A direct spinal cord-computer interface enables the control of the paralysed hand in spinal cord injury.

The paralysis of the muscles controlling the hand dramatically limits the quality of life of individuals living with spinal cord injury (SCI). Here, with a non-invasive neural interface, we demonstrate that eight motor complete SCI individuals (C5-C6) are still able to task-modulate in real-time the activity of populations of spinal motor neurons with residual neural pathways. In all SCI participants tested, we identified groups of motor units under voluntary control that encoded various hand movements. The motor unit discharges were mapped into more than 10 degrees of freedom, ranging from grasping to individual hand-digit flexion and extension. We then mapped the neural dynamics into a real-time controlled virtual hand. The SCI participants were able to match the cue hand posture by proportionally controlling four degrees of freedom (opening and closing the hand and index flexion/extension). These results demonstrate that wearable muscle sensors provide access to spared motor neurons that are fully under voluntary control in complete cervical SCI individuals. This non-invasive neural interface allows the investigation of motor neuron changes after the injury and has the potential to promote movement restoration when integrated with assistive devices.

Tissue engineering strategies for spiral ganglion neuron protection and regeneration.

Cochlear implants can directly activate the auditory system's primary sensory neurons, the spiral ganglion neurons (SGNs), via circumvention of defective cochlear hair cells. This bypass restores auditory input to the brainstem. SGN loss etiologies are complex, with limited mammalian regeneration. Protecting and revitalizing SGN is critical. Tissue engineering offers a novel therapeutic strategy, utilizing seed cells, biomolecules, and scaffold materials to create a cellular environment and regulate molecular cues. This review encapsulates the spectrum of both human and animal research, collating the factors contributing to SGN loss, the latest advancements in the utilization of exogenous stem cells for auditory nerve repair and preservation, the taxonomy and mechanism of action of standard biomolecules, and the architectural components of scaffold materials tailored for the inner ear. Furthermore, we delineate the potential and benefits of the biohybrid neural interface, an incipient technology in the realm of implantable devices. Nonetheless, tissue engineering requires refined cell selection and differentiation protocols for consistent SGN quality. In addition, strategies to improve stem cell survival, scaffold biocompatibility, and molecular cue timing are essential for biohybrid neural interface integration.

Responsive manipulation of neural circuit pathology by fully implantable, front-end multiplexed embedded neuroelectronics.

Responsive neurostimulation is increasingly required to probe neural circuit function and treat neuropsychiatric disorders. We introduce a multiplex-then-amplify (MTA) scheme that, in contrast to current approaches (which necessitate an equal number of amplifiers as number of channels), only requires one amplifier per multiplexer, significantly reducing the number of components and the size of electronics in multichannel acquisition systems. It also enables simultaneous stimulation of arbitrary waveforms on multiple independent channels. We validated the function of MTA by developing a fully implantable, responsive embedded system that merges the ability to acquire individual neural action potentials using conformable conducting polymer-based electrodes with real-time onboard processing, low-latency arbitrary waveform stimulation, and local data storage within a miniaturized physical footprint. We verified established responsive neurostimulation protocols and developed a network intervention to suppress pathological coupling between the hippocampus and cortex during interictal epileptiform discharges. The MTA design enables effective, self-contained, chronic neural network manipulation with translational relevance to the treatment of neuropsychiatric disease.

Ultraflexible Neural Probes for Multidirectional Neuronal Activity Recordings over Large Spatial and Temporal Scales.

The widespread dissemination of ultraflexible neural probes depends on the development of advanced materials and implementation strategies that can allow reliable implantation of ultraflexible neural probes into targeted brain regions, especially deep and difficult-to-access brain regions. Here, we report ultraflexible and multidirectional probes that are encapsulated in a biocompatible polymer alloy with controllable dissolution kinetics. Our probes can be reliably implanted into targeted brain regions over large spatial scales, including deep hindbrain regions that are anatomically difficult-to-access in vivo. Chronically implanted probes can enable long-term, multidirectional recordings from several hundreds of neurons across distributed brain regions. In particular, our results show that 87.0% of chronically recorded neurons in the hindbrain are interneurons, whereas only 41.9% of chronically recorded neurons in the cortex are interneurons. These results demonstrate that our ultraflexible neural probes are a promising tool for large-scale, long-term neural circuit dissection in the brain.

