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

Energy autonomous systems : future trends in devices, technology, and systems

The rapid evolution of electronic devices since the beginning of the nanoelectronics era has brought about exceptional computational power in an ever shrinking system footprint. This has enabled among others the wealth of nomadic battery powered wireless systems (smart phones, mp3 players, GPS, …) that society currently enjoys. Emerging integration technologies enabling even smaller volumes and the associated increased functional density may bring about a new revolution in systems targeting wearable healthcare, wellness, lifestyle and industrial monitoring applications

INJECTION-LOCKING TECHNIQUES FOR MULTI-CHANNEL ENERGY EFFICIENT TRANSMITTER

Ph.DDOCTOR OF PHILOSOPH

Wireless Implantable ICs for Energy-Efficient Long-Term Ambulatory EEG Monitoring

This thesis presents the design, development, and experimental characterization of wireless subcutaneous implantable integrated circuits and systems for long-term ambulatory EEG monitoring. Application-, system- and circuit-level requirements for such a device are discussed and a critical review of the state-of-the-art academic and currently available commercial solutions are provided. Two prototypes are presented: The first prototype presented in Chapter 2 is an 8-channel wireless implantable device with a 2.5×1.5 mm2 custom-designed integrated circuit implemented using CMOS 180nm technology at its core. The microchip is fabricated and the measurement results showing its efficacy in EEG signal recording in terms of input-referred noise, voltage gain, signal-to-noise ratio, and power consumption are presented. The chip is implemented together with a BLE 5.0 module on the same platform. Our vision and discussions on biocompatible encapsulation of this system, as well as its integration with a microelectrode array as also provided. The second prototype, also implemented in CMOS 180nm technology and presented in Chapter 3, employs a novel EEG recording channel architecture that enables long-term implantation of EEG monitoring devices through significant improvement of their energy efficiency. The channel leverages the inherent sparsity of the EEG signals and conducts recording in an activity-dependent adaptive manner. Thanks to the proposed fully dynamic spectral-compressing architecture, the recording channels power consumption is drastically reduced. More importantly, the proposed architecture reduces the required wireless transmission throughput by more than an order of magnitude. Our test results on 10 different patients’ pre-recorded human EEG data shows an average of 12.6× improvement in the device’s energy efficiency

Integrated Circuits and Systems for Smart Sensory Applications

Connected intelligent sensing reshapes our society by empowering people with increasing new ways of mutual interactions. As integration technologies keep their scaling roadmap, the horizon of sensory applications is rapidly widening, thanks to myriad light-weight low-power or, in same cases even self-powered, smart devices with high-connectivity capabilities. CMOS integrated circuits technology is the best candidate to supply the required smartness and to pioneer these emerging sensory systems. As a result, new challenges are arising around the design of these integrated circuits and systems for sensory applications in terms of low-power edge computing, power management strategies, low-range wireless communications, integration with sensing devices. In this Special Issue recent advances in application-specific integrated circuits (ASIC) and systems for smart sensory applications in the following five emerging topics: (I) dedicated short-range communications transceivers; (II) digital smart sensors, (III) implantable neural interfaces, (IV) Power Management Strategies in wireless sensor nodes and (V) neuromorphic hardware

