Restoring Fine Motor Skills through Neural Interface Technology.

Loss of motor function in the upper-limb, whether through paralysis or through loss of the limb itself, is a profound disability which affects a large population worldwide. Lifelike, fully-articulated prosthetic hands exist and are commercially available; however, there is currently no satisfactory method of controlling all of the available degrees of freedom. In order to generate better control signals for this technology, and help restore normal movement, it is necessary to interface directly with the nervous system. This thesis is intended to address several of the limitations of current neural interfaces and enable the long-term extraction of control signals for fine movements of the hand and fingers. The first study addresses the problems of low signal amplitudes and short implant lifetimes in peripheral nerve interfaces. In two rhesus macaques, we demonstrate the successful implantation of regenerative peripheral nerve interfaces (RPNI), which allowed us to record high amplitude, functionally-selective signals from peripheral nerves up to 20 months post-implantation. These signals could be accurately decoded into intended movement, and used to enable monkeys to control a virtual hand prosthesis. The second study presents a novel experimental paradigm for intracortical neural interfaces, which enables detailed investigation of fine motor information contained in primary motor cortex. We used this paradigm to demonstrate accurate decoding of continuous fingertip position and enable a monkey to control a virtual hand in closed-loop. This is the first demonstration of volitional control of fine motor skill enabled by a cortical neural interface. The final study presents the design and testing of a wireless implantable neural recording system. By extracting signal power in a single, configurable frequency band onboard the device, this system achieves low power consumption while maintaining decode performance, and is applicable to cortical, peripheral, and myoelectric signals. Taken together, these results represent a significant step towards clinical reality for neural interfaces, and towards restoration of full and dexterous movement for people with severe disabilities.PhDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/120648/1/irwinz_1.pd

Microwire regenerative peripheral nerve interfaces with wireless recording and stimulation capabilities

A scalable microwire peripheral nerve interface was developed, which interacted with regenerated peripheral nerves in microchannel scaffolds. Neural interface technologies are envisioned to facilitate direct connections between the nervous system and external technologies such as limb prosthetics or data acquisition systems for further processing. Presented here is an animal study using a handcrafted microwire regenerative peripheral nerve interface, a novel neural interface device for communicating with peripheral nerves. The neural interface studies using animal models are crucial in the evaluation of efficacy and safety of implantable medical devices before their use in clinical studies.16-electrode microwire microchannel scaffolds were developed for both peripheral nerve regeneration and peripheral nerve interfacing. The microchannels were used for nerve regeneration pathways as a scaffolding material and the embedded microwires were used as a recording electrode to capture neural signals from the regenerated peripheral nerves. Wireless stimulation and recording capabilities were also incorporated to the developed peripheral nerve interface which gave the freedom of the complex experimental setting of wired data acquisition systems and minimized the potential infection of the animals from the wire connections

Biointegrated and wirelessly powered implantable brain devices: a review

Implantable neural interfacing devices have added significantly to neural engineering by introducing the low-frequency oscillations of small populations of neurons known as local field potential as well as high-frequency action potentials of individual neurons. Regardless of the astounding progression as of late, conventional neural modulating system is still incapable to achieve the desired chronic in vivo implantation. The real constraint emerges from mechanical and physical diffierences between implants and brain tissue that initiates an inflammatory reaction and glial scar formation that reduces the recording and stimulation quality. Furthermore, traditional strategies consisting of rigid and tethered neural devices cause substantial tissue damage and impede the natural behaviour of an animal, thus hindering chronic in vivo measurements. Therefore, enabling fully implantable neural devices, requires biocompatibility, wireless power/data capability, biointegration using thin and flexible electronics, and chronic recording properties. This paper reviews biocompatibility and design approaches for developing biointegrated and wirelessly powered implantable neural devices in animals aimed at long-term neural interfacing and outlines current challenges toward developing the next generation of implantable neural devices