Applications of 2D Nanomaterials in Neural Interface.

Neural interfaces are crucial conduits between neural tissues and external devices, enabling the recording and modulation of neural activity. However, with increasing demand, simple neural interfaces are no longer adequate to meet the requirements for precision, functionality, and safety. There are three main challenges in fabricating advanced neural interfaces: sensitivity, heat management, and biocompatibility. The electrical, chemical, and optical properties of 2D nanomaterials enhance the sensitivity of various types of neural interfaces, while the newly developed interfaces do not exhibit adverse reactions in terms of heat management and biocompatibility. Additionally, 2D nanomaterials can further improve the functionality of these interfaces, including magnetic resonance imaging (MRI) compatibility, stretchability, and drug delivery. In this review, we examine the recent applications of 2D nanomaterials in neural interfaces, focusing on their contributions to enhancing performance and functionality. Finally, we summarize the advantages and disadvantages of these nanomaterials, analyze the importance of biocompatibility testing for 2D nanomaterials, and propose that improving and developing composite material structures to enhance interface performance will continue to lead the forefront of this field.

Assessing the manufacturable 32-channel cochlear electrode array: evaluation results for clinical trials.

Reliability evaluation results of a manufacturable 32-channel cochlear electrode array are reported in this paper. Applying automated laser micro-machining process and a layer-by-layer silicone deposition scheme, authors developed the manufacturing methods of the electrode array for fine patterning and mass production. The developed electrode array has been verified through the requirements specified by the ISO Standard 14708-7. And the insertion trauma of the electrode array has been evaluated based on human temporal bone studies. According to the specified requirements, the electrode array was assessed through elongation & insulation, flexural, and fatigue tests. In addition, Temporal bone study was performed using eight fresh-frozen cadaver temporal bones with the electrode arrays inserted via the round window. Following soaking in saline condition, the impedances between conducting wires of the electrode array were measured over 100 kΩ (the pass/fail criterion). After each required test, it was shown that the electrode array maintained the electrical continuity and insulation condition. The average insertion angle of the electrode array inside the scala tympani was 399.7°. The human temporal bone studies exhibited atraumatic insertion rate of 60.3% (grade 0 or 1). The reliability of the manufacturable electrode array is successfully verified in mechanical, electrical, and histological aspects. Following the completion of a 32-channel cochlear implant system, the performance and stability of the 32-channel electrode array will be evaluated in clinical trials.

Modulation of Early Stage Neuronal Outgrowth through Out-of-Plane Graphene.

The correct wiring of a neural network requires neuron to integrate an incredible repertoire of cues found in their extracellular environment. The astonishing efficiency of this process plays a pivotal role in the correct wiring of the brain during development and axon regeneration. Biologically inspired micro- and nanostructured substrates have been shown to regulate axonal outgrowth. In parallel, several studies investigated graphene's potential as a conductive neural interface, able to enhance cell adhesion, neurite sprouting and outgrowth. Here, we engineered a 3D single- to few-layer fuzzy graphene morphology (3DFG), 3DFG on a collapsed Si nanowire (SiNW) mesh template (NT-3DFGc), and 3DFG on a noncollapsed SiNW mesh template (NT-3DFGnc) as neural-instructive materials. The micrometric protruding features of the NWs templates dictated neuronal growth cone establishment, as well as influencing axon elongation and branching. Furthermore, neurons-to-graphene coupling was investigated with comprehensive view of integrin-mediated contact adhesion points and plasma membrane curvature processes.

Peripheral neurostimulation for encoding artificial somatosensations.

