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

Evaluating the impact of intracortical microstimulation on distant cortical brain regions for neuroprosthetic applications

Enhancing functional motor recovery after localized brain injury is a widely recognized priority in healthcare as disorders of the nervous system that cause motor impairment, such as stroke, are among the most common causes of adult-onset disability. Restoring physiological function in a dysfunctional brain to improve quality of life is a primary challenge in scientific and clinical research and could be driven by innovative therapeutic approaches. Recently, techniques using brain stimulation methodologies have been employed to promote post-injury neuroplasticity for the restitution of motor function. One type of closed-loop stimulation, i.e., activity-dependent stimulation (ADS), has been shown to modify existing functional connectivity within either healthy or injured cerebral cortices and used to increase behavioral recovery following cortical injury. The aim of this PhD thesis is to characterize the electrophysiological correlates of such behavioral recovery in both healthy and injured cortical networks using in vivo animal models. We tested the ability of two different intracortical micro-stimulation protocols, i.e., ADS and its randomized open-loop version (RS), to potentiate cortico-cortical connections between two distant cortical locations in both anaesthetized and awake behaving rats. Thus, this dissertation has the following three main goals: 1) to investigate the ability of ADS to induce changes in intra-cortical activity in healthy anesthetized rats, 2) to characterize the electrophysiological signs of brain injury and evaluate the capability of ADS to promote electrophysiological changes in the damaged network, and 3) to investigate the long-term effects of stimulation by repeating the treatment for 21 consecutive days in healthy awake behaving animals. The results of this study indicate that closed-loop activity-dependent stimulation induced greater changes than open-loop random stimulation, further strengthening the idea that Hebbian-inspired protocols might potentiate cortico-cortical connections between distant brain areas. The implications of these results have the potential to lead to novel treatments for various neurological diseases and disorders and inspire new neurorehabilitation therapies

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

Technology of deep brain stimulation: current status and future directions

Deep brain stimulation (DBS) is a neurosurgical procedure that allows targeted circuit-based neuromodulation. DBS is a standard of care in Parkinson disease, essential tremor and dystonia, and is also under active investigation for other conditions linked to pathological circuitry, including major depressive disorder and Alzheimer disease. Modern DBS systems, borrowed from the cardiac field, consist of an intracranial electrode, an extension wire and a pulse generator, and have evolved slowly over the past two decades. Advances in engineering and imaging along with an improved understanding of brain disorders are poised to reshape how DBS is viewed and delivered to patients. Breakthroughs in electrode and battery designs, stimulation paradigms, closed-loop and on-demand stimulation, and sensing technologies are expected to enhance the efficacy and tolerability of DBS. In this Review, we provide a comprehensive overview of the technical development of DBS, from its origins to its future. Understanding the evolution of DBS technology helps put the currently available systems in perspective and allows us to predict the next major technological advances and hurdles in the field.ope

Modeling and Analysis of Neural Spike Trains

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Embedded platform for electrical neural stimulation

