par Cury, Joaquin 
Président du jury Delchambre, Alain
Promoteur Nonclercq, Antoine
Co-Promoteur Gorza, Simon-Pierre
Publication Non publié, 2022-05-31
Président du jury Delchambre, Alain
Promoteur Nonclercq, Antoine
Co-Promoteur Gorza, Simon-Pierre
Publication Non publié, 2022-05-31
Thèse de doctorat
| Résumé : | This thesis aims at implementing light-based methods to stimulate peripheral nerves and record their activity. The rapid growth of neurotechnology and a better understanding of the neural circuits have contributed to the development of invasive and non-invasive therapies to treat a broad range of neurologic disorders. In this context, implantable neurostimulators have proved to play an important role in providing therapeutic solutions. These devices stimulate the neural tissue, producing a therapeutic effect. At-present, the stimulation and the recording of biomarkers related to the disorder are based on electrical means. In addition, magnetic resonance imaging (MRI) is the adopted methodology for diagnosis and postoperative ongoing surveillance of patients using an implantable neurostimulator.The increase prevalence of different neurological disorders and the advancements in minimally invasive neurosurgical procedures have driven a rise in the demand of these devices. However, it is important to note that while implantable neurostimulators are widely used, they exhibit several limitations, such as MRI incompatibility, limited spatial precision for stimulation and recording, mechanical strains at the tissue-electrode interface, stimulation artefacts that might difficult the recording of nerve activity close to the stimulation site and a non-physiological neural fibres recruitment.Direct optical methods to stimulate and record neural activity are attractive solutions that overcome the limitations present in electrical neurostimulators. They are more compatible with MRI-compatible and artefact-free. They provide a larger spatial precision and do not require a tissue-electrode interface. For stimulation, focused mid-infrared light alters the membrane potential, causing the generation of the nerve activity. For recording, intrinsic optical properties variations associated with nerve activity, such as birefringence changes, exhibit signals similar to potentiometric dyes.The first part of this thesis is related to the use of infrared pulsed light to stimulate neural tissue (infrared neurostimulation, INS). In the prospect of miniaturized applications, such as implants, light sources emitting wavelengths below 1500 nm are of great interest due to their small size and high output power. However, there is a lack of INS studies in literature using these wavelengths and consequently there is no information regarding parameters for an effective stimulation. For this reason, in this study, we designed and implemented a setup for ex-vivo optical stimulation for exploring the effect of several key parameters (optical power and pulse duration), activation features (threshold and spatial selectivity) and recovery characteristics (repeated stimuli) in rat peripheral nerves. A nerve chamber allowing ex-vivo electrical and optical stimulation was designed and built. A 1470 nm light source was chosen to stimulate the nerve, and a photodiode module was implemented to synchronize the electrical and optical channels. Compound neural action potentials (CNAPs) were successfully generated with infrared light pulses of 200–2000 μs duration and power in the range of 3–10 W. Recruitment curves were obtained by increasing durations at a constant power level. Neural activation threshold was reached at a mean radiant exposure of 3.16 ± 0.68 J cm−2 and mean pulse energy of 3.79 ± 0.72 mJ. Furthermore, repetition rates of 2–10 Hz were explored. In eight out of ten sciatic nerves (SNs), repeated light stimuli induced a sensitization effect in that the CNAP amplitude progressively grows, representing an increasing number of recruited fibers. In two out of ten SNs, CNAPs were composed of a succession of peaks corresponding to different conduction velocities. These results suggest that slow nerve fibres, characterized by a high stimulation threshold, can be activated optically.The second part of this thesis is related to the use of light to record nerve activity. In this regard, birefringence variations related to nerve activity is a promising label-free technique for sensing CNAPs. While widely applied in crustaceans, little is known about its efficiency on mammal peripheral nerves. In the second part of this thesis, we study the efficacy of birefringence recordings in myelinated and unmyelinated nerves. To this end, we designed an optical/electrical stimulation protocol and used a single optical setup to conduct birefringence recordings to detect CNAPs, and Stokes parameters measurements in rat and lobster nerves. Moreover, based on the Stokes formalism, we developed a simple model to infer the expected signal-to-noise-ratio of the birefringence signal, which takes into account birefringence (i.e., polarization rotation) and scattering effects. While single-trial detection of nerve activity in crustaceans was achieved successfully, no optical signal was detected in rats, even after extensive signal filtering and averaging. The Stokes parameters showed that a high degree of polarization of light is maintained in lobster samples, whereas an almost complete light depolarization occurs in rat nerves. Our results indicate depolarization itself is not sufficient to explain the absence of birefringence signals in rats. We hypothesize that this absence comes from the myelin sheets, which constrain the birefringence changes only to take place at the nodes of Ranvier.Altogether, this thesis contributes to the field of biomedical optics and neurosciences. Scientifically, it gives new insights into optical parameters for neurostimulation using wavelengths below 1500 nm, and it provides valuable data about the performance of birefringence-based methods in mammal peripheral nerves, poorly explored in literature. |
