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Graphene active sensors have demonstrated promising capabilities for the detection of electrophysiological signals in the brain. Their functional properties, together with their flexibility as well as their expected stability and biocompatibility have raised them as a promising building block for large-scale sensing neural interfaces. However, in order to provide reliable tools for neuroscience and biomedical engineering applications, the maturity of this technology must be thoroughly studied. Here, we evaluate the performance of 64-channel graphene sensor arrays in terms of homogeneity, sensitivity and stability using a wireless, quasi-commercial headstage and demonstrate the biocompatibility of epicortical graphene chronic implants. Furthermore, to illustrate the potential of the technology to detect cortical signals from infra-slow to high-gamma frequency bands, we perform proof-of-concept long-term wireless recording in a freely behaving rodent. Our work demonstrates the maturity of the graphene-based technology, which represents a promising candidate for chronic, wide frequency band neural sensing interfaces., This work has been funded by the European Union’s Horizon 2020 research and innovation program under Grant Agreement No. 732032 (BrainCom) and Graphene Flagship Grant Agreements No. 785219 (GrapheneCore2) and 881603 (GrapheneCore3). 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. R.G.C. is supported by the International Ph.D Program La Caixa-Severo Ochoa (Programa Internacional de Becas “la Caixa”-Severo Ochoa). This work has made use of the Spanish ICTS Network MICRONANOFABS partially supported by MICINN and the ICTS “NANBIOSIS”, more specifically by the Micro-NanoTechnology Unit of the CIBER in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN) at the IMB-CNM. This work is within the project FIS2017-85787-R funded by the “Ministerio de Ciencia, Innovación y Universidades” of Spain, the “Agencia Estatal de Investigación (AEI)”, and the “Fondo Europeo de Desarrollo Regional (FEDER/UE)”. A.S. and G.S. were also supported by Bundesministerium für Bildung und Forschung [grant number 01GQ0440]. R.G.C. acknowledges that this work has been done in the framework of the Ph.D in Electrical and Telecommunication Engineering at the Universitat Autònoma de Barcelona.

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.

Sensor arrays used to detect electrophysiological signals from the brain are paramount in neuroscience. However, the number of sensors that can be interfaced with macroscopic data acquisition systems currently limits their bandwidth. This bottleneck originates in the fact that, typically, sensors are addressed individually, requiring a connection for each of them. Herein, we present the concept of frequency-division multiplexing (FDM) of neural signals by graphene sensors. We demonstrate the high performance of graphene transistors as mixers to perform amplitude modulation (AM) of neural signals in situ, which is used to transmit multiple signals through a shared metal line. This technology eliminates the need for switches, remarkably simplifying the technical complexity of state-of-the-art multiplexed neural probes. Besides, the scalability of FDM graphene neural probes has been thoroughly evaluated and their sensitivity demonstrated in vivo. Using this technology, we envision a new generation of high-count conformal neural probes for high bandwidth brain machine interfaces., This work has been funded by the European Union’s Horizon 2020 research and innovation programme under Grant Agreement 732032 (BrainCom), Grant Agreement 85219 and 881603 (Graphene Flagship). The ICN2 is supported by the Severo Ochoa Centres of Excellence programme, funded by the Spanish Research Agency (AEI, Grant SEV-2017-0706), and by the CERCA Programme/Generalitat de Catalunya. R.G.C. and N.S. acknowledge that this work has been done in the framework of the Ph.D. in Electrical and Telecommunication Engineering at the Universitat Autonoma de Barcelona. R.G.C is supported by the International Ph.D. Programme La Caixa - Severo Ochoa (Programa Internacional de Becas “la Caixa”-Severo Ochoa). This work has made use of the Spanish ICTS Network MICRONANOFABS partially supported by MICINN and the ICTS “NANBIOSIS”, more specifically by the Micro-NanoTechnology Unit of the CIBER in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN) at the IMB-CNM. This work is within the project 2DTecBio (FIS2017-85787-R) funded by the “Ministerio de Ciencia, Innovacion y Universidades” of Spain, the “Agencia Estatal de Investigacion (AEI)”, and the “Fondo Europeo de Desarrollo Regional (FEDER/UE)” and has received funding from Generalitat de Cataluña 2017 SGR 1426.

