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.

Transparent intracortical microprobe array for simultaneous spatiotemporal optical stimulation and multichannel electrical recording.

Optogenetics, the selective excitation or inhibition of neural circuits by light, has become a transformative approach for dissecting functional brain microcircuits, particularly in in vivo rodent models, owing to the expanding libraries of opsins and promoters. Yet there is a lack of versatile devices that can deliver spatiotemporally patterned light while performing simultaneous sensing to map the dynamics of perturbed neural populations at the network level. We have created optoelectronic actuator and sensor microarrays that can be used as monolithic intracortical implants, fabricated from an optically transparent, electrically highly conducting semiconductor ZnO crystal. The devices can perform simultaneous light delivery and electrical readout in precise spatial registry across the microprobe array. We applied the device technology in transgenic mice to study light-perturbed cortical microcircuit dynamics and their effects on behavior. The functionality of this device can be further expanded to optical imaging and patterned electrical microstimulation.

Spontaneous dynamics of neural networks in deep layers of prefrontal cortex.

Cortical systems maintain and process information through the sustained activation of recurrent local networks of neurons. Layer 5 is known to have a major role in generating the recurrent activation associated with these functions, but relatively little is known about its intrinsic dynamics at the mesoscopic level of large numbers of neighboring neurons. Using calcium imaging, we measured the spontaneous activity of networks of deep-layer medial prefrontal cortical neurons in an acute slice model. Inferring the simultaneous activity of tens of neighboring neurons, we found that while the majority showed only sporadic activity, a subset of neurons engaged in sustained delta frequency rhythmic activity. Spontaneous activity under baseline conditions was weakly correlated between pairs of neurons, and rhythmic neurons showed little coherence in their oscillations. However, we consistently observed brief bouts of highly synchronous activity that must be attributed to network activity. NMDA-mediated stimulation enhanced rhythmicity, synchrony, and correlation within these local networks. These results characterize spontaneous prefrontal activity at a previously unexplored spatiotemporal scale and suggest that medial prefrontal cortex can act as an intrinsic generator of delta oscillations.NEW & NOTEWORTHY Using calcium imaging and a novel analytic framework, we characterized the spontaneous and NMDA-evoked activity of layer 5 prefrontal cortex at a largely unexplored spatiotemporal scale. Our results suggest that the mPFC microcircuitry is capable of intrinsically generating delta oscillations and sustaining synchronized network activity that is potentially relevant for understanding its contribution to cognitive processes.

Reusable Inorganic Templates for Electrostatic Self-Assembly of Individual Quantum Dots, Nanodiamonds, and Lanthanide-Doped Nanoparticles.

In this paper, we present an electrostatic self-assembly method for the controlled placement of individual nanoparticle emitters based on reusable inorganic templates. This method can be used to integrate quantum emitters into nanophotonic structures over macroscopic areas and is applicable to a variety of patterning materials and emitter systems. By utilizing surface-charge-mediated self-assembly, highly ordered arrays of nanoparticle emitters were created. To illustrate the broad applicability of this technique, we demonstrate self-assembly using colloidal quantum dots (QD), nitrogen vacancy (NV) centers in diamond nanoparticles, and lanthanide-doped upconversion nanoparticles (UCNP). Placement of single QDs and NV centers was confirmed by performing photon antibunching measurements using a Hanbury-Brown Twiss setup. In addition, template reusability was demonstrated through daily redeposition experiments over a one month period.

Spatiotemporal dynamics of optogenetically induced and spontaneous seizure transitions in primary generalized epilepsy.

Transitions into primary generalized epileptic seizures occur abruptly and synchronously across the brain. Their potential triggers remain unknown. We used optogenetics to causally test the hypothesis that rhythmic population bursting of excitatory neurons in a local neocortical region can rapidly trigger absence seizures. Most previous studies have been purely correlational, and it remains unclear whether epileptiform events induced by rhythmic stimulation (e.g., sensory/electrical) mimic actual spontaneous seizures, especially regarding their spatiotemporal dynamics. In this study, we used a novel combination of intracortical optogenetic stimulation and microelectrode array recordings in freely moving WAG/Rij rats, a model of absence epilepsy with a cortical focus in the somatosensory cortex (SI). We report three main findings: 1) Brief rhythmic bursting, evoked by optical stimulation of neocortical excitatory neurons at frequencies around 10 Hz, induced seizures consisting of self-sustained spike-wave discharges (SWDs) for about 10% of stimulation trials. The probability of inducing seizures was frequency-dependent, reaching a maximum at 10 Hz. 2) Local field potential power before stimulation and response amplitudes during stimulation both predicted seizure induction, demonstrating a modulatory effect of brain states and neural excitation levels. 3) Evoked responses during stimulation propagated as cortical waves, likely reaching the cortical focus, which in turn generated self-sustained SWDs after stimulation was terminated. Importantly, SWDs during induced and spontaneous seizures propagated with the same spatiotemporal dynamics. Our findings demonstrate that local rhythmic bursting of excitatory neurons in neocortex at particular frequencies, under susceptible ongoing brain states, is sufficient to trigger primary generalized seizures with stereotypical spatiotemporal dynamics.

