Restoring Upper Extremity Mobility through Functional Neuromuscular Stimulation using Macro Sieve Electrodes

The last decade has seen the advent of brain computer interfaces able to extract precise motor intentions from cortical activity of human subjects. It is possible to convert captured motor intentions into movement through coordinated, artificially induced, neuromuscular stimulation using peripheral nerve interfaces. Our lab has developed and tested a new type of peripheral nerve electrode called the Macro-Sieve electrode which exhibits excellent chronic stability and recruitment selectivity. Work presented in this thesis uses computational modeling to study the interaction between Macro-Sieve electrodes and regenerated peripheral nerves. It provides a detailed understanding of how regenerated fibers, both on an individual level and on a population level respond differently to functional electrical stimulation compared to non-disrupted axons. Despite significant efforts devoted to developing novel regenerative peripheral interfaces, the degree of spatial clustering between functionally related fibers in regenerated nerves is poorly understood. In this thesis, bioelectrical modeling is also used to predict the degree of topographical organization in regenerated nerve trunks. In addition, theoretical limits of the recruitment selectivity of the device is explored and a set of optimal stimulation paradigms used to selectively activate fibers in different regions of the nerve are determined. Finally, the bioelectrical model of the interface/nerve is integrated with a biomechanical model of the macaque upper limb to study the feasibility of using macro-sieve electrodes to achieve upper limb mobilization

Label-free polarisation-resolved optical imaging of biological samples

Myelin is a biological structure present in all the gnathostomata. It is a highly- ordered structure, in which many lipid-enriched and densely compacted phospho- lipid bilayers are rolled up in a cylindrical symmetry around a subgroup of axons. The myelin sheath increases the electrical transverse resistance and reduces the ca- pacitance making the saltatory conduction of action potentials possible and therefore leading to a critically improved performance in terms of nervous impulse conduc- tion speeds and travel lengths. Myelin pathologies are a large group of neurological diseases that often result in death or disability. In order to investigate the main causes of myelin damage and its temporal progression many microscopy techniques are currently employed, such as electron microscopy and histochemistry or fluorescence imaging. However, electron microscopy and histochemistry imaging require complex sample prepara- tion and are therefore unsuitable for live imaging. Fluorescence imaging, as well as its derivatives, confocal and two-photon imaging, relies on the use of fluorescent probes to generate the image contrast but fluorophores and the associated sample processing, when applicable to living specimens, might nonetheless modify the bi- ological properties of the target molecule and perturb the whole biological process under investigation; moreover, fluorescent immunostaining still requires the fixation of the cells. Coherent anti-Stokes Raman Scattering (CARS) microscopy, on the other hand, is a powerful and innovative imaging modality that permits the study of liv- ing specimens with excellent chemical contrast and spatial resolution and without the confounding and often tedious use of chemical or biological probes. This is par- ticularly important in clinical settings, where the patient biopsy must be explanted in order to stain the tissue. In these cases it may be useful to resort to a set of label-free microscopy techniques. Among these, CARS microscopy is an ideal tool to investigate myelin morphology and structure, thanks to its abundance of CH2 bonds. The chemical selectivity of CARS microscopy is based on the properties of the contrast-generating CARS process. This is a nonlinear process in which the energy difference of a pair of incoming photons (\u201cpump\u201d and \u201cStokes\u201d) matches the energy of one of the vibrational modes of a molecular bond of interest. This vibrational excited state is coherently probed by a third photon (\u201cprobe\u201d) and anti-Stokes radi- ation is emitted. In this thesis I shall discuss the development of a multimodal nonlinear opti- cal setup implementing CARS microscopy together with general Four-Wave Mix- ing, Second Harmonic Generation and Sum Frequency Generation microscopies. Moreover, I shall present a novel polarisation-resolved imaging scheme based on the CARS process, which I named Rotating-Polarisation (RP) CARS microscopy and implemented in the same setup. This technique, using a freely-rotating pump-and- probe-beam-polarisation plane, exploits the CARS polarisation-dependent rules in order to probe the degree of anisotropy of the chemical-bond spatial orientations inside the excitation point-spread function and their average orientation, allowing at the same time the acquisition of large-field-of-view images with minimal polarisa- tion distortions. I shall show that RP-CARS is an ideal tool to investigate the highly- ordered structure of myelinated nervous fibres thanks to the strong anisotropy and symmetry properties of the myelin molecular architecture. I shall also demonstrate that this technique allows the fully label-free assessment of the myelin health status both in a chemical model of myelin damage (lysophos- phatidylcholine-exposed mouse nerve) and in a genetic model (twitcher mouse) of a human leukodystrophy (Krabbe disease) while giving useful insights into the pathogenic mechanisms underlying the demyelination process. I shall also discuss the promises of this technique for applications in optical tractography of the nerve fibres in the central nervous system and for the investigation of the effects of ageing on the peripheral nervous system. Moreover, I shall demonstrate by means of numer- ical simulations that RP-CARS microscopy is extremely robust against the presence of scatterers (such as lipid vesicles, commonly found in the peripheral nervous sys- tem). Finally, I shall discuss the results of the exploitation of my multimodal setup in a different area at the boundary of biophysics and nanomedicine: the observation of the internalization of different kinds of nanoparticles (boron-nitride nanotubes, barium-titanate nanoparticles and barium-titanate-core/gold-shell nanoparticles) by cultured cells and the demonstration of the nanopatterned nature of a structure built with two-photon lithography

