Distortion-free sensing of neural activity using graphene transistors

Graphene solution-gated field-effect transistors (g-SGFETs) are promising sensing devices to transduce electrochemical potential signals in an electrolyte bath. However, distortion mechanisms in g-SGFET, which can affect signals of large amplitude or high frequency, have not been evaluated. Here, a detailed characterization and modeling of the harmonic distortion and non-ideal frequency response in g-SGFETs is presented. This accurate description of the input-output relation of the g-SGFETs allows to define the voltage- and frequency-dependent transfer functions, which can be used to correct distortions in the transduced signals. The effect of signal distortion and its subsequent calibration are shown for different types of electrophysiological signals, spanning from large amplitude and low frequency cortical spreading depression events to low amplitude and high frequency action potentials. The thorough description of the distortion mechanisms presented in this article demonstrates that g-SGFETs can be used as distortion-free signal transducers not only for neural sensing, but also for a broader range of applications in which g-SGFET sensors are used

Improved metal-graphene contacts for low-noise, high-density microtransistor arrays for neural sensing

Poor metal contact interfaces are one of the main limitations preventing unhampered access to the full potential of two-dimensional materials in electronics. Here we present graphene solution-gated field-effect-transistors (gSGFETs) with strongly improved linearity, homogeneity and sensitivity for small sensor sizes, resulting from ultraviolet ozone (UVO) contact treatment. The contribution of channel and contact region to the total device conductivity and flicker noise is explored experimentally and explained with a theoretical model. Finally, in-vitro recordings of flexible microelectrocorticography (μ-ECoG) probes were performed to validate the superior sensitivity of the UVO-treated gSGFET to brain-like activity. These results connote an important step towards the fabrication of high-density gSGFET μ-ECoG arrays with state-of-the-art sensitivity and homogeneity, thus demonstrating the potential of this technology as a versatile platform for the new generation of neural interfaces

Flexible Graphene Solution-Gated Field-Effect Transistors : Efficient Transducers for Micro-Electrocorticography

Brain-computer interfaces and neural prostheses based on the detection of electrocorticography (ECoG) signals are rapidly growing fields of research. Several technologies are currently competing to be the first to reach the market; however, none of them fulfill yet all the requirements of the ideal interface with neurons. Thanks to its biocompatibility, low dimensionality, mechanical flexibility, and electronic properties, graphene is one of the most promising material candidates for neural interfacing. After discussing the operation of graphene solution-gated field-effect transistors (SGFET) and characterizing their performance in saline solution, it is reported here that this technology is suitable for μ-ECoG recordings through studies of spontaneous slow-wave activity, sensory-evoked responses on the visual and auditory cortices, and synchronous activity in a rat model of epilepsy. An in-depth comparison of the signal-to-noise ratio of graphene SGFETs with that of platinum black electrodes confirms that graphene SGFET technology is approaching the performance of state-of-the art neural technologies

Flexible Graphene Solution-Gated Field-Effect Transistors : Efficient Transducers for Micro-Electrocorticography

Brain-computer interfaces and neural prostheses based on the detection of electrocorticography (ECoG) signals are rapidly growing fields of research. Several technologies are currently competing to be the first to reach the market; however, none of them fulfill yet all the requirements of the ideal interface with neurons. Thanks to its biocompatibility, low dimensionality, mechanical flexibility, and electronic properties, graphene is one of the most promising material candidates for neural interfacing. After discussing the operation of graphene solution-gated field-effect transistors (SGFET) and characterizing their performance in saline solution, it is reported here that this technology is suitable for μ-ECoG recordings through studies of spontaneous slow-wave activity, sensory-evoked responses on the visual and auditory cortices, and synchronous activity in a rat model of epilepsy. An in-depth comparison of the signal-to-noise ratio of graphene SGFETs with that of platinum black electrodes confirms that graphene SGFET technology is approaching the performance of state-of-the art neural technologies

Graphene microtransistors : a wide-bandwidth technology for recording brain field potentials