Tese de mestrado integrado em Engenharia Biomédica e Biofísica, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2015Atualmente, o número de tecnologias baseadas em neuro-estimulação está em crescimento, crescimento este que é promovido pelo facto de a neuro-estimulação ser uma área de investigação de elevado interesse devido às várias áreas de possível aplicação, tais como a terapia e tratamento, reabilitação e próteses. Na área da terapia e tratamentos, a possível aplicação da neuro-estimulação está relacionada com a neuro-regulação de órgãos do corpo humano, aplicação que tem sido vista já no campo dos distúrbios do sistema nervoso, tais como a doença de Parkinson e a epilepsia, no tratamento de dor crónica, no controlo do funcionamento cardíaco {no qual se insere uma das tecnologias mais conhecidas, o pacemaker { e está ainda a ser investigada para o controlo da libertação de insulina e a absorção renal de sais. Na área da reabilitação, a aplicação da neuro-estimulação tem sido vista em casos de lesões na medula espinal onde a utilização da técnica de estimulação eléctrica funcional, ou FES de Funcional Electrical Stimulation, resultou na recuperação de algumas funções motoras e de controlo de certos órgãos. Relativamente à área das próteses, a neuro-estimulação tem um papel muito importante principalmente no desenvolvimento de próteses funcionais, permitindo que estas próteses não só reajam a informação vinda do sistema de nervoso, realizando os movimentos desejados pelo utilizador, como também forneçam informação ao mesmo, permitindo assim que haja um mecanismo de feedback da prótese, aumentando assim a restituição que esta pode dar ao seu utilizador, tanto a nível funcional como emocional. Uma das mais conhecidas próteses que recorrem à neuro-estimulação é o implante coclear que permite uma recuperação parcial da capacidade auditiva recorrendo para isso a um conjunto de microfones no ouvido externo que deteta o som e o transmite à unidade de processamento que por sua vez transforma o som em impulsos eléctricos que são direccionados para eléctrodos no interior da cóclea e que irão estimular os nervos auditivos. A neuro-estimulação é então um procedimento baseado na estimulação de células excitáveis, como os neurónios, recorrendo para isso à utilização de eléctrodos, com o objectivo de iniciar ou inibir um potencial de acção. Esta possibilidade de iniciar um estímulo nervoso através de estímulos externos deve-se ao facto da activação e propagação de um sinal neural ser um fenómeno eletroquímico. Este fator torna possível o desenvolvimento de tecnologias que resultem numa maior, ou menor, recetividade da célula a um estímulo através da promoção de alterações do meio em que estão inseridas as células excitáveis ou de propriedades da membrana das mesmas. O desenvolvimento de tecnologias que recorram à neuro-estimulação está dependente de um estudo profundo dos tipos e estratégias de estimulação de forma a obter a estratégia que seja mais eficaz, segura e eficiente, sendo que esta varia de situação para situação, dependendo de fatores como o local de aplicação e mesmo o resultado que se espera do estímulo. Por estes motivos têm de ser realizados estudos comparativos válidos entre estratégias de estimulação e, para um estudo deste tipo ser valido, os vários estudos devem ser feitos nas mesmas condições com distâncias temporais preferencialmente curtas. Assim sendo, no âmbito da neuro-estimulação recorrendo a estímulos eléctricos, criou-se a necessidade de desenvolver sistemas que permitissem uma mais rápida variação dos parâmetros de estimulação comparativamente à montagem experimental clássica. De forma a cumprir estes requisitos, vários sistemas de rápida configuração de parâmetros tem vindo a ser propostos. O projeto relatado nesta Tese de Mestrado, desenvolvido durante um estágio de seis meses no Centre for Bio-Inspired Technologies, Imperial College London, apresenta-se então como uma plataforma de neuro-estimulação eléctrica para a realização de estudos comparativos tendo em vista a optimização da estratégia de estimulação, com o objectivo de ser uma versão melhorada dos sistemas já disponíveis. Esta plataforma é composta por três principais componentes: uma interface utilizador-sistema, que permite ao utilizador configurar a estimulação como pretende controlando características como o tipo de onda, a amplitude, a duração, a frequência, entre outros; um microcontrolador e uma placa de estimulação, em que o primeiro controla o segundo de acordo com o que foi configurado pelo utilizador sendo que a placa têm a responsabilidade de gerar e aplicar um estímulo eléctrico. O principal objetivo deste projeto era então desenvolver uma plataforma de neuro-estimulação eléctrica capaz de gerar e aplicar uma estimulação eléctrica bipolar com capacidade de equilíbrio de cargas, podendo fazê-lo através de quatro canais de estimulação. Ao mesmo tempo era objetivo que esta fosse pequena, de baixo custo, eficaz, eficiente, de fácil utilização proporcionando um maior leque de possibilidades de configuração comparativamente aos sistemas já desenvolvidos e que pudesse também ser facilmente recriado, alterado e, eventualmente, melhorado. Os resultados obtidos de testes realizados demonstraram que esta plataforma opera corretamente nos dois principais aspetos do seu funcionamento, nomeadamente a capacidade de gerar uma estimulação de acordo com todos os parâmetros tal como configurados pelo utilizador e a capacidade de cumprir os propósitos de equilíbrio de cargas após estimulação, em todos os tipos de ondas definidos. Existem no entanto ainda algumas limitações no funcionamento da plataforma. Estas limitações estão relacionadas com a amplitude máxima de estimulação que o sistema é capaz de aplicar, mais especialmente a amplitude máxima do output do DAC utilizado e também a amplitude máxima que o amplificador operacional escolhido consegue por no seu output; com a existência de algumas imprecisões temporais na aplicação do estímulo, resultantes do tempo de execução de algumas funções por parte do microcontrolador; com o consumo energético e ainda o facto de a ligação entre o computador e o microcontrolador ser feita através de um cabo USB, o que limita a mobilidade que se pode ter durante o trabalho experimental. Comparativamente a plataformas de estimulação eléctrica configuráveis existentes, o sistema aqui desenvolvido apresenta diversas vantagens. Para além de vantagens como baixo custo e facilidade de recriação, esta plataforma tem também um maior número de parâmetros da estimulação que o utilizador pode configurar e também permite uma estimulação através de quatro canais, de três formas diferentes: utilizando apenas um canal, utilizando mais do que um canal ao mesmo tempo ou ainda mais do que um canal de forma sequencial. No entanto, alguns dos sistemas já existentes não apresentam as limitações acima referidas e como tal os desafios futuros desta placa passam por ultrapassar essas limitações.Nowadays, neuro stimulation technologies have grown to reach a wide range of applications including therapy and treatment, rehabilitation and prosthetics and its range continues to grow as it still represents an interesting area of research. Neurostimulation is based on stimulation of excitable cells, such as nerve cells, through the use of electrodes, with the purpose of achieving initiation or inhibition of an action potential. This interaction is possible due to the electrophysiological base of activation and propagation of a neural signal. This neural signal characteristic makes it possible to use external technologies to promote changes in the nerve cell membrane voltage potential or the environment surrounding it, which can lead to the initiation of a neural signal in the cell or simply to a higher, or lower, receptivity of the cell to a stimulus. The use of neuro stimulation technologies in referred areas and future possibility of use in other applications depends on research developments. An important point of this research is the stimulation strategy, more specifically, the characteristics that a stimulation pulse should have to optimize results towards the intended objective and minimize safety risks. The present thesis reports a project developed during an internship at the Centre for Bio-Inspired Technologies, Imperial College London which consists in designing and building a full system for the study of stimulation strategies. This full system includes a user interface in a computer, so that the user can choose the stimulus characteristics, such as waveform and amplitude, and define the intended strategy, such as repetition rate and inter-stimulus increasing or decreasing rate; and a microcontroller for control of stimulus application through a front-end stimulation-output circuit, which will be responsible for generation of programmed current-controlled stimulus. The measurement results verify that the main objectives of this project were accomplished, namely, the capacity to generate a stimulation that meets the parameters as configured by the user and the capacity to carry a charge-balanced stimulation in all the preset waveforms. However, some limitations were also found related namely with the maximum stimulation amplitude, the small time inaccuracy during stimulation, the power consumption and the fact that connection between the computer and microcontroller is done via USB, limiting the mobility of an experimental procedure using this system. The system developed here presents some advantages compared to existing systems, such as low cost, easy to build, higher number of parameters that can be configured and can apply stimulation through four channels and do it either with only one, with two or more at the same time or with two or more sequentially. However some of these existing systems do not present some of the limitations mentioned and the challenge on the future of this platform is to overcome these limitations

