Charles Della Santina, M.D., Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Vestibular dysfunction due to ototoxic hair cell injury is a common cause of significant disability due to disequilibrium and inability to stabilize gaze during head movements. Although some patients with bilateral vestibular dysfunction are able to compensate through physical rehabilitation and reliance on other senses, those who fail to compensate currently have no good therapeutic options. Because the vestibular nerve should be intact in these patients, selectively applied electrical currents should be able to drive the nerve and elicit eye movements that can stabilize gaze. [unreadable] The central goal of this project is to further development toward an implantable neuroelectronic prosthesis capable of restoring vestibular function to people with symptomatic bilateral vestibular dysfunction. Although vestibular prosthesis development has lagged that of cochlear implants, one group has recently described a first prototype vestibular prosthesis. However, the eye movements it evoked were insufficient to stabilize gaze during natural head movements, and the experiments were performed on animals with normal vestibular function. It is unclear whether their results generalize to the case of a labyrinth damaged by ototoxicity or Meniere's disease. [unreadable] The proposed project will establish a physiologic and morphologic basis for vestibular prosthesis development, by refining a mammalian model of vestibular ototoxicity and by testing the biologic premises upon which prosthesis design is based. Because viable vestibular nerve afferents must exist for a prosthesis to stimulate, we will determine the effects of gentamicin toxicity on morphology and physiology of afferent fibers in semicircular canal crista. We will characterize the vestibulo-ocular reflex before and after bilateral treatment with ototoxic doses of intratympanic gentamicin. We will characterize the eye movements of bilaterally vestibular-deficient animals in response to single- and multi-canal patterned electrical stimulation of the semicircular canal cristae. We will test whether stimulation of canals in a single labyrinth can be combined to drive eye movements that cover the normal physiologic range. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Bilateral loss of vestibular function (inner ear balance sensation) due to ototoxic hair cell injury is disabling, with patients suffering disequilibrium and inability to maintain stable vision during head movements typical of daily life. While most individuals with partial loss compensate through rehabilitative strategies enlisting other senses, those who fail to compensate for profound loss have no good therapeutic options. Because the vestibular nerve should be intact in many of these patients, electrical stimuli encoding head rotation should be able to drive the nerve and restore sensation of head movement, much like a cochlear implant restores auditory function. The proposed research is guided by two broad goals. The first is to advance development toward an implantable neuroelectronic prosthesis that restores function to people disabled by bilateral loss of vestibular sensation. The second is to drive the field of vestibular neurophysiology though increased understanding of how vestibular nerve activity encodes head motion and through development of technologies that enable use of previously impossible experimental paradigms. This project builds upon significant progress we have already made toward this goal, including: (1) development of a multi-channel, head-mounted prosthesis able to encode three-dimensional (3D) head rotation via electrical stimulation of three or more vestibular nerve branches;(2) characterization of the 3D angular vestibulo-ocular reflex (AVOR), vestibular nerve activity and endorgan histology in chinchillas after vestibular ototoxic injury due to gentamicin treatment;and (3) partial restoration of the 3D AVOR via prosthetic stimulation. These studies have identified channel interaction causing misalignment of eye and head rotation as a key challenge to restoration of a normal 3D aVOR. We hypothesize that misalignment is mainly due to spurious electrical stimulation of bystander vestibular nerve branches by inadequately selective electrodes. In this project, we will: (1) characterize the dependence of 3D AVOR eye rotations on stimulus parameters;(2) determine the extent and time course of adaptation to chronic prosthetic input;and (3) extend our studies from chinchillas to macaque monkeys, which have inner ear dimensions similar to humans. We hypothesize that implanted macaques will exhibit much less misalignment than do chinchillas, and that the modeling and design techniques developed in chinchillas can generalize accurately to primates. Through extrapolation of electrode designs, stimulus optimization protocols, and surgical techniques from rodents to nonhuman primates, this project will set the stage for rational design and initial clinical studies of a multichannel vestibular prosthesis to aid individuals disabled by loss of vestibular sensation.

DESCRIPTION (provided by applicant): This research program is motivated by two interrelated goals. First, we seek to understand the neural mechanisms by which the brain recovers after loss of vestibular (inner ear balance) sensation on one or both sides. Second, we seek to advance development new treatment approaches to maximize quality of life for individuals disabled by disequilibrium and unsteady vision after loss of vestibular sensation. In the United States alone, about 150,000 people suffer disabling vertigo and unsteadiness each year due to acute unilateral loss of vestibular function, while about 250,000 suffer chronic imbalance and unsteady vision typical of severe bilateral loss that fails to resolve despite existing treatments. Sudden, permanent loss of vestibular nerve input from one labyrinth causes disequilibrium and visual blurring due to disruption of the vestibulo-ocular reflex (VOR), which normally maintains stable vision during head movements. This disruption is usually followed by impressive but incomplete recovery. During the previous funding period, we made excellent progress toward defining the dynamics of VOR compensation and the neural mechanisms upon which it depends. In the proposed research program, we will build upon this solid foundation of progress through three interrelated and synergistic aims. Experiments addressing Aim 1 will characterize the role of floccular target neurons [FTN] during VOR compensation after acute unilateral injury, examining dynamic changes in their sensitivity to vestibular, proprioceptive and efference copy signals. We predict that compensation involves a coordinated sequence of adaptive changes in two largely parallel paths (i.e., FTN and position-vestibular-pause [PVP] neurons), because our recent results show that changes in PVP neurons alone are insufficient to explain VOR recovery. Aim 2 is to characterize and optimize the pattern of vestibular nerve activity engendered by a multichannel vestibular prosthesis (MVP) we recently created to restore balance sensation to individuals disabled by loss of inner ear function. These experiments are essential for optimizing MVP performance prior to the start of a clinical trial. Finally, studies in Aim 3 will merge the approaches used in Aims 1 & 2, using the MVP to realize a previously impossible experimental paradigm that will characterize and correlate central vestibular neuron responses and VOR responses during both loss and restoration of sensory input from the vestibular labyrinth. Combined, these studies will (1) enhance our understanding of how the central nervous system adapts after initially disabling injuries; (2) advance development of a potentially revolutionary tool for replacement of labyrinthine sensation; and (3) clarify how neuronal mechanisms thought to underlie learning at a cellular level can be leveraged to optimize recovery of complex behaviors like the VOR in alert animals and, ultimately, in individuals disabled by loss of vestibular sensation.

