Vestibular Prosthesis Research Articles

Analysis of Vestibular Labyrinthine Geometry and Variation in the Human Temporal Bone.

Stable posture and body movement in humans is dictated by the precise functioning of the ampulla organs in the semi-circular canals. Statistical analysis of the interrelationship between bony and membranous compartments within the semi-circular canals is dependent on the visualization of soft tissue structures. Thirty-one human inner ears were prepared, post-fixed with osmium tetroxide and decalcified for soft tissue contrast enhancement. High resolution X-ray microtomography images at 15 μm voxel-size were manually segmented. This data served as templates for centerline generation and cross-sectional area extraction. Our estimates demonstrate the variability of individual specimens from averaged centerlines of both bony and membranous labyrinth. Centerline lengths and cross-sectional areas along these lines were identified from segmented data. Using centerlines weighted by the inverse squares of the cross-sectional areas, plane angles could be quantified. The fit planes indicate that the bony labyrinth resembles a Cartesian coordinate system more closely than the membranous labyrinth. A widening in the membranous labyrinth of the lateral semi-circular canal was observed in some of the specimens. Likewise, the cross-sectional areas in the perilymphatic spaces of the lateral canal differed from the other canals. For the first time we could precisely describe the geometry of the human membranous labyrinth based on a large sample size. Awareness of the variations in the canal geometry of the membranous and bony labyrinth would be a helpful reference in designing electrodes for future vestibular prosthesis and simulating fluid dynamics more precisely.

An Engineering Model to Test for Sensory Reweighting: Nonhuman Primates Serve as a Model for Human Postural Control and Vestibular Dysfunction.

Quantitative animal models are critically needed to provide proof of concept for the investigation of rehabilitative balance therapies (e.g., invasive vestibular prostheses) and treatment response prior to, or in conjunction with, human clinical trials. This paper describes a novel approach to modeling the nonhuman primate postural control system. Our observation that rhesus macaques and humans have even remotely similar postural control motivates the further application of the rhesus macaque as a model for studying the effects of vestibular dysfunction, as well as vestibular prosthesis-assisted states, on human postural control. Previously, system identification methodologies and models were only used to describe human posture. However, here we utilized pseudorandom, roll-tilt balance platform stimuli to perturb the posture of a rhesus monkey in normal and mild vestibular (equilibrium) loss states. The relationship between rhesus monkey trunk sway and platform roll-tilt was determined via stimulus-response curves and transfer function results. A feedback controller model was then used to explore sensory reweighting (i.e., changes in sensory reliance), which prevented the animal from falling off of the tilting platform. Conclusions involving sensory reweighting in the nonhuman primate for a normal sensory state and a state of mild vestibular loss led to meaningful insights. This first-phase effort to model the balance control system in nonhuman primates is essential for future investigations toward the effects of invasive rehabilitative (balance) technologies on postural control in primates, and ultimately, humans.

Severe streptomycin ototoxicity in the mouse utricle leads to a flat epithelium but the peripheral neural degeneration is delayed

The damaged vestibular sensory epithelium of mammals has a limited capacity for spontaneous hair cell regeneration, which largely depends on the transdifferentiation of surviving supporting cells. Little is known about the response of vestibular supporting cells to a severe insult. In the present study, we evaluated the impact of a severe ototoxic insult on the histology of utricular supporting cells and the changes in innervation that ensued. We infused a high dose of streptomycin into the mouse posterior semicircular canal to induce a severe lesion in the utricle. Both scanning electron microscopy and light microscopy of plastic sections showed replacement of the normal cytoarchitecture of the epithelial layer with a flat layer of cells in most of the samples. Immunofluorescence staining showed numerous cells in the severely damaged epithelial layer that were negative for hair cell and supporting cell markers. Nerve fibers under the flat epithelium had high density at the 1 month time point but very low density by 3 months. Similarly, the number of vestibular ganglion neurons was unchanged at 1 month after the lesion, but was significantly lower at 3 months. We therefore determined that the mouse utricular epithelium turns into a flat epithelium after a severe lesion, but the degeneration of neural components is slow, suggesting that treatments to restore balance by hair cell regeneration, stem cell therapy or vestibular prosthesis implantation will likely benefit from the short term preservation of the neural substrate.

Noisy galvanic vestibular stimulation: an emerging treatment option for bilateral vestibulopathy.