Neurotechnology for Brain Repair:Imaging, Enhancing and Restoring Human Motor Function

Neurotechnology is the application of scientific knowledge to the practical purpose of understanding, interacting and/or repairing the brain or, in a broader sense, the nervous system. The development of novel approaches to decode functional information from the brain, to enhance specific properties of neural tissue and to restore motor output in real end-users is a fundamental challenge to translate these novel solutions into clinical practice. In this Thesis, I introduce i) a novel imaging method to characterize movement-related electroencephalographic (EEG) potentials; ii) a brain stimulation strategy to improve brain-computer interface (BCI) control; iii) and a therapy for motor recovery involving a neuroprosthesis. Overall, results show i) that stable EEG topographies present a subject-independent organization that can be used to robustly decode actual or attempted movements in sub-acute stroke patients and healthy controls, with minimal a-priori information; ii) that transcranial direct-current stimulation (tDCS) enhances the modulability of sensorimotor rhythms used for brain-computer interaction in chronic Spinal Cord Injured (SCI) individuals and healthy controls; iii) that neuromuscular electrical stimulation (NMES) controlled via closed-loop neural activity induces significantly stronger upper limb functional recovery in chronic stroke patients than sham NMES therapy, and that these changes are clinically relevant. These results have or might have important implications in i) disease diagnostics and monitoring through EEG; ii) assistive technology and reduction of permanent disability following SCI; iii) rehabilitation and recovery of upper limb function following a stroke, also after several years of complete paralysis. Briefly, this Thesis provides the conceptual framework, scientific rationale, technical details and clinical evidence supporting translational Neurotechnology that improves, optimizes and disrupts current medical practice in monitoring, substituting and recovering lost upper limb function

Wireless tools for neuromodulation

Epilepsy is a spectrum of diseases characterized by recurrent seizures. It is estimated that 50 million individuals worldwide are affected and 30% of cases are medically refractory or drug resistant. Vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are the only FDA approved device based therapies. Neither therapy offers complete seizure freedom in a majority of users. Novel methodologies are needed to better understand mechanisms and chronic nature of epilepsy. Most tools for neuromodulation in rodents are tethered. The few wireless devices use batteries or are inductively powered. The tether restricts movement, limits behavioral tests, and increases the risk of infection. Batteries are large and heavy with a limited lifetime. Inductive powering suffers from rapid efficiency drops due to alignment mismatches and increased distances. Miniature wireless tools that offer behavioral freedom, data acquisition, and stimulation are needed. This dissertation presents a platform of electrical, optical and radiofrequency (RF) technologies for device based neuromodulation. The platform can be configured with features including: two channels differential recording, one channel electrical stimulation, and one channel optical stimulation. Typical device operation consumes less than 4 mW. The analog front end has a bandwidth of 0.7 Hz - 1 kHz and a gain of 60 dB, and the constant current driver provides biphasic electrical stimulation. For use with optogenetics, the deep brain optical stimulation module provides 27 mW/mm2 of blue light (473 nm) with 21.01 mA. Pairing of stimulating and recording technologies allows closed-loop operation. A wireless powering cage is designed using the resonantly coupled filter energy transfer (RCFET) methodology. RF energy is coupled through magnetic resonance. The cage has a PTE ranging from 1.8-6.28% for a volume of 11 x 11 x 11 in3. This is sufficient to chronically house subjects. The technologies are validated through various in vivo preparations. The tools are designed to study epilepsy, SUDEP, and urinary incontinence but can be configured for other studies. The broad application of these technologies can enable the scientific community to better study chronic diseases and closed-loop therapies

FLEXIBLE NEURAL INTERFACES FOR RECORDING AND STIMULATION OF PERIPHERAL AND VISCERAL NERVES

Ph.DDOCTOR OF PHILOSOPH