Restoration of 3D vestibular sensation in rhesus monkeys using a multichannel vestibular prosthesis

Abstract

Profound bilateral loss of vestibular hair cell function can cause chronically disabling loss of balance and inability to maintain stable vision during head and body movements. We have previously shown that chinchillas rendered bilaterally vestibular-deficient via intratympanic administration of the ototoxic antibiotic gentamicin regain a more nearly normal 3-dimensional vestibulo-ocular reflex (3D VOR) when head motion information sensed by a head-mounted multichannel vestibular prosthesis (MVP) is encoded via rate-modulated pulsatile stimulation of vestibular nerve branches. Despite significant improvement versus the unaided condition, animals still exhibited some 3D VOR misalignment (i.e., the 3D axis of eye movement responses did not precisely align with the axis of head rotation), presumably due to current spread between a given ampullary nerve's stimulating electrode(s) and afferent fibers in non-targeted branches of the vestibular nerve. Assuming that effects of current spread depend on relative orientation and separation between nerve branches, anatomic differences between chinchilla and human labyrinths may limit the extent to which results in chinchillas accurately predict MVP performance in humans. In this report, we describe the MVP-evoked 3D VOR measured in alert rhesus monkeys, which have labyrinths that are larger than chinchillas and temporal bone anatomy more similar to humans. Electrodes were implanted in five monkeys treated with intratympanic gentamicin to bilaterally ablate vestibular hair cell mechanosensitivity. Eye movements mediated by the 3D VOR were recorded during passive sinusoidal (0.2-5 Hz, peak 50°/s) and acceleration-step (1000°/s(2) to 150°/s) whole-body rotations in darkness about each semicircular canal axis. During constant 100 pulse/s stimulation (i.e., MVP powered ON but set to stimulate each ampullary nerve at a constant mean baseline rate not modulated by head motion), 3D VOR responses to head rotation exhibited profoundly low gain [(mean eye velocity amplitude)/(mean head velocity amplitude) < 0.1] and large misalignment between ideal and actual eye movements. In contrast, motion-modulated sinusoidal MVP stimuli elicited a 3D VOR with gain 0.4-0.7 and axis misalignment of 21-38°, and responses to high-acceleration transient head rotations exhibited gain and asymmetry closer to those of unilaterally gentamicin-treated animals (i.e., with one intact labyrinth) than to bilaterally gentamicin-treated animals without MVP stimulation. In comparison to responses observed under similar conditions in chinchillas, acute responses to MVP stimulation in rhesus macaque monkeys were slightly better aligned to the desired rotation axis. Responses during combined rotation and prosthetic stimulation were greater than when either stimulus was presented alone, suggesting that the central nervous system uses MVP input in the context of multisensory integration. Considering the similarity in temporal bone anatomy and VOR performance between rhesus monkeys and humans, these observations suggest that an MVP will likely restore a useful level of vestibular sensation and gaze stabilization in humans.

Copyright © 2011 Elsevier B.V. All rights reserved.

Figures

Fig.1. Electrode array placement

(A) Posterolateral view of 3D CT surface reconstruction showing electrode array leads implanted in the left labyrinth of a rhesus monkey via the mastoid cavity. a: lead to anterior and horizontal ampullae; b: lead to posterior ampulla; c: common crus reference electrode; d: neck reference electrode; M: mandibular ramus; Z: zygomatic arch; ANT, POST, SUP, INF: anterior, posterior, superior, inferior. (B) Oblique CT cut through the plane of the basal turn of the cochlea [Co], showing bifurcated electrode array [a] entering the ampullae of the superior [s-scc] and horizontal [h-scc] semicircular canals. Part of the neck reference electrode [d] is also visible, but the posterior SCC electrode array is not included in this section. AM, PL: anteriomedial, posterolateral. (Reproduced with permission from Dai et al., 2010).

Fig. 2

Prosthesis pulse rate vs. head velocity operating characteristic curves optionally employed by the MVP. Parameters shown correspond to those in Equation 1. The curve designated by C=2 was used for all channels of the MVP in each monkey studied. The bold/dashed/blue and bold/dotted/red curves, respectively, depict mean firing rates of regular and irregular vestibular nerve primary afferents reported for normal rhesus monkeys by Sadeghi, et al. (2007).

