Down-Conditioning of Soleus Reflex Activity using Mechanical Stimuli and EMG Biofeedback

Spasticity is a common syndrome caused by various brain and neural injuries, which can severely impair walking ability and functional independence. To improve functional independence, conditioning protocols are available aimed at reducing spasticity by facilitating spinal neuroplasticity. This down-conditioning can be performed using different types of stimuli, electrical or mechanical, and reflex activity measures, EMG or impedance, used as biofeedback variable. Still, current results on effectiveness of these conditioning protocols are incomplete, making comparisons difficult. We aimed to show the within-session task- dependent and across-session long-term adaptation of a conditioning protocol based on mechanical stimuli and EMG biofeedback. However, in contrast to literature, preliminary results show that subjects were unable to successfully obtain task-dependent modulation of their soleus short-latency stretch reflex magnitude

A Wireless, High-Voltage Compliant, and Energy-Efficient Visual Intracortical Microstimulator

RÉSUMÉ L’objectif général de ce projet de recherche est la conception, la mise en oeuvre et la validation d’une interface sans fil intracorticale implantable en technologie CMOS avancée pour aider les personnes ayant une déficience visuelle. Les défis majeurs de cette recherche sont de répondre à la conformité à haute tension nécessaire à travers l’interface d’électrode-tissu (IET), augmenter la flexibilité dans la microstimulation et la surveillance multicanale, minimiser le budget de puissance pour un dispositif biomédical implantable, réduire la taille de l’implant et améliorer le taux de transmission sans fil des données. Par conséquent, nous présentons dans cette thèse un système de microstimulation intracorticale multi-puce basée sur une nouvelle architecture pour la transmission des données sans fil et le transfert de l’énergie se servant de couplages inductifs et capacitifs. Une première puce, un générateur de stimuli (SG) éconergétique, et une autre qui est un amplificateur de haute impédance se connectant au réseau de microélectrodes de l’étage de sortie. Les 4 canaux de générateurs de stimuli produisent des impulsions rectangulaires, demi-sinus (DS), plateau-sinus (PS) et autres types d’impulsions de courant à haut rendement énergétique. Le SG comporte un contrôleur de faible puissance, des convertisseurs numérique-analogiques (DAC) opérant en mode courant, générateurs multi-forme d’ondes et miroirs de courants alimentés sous 1.2 et 3.3V se servant pour l’interface entre les deux technologies utilisées. Le courant de stimulation du SG varie entre 2.32 et 220μA pour chaque canal. La deuxième puce (pilote de microélectrodes (MED)), une interface entre le SG et de l’arrangement de microélectrodes (MEA), fournit quatre niveaux différents de courant avec la valeur maximale de 400μA par entrée et 100μA par canal de sortie simultanément pour 8 à 16 sites de stimulation à travers les microélectrodes, connectés soit en configuration bipolaire ou monopolaire. Cette étage de sortie est hautement configurable et capable de délivrer une tension élevée pour satisfaire les conditions de l’interface à travers l’impédance de IET par rapport aux systèmes précédemment rapportés. Les valeurs nominales de plus grandes tensions d’alimentation sont de ±10V. La sortie de tension mesurée est conformément 10V/phase (anodique ou cathodique) pour les tensions d’alimentation spécifiées. L’incrémentation de tensions d’alimentation à ±13V permet de produire un courant de stimulation de 220μA par canal de sortie permettant d’élever la tension de sortie jusqu’au 20V par phase. Cet étage de sortie regroupe un commutateur haute tension pour interfacer une matrice des miroirs de courant (3.3V /20V), un registre à décalage de 32-bits à entrée sérielle, sortie parallèle, et un circuit dédié pour bloquer des états interdits.----------ABSTRACT The general objective of this research project is the design, implementation and validation of an implantable wireless intracortical interface in advanced CMOS technology to aid the visually impaired people. The major challenges in this research are to meet the required highvoltage compliance across electrode-tissue interface (ETI), increase lexibility in multichannel microstimulation and monitoring, minimize power budget for an implantable biomedical device, reduce the implant size, and enhance the data rate in wireless transmission. Therefore, we present in this thesis a multi-chip intracortical microstimulation system based on a novel architecture for wireless data and power transmission comprising inductive and capacitive couplings. The first chip is an energy-efficient stimuli generator (SG) and the second one is a highimpedance microelectrode array driver output-stage. The 4-channel stimuli-generator produces rectangular, half-sine (HS), plateau-sine (PS), and other types of energy-efficient current pulse. The SG is featured with low-power controller, current mode source- and sinkdigital- to-analog converters (DACs), multi-waveform generators, and 1.2V/3.3V interface current mirrors. The stimulation current per channel of the SG ranges from 2.32 to 220μA per channel. The second chip (microelectrode driver (MED)), an interface between the SG and the microelectrode array (MEA), supplies four different current levels with the maximum value of 400μA per input and 100μA per output channel. These currents can be delivered simultaneously to 8 to 16 stimulation sites through microelectrodes, connected either in bipolar or monopolar configuration. This output stage is highly-configurable and able to deliver higher compliance voltage across ETI impedance compared to previously reported designs. The nominal values of largest supply voltages are ±10V. The measured output compliance voltage is 10V/phase (anodic or cathodic) for the specified supply voltages. Increment of supply voltages to ±13V allows 220μA stimulation current per output channel enhancing the output compliance voltage up to 20V per phase. This output-stage is featured with a high-voltage switch-matrix, 3.3V/20V current mirrors, an on-chip 32-bit serial-in parallel-out shift register, and the forbidden state logic building blocks. The SG and MED chips have been designed and fabricated in IBM 0.13μm CMOS and Teledyne DALSA 0.8μm 5V/20V CMOS/DMOS technologies with silicon areas occupied by them 1.75 x 1.75mm2 and 4 x 4mm2 respectively. The measured DC power budgets consumed by low-and mid-voltage microchips are 2.56 and 2.1mW consecutively

