MAPPING LOW-FREQUENCY FIELD POTENTIALS IN BRAIN CIRCUITS WITH HIGH-RESOLUTION CMOS ELECTRODE ARRAY RECORDINGS

Neurotechnologies based on microelectronic active electrode array devices are on the way to provide the capability to record electrophysiological neural activity from a thousands of closely spaced microelectrodes. This generates increasing volumes of experimental data to be analyzed, but also offers the unprecedented opportunity to observe bioelectrical signals at high spatial and temporal resolutions in large portions of brain circuits. The overall aim of this PhD was to study the application of high-resolution CMOS-based electrode arrays (CMOS-MEAs) for electrophysiological experiments and to investigate computational methods adapted to the analysis of the electrophysiological data generated by these devices. A large part of my work was carried out on cortico-hippocampal brain slices by focusing on the hippocampal circuit. In the history of neuroscience, a major technological advance for hippocampal research, and also for the field of neurobiology, was the development of the in vitro hippocampal slice preparation. Neurobiological principles that have been discovered from work on in vitro hippocampal preparations include, for instance, the identification of excitatory and inhibitory synapses and their localization, the characterization of transmitters and receptors, the discovery of long-term potentiation (LTP) and long-term depression (LTD) and the study of oscillations in neuronal networks. In this context, an initial aim of my work was to optimize the preparation and maintenance of acute cortico-hippocampal brain slices on planar CMOS-MEAs. At first, I focused on experimental methods and computational data analysis tools for drug-screening applications based on LTP quantifications. Although the majority of standard protocols still use two electrodes platforms for quantifying LTP, in my PhD I investigate the potential advantages of recording the electrical activity from many electrodes to spatiotemporally characterized electrically induced responses. This work also involved the collaboration with 3Brain AG and a CRO involved in drug-testing, and led to a software tool that was licensed for developing its exploitation. In a second part of my work I focused on exploiting the recording resolution of planar CMOS-MEAs to study the generation of sharp wave ripples (SPW-Rs) in the hippocampal circuit. This research activity was carried out also by visiting the laboratory of Prof. A. Sirota (Ludwig Maximilians University, Munich). In addition to set-up the experimental conditions to record SPW-Rs from planar CMOS-MEAs integrating 4096 microelectrodes, I also explored the implementation of a data analysis pipeline to identify spatiotemporal features that might characterize different type of in-vitro generated SPW-R events. Finally, I also contributed to the initial implementation of high-density implantable CMOS-probes for in-vivo electrophysiology with the aim of evaluating in vivo the algorithms that I developed and investigated on brain slices. With this aim, in the last period of my PhD I worked on the development of a Graphical User Interface for controlling active dense CMOS probes (or SiNAPS probes) under development in our laboratory. I participated to preliminary experimental recordings using 4-shank CMOS-probes featuring 1024 simultaneously recording electrodes and I contributed to the development of a software interface for executing these experiments

Microstimulation and multicellular analysis: A neural interfacing system for spatiotemporal stimulation

Willfully controlling the focus of an extracellular stimulus remains a significant challenge in the development of neural prosthetics and therapeutic devices. In part, this challenge is due to the vast set of complex interactions between the electric fields induced by the microelectrodes and the complex morphologies and dynamics of the neural tissue. Overcoming such issues to produce methodologies for targeted neural stimulation requires a system that is capable of (1) delivering precise, localized stimuli a function of the stimulating electrodes and (2) recording the locations and magnitudes of the resulting evoked responses a function of the cell geometry and membrane dynamics. In order to improve stimulus delivery, we developed microfabrication technologies that could specify the electrode geometry and electrical properties. Specifically, we developed a closed-loop electroplating strategy to monitor and control the morphology of surface coatings during deposition, and we implemented pulse-plating techniques as a means to produce robust, resilient microelectrodes that could withstand rigorous handling and harsh environments. In order to evaluate the responses evoked by these stimulating electrodes, we developed microscopy techniques and signal processing algorithms that could automatically identify and evaluate the electrical response of each individual neuron. Finally, by applying this simultaneous stimulation and optical recording system to the study of dissociated cortical cultures in multielectode arrays, we could evaluate the efficacy of excitatory and inhibitory waveforms. Although we found that the proximity of the electrode is a poor predictor of individual neural excitation thresholds, we have shown that it is possible to use inhibitory waveforms to globally reduce excitability in the vicinity of the electrode. Thus, the developed system was able to provide very high resolution insight into the complex set of interactions between the stimulating electrodes and populations of individual neurons.Ph.D.Committee Chair: Stephen P. DeWeerth; Committee Member: Bruce Wheeler; Committee Member: Michelle LaPlaca; Committee Member: Robert Lee; Committee Member: Steve Potte