Fig. 3

Mean eye and head angular velocities of normal and vestibular-deficient rhesus monkeys during 2 Hz, 50°/s head rotations in darkness about the horizontal (top row), left-anterior/right-posterior (LARP, middle row) and right-anterior/left-posterior (RALP, bottom row) SCC axes. Monkeys were reoriented as needed to align the SCC axis of interest with the rotating motor’s Earth-vertical axis. The curved arrow depicts the sense of a positive polarity head rotation for each axis. In data traces, head velocity is inverted to facilitate comparison, and eye velocities are displayed using the convention described it the text, for which excitation of the left horizontal (LH), left anterior (LA) and left posterior (LP) SCCs elicits negative horizontal, positive LARP and positive RALP half cycles of eye movement. A–C: Normal monkey prior to electrode implantation and gentamicin treatment. For comparison to the asymmetric responses of monkeys tested under other conditions, the SCC predominantly excited during each half-cycle is labeled. This pattern is the same for all data shown. D–F: After unilateral gentamicin treatment of the left labyrinth, leaving the right ear normal. Note asymmetry of responses, with VOR gain greater for half-cycles during right labyrinth excitation. G–I: After bilateral intratympanic gentamicin and electrode implantation in left labyrinth, with MVP pulsing at baseline rate on all channels but not modulating with head rotation. J–L: With MVP modulating to encode head rotation. Standard deviation of each trace at each time point is <10°/s. N≥20 cycles for each trace. Blinks and nystagmus quick phases were removed from analysis prior to averaging.

Fig. 4

Mean±SD gain (A–C) and phase (D–F) of slow phase eye movements with respect to the ideal response (−1 × head velocity) for the main component of the 3D VOR response during sinusoidal horizontal (A,D), LARP (B,E) and RALP (C,F) for rhesus monkeys during 50°/s peak, 0.05–5 Hz, passive whole body rotation in darkness. Solid lines: Normal monkeys (N=5). Dashed lines: Monkeys rendered bilaterally vestibular-deficient via intratympanic gentamicin treatment, with constant-rate MVP stimulation (N=4). Dotted lines: Those same monkeys while receiving motion-modulated stimulation via a head-mounted multichannel vestibular prosthesis. Across all frequencies tested, modulated MVP stimulation restores a more normal response.

Fig. 5

(A–C): Mean±SD eye and (inverted) head angular velocities of a normal rhesus monkey (M067RhF) during head impulse rotations (1000°/sec2 to a peak head velocity of 150°/sec) 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. Eye movement polarities conform to the convention described in the text and Fig. 3. The SCC being predominantly excited is designated for normal data here and consistent for all other panels. (D–F): Responses of the same monkey after left gentamicin treatment. Note the asymmetry of main component for each axis of rotation. (G–I): Same monkey after bilateral intratympanic gentamicin, plugging all SCCs, and electrode implantation in left labyrinth. Prosthesis pulsing at baseline stimulation rate of 100 pulses/sec on each channel, but not modulating with head rotation. Responses are minimal, indicating failure of the VOR. (J–L): Same animal with motion-modulated MVP input. Although responses are still asymmetric, they are similar to those achieved by a single normal ear (compare panels D–F).

Fig. 6

Average acceleration gain (GA) values (A–C) and latency (D–F) of the VOR measured during step of whole-body acceleration (1000°/s2) to velocity plateau (150°/s) in darkness, about the horizontal (A,D), left-anterior/right-posterior (LARP- B,E) and right-anterior/left-posterior (RALP – C,F) SCC axes. Normal: Prior to electrode implantation and gentamicin treatment. BVD: After bilateral intratympanic gentamicin and electrode implantation in left labyrinth, with the MVP pulsing constantly but not at rates modulated by head motion. Prosthesis: With head-motion-modulated MVP input, during either head rotation toward (Excite) or away from (Inhibit) the implanted ear.

Fig. 7

Mean 3D VOR eye responses of a bilaterally gentamicin-treated rhesus monkey during actual or simulated 50°/s peak, 2 Hz, passive whole body rotations in darkness. (A) Whole-body rotation only, with MVP set to baseline stimulation. (B) Body stationary but MVP horizontal channel stimulus set to pulse frequency modulation with the same timing that would usually occur during an actual head rotation of 50°/s peak, 2 Hz. (C) Responses to whole-body rotation with concurrent MVP stimulus rate modulation. The 3D VOR response is much more robust during the combined stimulation and is greater than the sum of responses to either mechanical or electrical stimuli alone.