Sensitivity study of neuronal excitation and cathodal blocking thresholds of myelinated axons for percutaneous auricular vagus nerve stimulation

Objective: Excitation of myelinated nerve fibers is investigated by means of numerical simulations, for the application of percutaneous auricular vagus nerve stimulation (pVNS). High sensitivity to axon diameter is of interest regarding the goal of targeting thicker fibers. Methods: Excitation and blocking thresholds for different pulse types, phase durations, axon depths, axon-electrode distances, temperatures and axon diameters are investigated. The used model consists of a 50 mm long axon and a centrally located needle electrode in a layered medium representing the auricle. Neuronal excitation is simulated using the Frankenhaeuser-Huxley equations for all combinations of parameter values. Results and conclusion: Multiple modes and locations of excitation along the axon were observed, depending on the pulse type and amplitude. When increasing the axon-electrode distance from 1 mm to 2 mm, sensitivity of thresholds to axon depth decreased with ca. 50%, while sensitivity to axon-electrode distance, axon diameter and phase duration each increased with ca. 15% to 20%, except from monophasic anodal pulses, showing a 45% decrease for axon-electrode distance. These trends for axon diameter and axon-electrode distance allow for more selective stimulation of thicker target fibers using monophasic anodal pulses at higher axon-electrode distances. Cathodal monophasic pulses did not perform well due to blocking of the thicker fibers, which was only rarely seen for other pulse types. Significance: Sensitivities of stimulation thresholds to these parameters by numerical simulation reveal how the stimulation parameters can be changed in order to increase therapeutic effect and comfort during pVNS by enabling more selective stimulation

Anodal block permits directional vagus nerve stimulation

© 2020, The Author(s). Vagus nerve stimulation (VNS) is a bioelectronic therapy for disorders of the brain and peripheral organs, and a tool to study the physiology of autonomic circuits. Selective activation of afferent or efferent vagal fibers can maximize efficacy and minimize off-target effects of VNS. Anodal block (ABL) has been used to achieve directional fiber activation in nerve stimulation. However, evidence for directional VNS with ABL has been scarce and inconsistent, and it is unknown whether ABL permits directional fiber activation with respect to functional effects of VNS. Through a series of vagotomies, we established physiological markers for afferent and efferent fiber activation by VNS: stimulus-elicited change in breathing rate (ΔBR) and heart rate (ΔHR), respectively. Bipolar VNS trains of both polarities elicited mixed ΔHR and ΔBR responses. Cathode cephalad polarity caused an afferent pattern of responses (relatively stronger ΔBR) whereas cathode caudad caused an efferent pattern (stronger ΔHR). Additionally, left VNS elicited a greater afferent and right VNS a greater efferent response. By analyzing stimulus-evoked compound nerve potentials, we confirmed that such polarity differences in functional responses to VNS can be explained by ABL of A- and B-fiber activation. We conclude that ABL is a mechanism that can be leveraged for directional VNS

Selective electrical stimulation of peripheral nerve fibers:accommodation based methods

project was motivated by the idea of using and adapting accommodation-based methods for selective electrical stimulation of motor fibers to the study of the human nociceptive system. This has not been without difficulties, but it has still been a rewarding process, as it has provided the opportunity to study interesting biophysical mechanisms and to enhance the understanding of accommodation based methods. Throughout this project, I am indebted to all the co-workers and friends at the Center of Sensory Motor Interaction and at the Faculty of Dentistry, University of Toronto that I have had the fortune to work with and learn from. I wish to express my sincerest gratitude to my supervisor Associate Prof. Ole K. Andersen and Professor Lars Arendt-Nielsen, the head of Center for Sensory Motor Interaction, for their never failing interest and enthusiasm. I will also like to express my deepest gratitude to my hosts at the Faculty of Dentistry, University of Toronto, Professor Barry J. Sessle and Professor James W. Hu. Furthermore, I will like to thank Dr. Alexandra Vuckovic for graciously offering her volume conducto

Enhancing selectivity of minimally invasive peripheral nerve interfaces using combined stimulation and high frequency block: from design to application