The direct neural stimulation of peripheral or central nervous systems has been shown as an effective tool to treat neurological conditions. The electrical activation of the nervous sensory pathway can be adopted to restore the artificial sense of touch and proprioception in people suffering from sensory-motor disorders. The modulation of the neural stimulation parameters has a direct effect on the electrically induced sensations, both when targeting the somatosensory cortex and the peripheral somatic nerves. The properties of the artificial sensations perceived, as their location, quality and intensity are strongly dependent on the direct modulation of pulse width, amplitude and frequency of the neural stimulation. Different sensory encoding schemes have been tested in patients showing distinct effects and outcomes according to their impact on the neural activation. Here, I reported the most adopted neural stimulation strategies to artificially encode somatosensation into the peripheral nervous system. The real-time implementation of these strategies in bionic devices is crucial to exploit the artificial sensory feedback in prosthetics. Thus, neural stimulation becomes a tool to directly communicate with the human nervous system. Given the importance of adding artificial sensory information to neuroprosthetic devices to improve their control and functionality, the choice of an optimal neural stimulation paradigm could increase the impact of prosthetic devices on the quality of life of people with sensorimotor disabilities.

Galvanic-coupled Trans-dural Data Transfer for High-bandwidth Intra-cortical Neural Sensing.

A digital-impulse galvanic coupling as a new high-speed trans-dural (from cortex to the skull) data transmission method has been presented in this paper. The proposed wireless telemetry replaces the tethered wires connected in between implants on the cortex and above the skull, allowing the brain implant to be "free-floating" for minimizing brain tissue damage. Such trans-dural wireless telemetry must have a wide channel bandwidth for high-speed data transfer and a small form factor for minimum invasiveness. To investigate the propagation property of the channel, a finite element model is developed and a channel characterization based on a liquid phantom and porcine tissue is performed. The results show that the trans-dural channel has a wide frequency response of up to 250 MHz. Propagation loss due to micro-motion and misalignments is also investigated in this work. The result indicates that the proposed transmission method is relatively insensitive to misalignment. It has approximately 1 dB extra loss when there is a horizontal misalignment of 1mm. A pulse-based transmitter ASIC and a miniature PCB module are designed and validated ex-vivo with a 10-mm thick porcine tissue. This work demonstrates a high-speed and miniature in-body galvanic-coupled pulse-based communication with a data rate up to 250 Mbps with an energy efficiency of 2 pJ/bit, and has a small module area of only 26 mm2.

An Energy-Efficient and High-Data-Rate IR-UWB Transmitter for Intracortical Neural Sensing Interfaces.

This paper presents an implantable impulse-radio ultra-wideband (IR-UWB) wireless telemetry system for intracortical neural sensing interfaces. A 3-dimensional (3-D) hybrid impulse modulation that comprises phase shift keying (PSK), pulse position modulation (PPM) and pulse amplitude modulation (PAM) is proposed to increase modulation order without significantly increasing the demodulation requirement, thus leading to a high data rate of 1.66 Gbps and an increased air-transmission range. Operating in 6 - 9 GHz UWB band, the presented transmitter (TX) supports the proposed hybrid modulation with a high energy efficiency of 5.8 pJ/bit and modulation quality (EVM< -21 dB). A low-noise injection-locked ring oscillator supports 8-PSK with a phase error of 2.6°. A calibration free delay generator realizes a 4-PPM with only 115 µW and avoids potential cross-modulation between PPM and PSK. A switch-cap power amplifier with an asynchronous pulse-shaping performs 4-PAM with high energy efficiency and linearity. The TX is implemented in 28 nm CMOS technology, occupying 0.155mm2 core area. The wireless module including a printed monopole antenna has a module area of only 1.05 cm2. The transmitter consumes in total 9.7 mW when transmitting -41.3 dBm/MHz output power. The wireless telemetry module has been validated ex-vivo with a 15-mm multi-layer porcine tissue, and achieves a communication (air) distance up to 15 cm, leading to at least 16× improvement in distance-moralized energy efficiency of 45 pJ/bit/meter compared to state-of-the-art.

In Vivo Penetrating Microelectrodes for Brain Electrophysiology.

In recent decades, microelectrodes have been widely used in neuroscience to understand the mechanisms behind brain functions, as well as the relationship between neural activity and behavior, perception and cognition. However, the recording of neuronal activity over a long period of time is limited for various reasons. In this review, we briefly consider the types of penetrating chronic microelectrodes, as well as the conductive and insulating materials for microelectrode manufacturing. Additionally, we consider the effects of penetrating microelectrode implantation on brain tissue. In conclusion, we review recent advances in the field of in vivo microelectrodes.

