Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Applications of PNS neural recordings <s> Electrical stimulation of upper airway (UAW) muscles has been under investigation as a treatment method for obstructive sleep apnea (OSA). Particular attention has been given to the electrical activation of the genioglossal muscle, either directly or via the stimulation of the hypoglossal nerve (HG), since the genioglossus is the main tongue protrusor muscle. Regardless of the stimulation site or method, an implantable electrical stimulation device for OSA patients will require a reliable method for detection of obstructive breaths to apply the stimulation when needed. In this paper, we test the hypothesis that the activity of the HG nerve can be used as a feedback signal for closed-loop stimulation of the HG nerve in an animal model of UAW obstruction where a force is applied on the submental region to physically narrow the airways. As an advantage, the method uses a single electrode for both recording and stimulation of the HG nerve. Simple linear filtering techniques were found to be adequate for producing the trigger signal for the electrical stimulation from the HG recordings. Esophageal pressure, which was used to estimate the size of the UAW passage, returned to the preloading values during closed-loop stimulation of the HG nerve. The data demonstrate the feasibility of the closed-loop stimulation of the HG nerve using its activity as the feedback signal. <s> BIB001 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Applications of PNS neural recordings <s> Electroneurograms (ENGs) from the vagus nerve (VN), the splanchnic nerve (SN) and the pancreatic nerve (PN) innervating the pancreas of a dog, were recorded with chronically implanted 33-electrode spiral cuffs (cuff) before and after the pancreas were stimulated with intravenously (i.v.) administered glucose. In the cuffs platinum electrodes were arranged in three parallel spiral groups containing 11 electrodes on the inner surface. The cuffs had an inner diameter of 2 mm and a length of 18 mm. In a two-year study, the cuffs were implanted into two Beagle dogs and were also used for pancreatic stimulation, although this is not described in this paper. In the VN, the cuff was installed on the nerve at the neck, whilst in the SN, the cuff was installed on the nerve before the celiac ganglion, and in the PN, the cuff was installed on the nerve just before it enters the pancreas. Six months after implantation, when the model of interpretation of the results was developed, three recordings of ENG in each animal were conducted. The first one was conducted in the unstimulated pancreas while the second and the third were conducted 1 and 8 min after a known amount of glucose was i.v. administered. Since the results obtained in both animals were actually quite similar, we present the results obtained in one animal. To evaluate the changes in superficial activity of the nerves, elicited by the administration of glucose, the power spectra corresponding to ENGs, recorded from the nerves before and after the administration of glucose, were integrated within the band of frequencies ranging from 1 to 5 kHz. Accordingly, the magnitude of the integrated power spectrum (MIPS), corresponding to the ENG recorded from the SN before administration of glucose, was 2.863 au. One minute after glucose was administered the value fell to 2.795 au while 8 min after the administration the value returned to 2.8 au. The MIPS corresponding to the ENG recorded from the PN before the administration of glucose was 3.236 au. One minute after the administration the value fell to 2.901 au while 8 min after the administration the value rose to 3.009 au. The MIPS, corresponding to the ENG recorded from the VN before the administration of glucose, was 3.656 au. One minute after the administration the value fell to 3.565 au. Eight minutes after the administration the value rose to 3.689 au. The results show that 1 min after glucose was administered superficial activity in all three nerves was reduced while 8 min after administration the activity in the nerves returned to the same level of activity before the glucose was administered. This information could be effectively used in a further study of pancreatic innervation and its function. Moreover, the results suggest that cuffs could also be useful in recording the ENGs from other nerves of the autonomic nervous system that innervate various glands and internal organs. <s> BIB002 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Applications of PNS neural recordings <s> Abstract Purpose It is not known whether motor and sensory pathways associated with a missing or denervated limb remain functionally intact over periods of many months or years after amputation or chronic peripheral nerve transection injury. We examined the extent to which activity on chronically severed motor nerve fibers could be controlled by human amputees and whether distally referred tactile and proprioceptive sensations could be induced by stimulation of sensory axons in the nerve stumps. Methods Amputees undergoing elective stump procedures were invited to participate in this study. Longitudinal intrafascicular electrodes were threaded percutaneously and implanted in severed nerves of human amputees. The electrodes were interfaced to an amplifier and stimulator system controlled by a laptop computer. Electrophysiologic tests were conducted for 2 consecutive days after recovery from the surgery. Results It was possible to record volitional motor nerve activity uniquely associated with missing limb movements. Electrical stimulation through the implanted electrodes elicited discrete, unitary, graded sensations of touch, joint movement, and position, referring to the missing limb. Conclusions These findings indicate that both central and peripheral motor and