Recent Advances in Neural Recording Microsystems

The accelerating pace of research in neuroscience has created a considerable demand for neural interfacing microsystems capable of monitoring the activity of large groups of neurons. These emerging tools have revealed a tremendous potential for the advancement of knowledge in brain research and for the development of useful clinical applications. They can extract the relevant control signals directly from the brain enabling individuals with severe disabilities to communicate their intentions to other devices, like computers or various prostheses. Such microsystems are self-contained devices composed of a neural probe attached with an integrated circuit for extracting neural signals from multiple channels, and transferring the data outside the body. The greatest challenge facing development of such emerging devices into viable clinical systems involves addressing their small form factor and low-power consumption constraints, while providing superior resolution. In this paper, we survey the recent progress in the design and the implementation of multi-channel neural recording Microsystems, with particular emphasis on the design of recording and telemetry electronics. An overview of the numerous neural signal modalities is given and the existing microsystem topologies are covered. We present energy-efficient sensory circuits to retrieve weak signals from neural probes and we compare them. We cover data management and smart power scheduling approaches, and we review advances in low-power telemetry. Finally, we conclude by summarizing the remaining challenges and by highlighting the emerging trends in the field

Dopamiinin hapettumisen lukija-anturirajapinta 65 nm CMOS teknologialla

Sensing and monitoring of neural activities within the central nervous system has become a fast-growing area of research due to the need to understand more about how neurons communicate. Several neurological disorders such as Parkinson’s disease, Schizophrenia, Alzeihmers and Epilepsy have been reported to be associated with imbalance in the concentration of neurotransmitters such as glutamate and dopamine [1] - [5]. Hence, this thesis proposes a solution for the measurement of dopamine concentration in the brain during neural communication. The proposed design of the dopamine oxidation readout sensor interface is based on a mixed-signal front-end architecture for minimizing noise and high resolution of detected current signals. The analog front-end is designed for acquisition and amplification of current signals resulting from oxidation and reduction at the biosensor electrodes in the brain. The digital signal processing (DSP) block is used for discretization of detected dopamine oxidation and reduction current signals that can be further processed by an external system. The results from the simulation of the proposed design show that the readout circuit has a current resolution of 100 pA and can detect minimum dopamine concentration of 10 μMol based on measured data from novel diamond-like carbon electrodes [6]. Higher dopamine concentration can be detected from the sensor interface due to its support for a wide current range of 1.2 μA(±600 nA). The digital code representation of the detected dopamine has a resolution of 14.3-bits with RMS conversion error of 0.18 LSB which results in an SNR of 88 dB at full current range input. However, the attained ENOB is 8-bits due to the effect of nonlinearity in the oscillator based ADC. Nonetheless, the achieved resolution of the readout circuit provides good sensitivity of released dopamine in the brain which is useful for further understanding of neurotransmitters and fostering research into improved treatments of related neurodegenerative diseases.Keskushermoston aktiivisuuden havainnointi ja tarkkailu on muodostunut tärkeäksi tutkimusalaksi, sillä tarve ymmärtää neuronien viestintää on kasvanut. Monien hermostollisten sairauksien kuten Parkinsonin taudin, skitsofrenian, Alzheimerin taudin ja epilepsian on huomattu aiheuttavan muutoksia välittäjäaineiden, kuten glutamaatin ja dopamiinin, pitoisuuksissa [1] - [5]. Aiheeseen liittyen tässä työssä esitetään ratkaisu dopamiinipitoisuuden mittaamiseksi aivoista. Esitetty dopamiinipitoisuuden lukijapiiri perustuu sekamuotoiseen etupäärakenteeseen, jolla saavutetaan matala kohinataso ja hyvä tarkkuus signaalien ilmaisemisessa. Suunniteltu analoginen etupää kykenee lukemaan ja vahvistamaan dopamiinipitoisuuden muutosten aiheuttamia virran muutoksia aivoihin asennetuista elektrodeista. Digitaalisen signaalinkäsittelyn avulla voidaan havaita dopamiinin hapettumis-ja pelkistymisvirtasignaalit, ja välittää ne edelleen ulkoisen järjestelmän muokattavaksi. Simulaatiotulokset osoittavat, että suunniteltu piiri saavuttaa 100 pA virran erottelukyvyn. Simuloinnin perustuessa hiilipohjaisiin dopamiinielektrodeihin piiri voi havaita 10 μMol dopamiinipitoisuuden [6]. Myös suurempia dopamiinipitoisuuksia voidaan havaita, sillä etupäärajapinta tukee 1.2 μA(±600 nA) virta-aluetta. Digitaalinen esitysmuoto tukee 14.3 bitin esitystarkkuutta 0.18 bitin RMS virheellä saavuttaen 88 dB dynaamisen virta-alueen. Saavutettu ENOB (tehollinen bittimäärä) on kuitenkin 8 bittiä oskillaattoripohjaisen ADC:n (analogia-digitaalimuuntimen) epälineaarisuuden takia. Saavutettu tarkkuus tuottaa hyvän herkkyyden dopamiinin havaitsemiseksi ja hyödyttää siten välittäjäainetutkimusta ja uusien hoitomuotojen kehittämistä hermostollisiin sairauksiin