The future of upper extremity rehabilitation robotics: research and practice

The loss of upper limb motor function can have a devastating effect on people’s lives. To restore upper limb control and functionality, researchers and clinicians have developed interfaces to interact directly with the human body’s motor system. In this invited review, we aim to provide details on the peripheral nerve interfaces and brain‐machine interfaces that have been developed in the past 30 years for upper extremity control, and we highlight the challenges that still remain to transition the technology into the clinical market. The findings show that peripheral nerve interfaces and brain‐machine interfaces have many similar characteristics that enable them to be concurrently developed. Decoding neural information from both interfaces may lead to novel physiological models that may one day fully restore upper limb motor function for a growing patient population.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155489/1/mus26860_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155489/2/mus26860.pd

Towards Natural Control of Artificial Limbs

The use of implantable electrodes has been long thought as the solution for a more natural control of artificial limbs, as these offer access to long-term stable and physiologically appropriate sources of control, as well as the possibility to elicit appropriate sensory feedback via neurostimulation. Although these ideas have been explored since the 1960’s, the lack of a long-term stable human-machine interface has prevented the utilization of even the simplest implanted electrodes in clinically viable limb prostheses.In this thesis, a novel human-machine interface for bidirectional communication between implanted electrodes and the artificial limb was developed and clinically implemented. The long-term stability was achieved via osseointegration, which has been shown to provide stable skeletal attachment. By enhancing this technology as a communication gateway, the longest clinical implementation of prosthetic control sourced by implanted electrodes has been achieved, as well as the first in modern times. The first recipient has used it uninterruptedly in daily and professional activities for over one year. Prosthetic control was found to improve in resolution while requiring less muscular effort, as well as to be resilient to motion artifacts, limb position, and environmental conditions.In order to support this work, the literature was reviewed in search of reliable and safe neuromuscular electrodes that could be immediately used in humans. Additional work was conducted to improve the signal-to-noise ratio and increase the amount of information retrievable from extraneural recordings. Different signal processing and pattern recognition algorithms were investigated and further developed towards real-time and simultaneous prediction of limb movements. These algorithms were used to demonstrate that higher functionality could be restored by intuitive control of distal joints, and that such control remains viable over time when using epimysial electrodes. Lastly, the long-term viability of direct nerve stimulation to produce intuitive sensory feedback was also demonstrated.The possibility to permanently and reliably access implanted electrodes, thus making them viable for prosthetic control, is potentially the main contribution of this work. Furthermore, the opportunity to chronically record and stimulate the neuromuscular system offers new venues for the prediction of complex limb motions and increased understanding of somatosensory perception. Therefore, the technology developed here, combining stable attachment with permanent and reliable human-machine communication, is considered by the author as a critical step towards more functional artificial limbs

The Use of Skeletal Muscle to Amplify Action Potentials in Transected Peripheral Nerves

Upper limb amputees suffer with problems associated with control and attachment of prostheses. Skin-surface electrodes placed over the stump, which detect myoelectric signals, are traditionally used to control hand movements. However, this method is unintuitive, the electrodes lift-off, and signal selectivity can be an issue. One solution to these limitations is to implant electrodes directly on muscles. Another approach is to implant electrodes directly into the nerves that innervate the muscles. A significant challenge with both solutions is the reliable transmission of biosignals across the skin barrier. In this thesis, I investigated the use of implantable muscle electrodes in an ovine model using myoelectrodes in combination with a bone-anchor, acting as a conduit for signal transmission. High-quality readings were obtained which were significantly better than skin-surface electrode readings. I further investigated the effect of electrode configurations to achieve the best signal quality. For direct recording from nerves, I tested the effect of adsorbed endoneural basement membrane proteins on nerve regeneration in vivo using microchannel neural interfaces implanted in rat sciatic nerves. Muscle and nerve signal recordings were obtained and improvements in sciatic nerve function were observed. Direct skeletal fixation of a prosthesis to the amputation stump using a bone-anchor has been proposed as a solution to skin problems associated with traditional socket-type prostheses. However, there remains a concern about the risk of infection between the implant and skin. Achieving a durable seal at this interface is therefore crucial, which formed the final part of the thesis. Bone-anchors were optimised for surface pore size and coatings to facilitate binding of human dermal fibroblasts to optimise skin-implant seal in an ovine model. Implants silanised with Arginine-Glycine-Aspartic Acid experienced significantly increased dermal tissue infiltration. This approach may therefore improve the soft tissue seal, and thus success of bone-anchored implants. By addressing both the way prostheses are attached to the amputation stump, by way of direct skeletal fixation, as well as providing high fidelity biosignals for high-level intuitive prosthetic control, I aim to further the field of limb loss rehabilitation

