Agnella D. Izzo

Optical Parameter Variability in Laser Nerve Stimulation: A Study of Pulse Duration, Repetition Rate, and Wavelength

Pulsed lasers can evoke neural activity from motor as well as sensory neurons in vivo. Lasers allow more selective spatial resolution of stimulation than the conventional electrical stimulation. To date, few studies have examined pulsed, mid-infrared laser stimulation of nerves and very little of the available optical parameter space has been studied. In this study, a pulsed diode laser, with wavelength between 1.844-1.873 mum, was used to elicit compound action potentials (CAPs) from the auditory system of the gerbil. We found that pulse durations as short as 35 mus elicit a CAP from the cochlea. In addition, repetition rates up to 13Hz can continually stimulate cochlear spiral ganglion cells for extended periods of time. Varying the wavelength and, therefore, the optical penetration depth, allowed different populations of neurons to be stimulated. The technology of optical stimulation could significantly improve cochlear implants, which are hampered by a lack of spatial selectivity

Laser Stimulation of Auditory Neurons: Effect of Shorter Pulse Duration and Penetration Depth

We have pioneered what we believe is a novel method of stimulating cochlear neurons, using pulsed infrared radiation, based on the hypothesis that optical radiation can provide more spatially selective stimulation of the cochlea than electric current. Very little of the available optical parameter space has been used for optical stimulation of neurons. Here, we use a pulsed diode laser (1.94 microm) to stimulate auditory neurons of the gerbil. Radiant exposures measured at CAP threshold are similar for pulse durations of 5, 10, 30, and 100 micros, but greater for 300-micros-long pulses. There is evidence that water absorption of optical radiation is a significant factor in optical stimulation. Heat-transfer-based analysis of the data indicates that potential structures involved in optical stimulation of cochlear neurons have a dimension on the order of approximately 10 microm. The implications of these data could direct further research and design of an optical cochlear implant.

Optical stimulation of the facial nerve : A new monitoring technique?

Objectives/ Hypothesis: One sequela of skull base surgery is iatrogenic damage to cranial nerves, which can be prevented if the nerve is identified. Devices that stimulate nerves with electric current assist in nerve identification. Contemporary devices have two main limitations: 1) the physical contact of the stimulating electrode and (2) the spread of the current through the tissue. In contrast to electrical stimulation, pulsed infrared optical radiation can be used to safely and selectively stimulate neural tissue and might be valuable for screening.

Optical stimulation of auditory neurons: effects of acute and chronic deafening.

In developing neural prostheses, particular success has been realized with cochlear implants. These devices bypass damaged hair cells in the auditory system and electrically stimulate the auditory nerve directly. In contemporary cochlear implants, however, the injected electric current spreads widely along the scala tympani and across turns. Consequently, stimulation of spatially discrete spiral ganglion cell populations is difficult. In contrast to electrical stimulation, it has been shown that extremely spatially selective stimulation is possible using infrared radiation (e.g. [Izzo, A.D., Su, H.S., Pathria, J., Walsh Jr., J.T., Whitlon, D.S., Richter, C.-P., 2007a. Selectivity of neural stimulation in the auditory system: a comparison of optic and electric stimuli. J. Biomed. Opt. 12, 1-7]). Here, we explore the correlation between surviving spiral ganglion cells, following acute and chronic deafness induced by neomycin application into the middle ear, and neural stimulation using optical radiation and electrical current. In vivo experiments were conducted in gerbils. Before the animals were deafened, acoustic thresholds were obtained and neurons were stimulated with optical radiation at various pulse durations, radiation exposures, and pulse repetition rates. In one group of animals, measurements were made immediately after deafening, while the other group was tested at least four weeks after deafening. Deafness was confirmed by measuring acoustically evoked compound action potentials. Optically and electrically evoked compound action potentials and auditory brainstem responses were determined for different radiation exposures and for different electrical current amplitudes, respectively. After completion of the experiments, the animals were euthanized and the cochleae were harvested for histology. Acoustically evoked compound action potential thresholds were elevated by more than 40 dB after neomycin application in acutely deaf and more than 60 dB in chronically deaf animals. Compound action potential thresholds, which were determined with optical radiation pulses, were not significantly elevated in acutely deaf animals. However, in chronically deaf animals optically evoked CAP thresholds were elevated. Changes correlated with the number of surviving spiral ganglion cells and the optical parameters that were used for stimulation.

Selectivity of neural stimulation in the auditory system: a comparison of optic and electric stimuli

Pulsed, mid-infrared lasers were recently investigated as a method to stimulate neural activity. There are significant benefits of optically stimulating nerves over electrically stimulating, in particular the application of more spatially confined neural stimulation. We report results from experiments in which the gerbil auditory system was stimulated by optical radiation, acoustic tones, or electric current. Immunohistochemical staining for the protein c-FOS revealed the spread of excitation. We demonstrate a spatially selective activation of neurons using a laser; only neurons in the direct optical path are stimulated. This pattern of c-FOS labeling is in contrast to that after electrical stimulation. Electrical stimulation leads to a large, more spatially extended population of labeled, activated neurons. In the auditory system, optical stimulation of nerves could have a significant impact on the performance of cochlear implants, which can be limited by the electric current spread.

