Quantification of Signal-to-Noise Ratio in Cerebral Cortex Recordings Using Flexible MEAs With Co-localized Platinum Black, Carbon Nanotubes, and Gold Electrodes

Developing new standardized tools to characterize brain recording devices is critical to evaluate neural probes and for translation to clinical use. The signal-to-noise ratio (SNR) measurement is the gold standard for quantifying the performance of brain recording devices. Given the drawbacks with the SNR measure, our first objective was to devise a new method to calculate the SNR of neural signals to distinguish signal from noise. Our second objective was to apply this new SNR method to evaluate electrodes of three different materials (platinum black, Pt; carbon nanotubes, CNTs; and gold, Au) co-localized in tritrodes to record from the same cortical area using specifically designed multielectrode arrays. Hence, we devised an approach to calculate SNR at different frequencies based on the features of cortical slow oscillations (SO). Since SO consist in the alternation of silent periods (Down states) and active periods (Up states) of neuronal activity, we used these as noise and signal, respectively. The spectral SNR was computed as the power spectral density (PSD) of Up states (signal) divided by the PSD of Down states (noise). We found that Pt and CNTs electrodes have better recording performance than Au electrodes for the explored frequency range (5–1500 Hz). Together with two proposed SNR estimators for the lower and upper frequency limits, these results substantiate our SNR calculation at different frequency bands. Our results provide a new validated SNR measure that provides rich information of the performance of recording devices at different brain activity frequency bands (<1500 Hz)

A 1024-Channel 10-Bit 36-μW/ch CMOS ROIC for Multiplexed GFET-Only Sensor Arrays in Brain Mapping

This paper presents a 1024-channel neural read-out integrated circuit (ROIC) for solution-gated GFET sensing probes in massive muECoG brain mapping. The proposed time-domain multiplexing of GFET-only arrays enables low-cost and scalable hybrid headstages. Low-power CMOS circuits are presented for the GFET analog frontend, including a CDS mechanism to improve preamplifier noise figures and 10-bit 10-kS/s A/D conversion. The 1024-channel ROIC has been fabricated in a standard 1.8-V 0.18-mum CMOS technology with 0.012 mm 2 and 36 mu W per channel. An automated methodology for the in-situ calibration of each GFET sensor is also proposed. Experimental ROIC tests are reported using a custom FPGA-based muECoG headstage with 16times 32 and 32times 32 GFET probes in saline solution and agar substrate. Compared to state-of-art neural ROICs, this work achieves the largest scalability in hybrid platforms and it allows the recording of infra-slow neural signals

Concurrent functional ultrasound imaging with graphene-based DC-coupled electrophysiology as a platform to study slow brain signals and cerebral blood flow under control and pathophysiological brain states

Current methodology used to investigate how shifts in brain states associated with regional cerebral blood volume (CBV) change in deep brain areas, are limited by either the spatiotemporal resolution of the CBV techniques, and/or compatibility with electrophysiological recordings; particularly in relation to spontaneous brain activity and the study of individual events. Additionally, infraslow brain signals (&lt;0.1 Hz), including spreading depolarisations, DC-shifts and infraslow oscillations (ISO), are poorly captured by traditional AC-coupled electrographic recordings; yet these very slow brain signals can profoundly change CBV. To gain an improved understanding of how infraslow brain signals couple to CBV we present a new method for concurrent CBV with wide bandwidth electrophysiological mapping using simultaneous functional ultrasound imaging (fUS) and graphene-based field effect transistor (gFET) DC-coupled electrophysiological acquisitions. To validate the feasibility of this methodology visually-evoked neurovascular coupling (NVC) responses were examined. gFET recordings are not affected by concurrent fUS imaging, and epidural placement of gFET arrays within the imaging window did not deteriorate fUS signal quality. To examine directly the impact of infra-slow potential shifts on CBV, cortical spreading depolarisations (CSDs) were induced. A biphasic pattern of decreased, followed by increased CBV, propagating throughout the ipsilateral cortex, and a delayed decrease in deeper subcortical brain regions was observed. In a model of acute seizures, CBV oscillations were observed prior to seizure initiation. Individual seizures occurred on the rising phase of both infraslow brain signal and CBV oscillations. When seizures co-occurred with CSDs, CBV responses were larger in amplitude, with delayed CBV decreases in subcortical structures. Overall, our data demonstrate that gFETs are highly compatible with fUS and allow concurrent examination of wide bandwidth electrophysiology and CBV. This graphene-enabled technological advance has the potential to improve our understanding of how infraslow brain signals relate to CBV changes in control and pathological brain states.</p

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

Novel methods and tools for corneal barrier function assessment through non-invasive impedance measurements

