Cervical transcutaneous spinal stimulation for spinal motor mapping.

Transcutaneous spinal stimulation (TSS) is a promising approach to restore upper-limb (UL) functions after spinal cord injury (SCI) in humans. We sought to demonstrate the selectivity of recruitment of individual UL motor pools during cervical TSS using different electrode placements. We demonstrated that TSS delivered over the rostrocaudal and mediolateral axes of the cervical spine resulted in a preferential activation of proximal, distal, and ipsilateral UL muscles. This was revealed by changes in motor threshold intensity, maximum amplitude, and the amount of post-activation depression of the evoked responses. We propose that an arrangement of electrodes targeting specific UL motor pools may result in superior efficacy, restoring more diverse motor activities after neurological injuries and disorders, including severe SCI.

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.

The effect of colonic tissue electrical stimulation and celiac branch of the abdominal vagus nerve neuromodulation on colonic motility in anesthetized pigs.

BACKGROUND: Knowledge on optimal electrical stimulation (ES) modalities and region-specific functional effects of colonic neuromodulation is lacking. We aimed to map the regional colonic motility in response to ES of (a) the colonic tissue and (b) celiac branch of the abdominal vagus nerve (CBVN) in an anesthetized porcine model. METHODS: In male Yucatan pigs, direct ES (10 Hz, 2 ms, 15 mA) of proximal (pC), transverse (tC), or distal (dC) colon was done using planar flexible multi-electrode array panels and CBVN ES (2 Hz, 0.3-4 ms, 5 mA) using pulse train (PT), continuous (10 min), or square-wave (SW) modalities, with or without afferent nerve block (200 Hz, 0.1 ms, 2 mA). The regional luminal manometric changes were quantified as area under the curve of contractions (AUC) and luminal pressure maps generated. Contractions frequency power spectral analysis was performed. Contraction propagation was assessed using video animation of motility changes. KEY RESULTS: Direct colon ES caused visible local circular (pC, tC) or longitudinal (dC) muscle contractions and increased luminal pressure AUC in pC, tC, and dC (143.0 ± 40.7%, 135.8 ± 59.7%, and 142.0 ± 62%, respectively). The colon displayed prominent phasic pressure frequencies ranging from 1 to 12 cpm. Direct pC and tC ES increased the dominant contraction frequency band (1-6 cpm) power locally. Pulse train CBVN ES (2 Hz, 4 ms, 5 mA) triggered pancolonic contractions, reduced by concurrent afferent block. Colon contractions propagated both orally and aborally in short distances. CONCLUSION AND INFERENCES: In anesthetized pigs, the dominant contraction frequency band is 1-6 cpm. Direct colonic ES causes primarily local contractions. The CBVN ES-induced pancolonic contractions involve central neural network.

A Wireless Implantable System for Facilitating Gastrointestinal Motility.

Gastrointestinal (GI) electrical stimulation has been shown in several studies to be a potential treatment option for GI motility disorders. Despite the promising preliminary research progress, however, its clinical applicability and usability are still unknown and limited due to the lack of a miniaturized versatile implantable stimulator supporting the investigation of effective stimulation patterns for facilitating GI dysmotility. In this paper, we present a wireless implantable GI modulation system to fill this technology gap. The system consists of a wireless extraluminal gastrointestinal modulation device (EGMD) performing GI electrical stimulation, and a rendezvous device (RD) and a custom-made graphical user interface (GUI) outside the body to wirelessly power and configure the EGMD to provide the desired stimuli for modulating GI smooth muscle activities. The system prototype was validated in bench-top and in vivo tests. The GI modulation system demonstrated its potential for facilitating intestinal transit in the preliminary in vivo chronic study using porcine models.

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.

Intestinal Electrical Stimulation to Increase the Rate of Peristalsis.