Implantable Micro-Device for Epilepsy Seizure Detection and Subsequent Treatment

RÉSUMÉ L’émergence des micro-dispositifs implantables est une voie prometteuse pour le traitement de troubles neurologiques. Ces systèmes biomédicaux ont été exploités comme traitements non-conventionnels sur des patients chez qui les remèdes habituels sont inefficaces. Les récents progrès qui ont été faits sur les interfaces neuronales directes ont permis aux chercheurs d’analyser l’activité EEG intracérébrale (icEEG) en temps réel pour des fins de traitements. Cette thèse présente un dispositif implantable à base de microsystèmes pouvant capter efficacement des signaux neuronaux, détecter des crises d’épilepsie et y apporter un traitement afin de l’arrêter. Les contributions principales présentées ici ont été rapportées dans cinq articles scientifiques, publiés ou acceptés pour publication dans les revues IEEE, et plusieurs autres tels que «Low Power Electronics» et «Emerging Technologies in Computing». Le microsystème proposé inclus un circuit intégré (CI) à faible consommation énergétique permettant la détection de crises d’épilepsie en temps réel. Cet CI comporte une pré-amplification initiale et un détecteur de crises d’épilepsie. Le pré-amplificateur est constitué d’une nouvelle topologie de stabilisateur d’hacheur réduisant le bruit et la puissance dissipée. Les CI fabriqués ont été testés sur des enregistrements d’icEEG provenant de sept patients épileptiques réfractaires au traitement antiépileptique. Le délai moyen de la détection d’une crise est de 13,5 secondes, soit avant le début des manifestations cliniques évidentes. La consommation totale d’énergie mesurée de cette puce est de 51 μW. Un neurostimulateur à boucle fermée (NSBF), quant à lui, détecte automatiquement les crises en se basant sur les signaux icEEG captés par des électrodes intracrâniennes et permet une rétroaction par une stimulation électrique au même endroit afin d’interrompre ces crises. La puce de détection de crises et le stimulateur électrique à base sur FPGA ont été assemblés à des électrodes afin de compléter la prothèse proposée. Ce NSBF a été validé en utilisant des enregistrements d’icEEG de dix patients souffrant d’épilepsie réfractaire. Les résultats révèlent une performance excellente pour la détection précoce de crises et pour l’auto-déclenchement subséquent d’une stimulation électrique. La consommation énergétique totale du NSBF est de 16 mW. Une autre alternative à la stimulation électrique est l’injection locale de médicaments, un traitement prometteur de l’épilepsie. Un système local de livraison de médicament basé sur un nouveau détecteur asynchrone des crises est présenté.----------ABSTRACT Emerging implantable microdevices hold great promise for the treatment of patients with neurological conditions. These biomedical systems have been exploited as unconventional treatment for the conventionally untreatable patients. Recent progress in brain-machine-interface activities has led the researchers to analyze the intracerebral EEG (icEEG) recording in real-time and deliver subsequent treatments. We present in this thesis a long-term safe and reliable low-power microsystem-based implantable device to perform efficient neural signal recording, seizure detection and subsequent treatment for epilepsy. The main contributions presented in this thesis are reported in five journal manuscripts, published or accepted for publication in IEEE Journals, and many others such as Low Power Electronics, and Emerging Technologies in Computing. The proposed microsystem includes a low-power integrated circuit (IC) intended for real-time epileptic seizure detection. This IC integrates a front-end preamplifier and epileptic seizure detector. The preamplifier is based on a new chopper stabilizer topology that reduces noise and power dissipation. The fabricated IC was tested using icEEG recordings from seven patients with drug-resistant epilepsy. The average seizure detection delay was 13.5 sec, well before the onset of clinical manifestations. The measured total power consumption of this chip is 51 µW. A closed-loop neurostimulator (CLNS) is next introduced, which is dedicated to automatically detect seizure based on icEEG recordings from intracranial electrode contacts and provide an electrical stimulation feedback to the same contacts in order to disrupt these seizures. The seizure detector chip and a dedicated FPGA-based electrical stimulator were assembled together with common recording electrodes to complete the proposed prosthesis. This CLNS was validated offline using recording from ten patients with refractory epilepsy, and showed excellent performance for early detection of seizures and subsequent self-triggering electrical stimulation. Total power consumption of the CLNS is 16 mW. Alternatively, focal drug injection is the promising treatment for epilepsy. A responsive focal drug delivery system based on a new asynchronous seizure detector is also presented. The later system with data-dependent computation reduces up to 49% power consumption compared to the previous synchronous neurostimulator

