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We describe a wireless RF network for capturing event-driven data from thousands of spatially distributed sensors. As asynchronous devices, each sensor detects events within its local environment. Information acquired by the full network can enable prediction of the time evolution of the system, whether a brain or cardiac circuit in the human body, or an assistive living environment, for example. We develop a communication concept inspired by principles of synaptic information processing in the brain which we mimic by a code-division multiple access strategy in a sparse network. Through extensive simulation, we optimize wireless transmission from ensembles of event-detecting sensors for efficient use of the power and spectrum at low error rates, which is then implemented on-chip to demonstrate the core communication scheme in silico. We also apply the concept to recordings from thirty thousand neurons in the primate cortex, to decode and predict forward state trajectories for hand movement.

Multichannel electrophysiological sensors and stimulators—particularly those used to study the nervous system—are usually based on monolithic microelectrode arrays. However, the architecture of such arrays limits flexibility in electrode placement and scaling to a large number of nodes, especially across non-contiguous locations. Here we report wirelessly networked and powered electronic microchips that can autonomously perform neural sensing and electrical microstimulation. The microchips, which we term neurograins, have an ~1 GHz electromagnetic transcutaneous link to an external telecom hub, providing bidirectional communication and control at the individual device level. To illustrate the potential of the approach, we show that 48 neurograins can be individually addressed on a rat cortical surface and used for the acute recording of neural activity. Theoretical calculations and experimental measurements show that the link configuration could potentially be scaled to 770 neurograins using a customized time-division multiple access protocol. Wirelessly powered microchips, which have an ~1 GHz electromagnetic transcutaneous link to an external telecom hub, can be used for multichannel in vivo neural sensing, stimulation and data acquisition.

A major challenge to high-resolution, closed-loop Brain Computer Interfaces (BCIs) is the availability of implantable technologies facilitating vastly parallel, large-scale access to cortical neural data representing complex, naturalistic tasks or sophisticated therapeutic neuromodulation. The current technological bottleneck is scalability of systems employing intra or epicortical electrode arrays with hard-wired tethers and bulky implant packaging. We address these challenges by employing an approach relying on spatially-distributed, completely wireless clusters of autonomous microscale neural interfaces, where each microdevice provides a single bidirectional channel (read-out and write-in) of neural access, and occupies a volume

Multichannel electrophysiological sensors and stimulators, especially those used for studying the nervous system, are most commonly based on monolithic microelectrode arrays. Such architecture limits the spatial flexibility of individual electrode placement, posing constraints for scaling to a large number of nodes, particularly across non-contiguous locations. We describe the design and fabrication of sub-millimeter size electronic microchips (“Neurograins”) which autonomously perform neural sensing or electrical microstimulation, with emphasis on their wireless networking and powering. An ∼1 GHz electromagnetic transcutaneous link to an external telecom hub enables bidirectional communication and control at the individual neurograin level. The link operates on a customized time division multiple access (TDMA) protocol designed to scale up to 1000 neurograins. The system is demonstrated as a cortical implant in a small animal (rat) model with anatomical limitations restricting the implant to 48 neurograins. We suggest that the neurograin approach can be generalized to overcome many scalability issues for wireless sensors and actuators as implantable microsystems.

This letter presents a miniaturized neural recording analog front-end (AFE) suitable for distributed sub-mm neural recording implants. Including reference generators, this AFE occupies an area of only 0.01 mm2, thanks to a mostly digital architecture with more than half of area being scalable digital logic. Implemented in 65-nm CMOS, the AFE is measured to consume 3.2 $ {\mu }\text{W}$ of power from 0.6-V supply, and achieves an input-referred noise of 2.2 $ {\mu {\mathrm{ V}}}_{\mathrm{rms}}$ over 500 Hz of bandwidth. The AFE is validated by integrating it into a neural sensing SoC with wireless power and data telemetry. In vitro experiments demonstrate reliable recording of the AFE in a fully wireless environment.

The technological ability to capture electrophysiological activity of populations of cortical neurons through chronic implantable devices has led to significant advancements in the field of brain-computer interfaces. Recent progress in the field has been driven by developments in integrated microelectronics, wireless communications, materials science, and computational neuroscience. Here, we review major device development landmarks in the arena of neural interfaces from FDA-approved clinical systems to prototype head-mounted and fully implantable wireless systems for multi-channel neural recording. Additionally, we provide an outlook toward next-generation, highly miniaturized technologies for minimally invasive, vastly parallel neural interfaces for naturalistic, closed-loop neuroprostheses.

