Natan S. Davidovics

Effects of Biphasic Current Pulse Frequency, Amplitude, Duration, and Interphase Gap on Eye Movement Responses to Prosthetic Electrical Stimulation of the Vestibular Nerve

An implantable prosthesis that stimulates vestibular nerve branches to restore sensation of head rotation and vision-stabilizing reflexes could benefit individuals disabled by bilateral loss of vestibular (inner ear balance) function. We developed a prosthesis that partly restores normal function in animals by delivering pulse frequency modulated (PFM) biphasic current pulses via electrodes implanted in semicircular canals. Because the optimal stimulus encoding strategy is not yet known, we investigated effects of varying biphasic current pulse frequency, amplitude, duration, and interphase gap on vestibulo-ocular reflex (VOR) eye movements in chinchillas. Increasing pulse frequency increased response amplitude while maintaining a relatively constant axis of rotation. Increasing pulse amplitude (range 0-325 μA) also increased response amplitude but spuriously shifted eye movement axis, probably due to current spread beyond the target nerve. Shorter pulse durations (range 28-340 μs) required less charge to elicit a given response amplitude and caused less axis shift than longer durations. Varying interphase gap (range 25-175 μs) had no significant effect. While specific values reported herein depend on microanatomy and electrode location in each case, we conclude that PFM with short duration biphasic pulses should form the foundation for further optimization of stimulus encoding strategies for vestibular prostheses intended to restore sensation of head rotation.

Vestibulo-Ocular Reflex Responses to a Multichannel Vestibular Prosthesis Incorporating a 3D Coordinate Transformation for Correction of Misalignment

There is no effective treatment available for individuals unable to compensate for bilateral profound loss of vestibular sensation, which causes chronic disequilibrium and blurs vision by disrupting vestibulo-ocular reflexes that normally stabilize the eyes during head movement. Previous work suggests that a multichannel vestibular prosthesis can emulate normal semicircular canals by electrically stimulating vestibular nerve branches to encode head movements detected by mutually orthogonal gyroscopes affixed to the skull. Until now, that approach has been limited by current spread resulting in distortion of the vestibular nerve activation pattern and consequent inability to accurately encode head movements throughout the full 3-dimensional (3D) range normally transduced by the labyrinths. We report that the electrically evoked 3D angular vestibulo-ocular reflex exhibits vector superposition and linearity to a sufficient degree that a multichannel vestibular prosthesis incorporating a precompensatory 3D coordinate transformation to correct misalignment can accurately emulate semicircular canals for head rotations throughout the range of 3D axes normally transduced by a healthy labyrinth.

Co-modulation of stimulus rate and current from elevated baselines expands head motion encoding range of the vestibular prosthesis

An implantable prosthesis that stimulates vestibular nerve branches to restore sensation of head rotation and vision-stabilizing reflexes could benefit individuals disabled by bilateral loss of vestibular sensation. The normal vestibular system encodes head movement by increasing or decreasing firing rate of the vestibular afferents about a baseline firing rate in proportion to head rotation velocity. Our multichannel vestibular prosthesis emulates this encoding scheme by modulating pulse rate and pulse current amplitude above and below a baseline stimulation rate (BSR) and a baseline stimulation current. Unilateral baseline prosthetic stimulation that mimics normal vestibular afferent baseline firing results in vestibulo-ocular reflex (VOR) eye responses with a wider range of eye velocity in response to stimuli modulated above baseline (excitatory) than below baseline (inhibitory). Stimulus modulation about higher than normal baselines resulted in increased range of inhibitory eye velocity, but decreased range of excitatory eye velocity. Simultaneous modulation of rate and current (co-modulation) above all tested baselines elicited a significantly wider range of excitatory eye velocity than rate or current modulation alone. Time constants associated with the recovery of VOR excitability following adaptation to elevated BSRs implicate synaptic vesicle depletion as a possible mechanism for the small range of excitatory eye velocity elicited by rate modulation alone. These findings can be used toward selecting optimal baseline levels for vestibular stimulation that would result in large inhibitory eye responses while maintaining a wide range of excitatory eye velocity via co-modulation.