BACKGROUND: Pediatric gastrointestinal motility disorders are a large and broad group. Some of these disorders have been effectively treated with electrical stimulation. The goal of our present study is to determine whether the rate of intestinal peristalsis can be increased with electrical stimulation. METHODS: Juvenile mini-Yucatan pigs were placed under general anesthesia and a short segment of the jejunum was transected. Ultrasound gel was placed inside the segment. The segment of the jejunum was first monitored for 20 min under no stimulation, followed by direct electrical stimulation using a planar electrode. The gel extruded out of the intestine via peristalsis was collected and weighed for each 20-min time interval. RESULTS: Effective delivery of the current to the intestine was confirmed via direct measurements. When there was no direct intestinal electrical stimulation, an average of 0.40 g of gel was expelled in 20 min, compared to 1.57 g of gel expelled during direct electrical stimulation (P < 0.01). CONCLUSIONS: Direct intestinal electrical stimulation accelerates the transit of gastrointestinal contents. This approach may be useful in the treatment of a range of pediatric motility disorders.

A Wireless Implant for Gastrointestinal Motility Disorders.

Implantable functional electrical stimulation (IFES) has demonstrated its effectiveness as an alternative treatment option for diseases incurable pharmaceutically (e.g., retinal prosthesis, cochlear implant, spinal cord implant for pain relief). However, the development of IFES for gastrointestinal (GI) tract modulation is still limited due to the poorly understood GI neural network (gut⁻brain axis) and the fundamental difference among activating/monitoring smooth muscles, skeletal muscles and neurons. This inevitably imposes different design specifications for GI implants. This paper thus addresses the design requirements for an implant to treat GI dysmotility and presents a miniaturized wireless implant capable of modulating and recording GI motility. This implant incorporates a custom-made system-on-a-chip (SoC) and a heterogeneous system-in-a-package (SiP) for device miniaturization and integration. An in vivo experiment using both rodent and porcine models is further conducted to validate the effectiveness of the implant.

A Wireless Platform to Support Pre-Clinical Trial of Neural Implant for Spinal Cord Injury.

The efficacy of many clinical applications of electrical stimulation is currently gauged only by patients' verbal feedback or through the use of an independent system, limiting physicians' ability to provide quality treatment. By integrating neural response recording into the system, though, more accurate measures of treatment effectiveness are possible. This paper presents a platform which enables wireless control of an implantable bioelectronic device which integrates functional electrical stimulation and simultaneous recording of neural activity for a wide range of potential applications including motor function prostheses for spinal cord injury, retinal prostheses, and treatments for various other conditions. The proposed wireless platform utilizes a mobile application to offer a user-friendly integrated interface that enables setup and execution of stimulation and collection of recording data in animal studies. This platform will also support the continuing development of closed-loop neuromodulation strategies for investigating potential therapies for various diseases.

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.

Towards Closed-Loop Neuromodulation: A Wireless Miniaturized Neural Implant SoC.

This work reports a platform technology toward the development of closed-loop neuromodulation. A neural implant based on the SoC developed in our laboratory is used as an example to illustrate the necessary functionalities for the efficacious implantable system. We also present an example of using the system to investigate the epidural stimulation for partial motor function recovery after spinal cord injury in a rat model. This hardware-software co-design tool demonstrate its promising potential towards an effective closed-loop neuromodulation for various biomedical applications.

An On-Chip Multi-Voltage Power Converter With Leakage Current Prevention Using 0.18 µm High-Voltage CMOS Process.

