Proc. SPIE 7180-21 V.

5 (2009)

Optical nerve stimulation for a vestibular prosthesis

David M. Harrisa, Steven M. Bierera, Jonathon D. Wellsb, James O. Phillipsa, a Univ. of Washington, Seattle WA, USA 98195; b Lockheed-Martin Aculight, Bothell WA, USA 98036
ABSTRACT Infrared Nerve Stimulation (INS) offers several advantages over electrical stimulation, including more precise spatial selectivity and improved surgical access. In this study, INS and electrical stimulation were compared in their ability to activate the vestibular branch of the VIIIth nerve, as a potential way to treat balance disorders. The superior and lateral canals of the vestibular system of Guinea pigs were identified and approached with the aid of precise 3-D reconstructions. A monopolar platinum stimulating electrode was positioned near the ampullae of the canals, and biphasic current pulses were used to stimulate vestibular evoked potentials and eye movements. Thresholds and input/output functions were measured for various stimulus conditions. A short pulsed diode laser (Capella, Lockheed Martin-Aculight, Inc., Bothell WA) was placed in the same anatomical position and various stimulus conditions were evaluated in their ability to evoke similar potentials and eye movements. Keywords: Vestibular, prosthesis, optical nerve stimulation. 1. INTRODUCTION Loss of vestibular function is a significant human health issue that affects the quality of life of millions of American adults and children. In severe cases, the destruction or impairment of vestibular hair cells in the inner ear results in reduced postural and eye movement reflexes, causing disorientation and imbalance. For these patients, artificial stimulation of the vestibular nerve, which effectively bypasses the hair cells, is the most realistic tool to provide the missing sensory information to the brain. To this end, researchers have begun to develop prosthetic systems for chronic implantation based on electrical stimulation of the vestibular end-organs1-4. These devices are designed to activate the afferent nerve endings of the semicircular canals, which convey information about rotational velocity of the head in three dimensions. Preliminary studies in guinea pigs and monkeys have demonstrated that application of electrical pulses to a canal produces deviations of the eyes in the direction appropriate for that canal plane. An extended train of such pulses produces cyclical eye movements with fast and slow phases, similar to that observed with the vestibularocular reflex during natural canal rotation. One major limitation of electrical-based prostheses is the potential for current to spread away from the targeted nerve tissue. In the case of a vestibular implant, such current spread might stimulate nerve fibers innervating the wrong canal, conveying false sensory information to the central vestibular pathways. An analogous situation occurs with cochlear implants5,6. At higher intensities, stray current might also activate the facial nerve, causing unwanted spasms or even pain. A second limitation relates to surgical access. Based on previous studies, selective electrical stimulation has been achieved only by drilling into the canal lumen and threading wire electrodes toward the nerve endings in the canal ampulla3,4. This invasive procedure may compromise any remaining function in the vestibular end-organ and possibly the nerve itself. Physiological evidence from several laboratories7-9 indicates that light from an infrared laser can functionally activate nerve fibers, suggesting a feasible alternative to electrical current for prosthetic vestibular

