An Implanted Vestibular Prosthesis Improves Spatial Orientation in Animals with Severe Vestibular Damage.

Gravity is a pervasive environmental stimulus, and accurate graviception is required for optimal spatial orientation and postural stability. The primary graviceptors are the vestibular organs, which include angular velocity (semicircular canals) and linear acceleration (otolith organs) sensors. Graviception is degraded in patients with vestibular damage, resulting in spatial misperception and imbalance. Since minimal therapy is available for these patients, substantial effort has focused on developing a vestibular prosthesis or vestibular implant (VI) that reproduces information normally provided by the canals (since reproducing otolith function is very challenging technically). Prior studies demonstrated that angular eye velocity responses could be driven by canal VI-mediated angular head velocity information, but it remains unknown whether a canal VI could improve spatial perception and posture since these behaviors require accurate estimates of angular head position in space relative to gravity. Here, we tested the hypothesis that a canal VI that transduces angular head velocity and provides this information to the brain via motion-modulated electrical stimulation of canal afferent nerves could improve the perception of angular head position relative to gravity in monkeys with severe vestibular damage. Using a subjective visual vertical task, we found that normal female monkeys accurately sensed the orientation of the head relative to gravity during dynamic tilts, that this ability was degraded following bilateral vestibular damage, and improved when the canal VI was used. These results demonstrate that a canal VI can improve graviception in vestibulopathic animals, suggesting that it could reduce the disabling perceptual and postural deficits experienced by patients with severe vestibular damage.SIGNIFICANCE STATEMENT Patients with vestibular damage experience impaired vision, spatial perception, and balance, symptoms that could potentially respond to a vestibular implant (VI). Anatomic features facilitate semicircular canal (angular velocity) prosthetics but inhibit approaches with the otolith (linear acceleration) organs, and canal VIs that sense angular head velocity can generate compensatory eye velocity responses in vestibulopathic subjects. Can the brain use canal VI head velocity information to improve estimates of head orientation (e.g., head position relative to gravity), which is a prerequisite for accurate spatial perception and posture? Here we show that a canal VI can improve the perception of head orientation in vestibulopathic monkeys, results that are highly significant because they suggest that VIs mimicking canal function can improve spatial orientation and balance in vestibulopathic patients.

Development, manufacturing and application of double-sided flexible implantable microelectrodes.

Many neuroprosthetic applications require the use of very small, flexible multi-channel microelectrodes (e.g. polyimide-based film-like electrodes) to fit anatomical constraints. By arranging the electrode contacts on both sides of the polyimide film, selectivity can be further increased without increasing size. In this work, two approaches to create such double-sided electrodes are described and compared: sandwich electrodes prepared by precisely gluing two single-sided structures together, and monolithic electrodes created using a new double-sided photolithography process. Both methods were successfully applied to manufacture double-sided electrodes for stimulation of the vestibular system. In a case study, the electrodes were implanted in the semicircular canals of three guinea pigs and proven to provide electrical stimulation of the vestibular nerve. For both the monolithic electrodes and the sandwich electrodes, long-term stability and functionality was observed over a period of more than 12 months. Comparing the two types of electrodes with respect to the manufacturing process, it can be concluded that monolithic electrodes are the preferred solution for very thin electrodes (<20 µm), while sandwich electrode technology is especially suitable for thicker electrodes (40-50 µm).

Electrical stimulation of semicircular canal afferents affects the perception of head orientation.

Patients with vestibular dysfunction have visual, perceptual, and postural deficits. While there is considerable evidence that a semicircular canal prosthesis that senses angular head velocity and stimulates canal ampullary nerves can improve vision by augmenting the vestibulo-ocular reflex, no information is available regarding the potential utility of a canal prosthesis to improve perceptual deficits. In this study, we investigated the possibility that electrical stimulation of canal afferents could be used to modify percepts of head orientation. Two rhesus monkeys were trained to align a light bar parallel to gravity, and were tested in the presence and absence of electrical stimulation provided by an electrode implanted in the right posterior canal. While the monkeys aligned the light bar close to the true earth-vertical without stimulation, when the right posterior canal was stimulated their responses deviated toward their left ear, consistent with a misperception of head tilt toward the right. The deviation of the light bar from the earth-vertical exceeded the torsional deviation of the eyes, indicating that the perceptual changes were not simply visual in origin. Eye movements recorded during electrical stimulation in the dark were consistent with isolated activation of right posterior canal afferents, with no evidence of otolith stimulation. These results demonstrate that electrical stimulation of canal afferents affects the perception of head orientation, and therefore suggest that motion-modulated stimulation of canal afferents by a vestibular prosthesis could potentially improve vestibular percepts in patients lacking normal vestibular function.

