Binocular 3-D otolith-ocular reflexes: responses of chinchillas to natural and prosthetic stimulation after ototoxic injury and vestibular implantation.

The otolith end organs inform the brain about gravitational and linear accelerations, driving the otolith-ocular reflex (OOR) to stabilize the eyes during translational motion (e.g., moving forward without rotating) and head tilt with respect to gravity. We previously characterized OOR responses of normal chinchillas to whole body tilt and translation and to prosthetic electrical stimulation targeting the utricle and saccule via electrodes implanted in otherwise normal ears. Here we extend that work to examine OOR responses to tilt and translation stimuli after unilateral intratympanic gentamicin injection and to natural/mechanical and prosthetic/electrical stimulation delivered separately or in combination to animals with bilateral vestibular hypofunction after right ear intratympanic gentamicin injection followed by surgical disruption of the left labyrinth at the time of electrode implantation. Unilateral intratympanic gentamicin injection decreased natural OOR response magnitude to about half of normal, without markedly changing OOR response direction or symmetry. Subsequent surgical disruption of the contralateral labyrinth at the time of electrode implantation surgery further decreased OOR magnitude during natural stimulation, consistent with bimodal-bilateral otolith end organ hypofunction (ototoxic on the right ear, surgical on the left ear). Delivery of pulse frequency- or pulse amplitude-modulated prosthetic/electrical stimulation targeting the left utricle and saccule in phase with whole body tilt and translation motion stimuli yielded responses closer to normal than the deficient OOR responses of those same animals in response to head tilt and translation alone.NEW & NOTEWORTHY Previous studies to expand the scope of prosthetic stimulation of the otolith end organs showed that selective stimulation of the utricle and saccule is possible. This article further defines those possibilities by characterizing a diseased animal model and subsequently studying its responses to electrical stimulation alone and in combination with mechanical motion. We show that we can partially restore responses to tilt and translation in animals with unilateral gentamicin ototoxic injury and contralateral surgical disruption.

The Evoked Compound Action Potential as a Predictor for Perception in Chronic Pain Patients: Tools for Automatic Spinal Cord Stimulator Programming and Control.

OBJECTIVES: Spinal cord stimulation (SCS) is a drug free treatment for chronic pain. Recent technological advances have enabled sensing of the evoked compound action potential (ECAP), a biopotential that represents neural activity elicited from SCS. The amplitudes of many SCS paradigms - both sub- and supra-threshold - are programmed relative to the patient's perception of SCS. The objective of this study, then, is to elucidate relationships between the ECAP and perception thresholds across posture and SCS pulse width. These relationships may be used for the automatic control and perceptually referenced programming of SCS systems. METHODS: ECAPs were acquired from 14 subjects across a range of postures and pulse widths with swept amplitude stimulation. Perception (PT) and discomfort (DT) thresholds were recorded. A stimulation artifact reduction scheme was employed, and growth curves were constructed from the sweeps. An estimate of the ECAP threshold (ET), was calculated from the growth curves using a novel approach. Relationships between ET, PT, and DT were assessed. RESULTS: ETs were estimated from 112 separate growth curves. For the postures and pulse widths assessed, the ET tightly correlated with both PT (r = 0.93; p < 0.0001) and DT (r = 0.93; p < 0.0001). The median accuracy of ET as a predictor for PT across both posture and pulse width was 0.5 dB. Intra-subject, ECAP amplitudes at DT varied up to threefold across posture. CONCLUSION: We provide evidence that the ET varies across both different positions and varying pulse widths and suggest that this variance may be the result of postural dependence of the recording electrode-tissue spacing. ET-informed SCS holds promise as a tool for SCS parameter configuration and may offer more accuracy over alternative approaches for neural and perceptual control in closed loop SCS systems.

Low-Noise Magnetic Coil System for Recording 3-Dimensional Eye Movements.