Optogenetically induced spatiotemporal gamma oscillations and neuronal spiking activity in primate motor cortex.

Transient gamma-band (40-80 Hz) spatiotemporal patterns are hypothesized to play important roles in cortical function. Here we report the direct observation of gamma oscillations as spatiotemporal waves induced by targeted optogenetic stimulation, recorded by intracortical multichannel extracellular techniques in macaque monkeys during their awake resting states. Microelectrode arrays integrating an optical fiber at their center were chronically implanted in primary motor (M1) and ventral premotor (PMv) cortices of two subjects. Targeted brain tissue was transduced with the red-shifted opsin C1V1(T/T). Constant (1-s square pulses) and ramp stimulation induced narrowband gamma oscillations during awake resting states. Recordings across 95 microelectrodes (4 × 4-mm array) enabled us to track the transient gamma spatiotemporal patterns manifested, e.g., as concentric expanding and spiral waves. Gamma oscillations were induced well beyond the light stimulation volume, via network interactions at distal electrode sites, depending on optical power. Despite stimulation-related modulation in spiking rates, neuronal spiking remained highly asynchronous during induced gamma oscillations. In one subject we examined stimulation effects during preparation and execution of a motor task and observed that movement execution largely attenuated optically induced gamma oscillations. Our findings demonstrate that, beyond previously reported induced gamma activity under periodic drive, a prolonged constant stimulus above a certain threshold may carry primate motor cortex network dynamics into gamma oscillations, likely via a Hopf bifurcation. More broadly, the experimental capability in combining microelectrode array recordings and optogenetic stimulation provides an important approach for probing spatiotemporal dynamics in primate cortical networks during various physiological and behavioral conditions.

Sensors and decoding for intracortical brain computer interfaces.

Intracortical brain computer interfaces (iBCIs) are being developed to enable people to drive an output device, such as a computer cursor, directly from their neural activity. One goal of the technology is to help people with severe paralysis or limb loss. Key elements of an iBCI are the implanted sensor that records the neural signals and the software that decodes the user's intended movement from those signals. Here, we focus on recent advances in these two areas, placing special attention on contributions that are or may soon be adopted by the iBCI research community. We discuss how these innovations increase the technology's capability, accuracy, and longevity, all important steps that are expanding the range of possible future clinical applications.

Surface-emitting red, green, and blue colloidal quantum dot distributed feedback lasers.

We demonstrate surface emitting distributed feedback (DFB) lasers across the red, green, and blue from densely packed colloidal quantum dot (CQD) films. The solid CQD films were deposited on periodic grating patterns to enable 2nd-order DFB lasing action at mere 120, 280, and 330 µJ/cm2 of optical pumping energy densities for red, green, and blue DFB lasers, respectively. The lasers operated in single mode operation with less than 1 nm of full-width-half-maximum. We measured far-field patterns showing high degree of spatial beam coherence. Specifically, by taking advantage of single exciton optical gain regime from our engineered CQDs, we can significantly suppress the Auger recombination to reduce lasing threshold and achieve quasi-steady state, optically pumped operation.

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.

An implantable neural sensing microsystem with fiber-optic data transmission and power delivery.

We have developed a prototype cortical neural sensing microsystem for brain implantable neuroengineering applications. Its key feature is that both the transmission of broadband, multichannel neural data and power required for the embedded microelectronics are provided by optical fiber access. The fiber-optic system is aimed at enabling neural recording from rodents and primates by converting cortical signals to a digital stream of infrared light pulses. In the full microsystem whose performance is summarized in this paper, an analog-to-digital converter and a low power digital controller IC have been integrated with a low threshold, semiconductor laser to extract the digitized neural signals optically from the implantable unit. The microsystem also acquires electrical power and synchronization clocks via optical fibers from an external laser by using a highly efficient photovoltaic cell on board. The implantable unit employs a flexible polymer substrate to integrate analog and digital microelectronics and on-chip optoelectronic components, while adapting to the anatomical and physiological constraints of the environment. A low power analog CMOS chip, which includes preamplifier and multiplexing circuitry, is directly flip-chip bonded to the microelectrode array to form the cortical neurosensor device.

Versatile On-Chip Programming of Circuit Hardware for Wearable and Implantable Biomedical Microdevices.