To dramatically increase the scale and spatial resolution for future chronic electrocorticography (ECoG) applications, we propose a wireless brain-machine interface (BMI) system based on a high number (up to 1000) of freely distributed, sub-mm sized (0.25 mm2) IC implants. The chip features an onchip antenna for RF energy harvesting at 900 MHz and data backscattering at 10 Mbps. In order to synchronize and time-multiplex the uplink data transmission of the untethered chips, while allowing their oscillators to free-run to save power, a robust Mbps ASK-PWM downlink data protocol based on digital counters was implemented. To the best of our knowledge, this paper presents the first experimental validation of simultaneous wireless power transfer and bi-directional RF data communications on a network of (32) brain implant ICs over a single inductive coupling link.

A vastly enhanced capability to bi-directionally interface with cortical microcircuits in a clinically viable way is the ultimate aspiration in neuroengineering. This necessitates a paradigm shift in neural interface system design beyond current bulky, monolithic constructs which are challenging to scale past 100-200 channels due to anatomic and engineering design constraints. A neural interface system relying on a spatially-distributed network of wireless microscale implantable sensors offers a highly scalable, robust and adaptive architecture for next-generation neural interfaces. We describe the development of a wireless network of sub-mm, untethered, individually addressable, fully wireless "Neurograin" sensors, in the context of an epicortical implant. Individual neurograin chiplets integrate a ~ 1 GHz wireless link for energy harvesting and telemetry with analog and digital electronics for neural signal amplification, on-chip storage, and networked communications via a TDMA protocol. Each neurograin thus forms a completely self-contained single channel of neural access and is implantable after post-process atomic layer deposition of thin-film (100 nm thick) barriers for hermetic sealing. Finally, ensembles of implantable neurograins form a fully wireless cortico-computer communication network (utilizing their unique device IDs). The implanted network is coordinated by a compact external "Epidermal Skinpatch" RF transceiver and data processing hub, which is implemented as a wearable module in order to be compatible with clinical implant considerations. We describe neurograin performance specifications and proof-of-concept in bench top and ex vivo and in vivo rodent platforms.

The technological ability to capture electrophysiological activity of populations of cortical neurons through chronic implantable devices has led to significant advancements in the field of brain-computer interfaces. Recent progress in the field has been driven by developments in integrated microelectronics, wireless communications, materials science, and computational neuroscience. Here, we review major device development landmarks in the arena of neural interfaces from FDA-approved clinical systems to prototype head-mounted and fully implantable wireless systems for multi-channel neural recording. Additionally, we provide an outlook toward next-generation, highly miniaturized technologies for minimally invasive, vastly parallel neural interfaces for naturalistic, closed-loop neuroprostheses.

We describe a custom wireless power and data transmission (WPDT) link and analyze its performance in a prototype implantable sensor system of ensembles of CMOS sensor ASICs (“Neurograins”) embedding 0.5 mm × 0.5 mm planar microcoil antennas. We use near-field RF at ~1 GHz for wireless powering in a resonant 3-coil architecture including an implanted relay coil in a quadrant layout architecture to maximize coverage area and RF transfer efficiency. We demonstrate successful WPDT across antenna cross-section in benchtop proxy physiological tests. Demodulation and analysis of backscattered signals validate the data link fidelity. Our results suggest that this electromagnetic coupling scheme can robustly support a chip density of 250/ cm2(up to 1024 individual Neurograins in a 2 cm × 2 cm area) and parallel transmitters can be combined to multiply the channel capacity without destructive interference.