Improving the mechanistic study of neuromuscular diseases through the development of a fully wireless and implantable recording device

Neuromuscular diseases manifest by a handful of known phenotypes affecting the peripheral nerves, skeletal muscle fibers, and neuromuscular junction. Common signs of these diseases include demyelination, myasthenia, atrophy, and aberrant muscle activity—all of which may be tracked over time using one or more electrophysiological markers. Mice, which are the predominant mammalian model for most human diseases, have been used to study congenital neuromuscular diseases for decades. However, our understanding of the mechanisms underlying these pathologies is still incomplete. This is in part due to the lack of instrumentation available to easily collect longitudinal, in vivo electrophysiological activity from mice. There remains a need for a fully wireless, batteryless, and implantable recording system that can be adapted for a variety of electrophysiological measurements and also enable long-term, continuous data collection in very small animals. To meet this need a miniature, chronically implantable device has been developed that is capable of wirelessly coupling energy from electromagnetic fields while implanted within a body. This device can both record and trigger bioelectric events and may be chronically implanted in rodents as small as mice. This grants investigators the ability to continuously observe electrophysiological changes corresponding to disease progression in a single, freely behaving, untethered animal. The fully wireless closed-loop system is an adaptable solution for a range of long-term mechanistic and diagnostic studies in rodent disease models. Its high level of functionality, adjustable parameters, accessible building blocks, reprogrammable firmware, and modular electrode interface offer flexibility that is distinctive among fully implantable recording or stimulating devices. The key significance of this work is that it has generated novel instrumentation in the form of a fully implantable bioelectric recording device having a much higher level of functionality than any other fully wireless system available for mouse work. This has incidentally led to contributions in the areas of wireless power transfer and neural interfaces for upper-limb prosthesis control. Herein the solution space for wireless power transfer is examined including a close inspection of far-field power transfer to implanted bioelectric sensors. Methods of design and characterization for the iterative development of the device are detailed. Furthermore, its performance and utility in remote bioelectric sensing applications is demonstrated with humans, rats, healthy mice, and mouse models for degenerative neuromuscular and motoneuron diseases

