Model-Based Design and Experimental Validation of Control Modules for Neuromodulation Devices

International audienceGoal - The goal of this paper is to propose a model-based control design framework, adapted to the development of control modules for medical devices. A particular example is presented in which instantaneous heart rate is regulated in real-time, by modulating, in an adaptive manner, the current delivered to the vagus nerve by a neuromodulator. Methods - The proposed framework couples a control module, based on a classical PI controller, a mathematical model of the medical device, and a physiological model representing the cardiovascular responses to vagus nerve stimulation (VNS). In order to analyze and evaluate the behavior of the device, different control parameters are tested on a "virtual population," generated with the model, according to the Latin Hypercube sampling method. In particular, sensitivity analyses are applied for the identification of a domain of interest in the space of the control parameters. The obtained control parameter domain has been validated in an experimental evaluation on six sheep. Results - A range of control parameters leading to accurate results was successfully estimated by the proposed model-based design method. Experimental evaluation of the control parameters inside such a domain led to the best compromise between accuracy and time response of the VNS control. Conclusion - The feasibility and usefulness of the proposed model-based design method were shown, leading to a functional, real-time closed-loop control of the VNS for the regulation of heart rate

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

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

Miniaturized wireless electronic device for application on rodents thermal neuromodulation

Dissertação de mestrado em Biomedical Engineering, Medical Electronics BranchA epilepsia é uma doença neurológica que afeta muitas pessoas em todo o mundo, e cerca de 30% dos pacientes epiléticos são resistentes aos medicamentos. Normalmente, estes são obrigados a ficar em casa, uma vez que a opção é uma cirurgia de ressecção focal, o que nem sempre é possível ou aceite. Portanto, e como em muitas patologias onde é possível o desenvolvimento de dispositivos médicos capazes de melhorar a qualidade de vida dos pacientes, a tecnologia pode-se associar à medicina e fornecer uma solução alternativa para tais pacientes. Dos vários estudos já realizados neste campo, a neuromodulação térmica é uma técnica promissora, uma vez que reduz ou possivelmente interrompe as crises epiléticas. Assim, a fim de potencializar uma solução futura para estes pacientes, é necessário primeiro realizar vários testes experimentais com modelos animais. Com o intuito de melhor compreender o funcionamento dos testes in vivo, foram realizados testes em GAERS no Grenoble Institute of Neuroscience com um dispositivo previamente desenvolvido, a fim de recolher dados sobre o efeito de arrefecimento nos neurónios. Isso permitiu alargar o conhecimento sobre o arrefecimento focal, mas também permitiu encontrar limitações no dispositivo utilizado, dado que era necessário que este estivesse conectado por fios para ser possível aplicar frio e gravar o EEG. Assim, o objetivo desta dissertação foi melhorar a comunicação sem fios de um dispositivo eletrónico capaz de controlar um Peltier e registar a atividade elétrica cerebral de um roedor. O sistema possui dois módulos, um que maioritariamente transmite dados e outro que os recebe. Nesse sentido, o transmissor possui toda a eletrónica associada à comunicação sem fios, à aquisição de sinais eletrofisiológicos e ao controlo do Peltier. Já o recetor possui a eletrónica para a comunicação sem fios e um conector USB para se conectar ao computador. Com o intuito de aumentar o débito binário da transação de dados, os dois módulos foram programados com o protocolo proprietário da Nordic Semiconductor, denominado Enhanced ShockBurst que opera na banda 2.4 GHz. Após a implementação do software, obteve-se um débito binário de 368640 bps, o que é 17 vezes superior ao protocolo usado anteriormente. Assim, é possível adquirir biossinais com frequências mais elevadas, ou então, com frequências mais baixas, mas com mais resolução e, ainda a visualização de mais do que um canal. De forma a validar todo o sistema, realizaram-se vários testes. Um dos testes foi colocar nos elétrodos uma onda sinusoidal e observar no computador se a onda recebida era igual à onda de entrada. O outro foi determinar a taxa de erros associada à comunicação e o tempo de vida da bateria.Epilepsy is a neurological disorder that affects numerous people worldwide, and around 30% of epileptic patients are drug resistant. Usually, they are restrained at home, since the option is a focal resection surgery, which is not always possible or accepted. Therefore, and as in many pathologies, where it allows the development of medical devices capable of improving patients’ quality of life, technology may be used here to help medicine providing an alternative solution for such patients. Of the many studies already conducted in this field, thermal neuromodulation is a promising technique as it reduces or possibly interrupts epileptic seizures. Thus, in order to leverage a future solution for these patients, it’s first necessary to run several experimental tests with animal models. To better understand how in vivo tests work, tests were initially performed on GAERS at the Grenoble Institute of Neuroscience with a previously developed device in order to collect data on the cooling effect on neurons. This allowed to extend the knowledge about focal cooling, but also allowed to find limitations in the device used, as it was required to be wired in order to be able to apply cold and record the EEG. Therefore, the aim of this dissertation was to improve the wireless communication of an electronic device capable of controlling a Peltier module and recording the electrical brain activity of a rodent. The system has two modules, one that mostly transmits data and another that receives them. In this sense, the transmitter has all the electronics associated with wireless communication, electrophysiological signal acquisition, and Peltier control. The receiver, on the other hand, has the electronics for wireless communication and a USB connector to connect to the computer. In order to increase the binary throughput of the data transaction, the two modules were programmed with the 2.4 GHz proprietary protocol from Nordic Semiconductor, called Enhanced ShockBurst. After implementation of the software, a binary throughput of 368640 bps was obtained, which is 17 times higher than the previously used protocol. Thus, it is possible to acquire biosignals at higher frequencies, or at lower frequencies but with more resolution, and to visualize more than one channel. In order to validate the whole system, several tests were performed. One of the tests was to place a sine wave on the electrodes and observe in the computer if the signal received was equal to the input wave. The other, on the other hand, was to determine the error rate associated with communication and battery life