Microelectronics-Based Biosensors Dedicated to the Detection of Neurotransmitters: A Review

Dysregulation of neurotransmitters (NTs) in the human body are related to diseases such as Parkinson's and Alzheimer's. The mechanisms of several neurological disorders, such as epilepsy, have been linked to NTs. Because the number of diagnosed cases is increasing, the diagnosis and treatment of such diseases are important. To detect biomolecules including NTs, microtechnology, micro and nanoelectronics have become popular in the form of the miniaturization of medical and clinical devices. They offer high-performance features in terms of sensitivity, as well as low-background noise. In this paper, we review various devices and circuit techniques used for monitoring NTs in vitro and in vivo and compare various methods described in recent publications

The potential of microelectrode arrays and microelectronics for biomedical research and diagnostics

Planar microelectrode arrays (MEAs) are devices that can be used in biomedical and basic in vitro research to provide extracellular electrophysiological information about biological systems at high spatial and temporal resolution. Complementary metal oxide semiconductor (CMOS) is a technology with which MEAs can be produced on a microscale featuring high spatial resolution and excellent signal-to-noise characteristics. CMOS MEAs are specialized for the analysis of complete electrogenic cellular networks at the cellular or subcellular level in dissociated cultures, organotypic cultures, and acute tissue slices; they can also function as biosensors to detect biochemical events. Models of disease or the response of cellular networks to pharmacological compounds can be studied in vitro, allowing one to investigate pathologies, such as cardiac arrhythmias, memory impairment due to Alzheimer's disease, or vision impairment caused by ganglion cell degeneration in the retin

Conception et fabrication d'un biocapteur à haute sensibilité pour la détection des neurotransmetteurs