소형동물의 뇌신경 자극을 위한 완전 이식형 신경자극기

학위논문(박사)--서울대학교 대학원 :공과대학 전기·정보공학부,2020. 2. 김성준.In this study, a fully implantable neural stimulator that is designed to stimulate the brain in the small animal is described. Electrical stimulation of the small animal is applicable to pre-clinical study, and behavior study for neuroscience research, etc. Especially, behavior study of the freely moving animal is useful to observe the modulation of sensory and motor functions by the stimulation. It involves conditioning animal's movement response through directional neural stimulation on the region of interest. The main technique that enables such applications is the development of an implantable neural stimulator. Implantable neural stimulator is used to modulate the behavior of the animal, while it ensures the free movement of the animals. Therefore, stable operation in vivo and device size are important issues in the design of implantable neural stimulators. Conventional neural stimulators for brain stimulation of small animal are comprised of electrodes implanted in the brain and a pulse generation circuit mounted on the back of the animal. The electrical stimulation generated from the circuit is conveyed to the target region by the electrodes wire-connected with the circuit. The devices are powered by a large battery, and controlled by a microcontroller unit. While it represents a simple approach, it is subject to various potential risks including short operation time, infection at the wound, mechanical failure of the device, and animals being hindered to move naturally, etc. A neural stimulator that is miniaturized, fully implantable, low-powered, and capable of wireless communication is required. In this dissertation, a fully implantable stimulator with remote controllability, compact size, and minimal power consumption is suggested for freely moving animal application. The stimulator consists of modular units of surface-type and depth-type arrays for accessing target brain area, package for accommodating the stimulating electronics all of which are assembled after independent fabrication and implantation using customized flat cables and connectors. The electronics in the package contains ZigBee telemetry for low-power wireless communication, inductive link for recharging lithium battery, and an ASIC that generates biphasic pulse for neural stimulation. A dual-mode power-saving scheme with a duty cycling was applied to minimize the power consumption. All modules were packaged using liquid crystal polymer (LCP) to avoid any chemical reaction after implantation. To evaluate the fabricated stimulator, wireless operation test was conducted. Signal-to-Noise Ratio (SNR) of the ZigBee telemetry were measured, and its communication range and data streaming capacity were tested. The amount of power delivered during the charging session depending on the coil distance was measured. After the evaluation of the device functionality, the stimulator was implanted into rats to train the animals to turn to the left (or right) following a directional cue applied to the barrel cortex. Functionality of the device was also demonstrated in a three-dimensional maze structure, by guiding the rats to navigate better in the maze. Finally, several aspects of the fabricated device were discussed further.본 연구에서는 소형 동물의 두뇌를 자극하기 위한 완전 이식형 신경자극기가 개발되었다. 소형 동물의 전기자극은 전임상 연구, 신경과학 연구를 위한 행동연구 등에 활용된다. 특히, 자유롭게 움직이는 동물을 대상으로 한 행동 연구는 자극에 의한 감각 및 운동 기능의 조절을 관찰하는 데 유용하게 활용된다. 행동 연구는 두뇌의 특정 관심 영역을 직접적으로 자극하여 동물의 행동반응을 조건화하는 방식으로 수행된다. 이러한 적용을 가능케 하는 핵심기술은 이식형 신경자극기의 개발이다. 이식형 신경자극기는 동물의 움직임을 방해하지 않으면서도 그 행동을 조절하기 위해 사용된다. 따라서 동물 내에서의 안정적인 동작과 장치의 크기가 이식형 신경자극기를 설계함에 있어 중요한 문제이다. 기존의 신경자극기는 두뇌에 이식되는 전극 부분과, 동물의 등 부분에 위치한 회로부분으로 구성된다. 회로에서 생산된 전기자극은 회로와 전선으로 연결된 전극을 통해 목표 지점으로 전달된다. 장치는 배터리에 의해 구동되며, 내장된 마이크로 컨트롤러에 의해 제어된다. 이는 쉽고 간단한 접근방식이지만, 짧은 동작시간, 이식부위의 감염이나 장치의 기계적 결함, 그리고 동물의 자연스러운 움직임 방해 등 여러 문제점을 야기할 수 있다. 이러한 문제의 개선을 위해 무선통신이 가능하고, 저전력, 소형화된 완전 이식형 신경자극기의 설계가 필요하다. 본 연구에서는 자유롭게 움직이는 동물에 적용하기 위하여 원격 제어가 가능하며, 크기가 작고, 소모전력이 최소화된 완전이식형 자극기를 제시한다. 