Central nervous system microstimulation: Towards selective micro-neuromodulation

Electrical stimulation technologies capable of modulating neural activity are well established for neuroscientific research and neurotherapeutics. Recent micro-neuromodulation experimental results continue to explain neural processing complexity and suggest the potential for assistive technologies capable of restoring or repairing of basic function. Nonetheless, performance is dependent upon the specificity of the stimulation. Increasingly specific stimulation is hypothesized to be achieved by progressively smaller interfaces. Miniaturization is a current focus of neural implants due to improvements in mitigation of the body's foreign body response. It is likely that these exciting technologies will offer the promise to provide large-scale micro-neuromodulation in the future. Here, we highlight recent successes of assistive technologies through bidirectional neuroprostheses currently being used to repair or restore basic brain functionality. Furthermore, we introduce recent neuromodulation technologies that might improve the effectiveness of these neuroprosthetic interfaces by increasing their chronic stability and microstimulation specificity. We suggest a vision where the natural progression of innovative technologies and scientific knowledge enables the ability to selectively micro-neuromodulate every neuron in the brain

Conformable transistors for bioelectronics

The diversity of network disruptions that occur in patients with neuropsychiatric disorders creates a strong demand for personalized medicine. Such approaches often take the form of implantable bioelectronic devices that are capable of monitoring pathophysiological activity for identifying biomarkers to allow for local and responsive delivery of intervention. They are also required to transmit this data outside of the body for evaluation of the treatment’s efficacy. However, the ability to perform these demanding electronic functions in the complex physiological environment with minimum disruption to the biological tissue remains a big challenge. An optimal fully implantable bioelectronic device would require each component from the front-end to the data transmission to be conformable and biocompatible. For this reason, organic material-based conformable electronics are ideal candidates for components of bioelectronic circuits due to their inherent flexibility, and soft nature. In this work, first an organic mixed-conducting particulate composite material (MCP) able to form functional electronic components and non-invasively acquire high–spatiotemporal resolution electrophysiological signals by directly interfacing human skin is presented. Secondly, we introduce organic electrochemical internal ion-gated transistors (IGTs) as a high-density, high-amplification sensing component as well as a low leakage, high-speed processing unit. Finally, a novel wireless, battery-free strategy for electrophysiological signal acquisition, processing, and transmission that employs IGTs and an ionic communication circuit (IC) is introduced. We show that the wirelessly-powered IGTs are able to acquire and modulate neurophysiological data in-vivo and transmit them transdermally, eliminating the need for any hard Si-based electronics in the implant