Current state-of-the-art Brain-Machine Interfaces (BMIs) rely on invasive “passive” microelectrode technologies, which are prohibitively challenging to scale beyond several hundred channels due to physical constraints. Further performance enhancement in BMIs relies on the ability to develop implantable sensor technologies that would be scalable to thousands of channels without significant biological overhead. In this work., we describe prototype testing of a distributed sensor system of CMOS “Neurograins,” which provide a high density network of autonomous implantable neural sensors. These Neurograins are wirelessly powered using near-field RF at ~1 GHz and at densities up to 250 chips/cm2, A 3-coil system is used to enhance the wireless signal transfer function. Telemetry is accomplished using RF backscatter with TDMA networking at a data rate of 10 Mbps, and Bit Error Rates (BER)

Acquiring neural signals at high spatial and temporal resolution directly from brain microcircuits and decoding their activity to interpret commands and/or prior planning activity, such as motion of an arm or a leg, is a prime goal of modern neurotechnology. Its practical aims include assistive devices for subjects whose normal neural information pathways are not functioning due to physical damage or disease. On the fundamental side, researchers are striving to decipher the code of multiple neural microcircuits which collectively make up nature's amazing computing machine, the brain. By implanting biocompatible neural sensor probes directly into the brain, in the form of microelectrode arrays, it is now possible to extract information from interacting populations of neural cells with spatial and temporal resolution at the single cell level. With parallel advances in application of statistical and mathematical techniques tools for deciphering the neural code, extracted populations or correlated neurons, significant understanding has been achieved of those brain commands that control, e.g., the motion of an arm in a primate (monkey or a human subject). These developments are accelerating the work on neural prosthetics where brain derived signals may be employed to bypass, e.g., an injured spinal cord. One key element in achieving the goals for practical and versatile neural prostheses is the development of fully implantable wireless microelectronic ?brain-interfaces? within the body, a point of special emphasis of this paper.

Targeted neural excitation coupled with simultaneous multineuron recording is desirable both for studying the real-time dynamics of neural circuits and for prospective clinical treatment of neurological diseases. Optical stimulation of genetically targeted neurons expressing the light sensitive channel protein Channelrhodopsin (ChR2) has recently been reported as a means for millisecond temporal control of neuronal spiking activity with cell-type selectivity. This offers the prospect of enabling local (cellular level) stimulation and the concomitant monitoring of neural activity by extracellular electrophysiological methods, both in the vicinity of and distant to the stimulation site. We report here a novel dual-modality hybrid device which consists of a tapered coaxial optical waveguide (“optrode”) directly integrated into a 100 element intra-cortical multi-electrode recording array. The dual-modality array device was used in ChR2 transfected mouse brain slices. Specifically, epileptiform events were reliably optically triggered by the optrode and their spatiotemporal patterns were simultaneously recorded by the multi-electrode array.

A multitude of neuroengineering challenges exist today in creating practical, chronic multichannel neural recording systems for primate research and human clinical application. Specifically, a) the persistent wired connections limit patient mobility from the recording system, b) the transfer of high bandwidth signals to external (even distant) electronics normally forces premature data reduction, and c) the chronic susceptibility to infection due to the percutaneous nature of the implants all severely hinder the success of neural prosthetic systems. Here we detail one approach to overcome these limitations: an entirely implantable, wirelessly communicating, integrated neural recording microsystem, dubbed the Brain Implantable Chip (BIC).

We have built a wireless implantable microelectronic device for transmitting cortical signals transcutaneously. The device is aimed at interfacing a cortical microelectrode array to an external computer for neural control applications. Our implantable microsystem enables 16-channel broadband neural recording in a nonhuman primate brain by converting these signals to a digital stream of infrared light pulses for transmission through the skin. The implantable unit employs a flexible polymer substrate onto which we have integrated ultra-low power amplification with analog multiplexing, an analog-to-digital converter, a low power digital controller chip, and infrared telemetry. The scalable 16-channel microsystem can employ any of several modalities of power supply, including radio frequency by induction, or infrared light via photovoltaic conversion. As of the time of this report, the implant has been tested as a subchronic unit in nonhuman primates ( approximately 1 month), yielding robust spike and broadband neural data on all available channels.

We report on the performance of a wireless, implantable, neural recording platform. A multitude of neuroengineering challenges exist today in creating practical, chronic multichannel neural recording systems for primate research and human clinical application. Specifically, a) the persistent wired connections limit patient mobility from the recording system, b) the transfer of high bandwidth signals to external (even distant) electronics normally forces premature data reduction, and c) the chronic susceptibility to infection due to the percutaneous nature of the implants all severely hinder the success of neural prosthetic systems. Here we detail a scalable 16-channel microsystem that can employ any of several modalities of power delivery (wire, radio frequency induction, and a photovoltaic energy converter) and data transmission (wire, and transcutaneous infrared laser transmission). Data is reported from a recent sub-chronic (~30 day) rhesus macaque MI implantation.