Adaptation of vestibular tone studied with electrical stimulation of semicircular canal afferents.

Damage to one vestibular labyrinth or nerve causes a central tone imbalance, reflected by prominent spontaneous nystagmus. Central adaptive mechanisms eliminate the nystagmus over several days, and the mechanisms underlying this process have received extensive study. The characteristics of vestibular compensation when the tone imbalance is presented gradually or repeatedly have never been studied. We used high-frequency electrical stimulation of semicircular canal afferents to generate a vestibular tone imbalance and recorded the nystagmus produced when the stimulation was started abruptly or gradually and when it was repeatedly cycled on and off. In the acute-onset protocol, brisk nystagmus occurred when stimulation started, gradually resolved within 1 day, and reversed direction when the stimulation was stopped after 1 week. Repeated stimulation cycles resulted in progressively smaller nystagmus responses. In the slow-onset protocol, minimal nystagmus occurred while the stimulation ramped-up to its maximum rate over 12 h, but a reversal still occurred when the stimulation was stopped after 1 week, and repeated stimulation cycles did not affect this pattern. The absence of nystagmus during the 12 h ramp of stimulation demonstrates that central vestibular tone can rebalance relatively quickly, and the reduction in the stimulation-off nystagmus with repeated cycles of the acute-onset but not the slow-onset stimulation suggests that dual-state adaptation may have occurred with the former paradigm but not the latter.

Spatial and temporal properties of eye movements produced by electrical stimulation of semicircular canal afferents.

To investigate the characteristics of eye movements produced by electrical stimulation of semicircular canal afferents, we studied the spatial and temporal features of eye movements elicited by short-term lateral canal stimulation in two squirrel monkeys with plugged lateral canals, with the head upright or statically tilted in the roll plane. The electrically induced vestibuloocular reflex (eVOR) evoked with the head upright decayed more quickly than the stimulation signal provided by the electrode, demonstrating an absence of the classic velocity storage effect that improves the dynamics of the low-frequency VOR. When stimulation was provided with the head tilted in roll, however, the eVOR decayed more rapidly than when the head was upright, and a cross-coupled vertical response developed that shifted the eye's rotational axis toward alignment with gravity. These results demonstrate that rotational information provided by electrical stimulation of canal afferents interacts with otolith inputs (or other graviceptive cues) in a qualitatively normal manner, a process that is thought to be mediated by the velocity storage network. The observed interaction between the eVOR and graviceptive cues is of critical importance for the development of a functionally useful vestibular prosthesis. Furthermore, the presence of gravity-dependent effects (dumping, spatial orientation) despite an absence of low-frequency augmentation of the eVOR has not been previously described in any experimental preparation.

Responses evoked by a vestibular implant providing chronic stimulation.

Patients with bilateral vestibular loss experience dehabilitating visual, perceptual, and postural difficulties, and an implantable vestibular prosthesis that could improve these symptoms would be of great benefit to these patients. In previous work, we have shown that a one-dimensional, unilateral canal prosthesis can improve the vestibulooccular reflex (VOR) in canal-plugged squirrel monkeys. In addition to the VOR, the potential effects of a vestibular prosthesis on more complex, highly integrative behaviors, such as the perception of head orientation and posture have remained unclear. We tested a one-dimensional, unilateral prosthesis in a rhesus monkey with bilateral vestibular loss and found that chronic electrical stimulation partially restored the compensatory VOR and also that percepts of head orientation relative to gravity were improved. However, the one-dimensional prosthetic stimulation had no clear effect on postural stability during quiet stance, but sway evoked by head-turns was modestly reduced. These results suggest that not only can the implementation of a vestibular prosthesis provide partial restitution of VOR but may also improve perception and posture in the presence of bilateral vestibular hypofunction (BVH). In this review, we provide an overview of our previous and current work directed towards the eventual clinical implementation of an implantable vestibular prosthesis.

Attenuation of eye movements evoked by a vestibular implant at the frequency of the baseline pulse rate.