Dans ce mémoire, nous présentons de nouvelles architectures de différents biocapteurs électrochimiques discrets et intégrés appelés potentiostats. Tous les potentiostats développés sont basés sur une structure entièrement différentielle pour une meilleure sensibilité et une meilleure précision. Deux conceptions discrètes à un et quatre canaux ont été proposées. La conception discrète à un canal détecte la molécule de dopamine avec un courant de l’ordre du nA et une consommation électrique de 120 mW. Cette architecture a été développée sur une carte de circuit imprimé (PCB) de 20 mm x 35 mm. L’architecture discrète à quatre canaux est la version améliorée de la précédente en termes de superficie, de sensibilité et de consommation électrique. Une autre version du potentiostat, implémentée sur un PCB de 15 mm x 15 mm, peut mesurer les courants d’oxydoréduction dans la plage du pA avec une consommation de puissance de 60 mW. L’avantage de la structure à multicanaux est qu’elle offre des sensibilités différentes allant du pA au mA pour chaque canal. Une chambre microfluidique de 7,5 mm x 5 mm avec deux entrées et une sortie a été déposée sur le PCB. Une solution saline tampon au phosphate (PBS) avec une solution de ferrocyanure a été utilisée pour tester la fonctionnalité du système réalisé. La voltampérométrie cyclique a été utilisée comme technique de détection. Un comportement linéaire a été observé lorsque la concentration des neurotransmetteurs change. De plus, un potentiostat intégré a été proposé et fabriqué en technologie CMOS 180 nm, basé sur une structure entièrement « différentiel de différence » (Fully Differential Diffrence Amplifier FDDA) pour une faible consommation de puissance et un système à haute sensibilité. Cette nouvelle configuration a été conçue pour la détection des neurotransmetteurs en très faible concentration avec un faible bruit et une plage dynamique élevée. Cette architecture intégrée peut détecter les courants dans une plage inférieure au pA avec un bruit d’entrée faible de 6,9 μVrms tout en consommant seulement 53,9 μW. Le potentiostat proposé est dédié aux dispositifs implantables à faible consommation de puissance et à sensibilité et linéarité élevées.In this thesis, we present different discrete and integrated electrochemical biosensors. All these designed potentiostats are based on fully-differential architecture to enhance sensitivity and accuracy. Two complete single channel and four-channel discrete designs were fabricated. The single channel discrete design imaged the dopamine neurotransmitter with the sensed current of approximately low nano-ampere and power consumption of 120 mW implemented on a 20 x 35 mm PCB. The four-channel discrete design was the improved version of previous one in terms of area, sensitivity and power consumption. The 15 x 15 mm PCB was able to measure the reduction-oxydation currents in the range of high pico-ampere while consuming 60 mW. The advantage of the multichannel architecture is to provide a system with different sensitivity going from pA to mA for each channel. A microfluidic 7.5 x 5 mm chamber with two inlets and one outlet was bonded to the PCB. A phosphate buffered saline (PBS) with ferrocyanide solution was used to test the functionality of the implemented system. Cyclic voltammetry has been used as a detection technique. A linear behavior had been observed when the neurotransmitter concentration changed. An integrated CMOS potentiostat was designed and fabricated in 180 nm technology based on a fully-differential-difference architecture for a low power consumption and also high sensitivity system. This new architecture was designed in order to sense ultra-low concentration of neurotransmitters with low noise and high dynamic range. This integrated design was able to image currents in the range of sub-pA with low input-referred noise of 6.9 µVrms while consuming only 53.9 µW. The proposed potentiostat is dedicated for implantable devices with low power consumption and high sensitivity and linearity

Development of a Smart Wireless Multisensor Platform for an Optogenetic Brain Implant

Implantable cell replacement therapies promise to completely restore the function of neural structures, possibly changing how we currently perceive the onset of neurodegenerative diseases. One of the major clinical hurdles for the routine implementation of stem cell therapies is poor cell retention and survival, demanding the need to better understand these mechanisms while providing precise and scalable approaches to monitor these cell-based therapies in both pre-clinical and clinical scenarios. This poses significant multidisciplinary challenges regarding planning, defining the methodology and requirements, prototyping and different stages of testing. Aiming toward an optogenetic neural stem cell implant controlled by a smart wireless electronic frontend, we show how an iterative development methodology coupled with a modular design philosophy can mitigate some of these challenges. In this study, we present a miniaturized, wireless-controlled, modular multisensor platform with fully interfaced electronics featuring three different modules: an impedance analyzer, a potentiostat and an optical stimulator. We show the application of the platform for electrical impedance spectroscopy-based cell monitoring, optical stimulation to induce dopamine release from optogenetically modified neurons and a potentiostat for cyclic voltammetry and amperometric detection of dopamine release. The multisensor platform is designed to be used as an opto-electric headstage for future in vivo animal experiments