Premi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2020-2021En aquesta tesi doctoral es desenvolupen interfícies neuronals basades en transistors de grafè d'efecte de camp modulats per electròlit (gSGFETs), s'avalua la seva viabilitat per al registre in vivo de potencials de camp cerebral i es compara amb tecnologies de registre d'última generació. S'han dissenyat sondes neuronals de superfície flexible que contenen matrius de gSGFETs i s'han desenvolupat procediments de microfabricació que permeten una producció a escala d'oblia reproduïble i amb un alt rendiment. Una àmplia caracterització elèctrica ha demostrat que les matrius de gSGFET fabricades tenen un guany constant en un ampli ample de banda (de CC a diversos kHz), una alta homogeneïtat i un soroll intrínsec comparables a les tecnologies estàndard. Atès que el registre de senyals cerebrals amb una configuració de transistor no és una tècnica habitual, s'ha desenvolupat i validat una metodologia d'adquisició i postprocessament complet que permet registrar senyals de voltatge amb alta fidelitat. A més, s'han estudiat les capacitats de registre dels gSGFET in vivo en rosegadors. S'han obtingut enregistraments aguts d'activitat espontània i evocada en rates anestesiades mitjançant gSGFET epicorticals amb una qualitat similar als microelectrodes d'última generació i s'ha estimat la relació senyal-soroll dels registres fets amb gSGFET, confirmant les excel·lents capacitats de registre. A més, s'ha dut a terme un estudi crònic que mostra l'estabilitat de les matrius de gSGFET durant tota la durada de l'implant, fins a cinc mesos, suggerint un límit inferior a les capacitats de registre crònic dels gSGFET. Una limitació actual de les matrius de microelèctrodes és que per inestabilitats electroquímiques relacionades amb el material sensor dificulten el registre de l'activitat infralenta (ISA, <0.1Hz). L'ISA reflecteix processos neuronals importants que són rellevants tant per a la cognició com per a estats patològics. Per tant, vam explorar si la tecnologia gSGFET podria tenir avantatges sobre les tecnologies actuals per al registre d'ISA. Per estudiar les capacitats de registre ISA es va escollir la ona de depressió cortical (CSD), un fenomen neurofisiològic que s'associa amb un empitjorament dels pronòstic en múltiples patologies neurològiques incloses l'epilèpsia, la migranya i l'ictus. Els resultats obtinguts mostren que els gSGFET registren CSD amb una fidelitat més alta que els microelectrodes metàl·lics, i de manera similar a les micropipetes de vidre, tot superant les seves limitacions de mapatge. Les excelents capacitats de mapatge d'ISA dels gSGFETs van ser explotades per a la investigació en neurociència. En combinació amb la modulació optogenètica de l'activitat cerebral, es van utilitzar gSGFETs per caracteritzar els efectes electrofisiològics de la CSD en ratolins desperts. A més, es va desenvolupar una metodologia experimental que facilita les investigacions sobre les CSD. Més enllà de la CSD, també es descriu i es discuteixen les aplicacions de la tecnologia gSGFET per registrar altres potencials cerebrals patològics relacionats amb l'ISA, com ara canvis en el potencial extracelular basal degut a crisis epilèptiques. Per ampliar encara més les aplicacions dels gSGFETs i accelerar les investigacions sobre ISA, es demostra la compatibilitat dels gSGFETs amb tècniques d'imatge cerebral d'última generació mitjançant experiments multimodals que combinen gSGFETs amb imatge per ultrasons funcionals o imatges mesoscòpiques de fluorescència d'indicadors codificats genèticament. En resum, els resultats presentats indiquen la tecnologia gSGFET com una alternativa superior a les matrius de microelectrodes per al registre d'ISA. La tecnologia gSGFET desenvolupada és madura i està llesta per ser adoptada per laboratoris de recerca, amb un potencial especial per a la investigació translacional bàsica i preclínica. Un desenvolupament tecnològic addicional enfocat a la translació clínica dels dispositius podria aportar als pacients els avantatges d'un millor monitoratge de la fisiologia cerebral.En esta tesis doctoral, se desarrollan interfaces neuronales basadas en transistores de efecto de campo modulados por solución de grafeno (gSGFET) y se evalúa su viabilidad para el registro del potencial de campo cerebral in vivo. Se han diseñado sondas neuronales de superficie flexible que contienen matrices de gSGFET y se han desarrollado procedimientos de microfabricación que permiten una producción reproducible a escala de obleas con alto rendimiento. La caracterización eléctrica extensa ha demostrado que las matrices de gSGFET fabricados tienen una ganancia constante en un ancho de banda amplio (de CC a varios kHz), alta homogeneidad y ruido intrínseco comparable a las tecnologías estándar. Tambien se ha desarrollado y validado una metodología de adquisición y posprocesamiento completa que permite registrar señales de voltaje con alta fidelidad. Además, se han estudiado las capacidades de grabación de gSGFET in vivo en roedores. Se obtuvieron registros agudos de actividad espontánea y evocada en ratas anestesiadas utilizando gSGFET epicorticales con un rendimiento similar al de los microelectrodos de última generación. Se determinó la relación señal-ruido de las grabaciones de gSGFET de actividad espontánea y epileptiforme en ratones despiertos, lo que confirma las excelentes capacidades de grabación. Además, se realizó un estudio piloto crónico que muestra la estabilidad de las matrices de gSGFET durante toda la duración del implante, hasta cinco meses, lo que sugiere un límite inferior de las capacidades de registro crónico de gSGFET. Una limitación actual de las matrices de microelectrodos es que por inestabilidades electroquímicas relacionadas con el material dificultan el registro de la actividad infralenta (ISA, <0,1 Hz). ISA refleja importantes procesos neuronales que son relevantes tanto para la cognición normal como para los estados patológicos. Por lo tanto, exploramos si la tecnología gSGFET podría tener ventajas sobre las tecnologías actuales para el registro ISA. Para estudiar las capacidades de registro de ISA, se eligió la depresión de propagación cortical (CSD), un fenómeno neurofisiológico que se asocia con un empeoramiento en múltiples patologías neurológicas, incluidas la epilepsia, la migraña