In this paper, we present an on-chip multi-voltage power converter incorporating of a quad-voltage timing-control rectifier and regulators to produce ±12 V and ±1.8 V simultaneously through inductive powering. The power converter achieves a PCE of 77.3% with the delivery of more than 100 mW to the implant. The proposed rectifier adopts a two-phase start-up scheme and mixed-voltage gate controller to avoid substrate leakage current. This current cannot be prevented by the conventional dynamic substrate biasing technique when using the high-voltage CMOS process with transistor threshold voltage higher than the turn-on voltage of parasitic diodes. High power conversion efficiency is achieved by 1) substrate leakage current prevention, 2) operating all rectifying transistors as switches with boosted gate control voltages, and 3) compensating the delayed turn-on and preventing reverse leakage current of rectifying switches with the proposed look-ahead comparator. This chip occupies an area of 970 µm × 4500 µm in a 0.18 µ m 32 V HV CMOS process. The quad-voltage timing-control rectifier alone is able to output a high DC voltage at the range of [2.5 V, 25 V]. With this power converter, both bench-top experiment and in-vivo power link test using a rat model were validated.

Wireless gigabit data telemetry for large-scale neural recording.

Implantable wireless neural recording from a large ensemble of simultaneously acting neurons is a critical component to thoroughly investigate neural interactions and brain dynamics from freely moving animals. Recent researches have shown the feasibility of simultaneously recording from hundreds of neurons and suggested that the ability of recording a larger number of neurons results in better signal quality. This massive recording inevitably demands a large amount of data transfer. For example, recording 2000 neurons while keeping the signal fidelity ( > 12 bit, > 40 KS/s per neuron) needs approximately a 1-Gb/s data link. Designing a wireless data telemetry system to support such (or higher) data rate while aiming to lower the power consumption of an implantable device imposes a grand challenge on neuroscience community. In this paper, we present a wireless gigabit data telemetry for future large-scale neural recording interface. This telemetry comprises of a pair of low-power gigabit transmitter and receiver operating at 60 GHz, and establishes a short-distance wireless link to transfer the massive amount of neural signals outward from the implanted device. The transmission distance of the received neural signal can be further extended by an externally rendezvous wireless transceiver, which is less power/heat-constraint since it is not at the immediate proximity of the cortex and its radiated signal is not seriously attenuated by the lossy tissue. The gigabit data link has been demonstrated to achieve a high data rate of 6 Gb/s with a bit-error-rate of 10(-12) at a transmission distance of 6 mm, an applicable separation between transmitter and receiver. This high data rate is able to support thousands of recording channels while ensuring a low energy cost per bit of 2.08 pJ/b.

Design and fabrication of a multi-electrode array for spinal cord epidural stimulation.

A detailed design, fabrication, characterization and test of a flexible multi-site platinum/polyimide based electrode array for electrical epidural stimulation in spinal cord prosthesis is described in this paper. Carefully designed 8.4 µm-thick structure fabrication flow achieves an electrode surface modification with 3.8 times enhanced effective surface area without extra process needed. Measured impedance and phase of two type of electrodes are 2.35±0.21 KΩ and 2.10±0.11 KΩ, -34.25±8.07° and -27.71±8.27° at 1K Hz, respectively. The fabricated arrays were then in-vitro tested by a multichannel neural stimulation system in physiological saline to validate the capability for electrical stimulation. The measured channel isolation on adjacent electrode is about -34dB. Randles cell model was used to investigate the charging waveforms, the model parameters were then extracted by various methods. The measured charge transfer resistance, double layer capacitance, and solution resistance are 1.9 KΩ, 220 nF and 15 KΩ, respectively. The results show that the fabricated array is applicable for electrical stimulation with well characterized parameters. Combined with a multichannel stimulator, this system provides a full solution for versatile neural stimulation applications.

Bio-impedance characterization technique with implantable neural stimulator using biphasic current stimulus.

