Continuous vestibular implant stimulation partially restores eye-stabilizing reflexes

Abstract

BACKGROUNDBilateral loss of vestibular (inner ear inertial) sensation causes chronically blurred vision during head movement, postural instability, and increased fall risk. Individuals who fail to compensate despite rehabilitation therapy have no adequate treatment options. Analogous to hearing restoration via cochlear implants, prosthetic electrical stimulation of vestibular nerve branches to encode head motion has garnered interest as a potential treatment, but prior studies in humans have not included continuous long-term stimulation or 3D binocular vestibulo-ocular reflex (VOR) oculography, without which one cannot determine whether an implant selectively stimulates the implanted ear's 3 semicircular canals.METHODSWe report binocular 3D VOR responses of 4 human subjects with ototoxic bilateral vestibular loss unilaterally implanted with a Labyrinth Devices Multichannel Vestibular Implant System vestibular implant, which provides continuous, long-term, motion-modulated prosthetic stimulation via electrodes in 3 semicircular canals.RESULTSInitiation of prosthetic stimulation evoked nystagmus that decayed within 30 minutes. Stimulation targeting 1 canal produced 3D VOR responses approximately aligned with that canal's anatomic axis. Targeting multiple canals yielded responses aligned with a vector sum of individual responses. Over 350-812 days of continuous 24 h/d use, modulated electrical stimulation produced stable VOR responses that grew with stimulus intensity and aligned approximately with any specified 3D head rotation axis.CONCLUSIONThese results demonstrate that a vestibular implant can selectively, continuously, and chronically provide artificial sensory input to all 3 implanted semicircular canals in individuals disabled by bilateral vestibular loss, driving reflexive VOR eye movements that approximately align in 3D with the head motion axis encoded by the implant.TRIAL REGISTRATIONClinicalTrials.gov: NCT02725463.FUNDINGNIH/National Institute on Deafness and Other Communication Disorders: R01DC013536 and 2T32DC000023; Labyrinth Devices, LLC; and Med-El GmbH.

Keywords: Medical devices; Neuroscience; Otology.

Conflict of interest statement

Conflict of interest: CCDS, GYF, and The Johns Hopkins University (JHU) hold royalty interests in pending and awarded patents related to technologies discussed in this manuscript (AU2014216248A1,CA2786717C, US7225028B2, US7647120B2, US8751012B2, US9242094B2, US20150223683A1). CCDS holds an equity interest in and is CEO/chief scientific officer of Labyrinth Devices, LLC. The terms of this arrangement are managed in accordance with JHU policies on conflicts of interest. At the time of their contributions to this work, MR, NSV, and NSD were employees of Labyrinth Devices, LLC, and AH, AMR, AM, RD, and AJ were employees of Med-El GmbH.

Figures

Figure 1. Coplanar pairs of semicircular canals in the vestibular labyrinths encode 3D head rotational velocity in 3 mutually orthogonal components.

Relative levels of activity within vestibular nerve branches innervating a labyrinth’s 3 semicircular canals encode 3 mutually orthogonal canal-aligned components of the head rotational velocity’s 3D axis. The vestibulo-ocular reflex (VOR) drives eye rotations that counteract head rotation to keep images stable on the retinae. (A) Pairs of coplanar canals normally encode 3 linearly independent components of head rotational velocity about axes perpendicular to the left horizontal (LH) and right horizontal canals (LHRH or +z axis), left anterior and right posterior canals (LARP), and right anterior and left posterior canals (RALP). By convention, positive rotations denote right-hand rule rotations as shown by black arrows. Each canal is most sensitive to rotation about an axis approximately perpendicular to its anatomic plane. (B–D) Head rotations about canal axes that excite the LA, LH, and LP canal, respectively, normally drive VOR responses that rotate both eyes in the opposite direction about the LARP, LHRH, and RALP axes. Physiologically excitatory directions (shown by gold arrows) are not always positive by the right-hand rule mathematical convention. (E) Head rotation about an arbitrary axis excites or inhibits each canal according to a cosine dependence on the angle between the axis of head rotation and the canal’s anatomic axis. (F) Relative activity on the 3 canals in each labyrinth (and their coplanar partners in the other ear) normally drives a VOR response that helps keep images of Earth-stationary objects stable on the retinae. Without the VOR, image slip on the retinae degrades vision during quick head rotations. Although most studies of the VOR measure and describe only yaw (z/LHRH in panel A, also called “horizontal”) and/or pitch (y/PITCH, also called “vertical”) components, all 3 components of the 3D VOR are required to maintain stable vision, and measurement of all 3 components is required to accurately estimate the relative levels of activity on each of a labyrinth’s 3 semicircular canals. Reproduced by permission from Labyrinth Devices, LLC, ©2019.

