James O. Phillips

Implantation of the Semicircular Canals with Preservation of Hearing and Rotational Sensitivity: a vestibular neurostimulator suitable for clinical research

Hypothesis It is possible to implant a stimulating electrode array in the semicircular canals without damaging rotational sensitivity or hearing. The electrodes will evoke robust and precisely controlled eye movements. Background A number of groups are attempting to develop a neural prosthesis to ameliorate abnormal vestibular function. Animal studies demonstrate that electrodes near the canal ampullae can produce electrically evoked eye movements. The target condition of these studies is typically bilateral vestibular hypofunction. Such a device could potentially be more widely useful clinically and would have a simpler roadmap to regulatory approval if it produced minimal or no damage to the native vestibular and auditory systems. Methods An electrode array was designed for insertion into the bony semicircular canal adjacent to the membranous canal. It was designed to be sufficiently narrow so as to not compress the membranous canal. The arrays were manufactured by Cochlear, Ltd., and linked to a Nucleus Freedom receiver/stimulator. Seven behaviorally trained rhesus macaques had arrays placed in 2 semicircular canals using a transmastoid approach and “soft surgical” procedures borrowed from Hybrid cochlear implant surgery. Postoperative vestibulo-ocular reflex was measured in a rotary chair. Click-evoked auditory brainstem responses were also measured in the 7 animals using the contralateral ear as a control. Results All animals had minimal postoperative vestibular signs and were eating within hours of surgery. Of 6 animals tested, all had normal postoperative sinusoidal gain. Of 7 animals, 6 had symmetric postoperative velocity step responses toward and away from the implanted ear. The 1 animal with significantly asymmetric velocity step responses also had a significant sensorineural hearing loss. One control animal that underwent canal plugging had substantial loss of the velocity step response toward the canal-plugged ear. In 5 animals, intraoperative electrically evoked vestibular compound action potential recordings facilitated electrode placement. Postoperatively, electrically evoked eye movements were obtained from electrodes associated with an electrically evoked vestibular compound action potential wave form. Hearing was largely preserved in 6 animals and lost in 1 animal. Conclusion It is possible to implant the vestibular system with prosthetic stimulating electrodes without loss of rotational sensitivity or hearing. Because electrically evoked eye movements can be reliably obtained with the assistance of intraoperative electrophysiology, it is appropriate to consider treatment of a variety of vestibular disorders using prosthetic electrical stimulation. Based on these findings, and others, a feasibility study for the treatment of human subjects with disabling Ménière’s disease has begun.

Automatic Postural Responses in the Cat: Responses to Headward and Tailward Translation*

SummaryEMG responses, vertical and A-P shear forces and kinematics of “automatic postural responses” to unexpected translational perturbations in the headward and tailward directions were studied in cats. Muscles acting on the major joints of the forelimbs and hindlimbs were studied. Movement of the animals in response to perturbation were highly stereotyped and consisted of two phases: (1) motion of the feet during platform movement while the trunk remained relatively stationary followed by (2) active correction of posture by movement of the trunk in the direction of perturbation.Vertical force changes occurred after the perturbation was well underway (latency 65 ms) and were related to the displacement of the center of mass and active correction of trunk position. Shear forces showed both passive (inertial) and active components and suggested that the majority of the torque necessary for po,stural correction was generated by the hindlimb.EMG responses in forelimb and shoulder muscles were most correlated with increase in vertical force, showing a generalized co-contraction in tailward translation (when these limbs were loaded) and little activity when the forelimbs were unloaded.EMG responses in hindlimb showed reciprocal activation of agonists and antagonists during perturbation with strong synergies of thigh and foot flexors in tailward translation and thigh and foot extensors in headward translation. The forelimb EMG patterns were most consistent with the conclusion that the forelimb is used primarily for vertical support during perturbation.It was concluded that hindlimb EMG responses were appropriate for both vertical support and performance of the postural correction. The hindlimb muscle synergies observed during translation are the “mirror image” of those observed in humans by other workers.

A novel DFNA9 mutation in the vWFA2 domain of COCH alters a conserved cysteine residue and intrachain disulfide bond formation resulting in progressive hearing loss and site-specific vestibular and central oculomotor dysfunction.

