Neural tissue stimulation is used in research and clinical applications. Neuroscientists use nerve stimulation to answer fundamental questions about the function of the nervous system and to research diseases such as Parkinson’s and Alzheimer’s as well as biological processes such as nerve regeneration. Clinically, neural tissue stimulation is used for applications including pain and depression management, control of tremors and seizures, brain mapping and guidance of surgical resection. Although electrical stimulation has traditionally served as the standard method to interface with neural tissue, researchers at Vanderbilt University in Nashville, Tenn., have developed an optical technique called transient optical nerve stimulation — a noncontact approach to neural activation. Electrical stimulation has several fundamental limitations. It requires physical contact with a metal electrode, often pierced into the tissue, which can cause tissue damage. Spatial precision of stimulation is often limited by the size of the electrodes and, more importantly,by the inherent induction of an electric field, which initiates a population response by recruiting multiple axons.1 Many neural stimulation applications require the stimulus to be precisely within a small target area of tissue. Electrodes designed to deliver precise stimulation have inherently high impedance characteristics, which, in turn, impose higher voltage requirements to deliver the same charge, as dictated by Ohm’s law. Electrophysiological recordings performed to observe the response to electrical stimulation are plagued with the presence of an inescapable “stimulation artifact” — especially when recording in the vicinity of stimulation. The result is a recorded signal that contains a stimulus-induced artifact that is typically much larger than the recorded action potential and that requires significant signal processing to tease out the intended signal.2,3 These limitations have driven researchers to pursue other means for neural stimulation, including magnetic, ultrasound and other mechanical methods. Transient optical nerve stimulation is a technique that optically stimulates neural tissue using mid-infrared light. The method relies on direct but transient (non-contact, pulsed) irradiation of the nerve surface with an IR laser. The laser uses an optimized radiant exposure and wavelength to generate (compound) action potentials and subsequent physiological effects; for example, muscle contraction or sensory response. The response is spatially precise, permitting selective targeting of individual nerve fascicles with no observed tissue damage.4,5 Moreover, optically induced action potentials exhibit no stimulation artifacts, allowing adjacent stimulation and recording from a single site. Optical stimulation is the direct induction of an evoked potential in response to a transient targeted deposition of optical energy. Only a pulsed source can be used for stimulation of neural tissue, and continuous-wave irradiation will not lead to compound action-potential generation. Transient optical nerve stimulation is fundamentally different from other biological light interactions, such as biostimulation or low-level light therapy, where low fluence levels at laser wavelengths that are weakly absorbed in tissue are applied continuously for several minutes to elucidate some biological effect: use of light to activate caged compounds or phototransduction in visual cortex mapping; or modulation of the excitability of nerves using light, where light is used to alter spontaneous or stimulated neural signals or potentials rather than being the primary source inducing that signal. Much of the preliminary work in optimizing this technique was performed in the peripheral nerve of rats in vivo. Theoretically, the most appropriate wavelengths for stimulation depend on the architecture of the target tissue. A typical rat sciatic nerve is approximately 1.5 mm in diameter and consists of numerous nerve fibers grouped together in fascicles, each of which typically innervates a specific muscle group. The number of fascicles per nerve varies greatly across mammalian species, albeit the typical fascicle thickness is constant and tends to be between 100 and 400 μm (Figure 1).6 Thus, the penetration depth of the laser light must be greater than the distance from the nerve surface to within the fascicle (~300 to 600 μm). Figure 1. For optical stimulation, laser light must penetrate about 300 to 600 μm. Careful wavelength tuning in the near- to mid-IR (>1400 nm), where the main absorber is the water in tissue, allows tunability of the optical penetration depth over several orders of magnitude. The researchers identified 2.1 and 4.0 μm as the optimal stimulation wavelengths for the peripheral nerve — those with maximum stimulation efficacy and minimum damage threshold. These wavelengths correspond to valleys in tissue absorption and have nearly equivalent absorption coefficients. Stated differently, the results showed that the most appropriate wavelengths for stimulation of the sciatic nerve are those where the optical penetration depth is matched to the target geometry; i.e., 2.12 μm has an optical penetration depth of 300 to 500 μm, which corresponds to the depth and size of one fascicle. Although there are few lasers that emit light at 4.0 μm, and fiber optic delivery at this wavelength is problematic, the Ho:YAG laser at 2.12 μm is commercially available and is currently used for a variety of clinical applications. The scientists used it successfully for neural stimulation with an average stimulation threshold radiant exposure of 0.32 J/cm2 and an associated ablation threshold of 2.0 J/cm2. They compared compound muscle-action potential and compound nerve-action potential traces from electrical and optical stimulations of a rat sciatic nerve (Figure 2). This demonstrated that the laser pulse can induce action potentials that are similar in shape and timing to electrically evoked potentials, with greater spatial selectivity — as indicated by fewer recruited axons and a lower amplitude — and