Dynamic electrical stimulation enhances the recruitment of spinal interneurons by corticospinal input.

Highly varying patterns of electrostimulation (Dynamic Stimulation, DS) delivered to the dorsal cord through an epidural array with 18 independent electrodes transiently facilitate corticospinal motor responses, even after spinal injury. To partly unravel how corticospinal input are affected by DS, we introduced a corticospinal platform that allows selective cortical stimulation during the multisite acquisition of cord dorsum potentials (CDPs) and the simultaneous supply of DS. Firstly, the epidural interface was validated by the acquisition of the classical multisite distribution of CDPs and their input-output profile elicited by pulses delivered to peripheral nerves. Apart from increased EMGs, DS selectively increased excitability of the spinal interneurons that first process corticospinal input, without changing the magnitude of commands descending from the motor cortex, suggesting a novel correlation between muscle recruitment and components of cortically-evoked CDPs. Finally, DS increases excitability of post-synaptic spinal interneurons at the stimulation site and their responsiveness to any residual supraspinal control, thus supporting the use of electrical neuromodulation whenever the motor output is jeopardized by a weak volitional input, due to a partial disconnection from supraspinal structures and/or neuronal brain dysfunctions.

Spinal facilitation of descending motor input.

Highly varying patterns of electrostimulation (Dynamic Stimulation, DS) delivered to the dorsal cord through an epidural array with 18 independent electrodes transiently facilitate corticospinal motor responses, even after spinal injury. To partly unravel how corticospinal input are affected by DS, we introduced a corticospinal platform that allows selective cortical stimulation during the multisite acquisition of cord dorsum potentials (CDPs) and the simultaneous supply of DS. Firstly, the epidural interface was validated by the acquisition of the classical multisite distribution of CDPs on the dorsal cord and their input-output profile elicited by pulses delivered to peripheral nerves. Apart from increased EMGs, DS selectively increased excitability of the spinal interneurons that first process corticospinal input, without changing the magnitude of commands descending from the motor cortex, suggesting a novel correlation between muscle recruitment and components of cortically-evoked CDPs. Finally, DS increases excitability of post-synaptic spinal interneurons at the stimulation site and their responsiveness to any residual supraspinal control, thus supporting the use of electrical neuromodulation whenever the motor output is jeopardized by a weak volitional input, due to a partial disconnection from supraspinal structures and/or neuronal brain dysfunctions.

An epidural stimulating interface unveils the intrinsic modulation of electrically motor evoked potentials in behaving rats.

In intact and spinal-injured anesthetized animals, stimulation levels that did not induce any visible muscle twitches were used to elicit motor evoked potentials (MEPs) of varying amplitude, reflecting the temporal and amplitude dynamics of the background excitability of spinal networks. To characterize the physiological excitability states of neuronal networks driving movement, we designed five experiments in awake rats chronically implanted with an epidural stimulating interface, with and without a spinal cord injury (SCI). First, an uninjured rat at rest underwent a series of single electrical pulses at sub-motor threshold intensity, which generated responses that were continuously recorded from flexor and extensor hindlimb muscles, showing an intrinsic patterned modulation of MEPs. Responses were recruited by increasing strengths of stimulation, and the amplitudes were moderately correlated between flexors and extensors. Next, after SCI, four awake rats at rest showed electrically induced MEPs, varying largely in amplitude, of both flexors and extensors that were mainly synchronously modulated. After full anesthesia, MEP amplitudes were largely reduced, although stimulation still generated random baseline changes, unveiling an intrinsic stochastic modulation. The present five cases demonstrate a methodology that can be feasibly replicated in a broader group of awake and behaving rats to further define experimental treatments involving neuroplasticity. Besides validating a new technology for a neural stimulating interface, the present data support the broader message that there is intrinsic patterned and stochastic modulation of baseline excitability reflecting the dynamics of physiological states of spinal networks.NEW & NOTEWORTHY Chronic implants of a new epidural stimulating interface trace dynamics of spinal excitability in awake rats, before and after injury. Motor evoked potentials induced by trains of pulses at sub-motor threshold intensity were continuously modulated in amplitude. Oscillatory patterns of amplitude modulation reduced with increasing strengths of stimulation and were replaced by an intrinsic stochastic tone under anesthesia. Variability of baseline excitability is a fundamental feature of spinal networks, affecting their responses to external input.

A Biomimetic, SoC-Based Neural Stimulator for Novel Arbitrary-Waveform Stimulation Protocols.

