Intranasal post-cardiac arrest treatment with orexin-A facilitates arousal from coma and ameliorates neuroinflammation.

Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Significant subsequent morbidity and mortality in post-CA patients are largely due to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia post-CA syndrome (PCAS). PCAS results in strong inflammatory responses including neuroinflammation response leading to poor outcome. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches to promote cortical or cognitive arousal following successful return of spontaneous circulation (ROSC). Hypothalamic orexinergic pathway is responsible for arousal and it is negatively affected by neuroinflammation. However, whether activation of the orexinergic pathway can curtail neuroinflammation is unknown. We hypothesize that targeting the orexinergic pathway via intranasal orexin-A (ORXA) treatment will enhance arousal from coma and decrease the production of proinflammatory cytokines resulting in improved functional outcome after resuscitation. We used a highly validated CA rat model to determine the effects of intranasal ORXA treatment 30-minute post resuscitation. At 4hrs post-CA, the mRNA levels of proinflammatory markers (IL1ß, iNOS, TNF-α, GFAP, CD11b) and orexin receptors (ORX1R and ORX2R) were examined in different brain regions. CA dramatically increased proinflammatory markers in all brain regions particularly in the prefrontal cortex, hippocampus and hypothalamus. Post-CA intranasal ORXA treatment significantly ameliorated the CA-induced neuroinflammatory markers in the hypothalamus. ORXA administration increased production of orexin receptors (ORX1R and ORX2R) particularly in hypothalamus. In addition, ORXA also resulted in early arousal as measured by quantitative electroencephalogram (EEG) markers, and recovery of the associated behavioral neurologic deficit scale score (NDS). Our results indicate that intranasal delivery of ORXA post-CA has an anti-inflammatory effect and accelerates cortical EEG and behavioral recovery. Beneficial outcomes from intranasal ORXA treatment lay the groundwork for therapeutic clinical approach to treating post-CA coma.

A CMOS Current Steering Neurostimulation Array With Integrated DAC Calibration and Charge Balancing.

An 8-channel current steerable, multi-phasic neural stimulator with on-chip current DAC calibration and residue nulling for precise charge balancing is presented. Each channel consists of two sub-binary radix DACs followed by wide-swing, high output impedance current buffers providing time-multiplexed source and sink outputs for anodic and cathodic stimulation. A single integrator is shared among channels and serves to calibrate DAC coefficients and to closely match the anodic and cathodic stimulation phases. Following calibration, the differential non-linearity is within ±0.3 LSB at 8-bit resolution, and the two stimulation phases are matched within 0.3%. Individual control in digital programming of stimulation coefficients across the array allows altering the spatial profile of current stimulation for selection of stimulation targets by current steering. Combined with the self-calibration and current matching functions, the current steering capabilities integrated on-chip support use in fully implanted neural interfaces with autonomous operation for and adaptive stimulation under variations in electrode and tissue conditions. As a proof-of-concept we applied current steering stimulation through a multi-channel cuff electrode on the sciatic nerve of a rat.

A Bidirectional Neural Interface IC With Chopper Stabilized BioADC Array and Charge Balanced Stimulator.

We present a bidirectional neural interface with a 4-channel biopotential analog-to-digital converter (bioADC) and a 4-channel current-mode stimulator in 180 nm CMOS. The bioADC directly transduces microvolt biopotentials into a digital representation without a voltage-amplification stage. Each bioADC channel comprises a continuous-time first-order ∆Σ modulator with a chopper-stabilized OTA input and current feedback, followed by a second-order comb-filter decimator with programmable oversampling ratio. Each stimulator channel contains two independent digital-to-analog converters for anodic and cathodic current generation. A shared calibration circuit matches the amplitude of the anodic and cathodic currents for charge balancing. Powered from a 1.5 V supply, the analog and digital circuits in each recording channel draw on average [Formula: see text] and [Formula: see text] of supply current, respectively. The bioADCs achieve an SNR of [Formula: see text] and a SFDR of [Formula: see text] , for better than 9-b ENOB. Intracranial EEG recordings from an anesthetized rat are shown and compared to simultaneous recordings from a commercial reference system to validate performance in-vivo . Additionally, we demonstrate bidirectional operation by recording cardiac modulation induced through vagus nerve stimulation, and closed-loop control of cardiac rhythm. The micropower operation, direct digital readout, and integration of electrical stimulation circuits make this interface ideally suited for closed-loop neuromodulation applications.

