw the eye to move the pupil toward the left ear.

FIG. 2

Mean 3D VOR eye responses of a rhesus monkey (F234RhD) during actual 50 °/s peak, 1 Hz, passive whole-body rotations measured in darkness 2 h after onset on of chronic, continuous motion-modulated stimulation on day 1 of the adaptation paradigm. A–C Normal responses before gentamicin treatment and MVP implantation, during rotations predominantly exciting the left and right horizontal (LH and RH, A), left anterior/right posterior (LARP, B), and right anterior/left posterior (RALP, C) canals. In each case, horizontal, LARP, and RALP components of the 3D VOR response are shown in red/solid, green/dashed, and blue/long dash lines, respectively, and the canal being excited during a given half cycle is designated. (By the right-hand rule convention used to describe 3D eye movements, VOR responses to LH excitation are negative, whereas responses to LA and LP excitation are positive.) D–F Responses to whole-body rotation measured after gentamicin and multichannel vestibular prosthesis (MVP) electrode implantation, with the MVP set to pulse at constant rates independent of head motion. G–O 3D VOR responses measured on the first day of continuous motion-modulated MVP stimulation (G–I), third day (J–L), and seventh day (M–O). Each panel shows mean of 10–20 cycles free of quick phases. SD < 5 °/s at every time point for every trace. P–R Cycle to cycle variation for the measurements shown in mean form in A, D, and M.

FIG. 3

Changes in axis of eye response for one rhesus monkey (F234RhD) over 7 days of continual motion-modulated stimulation. Each data vector depicts the 3D axis and magnitude of VOR responses during whole-body, 1 Hz, 50 °/s peak head rotations in darkness about the mean horizontal, LARP, and RALP semicircular canal axes. Vector length indicates the peak response velocity; for comparison, thick axes without markers depict inverse of 50 °/s peak head rotations about each canal axis. Data shown are for peak excitatory responses; curved arrows in inset show the direction of VOR response to excitation of the corresponding semicircular canal in the left labyrinth. Axes for responses to left horizontal SCC excitation are inverted to facilitate consolidation on a single plot, and the direction of rotation indicated by the red arrow is the rightward yaw rotation resulting from left horizontal SCC excitation. Progression over time toward the ideal response is apparent for each axis of head rotation. Each data vector shown on the plot has both a direction and a magnitude, conveying the axis and relative amplitude, respectively, of the VOR response.

FIG. 4

Gain of each component of 3D VOR responses for each of N = 4 monkeys during 1 Hz, 50 °/s, peak whole-body rotations about the horizontal, LARP, and RALP canal axes on the first, third, and seventh days of continuous stimulation using a head-mounted multichannel vestibular prosthesis. Before: values for each monkey measured in response to head movement with the prosthesis stimulating at constant pulse rates, independent of head velocity, 3–5 h after prosthesis activation. After: values measured 4–48 h after the prosthesis was powered off on day 7. Normal: Mean ± SD responses of five normal rhesus monkeys. Ev eye velocity; Hv head velocity.

FIG. 5

Mean ± SD gain (top) and eye/head 3D axis misalignment angle (bottom) for N = 4 rhesus monkeys, displayed for each component of the peak 3D VOR eye movement response during 50 °/s peak whole-body rotations in darkness at 1 Hz about the horizontal, LARP, and RALP canal axes on the first, third, and seventh days of continuous stimulation using a head-mounted multichannel vestibular prosthesis. The 3D VOR response maintained gain of the desired component while improving directional misalignment over 7 days of continuous prosthesis for every stimulus frequency, axis, and animal examined. Before: values measured to head movement with the prosthesis stimulating at constant pulse rates, independent of head velocity, 3–5 h after prosthesis activation. After: values measured 4–48 h after the prosthesis was powered off on day 7. Normal: Responses of five normal rhesus monkeys. Ev eye velocity; Hv head velocity.

FIG. 6

Mean ± SD gain for the component of the 3D VOR about the axis of head rotation (top), phase lead versus inverse of head velocity (middle), and eye/head misalignment angle (bottom) for N = 4 rhesus monkeys, displayed for 3D VOR eye movement responses during 50 °/s peak whole-body rotations in darkness at 0.05–5 Hz about the horizontal (square), LARP (triangle), and RALP (circle) canal axes on the first, third, and seventh days of continuous stimulation using a head-mounted multichannel vestibular prosthesis. In each case, gain is the ratio [(peak velocity of the VOR component about the axis of head rotation)/(peak velocity of whole-body rotation)], phase is expressed in degrees by which a best-fit sinusoid approximating the inverted eye velocity response’s main component leads a best-fit sinusoid fit to the head velocity, and misalignment is the angle between 3D vectors describing the actual and desired axes of 3D VOR eye movement response at the time of peak eye velocity. The 3D VOR response maintained gain of the desired component while phase did not significantly change and misalignment significantly improved over 7 days of continuous prosthesis for every stimulus frequency, axis, and animal examined. N normal.

FIG. 7

Mean ± SD asymmetry of VOR responses to actual 50 °/s peak, 1 Hz, passive whole-body rotations in darkness. We quantified gain asymmetry for VOR response by computing the ratio between the excitatory peak versus inhibitory peak difference in gain and the average gain, α = (G _E − G _I) / (G _E + G _I). This asymmetry is significantly reduced after the training (P > 0.05, ANOVA). Left normal; middle first day; right seventh day. Asterisk, significant in Student’s t test, P < 0.05; NS nonsignificant, P > 0.05.

FIG. 8

A–C Mean ± SD eye and (inverted) head angular velocities of a normal rhesus monkey (F234RhD) during head impulse rotations (1,000 °/s² to a peak head velocity of 150 °/s) in darkness, about the horizontal (A), left anterior/right posterior (LARP, B), and right anterior/left posterior (RALP, C) semicircular canal axes. Standard deviation of each trace at each time point is <10 °/s. Data are truncated at the onset of the first nystagmus quick phase. D–F Same monkey (F234RhD) after bilateral intratympanic gentamicin and electrode implantation in left labyrinth, with MVP pulsing at baseline stimulation rate of 94 pulses/s on each channel but not modulating with head rotation. Responses are minimal, indicating failure of the VOR. G–I Same animal with motion-modulated MVP input at first day of MVP modulation on. J–L Third day response with improvement of misalignment. M–O Seventh day response with further improvement of misalignment, but not significant improvement of asymmetry (P > 0.05). Head movement traces are inverted for comparison to eye data. Asterisks indicate head rotations that excite the left labyrinth. (By the convention used to describe 3D movements, rightward eye movements are negative, while responses to exciting the LA and LP SCCs are positive).