without artifacts. Figure 2. These graphs show compound nerve-action potential (CNAP) and compound muscle-action potential (CMAP) recordings from transient optical nerve stimulation with the infrared neural stimulator (0.4 J/cm2 and 2.7 ms) compared with those from electrical stimulation (0.7 V) at the same site. Note that the electrical stimulation masks the first 2 to 3 ms of the recorded nerve and muscle potential. Stimulation occurs at 2 ms. Spatial selectivity Electrical stimulation has an unconfined spread of charge radiating from the electrode. In the case of peripheral nerve stimulation, as the injected current required for stimulation increases, the volume of tissue affected by the electric field increases proportionally. As the energy applied increases, more fibers are recruited, resulting in larger-amplitude compound potentials. Thus, the compound nerve-action potential and compound muscle-action potential represent a population response to electrical stimulation, made up of individual all-or-none responses from many constituent axons, with a linear relationship between stimulation intensity and strength of the compound nerve-action potential response.7,8 Optical stimulation can be more spatially precise than electrical stimulation. The limited optical penetration depth, small spot size and lack of radial diffusion in tissue allow more selective excitation of fascicles, resulting in targeted muscle contraction. A demonstration of the spatial localization innate to optical stimulation is shown in Figure 3. Electrical stimulation excites the entire nerve and elicits a subsequent twitch response from all innervated muscles. Figure 3. Compound muscle-action potential recordings from electrical and optical stimulation were compared within the rat sciatic nerve using threshold energies for each modality. The researchers placed recording electrodes within the gastrocnemius and biceps femoris downstream muscles, approximately 40 and 55 mm from the site of stimulation, respectively. Electrical stimulation with threshold energy of 1.02 A/cm2 was delivered proximal to the first nerve branch point on the fascicle leading to the gastrocnemius, and the muscular responses within gastrocnemius and biceps femoris were simultaneously recorded. Using the minimum energy required to stimulate contraction of the gastrocnemius still resulted in stimulation of the neighboring biceps femoris fascicle, causing biceps femoris contraction (a). Laser stimulation at a threshold of 0.4 J/cm2 resulted in a potential that is more than an order of magnitude lower than that recorded with electrical stimulation in the gastrocnemius with no response observed in the biceps femoris (b). Stimulation occurs at 2 ms. Optical stimulation causes a contraction of the muscle innervated by the targeted nerve fascicle. Moving the laser spot across the nerve targets individual muscle groups, demonstrating the selective recruitment of nerve fibers with optical stimulation. Before any technique can be applied in living tissue, it is necessary to assess its safety and its limits. Toward this goal, the researchers have carried out extensive studies to determine if transient optical nerve stimulation might result in laser-induced damage to the stimulated tissue.5 They observed no neurological functional deficit in survival studies after stimulation at radiant exposures up to twice those needed to induce nerve stimulation. Histological analysis of acute and survival (three- to five-day) experiments confirmed these findings. Moreover, they believe that the stimulation thresholds that they have found to date represent a worst-case scenario because of the extreme endpoint of visible muscle contraction used in the experiments. To extend the application of transient optical nerve stimulation, the investigators teamed with Aculight Corp. in Bothell, Wash., to develop a small, portable and low-cost optical stimulator called the infrared neural stimulator. Based on the results of their wavelength optimization studies, they determined that a laser wavelength with an optical penetration depth of 300 to 600 μm is required to stimulate the peripheral nervous system. Although much of the research used the Ho:YAG laser to provide this penetration depth, a careful look at the water-absorption curve revealed that a diode laser with a wavelength of ~1.87 μm results in the same penetration depth. Aculight had developed this device under a government contract to produce nonstandard-wavelength lasers. A prototype laser for initial studies required only relatively minor customization for the application. A goal of the collaboration was to develop an optical stimulator that would be affordable and rugged enough for experimental or clinical use. The team chose diode technology for its simplicity, stability and cost-effectiveness. Diodes emitting near 1.85 μm form the basis of the device. In the commercial system, a single integrated housing contains the fiber-coupled diode and all requisite control electronics. As with electrical nerve stimulators, the control electronics in this unit enable manipulation and display of pulse energy, width and repetition rate. However, a unique feature is the ability to vary the emission wavelength, which allows adjustment of the tissue penetration depth. If required, an external pulse driver and trigger interface are available to allow the user to create pulse formats. The unit measures 13.25 x 12.5 x 4.74 in. and weighs 11 lb. The investigators tested the commercial prototype system at the Vanderbilt laboratory during nerve stimulation experiments similar to those of the initial research. The diode laser behaved similarly to the Ho:YAG, affirming that the wavelength selection and the stimulation threshold were similar as well. It provided safe, noncontact artifact-free peripheral nerve stimulation using optimized laser parameters — yet with the simplicity, reliability and ease of use of a diode-based system. Although the studies showed that optical stimulation is an effective and advantageous method for stimulation of neural tissue, the obvious