Miniaturised Wireless Power Transfer Systems for Neurostimulation: A Review

In neurostimulation, wireless power transfer is an efficient technology to overcome several limitations affecting medical devices currently used in clinical practice. Several methods were developed over the years for wireless power transfer. In this review article, we report and discuss the three most relevant methodologies for extremely miniaturised implantable neurostimulator: ultrasound coupling, inductive coupling and capacitive coupling. For each powering method, the discussion starts describing the physical working principle. In particular, we focus on the challenges given by the miniaturisation of the implanted integrated circuits and the related ad-hoc solutions for wireless power transfer. Then, we present recent developments and progresses in wireless power transfer for biomedical applications. Last, we compare each technique based on key performance indicators to highlight the most relevant and innovative solutions suitable for neurostimulation, with the gaze turned towards miniaturisation

Epileptic Seizure Detection on an Ultra-Low-Power Embedded RISC-V Processor Using a Convolutional Neural Network

The treatment of refractory epilepsy via closed-loop implantable devices that act on seizures either by drug release or electrostimulation is a highly attractive option. For such implantable medical devices, efficient and low energy consumption, small size, and efficient processing architectures are essential. To meet these requirements, epileptic seizure detection by analysis and classification of brain signals with a convolutional neural network (CNN) is an attractive approach. This work presents a CNN for epileptic seizure detection capable of running on an ultra-low-power microprocessor. The CNN is implemented and optimized in MATLAB. In addition, the CNN is also implemented on a GAP8 microprocessor with RISC-V architecture. The training, optimization, and evaluation of the proposed CNN are based on the CHB-MIT dataset. The CNN reaches a median sensitivity of 90% and a very high specificity over 99% corresponding to a median false positive rate of 6.8 s per hour. After implementation of the CNN on the microcontroller, a sensitivity of 85% is reached. The classification of 1 s of EEG data takes t=35 ms and consumes an average power of P≈140 μW. The proposed detector outperforms related approaches in terms of power consumption by a factor of 6. The universal applicability of the proposed CNN based detector is verified with recording of epileptic rats. This results enable the design of future medical devices for epilepsy treatment

