This research program is motivated by two goals. First, we seek to understand the neural mechanisms by which the brain adapts to changes in vestibular (inner ear balance) input. Second, we seek to advance development of a vestibular prosthesis/implant, a highly innovative treatment approach with potential to improve quality of life for individuals disabled by disequilibrium and unsteady vision after loss of vestibular sensation. In the United States alone, about 150,000 adults suffer disabling vertigo and unsteadiness each year due to acute unilateral loss of vestibular function, while about 65,000 suffer chronic imbalance and unsteady vision typical of severe bilateral sensory loss that fails to resolve despite existing treatments. Sudden, permanent loss of vestibular nerve input causes disequilibrium, visual blurring due to disruption of the vestibulo-ocular reflex (VOR), and postural instability due to disruption of vestibulo-spinal reflexes. These symptoms are usually followed by impressive but incomplete recovery. During the previous funding period, we made excellent progress toward defining the dynamics of compensation in pathways that mediate these vital reflexes. In addition, we established how these pathways respond acutely to activation of a multichannel vestibular prosthesis (MVP). In the proposed research program, we will build upon this solid foundation of progress through 3 synergistic aims. Experiments addressing Aim 1 will determine how central vestibular neurons adapt to the onset of constant prosthetic stimulation, to subsequent cessation of stimulation, and to motion-modulated stimulation. We predict that adaptation predominantly involves changes in one of two parallel paths, and that reduction of afferent discharge synchrony and/or addition of congruent extra-vestibular self-motion cues will further improve responses.
Aim 2 experiments will examine how central neurons process prosthetic vestibular input during natural behaviors such as vergence, active gaze shifts and VOR suppression, which all require context-specific integration of neuronal signals encoding non-vestibular senses and efferent commands. These experiments will extend our investigation beyond reflex pathways and provide both systems and neuronal-level insight into how the central nervous system (CNS) optimizes performance during complex behaviors typical of daily life. Experiments addressing Aim 3 will characterize central vestibular neuron adaptation to natural and prosthetic stimulation during a novel training paradigm designed to reduce VOR asymmetry. Combined, these studies in alert nonhuman primates will enhance understanding of how the CNS adapts to changes in vestibular input; advance development of a potentially revolutionary treatment for loss of inner ear function; and clarify how neuronal mechanisms that underlie learning at a cellular level can be leveraged to optimize recovery of individuals disabled by loss of vestibular sensation.

Public Health Relevance

After loss of vestibular (inner ear balance) sensation, some patients ultimately recover enough to perform daily activities, but many fail to fully compensate and remain disabled by chronic imbalance and inability to see clearly while moving. This research project will identify the neural mechanisms that underlie how the brain adapts to changes in vestibular input, and will advance development of an implantable bionic inner ear device that can help restore quality of life to thousands of individuals disabled by unilateral and bilateral loss of vestibular sensation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC002390-21A1
Application #
9596672
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Poremba, Amy
Project Start
1995-09-01
Project End
2023-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
21
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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Carriot, Jérome; Jamali, Mohsen; Chacron, Maurice J et al. (2017) The statistics of the vestibular input experienced during natural self-motion differ between rodents and primates. J Physiol 595:2751-2766
Mitchell, Diana E; Della Santina, Charles C; Cullen, Kathleen E (2017) Plasticity within excitatory and inhibitory pathways of the vestibulo-spinal circuitry guides changes in motor performance. Sci Rep 7:853
Mitchell, Diana E; Della Santina, Charles C; Cullen, Kathleen E (2016) Plasticity within non-cerebellar pathways rapidly shapes motor performance in vivo. Nat Commun 7:11238
Jamali, Mohsen; Chacron, Maurice J; Cullen, Kathleen E (2016) Self-motion evokes precise spike timing in the primate vestibular system. Nat Commun 7:13229
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Eron, Julia N; Davidovics, Natan; Della Santina, Charles C (2015) Contribution of vestibular efferent system alpha-9 nicotinic receptors to vestibulo-oculomotor interaction and short-term vestibular compensation after unilateral labyrinthectomy in mice. Neurosci Lett 602:156-61
Sun, Daniel Q; Lehar, Mohamed; Dai, Chenkai et al. (2015) Histopathologic Changes of the Inner ear in Rhesus Monkeys After Intratympanic Gentamicin Injection and Vestibular Prosthesis Electrode Array Implantation. J Assoc Res Otolaryngol 16:373-87

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