Novel neural stimulation protocols mimicking biological signals and patterns have demonstrated significant advantages as compared to traditional protocols based on uniform periodic square pulses. At the same time, the treatments for neural disorders which employ such protocols require the stimulator to be integrated into miniaturized wearable devices or implantable neural prostheses. Unfortunately, most miniaturized stimulator designs show none or very limited ability to deliver biomimetic protocols due to the architecture of their control logic, which generates the waveform. Most such designs are integrated into a single System-on-Chip (SoC) for the size reduction and the option to implement them as neural implants. But their on-chip stimulation controllers are fixed and limited in memory and computing power, preventing them from accommodating the amplitude and timing variances, and the waveform data parameters necessary to output biomimetic stimulation. To that end, a new stimulator architecture is proposed, which distributes the control logic over three component tiers - software, microcontroller firmware and digital circuits of the SoC, which is compatible with existing and future biomimetic protocols and with integration into implantable neural prosthetics. A portable prototype with the proposed architecture is designed and demonstrated in a bench-top test with various known biomimetic output waveforms. The prototype is also tested in vivo to deliver a complex, continuous biomimetic stimulation to a rat model of a spinal-cord injury. By delivering this unique biomimetic stimulation, the device is shown to successfully reestablish the connectivity of the spinal cord post-injury and thus restore motor outputs in the rat model.

Acute neuromodulation restores spinally-induced motor responses after severe spinal cord injury.

Epidural electrical spinal stimulation can facilitate recovery of volitional motor control in individuals that have been completely paralyzed for more than a year. We recently reported a novel neuromodulation method named Dynamic Stimulation (DS), which short-lastingly increased spinal excitability and generated a robust modulation of locomotor networks in fully-anesthetized intact adult rats. In the present study, we applied repetitive DS patterns to four lumbosacral segments acutely after a contusive injury at lumbar level. Repetitive DS delivery restored the spinally-evoked motor EMG responses that were previously suppressed by a calibrated spinal cord contusion. Sham experiments without DS delivery did not allow any spontaneous recovery. Thus, DS uniquely provides the potential for a greater long-term functional recovery after paralysis.

Using EMG to deliver lumbar dynamic electrical stimulation to facilitate cortico-spinal excitability.

BACKGROUND: Potentiation of synaptic activity in spinal networks is reflected in the magnitude of modulation of motor responses evoked by spinal and cortical input. After spinal cord injury, motor evoked responses can be facilitated by pairing cortical and peripheral nerve stimuli. OBJECTIVE: To facilitate synaptic potentiation of cortico-spinal input with epidural electrical stimulation, we designed a novel neuromodulation method called dynamic stimulation (DS), using patterns derived from hind limb EMG signal during stepping. METHODS: DS was applied dorsally to the lumbar enlargement through a high-density epidural array composed of independent platinum-based micro-electrodes. RESULTS: In fully anesthetized intact adult rats, at the interface array/spinal cord, the temporal and spatial features of DS neuromodulation affected the entire lumbosacral network, particularly the most rostral and caudal segments covered by the array. DS induced a transient (at least 1 min) increase in spinal cord excitability and, compared to tonic stimulation, generated a more robust potentiation of the motor output evoked by single pulses applied to the spinal cord. When sub-threshold pulses were selectively applied to a cortical motor area, EMG responses from the contralateral leg were facilitated by the delivery of DS to the lumbosacral cord. Finally, based on motor-evoked responses, DS was linked to a greater amplitude of motor output shortly after a calibrated spinal cord contusion. CONCLUSION: Compared to traditional tonic waveforms, DS amplifies both spinal and cortico-spinal input aimed at spinal networks, thus significantly increasing the potential and accelerating the rate of functional recovery after a severe spinal lesion.

A Novel Biomimetic Stimulator System for Neural Implant.

Electrical stimulation using non-periodic biomimetic stimulation pattern has been shown to be effective in various critical biomedical applications. However, the existing programmable stimulators that support this protocol are non-portable and have architectures that are not translatable to wearable or implantable applications. In this work, we present a 32-channel neural stimulator system based on an implantable System-On-Chip (SoC) that addresses these technological challenges. The system is designed to be portable, powered by a single battery, wirelessly controlled, and versatile to perform concurrent multi-channel stimulation with independent arbitrary waveforms. The experimental results demonstrate multi-channel stimulation mimicking electromyography (EMG) waveforms and randomly-spaced stimulation pulses mimicking neuronal firing patterns. This compact and highly flexible prototype can support various neuromodulation researches and animal studies and serves as a precursor for the development of the next generation implantable biomimetic stimulator.

Transparent arrays of bilayer-nanomesh microelectrodes for simultaneous electrophysiology and two-photon imaging in the brain.