Machine learning based brain signal decoding for intelligent adaptive deep brain stimulation

Sensing enabled implantable devices and next-generation neurotechnology allow real-time adjustments of invasive neuromodulation. The identification of symptom and disease-specific biomarkers in invasive brain signal recordings has inspired the idea of demand dependent adaptive deep brain stimulation (aDBS). Expanding the clinical utility of aDBS with machine learning may hold the potential for the next breakthrough in the therapeutic success of clinical brain computer interfaces. To this end, sophisticated machine learning algorithms optimized for decoding of brain states from neural time-series must be developed. To support this venture, this review summarizes the current state of machine learning studies for invasive neurophysiology. After a brief introduction to the machine learning terminology, the transformation of brain recordings into meaningful features for decoding of symptoms and behavior is described. Commonly used machine learning models are explained and analyzed from the perspective of utility for aDBS. This is followed by a critical review on good practices for training and testing to ensure conceptual and practical generalizability for real-time adaptation in clinical settings. Finally, first studies combining machine learning with aDBS are highlighted. This review takes a glimpse into the promising future of intelligent adaptive DBS (iDBS) and concludes by identifying four key ingredients on the road for successful clinical adoption: i) multidisciplinary research teams, ii) publicly available datasets, iii) open-source algorithmic solutions and iv) strong world-wide research collaborations.Fil: Merk, Timon. Charité – Universitätsmedizin Berlin; AlemaniaFil: Peterson, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Matemática Aplicada del Litoral. Universidad Nacional del Litoral. Instituto de Matemática Aplicada del Litoral; Argentina. Harvard Medical School; Estados UnidosFil: Köhler, Richard. Charité – Universitätsmedizin Berlin; AlemaniaFil: Haufe, Stefan. Charité – Universitätsmedizin Berlin; AlemaniaFil: Richardson, R. Mark. Harvard Medical School; Estados UnidosFil: Neumann, Wolf Julian. Charité – Universitätsmedizin Berlin; Alemani

Translingual neurostimulation combined with physical therapy to improve walking and balance in multiple sclerosis (NeuroMSTraLS): Study protocol for a randomized controlled trial

INTRODUCTION: Physical rehabilitation restores lost function and promotes brain plasticity in people with Multiple Sclerosis (MS). Research groups worldwide are testing the therapeutic effects of combining non-invasive neuromodulation with physical therapy (PT) to further improve functional outcomes in neurological disorders but with mixed results. Whether such devices enhance function is not clear. We present the rationale and study design for a randomized controlled trial evaluating if there is additional benefit to the synergistic pairing of translingual neurostimulation (TLNS) with PT to improve walking and balance in MS. METHODS AND ANALYSIS: A parallel group [PT + TLNS or PT + Sham], quadruple-blinded, randomized controlled trial. Participants (N = 52) with gait and balance deficits due to relapsing-remitting or progressive MS, who are between 18 and 70 years of age, will be recruited through patient registries in Newfoundland & Labrador and Saskatchewan, Canada. All participants will receive 14 weeks of PT while wearing either a TLNS or sham device. Dynamic Gait Index is the primary outcome. Secondary outcomes include fast walking speed, subjective ratings of fatigue, MS impact, and quality of life. Outcomes are assessed at baseline (Pre), after 14 weeks of therapy (Post), and 26 weeks (Follow Up). We employ multiple methods to ensure treatment fidelity including activity and device use monitoring. Primary and secondary outcomes will be analyzed using linear mixed-effect models. We will control for baseline score and site to test the effects of Time (Post vs. Follow-Up), Group and the Group x Time interaction as fixed effects. A random intercept of participant will account for the repeated measures in the Time variable. Participants must complete the Post testing to be included in the analysis. ETHICS AND DISSEMINATION: The Human Research Ethics Boards in Newfoundland & Labrador (HREB#2021.085) & Saskatchewan (HREB Bio 2578) approved the protocol. Dissemination avenues include peer-reviewed journals, conferences and patient-oriented communications

Innovative Techniques of Neuromodulation and Neuromodeling Based on Focal Non-Invasive Transcranial Magnetic Stimulation for Neurological Disorders