somatosensory pathways retain significant residual connectivity and function for many years after limb amputation. This implies that peripheral nerve interfaces could be used to provide amputees with prosthetic limbs that have more natural feel and control than is possible with current myoelectric and body-powered control systems. <s> BIB003 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Applications of PNS neural recordings <s> Evidence indicates that user acceptance of modern artificial limbs by amputees would be significantly enhanced by a system that provides appropriate, graded, distally referred sensations of touch and joint movement, and that the functionality of limb prostheses would be improved by a more natural control mechanism. We have recently demonstrated that it is possible to implant electrodes within individual fascicles of peripheral nerve stumps in amputees, that stimulation through these electrodes can produce graded, discrete sensations of touch or movement referred to the amputee's phantom hand, and that recordings of motor neuron activity associated with attempted movements of the phantom limb through these electrodes can be used as graded control signals. We report here that this approach allows amputees to both judge and set grip force and joint position in an artificial arm, in the absence of visual input, thus providing a substrate for better integration of the artificial limb into the amputee's body image. We believe this to be the first demonstration of direct neural feedback from and direct neural control of an artificial arm in amputees. <s> BIB004 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Applications of PNS neural recordings <s> Objectives: The principle underlying this project is that, despite nervous reorganization following upper limb amputation, original pathways and CNS relays partially maintain their function and can be exploited for interfacing prostheses. <s> BIB005 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Applications of PNS neural recordings <s> In this paper we present a compliant neural interface designed to record bladder afferent activity. We developed the implant's microfabrication process using multiple layers of silicone rubber and thin metal so that a gold microelectrode array is embedded within four parallel polydimethylsiloxane (PDMS) microchannels (5 mm long, 100 μm wide, 100 μm deep). Electrode impedance at 1 kHz was optimized using a reactive ion etching (RIE) step, which increased the porosity of the electrode surface. The electrodes did not deteriorate after a 3 month immersion in phosphate buffered saline (PBS) at 37 °C. Due to the unique microscopic topography of the metal film on PDMS, the electrodes are extremely compliant and can withstand handling during implantation (twisting and bending) without electrical failure. The device was transplanted acutely to anaesthetized rats, and strands of the dorsal branch of roots L6 and S1 were surgically teased and inserted in three microchannels under saline immersion to allow for simultaneous in vivo recordings in an acute setting. We utilized a tripole electrode configuration to maintain background noise low and improve the signal to noise ratio. The device could distinguish two types of afferent nerve activity related to increasing bladder filling and contraction. To our knowledge, this is the first report of multichannel recordings of bladder afferent activity. <s> BIB006 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Applications of PNS neural recordings <s> This paper describes a inductively powered multichannel bionic neural link (BNL) system-on-chip (SOC) for peripheral nerve function restoration. The BNL-SOC consists of 8 neural recording and 4 stimulation channels, and is implemented in a 0.35-μm CMOS technology. Full function of the BNL has been demonstrated with in-vivo animal experiments. The entire BNL SOC consumes 1.5mW and operates under a 3V supply with an external +/-9V multichannel stimulation output driver. <s> BIB007 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Applications of PNS neural recordings <s> Peripheral nerve injuries with large gaps and long nerve regrowth paths are difficult to repair using existing surgical techniques, due to nerve degeneration and muscle atrophy. This paper proposes a Bionic Neural Link (BNL) as an alternative way for peripheral nerve repair. The concept of the BNL is described, along with the hypothetical benefits. A prototype monolithic single channel BNL has been developed, which consists of 16 neural recording channels and one stimulation channel, and is implemented in a 0.35-µm CMOS technology. The BNL has been tested in in-vivo animal experiments. Full function of the BNL chip has been demonstrated. <s> BIB008 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Applications of PNS neural recordings <s> Advances in neuroscience research and clinical applications have increasingly called for the low-power low-noise simultaneous recording of neural signals from a large number of electrodes. The neural interface IC is one of the essential blocks to capture the weak neural signals. Presented is an energy-efficient low-noise neural recording amplifier with enhanced noise efficiency factor (NEF) for neural recording systems. Based on the conventional capacitive feedback and pseudo-resistor structure, the fully differential neural amplifier employs the current-reuse technique to achieve low noise and high current efficiency, consuming 800 nA at 1 V power supply. The measured thermal noise floor is 43nV/√Hz and the input-referred noise is 5.71 µVrms when integrated from 1 Hz to 50 kHz, leading to an NEF of 2.59. The entire neural amplifier has been fabricated using a 0.18 µm CMOS technology, occupying an area of 0.05 mm2. <s> BIB009 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Applications of PNS