Comparison of the Bi-Directional Performance of Micro-Channel Sieve and Thin-Film TIME Peripheral Nerve Interfaces

Sophisticated motorized prosthetic limbs contain multiple degrees of freedom of motion as well as embedded pressure and angle transducers to provide sensory feedback in amputees. Although several central neural recording and stimulation modalities exist for both controlling these motions and providing sensory feedback from a prosthetic limb, directly interfacing the peripheral nerves which originally innervated the limb has many advantages. A difficulty with this bi-directional approach is that electrically stimulating axons to provide haptic feedback creates stimulation artifacts at neighboring recording sites within the nerve that are several orders of magnitude larger than the electroneurogram used for control. In this dissertation, a novel micro-channel sieve electrode is designed, optimized and tested that can provide true bi-directional and concurrent electrical stimulation to sensory axons while simultaneously recording high-fidelity electroneurograms from motor axons in the same peripheral nerve. This research, through computational modeling, compares the concurrent bi-directional performance of both the novel micro-channel sieve electrode designed in this dissertation and the gold standard intrafascicular electrode (tfTIME) used in current clinical research studies in human amputees. The novel micro-channel sieve electrode was found to significantly outperform the tfTIME electrode by increasing recording levels and decreasing stimulation artifact yielding a signal to artifact ratio greater than 50 dB compared to -56.4 dB for the tfTIME. The novel micro-channel sieve electrode developed in this dissertation could provide the first concurrentl, bi-directional peripheral nerve interface for clinical applications

Temporal modulation of the response of sensory fibers to paired-pulse stimulation

Multi-channel nerve cuff electrode arrays can provide sensory feedback to prosthesis users. To develop efficacious stimulation protocols, an understanding of the impact that spatio-temporal patterned stimulation can have on the response of sensory fibers is crucial. We used experimental and modelling methods to investigate the response of nerve fibers to paired-pulse stimulation. Nerve cuff electrode arrays were implanted for stimulation of the sciatic nerves of rats and the sensory compound action potentials were recorded from the L4 dorsal root. A model of the nerve cuff electrode array and sciatic nerve was also developed. The experimental and modelling results were compared. Experiments showed that it took 8 ms for the sensory fibers to completely recover from a conditioning stimulus, regardless of the relative position of the electrodes used for stimulation. The results demonstrate that the electrodes on the cuff cannot be considered independent. Additionally, at 120% of the threshold, there is a large overlap in the fibers that were activated by the different electrodes. If a stimulus paradigm considered the electrodes as independent, stimuli from the different electrodes would need to be interleaved, and the intervals between the stimuli should be greater than 8 ms

Shielding effects of myelin sheath on axolemma depolarization under transverse electric field stimulation

