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

Low-Power Implantable Device for Onset Detection and Subsequent Treatment of Epileptic Seizures: A Review

Over the past few years, there has been growing interest in neuro-responsive intracerebral local treatments of seizures, such as focal drug delivery, focal cooling, or electrical stimulation. This mode of treatment requires an effective intracerebral electroencephalographic acquisition system, seizure detector, brain stimulator, and wireless system that consume ultra-low power. This review focuses on alternative brain stimulation treatments for medically intractable epilepsy patients. We mainly discuss clinical studies of long-term responsive stimulation and suggest safer optimized therapeutic options for epilepsy. Finally, we conclude our study with the proposed low-power, implantable fully integrated device that automatically detects low-voltage fast activity ictal onsets and triggers focal treatment to disrupt seizure progression. The detection performance was verified using intracerebral electroencephalographic recordings from two patients with epilepsy. Further experimental validation of this prototype is underway

Implantable Asynchronous Epilectic Seizure Detector

RÉSUMÉ Plusieurs algorithmes de détection à faible consommation ont été proposés pour le traitement de l'épilepsie focale. La gestion de l'énergie dans ces microsystèmes est une question importante qui dépend principalement de la charge et de la décharge des capacités parasites des transistors et des courants de court-circuit pendant les commutations. Dans ce mémoire, un détecteur asynchrone de crise pour le traitement de l'épilepsie focale est présenté. Ce système fait partie d'un dispositif implantable intégré pour stopper la propagation de la crise. L'objectif de ce travail est de réduire la dissipation de puissance en évitant les transitions inutiles de signaux grâce à la technique du « clock tree » ; en conséquence, les transistors ne changent pas d'état transitoire dans ce mode d'économie d'énergie (période de surveillance des EEG intracrâniens), sauf si un événement anormal est détecté. Le dispositif intégré proposé comporte un bio-amplificateur en amont (front-end) à faible bruit, un processeur de signal numérique et un détecteur. Un délai variable et quatre détecteurs de fenêtres de tensions variables en parallèles sont utilisés pour extraire de l’information sur le déclenchement des crises. La sensibilité du détecteur est améliorée en optimisant les paramètres variables en fonction des activités de foyers épileptiques de chaque patient lors du début des crises. Le détecteur de crises asynchrone proposé a été implémenté premièrement en tant que prototype sur un circuit imprimé circulaire, ensuite nous l’avons intégré sur une seule puce dans la technologie standard CMOS 0.13μm. La puce fabriquée a été validée in vitro en utilisant un total de 34 enregistrements EEG intracrâniens avec la durée moyenne de chaque enregistrement de 1 min. Parmi ces jeux de données, 15 d’entre eux correspondaient à des enregistrements de crises, tandis que les 19 autres provenaient d’enregistrements variables de patients tels que de brèves crises électriques, des mouvements du corps et des variations durant le sommeil. Le système proposé a réalisé une performance de détection précise avec une sensibilité de 100% et 100% de spécificité pour ces 34 signaux icEEG enregistrés. Le délai de détection moyen était de 13,7 s après le début de la crise, bien avant l'apparition des manifestations cliniques, et une consommation d'énergie de 9 µW a été obtenue à partir d'essais expérimentaux.----------ABSTRACT Several power efficient detection algorithms have been proposed for treatment of focal epilepsy. Power management in these microsystems is an important issue which is mainly dependent on charging and discharging of the parasitic capacitances in transistors and short-circuit currents during switching. In this thesis, an asynchronous seizure detector for treatment of the focal epilepsy is presented. This system is part of an implantable integrated device to block the seizure progression. The objective of this work is reducing the power dissipation by avoiding the unnecessary signal transition and clock tree; as a result, transistors do not change their transient state in power saving mode (icEEG monitoring period) unless an abnormal event detected. The proposed integrated device contains a low noise front-end bioamplifier, a digital signal processor and a detector. A variable time frame and four concurrent variable voltage window detectors are used to extract seizure onset information. The sensitivity of the detector is enhanced by optimizing the variable parameters based on specific electrographic seizure onset activities of each patient. The proposed asynchronous seizure detector was first implemented as a prototype on a PCB and then integrated in standard 0.13 μm CMOS process. The fabricated chip was validated offline using a total of 34 intracranial EEG recordings with the average time duration of 1 min. 15 of these datasets corresponded to seizure activities while the remaining 19 signals were related to variable patient activities such as brief electrical seizures, body movement, and sleep patterns. The proposed system achieved an accurate detection performance with 100% sensitivity and 100 % specificity for these 34 recorded icEEG signals. The average detection delay was 13.7 s after seizure onset, well before the onset of the clinical manifestations. Finally, power consumption of the chip is 9 µW obtained from experimental tests