Charge Pumps for Implantable Microstimulators in Low and High-Voltage Technologies

RÉSUMÉ L'objectif principal de cette thèse est de concevoir et mettre en œuvre une pompe de charge qui peut produire suffisamment de tension afin de l’implémenter à un système de prothèse visuelle, conçue par le laboratoire PolyStim neurotechnologies. Il a été constaté que l'une des parties les plus consommatrices d'énergie de l'ensemble du système de prothèse visuelle est la pompe de charge. En raison de la nature variable du tissu nerveux et de l'interface d’électrode, la tension nécessaire par stimuler le tissu nerveux est très élevé et consomme extrêmement d’énergie. En outre, afin de fournir du courant biphasique aux électrodes il faut produire des tensions positives et négatives. La génération de tension négative est très difficile, surtout dans les technologies à faible tension compte tenu des limites de la technologie. Le premier objectif du projet est de générer la haute tension nécessaire qui va consommer une faible puissance statique. La technologie de haute tension a été utilisée dans le but d’atteindre cet objectif. Le deuxième objectif est de générer la tension requise dans la technologie de basse tension et ainsi surmonter les limites de la technologie. Dans les deux cas, une attention particulière a été portée afin que personne ne latch-up apparaît pour le cycle négatif. L'architecture de la conception proposée a été présentée dans cette thèse. La pompe de charge a été conçu et mis en oeuvre à la fois dans la technologie CMOS 0,8 μm offert par TELEDYNE DALSA et technologie 0,13 μm CMOS offert par IBM. En raison de la tension requise, 0,8 μm technologie a été utilisée pour atteindre la sortie et conçu pour minimiser la consommation de puissance statique. La même architecture a été mise en oeuvre en technologie 0,13 μm pour enquêter sur la tension de sortie obtenue avec une faible consommation électrique. Les deux puces ont été testées en laboratoire PolyStim. Les résultats testés ont montré une variation moyenne très faible de déviation inférieure à 5% par rapport au résultat de simulation. Pour la conception en 0,8 µm, nous avons été en mesure d'obtenir plus de 25 V avec une consommation électrique très faible d’énergie statique de 3,846 mW et une charge d'entraînement maximum de 2 mA avec un maximum d'efficacité de 84,2%. Pour le même processus en 0,13 µm, les resultats ont été plus que 20V, 0,913 mW, 500 µA, et 85,2% respectivement.----------ABSTRACT The main objective of the thesis is to design and implement a charge pump that can produce enough voltage required to be implemented to the visual prosthesis system, designed by the PolyStim Neurotechnologies laboratory. It has been found that one of the most power consuming parts of the whole visual prosthesis system is the charge pump. Due to the variable nature of the nerve tissue and electrode interface, the required voltage of stimulating the nerve tissue is very high and thus extremely power consuming. Also, in order to provide biphasic current to the electrodes, there is a requirement of generating both positive and negative voltages. Generating negative voltage is very hard especially in low voltage technologies considering the technology limitations. The first objective of the project is to generate required high voltage that will consume low static power. High voltage technology has been used to achieve the goal. The second objective is to generate the required voltage in low voltage technology overcoming the technology limitations. In both cases, special care has been taken so that no latch-up occurs for the negative cycle. Architecture of the proposed design has been presented in this thesis. The charge pump has been designed and implemented in both 0.8 µm CMOS technology offered by TELEDYNE DALSA and 0.13 µm CMOS technology offered by IBM. Because of the required voltage, 0.8 µm technology has been used to achieve the output and designed to minimize the static power consumption. The same architecture has been implemented in 0.13 µm technology to investigate the achievable output voltage with low power consumption. Both the chips have been tested in polyStim laboratory. The tested results have shown very low variation of less than 5% average deflection from the simulation output. For the design in 0.8 µm, we have been able to get more than 25 V output with very low static power consumption of 3.846 mW and maximum drive load of 2 mA with maximum efficiency of 84.2%. For the same design in 0.13 µm, the outputs were more than 20V, 0.913 mW, 500 µA, and 85.2% respectively