Laser stimulation of auditory neurons at high-repetition rate

Pulsed, mid-infrared lasers can evoke neural activity from motor as well as sensory neurons in vivo. Lasers allow more selective spatial resolution of stimulation than the conventional electrical stimulation. To date, few studies have examined pulsed, mid-infrared neural stimulation and very little of the available optical parameter space has been studied. We found that pulse durations as short as 20 ?s elicit a compound action potential from the gerbil cochlea. Moreover, stimulation thresholds are not a function of absolute energy or absolute power deposited. Compound action potential peak-to-peak amplitude remained constant over extended periods of stimulation. Stimulation occurred up six hours continuously and up to 50 Hz in repetition rate. Single fiber experiments were made using repetition rates of up to 1 kHz. Action potentials occurred 2.5-4 ms after the laser pulse. Maximum rates of discharge were up to 250 action potentials per second. With increasing stimulation rate (300 Hz), the action potentials did not respond strictly after the light pulse. The results from these experiments are important for designing the next generation of neuroprostheses, specifically cochlear implants.

Selectivity of optical stimulation in the auditory system

It is known that electrical current injected from cochlear implant contacts spreads within the cochlea, causing overlapping stimulation fields and possibly limiting the performance of cochlear implant users. We have investigated an alternative mechanism to stimulate auditory neurons in the gerbil cochlea using a laser, rather than electrical current. With the laser, it is possible to direct the light to a selected, known volume of tissue that is smaller than the electrically stimulated population of cells. In the present experiments, a transiently expressed transcription factor, c-FOS, was used to stain activated nerve cells. Immunohistochemical staining for c-FOS in the cochlea shows a small area of optical stimulation, which occurs directly opposite to the optical fiber. Additionally, masking data indicate that the laser can stimulate a small population of cells similar to an acoustic toneburst. Smaller populations of stimulated cells could reduce the amount of overlap in stimulation fields and allow more stimulation contacts in a neuroprothesis.

Characterization of single auditory nerve fibers in response to laser stimulation

One drawback with traditional cochlear implants, which use electrical currents to stimulate spiral ganglion cells, is the ability to stimulate spatially discrete cells without overlap and electric current spread. We have recently demonstrated that spatially selective stimulation of the cochlea is possible with optical stimulation. However, for light to be a useful stimulation paradigm for stimulation of neurons, including cochlear implants, the neurons must be stimulated at high stimulus repetition rates. In this paper we utilize single fiber recordings from the auditory nerve to demonstrate that stimulation is possible at high repetition rates of the light pulses. Results showed that action potentials occurred 2.5-4. ms after the laser pulse. Maximum rates of discharge were up to 300 Hz. The action potentials did not respond strictly after the light pulse with high stimulation rates, i.e. >300 pulses per second. The correlation between the action potentials and the laser pulses decreased drastically for laser pulse repetition rate larger than 300 pulses per second.

Laser stimulation of the auditory system at 1.94 μm and microsecond pulse durations

Light can artificially stimulate nerve activity in vivo. A significant advantage of optical neural stimulation is the potential for higher spatial selectivity when compared with electrical stimulation. An increased spatial selectivity of stimulation could improve significantly the function of neuroprosthetics, such as cochlear implants. Cochlear implants restore a sense of hearing and communication to deaf individuals by directly electrically stimulating the remaining neural cells in the cochlea. However, performance is limited by overlapping electric fields from neighboring electrodes. Here, we report on experiments with a new laser, offering a previously unavailable wavelength, 1.94μm, and pulse durations down to 5μs, to stimulate cochlear neurons. Compound action potentials (CAP) were evoked from the gerbil cochlea with pulse durations as short as 1μs. Data show that water absorption of light is a significant factor in optical stimulation, as evidenced by the required distance between the optical fiber and the neurons during stimulation. CAP threshold measurements indicate that there is an optimal range of pulse durations over which to deposit the laser energy, less than ~100μs. The implications of these data could direct further research and design of an optical cochlear implant.

Frontiers in optical stimulation of neural tissues: past, present, and future

Since lasers were first used in medicine and biomedical related research there have been a variety of documented effects following the irradiation of neural tissues. The first systematic studies to report the direct stimulatory effect of infrared light on neural tissues were performed by researchers at Vanderbilt University in the rat sciatic nerve. These initial studies demonstrated a set of associated advantages of standard stimulation methods, which lead to much excitement and anticipation from the neuroscience community and industry. The inception of this new field included a partnership between industry and academia to foster the development, not only of the applications but also a series of devices to support the research and ultimate commercialization of technology. Currently several institutions are actively utilizing this technique in various applications including in the cochlear and vestibular systems. As more researchers enter the field and new devices are developed we anticipate the number of applications will continue to grow. Some of the next steps will include the establishment of the safety and efficacy data to move this technique to clinical trials and human use.