Towards a Fully Implantable Closed-Loop Opto-Electro Stimulation Interface for Motor Neuron Disease Treatment

This paper presents a fully-implantable closed-loop opto-electro stimulation interface for motor neuron disease studies, designed for experiments with freely moving rodents. A low power consumption Bluetooth data link is used to wirelessly control 64 opto-electro stimulation channels and receive neural recording data. The implant is powered by a wirelessly rechargeable lithium-ion battery, which can support 2.5 hours continuous operation with a stimulation output up to 10 mA. The battery is recharged using a QI standard wireless inductive power link, which can deliver >100mW power at a distance of 2 cm. The total size of the implant system is 29 mm × 20 mm × 13 mm. Its performance is compared with the state-of-the-art

Système électro-optique pour l'optogénétique cardiaque et l'enregistrement d'ECG

Depuis quelques temps, l'optogénétique est utilisée en recherche pour remplacer la stimulation électrique de neurones par la photo-stimulation. Des scientifiques cherchent désormais à étendre l'optogénétique à la recherche sur le coeur. Plusieurs ont prouvés la possibilité de contrôler les battements cardiaques à l'aide de lumière en laboratoire sur des rongeurs. Les expérimentations effectuées sur le coeur jusqu'à maintenant reposent sur des systèmes filaires et encombrants qui permettent la mesure de l'électrocardiogramme (ECG) à l'aide d'électrode et la photo-stimulation à l'aide d'une fibre optique. Ces systèmes augmentent le stress chez les animaux de laboratoire ce qui peut induire des erreurs dans les mesures. Ce mémoire décrit la conception d'un système répondant à cette problématique. Le système développé permet la photo-stimulation cardiaque et l'enregistrement d'ECG sans-fil à l'aide d'un implant et d'un circuit basse consommation, le tout alimenté par batterie. Étant donné la présence d'artefact de mouvement dans les ECG mesurés lors de tests préliminaires, le système comporte aussi un algorithme de filtrage des artefacts en temps réel. Finalement, le fonctionnement du prototype est démontré par différents tests in-vivo.In the past few years, optogenetics was used in research to replace electrical stimulation of neurons by photo-stimulation. Scientists now search a way to extend optogenetics to cardiac research. Many were able to control the heartbeat of rodents using light. These experiments were conducted using wired and cumbersome equiments with electrocardiogram (ECG) recording using electrodes and photo-stimulation using optical fibers. These systems increase tests subjects stress which can induce measurements errors. This master's thesis describes the design of a device answering this problem. The developed system enables cardiac photostimulation and ECG recording wirelessly with an implant and a low power electronic circuit. The device also includes a real-time algorithm to reduce motion artifacts shown in preliminary testing. Finally, the operation of the prototype is demonstrated during in-vivo experiments

A Fully Implantable Opto-Electro Closed-Loop Neural Interface for Motor Neuron Disease Studies

This paper presents a fully implantable closed-loop device for use in freely moving rodents to investigate new treatments for motor neuron disease. The 0.18 µm CMOS integrated circuit comprises 4 stimulators, each featuring 16 channels for optical and electrical stimulation using arbitrary current waveforms at frequencies from 1.5 Hz to 50 kHz, and a bandwidth programmable front-end for neural recording. The implant uses a Qi wireless inductive link which can deliver >100 mW power at a maximum distance of 2 cm for a freely moving rodent. A backup rechargeable battery can support 10 mA continuous stimulation currents for 2.5 hours in the absence of an inductive power link. The implant is controlled by a graphic user interface with broad programmable parameters via a Bluetooth low energy bidirectional data telemetry link. The encapsulated implant is 40 mm × 20 mm × 10 mm. Measured results are presented showing the electrical performance of the electronics and the packaging method

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

Sympathetic innervation controls cardiac trophism and physiology

In this thesis I investigated the characteristics of SN-CM interaction, to elucidate if the control of CM activity by SNs occur through a direct cell to cell interaction. I studied SN-CM interaction at the level of the working myocardium, to assess if SN innervation is able to modulate locally CM structural properties. Moreover, using an in vitro model of SNs and CMs coculture I tested the hypothesis of the direct interaction between SN and CM and, evaluated the functional effects of this interaction, in vivo, at the level of the sinoatrial node, exploting the advantages of a novel optogenetic approach. To reach this aim, I implemented cardiac optogenetics on CM, Purkinje fibers and SNs. Finally, I inquired possible translational applications of cardiac optogenetics for clinically relevant situations. The understanding of the mechanism of SN-CM interaction is of great clinical relevance since cardiac innervation impairment has been associated to a growing amount of pathological situations, such as myocardial infarction, diabetes and different types of cardiomyopathies

Development and application of novel processing tools and methods for cardiac optical mapping

Cardiac optical mapping provides unparalleled spatio-temporal resolution information of cardiac electrophysiology. It has hence emerged as an important technology in understanding cardiac electrical behaviour in physiological and pathophysiological states. There is a requirement for effective data analysis tools that are high-throughput, robustly characterised and flexible with regards to a growing array of experimental models. In this thesis a MATLAB based software, ElectroMap, was developed for analysis of diverse optical mapping datasets. ElectroMap incorporates existing and novel methods to allow quantification and mapping of action potential and calcium transient morphology and activation/repolarisation times. Automated pacing cycle length detection and segmentation were implemented, realising high-throughput analysis of beat-to-beat responses and transient behaviour. Standalone modules dedicated to calculation of conduction velocity and alternans were introduced, allowing thorough integration of key factors in arrhythmogenesis. Semi-automated analysis of temporal variations in wave morphology were developed from previous methodologies for electrogram analysis. Algorithms to use fractional rate of change of fluorescence as a measure of conduction were also introduced to the software. Algorithms were tested in silico datasets, mouse and guinea pig optical mapping datasets and preliminary experiments also showed use for in vivo human electrogram mapping of atrial fibrillation

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