High-frequency alternating current block using macro-sieve electrodes: A pilot study

Background and objective High-frequency alternating current (HFAC) can yield a rapid-acting and reversible nerve conduction block. The present study aimed to demonstrate the successful implementation of HFAC block delivery via regenerative macro-sieve electrodes (MSEs). Methods Dual-electrode assemblies in two configurations [dual macro-sieve electrode-1 (DMSE-I), DMSE-II] were fabricated from pairs of MSEs and implanted in the transected and subsequently repaired sciatic nerves of two male Lewis rats. After four months of postoperative nerve regeneration through the MSEs\u27 transit zones, the efficacy of acute HFAC block was tested for both configurations. Frequencies ranging from 10 kHz to 42 kHz, and stimulus amplitudes with peak-to-peak voltages ranging from 2 V to 20 V were tested. Evoked muscle force measurement was used to quantify the nerve conduction block. Results HFAC stimulation delivered via DMSE assemblies obtained a complete block at frequencies of 14 to 26 kHz and stimulus amplitudes of 12 to 20 V p-p. The threshold voltage for the complete block showed an approximately linear dependence on frequency. The threshold voltage for the partial conduction block was also approximately linear. For those frequencies that displayed both partial and complete block, the partial block thresholds were consistently lower. Conclusion This study provides a proof of concept that regenerative MSEs can achieve complete and reversible conduction block via HFAC stimulation of regenerated nerve tissue. A chronically interfaced DMSE assembly may thereby facilitate the inactivation of targeted nerves in cases wherein pathologic neuronal hyperactivity is involved

Biophysical Determinants of the Behaviour of Human Myelinated Axons

This thesis investigates the role of the hyperpolarization-activated current, Ih, on the excitability of human axons. It exploits the unique characteristics of the underlying hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels to improve existing and create new techniques for studying Ih. An isolated amplifier with low-noise and high common-mode rejection was developed, and threshold tracking techniques were modified to allow the measurement of the excitability of low-threshold sensory axons and of cutaneous afferents close to their receptors. These developments open up the possibility of studying changes in polyneuropathies, where symptoms and possibly the underlying pathology are more apparent distally in the limbs. Strong and long-lasting hyperpolarization was used to open more HCN channels and to examine their contribution to the excitability of motor and sensory axons. A mathematical model of myelinated motor axons was adapted to account for the response to strong and long-lasting hyperpolarization. Without structural changes the model was then modified to fit the observed excitability of sensory axons. Changes in the excitability and safety margin during focal hyperthermia were studied in both motor and sensory axons of the median nerve, and the underlying mechanisms were explored using the new mathematical model. Finally, the involvement of Ih in the frequency preference of oscillation in human axons was investigated by developing resonance techniques that have hitherto never been used to study axonal function

Functional impairment following axonal injury

Following trauma or other neurological disorders, a series of events happen that cause axonal dysfunction or ultimately lead to axonal death. Computational modeling of the nervous system facilitates systematic study of the effects of each injury parameter on the output. The overall goal of this research was to develop a new method of simulating axon damage in a biophysical model and quantify the effects of structural damage on signal conduction. To achieve this, three objectives were addressed 1) quantify the effects of normal morphological variation and demyelination on axonal conduction characteristics, 2) develop a new computationally efficient method for modeling damage in axons, and 3) characterize the structure changes observed in human axons and quantify the relationship between these observed changes and axonal function. Biophysical computational models developed in NEURON were employed to characterize morphological changes in damaged axons and study the effects of some of the most common axonal injuries such as myelin damage and spheroid formation on signal propagation in axons with different calibers. To facilitate efficient computational simulation, a new approach for increasing geometrical resolution in NEURON was developed and assessed. To investigate the effects of axonal swelling on action potential conduction in myelinated axons, the morphological properties of axonal spheroids were characterized by analyzing a series of confocal images captured from post-mortem human brain samples of patients with MS and infarction. Our results indicate that subtle abnormalities in nodal, paranodal and juxtaparanodal regions may have sizable effects on action potential amplitude and velocity and more targeted treatments need to be developed that focus on these regions. In addition, the results of our histopathological and computational studies suggest that axons with different diameters may respond differently to injuries and diseases. Therefore, it is important to perform experimental injury models across a wide range of axons to get a more comprehensive understanding of the relationship between axonal morphological features, injury parameters and functional responses. We expect this research to lay the quantitative foundation for finding new potential functional markers of white matter tissue damage and provide further insights into how myelin damage and axonal spheroids may affect function

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

Characterization of the high frequency alternating current block in the rat sciatic nerve using cuff electrodes and macro-sieve electrodes

Tripolar cuff electrodes were designed, fabricated and non-chronically implanted in the sciatic nerve of two-month-old Lewis rats. A proximal constant current stimulus to the nerve was blocked by applying a high frequency sinusoidal signal to the distally placed tripolar cuff electrode. The frequency voltage characteristic of the blocking signal was obtained. Complete block was not achieved using variants of the tripolar cuff design and bipolar cuff electrodes. Single and dual macro-sieve electrode assemblies were designed, fabricated and chronically implanted in the sciatic nerve of Lewis rats. After a four-month period for regeneration four different electrode configurations were tested to enable a high frequency block. A complete and quickly reversible block was obtained using both the macro-sieve electrodes for the HFAC block – proximal macro-sieve as anode and distal macro-sieve as cathode. Finite element modelling and axon modelling was done to determine the optimal parameters for effecting a high frequency block in the nerve