Wireless Simultaneous Stimulation-and-Recording Device (SRD) to Train Cortical Circuits in Rat Somatosensory Cortex

The primary goal of this project is to develop a wireless system for simultaneous recording-and-stimulation (SRD) to deliver low amplitude current pulses to the primary somatosensory cortex (SI) of rats to activate and enhance an interhemispheric cortical pathway. Despite the existence of an interhemispheric connection between similar forelimb representations of SI cortices, forelimb cortical neurons respond only to input from the contralateral (opposite side) forelimb and not to input from the ipsilateral (same side) forelimb. Given the existence of this interhemispheric pathway we have been able to strengthen/enhance the pathway through chronic intracortical microstimulation (ICMS) in previous acute experiments of anesthetized rats. In these acute experiments strengthening the interhemispheric pathway also brings about functional reorganization whereby cortical neurons in forelimb cortex respond to new input from the ipsilateral forelimb. Having the ability to modify cortical circuitry will have important applications in stroke patients and could serve to rescue and/or enhance responsiveness in surviving cells around the stroke region. Also, the ability to induce functional reorganization within the deafferented cortical map, which follows limb amputation, will also provide a vehicle for modulating maladaptive cortical reorganization often associated with phantom limb pain leading to reduced pain. In order to increase our understanding of the observed functional reorganization and enhanced pathway, we need to be able to test these observations in awake and behaving animals and eventually study how these changes persist over a prolonged period of time. To accomplish this a system was needed to allow simultaneous recording and stimulation in awake rats. However, no such commercial or research system exists that meets all requirements for such an experiment. In this project we describe the (1) system design, (2) system testing, (3) system evaluation, and (4) system implementation of a wireless simultaneous stimulation-and-recording device (SRD) to be used to modulate cortical circuits in an awake rodent animal model

Neurostimulator with Waveforms Inspired by Nature for Wearable Electro-Acupuncture

The work presented here has 3 goals: establish the need for novel neurostimulation waveform solutions through a literature review, develop a neurostimulation pulse generator, and verify the operation of the device for neurostimulation applications. The literature review discusses the importance of stimulation waveforms on the outcomes of neurostimulation, and proposes new directions for neurostimulation research that would help in improving the reproducibility and comparability between studies. The pulse generator circuit is then described that generates signals inspired by the shape of excitatory or inhibitory post-synaptic potentials (EPSP, IPSP). The circuit analytical equations are presented, and the effects of the circuit design components are discussed. The circuit is also analyzed with a capacitive load using a simplified Randles model to represent the electrode-electrolyte interface, and the output is measured in phosphate-buffered saline (PBS) solution as the load with acupuncture needles as electrodes. The circuit is designed to be used in different types of neurostimulators depending on the needs of the application, and to study the effects of varying neurostimulation waveforms. The circuit is used to develop a remote-controlled wearable veterinary electro-acupuncture machine. The device has a small form-factor and 3D printed enclosure, and has a weight of 75 g with leads attached. The device is powered by a 500 mAh lithium polymer battery, and was tested to last 6 hours. The device is tested in an electro-acupuncture animal study on cats performed at the Louisiana State University School of Veterinary Medicine, where it showed expected electro-acupuncture effects. Then, a 2-channel implementation of the device is presented, and tested to show independent output amplitude, frequency, and stimulation duration per channel. Finally, the software and hardware requirements for control of the wearable veterinary electro-acupuncture machine are detailed. The number of output channels is limited to the number of hardware PWM timers available for use. The Arduino software implements PWM control for the output amplitude and frequency. The stimulation duration control is provided using software timers. The communications protocol between the microcontroller board and Android App are described, and communications are performed via Bluetooth