and intriguing question of the underlying mechanism remains largely unanswered. Exactly what biophysical stimulus does the absorbed laser light induce in the tissue that ultimately results in an action potential? And, given this stimulus, what is the biological mechanism responsible for the transduction into action potentials? To a large extent, unraveling these mechanisms is still in its infancy. At present, the scientists have strong evidence that the underlying biophysical mechanism requires a temperature gradient, either spatial or temporal. However, exactly how this is transduced into a functional action potential remains an open question. Future directions The transient optical nerve stimulation project is moving forward on several fronts. In addition to working on unraveling the underlying mechanisms of optical stimulation, the researchers are proceeding toward demonstrating stimulation in cells and tissues of the central nervous system. After the launch of the commercial stimulator, they plan to develop specific clinical peripheral nerve stimulators based on input from the nerve stimulation research community and on further market research. They also expect to address clinical applications and stimulation of the central nervous system. This technology would enable many as yet unrealized applications, including real-time multiplexed cortical surface mapping for clinical and research purposes. The initial focus in the commercialization of this device will be for a research-based infrared neural stimulator for use in in vitro neurophysiological experiments as well as in in vivo animal studies. In the long term, the collaborators plan to pursue the clinical implementation of this device for peripheral and central nervous system procedures. The long-range plan will focus on implantable devices, potentially including vagus nerve stimulators, cochlear implants and other nerve stimulation devices. Meet the authors Jonathon Wells is a PhD candidate in the department of biomedical engineering; Anita Mahadevan-Jansen, an associate professor of biomedical engineering; Chris Kao, an assistant professor of neurosurgery; and E. Duco Jansen, an associate professor of biomedical engineering and neurosurgery, all at Vanderbilt University in Nashville, Tenn; e-mail: duco.jansen@vanderbilt.edu. Mark Bendett is the director of medical projects; Jim Webb, a project manager; and Heather Ralph, development engineer, all at Aculight Corp. in Bothell, Wash.; e-mail: mark.bendett@aculight.com. Peter Konrad is associate professor of neurosurgery and director of functional neurosurgery at Vanderbilt University Medical Center in Nashville, Tenn., e-mail: peter.konrad@vanderbilt.edu. References 1. D. Palanker et al (2005). Design of a high-resolution optoelectronic retinal prosthesis. J NEURAL ENG, Vol. 2, pp. S105-120. 2. C. Miller et al (2000). An improved method of reducing stimulus artifact in the electrically evoked whole-nerve potential. EAR HEAR, Vol. 21, pp. 280-290. 3. K. McGill et al (1982). On the nature and elimination of stimulus artifact in nerve signals evoked and recorded using surface electrodes. IEEE TRANS BIOMED ENG, Vol. 29, pp. 129-137. 4. J.D. Wells et al (2005). Optical stimulation of neural tissue in vivo. OPT LETT, Vol. 30, pp. 504-507. 5. J.D. Wells et al (2005). Application of infrared light for in vivo neural stimulation. JOURNAL OF BIOMEDICAL OPTICS, Vol. 10, 064003. 6. G. Paxinos (2004). The Rat Nervous System. Third edition. Elsevier. 7. L.A. Geddes et al (1985). Tissue stimulation: theoretical considerations and practical applications. MED BIOL ENG COMPUT, Vol. 23, pp. 131-137. 8. L.A. Geddes and J.D. Bourland (1985). The strength-duration curve. IEEE TRANS BIOMED ENG, Vol. 32, pp. 458-459. Optical Stimulation of Auditory Neurons Dr. Claus-Peter Richter, Northwestern University One of the most promising uses for optical stimulation appears to be in the area of cochlear implants. Cochlear prostheses bypass damaged hair cells in the auditory system by direct electrical stimulation of the auditory nerve. Multiple-electrode cochlear implants are designed to stimulate discrete spiral ganglion cell populations along the cochlea. However, discrete neural populations cannot always be electrically activated. In fact, with closely spaced electrode pairs at high current levels, a broad region of auditory neurons is activated. When this occurs, sound sensation may be confused or indistinguishable, reducing the number of independent channels of information that can be conveyed to the cochlear implant user. Research at Northwestern University in Evanston, Ill., is focused on the design of cochlear implants that stimulate smaller populations of spiral ganglion cells. We are finding that optical stimulation is an effective technique for neural interfaces. Its advantages over electrical stimulation are its spatial selectivity and its noninvasive character. We have demonstrated in a gerbil that extremely small populations of cochlear spiral ganglion cells can be optically stimulated over extended periods of time. Our first experiments, made with a Ho:YAG laser with a 2.12-μm wavelength and a 250-μs pulse duration, demonstrated that optical radiation evokes electrical responses from the auditory nerve in animals with normal hearing and in those that are deaf. Laser radiation could be increased by 30 to 40 dB until drastic changes were seen in cochlear function. Cochlear responses to optical radiation were stable over extended stimulation times. More recent experiments with a fiber-coupled diode laser from Aculight Corp. of Bothell, Wash., employed stimulation rates up to 1 kHz. The experiments showed that single auditory nerve fibers could follow light-pulse repetition rates up to around 300 pulses per second and that such rates did not result in obvious neural tissue damage. With Aculight’s recent development of smaller stimulation units, we plan to chronically implant the devices in an animal model. In the future, we hope to develop laser-based cochlear implants that allow parallel processing of information on many channels.