Macrophages that are recruited to the site of implanted biomaterials undergo fusion to form surface-damaging foreign body giant cells. Exposure of peripheral blood monocytes to interleukin-4 can recapitulate the fusion process in vitro. In this study, we used interleukin-4 to induce multinucleation of murine bone marrow-derived macrophages and observed changes in cell shape, including elongation and lamellipodia formation, before fusion. Because cytoskeletal rearrangements are regulated by small GTPases, we examined the effects of inhibitors of Rho kinase (Y-32885) and Rac activation (NSC23766) on fusion. Y-32885 did not prevent cytoskeletal changes or fusion but limited the extent of multinucleation. NSC23766, on the other hand, inhibited lamellipodia formation and fusion in a dose-dependent manner. In addition, we found that in control cells, these changes were preceded by Rac1 activation. However, NSC23766 did not block the uptake of polystyrene microspheres. Likewise, short interfering RNA knockdown of Rac1 limited fusion without limiting phagocytosis. Thus, phagocytosis and fusion can be partially decoupled based on their susceptibility to NSC23766. Furthermore, poly(ethylene-co-vinyl acetate) scaffolds containing NSC23766 attenuated foreign body giant cell formation in vivo. These observations suggest that targeting Rac1 activation could protect biomaterials without compromising the ability of macrophages to perform beneficial phagocytic functions at implantation sites.

We designed and tested an integrated patch-clamp amplifier capable of recording from pico to tens of microamperes of current. The high-dynamic range of seven decades and the picoampere sensitivity of the instrument was targeted to whole-cell patch-clamp recordings. The prototype was fabricated on a 0.5-mum silicon-on-sapphire process. The device employs an integrating headstage with a pulse frequency modulated output, ranging from 3 Hz to 10 MHz. A digital interface produces a 16-bit output conversion of the input currents. We report on electronic characterization of the fabricated device, dynamic performance, and examples of measurements on biological cells for patch-clamp applications. The device will be used in an advanced planar high-throughput patch-clamp screening system for testing medicines

We fabricated an integrated patch-clamp amplifier capable of recording from pico- to tens of micro-amperes of current. The high-dynamic range of seven decades and the pico-ampere sensitivity of the instrument was designed for whole-cell patch-clamp recordings. The prototype was fabricated on a 0.5 mum silicon-on-sapphire process. The device employs an integrating headstage with a frequency-modulated output pulse ranging from 3 Hz to 10 MHz. A digital interface produces a 16bit output conversion of the input currents. We report on electrical measurements from the fabricated device, and measurements conducted on cells in a typical patch-clamp experiment

Neural stimulation with high spatial and temporal precision is desirable both for studying the real-time dynamics of neural networks and for prospective clinical treatment of neurological diseases. Optical stimulation of genetically targeted neurons expressing the light sensitive channel protein Channelrhodopsin (ChR2) has recently been reported as a means for millisecond temporal control of neuronal spiking activities with cell-type selectivity. This offers the prospect of enabling local delivery of optical stimulation and the simultaneous monitoring of the neural activity by electrophysiological means, both in the vicinity of and distant to the stimulation site. We report here a novel dual-modality hybrid device, which consists of a tapered coaxial optical waveguide (‘optrode’) integrated into a 100 element intra-cortical multi-electrode recording array. We first demonstrate the dual optical delivery and electrical recording capability of the single optrode in in vitro preparations of mouse retina, photo-stimulating the native retinal photoreceptors while recording light-responsive activities from ganglion cells. The dual-modality array device was then used in ChR2 transfected mouse brain slices. Specifically, epileptiform events were reliably optically triggered by the optrode and their spatiotemporal patterns were simultaneously recorded by the multi-electrode array.

Genetically targeted neurons in brain expressing light sensitive channel Channelrhodopsin can be stimulated optically. We report a novel optical waveguide probe for simultaneous optical stimulation and electrical recording of neurons to modulate neural network behavior.