Future of Neural Interfaces.

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.

An asynchronous wireless network for capturing event-driven data from large populations of autonomous sensors.

Networks of spatially distributed radiofrequency identification sensors could be used to collect data in wearable or implantable biomedical applications. However, the development of scalable networks remains challenging. Here we report a wireless radiofrequency network approach that can capture sparse event-driven data from large populations of spatially distributed autonomous microsensors. We use a spectrally efficient, low-error-rate asynchronous networking concept based on a code-division multiple-access method. We experimentally demonstrate the network performance of several dozen submillimetre-sized silicon microchips and complement this with large-scale in silico simulations. To test the notion that spike-based wireless communication can be matched with downstream sensor population analysis by neuromorphic computing techniques, we use a spiking neural network machine learning model to decode prerecorded open source data from eight thousand spiking neurons in the primate cortex for accurate prediction of hand movement in a cursor control task.

Listening to Brain Microcircuits for Interfacing With External World-Progress in Wireless Implantable Microelectronic Neuroengineering Devices: Experimental systems are described for electrical recording in the brain using multiple microelectrodes and short range implantable or wearable broadcasting units.

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.

A Scalable and Low Stress Post-CMOS Processing Technique for Implantable Microsensors.

Implantable active electronic microchips are being developed as multinode in-body sensors and actuators. There is a need to develop high throughput microfabrication techniques applicable to complementary metal-oxide-semiconductor (CMOS)-based silicon electronics in order to process bare dies from a foundry to physiologically compatible implant ensembles. Post-processing of a miniature CMOS chip by usual methods is challenging as the typically sub-mm size small dies are hard to handle and not readily compatible with the standard microfabrication, e.g., photolithography. Here, we present a soft material-based, low chemical and mechanical stress, scalable microchip post-CMOS processing method that enables photolithography and electron-beam deposition on hundreds of micrometers scale dies. The technique builds on the use of a polydimethylsiloxane (PDMS) carrier substrate, in which the CMOS chips were embedded and precisely aligned, thereby enabling batch post-processing without complication from additional micromachining or chip treatments. We have demonstrated our technique with 650 µm × 650 µm and 280 µm × 280 µm chips, designed for electrophysiological neural recording and microstimulation implants by monolithic integration of patterned gold and PEDOT:PSS electrodes on the chips and assessed their electrical properties. The functionality of the post-processed chips was verified in saline, and ex vivo experiments using wireless power and data link, to demonstrate the recording and stimulation performance of the microscale electrode interfaces.

A Distributed Wireless Network of Implantable Sub-mm Cortical Microstimulators for Brain-Computer Interfaces.

Scalability of implantable neural interface devices is a critical bottleneck in enhancing the performance of cortical Brain-Computer Interfaces (BCIs) through access to high density and multi-areal cortical signals. This is challenging to achieve through current monolithic constructs with 100-200 channels, often with bulky tethering and packaging, and a spatially distributed sensor approach has recently been explored by a few groups, including our laboratories [1]. In this paper, we describe a microscale (500 µm) programmable neural stimulator in the context of an epicortical wireless networked system of sub-mm "Neurograins" with wireless energy harvesting (near 1 GHz) and bidirectional telemetry. Stimulation neurograins are post-processed to integrate poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) planar electrodes or intracortical penetrating microwires, and ensembles of microdevices are hermetically encapsulated using liquid-crystal polymer (LCP) thermocompression for chronic implantability. Radio-frequency power and telecommunications management are handled by a wearable external "Epidermal Skinpatch" unit to cater to chronic clinical implant considerations. We describe the stimulation neurograin performance specifications and proof-of-concept in bench top and ex vivo rodent platforms.

Integrated device for optical stimulation and spatiotemporal electrical recording of neural activity in light-sensitized brain tissue.

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.

Wireless, high-bandwidth recordings from non-human primate motor cortex using a scalable 16-Ch implantable microsystem.

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).

A microelectrode array incorporating an optical waveguide device for stimulation and spatiotemporal electrical recording of neural activity.

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.

Foreign body giant cell formation is preceded by lamellipodia formation and can be attenuated by inhibition of Rac1 activation.

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.