Patients with bilateral vestibulopathy (BVP) suffer from persistent imbalance during standing and walking as well as an impaired gaze stabilization during head movements. Disabilities associated with BVP severely compromise patients' daily activities and are often linked to an increased risk of falls. Currently, the only established treatment option in BVP is physical therapy. However, treatment effects of physical therapy in BVP are most often limited and many patients do not adequately recover performance. Therefore, a number of technical therapeutic approaches are being explored that either try to substitute lost vestibular sensation with a congruent stimulation of other sense modalities or to artificially mimic vestibular function by means of an implantable vestibular prosthesis. Besides, attempts have recently been made to augment and optimize residual vestibular function in patients with BVP using an imperceptible noisy galvanic vestibular stimulation (nGVS). This approach is based on the natural phenomenon of stochastic resonance, wherein the signal processing in sensory systems can be improved by adding an appropriate level of noise to the system. Promising first study outcomes of nGVS treatment in patients with BVP indicate the feasibility of a future non-invasive sensory prosthetic device for BVP rehabilitation. This paper gives an overview about recent research on nGVS treatment in patients with BVP and discusses future research perspectives in this field.

A dual-axis single-proof-mass angular accelerometer for a vestibular prosthesis.

A dual-axis single-proof-mass angular accelerometer has been developed for a vestibular prosthesis. Designed to sense head rotations both in the yaw and the pitch planes, the output of the inertial sensor may be coded as amplitude or rate modulated biphasic current pulses to stimulate vestibular nerves. Fabricated with a high aspect ratio commercial process, a sensor with small form factor (1.4 mm × 0.8 mm) is achieved with a scale factor of 95.5 μV/rad/sec2 and 145.8 μV/rad/sec2 in the yaw and the pitch planes, respectively. Superior linear acceleration rejection was demonstrated for both rotating axis, and an overall power consumption of 296 μW was estimated including sensor and interface circuit.

Design of a Vestibular Prosthesis for Sensation of Gravitoinertial Acceleration1

Design of a Vestibular Prosthesis for Sensation of Gravitoinertial Acceleration1

Anatomy and surgical approach of rat’s vestibular sensors and nerves

BackgroundThe rat is one of the most used species in the neurosciences, but how to selectively reach each of its 5 vestibular sensors has never been described. Besides, new functions of the vestibular system have been recently discovered in the rat involving vegetative, circadian and cognitive functions. But the central pathways sustaining these functions and the role of each of the vestibular sensors are not clear. New methodsHere we want to describe the anatomy and look for a direct surgical approach to the 5 vestibular sensors in rats, as an indispensable technique to further study the central vestibular pathways.To do so we studied 10 rats either by microtomography with osmium tetroxide staining, histology with hematoxilyn-eosine staining or microsurgical dissection. ResultsThe microtomography allows a 3D representation of the 5 vestibular sensors and their nerves, with precise landmarks confirmed by the histological analysis. Each of the landmarks are illustrated and a selective surgical approach to each sensor and their nerves, is described step by step. Comparison with existing methodSelective approaches to the vestibular sensors have been used in other species such as cats, monkeys and recently humans but the current study is the first allowing this technique in rats. ConclusionEach vestibular sensor of the rat can be reached by a selective surgical approach. This allows further techniques such as electrophysiology or neurotracing of the central vestibular pathways. This also indicates the rat as a potential model for vestibular prostheses.

A Low-Power ASIC Signal Processor for a Vestibular Prosthesis.

A low-power ASIC signal processor for a vestibular prosthesis (VP) is reported. Fabricated with TI 0.35 μm CMOS technology and designed to interface with implanted inertial sensors, the digitally assisted analog signal processor operates extensively in the CMOS subthreshold region. During its operation the ASIC encodes head motion signals captured by the inertial sensors as electrical pulses ultimately targeted for in-vivo stimulation of vestibular nerve fibers. To achieve this, the ASIC implements a coordinate system transformation to correct for misalignment between natural sensors and implanted inertial sensors. It also mimics the frequency response characteristics and frequency encoding mappings of angular and linear head motions observed at the peripheral sense organs, semicircular canals and otolith. Overall the design occupies an area of 6.22 mm (2) and consumes 1.24 mW when supplied with ± 1.6 V.