설계된 신경자극기는 목표로 하는 두뇌 영역에 접근할 수 있는 표면형 전극과 탐침형 전극, 그리고 자극 펄스 생성 회로를 포함하는 패키지 등의 모듈들로 구성되며, 각각의 모듈은 독립적으로 제작되어 동물에 이식된 뒤 케이블과 커넥터로 연결된다. 패키지 내부의 회로는 저전력 무선통신을 위한 지그비 트랜시버, 리튬 배터리의 재충전을 위한 인덕티브 링크, 그리고 신경자극을 위한 이상성 자극파형을 생성하는 ASIC으로 구성된다. 전력 절감을 위해 두 개의 모드를 통해 사용률을 조절하는 방식이 장치에 적용된다. 모든 모듈들은 이식 후의 생물학적, 화학적 안정성을 위해 액정 폴리머로 패키징되었다. 제작된 신경자극기를 평가하기 위해 무선 동작 테스트가 수행되었다. 지그비 통신의 신호 대 잡음비가 측정되었으며, 해당 통신의 동작거리 및 데이터 스트리밍 성능이 검사되었고, 장치의 충전이 수행될 때 코일간의 거리에 따라 전송되는 전력의 크기가 측정되었다. 장치의 평가 이후, 신경자극기는 쥐에 이식되었으며, 해당 동물은 이식된 장치를 이용해 방향 신호에 따라 좌우로 이동하도록 훈련되었다. 또한, 3차원 미로 구조에서 쥐의 이동방향을 유도하는 실험을 통하여 장치의 기능성을 추가적으로 검증하였다. 마지막으로, 제작된 장치의 특징이 여러 측면에서 심층적으로 논의되었다.Chapter 1 : Introduction 1 1.1. Neural Interface 2 1.1.1. Concept 2 1.1.2. Major Approaches 3 1.2. Neural Stimulator for Animal Brain Stimulation 5 1.2.1. Concept 5 1.2.2. Neural Stimulator for Freely Moving Small Animal 7 1.3. Suggested Approaches 8 1.3.1. Wireless Communication 8 1.3.2. Power Management 9 1.3.2.1. Wireless Power Transmission 10 1.3.2.2. Energy Harvesting 11 1.3.3. Full implantation 14 1.3.3.1. Polymer Packaging 14 1.3.3.2. Modular Configuration 16 1.4. Objectives of This Dissertation 16 Chapter 2 : Methods 18 2.1. Overview 19 2.1.1. Circuit Description 20 2.1.1.1. Pulse Generator ASIC 21 2.1.1.2. ZigBee Transceiver 23 2.1.1.3. Inductive Link 24 2.1.1.4. Energy Harvester 25 2.1.1.5. Surrounding Circuitries 26 2.1.2. Software Description 27 2.2. Antenna Design 29 2.2.1. RF Antenna 30 2.2.1.1. Design of Monopole Antenna 31 2.2.1.2. FEM Simulation 31 2.2.2. Inductive Link 36 2.2.2.1. Design of Coil Antenna 36 2.2.2.2. FEM Simulation 38 2.3. Device Fabrication 41 2.3.1. Circuit Assembly 41 2.3.2. Packaging 42 2.3.3. Electrode, Feedthrough, Cable, and Connector 43 2.4. Evaluations 45 2.4.1. Wireless Operation Test 46 2.4.1.1. Signal-to-Noise Ratio (SNR) Measurement 46 2.4.1.2. Communication Range Test 47 2.4.1.3. Device Operation Monitoring Test 48 2.4.2. Wireless Power Transmission 49 2.4.3. Electrochemical Measurements In Vitro 50 2.4.4. Animal Testing In Vivo 52 Chapter 3 : Results 57 3.1. Fabricated System 58 3.2. Wireless Operation Test 59 3.2.1. Signal-to-Noise Ratio Measurement 59 3.2.2. Communication Range Test 61 3.2.3. Device Operation Monitoring Test 62 3.3. Wireless Power Transmission 64 3.4. Electrochemical Measurements In Vitro 65 3.5. Animal Testing In Vivo 67 Chapter 4 : Discussion 73 4.1. Comparison with Conventional Devices 74 4.2. Safety of Device Operation 76 4.2.1. Safe Electrical Stimulation 76 4.2.2. Safe Wireless Power Transmission 80 4.3. Potential Applications 84 4.4. Opportunities for Further Improvements 86 4.4.1. Weight and Size 86 4.4.2. Long-Term Reliability 93 Chapter 5 : Conclusion 96 Reference 98 Appendix - Liquid Crystal Polymer (LCP) -Based Spinal Cord Stimulator 107 국문 초록 138 감사의 글 140Docto

A Versatile Hermetically Sealed Microelectronic Implant for Peripheral Nerve Stimulation Applications

This article presents a versatile neurostimulation platform featuring a fully implantable multi-channel neural stimulator for chronic experimental studies with freely moving large animal models involving peripheral nerves. The implant is hermetically sealed in a ceramic enclosure and encapsulated in medical grade silicone rubber, and then underwent active tests at accelerated aging conditions at 100°C for 15 consecutive days. The stimulator microelectronics are implemented in a 0.6-μm CMOS technology, with a crosstalk reduction scheme to minimize cross-channel interference, and high-speed power and data telemetry for battery-less operation. A wearable transmitter equipped with a Bluetooth Low Energy radio link, and a custom graphical user interface provide real-time, remotely controlled stimulation. Three parallel stimulators provide independent stimulation on three channels, where each stimulator supports six stimulating sites and two return sites through multiplexing, hence the implant can facilitate stimulation at up to 36 different electrode pairs. The design of the electronics, method of hermetic packaging and electrical performance as well as in vitro testing with electrodes in saline are presented