Dimensionality Reduction and Prediction of Impedance Data of Biointerface.

Electrochemical impedance spectroscopy (EIS) is the golden tool for many emerging biomedical applications that describes the behavior, stability, and long-term durability of physical interfaces in a specific range of frequency. Impedance measurements of any biointerface during in vivo and clinical applications could be used for assessing long-term biopotential measurements and diagnostic purposes. In this paper, a novel approach to predicting impedance behavior is presented and consists of a dimensional reduction procedure by converting EIS data over many days of an experiment into a one-dimensional sequence of values using a novel formula called day factor (DF) and then using a long short-term memory (LSTM) network to predict the future behavior of the DF. Three neural interfaces of different material compositions with long-term in vitro aging tests were used to validate the proposed approach. The results showed good accuracy in predicting the quantitative change in the impedance behavior (i.e., higher than 75%), in addition to good prediction of the similarity between the actual and the predicted DF signals, which expresses the impedance fluctuations among soaking days. The DF approach showed a lower computational time and algorithmic complexity compared with principal component analysis (PCA) and provided the ability to involve or emphasize several important frequencies or impedance range in a more flexible way.

All-Tissue-like Multifunctional Optoelectronic Mesh for Deep-Brain Modulation and Mapping.

The development of a multifunctional device that achieves optogenetic neuromodulation and extracellular neural mapping is crucial for understanding neural circuits and treating brain disorders. Although various devices have been explored for this purpose, it is challenging to develop biocompatible optogenetic devices that can seamlessly interface with the brain. Herein, we present a tissue-like optoelectronic mesh with a compact interface that enables not only high spatial and temporal resolutions of optical stimulation but also the sampling of optically evoked neural activities. An in vitro experiment in hydrogel showed efficient light propagation through a freestanding SU-8 waveguide that was integrated with flexible mesh electronics. Additionally, an in vivo implantation of the tissue-like optoelectronic mesh in the brain of a live transgenic mouse enabled the sampling of optically evoked neural signals. Therefore, this multifunctional device can aid the chronic modulation of neural circuits and behavior studies for developing biological and therapeutic applications.

A Therapeutic Strategy for Lower Motor Neuron Disease and Injury Integrating Neural Stem Cell Transplantation and Functional Electrical Stimulation in a Rat Model.

Promising treatments for upper motor neuron disease are emerging in which motor function is restored by brain-computer interfaces and functional electrical stimulation. At present, such technologies and procedures are not applicable to lower motor neuron disease. We propose a novel therapeutic strategy for lower motor neuron disease and injury integrating neural stem cell transplantation with our new functional electrical stimulation control system. In a rat sciatic nerve transection model, we transplanted embryonic spinal neural stem cells into the distal stump of the peripheral nerve to reinnervate denervated muscle, and subsequently demonstrated that highly responsive limb movement similar to that of a healthy limb could be attained with a wirelessly powered two-channel neurostimulator that we developed. This unique technology, which can reinnervate and precisely move previously denervated muscles that were unresponsive to electrical stimulation, contributes to improving the condition of patients suffering from intractable diseases of paralysis and traumatic injury.

Discriminability of multiple cutaneous and proprioceptive hand percepts evoked by intraneural stimulation with Utah slanted electrode arrays in human amputees.