Knowledge of the bio-impedance and its equivalent circuit model at the electrode-electrolyte/tissue interface is important in the application of functional electrical stimulation. Impedance can be used as a merit to evaluate the proximity between electrodes and targeted tissues. Understanding the equivalent circuit parameters of the electrode can further be leveraged to set a safe boundary for stimulus parameters in order not to exceed the water window of electrodes. In this paper, we present an impedance characterization technique and implement a proof-of-concept system using an implantable neural stimulator and an off-the-shelf microcontroller. The proposed technique yields the parameters of the equivalent circuit of an electrode through large signal analysis by injecting a single low-intensity biphasic current stimulus with deliberately inserted inter-pulse delay and by acquiring the transient electrode voltage at three well-specified timings. Using low-intensity stimulus allows the derivation of electrode double layer capacitance since capacitive charge-injection dominates when electrode overpotential is small. Insertion of the inter-pulse delay creates a controlled discharge time to estimate the Faradic resistance. The proposed method has been validated by measuring the impedance of a) an emulated Randles cells made of discrete circuit components and b) a custom-made platinum electrode array in-vitro, and comparing estimated parameters with the results derived from an impedance analyzer. The proposed technique can be integrated into implantable or commercial neural stimulator system at low extra power consumption, low extra-hardware cost, and light computation.

A system verification platform for high-density epiretinal prostheses.

Retinal prostheses have restored light perception to people worldwide who have poor or no vision as a consequence of retinal degeneration. To advance the quality of visual stimulation for retinal implant recipients, a higher number of stimulation channels is expected in the next generation retinal prostheses, which poses a great challenge to system design and verification. This paper presents a system verification platform dedicated to the development of retinal prostheses. The system includes primary processing, dual-band power and data telemetry, a high-density stimulator array, and two methods for output verification. End-to-end system validation and individual functional block characterization can be achieved with this platform through visual inspection and software analysis. Custom-built software running on the computers also provides a good way for testing new features before they are realized by the ICs. Real-time visual feedbacks through the video displays make it easy to monitor and debug the system. The characterization of the wireless telemetry and the demonstration of the visual display are reported in this paper using a 256-channel retinal prosthetic IC as an example.

A fully-integrated high-compliance voltage SoC for epi-retinal and neural prostheses.

This paper presents a fully functionally integrated 1024-channel mixed-mode and mixed-voltage system-on-a-chip (SoC) for epi-retinal and neural prostheses. Taking an AC input, an integrated power telemetry circuits is capable of generating multiple DC voltages with a voltage conversion efficiency of 83% at a load of 100 mW without external diodes or separate power integrated circuits, reducing the form factor of the prosthetic device. A wireless DPSK receiver with a novel noise reduction scheme supports a data rate of 2 Mb/s at a bit-error-rate of 2 ×10⁻7. The 1024-channel stimulator array meets an output compliance voltage of ±10 V and provides flexible stimulation waveforms. Through chip-clustering, the stimulator array can be further expanded to 4096 channels. This SoC is designed and fabricated in TSMC 0.18 µm high-voltage 32 V CMOS process and occupies a chip area of 5.7 mm × 6.6 mm. Using this SoC, a retinal implant bench-top test system is set up with real-time visual verification. In-vitro experiment conducted in artificial vitreous humor is designed and set-up to investigate stimulation waveforms for better visual resolution. In our in-vivo experiment, a hind-limb paralyzed rat with spinal cord transection and implanted chronic epidural electrodes has been shown to regain stepping and standing abilities using stimulus provided by the SoC.

A 64-channel neuron recording system.

This paper presents a fully integrated low-power neuron recording front-end system in TSMC 65 nm 1p6m CMOS technology. The proposed system is comprised of two recording modules, each containing 32 recording channels with tunable bandwidth and gain, a 32-to-1 multiplexer, one differential successive approximation register (SAR) analog-to-digital converter (ADC) with programmable sampling rate on each channel, and a digital control module to govern the signal digitization as well as to encode and serialize the digitized neuron signal from two ADCs. The recording amplifier presents a low power and low noise merits of 6 µW and input-referred noise of 3.8 µV(rms). The ADC digitizes the neural signal at a sampling rate of 40 kS/s with 9-bit resolution. The overall power consumption of the entire system is 2.56 mW and occupies an area of 3 × 4mm(2).