We are developing a vestibular implant to electrically stimulate vestibular neurons in the semicircular canals in order to alleviate vertigo, which is a commonly occurring problem. However, since electrical stimulation causes synchronous (phase-locked) neural responses, such electrical stimulation might also cause inappropriate vestibuloocular eye movements, which might, in turn, cause visual blurring. We investigated the eye movements evoked in the guinea pig using electric stimulation with a constant rate of 250 pulses per second (pps), and measured 0.010(°) peak-to-peak eye movements on an average at 250 Hz, with an average peak velocity amplitude of 8.1(°)/s, which might cause visual blurring. However, after half an hour of stimulation, that component reduced to 1.6(°)/s (0.0020(°) peak-to-peak). The average time constant for this reduction was 5.0 min. After one week of constant stimulation, the 250-Hz response component was only slightly smaller, at 1.2(°)/s (0.0015(°) peak-to-peak). We conclude that although an electrical prosthesis with a resting rate of 250 pps may cause some visual blurring when first turned on, such blurring is very likely to attenuate and be imperceptible within several minutes.

Vestibular prosthesis tested in rhesus monkeys.

We are studying the effectiveness of a semicircular canal prosthesis to improve postural control, perception of spatial orientation, and the VOR in rhesus monkeys with bilateral vestibular hypofunction. Balance is examined by measuring spontaneous sway of the body during quiet stance and postural responses evoked by head turns and rotation of the support surface; perception is measured with a task derived from the subjective visual vertical (SVV) test during static and dynamic rotation in the roll plane; and the angular VOR is measured during rotation about the roll, pitch, and yaw axes. After the normal responses are characterized, bilateral vestibular loss is induced with intratympanic gentamicin, and then multisite stimulating electrodes are chronically implanted into the ampullae of all three canals in one ear. The postural, perceptual, and VOR responses are then characterized in the ablated state, and then bilateral, chronic electrical stimulation is applied to the ampullary nerves using a prosthesis that senses angular head velocity in three-dimensions and uses this information to modulate the rate of current pulses provided by the implanted electrodes. We are currently characterizing two normal monkeys with these paradigms, and vestibular ablation and electrode implantation are planned for the near future. In one prior rhesus monkey tested with this approach, we found that a one-dimensional (posterior canal) prosthesis improved balance during head turns, perceived head orientation during roll tilts, and the VOR in the plane of the instrumented canal. We therefore predict that the more complete information provided by a three-dimensional prosthesis that modulates activity in bilaterally-paired canals will exceed the benefits provided by the one-dimensional, unilateral approach used in our preliminary studies.

Vestibuloocular reflex adaptation investigated with chronic motion-modulated electrical stimulation of semicircular canal afferents.

To investigate vestibuloocular reflex (VOR) adaptation produced by changes in peripheral vestibular afference, we developed and tested a vestibular "prosthesis" that senses yaw-axis angular head velocity and uses this information to modulate the rate of electrical pulses applied to the lateral canal ampullary nerve. The ability of the brain to adapt the different components of the VOR (gain, phase, axis, and symmetry) during chronic prosthetic electrical stimulation was studied in two squirrel monkeys. After characterizing the normal yaw-axis VOR, electrodes were implanted in both lateral canals and the canals were plugged. The VOR in the canal-plugged/instrumented state was measured and then unilateral stimulation was applied by the prosthesis. The VOR was repeatedly measured over several months while the prosthetic stimulation was cycled between off, low-sensitivity, and high-sensitivity stimulation states. The VOR response initially demonstrated a low gain, abnormal rotational axis, and substantial asymmetry. During chronic stimulation the gain increased, the rotational axis improved, and the VOR became more symmetric. Gain changes were augmented by cycling the stimulation between the off and both low- and high-sensitivity states every few weeks. The VOR time constant remained low throughout the period of chronic stimulation. These results demonstrate that the brain can adaptively modify the gain, axis, and symmetry of the VOR when provided with chronic motion-modulated electrical stimulation by a canal prosthesis.

Vestibulo-ocular responses evoked via bilateral electrical stimulation of the lateral semicircular canals.

We investigated the vestibulo-ocular responses (VORs) evoked by bilateral electrical stimulation of the nerves innervating horizontal semicircular canals in squirrel monkeys and compared these responses to those evoked by unilateral stimulation. In response to sinusoidal modulation of the electrical pulse rate, the VOR for bilateral stimulation roughly equals the addition of the responses evoked by unilateral right ear and unilateral left ear stimulation; the VOR time constants were about the same for bilateral and unilateral stimulation and both were much shorter than for normal animals. In response to individual pulse stimulation, the VOR evoked by bilateral stimulation closely matches the point-by-point addition of responses evoked by unilateral right ear and unilateral left ear stimulation. We conclude that, to first order, the VOR responses evoked by bilateral stimulation are the summation of the responses evoked by unilateral stimulation. These findings suggest that--from a physiologic viewpoint--unilateral and bilateral vestibular prostheses are about equally viable. Given these findings, one possible advantage of a bilateral prosthesis is higher gain. However, at least for short-term stimulation such as that studied herein, no inherent advantage in terms of the response time constant ("velocity storage") was found.