Implantable neurotechnologies: bidirectional neural interfaces--applications and VLSI circuit implementations.

A bidirectional neural interface is a device that transfers information into and out of the nervous system. This class of devices has potential to improve treatment and therapy in several patient populations. Progress in very large-scale integration has advanced the design of complex integrated circuits. System-on-chip devices are capable of recording neural electrical activity and altering natural activity with electrical stimulation. Often, these devices include wireless powering and telemetry functions. This review presents the state of the art of bidirectional circuits as applied to neuroprosthetic, neurorepair, and neurotherapeutic systems.

Implantable neurotechnologies: a review of integrated circuit neural amplifiers.

Neural signal recording is critical in modern day neuroscience research and emerging neural prosthesis programs. Neural recording requires the use of precise, low-noise amplifier systems to acquire and condition the weak neural signals that are transduced through electrode interfaces. Neural amplifiers and amplifier-based systems are available commercially or can be designed in-house and fabricated using integrated circuit (IC) technologies, resulting in very large-scale integration or application-specific integrated circuit solutions. IC-based neural amplifiers are now used to acquire untethered/portable neural recordings, as they meet the requirements of a miniaturized form factor, light weight and low power consumption. Furthermore, such miniaturized and low-power IC neural amplifiers are now being used in emerging implantable neural prosthesis technologies. This review focuses on neural amplifier-based devices and is presented in two interrelated parts. First, neural signal recording is reviewed, and practical challenges are highlighted. Current amplifier designs with increased functionality and performance and without penalties in chip size and power are featured. Second, applications of IC-based neural amplifiers in basic science experiments (e.g., cortical studies using animal models), neural prostheses (e.g., brain/nerve machine interfaces) and treatment of neuronal diseases (e.g., DBS for treatment of epilepsy) are highlighted. The review concludes with future outlooks of this technology and important challenges with regard to neural signal amplification.

Bidirectional peripheral nerve interface and applications.

Peripheral nerves, due to their small size and complex innervation to organs and complex physiology, pose particularly significant challenges towards interfacing electrodes and electronics to enable neuromodulation. Here, we present a review of the technology for building such interface, including recording and stimulating electrodes and low power electronics, as well as powering. Of particular advantage to building a miniature implanted device is a "bidirectional" system that both senses from the nerves or surrogate organs and stimulates the nerves to affect the organ function. This review and presentation will cover a range of electrodes, electronics, wireless power and data schemes and system integration, and will end with some examples and applications.

VLSI circuits for bidirectional interface to peripheral and visceral nerves.

This paper presents an architecture for sensing nerve signals and delivering functional electrical stimulation to peripheral and visceral nerves. The design is based on the very large scale integration (VLSI) technology and amenable to interface to microelectrodes and building a fully implantable system. The proposed stimulator was tested on the vagus nerve and is under further evaluation and testing of various visceral nerves and their functional effects on the innervated organs.

Design and characterization of a miniaturized epi-illuminated microscope.

The ability to observe functional and morphological changes in the brain is critical in understanding behavioral and developmental neuroscience. With advances in electronics and miniaturization, electrophysiological recordings from awake, behaving animals has allowed investigators to perform a multitude of behavioral studies by observing changes as an animal is engaged in certain tasks. Imaging offers advantages of observing structure as well as function, and the ability to monitor activity over large areas. However, imaging from an awake, behaving animal has not been explored well. We present the design and characterization of a miniaturized epi-illuminated optical system that is part of a larger goal to perform optical imaging in awake, behaving animals. The system comprises of a tunable light source and imaging optics in a small footprint of 18 mm diameter, 18 mm height and weight 5.7 grams. It offers a spatial illumination non-uniformity of 3.2% over a maximum field of view of 1.5 mm x 1.5 mm, negligible temporal illumination and temperature variation and controllable magnification. Uncorrected radial distortion was 5.3% (corrected to 1.8%) and the spatial frequency response was comparable to a reference system. The system was used to image cortical vasculature in an anesthetized rat.