Wearable and implantable microscale electronic sensors have been developed for a range of biomedical applications. The sensors, typically millimeter size silicon microchips, are sought for multiple sensing functions but are severely constrained by size and power. To address these challenges, a hardware programmable application-specific integrated circuit design is proposed and post-process methodology is exemplified by the design of battery-less wireless microchips. Specifically, both mixed-signal and radio frequency circuits are designed by incorporating metal fuses and anti-fuses on the top metal layer to enable programmability of any number of features in hardware of the system-on-chip (SoC) designs. This is accomplished in post-foundry editing by combining laser ablation and focused ion beam processing. The programmability provided by the technique can significantly accelerate the SoC chip development process by enabling the exploration of multiple internal circuit parameters without the requirement of additional programming pads or extra power consumption. As examples, experimental results are described for sub-millimeter size complementary metal-oxide-semiconductor microchips being developed for wireless electroencephalogram sensors and as implantable microstimulators for neural interfaces. The editing technique can be broadly applicable for miniaturized biomedical wearables and implants, opening up new possibilities for their expedited development and adoption in the field of smart healthcare.

Visual experience-dependent maturation of correlated neuronal activity patterns in a developing visual system.

The functional properties of neural circuits become increasingly robust over development. This allows circuits to optimize their output in response to a variety of input. However, it is not clear whether this optimization is a function of hardwired circuit elements, or whether it requires neural experience to develop. We performed rapid in vivo imaging of calcium signals from bulk-labeled neurons in the Xenopus laevis optic tectum to resolve the rapid spatiotemporal response properties of populations of developing tectal neurons in response to visual stimuli. We found that during a critical time in tectal development, network activity becomes increasingly robust, more correlated, and more synchronous. These developmental changes require normal visual input during development and are disrupted by NMDAR blockade. Our data show that visual activity and NMDAR activation are critical for the maturation of tectal network dynamics during visual system development.

Sub-mm resolution tomographic imaging in turbid media by an ultra-high density multichannel approach.

We demonstrate an ultra-high-density source-detector (SD) diffuse optical tomography system scalable to thousands of combinatorial SD pairs per cm3 of total voxel volume. We demonstrate the imaging of dynamic targets (including phantom arteries) with 100 um resolution at over 10 Hz frame rate within turbid media (> 60 MFP). Further, as a step toward a wearable mobile imager, we introduce monolithic mm-size dense semiconductor laser array chips as sources for potential unobtrusive epidermal tomographic use.

Grasp-squeeze adaptation to changes in object compliance leads to dynamic beta-band communication between primary somatosensory and motor cortices.

In asking the question of how the brain adapts to changes in the softness of manipulated objects, we studied dynamic communication between the primary sensory and motor cortical areas when nonhuman primates grasp and squeeze an elastically deformable manipulandum to attain an instructed force level. We focused on local field potentials recorded from S1 and M1 via intracortical microelectrode arrays. We computed nonparametric spectral Granger Causality to assess directed cortico-cortical interactions between these two areas. We demonstrate that the time-causal relationship between M1 and S1 is bidirectional in the beta-band (15-30 Hz) and that this interareal communication develops dynamically as the subjects adjust the force of hand squeeze to reach the target level. In particular, the directed interaction is strongest when subjects are focused on maintaining the instructed force of hand squeeze in a steady state for several seconds. When the manipulandum's compliance is abruptly changed, beta-band interareal communication is interrupted for a short period (~ 1 s) and then is re-established once the subject has reached a new steady state. These results suggest that transient beta oscillations can provide a communication subspace for dynamic cortico-cortical S1-M1 interactions during maintenance of steady sensorimotor states.

Wireless Addressable Cortical Microstimulators Powered by Near-Infrared Harvesting.

Ensembles of autonomous, spatially distributed wireless stimulators can offer a versatile approach to patterned microstimulation of biological circuits such as the cortex. Here, we demonstrate the concept of a distributed, untethered, and addressable microstimulator, integrating an ultraminiaturized ASIC with a custom-designed GaAs photovoltaic (PV) microscale energy harvester, dubbed as an "optical neurograin (ONG)". An on-board Manchester-encoded near-infrared downlink delivers incident IR power and provides a synchronous clock across an ensemble of microdevices, triggering stimulus events by remote command. Each ONG has a unique device address and, when an incoming downlink bit sequence matches with this device identification (ID), the implant delivers a charge-balanced current stimulus to the target cortex. Present devices use 7-bit metal fuses fabricated during the CMOS process for their device ID, laser-scribed in post-processing, allowing in principle for a stimulator network of up to 128 nodes. We have characterized small ensembles of ONGs and shown a proof of concept of the system both on benchtop and in vivo rat rodent model.