BACKGROUND: Electrical stimulation of residual afferent nerve fibers can evoke sensations from a missing limb after amputation, and bionic arms endowed with artificial sensory feedback have been shown to confer functional and psychological benefits. Here we explore the extent to which artificial sensations can be discriminated based on location, quality, and intensity. METHODS: We implanted Utah Slanted Electrode Arrays (USEAs) in the arm nerves of three transradial amputees and delivered electrical stimulation via different electrodes and frequencies to produce sensations on the missing hand with various locations, qualities, and intensities. Participants performed blind discrimination trials to discriminate among these artificial sensations. RESULTS: Participants successfully discriminated cutaneous and proprioceptive sensations ranging in location, quality and intensity. Performance was significantly greater than chance for all discrimination tasks, including discrimination among up to ten different cutaneous location-intensity combinations (15/30 successes, p < 0.0001) and seven different proprioceptive location-intensity combinations (21/40 successes, p < 0.0001). Variations in the site of stimulation within the nerve, via electrode selection, enabled discrimination among up to five locations and qualities (35/35 successes, p < 0.0001). Variations in the stimulation frequency enabled discrimination among four different intensities at the same location (13/20 successes, p < 0.0005). One participant also discriminated among individual stimulation of two different USEA electrodes, simultaneous stimulation on both electrodes, and interleaved stimulation on both electrodes (20/24 successes, p < 0.0001). CONCLUSION: Electrode location, stimulation frequency, and stimulation pattern can be modulated to evoke functionally discriminable sensations with a range of locations, qualities, and intensities. This rich source of artificial sensory feedback may enhance functional performance and embodiment of bionic arms endowed with a sense of touch.

A Low-Power Opamp-Less Second-Order Delta-Sigma Modulator for Bioelectrical Signals in 0.18 µm CMOS.

This article reports on a compact and low-power CMOS readout circuit for bioelectrical signals based on a second-order delta-sigma modulator. The converter uses a voltage-controlled, oscillator-based quantizer, achieving second-order noise shaping with a single opamp-less integrator and minimal analog circuitry. A prototype has been implemented using 0.18 µm CMOS technology and includes two different variants of the same modulator topology. The main modulator has been optimized for low-noise, neural-action-potential detection in the 300 Hz-6 kHz band, with an input-referred noise of 5.0 µVrms, and occupies an area of 0.0045 mm2. An alternative configuration features a larger input stage to reduce low-frequency noise, achieving 8.7 µVrms in the 1 Hz-10 kHz band, and occupies an area of 0.006 mm2. The modulator is powered at 1.8 V with an estimated power consumption of 3.5 µW.

Local delivery of minocycline-loaded PLGA nanoparticles from gelatin-coated neural implants attenuates acute brain tissue responses in mice.

BACKGROUND: Neural interfaces often elicit inflammatory responses and neuronal loss in the surrounding tissue which adversely affect the function and longevity of the implanted device. Minocycline, an anti-inflammatory pharmaceutics with neuroprotective properties, may be used for reducing the acute brain tissue responses after implantation. However, conventional administration routes require high doses which can cause adverse systemic side effects. Therefore, the aim of this study was to develop and evaluate a new drug-delivery-system for local and sustained administration of minocycline in the brain. METHODS: Stainless steel needles insulated with Parylene-C were dip-coated with non-crosslinked gelatin and minocycline-loaded PLGA nanoparticles (MC-NPs) were incorporated into the gelatin-coatings by an absorption method and subsequently trapped by drying the gelatin. Parylene-C insulated needles coated only with gelatin were used as controls. The expression of markers for activated microglia (CD68), all microglia (CX3CR1-GFP), reactive astrocytes (GFAP), neurons (NeuN) and all cell nuclei (DAPI) surrounding the implantation sites were quantified at 3 and 7 days after implantation in mice. RESULTS: MC-NPs were successfully incorporated into gelatin-coatings of neural implants by an absorption method suitable for thermosensitive drug-loads. Immunohistochemical analysis of the in vivo brain tissue responses, showed that MC-NPs significantly attenuate the activation of microglial cells without effecting the overall population of microglial cells around the implantation sites. A delayed but significant reduction of the astrocytic response was also found in comparison to control implants. No effect on neurons or total cell count was found which may suggest that the MC-NPs are non-toxic to the central nervous system. CONCLUSIONS: A novel drug-nanoparticle-delivery-system was developed for neural interfaces and thermosensitive drug-loads. The local delivery of MC-NPs was shown to attenuate the acute brain tissue responses nearby an implant and therefore may be useful for improving biocompatibility of implanted neuro-electronic interfaces. The developed drug-delivery-system may potentially also be used for other pharmaceutics to provide highly localized and therefore more specific effects as compared to systemic administration.