Cortical Dynamics Underlying Seizure Mapping and Control

In one-third of epilepsy patients, antiepileptic drugs do not effectively control seizures, leaving resective surgery as the primary treatment option. In the absence of discrete focal lesions, long-term outcome after surgery is modest and often associated with side effects. In many cases, surgery cannot be performed due to the lack of a discrete region generating seizures. For these reasons, new therapeutic technologies have been developed to treat drug-resistant epilepsy with electrical stimulation. These devices are promising, but the efficacy of first-generation implants has been limited. The work in this thesis aims to advance current approaches to seizure monitoring and control by developing better hardware and building the foundational knowledge behind the cortical dynamics underlying seizure generation, propagation and neural stimulation. In this thesis, I first develop new technologies that sample local field potentials on the cortical surface with high spatial and temporal resolutions. These devices capture complex spatiotemporal patterns of epileptiform activity that are not detected on current clinical electrodes. By adding stimulation functionalities to these arrays, we position them as an ideal candidate for responsive, therapeutic neurostimulation. Next, I explore the effect of direct electrical stimulation in the cortex by recording responses with high spatial resolution on the surface and within the cortical laminae. The findings detail the capabilities and limitations of electrical stimulation as a means of modulating seizures. Finally, I use the same three-dimensional recording paradigm in feline neocortex to investigate the genesis and propagation of epileptiform activity in an isolated, chemically-induced epilepsy model. These experiments demonstrate that important circuit elements involved in seizure propagation are found deeper in the cortex and are not reflected in surface recordings. My investigations also present potential stimulation strategies to more effectively disrupt the spread of seizures in the neocortex. It is my hope that the results of this work will inform future technologies to better detect and prevent seizures, ultimately improving the lives of drug-resistant epilepsy patients through the next generation of implantable devices

Algorithm-circuit co-design for detecting symptomatic patterns in biological signals

The advancement in scaled Silicon technology has accelerated the development of a wide range of applications in various fields including medical technology. It has immensely contributed to finding solutions for monitoring general health as well as alleviating intractable disorders in the form of implantable and wearable systems. This necessitates the development of energy efficient and functionally efficacious systems. This thesis has explored the algorithm-circuit co-design approach for developing an energy efficient epileptic seizure detection processor which could be used for implantable epilepsy prosthesis. Novel wavelet transform based algorithms are proposed for accurate detection of epileptic seizures. Energy efficient techniques at circuit level such as power and clock gating are utilized along with error resiliency at algorithm level to implement these algorithms in TSMC $65$nm bulk-Si technology. Furthermore, the methodology is extended to develop a generic pattern detection system, which could be used for health monitoring. The wavelet transform along with mathematical metrics and Mel cepstrum are used to develop an algorithm which can detect generic patterns in biological audio signals. The application of algorithm-circuit co-design methodology helps in practically implementing this system into a low power design. Using approximation of coefficients and multiplier-less implementation, the Mel cepstrum algorithm is modified to optimize the hardware cost without losing its functional efficacy. The system is user-specific and scalable for detecting various patterns in biological signals. The methodologies mentioned in this thesis are intended towards development of user-scalable, energy efficient and highly efficacious systems for detection of patterns in variety of biological signals

A Comparison of Machine Learning Classifiers for Energy-Efficient Implementation of Seizure Detection

The closed-loop application of electrical stimulation via chronically implanted electrodes is a novel approach to stop seizures in patients with focal-onset epilepsy. To this end, an energy efficient seizure detector that can be implemented in an implantable device is of crucial importance. In this study, we first evaluated the performance of two machine learning algorithms (Random Forest classifier and support vector machine (SVM)) by using selected time and frequency domain features with a limited need of computational resources. Performance of the algorithms was further compared to a detection strategy implemented in an existing closed loop neurostimulation device for the treatment of epilepsy. The results show a superior performance of the Random Forest classifier compared to the SVM classifier and the reference approach. Next, we implemented the feature extraction and classification process of the Random Forest classifier on a microcontroller to evaluate the energy efficiency of this seizure detector. In conclusion, the feature set in combination with Random Forest classifier is an energy efficient hardware implementation that shows an improvement of detection sensitivity and specificity compared to the presently available closed-loop intervention in epilepsy while preserving a low detection delay