Altres ajuts: this work has made use of the Spanish ICTS Network MICRONANOFABS partially supported by MICINN and the ICTS 'NANBIOSIS', more specifically by the Micro-NanoTechnology Unit of the CIBER in Bioengineering, Biomaterials and Nanomedicine (CIBERBBN) at the IMB-CNM. Electrocorticography (ECoG) is a well-established technique to monitor electrophysiological activity from the surface of the brain and has proved crucial for the current generation of neural prostheses and brain-computer interfaces. However, existing ECoG technologies still fail to provide the resolution necessary to accurately map highly localized activity across large brain areas, due to the rapidly increasing size of connector footprint with sensor count. This work demonstrates the use of a flexible array of graphene solution-gated field-effect transistors (gSGFET), exploring the concept of multiplexed readout using an external switching matrix. This approach does not only allow for an increased sensor count, but due to the use of active sensing devices (i.e. transistors) over microelectrodes it makes additional buffer transistors redundant, which drastically eases the complexity of device fabrication on flexible substrates. The presented results pave the way for upscaling the gSGFET technology towards large-scale, high-density μECoG-arrays, eventually capable of resolving neural activity down to a single neuron level, while simultaneously mapping large brain regions.

The advent of implantable active dense CMOS neural probes opened a new era for electrophysiology in neuroscience. These single shank electrode arrays, and the emerging tailored analysis tools, provide for the first time to neuroscientists the neurotechnology means to spatiotemporally resolve the activity of hundreds of different single-neurons in multiple vertically aligned brain structures. However, while these unprecedented experimental capabilities to study columnar brain properties are a big leap forward in neuroscience, there is the need to spatially distribute electrodes also horizontally. Closely spacing and consistently placing in well-defined geometrical arrangement multiple isolated single-shank probes is methodologically and economically impractical. Here, we present the first high-density CMOS neural probe with multiple shanks integrating thousand’s of closely spaced and simultaneously recording microelectrodes to map neural activity across 2D lattice. Taking advantage from the high-modularity of our electrode-pixels-based SiNAPS technology, we realized a four shanks active dense probe with 256 electrode-pixels/shank and a pitch of 28 µm, for a total of 1024 simultaneously recording channels. The achieved performances allow for full-band, whole-array read-outs at 25 kHz/channel, show a measured input referred noise in the action potential band (300-7000 Hz) of 6.5 ± 2.1µVRMS, and a power consumption µW/electrode-pixel. Preliminary recordings in awake behaving mice demonstrated the capability of multi-shanks SiNAPS probes to simultaneously record neural activity (both LFPs and spikes) from a brain area >6 mm2, spanning cortical, hippocampal and thalamic regions. High-density 2D array enables combining large population unit recording across distributed networks with precise intra- and interlaminar/nuclear mapping of the oscillatory dynamics. These results pave the way to a new generation of high-density and extremely compact multi-shanks CMOS-probes with tunable layouts for electrophysiological mapping of brain activity at the single-neurons resolution.

Neuropeptide Y (NPY) reduces anxiety-related behavior in various animal models. Since activity in the lateral amygdala (LA) seems crucial for fear expression of behavior, we studied the mechanisms of NPY in LA projection neurons using whole-cell patch-clamp recordings in slices of the rat amygdala in vitro. Application of NPY activated a membrane K(+) current with inwardly rectifying properties in 92% of tested neurons. Pharmacological properties were indicative of mediation via Y1 receptors. Nonhydrolyzable analogues of guanine nucleotides and SCH23390 blocked the NPY-activated current. Single-cell RT-PCR demonstrated expression of G-protein-coupled inwardly rectifying K(+) channel (GIRK) subunits GIRK1, GIRK2 and GIRK3, suggesting mediation of the NPY response through GIRK type channels. The NPY-activated current depressed action potential firing in LA projection neurons, through membrane hyperpolarization and decreased input resistance. Functionally, the dampening of excitability in projection neurons of the amygdala may contribute to the decrease in anxiogenic behavior during action of NPY.

Graphene active sensors have demonstrated promising capabilities for the detection of electrophysiological signals in the brain. Their functional properties, together with their flexibility as well as their expected stability and biocompatibility have raised them as a promising building block for large-scale sensing neural interfaces. However, in order to provide reliable tools for neuroscience and biomedical engineering applications, the maturity of this technology must be thoroughly studied. Here, we evaluate the performance of 64-channel graphene sensor arrays in terms of homogeneity, sensitivity and stability using a wireless, quasi-commercial headstage and demonstrate the biocompatibility of epicortical graphene chronic implants. Furthermore, to illustrate the potential of the technology to detect cortical signals from infra-slow to high-gamma frequency bands, we perform proof-of-concept long-term wireless recording in a freely behaving rodent. Our work demonstrates the maturity of the graphene-based technology, which represents a promising candidate for chronic, wide frequency band neural sensing interfaces.