y el accidente cerebrovascular. Los resultados obtenidos demuestran que los gSGFET registran CSD, con mayor fidelidad que los microelectrodos metálicos, y de manera similar que las micropipetas de vidrio de un solo punto estándar de oro, al tiempo que superan sus limitaciones de muestreo espacial. Las excelentes capacidades de mapeo ISA de los gSGFET se aprovecharon para la investigación en neurociencia. En combinación con la modulación optogenética de la actividad cerebral, se utilizaron gSGFET para caracterizar los efectos electrofisiológicos de las CSD. Además, se desarrolló una metodología experimental que facilita la investigación de las CSD. También se informan y discuten las aplicaciones de la tecnología gSGFET para registrar otros potenciales cerebrales patológicos relacionados con ISA. La compatibilidad de los gSGFET con las técnicas de imágenes cerebrales de última generación se demuestra mediante experimentos multimodales que combinan los gSGFET con ultrasonidos funcionales o imágenes mesoscópicas de indicadores codificados genéticamente. En conlcusión, los resultados presentados en esta tesis doctoral demuestran que la tecnología gSGFET supera las limitaciones de las tecnologías actuales de microelectrodos pasivos para el mapeo con potenciales de campo cerebral de alta fidelidad y resolución espacial en una ancha banda de frecuencia. Por lo tanto, los resultados presentados establecen la tecnología gSGFET como una alternativa superior a las rejillas de microelectrodos para la grabación ISA. La tecnología gSGFET desarrollada es madura y está lista para ser adoptada por laboratorios de investigación, con un potencial especial para la investigación traslacional básica y preclínica. Un mayor desarrollo tecnológico hacia la translación clínica de los dispositivos podría aportar a los pacientes los beneficios de una mejor monitorización cerebral.High density recordings of neural activity within and across brain regions are vital in research focused to uncover the underlying processes of complex brain functions and pathophysiology; have applications in medical diagnosis, prognosis and treatment monitoring and are the base of assistive neuroprosthesis. However, current recording technologies are unable to meet all the requirements of a reliable, high fidelity neural interface. In this PhD dissertation, neural interfaces based on graphene solution-gated field-effect transistors (gSGFETs) are developed and their feasibility for in vivo brain field potential recording is evaluated and benchmarked against state-of-the-art technologies. Flexible surface neural probes containing arrays of gSGFETs have been designed and microfabrication procedures developed allowing reproducible wafer-scale production with high yield. Extensive electrical characterization has shown that the fabricated gSGFET arrays have a constant-gain over a wide bandwidth (from DC to several kHz), high homogeneity and intrinsic noise comparable to standard technologies. Since recording brain signals with a transistor configuration is not a common technique, a full acquisition and post-processing methodology has been developed and validated allowing to record voltage signals with high fidelity. Furthermore, in vivo gSGFET recording capabilities have been studied in rodents. Acute recordings of spontaneous and evoked activity in anesthesized rats were obtained using epicortical gSGFETs with similar performance than state-of-the-art microelectrodes. The signal-to-noise ratio of gSGFET recordings of spontaneous and epileptiform activity in awake mice was determined, confirming the excellent recording capabilities. In addition, a pilot chronic study was conducted showing stability of the gSGFET arrays for the whole implant duration, up to five months, suggesting a lower bound of gSGFET chronic recording capabilities. A current limitation of microelectrode grids is that due to material-related electrochemical unstabilities the recording of infraslow activity (ISA, < 0.1Hz) is hampered. There is now increasing appreciation that ISA reflects important neural processes that are relevant to both normal cognition and disease states. We therefore explored if gSGFET technology could have advantages over current technologies for ISA recording. Cortical spreading depression (CSD), a neurophysiological phenomenon that is associated with worsening outcomes in multiple neurological pathologies including epilepsy, migraine and stroke was chosen to study ISA recording capabilities. Results obtained demonstrate that gSGFETs record CSD, with higher fidelity than metal microelectrodes, and similarly than gold-standard single-point glass micropipettes while overcoming their spatial sampling limitations. The excellent ISA mapping capabilities of gSGFETs were exploited for neuroscience research. In combination with optogenetic modulation of brain activity, gSGFETs were used to characterize the electrophysiological effects of CSD in awake mice. Moreover, an experimental methodology that facilitates investigations into CSDs was developed. Beyond CSD, the applications of gSGFET technology to record other ISA-related pathological brain potentials such as epileptic ictal baseline shifts are also reported and discussed. To further extend the applications of gSGFETs and accelerate investigations into ISA, the compatibility of gSGFETs with state-of-the-art brain imaging techniques is demonstrated by multimodal experiments combining gSGFETs with functional ultrasound or mesoscopic imaging of genetically encoded indicators. Overall, the results presented in this PhD dissertation demonstrate that gSGFET technology overcomes the limitations of current passive microelectrode technologies for mapping with high fidelity and spatial resolution brain field potentials in a wide frequency bandwidth that includes both classical local field potentials as well as infraslow oscillations and baseline potential shifts. Therefore, the presented results state gSGFET technology as a superior alternative to microelectrode grids for ISA recording. The gSGFET technology developed is mature and ready to be adopted by research laboratories, holding special potential for basic and preclinical translational research. Further technology development towards clinical translation of the devices could bring to patients the benefits of improved brain monitoring