Perception of Discomfort Caused by a Unilateral Hearing Loss in People Suffering from a Total Bilateral Vestibular Loss

The quality of life of patients suffering from a bilateral vestibular loss is severely altered. Patients mainly complain of oscillopsia, imbalance, and spatial disorientation. Up to now, there is no efficient treatment. Some teams around the world are working on the development of a vestibular implant for the restoration of the vestibular function based on the concept similar to that of a cochlear implant, stimulating the neural vestibular pathways through electrical pulses. There are different potential stimulation sites of the vestibular system, all raising the major concern about a potential hearing loss in the implanted ear. As this implant does not exist yet, patients cannot be informed of the risk of hearing loss due to the surgical intervention versus the benefits brought by the vestibular prosthesis. In order to better inform future vestibular implant candidates, we need to evaluate the handicap of patients with an actual unilateral hearing loss, and to compare it to the way that patients suffering from a bilateral vestibular loss perceive a potential unilateral hearing loss. For this, we used the HHIA questionnaire (Hearing Handicap Inventory for Adults) on 3 groups of participants, i.e. patients with a unilateral hearing loss, patients suffering from a bilateral vestibular loss but having normal hearing, and healthy subjects. The scores reported by patients with a unilateral hearing loss were much lower than those of the other 2 groups, indicating that people whose hearing is normal overstate the disability related to a unilateral hearing loss. Patients to whom a vestibular implant is proposed in order to correct their balance disorders may use this information to decide whether or not to choose an operation.

A CMOS Neural Interface for a Multichannel Vestibular Prosthesis.

We present a high-voltage CMOS neural-interface chip for a multichannel vestibular prosthesis (MVP) that measures head motion and modulates vestibular nerve activity to restore vision- and posture-stabilizing reflexes. This application specific integrated circuit neural interface (ASIC-NI) chip was designed to work with a commercially available microcontroller, which controls the ASIC-NI via a fast parallel interface to deliver biphasic stimulation pulses with 9-bit programmable current amplitude via 16 stimulation channels. The chip was fabricated in the ONSemi C5 0.5 micron, high-voltage CMOS process and can accommodate compliance voltages up to 12 V, stimulating vestibular nerve branches using biphasic current pulses up to 1.45±0.06 mA with durations as short as 10 μs/phase. The ASIC-NI includes a dedicated digital-to-analog converter for each channel, enabling it to perform complex multipolar stimulation. The ASIC-NI replaces discrete components that cover nearly half of the 2nd generation MVP (MVP2) printed circuit board, reducing the MVP system size by 48% and power consumption by 17%. Physiological tests of the ASIC-based MVP system (MVP2A) in a rhesus monkey produced reflexive eye movement responses to prosthetic stimulation similar to those observed when using the MVP2. Sinusoidal modulation of stimulus pulse rate from 68-130 pulses per second at frequencies from 0.1 to 5 Hz elicited appropriately-directed slow phase eye velocities ranging in amplitude from 1.9-16.7 °/s for the MVP2 and 2.0-14.2 °/s for the MVP2A. The eye velocities evoked by MVP2 and MVP2A showed no significant difference ( t-test, p=0.34), suggesting that the MVP2A achieves performance at least as good as the larger MVP2.

Lessons learned from cochlear implants that are relevant to a vestibular prosthesis

In October, 2010, we began human studies of a vestibular prosthesis. Our goal is to develop a device for the management of several vestibular disorders that defy existing treatment modalities. We have long-term data on four human subjects and ten non-human primates and are awaiting regulatory approval of our second-generation device, modified based on that data. We have been guided by a wealth of information based on lessons learned from cochlear implants. These lessons include first and foremost the otherwise hubristic idea that an effective vestibular prosthesis is technically feasible. Indeed the extraordinary compensation mechanisms of the central vestibular system convince us that such a prosthesis could be even more effective than for hearing. Second, the ability to leverage CI engineering expertise and industry relationships has been critical to our success so far. Third, the regulatory comfort with the success and favorable risk profile of cochlear implants has greatly speeded up human translation. Fourth, surgical familiarity with these devices has greatly enabled our research and facilitates future multicenter studies. Lastly, experience with “soft-surgery”, hearing preservation, and single-sided deafness cochlear implantation holds forth alluring possibilities for the range of vestibular disorders that may eventually succumb to this closely related technology.