OBJECTIVE: Vestibular and oculomotor research often requires measurement of 3-dimensional (3D) eye orientation and movement with high spatial and temporal precision and accuracy. We describe the design, implementation, validation and use of a new magnetic coil system optimized for recording 3D eye movements using small scleral coils in animals. METHODS: Like older systems, the system design uses off-the-shelf components to drive three mutually orthogonal alternating magnetic fields at different frequencies. The scleral coil voltage induced by those fields is decomposed into 3 signals, each related to the coil's orientation relative to the axis of one field component. Unlike older systems based on analog demodulation and filtering, this system uses a field-programmable gate array (FPGA) to oversample each induced scleral coil voltage (at 25 Msamples/s), demodulate in the digital domain, and average over 25 ksamples per data point to generate 1 ksamples/s output in real time. RESULTS: Noise floor is <0.036° peak-to-peak and linearity error is < 0.1° during 345° rotations in all three dimensions. CONCLUSION AND SIGNIFICANCE: This FPGA-based design, which is both reprogrammable and freely available upon request, delivers sufficient performance to record eye movements at high spatial and temporal precision and accuracy using coils small enough for use with small animals.

Binocular 3D otolith-ocular reflexes: responses of chinchillas to prosthetic electrical stimulation targeting the utricle and saccule.

From animal experiments by Cohen and Suzuki et al. in the 1960s to the first-in-human clinical trials now in progress, prosthetic electrical stimulation targeting semicircular canal branches of the vestibular nerve has proven effective at driving directionally appropriate vestibulo-ocular reflex eye movements, postural responses, and perception. That work was considerably facilitated by the fact that all hair cells and primary afferent neurons in each canal have the same directional sensitivity to head rotation, the three canals' ampullary nerves are geometrically distinct from one another, and electrically evoked three-dimensional (3D) canal-ocular reflex responses approximate a simple vector sum of linearly independent components representing relative excitation of each of the three canals. In contrast, selective prosthetic stimulation of the utricle and saccule has been difficult to achieve, because hair cells and afferents with many different directional sensitivities are densely packed in those endorgans and the relationship between 3D otolith-ocular reflex responses and the natural and/or prosthetic stimuli that elicit them is more complex. As a result, controversy exists regarding whether selective, controllable stimulation of electrically evoked otolith-ocular reflexes (eeOOR) is possible. Using micromachined, planar arrays of electrodes implanted in the labyrinth, we quantified 3D, binocular eeOOR responses to prosthetic electrical stimulation targeting the utricle, saccule, and semicircular canals of alert chinchillas. Stimuli delivered via near-bipolar electrode pairs near the maculae elicited sustained ocular countertilt responses that grew reliably with pulse rate and pulse amplitude, varied in direction according to which stimulating electrode was employed, and exhibited temporal dynamics consistent with responses expected for isolated macular stimulation.NEW & NOTEWORTHY As the second in a pair of papers on Binocular 3D Otolith-Ocular Reflexes, this paper describes new planar electrode arrays and vestibular prosthesis architecture designed to target the three semicircular canals and the utricle and saccule. With this technological advancement, electrically evoked otolith-ocular reflexes due to stimulation via utricle- and saccule-targeted electrodes were recorded in chinchillas. Results demonstrate advances toward achieving selective stimulation of the utricle and saccule.

Binocular 3D otolith-ocular reflexes: responses of normal chinchillas to tilt and translation.

Head rotation, translation, and tilt with respect to a gravitational field elicit reflexive eye movements that partially stabilize images of Earth-fixed objects on the retinas of humans and other vertebrates. Compared with the angular vestibulo-ocular reflex, responses to translation and tilt, collectively called the otolith-ocular reflex (OOR), are less completely characterized, typically smaller, generally disconjugate (different for the 2 eyes) and more complicated in their relationship to the natural stimuli that elicit them. We measured binocular 3-dimensional OOR responses of 6 alert normal chinchillas in darkness during whole body tilts around 16 Earth-horizontal axes and translations along 21 axes in horizontal, coronal, and sagittal planes. Ocular countertilt responses to 40-s whole body tilts about Earth-horizontal axes grew linearly with head tilt amplitude, but responses were disconjugate, with each eye's response greatest for whole body tilts about axes near the other eye's resting line of sight. OOR response magnitude during 1-Hz sinusoidal whole body translations along Earth-horizontal axes also grew with stimulus amplitude. Translational OOR responses were similarly disconjugate, with each eye's response greatest for whole body translations along its resting line of sight. Responses to Earth-horizontal translation were similar to those that would be expected for tilts that would cause a similar peak deviation of the gravitoinertial acceleration (GIA) vector with respect to the head, consistent with the "perceived tilt" model of the OOR. However, that model poorly fit responses to translations along non-Earth-horizontal axes and was insufficient to explain why responses are larger for the eye toward which the GIA vector deviates.NEW & NOTEWORTHY As the first in a pair of papers on Binocular 3D Otolith-Ocular Reflexes, this paper characterizes binocular 3D eye movements in normal chinchillas during tilts and translations. The eye movement responses were used to create a data set to fully define the normal otolith-ocular reflexes in chinchillas. This data set provides the foundation to use otolith-ocular reflexes to back-project direction and magnitude of eye movement to predict tilt axis as discussed in the companion paper.