DESCRIPTION (provided by applicant): Bilateral loss of vestibular function (inner ear balance sensation) is disabling, with affected individuals suffering chronic disequilibrium, increased risk of falls, and inability to maintain stable vision during head movements typical of daily life. Whil most individuals with partial loss compensate through rehabilitative strategies enlisting other senses, those with profound loss who fail to compensate have no good therapeutic options. Because the vestibular nerves are intact in many such cases, electrical stimuli encoding head rotation should be able to drive the nerve and restore sensation of head movement, much like a cochlear implant restores auditory function. The proposed research program represents the fourth step of a five-step plan to develop an effective treatment for individuals disabled by bilateral vestibular deficiency. Step 1 was to establish a neurophysiologic foundation for prosthetic restoration of the 3D VOR in rodents. Step 2 comprised development of the first multichannel, head-mounted vestibular prosthesis able to restore sensation of 3D head rotation. Step 3 optimized stimulus protocols and electrode designs in rodents and then transitioned experiments from acute to chronic and from rodents to nonhuman primates. Step 4 - the current proposal - will translate MVP technology from rhesus monkeys to humans via an early feasibility study of a modified cochlear implant adapted to serve as a vestibular prosthesis, setting the stage for final revisions to MVP designs and a subsequent, large-scale pivotal trial.

Project Summary The central goal of this project is to advance the therapeutic application and the development of an exciting novel neuroprosthetic technology, Safe Direct Current Stimulation (SDCS). Direct current (DC) compared to biphasic charge balanced pulses normally used by neural prostheses to interface to the nervous system, can more naturally control neural activity. Unlike biphasic current pulses used to excite neurons, DC can excite, inhibit, and modulate sensitivity of neurons. However using DC for implantable prosthetic applications has not been possible due to the DC?s inherent violation of the charge injection safety constraints at the metal electrode interfaces. Safe DC overcomes these constraints and opens a new avenue for research into exciting possibilities of using DC to interface to the nervous system. We will optimize the use of SDCS to improve the performance of the vestibular prosthetic for balance disorders. This type of neural implant is designed to deliver the sensation of head motion directly to the vestibular nerve for those suffering from bilateral vestibular dysfunction. We obtained preliminary data in a chinchilla animal model showing that using DC in contrast to the more conventional pulsatile stimulation can dramatically increase the range of head velocities that can be encoded by the device. Here we propose to consider biological safety of long-duration SDCS prosthetic stimulation, and advance the technology SDCS toward primate implantation. Aim 1) Conduct acute behavioral studies in nonhuman primates. Aim 2) Determine whether prolonged DC delivery from the SDCS causes physiologic or histologic signs of damage in chinchillas. Aim 3) Develop a three channel SDCS, lead, and DCtubes designed for future primate chronic vestibular implant studies.

Project Summary Bilateral loss of vestibular sensation is disabling, with affected individuals suffering chronic disequilibrium, increased risk of falls, and inability to maintain stable vision during head movements typical of daily life. While most individuals with milder loss compensate through rehabilitative strategies enlisting other senses, those with severe loss who fail to compensate have no good therapeutic options. When the vestibular nerves are anatomically intact, as is true in most such cases, electrical stimuli encoding head rotation can drive nerve activity and partially restore vestibular sensation, much as a cochlear implant partially restores auditory sensation. In an on-going first-in-human early feasibility study of six adults disabled by bilateral vestibular hypofunction after ototoxic hair cell injury, we found that vestibular implantation and motion-modulated prosthetic stimulation targeting the implanted ear's three semicircular canals is a feasible, safe and effective treatment for ototoxic loss, as evidenced by directionally-aligned vestibulo-ocular reflexes reliably elicited during >3 years of continuous use, improvements in objective measures of posture and gait performance, and improvement of patient-reported dizziness handicap and vestibular-related disability. On the strength of those results, the United States Food & Drug Administration (FDA) has invited a request for humanitarian device exemption for treatment of ototoxic loss; however, FDA advised that additional data would be required to support expanding availability of this treatment to individuals with idiopathic loss, who make up the largest proportion of bilateral vestibular hypofunction cases. Drawing on a well-established design, intact study team, and protocol that yielded highly impactful results in the early feasibility study of subjects with ototoxic loss, the proposed research program will extend this approach to adults disabled by idiopathic adult-onset bilateral vestibular hypofunction. Results of this research are highly likely to yield broad, sustained impact, either through support of early regulatory approval (if results of vestibular implantation for treatment of idiopathic loss are as favorable as the results already obtained for ototoxic loss) or by providing the necessary foundational data to support design of a subsequent, large-scale pivotal trial of vestibular implantation for idiopathic loss.