Home Use of a Percutaneous Wireless Intracortical Brain-Computer Interface by Individuals With Tetraplegia.

OBJECTIVE: Individuals with neurological disease or injury such as amyotrophic lateral sclerosis, spinal cord injury or stroke may become tetraplegic, unable to speak or even locked-in. For people with these conditions, current assistive technologies are often ineffective. Brain-computer interfaces are being developed to enhance independence and restore communication in the absence of physical movement. Over the past decade, individuals with tetraplegia have achieved rapid on-screen typing and point-and-click control of tablet apps using intracortical brain-computer interfaces (iBCIs) that decode intended arm and hand movements from neural signals recorded by implanted microelectrode arrays. However, cables used to convey neural signals from the brain tether participants to amplifiers and decoding computers and require expert oversight, severely limiting when and where iBCIs could be available for use. Here, we demonstrate the first human use of a wireless broadband iBCI. METHODS: Based on a prototype system previously used in pre-clinical research, we replaced the external cables of a 192-electrode iBCI with wireless transmitters and achieved high-resolution recording and decoding of broadband field potentials and spiking activity from people with paralysis. Two participants in an ongoing pilot clinical trial completed on-screen item selection tasks to assess iBCI-enabled cursor control. RESULTS: Communication bitrates were equivalent between cabled and wireless configurations. Participants also used the wireless iBCI to control a standard commercial tablet computer to browse the web and use several mobile applications. Within-day comparison of cabled and wireless interfaces evaluated bit error rate, packet loss, and the recovery of spike rates and spike waveforms from the recorded neural signals. In a representative use case, the wireless system recorded intracortical signals from two arrays in one participant continuously through a 24-hour period at home. SIGNIFICANCE: Wireless multi-electrode recording of broadband neural signals over extended periods introduces a valuable tool for human neuroscience research and is an important step toward practical deployment of iBCI technology for independent use by individuals with paralysis. On-demand access to high-performance iBCI technology in the home promises to enhance independence and restore communication and mobility for individuals with severe motor impairment.

Si nanowire metal-insulator-semiconductor photodetectors as efficient light harvesters.

Novel ITO-Si nanowire (NW) metal-insulator-semiconductor (MIS) photodetectors were fabricated by using n-type Si NWs as detection units and ITO films as top gate electrodes. Measurements on the Si NW based device reveal a significant photoresponse, including photocurrent generation with an external quantum efficiency (EQE) of approximately 35% at a peak wavelength of 600 nm at zero external bias, and with an EQE of 70% at a peak wavelength of 800 nm at - 0.5 V bias. The NW device shows a flat and low reflectance and almost constant EQE up to a 60 degrees incident angle of illumination, demonstrating efficient visible-light harvesting by the Si NW antenna.

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.

Challenges for Large-Scale Cortical Interfaces.

This Perspective examines the status of large-scale cortical interfaces through the lens of potential applications to active implants for brain-machine interfaces. Examples of research and development in a still embryonic field are discussed from a neuroengineer's perspective, touching on the design of scalable electrophysiological sensors with the ambition to access thousands of cortical points at near-cellular-level resolution. Important issues include microscale geometry of neural probes, design of implantable ultra-low-power electronics, implementation of high-data-rate wireless telemetry, and compatible device packaging-all requiring advanced solutions along a translational path for chronic human use.

A method for large-scale implantation of 3D microdevice ensembles into brain and soft tissue.

Wireless networks of implantable electronic sensors and actuators at the microscale (sub-mm) level are being explored for monitoring and modulation of physiological activity for medical diagnostics and therapeutic purposes. Beyond the requirement of integrating multiple electronic or chemical functions within small device volumes, a key challenge is the development of high-throughput methods for the implantation of large numbers of microdevices into soft tissues with minimal damage. To that end, we have developed a method for high-throughput implantation of ~100-200 µm size devices, which are here simulated by proxy microparticle ensembles. While generally applicable to subdermal tissue, our main focus and experimental testbed is the implantation of microparticles into the brain. The method deploys a scalable delivery tool composed of a 2-dimensional array of polyethylene glycol-tipped microneedles that confine the microparticle payloads. Upon dissolution of the bioresorbable polyethylene glycol, the supporting array structure is retrieved, and the microparticles remain embedded in the tissue, distributed spatially and geometrically according to the design of the microfabricated delivery tool. We first evaluated the method in an agarose testbed in terms of spatial precision and throughput for up to 1000 passive spherical and planar microparticles acting as proxy devices. We then performed the same evaluations by implanting particles into the rat cortex under acute conditions and assessed the tissue injury produced by our method of implantation under chronic conditions.