Mutations within the COCH gene (encoding the cochlin protein) lead to auditory and vestibular impairment in the DFNA9 disorder. In this study, we describe the genetic mapping of progressive autosomal dominant sensorineural hearing loss first affecting high‐frequency auditory thresholds within a human pedigree to the long arm of chromosome 14 in band q12. A maximal pairwise LOD score of 7.08 was obtained with marker D14S1021. We identified a c.1625G > T mutation in exon 12 of COCH that co‐segregates with auditory dysfunction in the pedigree. The mutation results in a predicted p.C542F substitution at an evolutionarily conserved cysteine residue in the C‐terminus of cochlin. The c.1625G > T transversion in COCH exon 12 represents the first reported mutation outside of the LCCL domain which is encoded by exons 4 and 5. The 542F mutant cochlin is translated and secreted by transfected mammalian cells. Western blot analysis under non‐reducing and reducing conditions suggests that the 542F mutation alters intramolecular cochlin disulfide bond formation. In the vestibular system, a progressive horizontal canal hypofunction and a probable saccular otolith challenge were detected in family members with the c.1625G > T COCH alteration. Abnormal central oculomotor test results in family members with the c.1625G > T COCH alteration imply a possible central nervous system change not previously noted in DFNA9 pedigrees harboring mutations within the LCCL domain.

Smooth pursuit in 1- to 4-month-old human infants

The ability of human infants < or = 4 months of age to pursue objects smoothly with their eyes was assessed by presenting small target spots moving with hold-ramp-hold trajectories at ramp velocities of 4-32 deg/sec. Infants as young as 1 month old followed such target motions with a combination of smooth-pursuit and saccadic eye movements interrupted occasionally by periods when the eyes remained stationary. The slowest targets produced variable performance, but targets moving 8-32 deg/sec produced consistent pursuit behavior, even in the youngest infants. By the fourth month, eye-movement latency decreased and smooth-pursuit gain and the percentage of smooth pursuit per trial increased for all target velocities, though these measures had not yet reached adult levels.

Prosthetic implantation of the human vestibular system

Hypothesis 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. Background 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. Methods 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. Results 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. Conclusion 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.

Characterization of the electrically-evoked compound action potential of the vestibular nerve

Objective: We recorded intraoperative and postoperative electrically evoked compound action potentials (ECAPs) in rhesus monkeys implanted with a vestibular neurostimulator. The objectives were to correlate the generation of slow-phase nystagmus or eye twitches induced by electrical stimulation of the implanted semicircular canal with the presence or absence of the vestibular ECAP responses and to assess the effectiveness of ECAP monitoring during surgery to guide surgical insertion of electrode arrays into the canals. Design: Four rhesus monkeys (a total of 7 canals) were implanted with a vestibular neurostimulator modified from the Nucleus Freedom cochlear implant. ECAP recordings were obtained during surgery or at various intervals after surgery using the Neural Response Telemetry feature of the clinical Custom Sound EP software. Eye movements during electrical stimulation of individual canals were recorded with a scleral search coil system in the same animals. Results: Measurable vestibular ECAPs were observed intraoperatively or postoperatively in 3 implanted animals. Robust and sustained ECAPs were obtained in 3 monkeys at the test intervals of 0, 7, or greater than 100 days after implantation surgery. In all 3 animals, stimulation with electrical pulse trains produced measurable eye movements in a direction consistent with the vestibulo-ocular reflex from the implanted semicircular canal. In contrast, electrically evoked eye movements could not be measured in 3 of the 7 implanted canals, none of which produced distinct vestibular ECAPs. In 2 animals, ECAP waveforms were systematically monitored during surgery, and the procedure proved crucial to the success of vestibular implantation. Conclusion: Vestibular ECAPs exhibit similar morphology and growth characteristics to cochlear ECAPs from human cochlear implant patients. The ECAP measure is well correlated with the functional activation of eye movements by electrical stimulation after implantation surgery. The intraoperative ECAP recording technique is an efficient tool to guide the placement of electrode array into the semicircular canals.