Nonhuman primate vestibuloocular reflex responses to prosthetic vestibular stimulation are robust to pulse timing errors caused by temporal discretization.

Electrical stimulation of vestibular afferent neurons to partially restore semicircular canal sensation of head rotation and the stabilizing reflexes that sensation supports has potential to effectively treat individuals disabled by bilateral vestibular hypofunction. Ideally, a vestibular implant system using this approach would be integrated with a cochlear implant, which would provide clinicians with a means to simultaneously treat loss of both vestibular and auditory sensation. Despite obvious similarities, merging these technologies poses several challenges, including stimulus pulse timing errors that arise when a system must implement a pulse frequency modulation-encoding scheme (as is used in vestibular implants to mimic normal vestibular nerve encoding of head movement) within fixed-rate continuous interleaved sampling (CIS) strategies used in cochlear implants. Pulse timing errors caused by temporal discretization inherent to CIS create stair step discontinuities of the vestibular implant's smooth mapping of head velocity to stimulus pulse frequency. In this study, we assayed electrically evoked vestibuloocular reflex responses in two rhesus macaques using both a smooth pulse frequency modulation map and a discretized map corrupted by temporal errors typical of those arising in a combined cochlear-vestibular implant. Responses were measured using three-dimensional scleral coil oculography for prosthetic electrical stimuli representing sinusoidal head velocity waveforms that varied over 50-400°/s and 0.1-5 Hz. Pulse timing errors produced negligible effects on responses across all canals in both animals, indicating that temporal discretization inherent to implementing a pulse frequency modulation-coding scheme within a cochlear implant's CIS fixed pulse timing framework need not sacrifice performance of the combined system's vestibular implant portion. NEW & NOTEWORTHY Merging a vestibular implant system with existing cochlear implant technology can provide clinicians with a means to restore both vestibular and auditory sensation. Pulse timing errors inherent to integration of pulse frequency modulation vestibular stimulation with fixed-rate, continuous interleaved sampling cochlear implant stimulation would discretize the smooth head velocity encoding of a combined device. In this study, we show these pulse timing errors produce negligible effects on electrically evoked vestibulo-ocular reflex responses in two rhesus macaques.

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.

Development of a multichannel vestibular prosthesis prototype by modification of a commercially available cochlear implant.

No adequate treatment exists for individuals who remain disabled by bilateral loss of vestibular (inner ear inertial) sensation despite rehabilitation. We have restored vestibular reflexes using lab-built multichannel vestibular prostheses (MVPs) in animals, but translation to clinical practice may be best accomplished by modification of a commercially available cochlear implant (CI). In this interim report, we describe preliminary efforts toward that goal. We developed software and circuitry to sense head rotation and drive a CI's implanted stimulator (IS) to deliver up to 1 K pulses/s via nine electrodes implanted near vestibular nerve branches. Studies in two rhesus monkeys using the modified CI revealed in vivo performance similar to our existing dedicated MVPs. A key focus of our study was the head-worn unit (HWU), which magnetically couples across the scalp to the IS. The HWU must remain securely fixed to the skull to faithfully sense head motion and maintain continuous stimulation. We measured normal and shear force thresholds at which HWU-IS decoupling occurred as a function of scalp thickness and calculated pressure exerted on the scalp. The HWU remained attached for human scalp thicknesses from 3-7.8 mm for forces experienced during routine daily activities, while pressure on the scalp remained below capillary perfusion pressure.