The advantages of mapping slow brain potentials using DC‐coupled graphene micro‐transistors: Clinical and translational applications

There is growing interest in examining oscillations and brain signals outside traditional EEG bands (0.3–80 Hz), as these regimes contain useful electrographic biomarkers for the diagnosis, monitoring...R.W. is funded by a Senior Research Fellowship awarded by the Worshipful Company of Pewterers. This work has received funding from the European Union's Horizon 2020 research and innovation programme under Grant Agreement No 881603 (GrapheneCore3).Peer reviewe

Novel transducers for high-channel-count neuroelectronic recording interfaces

Neuroelectronic interfaces with the nervous system are an essential technology in state-of-the-art neuroscience research aiming to uncover the fundamental working mechanisms of the brain. Progress towards increased spatio-temporal resolution has been tightly linked to the advance of microelectronics technology and novel materials. Translation of these technologies to neuroscience has resulted in multichannel neural probes and acquisition systems enabling the recording of brain signals using thousands of channels. This review provides an overview of state-of-the-art neuroelectronic technologies, with emphasis on recording site architectures which enable the implementation of addressable arrays for high-channel-count neural interfaces. In this field, active transduction mechanisms are gaining importance fueled by novel materials, as they facilitate the implementation of high density addressable arrays.This work has been funded by the European Union’s Horizon 2020 research and innovation program under Grant Agreement No. 732032(BrainCom) and Grant Agreement No. 881603 (Graphene Flagship) and co-funded by the European Regional Development Funds (ERDF) allocated to the Programa operatiu FEDER de Catalunya 2014–2020, with the support of the Secretaria d’Universitats i Recerca of the Departament d’Empresa i Coneixement of the Generalitat de Catalunya for emerging technology clusters devoted to the valorization and transfer of research results (GraphCAT 001-P-001702). The ICN2 is supported by the Severo Ochoa Centres of Excellence program, funded by the Spanish Research Agency (AEI, grant no. SEV-2017-0706), and by the CERCA Program/Generalitat de Catalunya