Histopathologic Changes of the Inner ear in Rhesus Monkeys After Intratympanic Gentamicin Injection and Vestibular Prosthesis Electrode Array Implantation.

Bilateral vestibular deficiency (BVD) due to gentamicin ototoxicity can significantly impact quality of life and result in large socioeconomic burdens. Restoring sensation of head rotation using an implantable multichannel vestibular prosthesis (MVP) is a promising treatment approach that has been tested in animals and humans. However, uncertainty remains regarding the histopathologic effects of gentamicin ototoxicity alone or in combination with electrode implantation. Understanding these histological changes is important because selective MVP-driven stimulation of semicircular canals (SCCs) depends on persistence of primary afferent innervation in each SCC crista despite both the primary cause of BVD (e.g., ototoxic injury) and surgical trauma associated with MVP implantation. Retraction of primary afferents out of the cristae and back toward Scarpa's ganglion would render spatially selective stimulation difficult to achieve and could limit utility of an MVP that relies on electrodes implanted in the lumen of each ampulla. We investigated histopathologic changes of the inner ear associated with intratympanic gentamicin (ITG) injection and/or MVP electrode array implantation in 11 temporal bones from six rhesus macaque monkeys. Hematoxylin and eosin-stained 10-μm temporal bone sections were examined under light microscopy for four treatment groups: normal (three ears), ITG-only (two ears), MVP-only (two ears), and ITG + MVP (four ears). We estimated vestibular hair cell (HC) surface densities for each sensory neuroepithelium and compared findings across end organs and treatment groups. In ITG-only, MVP-only, and ITG + MVP ears, we observed decreased but persistent ampullary nerve fibers of SCC cristae despite ITG treatment and/or MVP electrode implantation. ITG-only and ITG + MVP ears exhibited neuroepithelial thinning and loss of type I HCs in the cristae but little effect on the maculae. MVP-only and ITG + MVP ears exhibited no signs of trauma to the cochlea or otolith end organs except in a single case of saccular injury due to over-insertion of the posterior SCC electrode. While implanted electrodes reached to within 50-760 μm of the target cristae and were usually ensheathed in a thin fibrotic capsule, dense fibrotic reaction and osteoneogenesis were each observed in only one of six electrode tracts examined. Consistent with physiologic studies that have demonstrated directionally appropriate vestibulo-ocular reflex responses to MVP electrical stimulation years after implantation in these animals, histologic findings in the present study indicate that although intralabyrinthine MVP implantation causes some inner ear trauma, it can be accomplished without destroying the distal afferent fibers an MVP is designed to excite.

A Computational Framework for Electrical Stimulation of Vestibular Nerve.

The vestibular organs are very important to generate reflexes critical for stabilizing gaze and body posture. Vestibular diseases significantly reduce the quality of life of people who are affected by them. Some research groups have recently started developing vestibular neuroprostheses to mitigate these symptoms. However, many scientific and technological issues need to be addressed to optimise their use in clinical trials. We developed a computational model able to mimic the response of human vestibular nerves and which can be exploited for "in-silico" testing of new strategies to design implantable vestibular prostheses. First, a digital model of the vestibular system was reconstructed from anatomical data. Monopolar stimulation was delivered at different positions and distances from ampullary nerves. The electrical potential induced by the injected current was computed through finite-element methods and drove extra-cellular stimulation of fibers in the vestibular, facial, and cochlear nerves. The electrical activity of vestibular nerves and the resulting eye movements elicited by different stimulation protocols were investigated. A set of electrode configurations was analyzed in terms of selectivity at increasing injected current. Electrode position along the nerve plays a major role in producing undesired activity in other nontargeted nerves, whereas distance from the fiber does not significantly affect selectivity. Indications are provided to minimize misalignment in nonoptimal electrode locations. Eye movements elicited by the different stimulation protocols are calculated and compared to experimental values, for the purpose of model validation.

Vestibular implantation and longitudinal electrical stimulation of the semicircular canal afferents in human subjects.