Axonal stimulation with electric currents is an effective method for controlling neural activity. An electric field parallel to the axon is widely accepted as the predominant component in the activation of an axon. However, recent studies indicate that the transverse component to the axolemma is also effective in depolarizing the axon. To quantitatively investigate the amount of axolemma polarization induced by a transverse electric field, we computed the transmembrane potential (Vm) for a conductive body that represents an unmyelinated axon (or the bare axon between the myelin sheath in a myelinated axon). We also computed the transmembrane potential of the sheath-covered axonal segment in a myelinated axon. We then systematically analyzed the biophysical factors that affect axonal polarization under transverse electric stimulation for both the bare and sheath-covered axons. Geometrical patterns of polarization of both axon types were dependent on field properties (magnitude and field orientation to the axon). Polarization of both axons was also dependent on their axolemma radii and electrical conductivities. The myelin provided a significant “shielding effect” against the transverse electric fields, preventing excessive axolemma depolarization. Demyelination could allow for prominent axolemma depolarization in the transverse electric field, via a significant increase in myelin conductivity. This shifts the voltage drop of the myelin sheath to the axolemma. Pathological changes at a cellular level should be considered when electric fields are used for the treatment of demyelination diseases. The calculated term for membrane polarization (Vm) could be used to modify the current cable equation that describes axon excitation by an external electric field to account for the activating effects of both parallel and transverse fields surrounding the target axon

An Instrumented Cochlea Model for the Evaluation of Cochlear Implant Electrical Stimulus Spread.

Cochlear implants use electrical stimulation of the auditory nerve to restore the sensation of hearing to deaf people. Unfortunately, the stimulation current spreads extensively within the cochlea, resulting in "blurring" of the signal, and hearing that is far from normal. Current spread can be indirectly measured using the implant electrodes for both stimulating and sensing, but this provides incomplete information near the stimulating electrode due to electrode-electrolyte interface effects. Here, we present a 3D-printed "unwrapped" physical cochlea model with integrated sensing wires. We integrate resistors into the walls of the model to simulate current spread through the cochlear bony wall, and "tune" these resistances by calibration with an in-vivo electrical measurement from a cochlear implant patient. We then use this model to compare electrical current spread under different stimulation modes including monopolar, bipolar and tripolar configurations. Importantly, a trade-off is observed between stimulation amplitude and current focusing among different stimulation modes. By combining different stimulation modes and changing intracochlear current sinking configurations in the model, we explore this trade-off between stimulation amplitude and focusing further. These results will inform clinical strategies for use in delivering speech signals to cochlear implant patients

Modeling the electrical stimulation of peripheral vestibular nerves

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2006.Includes bibliographical references (p. 137-143).The research conducted for this thesis investigated the theoretical placement of electrodes for a proposed implantable vestibular prosthesis to aid patients suffering from balance related disorders. The most likely sites of stimulation for the first-generation of such a device are the peripheral nerves responsible for transmitting rotational information to the brain. Although stimulation of such nerves has been performed in human and animal patients, little is known about the mechanisms responsible for the eliciting nerve responses. Models of the inferior and superior divisions of peripheral vestibular nerve were created to characterize the stimulus threshold behavior across the parameters of fiber diameter and location within the nerve. Current-distance relations were derived for nerve fibers excited by six commonly used electrode configurations. The threshold relations were used as a guide to determine the electrode configuration and location best-suited to stimulate the inferior vestibular nerve and selectively stimulate the branches of the superior vestibular nerve. The criteria used determine optimal placement included minimum current thresholds, configuration simplicity, and distance to the electrode. For the inferior nerve case, a cathodal stimulus located at a distance of 100 pm or 200 ym from the nerve and driven with a stimulus current of 56 pA or 76 pIA was recommended. For the superior vestibular nerve case we were interested in selectively stimulating each branch, imposing a further criteria to maximize the threshold ratio between stimulation of the respective branches. A transverse dipole electrode configurations was suggested that allowed selective stimulation of either branch. The configuration included a cathode located 300m from Branch 1 and an anode centrally located between both branches.(cont.) When driven with a cathodal stimulus of strength 51 pA, only Branch I was excited, while driving both electrodes with a magnitude of 106 jIA excited only Branch II. The proximity to the facial nerve was considered in the choicesby Ketul M. Parikh.M.Eng