Optimizing the neuron-electrode interface for chronic bioelectronic interfacing.

Engineering approaches have vast potential to improve the treatment of disease. Brain-machine interfaces have become a well-established means of treating some otherwise medically refractory neurological diseases, and they have shown promise in many more areas. More widespread use of implanted stimulating and recording electrodes for long-term intervention is, however, limited by the difficulty in maintaining a stable interface between implanted electrodes and the local tissue for reliable recording and stimulation.This loss of performance at the neuron-electrode interface is due to a combination of inflammation and glial scar formation in response to the implanted material, as well as electrical factors contributing to a reduction in function over time. An increasing understanding of the factors at play at the neural interface has led to greater focus on the optimization of this neuron-electrode interface in order to maintain long-term implant viability.A wide variety of approaches to improving device interfacing have emerged, targeting the mechanical, electrical, and biological interactions between implanted electrodes and the neural tissue. These approaches are aimed at reducing the initial trauma and long-term tissue reaction through device coatings, optimization of mechanical characteristics for maximal biocompatibility, and implantation techniques. Improved electrode features, optimized stimulation parameters, and novel electrode materials further aim to stabilize the electrical interface, while the integration of biological interventions to reduce inflammation and improve tissue integration has also shown promise.Optimization of the neuron-electrode interface allows the use of long-term, high-resolution stimulation and recording, opening the door to responsive closed-loop systems with highly selective modulation. These new approaches and technologies offer a broad range of options for neural interfacing, representing the possibility of developing specific implant technologies tailor-made to a given task, allowing truly personalized, optimized implant technology for chronic neural interfacing.

A systematic review of endovascular stent-electrode arrays, a minimally invasive approach to brain-machine interfaces.

OBJECTIVE: The goal of this study was to systematically review the feasibility and safety of minimally invasive neurovascular approaches to brain-machine interfaces (BMIs). METHODS: A systematic literature review was performed using the PubMed database for studies published between 1986 and 2019. All studies assessing endovascular neural interfaces were included. Additional studies were selected based on review of references of selected articles and review articles. RESULTS: Of the 53 total articles identified in the original literature search, 12 studies were ultimately selected. An additional 10 articles were included from other sources, resulting in a total of 22 studies included in this systematic review. This includes primarily preclinical studies comparing endovascular electrode recordings with subdural and epidural electrodes, as well as studies evaluating stent-electrode gauge and material type. In addition, several clinical studies are also included. CONCLUSIONS: Endovascular stent-electrode arrays provide a minimally invasive approach to BMIs. Stent-electrode placement has been shown to be both efficacious and safe, although further data are necessary to draw comparisons between subdural and epidural electrode measurements given the heterogeneity of the studies included. Greater access to deep-seated brain regions is now more feasible with stent-electrode arrays; however, further validation is needed in large clinical trials to optimize this neural interface. This includes the determination of ideal electrode material type, venous versus arterial approaches, the feasibility of deep brain stimulation, and more streamlined computational decoding techniques.

Selective Formation of Porous Pt Nanorods for Highly Electrochemically Efficient Neural Electrode Interfaces.

The enhanced electrochemical activity of nanostructured materials is readily exploited in energy devices, but their utility in scalable and human-compatible implantable neural interfaces can significantly advance the performance of clinical and research electrodes. We utilize low-temperature selective dealloying to develop scalable and biocompatible one-dimensional platinum nanorod (PtNR) arrays that exhibit superb electrochemical properties at various length scales, stability, and biocompatibility for high performance neurotechnologies. PtNR arrays record brain activity with cellular resolution from the cortical surfaces in birds and nonhuman primates. Significantly, strong modulation of surface recorded single unit activity by auditory stimuli is demonstrated in European Starling birds as well as the modulation of local field potentials in the visual cortex by light stimuli in a nonhuman primate and responses to electrical stimulation in mice. PtNRs record behaviorally and physiologically relevant neuronal dynamics from the surface of the brain with high spatiotemporal resolution, which paves the way for less invasive brain-machine interfaces.