Animal experiments and limited data in humans suggest that electrical stimulation of the vestibular end organs could be used to treat loss of vestibular function. In this paper we demonstrate that canal-specific two-dimensionally (2D) measured eye velocities are elicited from intermittent brief 2 s biphasic pulse electrical stimulation in four human subjects implanted with a vestibular prosthesis. The 2D measured direction of the slow phase eye movements changed with the canal stimulated. Increasing pulse current over a 0-400 μA range typically produced a monotonic increase in slow phase eye velocity. The responses decremented or in some cases fluctuated over time in most implanted canals but could be partially restored by changing the return path of the stimulation current. Implantation of the device in Meniere's patients produced hearing and vestibular loss in the implanted ear. Electrical stimulation was well tolerated, producing no sensation of pain, nausea, or auditory percept with stimulation that elicited robust eye movements. There were changes in slow phase eye velocity with current and over time, and changes in electrically evoked compound action potentials produced by stimulation and recorded with the implanted device. Perceived rotation in subjects was consistent with the slow phase eye movements in direction and scaled with stimulation current in magnitude. These results suggest that electrical stimulation of the vestibular end organ in human subjects provided controlled vestibular inputs over time, but in Meniere's patients this apparently came at the cost of hearing and vestibular function in the implanted ear.

Longitudinal performance of an implantable vestibular prosthesis

Loss of vestibular function may be treatable with an implantable vestibular prosthesis that stimulates semicircular canal afferents with biphasic pulse trains. Several studies have demonstrated short-term activation of the vestibulo-ocular reflex (VOR) with electrical stimulation. Fewer long-term studies have been restricted to small numbers of animals and stimulation designed to produce adaptive changes in the electrically elicited response. This study is the first large consecutive series of implanted rhesus macaque to be studied longitudinally using brief stimuli designed to limit adaptive changes in response, so that the efficacy of electrical activation can be studied over time, across surgeries, canals and animals. The implantation of a vestibular prosthesis in animals with intact vestibular end organs produces variable responses to electrical stimulation across canals and animals, which change in threshold for electrical activation of eye movements and in elicited slow phase velocities over time. These thresholds are consistently lower, and the slow phase velocities higher, than those obtained in human subjects. The changes do not appear to be correlated with changes in electrode impedance. The variability in response suggests that empirically derived transfer functions may be required to optimize the response of individual canals to a vestibular prosthesis, and that this function may need to be remapped over time.This article is part of a Special Issue entitled <Lasker Award>.

A low-power, time-division-multiplexed vector matrix-multiplier for a vestibular prosthesis.

A custom analog vector matrix multiplier (VMM) for a vestibular prosthesis is reported. The VMM functions to reduce misalignment between implanted angular rate sensors and associated peripheral sense organs and precompensate for spurious electrical stimulation of vestibular neurons. Operating in the CMOS subthreshold region, the VMM performs a 3-by-3 vector matrix multiplication of rate sensor outputs, magnitude <; ±250 mV, and bandwidth <; 1.25 kHz. To reduce susceptibility to device mismatches, time-division-multiplexed multiplication is employed requiring 727 μs for a complete operation cycle. Fabricated with TSMC 0.35 μm CMOS technology, the footprint is 1523 μm × 1548 μm and consumes 5.37 μW of power.

A vestibular prosthesis with highly-isolated parallel multichannel stimulation.

This paper presents an implantable vestibular stimulation system capable of providing high flexibility independent parallel stimulation to the semicircular canals in the inner ear for restoring three-dimensional sensation of head movements. To minimize channel interaction during parallel stimulation, the system is implemented with a power isolation method for crosstalk reduction. Experimental results demonstrate that, with this method, electrodes for different stimulation channels located in close proximity ( mm) can deliver current pulses simultaneously with minimum inter-channel crosstalk. The design features a memory-based scheme that manages stimulation to the three canals in parallel. A vestibular evoked potential (VEP) recording unit is included for closed-loop adaptive stimulation control. The main components of the prototype vestibular prosthesis are three ASICs, all implemented in a 0.6- μm high-voltage CMOS technology. The measured performance was verified using vestibular electrodes in vitro.

Pulsed infrared radiation excites cultured neonatal spiral and vestibular ganglion neurons by modulating mitochondrial calcium cycling.