Ultra-Low-Power Sensors and Receivers for IoT Applications

The combination of ultra-low power analog front-ends and CMOS-compatible transducers enable new applications, such as environmental monitors, household appliances, health trackers, etc. that are seamlessly integrated into our daily lives. Furthermore, wireless connectivity allows many of these sensors to operate both independently and collectively. These techniques collectively fulfil the recent surge of internet-of-things (IoT) applications that have the potential to fundamentally change daily life for millions of people.In this dissertation, the circuit and system design of wireless receivers and sensors is presented that explores the challenges of implementing long lifespan, high accuracy, and large coverage range IoT sensor networks. The first is a wake-up receiver (WuRX), which continuously monitors the RF environment to wake up a higher-power radio upon detection of a predetermined RF signature. This work both improves sensitivity and reduces power over prior art through a multi-faceted design featuring an impedance transformation network with large passive voltage gain, an active envelope detector with high input impedance to facilitate large passive voltage gain, a low-power precision comparator, and a low-leakage digital baseband correlator.Although pushing the prior WuRX performance boundary by orders of magnitude, the first work shows moderate sensitivity, inferior temperature robustness, and large area with external lumped components. Thus, the second work shows a miniaturized WuRX that is temperature-compensated, yet still consumes only nano-watt power and millimeter area while operating at 9 GHz. To further reduce the area, a global common-mode feedback is utilized across the envelope detector and baseband amplifier that eliminates the need for off-chip ac-coupling components. Multiple temperature-compensation techniques are proposed to maintain constant bandwidth of the signal path and constant clock frequency. Both WuRXs operate at 0.4 V supply, consume near-zero power and achieve ~-70 dBm sensitivity.Lastly, the first reported CMOS 2-in-1 relative humidity and temperature sensor is presented. A unified analog front-end interfaces on-chip transducers and converts the inputs into a frequency vis a high-linearity frequency-locked loop. An incomplete-settling switched-capacitor-based Wheatstone bridge is proposed to sense the inputs in a power-efficient fashion

Antenna Systems

This book offers an up-to-date and comprehensive review of modern antenna systems and their applications in the fields of contemporary wireless systems. It constitutes a useful resource of new material, including stochastic versus ray tracing wireless channel modeling for 5G and V2X applications and implantable devices. Chapters discuss modern metalens antennas in microwaves, terahertz, and optical domain. Moreover, the book presents new material on antenna arrays for 5G massive MIMO beamforming. Finally, it discusses new methods, devices, and technologies to enhance the performance of antenna systems

Bidirectional Neural Interface Circuits with On-Chip Stimulation Artifact Reduction Schemes

Bidirectional neural interfaces are tools designed to “communicate” with the brain via recording and modulation of neuronal activity. The bidirectional interface systems have been adopted for many applications. Neuroscientists employ them to map neuronal circuits through precise stimulation and recording. Medical doctors deploy them as adaptable medical devices which control therapeutic stimulation parameters based on monitoring real-time neural activity. Brain-machine-interface (BMI) researchers use neural interfaces to bypass the nervous system and directly control neuroprosthetics or brain-computer-interface (BCI) spellers. In bidirectional interfaces, the implantable transducers as well as the corresponding electronic circuits and systems face several challenges. A high channel count, low power consumption, and reduced system size are desirable for potential chronic deployment and wider applicability. Moreover, a neural interface designed for robust closed-loop operation requires the mitigation of stimulation artifacts which corrupt the recorded signals. This dissertation introduces several techniques targeting low power consumption, small size, and reduction of stimulation artifacts. These techniques are implemented for extracellular electrophysiological recording and two stimulation modalities: direct current stimulation for closed-loop control of seizure detection/quench and optical stimulation for optogenetic studies. While the two modalities differ in their mechanisms, hardware implementation, and applications, they share many crucial system-level challenges. The first method aims at solving the critical issue of stimulation artifacts saturating the preamplifier in the recording front-end. To prevent saturation, a novel mixed-signal stimulation artifact cancellation circuit is devised to subtract the artifact before amplification and maintain the standard input range of a power-hungry preamplifier. Additional novel techniques have been also implemented to lower the noise and power consumption. A common average referencing (CAR) front-end circuit eliminates the cross-channel common mode noise by averaging and subtracting it in analog domain. A range-adapting SAR ADC saves additional power by eliminating unnecessary conversion cycles when the input signal is small. Measurements of an integrated circuit (IC) prototype demonstrate the attenuation of stimulation artifacts by up to 42 dB and cross-channel noise suppression by up to 39.8 dB. The power consumption per channel is maintained at 330 nW, while the area per channel is only 0.17 mm2. The second system implements a compact headstage for closed-loop optogenetic stimulation and electrophysiological recording. This design targets a miniaturized form factor, high channel count, and high-precision stimulation control suitable for rodent in-vivo optogenetic studies. Monolithically integrated optoelectrodes (which include 12 µLEDs for optical stimulation and 12 electrical recording sites) are combined with an off-the-shelf recording IC and a custom-designed high-precision LED driver. 32 recording and 12 stimulation channels can be individually accessed and controlled on a small headstage with dimensions of 2.16 x 2.38 x 0.35 cm and mass of 1.9 g. A third system prototype improves the optogenetic headstage prototype by furthering system integration and improving power efficiency facilitating wireless operation. The custom application-specific integrated circuit (ASIC) combines recording and stimulation channels with a power management unit, allowing the system to be powered by an ultra-light Li-ion battery. Additionally, the µLED drivers include a high-resolution arbitrary waveform generation mode for shaping of µLED current pulses to preemptively reduce artifacts. A prototype IC occupies 7.66 mm2, consumes 3.04 mW under typical operating conditions, and the optical pulse shaping scheme can attenuate stimulation artifacts by up to 3x with a Gaussian-rise pulse rise time under 1 ms.PHDElectrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/147674/1/mendrela_1.pd