Transparent microelectrode arrays have emerged as increasingly important tools for neuroscience by allowing simultaneous coupling of big and time-resolved electrophysiology data with optically measured, spatially and type resolved single neuron activity. Scaling down transparent electrodes to the length scale of a single neuron is challenging since conventional transparent conductors are limited by their capacitive electrode/electrolyte interface. In this study, we establish transparent microelectrode arrays with high performance, great biocompatibility, and comprehensive in vivo validations from a recently developed, bilayer-nanomesh material composite, where a metal layer and a low-impedance faradaic interfacial layer are stacked reliably together in a same transparent nanomesh pattern. Specifically, flexible arrays from 32 bilayer-nanomesh microelectrodes demonstrated near-unity yield with high uniformity, excellent biocompatibility, and great compatibility with state-of-the-art wireless recording and real-time artifact rejection system. The electrodes are highly scalable, with 130 kilohms at 1 kHz at 20 µm in diameter, comparable to the performance of microelectrodes in nontransparent Michigan arrays. The highly transparent, bilayer-nanomesh microelectrode arrays allowed in vivo two-photon imaging of single neurons in layer 2/3 of the visual cortex of awake mice, along with high-fidelity, simultaneous electrical recordings of visual-evoked activity, both in the multi-unit activity band and at lower frequencies by measuring the visual-evoked potential in the time domain. Together, these advances reveal the great potential of transparent arrays from bilayer-nanomesh microelectrodes for a broad range of utility in neuroscience and medical practices.

Online Artifact Cancelation in Same-Electrode Neural Stimulation and Recording Using a Combined Hardware and Software Architecture.

Advancing studies of neural network dynamics and developments of closed-loop neural interfaces requires the ability to simultaneously stimulate and record the neural cells. Recording adjacent to or at the stimulation site produces artifact signals that are orders of magnitude larger than the neural responses of interest. These signals often saturate the recording amplifier causing distortion or loss of short-latency evoked responses. This paper proposes a method to cancel the artifact in simultaneous neural recording and stimulation on the same electrode. By combining a novel hardware architecture with concurrent software processing, the design achieves neural signal recovery in a wide range of conditions. The proposed system uniquely demonstrates same-electrode stimulation and recording, with neural signal recovery in presence of stimulation artifact 100 dB larger in magnitude than the underlying signals. The system is tested both in vitro and in vivo, during concurrent stimulation and recording on the same electrode. In vivo results in a rodent model are compared to recordings made by a commercial neural amplifier system connected in parallel.

A Fully Integrated Wireless SoC for Motor Function Recovery After Spinal Cord Injury.

This paper presents a wirelessly powered, fully integrated system-on-a-chip (SoC) supporting 160-channel stimulation, 16-channel recording, and 48-channel bio-impedance characterization to enable partial motor function recovery through epidural spinal cord electrical stimulation. A wireless transceiver is designed to support quasi full-duplex data telemetry at a data rate of 2 Mb/s. Furthermore, a unique in situ bio-impedance characterization scheme based on time-domain analysis is implemented to derive the Randles cell electrode model of the electrode-electrolyte interface. The SoC supports concurrent stimulation and recording while the high-density stimulator array meets an output compliance voltage of up to ±10 V with versatile stimulus programmability. The SoC consumes 18 mW and occupies a chip area of 5.7 mm × 4.4 mm using 0.18 µm high-voltage CMOS process. In our in vivo rodent experiment, the SoC is used to perform wireless recording of EMG responses while stimulation is applied to enable the standing and stepping of a paralyzed rat. To facilitate the system integration, a novel thin film polymer packaging technique is developed to provide a heterogeneous integration of the SoC, coils, discrete components, and high-density flexible electrode array, resulting in a miniaturized prototype implant with a weight and form factor of 0.7 g and 0.5 cm3, respectively.

A hybrid hardware and software approach for cancelling stimulus artifacts during same-electrode neural stimulation and recording.

Recovering neural responses from electrode recordings is fundamental for understanding the dynamics of neural networks. This effort is often obscured by stimulus artifacts in the recordings, which result from stimuli injected into the electrode-tissue interface. Stimulus artifacts, which can be orders of magnitude larger than the neural responses of interest, can mask short-latency evoked responses. Furthermore, simultaneous neural stimulation and recording on the same electrode generates artifacts with larger amplitudes compared to a separate electrode setup, which inevitably overwhelm the amplifier operation and cause unrecoverable neural signal loss. This paper proposes an end-to-end system combining hardware and software techniques for actively cancelling stimulus artifacts, avoiding amplifier saturation, and recovering neural responses during current-controlled in-vivo neural stimulation and recording. The proposed system is tested in-vitro under various stimulation settings by stimulating and recording on the same electrode with a superimposed pre-recorded neural signal. Experimental results show that neural responses can be recovered with minimal distortion even during stimulus artifacts that are several orders greater in magnitude.