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stimulation. Recently, Richter and colleagues8-9 evoked compound action potentials from the VIIIth nerve in response to photonic pulses targeting the cochlear spiral ganglion. Additional tone-on-light masking experiments revealed that the population of laser-stimulated ganglion cells was fairly restricted along the frequency representation of the cochlea10. Furthermore, activation of the nerve could be achieved even with a layer of bone separating the laser fiber from the spiral ganglion. These findings suggest that INS may be more spatially restricted and less invasive than electrical stimulation. 2. METHODS 2.1 Guinea pig preparation.. Adult pigmented guinea pigs, in accordance with approved animal-use policies at the University of Washington, were anesthetized with an intramuscular administration of a mixture of ketamine (20-40 mg/kg) and xylazine (1-10 mg/kg). An initial dose of glycopyrrolate (0.011 mg/kg) was given to reduce tracheobronchial secretions. Breathing and heart rate were continuously monitored and core temperature was maintained at 37oC. 2.2 Surgical procedures. Two guinea pigs were used to demonstrate photonic stimulation of afferent vestibular fibers. The superior branch of the vestibular nerve, as it passes through the internal meatus, was approached and visualized through a dorsal craniotomy11. A monopolar electrode was placed on the dorsal/superior aspect of the nerve (green dot in Figure 1). In all other animals, a dorsal-lateral surgical approach was accomplished by entering the middle ear cavities through a retro auricular opening in the temporal bone. Twin boney prominences indicated the ampullae of the superior and lateral canal and a boney ridge contained the peripheral branch of the facial nerve. Ampullae were stimulated by placing an electrode on the bone or by drilling a small window into the canal and threading either a wire electrode or an optical fiber through the endolymphatic space to approach the canal ampulla (red dots in Figure 1). In some animals, the facial canal, containing the VIIth (facial) nerve, was also identified and stimulated. 2.3 Stimulus and recording system. Photonic stimulation was generated with a Capella R-1850 Infrared Neural Stimulator (Aculight) coupled to a 300-m diameter optical fiber. The output wavelength was variable from 1.824 to 1.842-m, and either single pulses or pulse trains could be produced. The calibrated peak power was adjustable from 0 to 1.26 Watts and pulse duration was varied from continuous to 10-sec. Electrical stimulation was generated with a custom voltage-to-current converter. The electrodes were fashioned from Teflon-coated platinum wire with the tips exposed. Both stimulation and evoked potential (EP) recording were performed on a multi-channel A/D board (M-Audio), controlled via custom software. EPs were obtained using subdermal electrodes placed at the vertex of the skull (+) and the ipsilateral mastoid (-), referenced to an electrode in the neck.. The amplified recordings were synchronized with the beginning of the generated stimulus, either variable-amplitude pulse trains (electrical) or single 5volt TTL pulses (optical).

Figure 1. Diagram of mammalian inner ear. Green dot: vestibular nerve stimulation location. Red dots: Superior SSC and Lateral SSC stimulation locations.

2.4 Thresholds, dose/response functions. In each animal, both electrical and INS stimulation were compared. Intensity versus averaged vestibular evoked potential amplitude functions and threshold for activation were obtained for several stimulus parameters. Parameters common to laser and electrical stimulation included pulse amplitude and pulse duration.

Proc. SPIE 7180-21 V. 5 (2009)

3. RESULTS

Figure 2. Photonic evoked potentials from the mixed VIIIth Nerve at various energy levels (left column, 1.0 ms fixed pulse width) and various pulse widths (middle column, 1.26 W fixed peak power).

Figure 3. Peak-to-peak amplitudes of potentials in Figure 2.

3.1 Stimulation of mixed nerve in internal meatus. Figure 2 (left) shows a series of evoked potentials (N=500) evoked by a 1.0-msec laser pulse with a peak power setting ranging from 1.26 mJ (100%) to 0.20 mJ (16%). Figure 2 (right) shows a comparable set of potentials evoked by decreasing pulse durations from 1.0-msec to 10-sec with the peak power fixed. When the stimuli from the two data series are expressed as energy per pulse, the latter has a lower .threshold (< .013 mJ compared to > .15 mJ). The figure also shows that the evoked potential amplitudes decrease rapidly with decreasing peak power, but remain relatively constant as pulse duration is decreased from 1000 to 200-sec. This relation is shown more clearly in Figure 3, which displays the peak-to-peak amplitudes of the first negative

Proc. SPIE 7180-21 V. 5 (2009)