Optimized Sampling Rate for Voltammetry-Based Electrochemical Sensing in Wearable and IoT Applications

The recent advancements in electrochemical measurements are guiding the development of new platforms for in-situ point-of-care monitoring of human-metabolite, markers and drugs. Despite this, the application of Voltammetry-Based Sensing (VBS) techniques is still limited in wearable, portable, or IoT systems. In order to use VBS approaches to measure analytes in small and low-power electronic platforms for diagnostics, several improvements are required. For example, the definition of a method to achieve the right trade-off between sample rate and sensing performance is still missing. To develop a method to define the best sampling rate, we present here an extensive analysis of experimental data to prove that is feasible to detect drugs such as paracetamol by Staircase Cyclic Voltammetry (SCV) or Differential Pulse Voltammetry (DVP) direct detection methods, with low sampling frequency. Our results prove that the proposed method helps the development of systems capable of discriminating the minimum pharmacology concentration of the metabolite under analysis with a massive reduction of the sampling frequency

Novel membrane-based electrochemical sensor for real-time bio-applications.

This article presents a novel membrane-based sensor for real-time electrochemical investigations of cellular- or tissue cultures. The membrane sensor enables recording of electrical signals from a cell culture without any signal dilution, thus avoiding loss of sensitivity. Moreover, the porosity of the membrane provides optimal culturing conditions similar to existing culturing techniques allowing more efficient nutrient uptake and molecule release. The patterned sensor electrodes were fabricated on a porous membrane by electron-beam evaporation. The electrochemical performance of the membrane electrodes was characterized by cyclic voltammetry and chronoamperometry, and the detection of synthetic dopamine was demonstrated down to a concentration of 3.1 pM. Furthermore, to present the membrane-sensor functionality the dopamine release from cultured PC12 cells was successfully measured. The PC12 cells culturing experiments showed that the membrane-sensor was suitable as a cell culturing substrate for bio-applications. Real-time measurements of dopamine exocytosis in cell cultures were performed, where the transmitter release was recorded at the point of release. The developed membrane-sensor provides a new functionality to the standard culturing methods, enabling sensitive continuous in vitro monitoring and closely mimicking the in vivo conditions

Biocapteur ampérométrique intégré pour une unité de détection dédiée aux neurotransmetteurs