Figure 2. Overview of the Labyrinth Devices MVI and study.

(A) The MVI stimulator comprises 3 fixation magnets, an inductive coil link, electrical current stimulator circuitry, stimulation electrode array, a stimulation reference electrode, and a recording reference electrode. The electrode array includes a 3-electrode shank for the (B, E3–E5) posterior canal, a forked subarray with 2 shanks for the (C, E6–E8) horizontal, and (D, E9–E11) anterior canals, and a stimulation reference electrode. (E) Surgical diagram illustrating electrode implantation sites, comprising surgical openings drilled in each of 3 canal ampullae and the common crus of 1 labyrinth. (F) The head-worn unit (HWU), magnetically coupled to subject MVI001’s scalp over his implanted stimulator, houses a 3D motion sensor and inductively supplies power and control signals to the implant. (G) The power and control unit (PCU, hanging on lanyard) houses a battery and control circuity. A Labyrinth Devices 3DBinoc video-oculography system (top) records horizontal, vertical, and torsional components of 3D eye position during VOR responses to natural and/or prosthetic stimulation. (H) Example 3D head velocity waveforms (corresponding to vectors in Figure 1D) modulate MVI pulse rate and amplitude. Input waveforms can be either actual head motion sensed by the HWU or synthetically generated by MVI fitting software. (I) Example pulse rate and amplitude modulation maps for each left ear canal. Top image portrays head velocity to pulse rate map; lower plot displays maps for pulse amplitude. Maps use non-zero pulse rate and current amplitude for 0°/s to evoke neural activity mimicking spontaneous afferent neuron discharge (dashed lines). The MVI encodes excitatory and inhibitory head motions via coordinated up- and downmodulation of pulse rate and amplitude (J and K). (L) This is an open-label, nonrandomized, early feasibility study of applicants self-identified as potential trial candidates. Reproduced by permission from Labyrinth Devices, LLC, ©2019.

Figure 3. MVI stimulation evokes 3D VOR responses align with targeted semicircular canal.

Mean ± SD cycle-averaged binocular 3D VOR eye velocity responses of subject MVI002 during n cycles of 2 Hz, 40% duty cycle, square-wave-modulated (200 pulses/s for 200 ms, 300 ms off), biphasic, charge-balanced 100 μs/phase current pulse trains. (A) Stimulation via electrode E3 in LP canal ampulla with pulses of 300–599 μA. (B) Stimulation via electrode E6 in LH canal with pulses of 50–448 μA produces a rightward slow phase eye velocity (negative by convention). (C) Stimulation via electrode E9 in LA canal with pulses of 151–448 μA. Right eye response for 396 μA stimulus is missing due to video-oculography tracking failure. (D) Dashed lines denote anatomic semicircular canal axes. Solid vectors depict mean rotation axis for each eye during peak excitatory slow phase response eye velocity for electrodes and currents in adjacent legends. Conic sections denote VOR variability via eigenvalue decomposition of the 3D angular velocity covariance matrix. (E) Canal axes relative to skull landmarks. (F) Same data as D but viewed from above (i.e., from +z/LHRH axis).

Figure 4. MVI002 VOR response magnitude depends on electrode location and stimulus intensity.

Peak left eye excitatory slow phase velocity component about the target canal’s axis as a function of percentage of current amplitude intensity during initial stimulation of subject MVI002 via all functional electrodes in the left (A) posterior, (B) horizontal, and (C) anterior semicircular canals using 2-Hz–modulated, 40% duty cycle pulse train alternating between 0 and 200 pps. Each data point depicts mean ± SD for n = 7–19 (median 14) cycles. Current intensity 10% denotes minimum current that evoked a detectable eye movement response; 100% denotes maximum current tested for that electrode contact and phase duration. E11 not tested due to a high impedance (>25 kΩ). Supplemental Table 3 shows complete mappings of current intensity to pulse amplitude in microamps for each subject. For each ampulla in MVI002, 1 of 3 electrodes clearly outperforms other contacts 700–1100 μm away.