Cochlear implants are currently the most effective solution for profound sensorineural hearing loss, and vestibular prostheses are under development to treat bilateral vestibulopathies. Electrical current spread in these neuroprostheses limits channel independence and, in some cases, may impair their performance. In comparison, optical stimuli that are spatially confined may result in a significant functional improvement. Pulsed infrared radiation (IR) has previously been shown to elicit responses in neurons. This study analyzes the response of neonatal rat spiral and vestibular ganglion neurons in vitro to IR (wavelength = 1,863 nm) using Ca(2+) imaging. Both types of neurons responded consistently with robust intracellular Ca(2+) ([Ca(2+)]i) transients that matched the low-frequency IR pulses applied (4 ms, 0.25-1 pps). Radiant exposures of ∼637 mJ/cm(2) resulted in continual neuronal activation. Temperature or [Ca(2+)] variations in the media did not alter the IR-evoked transients, ruling out extracellular Ca(2+) involvement or primary mediation by thermal effects on the plasma membrane. While blockage of Na(+), K(+), and Ca(2+) plasma membrane channels did not alter the IR-evoked response, blocking of mitochondrial Ca(2+) cycling with CGP-37157 or ruthenium red reversibly inhibited the IR-evoked [Ca(2+)]i transients. Additionally, the magnitude of the IR-evoked transients was dependent on ryanodine and cyclopiazonic acid-dependent Ca(2+) release. These results suggest that IR modulation of intracellular calcium cycling contributes to stimulation of spiral and vestibular ganglion neurons. As a whole, the results suggest selective excitation of neurons in the IR beam path and the potential of IR stimulation in future auditory and vestibular prostheses.

Prosthetic Implantation of the Human Vestibular System

A functional vestibular prosthesis can be implanted in human such that electrical stimulation of each semicircular canal produces canal-specific eye movements while preserving vestibular and auditory function. A number of vestibular disorders could be treated with prosthetic stimulation of the vestibular end organs. We have previously demonstrated in rhesus monkeys that a vestibular neurostimulator, based on the Nucleus Freedom cochlear implant, can produce canal-specific electrically evoked eye movements while preserving auditory and vestibular function. An investigational device exemption has been obtained from the FDA to study the feasibility of treating uncontrolled Ménière's disease with the device. The UW/Nucleus vestibular implant was implanted in the perilymphatic space adjacent to the three semicircular canal ampullae of a human subject with uncontrolled Ménière's disease. Preoperative and postoperative vestibular and auditory function was assessed. Electrically evoked eye movements were measured at 2 time points postoperatively. Implantation of all semicircular canals was technically feasible. Horizontal canal and auditory function were largely, but not totally, lost. Electrode stimulation in 2 of 3 canals resulted in canal-appropriate eye movements. Over time, stimulation thresholds increased. Prosthetic implantation of the semicircular canals in humans is technically feasible. Electrical stimulation resulted in canal-specific eye movements, although thresholds increased over time. Preservation of native auditory and vestibular function, previously observed in animals, was not demonstrated in a single subject with advanced Ménière's disease.

Head movements evoked in alert rhesus monkey by vestibular prosthesis stimulation: implications for postural and gaze stabilization.

The vestibular system detects motion of the head in space and in turn generates reflexes that are vital for our daily activities. The eye movements produced by the vestibulo-ocular reflex (VOR) play an essential role in stabilizing the visual axis (gaze), while vestibulo-spinal reflexes ensure the maintenance of head and body posture. The neuronal pathways from the vestibular periphery to the cervical spinal cord potentially serve a dual role, since they function to stabilize the head relative to inertial space and could thus contribute to gaze (eye-in-head + head-in-space) and posture stabilization. To date, however, the functional significance of vestibular-neck pathways in alert primates remains a matter of debate. Here we used a vestibular prosthesis to 1) quantify vestibularly-driven head movements in primates, and 2) assess whether these evoked head movements make a significant contribution to gaze as well as postural stabilization. We stimulated electrodes implanted in the horizontal semicircular canal of alert rhesus monkeys, and measured the head and eye movements evoked during a 100ms time period for which the contribution of longer latency voluntary inputs to the neck would be minimal. Our results show that prosthetic stimulation evoked significant head movements with latencies consistent with known vestibulo-spinal pathways. Furthermore, while the evoked head movements were substantially smaller than the coincidently evoked eye movements, they made a significant contribution to gaze stabilization, complementing the VOR to ensure that the appropriate gaze response is achieved. We speculate that analogous compensatory head movements will be evoked when implanted prosthetic devices are transitioned to human patients.