Current and Future Management of Bilateral Loss of Vestibular Sensation - An update on the Johns Hopkins Multichannel Vestibular Prosthesis Project

Abstract Bilateral loss of vestibular sensation can disable individuals whose vestibular hair cells are injured by ototoxic medications, infection, Ménières disease or other insults to the labyrinth including surgical trauma during cochlear implantation. Without input to vestibulo-ocular and vestibulo-spinal reflexes that normally stabilize the eyes and body, affected patients suffer blurred vision during head movement, postural instability, and chronic disequilibrium. While individuals with some residual sensation often compensate for their loss through rehabilitation exercises, those who fail to do so are left with no adequate treatment options. An implantable neuroelectronic vestibular prosthesis that emulates the normal labyrinth by sensing head movement and modulating activity on appropriate branches of the vestibular nerve could significantly improve quality of life for these otherwise chronically dizzy patients. This brief review describes the impact and current management of bilateral loss of vestibular sensation, animal studies supporting the feasibility of prosthetic vestibular stimulation, and a vestibular prosthesis designed to restore sensation of head rotation in all directions. Similar to a cochlear implant in concept and size, the Johns Hopkins Multichannel Vestibular Prosthesis (MVP) includes miniature gyroscopes to sense head rotation, a microcontroller to process inputs and control stimulus timing, and current sources switched between pairs of electrodes implanted within the vestibular labyrinth. In rodents and rhesus monkeys rendered bilaterally vestibulardeficient via treatment with gentamicin and/or plugging of semicircular canals, the MVP partially restores the vestibulo-ocular reflex for head rotations about any axis of rotation in 3-dimensional space. Our efforts now focus on addressing issues prerequisite to human implantation, including refinement of electrode designs and surgical technique to enhance stimulus selectivity and preserve cochlear function, optimization of stimulus protocols, and reduction of device size and power consumption.

Multichannel Vestibular Prosthesis Employing Modulation of Pulse Rate and Current with Alignment Precompensation Elicits Improved VOR Performance in Monkeys

An implantable prosthesis that stimulates vestibular nerve branches to restore the sensation of head rotation and the three-dimensional (3D) vestibular ocular reflex (VOR) could benefit individuals disabled by bilateral loss of vestibular sensation. Our group has developed a vestibular prosthesis that partly restores normal function in animals by delivering biphasic current pulses via electrodes implanted in semicircular canals. Despite otherwise promising results, this approach has been limited by insufficient velocity of VOR response to head movements that should inhibit the implanted labyrinth and by misalignment between direction of head motion and prosthetically elicited VOR. We report that significantly larger VOR eye velocities in the inhibitory direction can be elicited by adapting a monkey to elevated baseline stimulation rate and current prior to stimulus modulation and then concurrently modulating (“co-modulating”) both rate and current below baseline levels to encode inhibitory angular head velocity. Co-modulation of pulse rate and current amplitude above baseline can also elicit larger VOR eye responses in the excitatory direction than do either pulse rate modulation or current modulation alone. Combining these stimulation strategies with a precompensatory 3D coordinate transformation improves alignment and magnitude of evoked VOR eye responses. By demonstrating that a combination of co-modulation and precompensatory transformation strategies achieves a robust VOR response in all directions with significantly improved alignment in an animal model that closely resembles humans with vestibular loss, these findings provide a solid preclinical foundation for application of vestibular stimulation in humans.

Contribution of vestibular efferent system alpha-9 nicotinic receptors to vestibulo-oculomotor interaction and short-term vestibular compensation after unilateral labyrinthectomy in mice.