RÉSUMÉ La signalisation chimique intercellulaire façonnée par l’interaction des neurotransmetteurs joue un rôle capital dans le fonctionnement des processus cérébraux. L’analyse de l’activité neuronale chimique en temps réel dans toute sa complexité aiderait les neuroscientifiques à comprendre les mécanismes du cerveau humain et de ses pathologies neurodégénératives. Les systèmes actuellement employés dans les laboratoires de neuroscience sont limités dans leur capacité à fournir des mesures précises et adaptées aux évènements hétérogènes associées à l’activité de plusieurs neurotransmetteurs. Pour ce faire, le laboratoire de neurotechnologies Polystim envisage la conception d’un laboratoire sur puce (LSP) implantable, dédié au monitorage des substances neurochimiques circulant dans l’espace intercellulaire cérébral. Ce mémoire propose une unité de détection électrochimique associée à un tel système et conçue pour la quantification des neurotransmetteurs du liquide intercérébral. Nous proposons une architecture composée de biocapteurs utilisant un potentiostat intégré avec la technologie CMOS comme transducteur et des électrodes de mesure fonctionnalisées avec des nanotubes de carbone pour une détection sensible et sélective. Le potentiostat intégré proposé génère des mesures de temps facilement traitables numériquement qui sont proportionnelles aux courants d’oxydo-réduction produits à l’interface des électrodes de mesure. Sa configuration quantifie séparément les courants d’oxydation et de réduction à l’aide de deux canaux de mesures, selon une technique d’ampérometrie à tension constante. L’architecture est composée d’un amplificateur, d’un comparateur haute vitesse et d’un convertisseur numérique à analogique (Digital to Analog Converter - DAC). Ce dernier est partagé entre les deux canaux de sorte à réduire le temps de mesure total en fonction de l’amplitude des courants détectés. Cette topologie procure un compromis entre la plage dynamique d’entrée, la fréquence d’échantillonnage et la résolution de mesures, trois paramètres importants pour accommoder la détection et la quantification d’une grande variété de neurotransmetteurs en temps-réel. Afin de valider le prototype du potentiostat implémenté, une plateforme multi-électrodes de mesure est fabriquée et fonctionnalisée avec des films composites à base de nanotubes de carbone (Carbon Nanotubes - CNT), pour une détection sélective à la dopamine et au glutamate, deux neurotransmetteurs communs. Le circuit intégré du potentiostat est implémenté avec la technologie 0,13 µm CMOS d’IBM. Un circuit imprimé (Printed Circuit Board - PCB) comprenant un FPGA pour la gestion des signaux de contrôle et l’acquisition des données a été fabriqué pour la caractérisation expérimentale du circuit. Malgré une non-linéarité du DAC intégré fabriqué, des courants d’oxydation et de réduction d’une plage de 600 nA à 20 pA à une fréquence d’échantillonnage minimale de 1,25 kHz ont pu être mesurés expérimentalement en utilisant un DAC commercial externe. Également, le biocapteur formé du potentiostat fabriqué et de la plateforme d’électrodes fonctionnalisées est validé par des mesures biologiques en milieu in vitro concluantes pour différentes concentrations de dopamine et de glutamate en solution, en termes de sensibilité et de sélectivité des mesures ampérométriques obtenues. Ces résultats fondent la preuve de concept du biocapteur proposé comme composant de base de l’unité de détection.----------ABSTRACT Intercellular chemical signaling shaped by the interaction of neurotransmitters plays a crucial role in the functioning of brain processes. The analysis of chemical neural activity in real time in all its complexity would help neuroscientists understand the mechanisms of the human brain and its neurodegenerative diseases. Systems currently used in neuroscience laboratories are limited in their ability to provide accurate and appropriate measurements to the heterogeneous events associated with the activity of several neurotransmitters. Polystim Neurotechnologies Laboratory is therefore designing an implantable Lab on Chip (LOC) dedicated to the monitoring of neurochemicals circulating in the brain's intercellular space that provides the needed features. This thesis presents an electrochemical detection unit associated with such system, designed for the quantification of neurotransmitters in the intracerebral liquid. We propose an architecture composed of biosensors using a potentiostat integrated with CMOS technology as transducer, and measuring electrodes with functionalized carbon nanotubes for sensitive and selective measurements. The proposed integrated potentiostat generates time measurements easily treatable digitally, which are proportional to redox currents produced at the interface of the measuring electrodes. Its configuration separately quantizes oxidation and reduction currents by using two measuring channels, according to a constant voltage amperometry technique. The architecture consists of an amplifier, a high-speed comparator and a digital-to-analog converter (DAC). The latter is shared between the two channels in order to reduce the total measurement time as a function of the detected currents amplitude. This topology provides a compromise between the input dynamic range, sampling frequency and resolution measurements, three important parameters to accommodate the detection and quantification of a wide variety of neurotransmitters in real time. To validate the prototype of the implemented potentiostat, a multi-electrode measuring platform is fabricated and functionalized with composite films based on carbon nanotubes (CNTs), for dopamine and glutamate, two common neurotransmitters, selective detection. The potentiostat integrated circuit is implemented with IBM 0.13 µm CMOS technology. A printed circuit board (PCB) containing an FPGA managing control signals and data acquisition, was made to experimentally characterize the fabricated circuit. Despite the non-linearity of the manufactured integrated DAC, oxidation and reduction currents ranging from 600 nA to 20 pA at a minimum sampling frequency of 1.25 kHz could be measured experimentally using an external commercial DAC. Also, the biosensor formed by the potentiostat and the functionalized electrodes platform is validated by conclusive in vitro biological measurements of dopamine and glutamate in solutions, in terms of sensitivity and selectivity. These results forms the proof of concept of the proposed biosensor as the base component of the detection unit

