Bio-impedance method to monitor colon motility response to direct distal colon stimulation in anesthetized pigs.

Electrical stimulation has been demonstrated as an alternative approach to alleviate intractable colonic motor disorders, whose effectiveness can be evaluated through colonic motility assessment. Various methods have been proposed to monitor the colonic motility and while each has contributed towards better understanding of colon motility, a significant limitation has been the spatial and temporal low-resolution colon motility data acquisition and analysis. This paper presents the study of employing bio-impedance characterization to monitor colonic motor activity. Direct distal colon stimulation was undertaken in anesthetized pigs to validate the bio-impedance scheme simultaneous with luminal manometry monitoring. The results indicated that the significant decreases of bio-impedance corresponded to strong colonic contraction in response to the electrical stimulation in the distal colon. The magnitude/power of the dominant frequencies of phasic colonic contractions identified at baseline (in the range 2-3 cycles per minute (cpm)) were increased after the stimulation. In addition, positive correlations have been found between bio-impedance and manometry. The proposed bio-impedance-based method can be a viable candidate for monitoring colonic motor pattern with high spatial and temporal resolution. The presented technique can be integrated into a closed-loop therapeutic device in order to optimize its stimulation protocol in real-time.

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.

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.

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.

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.