Selective electrical and optical neuromodulation of the central nervous system with conformable microfabricated implants

Neuroprosthetic systems are designed to interface with the nervous system, for the replacement or restoration of damaged functions in the motor and/or sensory systems. In order to have an efficient communication with the nervous tissue leading to optimized clinical outcomes, achieving neural stimulation with high selectivity is essential. This thesis aims at finding technological routes to enable spatial, structural and cell-type selective surface neuromodulation using electrical and optogenetic stimulation and to validate them in in vivo models. Thin and conformable electrode arrays enable close contact with the target tissue, thereby leading to minimal distances with the target neurons and maximal spatial selectivity. Flexible polymer technologies based on polyimide (PI) are used to design thin (< 10 ÎŒm thick) electrode arrays with small feature size (< 100 ÎŒm), resulting in miniaturized conformable arrays for surface stimulation. PEDOT conducting polymer coatings are used on the miniaturized electrical stimulation sites (100 ÎŒm diameter) to improve their charge injection properties. This implant is used for auditory brainstem stimulation in a rat model, and is shown to generate robust activation of the auditory system. Analysis of the multiunit recordings obtained from the inferior colliculus (IC), an auditory structure of the midbrain, led to the identification of different phases in the responses, with various frequency tuning properties. The stimulation configuration is shown to influence the tonotopic organisation of the frequency-tuned responses. Bipolar stimulation with small interelectrode distances (400 ÎŒm) is shown to generate responses that are more frequency-selective than with larger interelectrode distances (800 ÎŒm). The orientation of the electrode pair and the waveformof stimulation current are also shown to influence the response properties. An updated design of the clinical auditory brainstem implant(ABI) is then proposed, integrating higher electrode density and guidelines for a more tissue-conformal format. The main steps in the road towards improvement of ABI outcomes are then discussed, with proposed changes in the stimulation protocol and electrode array in parallel. Another approach to cell-specific neuromodulation is the implementation of optogenetics. This requires not only genetic engineering of the neurons but also the manufacturing of implantable light-emitting devices. Here, we introduce a fabrication process for the integration of thin (50 ÎŒm) LEDs into a polyimide-based device. A proof-of-concept in vivo study shows that stimulation of the spinal cord of a mouse model generates robust EMG responses in both legs over the course of several weeks. The walking integrity is confirmed, showing the absence of functional damages to the spinal cord. These results show that the presented LED array can provide a way of stimulating key elements of the locomotor neural circuitry, potentially leading to a greater understanding of the role of each neuronal subtypes in the spinal cord. Through the applications of ABI and spinal cord stimulation, this thesis thus highlights the importance and potential use of specifically tailored technologies enabling selective surface stimulation of the nervous system

The temporal pattern of impulses in primary afferents analogously encodes touch and hearing information

An open question in neuroscience is the contribution of temporal relations between individual impulses in primary afferents in conveying sensory information. We investigated this question in touch and hearing, while looking for any shared coding scheme. In both systems, we artificially induced temporally diverse afferent impulse trains and probed the evoked perceptions in human subjects using psychophysical techniques. First, we investigated whether the temporal structure of a fixed number of impulses conveys information about the magnitude of tactile intensity. We found that clustering the impulses into periodic bursts elicited graded increases of intensity as a function of burst impulse count, even though fewer afferents were recruited throughout the longer bursts. The interval between successive bursts of peripheral neural activity (the burst-gap) has been demonstrated in our lab to be the most prominent temporal feature for coding skin vibration frequency, as opposed to either spike rate or periodicity. Given the similarities between tactile and auditory systems, second, we explored the auditory system for an equivalent neural coding strategy. By using brief acoustic pulses, we showed that the burst-gap is a shared temporal code for pitch perception between the modalities. Following this evidence of parallels in temporal frequency processing, we next assessed the perceptual frequency equivalence between the two modalities using auditory and tactile pulse stimuli of simple and complex temporal features in cross-sensory frequency discrimination experiments. Identical temporal stimulation patterns in tactile and auditory afferents produced equivalent perceived frequencies, suggesting an analogous temporal frequency computation mechanism. The new insights into encoding tactile intensity through clustering of fixed charge electric pulses into bursts suggest a novel approach to convey varying contact forces to neural interface users, requiring no modulation of either stimulation current or base pulse frequency. Increasing control of the temporal patterning of pulses in cochlear implant users might improve pitch perception and speech comprehension. The perceptual correspondence between touch and hearing not only suggests the possibility of establishing cross-modal comparison standards for robust psychophysical investigations, but also supports the plausibility of cross-sensory substitution devices