액정폴리머를 기반의 소형, 안구밀착형, 장기안정적인 인공망막장치

학위논문 (박사)-- 서울대학교 대학원 : 전기·컴퓨터공학부, 2015. 8. 김성준.A novel retinal prosthetic device was developed using liquid crystal polymer (LCP) to address the problems associated with conventional metal- and polymer-based devices: the hermetic metal package is bulky, heavy and labor-intensive, whereas a thin, flexible and MEMS-compatible polymer-based system is not durable enough for chronic implantation. Exploiting the advantageous properties of LCP such as a low moisture absorption rate, thermo-bonding and thermo-forming, a small, light-weight, long-term reliable retinal prosthesis was fabricated that can be conformally attached on the eye-surface. A LCP fabrication process using monolithic integration and conformal deformation was established enabling miniaturization and a batch manufacturing process as well as eliminating the need for feed-through technology. The fabricated 16-channels LCP-based retinal implant had 14 mm-diameter with the maximum thickness of 1.4 mm and weight of 0.4 g and could be operated wirelessly up to 16 mm of distance in the air. The long-term reliability of the all-LCP retinal device was evaluated in vitro as well as in vivo. Because an all-polymer implant introduces intrinsic gas permeation for which the traditional helium leak test for metallic packages was not designed to quantify, a new set of reliability tests were designed and carried out specifically for all-polymer implants. Moisture ingress through various pathways were classified into polymer surface, polymer-polymer and polymer-metal adhesions each of which were quantitatively investigated by analytic calculation, in vitro aging test of electrode part and package part, respectively. The functionality and long-term implantation stability of the device was verified through in vivo animal experiments by measuring the cortical potential and monitoring implanted dummy devices for more than a year, respectively. Samples of the LCP electrodes array failed after 114 days in 87°C salin as a result of water penetration through the LCP-metal interface. An eye-confirmable LCP package survived more than 35 days in an accelerated condition at 87°C. The in vivo results confirmed that no adverse effects around the retina were observed after implantation of the device for more than a year.ABSTRACT i Contents iv List of Figures xi List of Tables xxi Chapter 1 : Introduction 1 1.1. Neuroprosthetic devices 1 1.2. Retinal prosthesis 2 1.2.1. Concept 2 1.2.2. Three approaches 3 1.2.3. Camera vs. Photodiode 4 1.3. Conventional devices 5 1.4. Liquid Crystal Polymer (LCP) 7 1.4.1. Low moisture absorption and permeability 9 1.4.2. Thermoplastic property 9 1.4.3. Compatibility with MEMS technologies 10 1.4.4. RF characteristics 10 1.5. LCP-based retinal prosthesis 11 1.6. Long-term reliability 12 1.7. Dissertation outline 14 Chapter 2: Methods 16 2.1. System Overview 16 2.2. Microfabrication on LCP 18 2.2.1. Limitations of the previous microfabrication technique on LCP 19 2.2.2. Improved LCP-based microfabrication 22 2.2.2.1. Electroplated micro-patterning 23 2.2.2.2. Laser-thinning for higher flexibility 24 2.2.2.3. Laser-ablation for site opening 25 2.3. All-LCP Monolithic Fabrication 26 2.3.1. Multilayered integration 29 2.3.1.1. Electrical components 29 2.3.1.2. Thermal lamination 32 2.3.1.3. Layer configuration 34 2.3.2. Thermal deformation 35 2.3.2.1. Deformation process 35 2.3.2.2. Wavy lines for stretchability 36 2.3.2.3. Electrical properties of the deformed coil 40 2.3.3. Circuit Assembly 40 2.3.3.1. Stimulation ASIC 40 2.3.3.2. Surrounding circuitries 41 2.3.4. Packaging 43 2.3.5. Laser Machining 44 2.4. Device characterization 44 2.4.1. Transmitter Circuit and Wireless Operation 45 2.4.1.1. Transmitter circuit 45 2.4.1.2. Transmitter coil 46 2.4.1.3. Wireless operation test 46 2.4.2. Electrochemical measurements 48 2.5. Long-term reliability tests in vitro 49 2.5.1. Failure mechanisms of an all-LCP device 49 2.5.2. Analytic calculation 51 2.5.3. Long-term reliability tests in accelerated environment 55 2.5.3.1. Long-term reliability of electrode array 55 2.5.3.2. Long-term reliability of package 57 2.5.3.3. Long-term reliability of complete device 58 2.5.4. Long-term electrochemical stability 59 2.6. Acute and Chronic Evaluation in vivo 60 2.6.1. Surgical implantation 60 2.6.2. Acute functionality test 62 2.6.3. Long-term implantation stability 63 Chapter 3: Results 64 3.1. Microfabrication on LCP 64 3.1.1. Electroplated micro-patterning 64 3.1.2. Laser-ablation for site opening 67 3.1.3. Laser-thinning for higher flexibility 69 3.2. All-LCP Monolithic fabrication 71 3.2.1. Multilayered integration 71 3.2.2. Thermal deformation 73 3.2.2.1. Deformation results 73 3.2.2.2. Wavy lines for stretchability 74 3.2.2.3. Effect on the electrical properties 74 3.2.3. Circuit assembly 76 3.2.4. Packaging 77 3.2.5. Laser machining 79 3.3. Device Characterization 80 3.3.1. General specifications 81 3.3.2. Transmitter circuit and coil 83 3.3.3. Wireless operation 83 3.3.4. Electrochemical measurements 84 3.4. Long-term reliability tests in vitro 86 3.4.1. Analytic calculation 87 3.4.2. Long-term reliability tests in accelerated condition 90 3.4.2.1. Long-term reliability of electrode arrays 90 3.4.2.2. Long-term reliability of package 92 3.4.2.3. Long-term reliability of complete device 93 3.4.3. Long-term Electrochemical stability 93 3.5. Acute and chronic evaluation in vivo 95 3.5.1. Surgical implantation 95 3.5.2. Acute functionality test 96 3.5.3. Long-term implantation stability 97 Chapter 4: Discussion 100 4.1. Comparison with conventional devices 100 4.2. Potential applications 102 4.3. Opportunities for further improvements 102 4.4. Long-term reliability 104 Chapter 5: Conclusion 108 Reference 110 국문초록 118 감사의 글 121Docto

