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

An external control unit implemented for stimulator ASIC testing

This paper presents the design and development of an external control unit (ECU) for a stimulator ASIC testing purposes. The ECU consists of a graphical user interface (GUI) from the PC, a data transceiver and a power transmitter. The GUI was developed using MATLAB for stimulation data setup. The data transceiver was designed using hardware description language (HDL) Verilog code and was implemented in a Virtex-II Pro FPGA board. The overall stimulator ASIC design architecture and its operation for an epiretinal implant application are briefly explained to correlate with the ECU’s design requirements. The flexible multichannel stimulator ASIC was successfully fabricated in a 0.35μm AMS HVCMOS technology. Conducted simulation and measurement results on stimulation waveform generation, supply voltage compliance and external control of supply voltage adaptation validate the functionality of the designed ECU and the stimulator ASIC.Keywords: external control unit; data transceiver; stimulator ASIC; retinal prosthesis; epiretinal implant; stimulation waveform; Manchester data; voltage compliance

Implantable Neural Probes for Brain-Machine Interfaces - Current Developments and Future Prospects

A Brain-Machine interface (BMI) allows for direct communication between the brain and machines. Neural probes for recording neural signals are among the essential components of a BMI system. In this report, we review research regarding implantable neural probes and their applications to BMIs. We first discuss conventional neural probes such as the tetrode, Utah array, Michigan probe, and electroencephalography (ECoG), following which we cover advancements in next-generation neural probes. These next-generation probes are associated with improvements in electrical properties, mechanical durability, biocompatibility, and offer a high degree of freedom in practical settings. Specifically, we focus on three key topics: (1) novel implantable neural probes that decrease the level of invasiveness without sacrificing performance, (2) multi-modal neural probes that measure both electrical and optical signals, (3) and neural probes developed using advanced materials. Because safety and precision are critical for practical applications of BMI systems, future studies should aim to enhance these properties when developing next-generation neural probes

Designing a Clinically Viable Brain Computer Interface for the Control of Neuroprosthetics

Currently no brain computer interfaces exist that can control the individual fingers of a hand prosthesis and is suitable for permanent implantation in and individual with a single limb amputation. Within this thesis a design for a novel minimally invasive brain computer interface system is proposed that would be relatively low risk, allow for control of a prosthesis using existing cortical structures and be suitable for patients with loss of a single limb. The early stage development and proof of concept work has been done taking into account relevant regulatory requirements, so that a finalised version of the design would be suitable for regulatory certification. This novel design is found to be worth pursuing and may in turn open up new research opportunities

Neuromorphic hardware for somatosensory neuroprostheses

In individuals with sensory-motor impairments, missing limb functions can be restored using neuroprosthetic devices that directly interface with the nervous system. However, restoring the natural tactile experience through electrical neural stimulation requires complex encoding strategies. Indeed, they are presently limited in effectively conveying or restoring tactile sensations by bandwidth constraints. Neuromorphic technology, which mimics the natural behavior of neurons and synapses, holds promise for replicating the encoding of natural touch, potentially informing neurostimulation design. In this perspective, we propose that incorporating neuromorphic technologies into neuroprostheses could be an effective approach for developing more natural human-machine interfaces, potentially leading to advancements in device performance, acceptability, and embeddability. We also highlight ongoing challenges and the required actions to facilitate the future integration of these advanced technologies