La còrnia és una estructura transparent ubicada a la part frontal de l’ull que permet la transmissió de la llum i protegeix globus ocular d’agressions externes. La principal característica de la còrnia és la seva transparència. Aquesta depèn del nivell de hidratació de l’estroma, que ha de mantenir-se en un constant estat de deshidratació. Aquest nivell de hidratació depèn d’un equilibri dinàmic entre els fluxos iònics que travessen les capes endotelials i epitelials. Per tant, la permeabilitat d’aquestes capes resulta un factor determinant per mantenir la homeòstasis corneal i conseqüentment, la transparència corneal. Malgrat això, no existeixen mètodes apropiats per avaluar la funció barrera corneal de forma no invasiva i que puguin ser utilitzats in vivo. Ja que la permeabilitat iònica té molta importància en les propietats elèctriques passives dels teixits vius, els mètodes basats en aquestes propietats són àmpliament utilitzats en estudis in vitro de la funcionalitat de les capes corneals. Aquesta tesis doctoral es centra en el desenvolupament i validació d’un mètode no invasiu per l’avaluació de l’estat funcional de les principals capes corneals que pugui ser utilitzat in vivo. Per avaluar la viabilitat del mètode proposat s’ha desenvolupat un model numèric basat en elements finits (FEM). Els resultats de les simulacions indiquen que les mesures obtingudes mitjançant elèctrodes col·locats sobre la superfície corneal són suficientment sensibles als canvis de les propietats elèctriques de l’endoteli i de l’epiteli. Una primera versió del sensor d’impedància s’ha fabricat utilitzant un substrat de Pyrex®. De forma que s’ha d’aplicar una certa pressió per tal d’aplanar la curvatura corneal i assegurar el contacte elèctric entre la superfície corneal i els elèctrodes. Malgrat la pressió exercida, sols es pot assegurar el contacte elèctric per la configuració d’elèctrodes més pròxima. Malgrat aquesta limitació, s’ha validat la capacitat del mètode per avaluar in vivo la funció barrera de la còrnia. Per tal de superar les limitacions del substrat rígid, s’ha desenvolupat un sensor de impedància flexible basat en un substrat polimèric de SU-8. D’aquesta forma, la facilitat d’ús i aplicabilitat del mètode proposat milloren notablement ja que no es requereix pressió per aplicar el sensor. La viabilitat del mètode ha estat avaluada incrementant farmacològicament la permeabilitat epitelial de conills i monitoritzant el procés de cicatrització de l’epiteli. Els resultats obtinguts s’han comparat satisfactòriament amb mesures de permeabilitat a la fluoresceïna, un mètode destructiu que es relaciona directament amb la permeabilitat. També s’ha observat que la resolució de les mesures realitzades està principalment limitada per variacions en el gruix de la llàgrima entre el sensor i la superfície corneal. De la mateixa forma, s’ha observat que la contribució de la llàgrima a la impedància mesurada es pot minimitzar augmentant la separació. En paral·lel amb el desenvolupament del sistema in vivo, s’ha estudiat la possibilitat d’aplicar el mètode a l’avaluació de la funció barrera de l’endoteli en còrnies extretes. Aquest nou desenvolupament podria ser molt útil per avaluar la funcionalitat corneal abans d’un transplantament. El mètode proposat permetrà la simplificació dels procediments experimentals utilitzats actualment, que requereixen de l’eliminació de l’epiteli abans de fer la mesura. Les mesures d’impedància obtingudes s’han comparat satisfactòriament amb tècniques microscòpiques de tinció immunològiques. El treball multidisciplinar presentat en aquesta tesis doctoral ha resultat en un nou mètode per a l’avaluació in vivo de la funció barrera corneal de forma no invasiva. Els excel·lents resultats obtingut han permès la transferència tecnològica del mètode proposat a la pràctica clínica. D’aquesta forma, el microsistema desenvolupat ha estat acceptat com a dispositiu mèdic per l’Agència Espanyola dels Medicaments i Productes Sanitaris (AEMPS) per ser utilitzat en humans. Actualment, el mètode desenvolupat es troba en fase d’assaig clínic.The cornea is a hemispherical transparent structure located in front of the eye that allows the transmission of light and protects the ocular globe against external aggressions. The corneal transparency depends on the hydration of the stroma, which has to remain in a constant state of dehydration. This hydration level depends on a dynamic equilibrium between the ion fluxes through the endothelial and epithelial layer. Thus, the permeability of those layers plays the most important role to maintain the corneal homeostasis, and finally, the corneal transparency. However, there is a lack of proper non-invasive methods for assessing the corneal barrier function in in vivo conditions. Since ionic permeability has a fundamental impact on the passive electrical properties of living tissues, methods based on the study of those properties have consistently been used in in vitro studies of the corneal layers functionality. This dissertation is focused on the development and validation of a non-invasive method to assess the functional state of the main corneal layers in in vivo conditions. An electrical model of the cornea has been developed and analyzed by means of finite elements method (FEM). The simulation results indicate that the measurements performed by electrodes placed on the corneal surface are indeed sufficiently sensitive to the changes in the electrical properties of the epithelial and endothelial layers. The impedance sensor was firstly fabricated using a rigid Pyrex substrate. Consequently, in order to flatten the corneal curvature and ensure the electric contact between the electrodes and the corneal surface a reasonable pressure must be applied. However, the proper electric contact can only be achieved with the closest electrode configuration. Despite this limitation, the capability to in vivo assess the corneal barrier function was successfully evaluated. To overcome the limitations of the rigid substrate, a flexible impedance sensor has been developed using a polymeric SU-8 substrate. Therefore, the usability and performance of the proposed method is increased since no pressure is needed to place the sensor on the corneal surface. Its feasibility was evaluated in vivo by pharmacologically increasing the epithelial permeability and monitoring a corneal epithelium wound-healing process. The obtained impedance results were successfully compared to the measurements of permeability to sodium fluorescein, a well-known destructive method directly related with the permeability. It was also observed that the resolution of the performed measurements is mainly limited by variations in the tear film thickness between the sensor and the corneal surface. However, it was observed that the contribution of the tear film to the measured impedance can be minimized by increasing the separation between electrodes. In parallel with the development of the in vivo system, it has been studied the possibility to apply the method to assess the endothelium barrier function of excised corneas. This new development could be a helpful tool for evaluating the corneal functionality before grafting. The proposed method will allow the simplification of the currently used experimental procedures, which requires the remove of the epithelium to perform the measurement. The obtained impedance results were successfully compared with microscopy immunostaining techniques. The multidisciplinary work described in this dissertation has given rise to a novel method for in vivo assessment of the corneal barrier function in a non-invasive way. The excellent results obtained in the experimental field have allowed transferring the proposed method to the clinical practice. Thus, the developed microsystem has been accepted as a medical device by Spanish Agency of Medicines and Medical Devices(AEMPS)to be used in humans. Currently, the developed method is clinical assay phase