This dissertation aims to develop alternative technology that improves the current range of application of transcranial magnetic stimulation (TMS), on a scale that would permit defining specific non-invasive treatments for Parkinson’s disease and other neurological disorders. This is accomplished through three specific objectives. 1) The design of a neurostimulation system that increases the focality in TMS to regions of narrow target areas and variable depths in the brain cortex. 2) The assessment of the feasibility of novel high-frequency neuromodulation techniques that would allow increasing the focality in deeper areas beyond the cortical surface. 3) The development of a computational model of the motor pathway that allows studying the underlying mechanisms that originate PD symptoms, and the effects of TMS for the development of new treatments. The results successfully demonstrated the feasibility of using the novel high-frequency neuromodulation technique as an effective manner to reduce the necessary current in TMS coils. This reduction, which reached an order of magnitude of 100 times compared to commercial TMS technology, made it possible to reduce the coil sizes, making them more focal to targets (in the order of a few millimeters square). Finally, our innovative oscillatory model of the motor pathway allowed us to conclude that an internal regulatory mechanism that we believe neurons activate in advanced PD stages seems to be the pathological response of some neural subpopulations to dopamine depletion, trying to compensate for the downstream effects in the system. We also found that such a mechanism seems to the burstiness in PD

Feasibility of Using the Utah Array for Long-Term Fully Implantable Neuroprosthesis Systems

Damage to the spinal cord can disrupt the pathway of signals sent between the brain and the body and may result in partial or complete loss of both motor and sensory functions. The loss of these functions can have devastating implications on the quality of one’s life, interfering with activities of daily living related to walking, bladder and bowel control, trunk stability, and arm and hand function. Current approaches used to help improve and restore mobility require residual movement to control, which can be unintuitive and inoperative by individuals with higher level cervical injuries. In order to develop technology used by individuals of all levels of injury, it is necessary to generate control signals directly from the brain. This thesis is intended to address the clinical limitations of implantable neural recording systems, and thus lay the foundation for the development of a design and safety profile for a fully implantable intracortical system for motor restoration. We first present the design and testing of a 96-channel neural recording device used to mate with an existing functional electrical stimulation (FES) system in order to facilitate brain-controlled FES. By extracting signal power within a narrow frequency bandwidth and reducing overhead processor operations, a 25% power reduction is achieved. This establishes the feasibility for an implantable system and enables the integration of the neural recording device with implantable FES system. The specifications of this platform can be used as a guide to develop further application specific modules and dramatically accelerate the overall process to a clinically viable system. With a functional device, the next step is to move towards a clinical trial. Here we investigate the potential safety risks of future modular, implantable neuroprosthetic systems. A systematic review of 240 articles was used to identify and quantitatively summarize the hardware-related complications of the most established intracranial clinical system, deep brain stimulation, and the most widespread experimental human intracranial system, the NeuroPort, including the Utah microelectrode array. The safety and longevity data collected here will be used to better inform future device and clinical trial design and satisfy regulatory requirements. The stability and longevity of the Utah array are critical factors for determining whether the clinical benefit outweighs the risk for potential users. We investigate the biological adverse response to the insertion of the Utah array in a rhesus macaque. We examined the density of neurons around the shanks of the array in comparison to control brain. Non-human primate animal models allow us to further examine the effects of the implantation of the Utah array on neural tissue, which cannot be done with humans. Information gained through this will continue to increase the pool of safety data for the Utah array and emerging intracranial devices. Overall, we developed a neural recording device to be used for brain-controlled FES and examined the potential safety concerns reported in the human literature and experimentally using non-human primates. These results represent significant progress towards a clinically-viable system for motor restoration in people suffering from spinal cord injury.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/149940/1/ajbull_1.pd

Reversible Integration of Microfluidic Devices with Microelectrode Arrays for Neurobiological Applications

The majority of current state-of-the-art microfluidic devices are fabricated via replica molding of the fluidic channels into PDMS elastomer and then permanently bonding it to a Pyrex surface using plasma oxidation. This method presents a number of problems associated with the bond strengths, versatility, applicability to alternative substrates, and practicality. Thus, the aim of this study was to investigate a more practical method of integrating microfluidics which is superior in terms of bond strengths, reversible, and applicable to a larger variety of substrates, including microfabricated devices. To achieve the above aims, a modular microfluidic system, capable of reversible microfluidic device integration, simultaneous surface patterning and multichannel fluidic perfusion, was built. To demonstrate the system’s potential, the ability to control the distribution of A549 cells inside a microfluidic channel was tested. Then, the system was integrated with a chemically patterned microelectrode array, and used it to culture primary, rat embryo spinal cord neurons in a dynamic fluidic environment. The results of this study showed that this system has the potential to be a cost effective and importantly, a practical means of integrating microfluidics. The system’s robustness and the ability to withstand extensive manual handling have the additional benefit of reducing the workload. It also has the potential to be easily integrated with alternative substrates such as stainless steel or gold without extensive chemical modifications. The results of this study are of significant relevance to research involving neurobiological applications, where primary cell cultures on microelectrode arrays require this type of flexible integrated solution