Crexens™: an expandable general-purpose electrochemical analyzer

2019 Fall.Includes bibliographical references.Electrochemical analysis has gained a great deal of attention of late due to its low-cost, easy-to-perform, and easy-to-miniaturize, especially in personal health care where accuracy and mobility are key factors to bring diagnostics to patients. According to data from Centers for Medicare & Medicaid Services (CMS) in the US, the share of health expenditure in the US has been kept growing in the past 3 decades and reached 17.9% of its overall Gross Domestic Product till 2016, which is equivalent to $10,348 for every person in the US per year. On the other hand, health care resources are often limited not only in rural area but also appeared in well-developed countries. The urgent need and the lack of health resource brings to front the research interest of Point-of-Care (PoC) diagnosis devices. Electrochemical methods have been largely adopted by chemist and biologist for their research purposes. However, several issues exist within current commercial benchtop instruments for electrochemical measurement. First of all, the current commercial instruments are usually bulky and do not have handheld feature for point-of-care applications and the cost are easily near$5,000 each or above. Secondly, most of the instruments do not have good integration level that can perform different types of electrochemical measurements for different applications. The last but not the least, the existing generic benchtops instruments for electrochemical measurements have complex operational procedures that require users to have a sufficient biochemistry and electrochemistry background to operate them correctly. The proposed Crexens™ analyzer platform is aimed to present an affordable electrochemical analyzerwhile achieving comparable performance to the existing commercial instruments, thus, making general electrochemical measurement applications accessible to general public. In this dissertation, the overall Crexens™ electrochemical analyzer architecture and its evolution are presented. The foundation of the Crexens™ architecture was derived from two separate but related research in electrochemical sensing. One of them is a microelectrode sensor array using CMOS for neurotransmitter sensing; the other one is a DNA affinity-based capacitive sensor for infectious disease, such as ZIKA. The CMOS microelectrode sensor array achieved a 320uM sensitivity for norepinephrine, whereas the capacitive sensor achieved a dynamic range of detection from 1 /uL to 105 /uL target molecules (20 to 2 million targets), which makes it be within the detection range in a typical clinical application environment. This dissertation also covers the design details of the CMOS microelectrode array sensor and the capacitive sensor design as a prelude to the development of the Crexens™ analyzer architecture. Finally, an expandable integrated electrochemical analyzer architecture (Crexens™) has been designed for mobile point-of-care (POC) applications. Electrochemical methods have been explored in detecting various bio-molecules such as glucose, lactate, protein, DNA, neurotransmitter, steroid hormone, which resulted in good sensitivity and selectivity. The proposed system is capable of running electrochemical experiments including cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), electrochemical capacitive spectroscopy (ECS), amperometry, potentiometry, and other derived electrochemical based tests. This system consist of a front-end interface to sensor electrodes, a back-end user interface on smart phone and PC, a base unit as master module, a low-noise add-on module, a high-speed add-on module, and a multi-channel add-on module. The architecture allows LEGO™-like capability to stack add-on modules on to the base-unit for performance enhancements in noise, speed or parallelism. The analyzer is capable of performing up to 1900 V/s CV with 10 mV step, up to 12 kHz EIS scan range and a limit of detection at 637 pA for amperometric applications with the base module. With high performance module, the EIS scan range can be extended upto 5 MHz. The limit of detection can be further improved to be at 333 fA using the low-noise module. The form factor of the electrochemical analyzer is designed for its mobile/point-of-care applications, integrating its entire functionality on to a 70 cm² area of surface space. A glutamine enzymatic sensor was used to valid the capability of the proposed electrochemical analyzer and turned out to give good linearity and reached a limit of detection at 50 uM