component for the two series as a function of energy per pulse. The minimal changes in EP amplitude at pulse durations beyond ~100-sec suggest that the nerve is responding to the onset of the pulse, rather than the energy integrated over the duration of the pulse. We are uncertain that the potentials in Figure 2 are solely attributable to stimulation of the vestibular nerve. The first 5-msec closely resemble a compound action potential, but the later components (10-30-msec) may reflect activation of the facial nerve. 3.2 Electrical stimulation of facial nerve. The facial nerve courses through a canal in the temporal bone in very close proximity to the cochlea and the ampullae of the superior and lateral semicircular canals (SSC). Biphasic current pulses through bone or on the exposed nerve evoked short latency potentials and characteristic input/output functions. In Figure 4 stimulation of the exposed facial nerve evoked a small positive component with latency of 2-msec at threshold (280-A) and a large negative component with a 3-ms latency. The response saturates at 900-A providing a dynamic range of about 10dB. 3.3 Photonic stimulation of facial nerve. Stimulation of the facial nerve branch with the Capella produced the characteristic response shown in Figure 5 (=1848-nm, 1.0-msec duration 2.0-mJ (100%) pulse. An initial negative deflection with a latency of 2.1msec is followed by a series of 2-3 negative potentials that resemble a compound action potential and subsequent propagation to the brainstem. A late slow wave component has a latency of 10 to 20-msec that could represent an EMG response, sometimes accompanied by facial muscle twitches. In the experiment shown in Figure 5, the animal was euthanized with an injection of Nembutol and physiological potentials disappeared upon death.

Figure 5. EPs elicited by photonic stimulation of the facial nerve through overlying bone, before and after a euthanizing injection of nembutol. The late waveforms are EMG potentials. The response disappeared at death indicating its physiological origin.

Figure 6. Facial nerve EPs elicited by photonic stimulation over a range of pulse widths. For widths longer than 1 ms, the separate on and off components of the EP become evident. (Fiber placement is the same as Fig. 5, but the plotting time scale is different.)

Proc. SPIE 7180-21 V. 5 (2009)

In one experiment the pulse duration was increased from 250-sec to 4.0-msec (Figure 6). A negative EP component with a latency of exactly 1.9-msec was observed after the end of the light pulse, regardless of its duration. At a pulse width of 4 msec, the on and off responses can be easily compared. In this example the off component appears to have greater amplitude than the response to the onset of the light pulse. 3.4 Electrical stimulation of ampulla. A monopolar electrode was placed on the surface of the bone overlying the superior semi-circular canal. Pulse trains produced vigorous vertical eye movements at the location, consistent with the known role of the superior canal in mediating vertical eye movements. The threshold current needed to evoke a response through bone was 450-A (Figure 7A). A small hole trephined into the lumen of the lateral SCC allowed insertion of the electrode or fiber optic into the canal to approach the ampulla. Under these conditions current thresholds were significantly lower (250-A, Figure 7B). Stimulation of the lateral canal ampulla with pulse trains evoked robust, mostly horizontal eye movements. In some cases, the threshold for observing facial twitches was only 2-3 dB above EP threshold. In Figure 7C are evoked potentials from stimulation of the lateral canal. There is a late component at 500-A current level that corresponds with observation of eye twitches (facial nerve activation) at that level.

Figure 7. Electrical-evoked potentials from SCC ampulla. A. Stimulating electrode placed on the bone surface overlying the superior SCC ampulla. B. Stimulation with electrode place into the lumen of the superior canal. Notice the difference in threshold between A and B. C. Electrical stimulation of the lateral SCC ampulla. The late component evoked at 500-A was accompanied by facial twitching.

Figure 8. Photonic stimulation of the superior SSC. W.l = 1842-nm, energy = 2-mJ (100%) delivered through the overlying bone. The bottom trace, in which the laser light was blocked, demonstrates that the observed waveforms were not merely artifact.