The discovery of the excitable property of nerves was a fundamental step forward in our knowledge of the nervous system and our ability to interact with it. As the injection of charge into tissue can drive its artificial activation, devices have been conceived that can serve healthcare by substituting the input or output of the peripheral nervous system when damage or disease has rendered it inaccessible or its action pathological. Applications are far-ranging and transformational as can be attested by the success of neuroprosthetics such as the cochlear implant. However, the body’s immune response to invasive implants have prevented the use of more selective interfaces, leading to therapy side-effects and off-target activation. The inherent tradeoff between the selectivity and invasiveness of neural interfaces, and the consequences thereof, is still a defining problem for the field. More recently, continued research into how nervous tissue responds to stimulation has led to the discovery of High Frequency Alternating Current (HFAC) block as a stimulation method with inhibitory effects for nerve conduction. While leveraging the structure of the peripheral nervous system, this neuromodulation technique could be a key component in efforts to improve the selectivity-invasiveness tradeoff and provide more effective neuroprosthetic therapy while retaining the safety and reliability of minimally invasive neural interfaces. This thesis describes work investigating the use of HFAC block to improve the selectivity of peripheral nerve interfaces, towards applications such as bladder control or vagus nerve stimulation where selective peripheral nerve interfaces cannot be used, and yet there is an unmet need for more selectivity from stimulation-based therapy. An overview of the underlying neuroanatomy and electrophysiology of the peripheral nervous system combined with a review of existing electrode interfaces and electrochemistry will serve to inform the problem space. Original contributions are the design of a custom multi-channel stimulator able to combine conventional and high frequency stimulation, establishing a suitable experimental platform for ex-vivo electrophysiology of the rat sciatic nerve model for HFAC block, and exploratory experiments to determine the feasibility of using HFAC block in combination with conventional stimulation to enhance the selectivity of minimally-invasive peripheral nerve interfaces.Open Acces

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

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

Novel methods and circuits for field shaping in deep brain stimulation

Deep Brain Stimulation (DBS) is a clinical tool used to treat various neurological disorders, including tremor, Parkinson’s disease (PD) and dystonia. Today’s routine use of this therapy is a result of the pioneering work of Benabid and colleagues, who assessed the benefits of applying high-frequency stimulation to the ventral intermediate nucleus and reported substantial long-term improvements in PD patients. Clinical applications of DBS, however, have preceded research and left a number of challenges to optimise this therapeutic technique in terms of quality, therapy costs and understanding of its underlying mechanisms. DBS is based on monopolar or bipolar stimulation techniques, which are characterised by a limited control over the effects of stimulation and, in particular, over the shape and direction of the electric field propagating around the electrode. This thesis proposes two approaches to achieve dynamic electric field control during deep brain stimulation. The first method is based on the use of current-steering multipolar electrode drive, adopted to split the stimulation current between 2 or more contacts, in order to shift the stimulation field to a desired location. The work included the design, development and testing of an integrated circuit current-steering tripolar current source, developed in AMS 0.35μm technology. The second method is based on the use of phased arrays (PAs) in order to create an electromagnetic beam, which can be steered to a desired location. Computational models have shown the ability to steer and focus the electromagnetic fields in brain tissue by varying the phase and frequency of stimulation. Modelling simulations have shown that the use of multipolar electrode configurations is essential to achieve dynamic control over the shape and area of tissue stimulated. Configurations with larger number of cathodes allow for several stimulation patterns, making this stimulation approach beneficial in a clinical environment. Tests on the performance of the integrated tripolar current source have shown its capability to generate stimulation currents up to 1.86mA, to linearly steer the stimulation current to one of the anodes and to generate biphasic square and exponential current pulses, with time constant up to 28ms. In vitro experiments, carried out to map the electric potential generated by a dynamic tripolar current source, validated the model results, by showing the ability to shape the potential distribution around the electrode during stimulation. Finally, models of the behaviour of PA fields in brain tissue have shown that PAs could be introduced to DBS to allow for more accurate field steering and shaping in DBS. This thesis presents methods and implementations to achieve dynamic field shaping in DBS, which can greatly ameliorate the efficacy of clinical DBS