Sudden unilateral loss of vestibular afferent input causes nystagmus, ocular misalignment, postural instability and vertigo, all of which improve significantly over the first few days after injury through a process called vestibular compensation (VC). Efferent neuronal signals to the labyrinth are thought to be required for VC. To better understand efferent contributions to VC, we compared the time course of VC in wild-type (WT) mice and α9 knockout (α9(-/-)) mice, the latter lacking the α9 subunit of nicotinic acetylcholine receptors (nAChRs), which is thought to represent one signaling arm activated by the efferent vestibular system (EVS). Specifically, we investigated the time course of changes in the fast/direct and slow/indirect components of the angular vestibulo-ocular reflex (VOR) before and after unilateral labyrinthectomy (UL). Eye movements were recorded using infrared video oculography in darkness with the animal stationary and during sinusoidal (50 and 100°/s, 0.5-5 Hz) and velocity step (150°/s for 7-10s, peak acceleration 3000°/s(2)) passive whole-body rotations about an Earth-vertical axis. Eye movements were measured before and 0.5, 2, 4, 6 and 9 days after UL. Before UL, we found frequency- and velocity-dependent differences between WT and α9(-/-) mice in generation of VOR quick phases. The VOR slow phase time constant (TC) during velocity steps, which quantifies contributions of the indirect component of the VOR, was longer in α9(-/-) mutants relative to WT mice. After UL, spontaneous nystagmus (SN) was suppressed significantly earlier in WT mice than in α9(-/-) mice, but mutants achieved greater recovery of TC symmetry and VOR quick phases. These data suggest (1) there are significant differences in vestibular and oculomotor functions between these two types of mice, and (2) efferent signals mediated by α9 nicotinic AChRs play a role during VC after UL.

Restoring the 3D vestibulo-ocular reflex via electrical stimulation: The Johns Hopkins multichannel vestibular prosthesis project

Bilateral loss of vestibular sensation causes difficulty maintaining stable vision, posture and gait. An implantable prosthesis that partly restores normal activity on branches of the vestibular nerve should improve quality of life for individuals disabled by this disorder. We have developed a head-mounted multichannel vestibular prosthesis that restores sufficient semicircular canal function to partially recreate a normal 3-dimensional angular vestibulo-ocular reflex in animals. Here we describe several parallel lines of investigation directed toward refinement of this approach toward eventual clinical application.

Including planning activity in feature space distributes activation over a broader neuron population

In neuroprosthetic systems, decoding based on a sparse population of task-related neurons is impractical because micro-electrode arrays often drift gradually in the cortex. Since the neuronal population being recorded from is dynamic, it is favorable to have a larger number of neurons containing information relevant to movement decoding and to decrease the relative importance of individual neurons. We have shown that a feature space comprised of neural firing rates from planning as well as movement periods exists in a broader distribution of neurons, as compared to a feature space that is derived from the movement period alone. For this study, spike train data from 297 neurons located in Ml and PM areas was analyzed to validate the hypothesis. The data was from a rhesus monkey performing reach to grasp task with measured wrist supination/pronation. Artificial neural networks were used to model encoding of wrist angle, and a sensitivity analysis was performed to attribute the relative importance of the input neurons. A classifier trained on only the least important neurons, as determined by their relative contribution to the decoded variable, had an average 20% better decoding accuracy when the new method of feature selection was used. This indicates that there is valuable information content within the distributed neuronal population.

NETI: the NeuroEngineering Training Initiative

Summary form only given. Neuroengineering is defined as the interdisciplinary field of engineering and computational approaches, as applied to problems in basic and clinical neuroscience. The NeuroEngineering Training Initiative at Johns Hopkins seeks to balance engineering, mathematics, and computer science with molecular, cellular, and systems neurosciences. The program leverages the educational and research resources of both the engineering and medical schools. The life sciences training consists of courses taught either through the medical school or through the basic biomedical science curriculum. The engineering training consists of rigorous coursework in mathematics, computation, and other engineering subjects appropriate for the particular students focus. NETI trainees also forge collaborations between faculty members, participate in weekly seminars, and present their research at various conferences. Through schoolwork, seminars, social events, conferences, and collaborative interactions, our students provide the nexus between basic science, clinical, and engineering research. The NIH has recognized the importance of this initiative and has provided funding for the program. NETI trainees have the unique opportunity to be part of the pioneer program in neuroengineering training while taking advantage of the world class institution that is Johns Hopkins