VLSI Circuits for Bidirectional Neural Interfaces

Medical devices that deliver electrical stimulation to neural tissue are important clinical tools that can augment or replace pharmacological therapies. The success of such devices has led to an explosion of interest in the field, termed neuromodulation, with a diverse set of disorders being targeted for device-based treatment. Nevertheless, a large degree of uncertainty surrounds how and why these devices are effective. This uncertainty limits the ability to optimize therapy and gives rise to deleterious side effects. An emerging approach to improve neuromodulation efficacy and to better understand its mechanisms is to record bioelectric activity during stimulation. Understanding how stimulation affects electrophysiology can provide insights into disease, and also provides a feedback signal to autonomously tune stimulation parameters to improve efficacy or decrease side-effects. The aims of this work were taken up to advance the state-of-the-art in neuro-interface technology to enable closed-loop neuromodulation therapies. Long term monitoring of neuronal activity in awake and behaving subjects can provide critical insights into brain dynamics that can inform system-level design of closed-loop neuromodulation systems. Thus, first we designed a system that wirelessly telemetered electrocorticography signals from awake-behaving rats. We hypothesized that such a system could be useful for detecting sporadic but clinically relevant electrophysiological events. In an 18-hour, overnight recording, seizure activity was detected in a pre-clinical rodent model of global ischemic brain injury. We subsequently turned to the design of neurostimulation circuits. Three critical features of neurostimulation devices are safety, programmability, and specificity. We conceived and implemented a neurostimulator architecture that utilizes a compact on-chip circuit for charge balancing (safety), digital-to-analog converter calibration (programmability) and current steering (specificity). Charge balancing accuracy was measured at better than 0.3%, the digital-to-analog converters achieved 8-bit resolution, and physiological effects of current steering stimulation were demonstrated in an anesthetized rat. Lastly, to implement a bidirectional neural interface, both the recording and stimulation circuits were fabricated on a single chip. In doing so, we implemented a low noise, ultra-low power recording front end with a high dynamic range. The recording circuits achieved a signal-to-noise ratio of 58 dB and a spurious-free dynamic range of better than 70 dB, while consuming 5.5 μW per channel. We demonstrated bidirectional operation of the chip by recording cardiac modulation induced through vagus nerve stimulation, and demonstrated closed-loop control of cardiac rhythm

Stretchable multichannel antennas in soft wireless optoelectronic implants for optogenetics

Optogenetic methods to modulate cells and signaling pathways via targeted expression and activation of light-sensitive proteins have greatly accelerated the process of mapping complex neural circuits and defining their roles in physiological and pathological contexts. Recently demonstrated technologies based on injectable, microscale inorganic light-emitting diodes (μ-ILEDs) with wireless control and power delivery strategies offer important functionality in such experiments, by eliminating the external tethers associated with traditional fiber optic approaches. Existing wireless μ-ILED embodiments allow, however, illumination only at a single targeted region of the brain with a single optical wavelength and over spatial ranges of operation that are constrained by the radio frequency power transmission hardware. Here we report stretchable, multiresonance antennas and battery-free schemes for multichannel wireless operation of independently addressable, multicolor μ-ILEDs with fully implantable, miniaturized platforms. This advance, as demonstrated through in vitro and in vivo studies using thin, mechanically soft systems that separately control as many as three different μ-ILEDs, relies on specially designed stretchable antennas in which parallel capacitive coupling circuits yield several independent, well-separated operating frequencies, as verified through experimental and modeling results. When used in combination with active motion-tracking antenna arrays, these devices enable multichannel optogenetic research on complex behavioral responses in groups of animals over large areas at low levels of radio frequency power (<1 W). Studies of the regions of the brain that are involved in sleep arousal (locus coeruleus) and preference/aversion (nucleus accumbens) demonstrate the unique capabilities of these technologies