Figure 5. Initial MVI activation elicited robust nystagmus that decayed within 30 minutes.

Three weeks after implantation, continuous electrical stimulation was initiated in subject MVI002 using at 100 pps 100 μs/phase biphasic, charge-balanced current pulses on electrodes in the LP (E3, 599 μA), horizontal (E6, 151 μA) and anterior (E9, 599 μA) canals (black bar at top of figure). Eye movements were monitored for 5-minute cycles of about 1 minute in darkness, then about 4 minutes in light with an Earth-fixed visible target for more than 35 minutes. Each point represents 1 slow phase nystagmus segment. Second-order exponential fits to left eye slow phase velocity in darkness produced dominant time constant estimates of 28.2, 3.33, and 3.0 minutes for roll, pitch, and yaw components, respectively (RMSEx = 6.6°/s, RMSEy = 2.7°/s, and RMSEz = 2.7°/s). Insets show (A) robust nystagmus dominated by positive slow phase torsional component at onset of stimulation, (B) extinction of the horizontal nystagmus component in darkness by t = 1 minutes, (C) suppression of all but the ~18°/s torsional response during lights-on testing, and (D) a reduction of the torsional component to ~5°/s by t = 30 minutes.

Figure 6. Electrically evoked eye movement responses remain stable after 8 weeks of continuous motion-modulated stimulation.

Peak excitatory half-cycle slow phase 3D eye velocity of MVI002’s (A–C) left and (D–F) right eyes during stimulus modulation emulating 2-Hz sinusoidal head rotation (with head actually stationary) at modulation depth 5%–100% (representing 20–400°/s head velocity) about axes of left posterior (A and D, electrode E3), horizontal (B and E, E6), and anterior (C and F, E9) canals, which would ideally drive conjugate (same for both eyes), purely RALP, horizontal LHRH, and LARP responses, respectively. Stimulus parameters are detailed in Supplemental Table 3. Each data point depicts mean ± SD for n = 9–19 (median 15) cycles.

Figure 7. Coordinated multi-electrode input encodes 3D head rotation axis.

Simultaneous selective stimulation of multiple ampullary nerves scaled to represent the 3 canal axis components of 3D head rotation can drive 3D VOR responses about an axis that approximates the head rotation axis encoded by the implant. (A) Anatomic canal axes (+LARP, +RALP, +LHRH), naso-occipital (+x) axis, and interaural (+y) axis. Trapezoidal 50% modulation depth equivalent head velocity stimulation via MVI002’s (B, electrode E6) LH, (C, E9) anterior, and (D, E3) posterior canals individually each evoked 3D eye velocities approximately aligned with target canal axis. Data are shown as mean ± SD for n cycles. (E) Simultaneous in-phase stimulation via LA E9 and LP E3 yields roll eye response aligned with +x axis, and (F) counter-phase stimulation yields pitch response aligned with +y axis. (G) In each case, mean response axis for each eye aligns approximately with intended head rotation axis as viewed in 3D (H, same data from top-down view). Elliptical cones illustrate eigenvalues of response axis covariance matrices.

Figure 8. Prosthetic stimulation enhances VOR response to whole-body rotation in darkness.

Mean ± SD horizontal VOR responses to 100°/s peak velocity 0.1–2 Hz 100°/s sinusoidal whole-body rotations in darkness on an Earth-vertical axis rotary chair were tested for subjects MVI002–MVI004 before surgery (preop); 3 weeks after surgery, just before implant activation (postop); and at the most recent study visit (after 812, 738, 782, and 354 days of continuous stimulation, respectively) with MVI motion modulation on (modulation ON) or with a placebo constant-rate stimulus (modulation OFF). VOR (A) gain and (B) phase lead are shown individually for each subject. Each data point is the cycle-averaged mean for n = 2–32 (median 12.5) cycles. Phase lead is positive when rightward eye velocity leads leftward head velocity and was computed when VOR responses were more than 1.5°/s. Population mean ± SD is shown when data are present for all 3 subjects. Normal mean and ranges within ± 1 SD and ± 2 SD are shown for normal 50- to 69-year-old subjects as reported by Wall et al. (49). Supplemental Figure 6 details data individually for each subject, including MVI001, who did not undergo preoperative testing with this paradigm.