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

Biosensor inalámbrico, portátil y reutilizable

Biosensor inalámbrico, portátil y reutilizable. La presente invención se refiere a un dispositivo biosensor para la determinación de analitos, no invasivo mediante la visualización de un cambio de color, y a partir de una muestra de líquido. La presente invención se enmarca en el ámbito dispositivos para la salud, control durante realización de deporte, la seguridad laboral y la industria alimentaria.Peer reviewedConsejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic

Novel methods and tools for corneal barrier function assessment through non-invasive impedance measurements

La còrnia és una estructura transparent ubicada a la part frontal de l'ull que permet la transmissió de la llum i protegeix globus ocular d'agressions externes. La principal característica de la còrnia és la seva transparència. Aquesta depèn del nivell de hidratació de l'estroma, que ha de mantenir-se en un constant estat de deshidratació. Aquest nivell de hidratació depèn d'un equilibri dinàmic entre els fluxos iònics que travessen les capes endotelials i epitelials. Per tant, la permeabilitat d'aquestes capes resulta un factor determinant per mantenir la homeòstasis corneal i conseqüentment, la transparència corneal. Malgrat això, no existeixen mètodes apropiats per avaluar la funció barrera corneal de forma no invasiva i que puguin ser utilitzats in vivo. Ja que la permeabilitat iònica té molta importància en les propietats elèctriques passives dels teixits vius, els mètodes basats en aquestes propietats són àmpliament utilitzats en estudis in vitro de la funcionalitat de les capes corneals. Aquesta tesis doctoral es centra en el desenvolupament i validació d'un mètode no invasiu per l'avaluació de l'estat funcional de les principals capes corneals que pugui ser utilitzat in vivo. Per avaluar la viabilitat del mètode proposat s'ha desenvolupat un model numèric basat en elements finits (FEM). Els resultats de les simulacions indiquen que les mesures obtingudes mitjançant elèctrodes col·locats sobre la superfície corneal són suficientment sensibles als canvis de les propietats elèctriques de l'endoteli i de l'epiteli. Una primera versió del sensor d'impedància s'ha fabricat utilitzant un substrat de Pyrex®. De forma que s'ha d'aplicar una certa pressió per tal d'aplanar la curvatura corneal i assegurar el contacte elèctric entre la superfície corneal i els elèctrodes. Malgrat la pressió exercida, sols es pot assegurar el contacte elèctric per la configuració d'elèctrodes més pròxima. Malgrat aquesta limitació, s'ha validat la capacitat del mètode per avaluar in vivo la funció barrera de la còrnia. Per tal de superar les limitacions del substrat rígid, s'ha desenvolupat un sensor de impedància flexible basat en un substrat polimèric de SU-8. D'aquesta forma, la facilitat d'ús i aplicabilitat del mètode proposat milloren notablement ja que no es requereix pressió per aplicar el sensor. La viabilitat del mètode ha estat avaluada incrementant farmacològicament la permeabilitat epitelial de conills i monitoritzant el procés de cicatrització de l'epiteli. Els resultats obtinguts s'han comparat satisfactòriament amb mesures de permeabilitat a la fluoresceïna, un mètode destructiu que es relaciona directament amb la permeabilitat. També s'ha observat que la resolució de les mesures realitzades està principalment limitada per variacions en el gruix de la llàgrima entre el sensor i la superfície corneal. De la mateixa forma, s'ha observat que la contribució de la llàgrima a la impedància mesurada es pot minimitzar augmentant la separació. En paral·lel amb el desenvolupament del sistema in vivo, s'ha estudiat la possibilitat d'aplicar el mètode a l'avaluació de la funció barrera de l'endoteli en còrnies extretes. Aquest nou desenvolupament podria ser molt útil per avaluar la funcionalitat corneal abans d'un transplantament. El mètode proposat permetrà la simplificació dels procediments experimentals utilitzats actualment, que requereixen de l'eliminació de l'epiteli abans de fer la mesura. Les mesures d'impedància obtingudes s'han comparat satisfactòriament amb tècniques microscòpiques de tinció immunològiques. El treball multidisciplinar presentat en aquesta tesis doctoral ha resultat en un nou mètode per a l'avaluació in vivo de