Sistema de transistores de grafeno para medir señales electrofisiológicas

Basado en matrices flexibles de transistores grafeno de efecto de campo epicorticales y intracorticales, que pueden registrar señales infralentas y señales en un ancho de banda típico de potenciales de campo local. El objeto de la invención se basa en el sistema del transistor del grafeno para medir señales electrofisiológicas, comprendiendo una unidad de proceso, y al menos un transistor del grafeno con el grafeno como material del canal contactado por dos terminales, a los cuales se une una fuente de tensión variable en los terminales de drenador y de fuente del transistor referido a la tensión de la puerta, y al menos un filtro de adquisición y división de la señal del transistor en al menos dos bandas de frecuencia, baja y alta, en el que las señales primera y segunda se amplifican respectivamente con un valor de ganancia. [ES]The invention is based on flexible matrices of graphene transistors with epicortical and intracortical field effects, which can register infraslow signals and signals in a bandwidth that is typical of local field potentials. The object of the invention is based on the graphene transistor system for measuring electrophysiological signals, comprising a processing unit and at least one graphene transistor with the graphene as the channel material contacted via two terminals, to which a variable voltage source is joined at the drain and source terminals of the transistor, with a reference as a gate terminal, and at least one filter for acquiring and dividing the signal of the transistor into at least two frequency bands, low and high, in which the first and second signals are amplified respectively with a gain value. [EN]Peer reviewedConsejo Superior de Investigaciones Científicas (España), Consorcio Centro de Investigación Biomédica en Red, Institució Catalana de Recerca I Estudis Avançats (ICREA), Fundació Institut Català de Nanociència i Nanotecnologia, Instituto de Investigaciones Biomédicas August Pi SunyierA1 Solicitud de patente con informe sobre el estado de la técnic

Sistema de transistores de grafeno para medir señales electrofisiológicas

Sistema de transistores de grafeno para medir señales electrofisiológicas. El objeto de la invención se basa en las matrices flexibles de transistores grafeno de efecto de campo (gSGFETs) epicorticales y intracorticales, que pueden registrar señales infralentas junto con señales en un ancho de banda típico de potenciales de campo local. El objeto de la invención se basa en el sistema del transistor del grafeno para medir las señales electrofisiológicas, comprendiendo una unidad de proceso, y por lo menos un transistor del grafeno (gSGFET) que comprende el grafeno como material del canal contactado por dos terminales, a los cuales se une una fuente de tensión variable en los terminales de drenador y de fuente del transistor (gSGFET) referido a la tensión de la puerta, y al menos un filtro configurado para adquirir y dividir la señal del transistor en al menos dos bandas de frecuencia, banda de baja frecuencia y banda de alta frecuencia, en el que las señales primera y segunda se amplifican respectivamente con un valor de ganancia.Peer reviewedConsejo Superior de Investigaciones Científicas (España), Consorcio Centro de investigación Biomédica en Red, Institució Catalana de Recerca i Estudis Avançats, Fundació Institut Català de Nanociència i Nanotecnología, Instituto de Investigaciones Biomédicas August Pi SunyerA1 Solicitud de patente con informe sobre el estado de la técnic

Dispositif d'acquisition pour limiter le courant de fuite dans des dispositifs d'enregistrement de signal électrophysiologique

The device limits the leakage current in an electronic system for recording electrophysiological signals, where the transducer element is an active device, the device comprising an active transducer (1), intended to contact a human tissue, connected to a transimpedance amplifier (2), and a first resistor (6) connected parallel to the transimpedance amplifier (2), an alternate voltage source (7) and a direct voltage source (8), both connected to the active transducer (1), a first capacitor (3) connected between the alternate voltage source (7) and the active transducer (1), a second resistor (4) connected between the direct voltage source (8) and the active transducer (1), parallel with the first capacitor (3) and the alternate voltage source (7), and a second capacitor (5), connected between the active transducer (1) and the transimpedance amplifier (2).NoConsejo Superior de Investigaciones Científicas (CSIC), Consorcio Centro de Investigación Biomédica En Red, M.P., ICREA, Institut Català de Nanociència i Nanotecnologia (ICN2)A1 Solicitud de patente con informe sobre el estado de la técnic