Evaluation of vestibular function in young children

Together, these tests provide a full evaluation of vestibular function in infants and small children. If attention is paid to creating the appropriate testing environment, and interpretation of the tests takes into account the unique properties of the responses of infants and young children, this testing can provide a useful adjunct to audiometric evaluation in young children.

Eye movement abnormalities in Joubert syndrome.

PURPOSE Joubert syndrome is a genetic disorder characterized by hypoplasia of the midline cerebellum and deficiency of crossed connections between neural structures in the brain stem that control eye movements. The goal of the study was to quantify the eye movement abnormalities that occur in Joubert syndrome. METHODS Eye movements were recorded in response to stationary stimuli and stimuli designed to elicit smooth pursuit, saccades, optokinetic nystagmus (OKN), vestibulo-ocular reflex (VOR), and vergence using video-oculography or Skalar search coils in 8 patients with Joubert syndrome. All patients underwent high-resolution magnetic resonance imaging (MRI). RESULTS All patients had the highly characteristic molar tooth sign on brain MRI. Six patients had conjugate pendular (n = 4) or see-saw nystagmus (n = 2); gaze holding was stable in four patients. Smooth-pursuit gains were 0.28 to 1.19, 0.11 to 0.68, and 0.33 to 0.73 at peak stimulus velocities of 10, 20, and 30 deg/s in six patients; smooth pursuit could not be elicited in four patients. Saccade gains in five patients ranged from 0.35 to 0.91 and velocities ranged from 60.9 to 259.5 deg/s. Targeted saccades could not be elicited in five patients. Horizontal OKN gain was uniformly reduced across gratings drifted at velocities of 15, 30, and 45 deg/s. VOR gain was 0.8 or higher and phase appropriate in three of seven subjects; VOR gain was 0.3 or less and phase was indeterminate in four subjects. CONCLUSIONS The abnormalities in gaze-holding and eye movements are consistent with the distributed abnormalities of midline cerebellum and brain stem regions associated with Joubert syndrome.

An Experimental Vestibular Neural Prosthesis: Design and Preliminary Results With Rhesus Monkeys Stimulated With Modulated Pulses

A vestibular neural prosthesis was designed on the basis of a cochlear implant for treatment of Menieres disease and other vestibular disorders. Computer control software was developed to generate patterned pulse stimuli for exploring optimal parameters to activate the vestibular nerve. Two rhesus monkeys were implanted with the prototype vestibular prosthesis and they were behaviorally evaluated post implantation surgery. Horizontal and vertical eye movement responses to patterned electrical pulse stimulations were collected on both monkeys. Pulse amplitude modulated (PAM) and pulse rate modulated (PRM) trains were applied to the lateral canal of each implanted animal. Robust slow-phase nystagmus responses following the PAM or PRM modulation pattern were observed in both implanted monkeys in the direction consistent with the activation of the implanted canal. Both PAM and PRM pulse trains can elicit a significant amount of in-phase modulated eye velocity changes and they could potentially be used for efficiently coding head rotational signals in future vestibular neural prostheses.

Congenital and compensated vestibular dysfunction in childhood: an overlooked entity.

We report five children with previously unrecognized vestibular dysfunction detected by clinical examination and confirmed by quantitative vestibular testing. Patient 1 presented with fluctuating visual acuity and intermittent nystagmus. Patient 2 had congenital hearing loss associated with imbalance, delayed motor development, and cyclic vomiting. Patient 3 had neurotrophic keratitis with an intermittent head tilt, imbalance, and motor delays. Patient 4 showed ataxia and eye movement abnormalities following traumatic brain injury and had reading difficulties. Patient 5 had episodic vertigo and eye movement abnormalities from infancy. Clinical vestibular testing emphasized spontaneous nystagmus, rapid head thrust, and assessment of post—rotatory nystagmus. Quantitative vestibular testing included the sinusoidal chair rotation and velocity step tests, measurement of dynamic visual acuity, post—head-shake nystagmus, and computerized platform posturography. Pediatric neurologists encounter children with congenital and compensated vestibular dysfunction, which can be recognized on the basis of relevant history and clinical abnormalities of the ocular-ocular reflex. (J Child Neurol 2006;21:572—579; DOI 10.2310/7010.2006.00151).