Chronic vestibulo-ocular reflexes evoked by a vestibular prosthesis.

We are developing prosthetics for patients suffering from peripheral vestibular dysfunction. We tested a sensory-replacement prosthesis that stimulates neurons innervating the vestibular system by providing chronic pulsatile stimulation to electrodes placed in monkeys' lateral semicircular canals, which were plugged bilaterally, and used head angular velocity to modulate the current pulse rate. As an encouraging finding, we observed vestibulo-ocular reflexes that continued to be evoked by the motion-modulated stimulation months after the nystagmus evoked by the constant-rate baseline stimulation had dissipated. This suggests that long-term functional replacement of absent vestibular function is feasible.

Acclimation to chronic constant-rate peripheral stimulation provided by a vestibular prosthesis.

We are developing two types of vestibular prosthetics that electrically stimulate afferent neurons. One type replaces absent sensory function by providing stimulation that modulates above and below a baseline established with the head stationary. The other type provides constant stimulation and is turned on only when necessary, for example, to override unnatural variations like those experienced by patients suffering from Ménère's syndrome; this prosthesis does not provide motion information. Both prostheses require neural plasticity, which we investigated by providing chronic constant-rate stimulation to semicircular canal neurons in three guinea pigs. The stimulation was alternately switched on or off for eight consecutive weeks before being switched daily. A brisk horizontal nystagmus was measured when the stimulation was first turned on and then dissipated over the course of a day. The nystagmus demonstrated an after-effect in the opposite direction when the stimulation was turned off. The nystagmus that we measured after just a few (2 to 5) off-to-on transitions returned to baseline more rapidly than when first turned on. In fact, after many such off-to-on or on-to-off transitions, little nystagmus was evoked by turning the stimulation on or off. These findings show that the brain acclimates to constant-rate stimulation.

System design and performance of a unilateral horizontal semicircular canal prosthesis.

We have reported preliminary results regarding a prototype semicircular canal prosthesis and concluded that it can provide rotational cues to the nervous system. This paper presents the system design of the prosthesis, and also reports the prosthesis system performance and effectiveness. The prosthesis delivers electrical pulses to the nerve branch innervating the horizontal semicircular canal on one side via implanted electrodes. To allow us to encode both directions of angular velocity, the baseline stimulation pulse frequency was set at 150 Hz, which is somewhat higher than the average firing rate of afferents innervating the semicircular canals in normal guinea pigs (approximately 60Hz). A sensor measures angular velocity to modulate (increase or decrease) the pulse rate. The prosthetic system was provided to a guinea pig whose horizontal canals were surgically plugged. The animal responded to the baseline stimulation initially and adapted to the baseline stimulation in roughly one day. After this baseline adaptation the animal responded to yaw rotation, showing that the function of the canals was partially restored. The experiments also show that the nervous system adapts to the artificial rotational cue provided via electrical stimulation.

Vestibular adaptation studied with a prosthetic semicircular canal.

We have developed and tested a prosthetic semicircular canal that senses angular head velocity and uses this information to modulate the rate of current pulses applied to the vestibular nerve via a stimulating electrode. In one squirrel monkey, the lateral canals were plugged bilaterally and the prosthesis was secured to the animal's head with the angular velocity sensor parallel to the axis of the lateral canals. In the first experiment, the stimulating electrode was placed near the ampullary nerve of one lateral canal. Over a period of two weeks, the gain of the horizontal VOR during yaw axis rotation gradually increased, although the response magnitude remained relatively small. In the second experiment, the stimulating electrode was placed near the ampullary nerve of the posterior canal, but the orientation of the velocity sensor remained parallel to the axis of the lateral canals. Over a one-week period, the axis of the VOR response gradually shifted towards alignment with the (yaw) axis of head rotation. Chronic patterned stimulation of the eighth nerve can therefore provide adequate information to the brain to generate a measurable VOR response, and this can occur even if the prosthetic yaw rotation cue is provided via a branch of the VIIIth nerve that doesn't normally carry yaw rotational cues. The results provided by this pilot study suggest that it may be feasible to study central adaptation by chronically modifying the afferent vestibular cue with a prosthetic semicircular canal.