Brain-Computer Interfaces using Electrocorticography and Surface Stimulation

The brain connects to, modulates, and receives information from every organ in the body. As such, brain-computer interfaces (BCIs) have vast potential for diagnostics, medical therapies, and even augmentation or enhancement of normal functions. BCIs provide a means to explore the furthest corners of what it means to think, to feel, and to act—to experience the world and to be who you are. This work focuses on the development of a chronic bi-directional BCI for sensorimotor restoration through the use of separable frequency bands for recording motor intent and providing sensory feedback via electrocortical stimulation. Epidural cortical surface electrodes are used to both record electrocorticographic (ECoG) signals and provide stimulation without adverse effects associated with penetration through the protective dural barrier of brain. Chronic changes in electrode properties and signal characteristics are discussed, which inform optimal electrode designs and co-adaptive algorithms for decoding high-dimensional information. Additionally, a multi-layered approach to artifact suppression is presented, which includes a systems-level design of electronics, signal processing, and stimulus waveforms. The results of this work are relevant to a wider range of applications beyond ECoG and BCIs that involve closed-loop recording and stimulation throughout the body. By enabling simultaneous recording and stimulation through the techniques described here, responsive therapies can be developed that are tuned to individual patients and provide precision therapies at exactly the right place and time. This has the potential to improve targeted therapeutic outcomes while reducing undesirable side effects

Systems, methods and devices for treating tinnitus

Systems, methods and devices for paired training include timing controls so that training and neural stimulation can be provided simultaneously. Paired trainings may include therapies, rehabilitation and performance enhancement training. Stimulations of nerves such as the vagus nerve that affect subcortical regions such as the nucleus basalis, locus coeruleus or amygdala induce plasticity in the brain, enhancing the effects of a variety of therapies, such as those used to treat tinnitus, stroke, traumatic brain injury and post-traumatic stress disorder.Board of Regents, University of Texas Syste

Closed-loop approaches for innovative neuroprostheses

The goal of this thesis is to study new ways to interact with the nervous system in case of damage or pathology. In particular, I focused my effort towards the development of innovative, closed-loop stimulation protocols in various scenarios: in vitro, ex vivo, in vivo

Nano-Watt Modular Integrated Circuits for Wireless Neural Interface.

In this work, a nano-watt modular neural interface circuit is proposed for ECoG neuroprosthetics. The main purposes of this work are threefold: (1) optimizing the power-performance of the neural interface circuits based on ECoG signal characteristics, (2) equipping a stimulation capability, and (3) providing a modular system solution to expand functionality. To achieve these aims, the proposed system introduces the following contributions/innovations: (1) power-noise optimization based on the ECoG signal driven analysis, (2) extreme low-power analog front-ends, (3) Manchester clock-edge modulation clock data recovery, (4) power-efficient data compression, (5) integrated stimulator with fully programmable waveform, (6) wireless signal transmission through skin, and (7) modular expandable design. Towards these challenges and contributions, three different ECoG neural interface systems, ENI-1, ENI-16, and ENI-32, have been designed, fabricated, and tested. The first ENI system(ENI-1) is a one-channel analog front-end and fabricated in a 0.25µm CMOS process with chopper stabilized pseudo open-loop preamplifier and area-efficient SAR ADC. The measured channel power, noise and area are 1.68µW at 2.5V power-supply, 1.69µVrms (NEF=2.43), and 0.0694mm^2, respectively. The fabricated IC is packaged with customized miniaturized package. In-vivo human EEG is successfully measured with the fabricated ENI-1-IC. To demonstrate a system expandability and wireless link, ENI-16 IC is fabricated in 0.25µm CMOS process and has sixteen channels with a push-pull preamplifier, asynchronous SAR ADC, and intra-skin communication(ISCOM) which is a new way of transmitting the signal through skin. The measured channel power, noise and area are 780nW, 4.26µVrms (NEF=5.2), and 2.88mm^2, respectively. With the fabricated ENI-16-IC, in-vivo epidural ECoG from monkey is successfully measured. As a closed-loop system, ENI-32 focuses on optimizing the power performance based on a bio-signal property and integrating stimulator. ENI-32 is fabricated in 0.18µm CMOS process and has thirty-two recording channels and four stimulation channels with a cyclic preamplifier, data compression, asymmetric wireless transceiver (Tx/Rx). The measured channel power, noise and area are 140nW (680nW including ISCOM), 3.26µVrms (NEF=1.6), and 5.76mm^2, respectively. The ENI-32 achieves an order of magnitude power reduction while maintaining the system performance. The proposed nano-watt ENI-32 can be the first practical wireless closed-loop solution with a practically miniaturized implantable device.PhDElectrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/98064/1/schang_1.pd