la funció barrera corneal de forma no invasiva. Els excel·lents resultats obtingut han permès la transferència tecnològica del mètode proposat a la pràctica clínica. D'aquesta forma, el microsistema desenvolupat ha estat acceptat com a dispositiu mèdic per l'Agència Espanyola dels Medicaments i Productes Sanitaris (AEMPS) per ser utilitzat en humans. Actualment, el mètode desenvolupat es troba en fase d'assaig clínic.The cornea is a hemispherical transparent structure located in front of the eye that allows the transmission of light and protects the ocular globe against external aggressions. The corneal transparency depends on the hydration of the stroma, which has to remain in a constant state of dehydration. This hydration level depends on a dynamic equilibrium between the ion fluxes through the endothelial and epithelial layer. Thus, the permeability of those layers plays the most important role to maintain the corneal homeostasis, and finally, the corneal transparency. However, there is a lack of proper non-invasive methods for assessing the corneal barrier function in in vivo conditions. Since ionic permeability has a fundamental impact on the passive electrical properties of living tissues, methods based on the study of those properties have consistently been used in in vitro studies of the corneal layers functionality. This dissertation is focused on the development and validation of a non-invasive method to assess the functional state of the main corneal layers in in vivo conditions. An electrical model of the cornea has been developed and analyzed by means of finite elements method (FEM). The simulation results indicate that the measurements performed by electrodes placed on the corneal surface are indeed sufficiently sensitive to the changes in the electrical properties of the epithelial and endothelial layers. The impedance sensor was firstly fabricated using a rigid Pyrex substrate. Consequently, in order to flatten the corneal curvature and ensure the electric contact between the electrodes and the corneal surface a reasonable pressure must be applied. However, the proper electric contact can only be achieved with the closest electrode configuration. Despite this limitation, the capability to in vivo assess the corneal barrier function was successfully evaluated. To overcome the limitations of the rigid substrate, a flexible impedance sensor has been developed using a polymeric SU-8 substrate. Therefore, the usability and performance of the proposed method is increased since no pressure is needed to place the sensor on the corneal surface. Its feasibility was evaluated in vivo by pharmacologically increasing the epithelial permeability and monitoring a corneal epithelium wound-healing process. The obtained impedance results were successfully compared to the measurements of permeability to sodium fluorescein, a well-known destructive method directly related with the permeability. It was also observed that the resolution of the performed measurements is mainly limited by variations in the tear film thickness between the sensor and the corneal surface. However, it was observed that the contribution of the tear film to the measured impedance can be minimized by increasing the separation between electrodes. In parallel with the development of the in vivo system, it has been studied the possibility to apply the method to assess the endothelium barrier function of excised corneas. This new development could be a helpful tool for evaluating the corneal functionality before grafting. The proposed method will allow the simplification of the currently used experimental procedures, which requires the remove of the epithelium to perform the measurement. The obtained impedance results were successfully compared with microscopy immunostaining techniques. The multidisciplinary work described in this dissertation has given rise to a novel method for in vivo assessment of the corneal barrier function in a non-invasive way. The excellent results obtained in the experimental field have allowed transferring the proposed method to the clinical practice. Thus, the developed microsystem has been accepted as a medical device by Spanish Agency of Medicines and Medical Devices(AEMPS)to be used in humans. Currently, the developed method is clinical assay phase

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