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3.5 Photonic stimulation of ampulla. We were successful at optically evoking physiological activity from the vestibular nerve intracranially. We also observed evoked potentials and facial twitching with optical stimulation of the facial nerve. Although potentials and eye movements can be evoked by stimulation of SSC ampulla with electrical current, optical stimulation of the SSC has remained elusive. In two animals we evoked threshold superior SSC responses at 100% output of the Capella (Figure 8). 4. DISCUSSION We found that optical stimulation with infrared light at 1842-nm of vestibular and facial nerve is effective to evoke compound nerve potentials and, in the case of the facial nerve, muscular activity (twitching). Our objective, however, was to selectively stimulate the vestibular semicircular canals. Superior and lateral canals could be stimulated separately with current pulse trains as evidenced by either vertical (superior SSC) or horizontal (lateral SSC) eye movements. Often electrical stimulation of the lateral canal ampulla also activated facial nerve. Optical stimulation directed at the ampullae did produce a minimal evoked potential at the maximum output of the Capella. It did not evoke eye movements. It may be that the Crista ampullaris (sensory organs containing vestibular hair cells) are insensitive to optical stimuli and we were remotely stimulating afferent dendrites of the vestibular nerve. Although optical stimulation of the vestibular nerve appears feasible, it is uncertain that selective stimulation of afferents from individual canals can be achieved once they have collected in the nerve trunk. Selective stimulation of canal afferents is still possible at a location distal to Scarpas ganglia (Figure 1), but a different, more invasive surgical approach needs to be attempted. Perhaps the most interesting result from these studies was observed by chance (Figure 6). In an attempt to optically evoke a larger response in the facial nerve we lengthened the pulse duration to 4 msec. Separate on and off components of the EP became evident for durations greater than 1 ms,. In fact, in this one case the off potential was greater in amplitude than the on response. It is difficult to imagine how turning off the light stimulates nerve, yet, if verified in future studies, this relation needs to be explained in theories explaining the INS mechanism of action. 5. REFERENCES CITED [1] [2] [3] Gong, W. and Merfeld, D.M., "Prototype neural semicircular canal prosthesis using patterned electrical stimulation," Ann Biomed Eng 28(5): 572-81 (2000). Della Santina, C., Migliaccio, A., and Patel, A., "Electrical stimulation to restore vestibular function development of a 3-d vestibular prosthesis," Proc. IEEE Eng. Med. Biol. Soc., 7, 7380-7385 (2005). Merfeld, D.M., Gong, W., Morrissey, J., Saginaw, M., Haburcakova, C., and Lewis, R.F., "Acclimation to chronic constant-rate peripheral stimulation provided by a vestibular prosthesis," IEEE Trans. Biomed. Eng., 53(11), 2362-72 (2006). Phillips, J.O., Bierer, S.M., Fuchs, A.F., Kaneko, C.S., Ling, L., Nie, K., and Rubinstein, J.T., Comparison of Distal and Proximal 8th Nerve Stimulation for a Vestibular Prosthesis, Barany Society Meeting, Kyoto, Japan (2008). Shannon, R.V., "Multichannel electrical stimulation of the auditory nerve in man. II. Channel interaction," Hear. Res., 12(1), 1-16 (1983). White, M.W., Merzenich, M.M., and Gardi, J.N., "Multichannel cochlear implants. Channel interactions and processor design," Arch. Otolaryngol., 110(8), 493-501 (1984). Wells J., C. Kao, K. Mariappan, J. Albea, E. D. Jansen, P. Konrad, and A. Mahadevan-Jansen. Optical stimulation of neural tissue in vivo, Optics. Lett., 31, 235238 (2005).

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Richter, C.P., Bayon, R., Izzo, A.D., Otting, M., Suh, E., Goyal, S., Hotaling, J., and Walsh, J.T. Jr., Optical stimulation of auditory neurons: effects of acute and chronic deafening, Hear. Res., 242(12), 42-51 (2008). Izzo, A.D., Richter, C.P., Jansen, E.D., Walsh, J.T. Jr., "Laser stimulation of the auditory nerve," Lasers Surg. Med., 38(8), 745-53 (2006). Izzo, A.D., Lin, A., Oberoi, M., Richter, C.P., Tone-on-light masking reveals spatial selectivity of optical stimulation in the gerbil cochlea, Assoc. Res. Otol., Denver, CO (2007). Hildesheimer, M., Muchnik, C., and Rubinstein, M., Surgical approach to the superior vestibular nerve in guinea pigs, Hear. Res., 31, 193-196 (1987). 6. ACKNOWLEDGMENT

Supported by NIH-NIDCD SBIR 1R44DC009386 (JDW) and contract HHS-N-260-2006-00005-C (JOP).