Instrumentation for the Control of Biological Function through Electrical Stimulation

Electrical signals play a vital role in the makeup and processing of biological systems. While crucial for desired biological functions, they are also directly involved in degenerative and undesirable activity in these systems. Controlling biological function through targeted electrical stimulation is possible in both non-excitable cells and excitable cells. For each cell type, instrumentation for one specific application is covered in the following. Firstly, this thesis studies electrical stimulation setups and instrumentation for the enhancement of transgene expression in gene therapy. Although the applications of this work are manifold, the focus here is on improving wound healing and tissue regeneration, which is especially important in the treatment of non-closing wounds. Specifically, the ability of iontophoresis to enhance transgene expression in dermal and epidermal cells is assessed. For this, an electrical stimulation circuit with electrodes is developed and employed in in vivo experiments. The genes, in the form of charged DNA plasmids, are injected subcutaneously at the wound border of an adult rat model. An electrical field is applied to the tissue via the electrodes, which forces the plasmids onto a trajectory and forms pores in the cell's membranes to enhance transfection. Various stimulation parameters and setups, as well as different luciferase encoding plasmids, are tested to determine the optimal experimental setup for transgene expression. Secondly, this thesis studies neural implants for the excitation and inhibition of neurons. Neural implants are vital in the treatment of neurological diseases, and allow us to better understand how the brain processes information. The brain is a complex organ which is known to function by its multiple parts working together. Wireless sub-millimeter implants placed individually throughout the brain can imitate natural spatio-temporal stimulation patterns, while causing only minimal tissue destruction. In this thesis, the design of such an implant is elucidated in its entirety, with special focus on the wireless power link. Power from an external primary inductor will inductively be transferred to a secondary inductor that is implanted in the brain. The design trade-offs in selecting the geometry and configuration of the inductors are described and the analysis, simulation, and testing results are presented with the suggestion of an optimal design