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The technological approach and the high level of innovation make bioengineering extremely dynamic and this forces researchers to continuous updating. It involves the publication of the results of the latest scientific research. This book covers a wide range of aspects and issues related to advances in bioengineering research with a particular focus on innovative technologies and applications. The book consists of 13 scientific contributions divided in four sections: Materials Science; Biosensors. Electronics and Telemetry; Light Therapy; Computing and Analysis Techniques

A Novel Power-Efficient Wireless Multi-channel Recording System for the Telemonitoring of Electroencephalography (EEG)

This research introduces the development of a novel EEG recording system that is modular, batteryless, and wireless (untethered) with the supporting theoretical foundation in wireless communications and related design elements and circuitry. Its modular construct overcomes the EEG scaling problem and makes it easier for reconfiguring the hardware design in terms of the number and placement of electrodes and type of standard EEG system contemplated for use. In this development, portability, lightweight, and applicability to other clinical applications that rely on EEG data are sought. Due to printer tolerance, the 3D printed cap consists of 61 electrode placements. This recording capacity can however extend from 21 (as in the international 10-20 systems) up to 61 EEG channels at sample rates ranging from 250 to 1000 Hz and the transfer of the raw EEG signal using a standard allocated frequency as a data carrier. The main objectives of this dissertation are to (1) eliminate the need for heavy mounted batteries, (2) overcome the requirement for bulky power systems, and (3) avoid the use of data cables to untether the EEG system from the subject for a more practical and less restrictive setting. Unpredictability and temporal variations of the EEG input make developing a battery-free and cable-free EEG reading device challenging. Professional high-quality and high-resolution analog front ends are required to capture non-stationary EEG signals at microvolt levels. The primary components of the proposed setup are the wireless power transmission unit, which consists of a power amplifier, highly efficient resonant-inductive link, rectification, regulation, and power management units, as well as the analog front end, which consists of an analog to digital converter, pre-amplification unit, filtering unit, host microprocessor, and the wireless communication unit. These must all be compatible with the rest of the system and must use the least amount of power possible while minimizing the presence of noise and the attenuation of the recorded signal A highly efficient resonant-inductive coupling link is developed to decrease power transmission dissipation. Magnetized materials were utilized to steer electromagnetic flux and decrease route and medium loss while transmitting the required energy with low dissipation. Signal pre-amplification is handled by the front-end active electrodes. Standard bio-amplifier design approaches are combined to accomplish this purpose, and a thorough investigation of the optimum ADC, microcontroller, and transceiver units has been carried out. We can minimize overall system weight and power consumption by employing battery-less and cable-free EEG readout system designs, consequently giving patients more comfort and freedom of movement. Similarly, the solutions are designed to match the performance of medical-grade equipment. The captured electrical impulses using the proposed setup can be stored for various uses, including classification, prediction, 3D source localization, and for monitoring and diagnosing different brain disorders. All the proposed designs and supporting mathematical derivations were validated through empirical and software-simulated experiments. Many of the proposed designs, including the 3D head cap, the wireless power transmission unit, and the pre-amplification unit, are already fabricated, and the schematic circuits and simulation results were based on Spice, Altium, and high-frequency structure simulator (HFSS) software. The fully integrated head cap to be fabricated would require embedding the active electrodes into the 3D headset and applying current technological advances to miniaturize some of the design elements developed in this dissertation