neural recordings <s> A severe complication of spinal cord injury is loss of bladder function (neurogenic bladder), which is characterized by loss of bladder sensation and voluntary control of micturition (urination), and spontaneous hyperreflexive voiding against a closed sphincter (detrusor-sphincter dyssynergia). A sacral anterior root stimulator at low frequency can drive volitional bladder voiding, but surgical rhizotomy of the lumbosacral dorsal roots is needed to prevent spontaneous voiding and dyssynergia. However, rhizotomy is irreversible and eliminates sexual function, and the stimulator gives no information on bladder fullness. We designed a closed-loop neuroprosthetic interface that measures bladder fullness and prevents spontaneous voiding episodes without the need for dorsal rhizotomy in a rat model. To obtain bladder sensory information, we implanted teased dorsal roots (rootlets) within the rat vertebral column into microchannel electrodes, which provided signal amplification and noise suppression. As long as they were attached to the spinal cord, these rootlets survived for up to 3 months and contained axons and blood vessels. Electrophysiological recordings showed that half of the rootlets propagated action potentials, with firing frequency correlated to bladder fullness. When the bladder became full enough to initiate spontaneous voiding, high-frequency/amplitude sensory activity was detected. Voiding was abolished using a high-frequency depolarizing block to the ventral roots. A ventral root stimulator initiated bladder emptying at low frequency and prevented unwanted contraction at high frequency. These data suggest that sensory information from the dorsal root together with a ventral root stimulator could form the basis for a closed-loop bladder neuroprosthetic. <s> BIB010 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Applications of PNS neural recordings <s> Refractive urinary dysfunction in individuals suffering from neurogenic bladder syndrome can be treated with implanted neurostimulators that restore, to some degree, the control of the urinary bladder. A sensor capable of relaying feedback from bladder activity to the implanted neurostimulator is required to implement a closed-loop system to improve overall implant efficacy and minimize deleterious effects to neural tissue caused by continuous electrical stimulation. In this paper, we present a method that allows real-time estimation of bladder volume from the primary afferent activity of bladder mechanoreceptors. Our method was validated with data acquired from anesthetized rats in acute experiments. It was possible to qualitatively estimate three states of bladder fullness in 100% of trials when the recorded afferent activity exhibited a Spearman's correlation coefficient of 0.6 or better. Furthermore, we could quantitatively estimate bladder volume, and also its pressure, using timeframes of properly chosen duration. The mean volume estimation error was 5.8 ±3.1%. Our results also demonstrate that it is possible to quantify both phasic and tonic bladder responses during slow filling and isovolumetric measurements, respectively. <s> BIB011 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Applications of PNS neural recordings <s> Widely utilized in the field of Neuroscience, implantable neural recording devices could capture neuron activities with an acquisition rate on the order of megabytes per second. In order to efficiently transmit neural signals through wireless channels, these devices require compression methods that reduce power consumption. Although recent Compressed Sensing (CS) approaches have successfully demonstrated their power, their full potential is yet to be explored. Built upon our previous on-chip CS implementation, we propose an energy efficient multi-mode CS framework that focuses on improving the off-chip components, including (i) a two-stage sensing strategy, (ii) a sparsifying dictionary directly using data, (iii) enhanced compression performance from Full Signal CS mode and Spike Restoration mode to Spike CS + Restoration mode and; (iv) extension of our framework to the Tetrode CS recovery using joint sparsity. This new framework achieves energy efficiency, implementation simplicity and system flexibility simultaneously. Extensive experiments are performed on simulation and real datasets. For our Spike CS + Restoration mode, we achieve a compression ratio of 6% with a reconstruction SNDR > 10 dB and a classification accuracy > 95% for synthetic datasets. For real datasets, we get a 10% compression ratio with ~ 10 dB for Spike CS + Restoration mode. <s> BIB012
A promising use of PNS neural recording amplifiers is in neuromodulation and neuroprosthesis systems. Recently, a peripheral nerve-based neuromodulation system for bladder control was demonstrated in rats BIB010 BIB006 BIB011 . Such a device, in human patients, could restore bladder control lost due to spinal cord injury. In this system, neural amplifiers were used to record the afferent activity of bladder sensory nerves and to predict the fullness of the bladder. Upon detecting a full bladder, a neurostimulator issued an electrical current to the ventral roots BIB010 to activate bladder emptying. Additionally, high-frequency, blocking stimulation was used to prevent inadvertent bladder emptying. Similarly, Sahin et al. BIB001 demonstrated a closed-loop PNS neuromodulation device to treat obstructive sleep apnea. In a canine model, neural activity was recorded from the hypoglossal nerve and was processed to detect blockages to the upper airway. When a blockage was detected, the system triggered stimulation of the same nerve to open the upper airway and mitigate the blockage. Recently, peripheral nerve-based motor neuroprosthesis systems have also been reported. Dhillon et al. BIB004 BIB003 demonstrated the control of a robotic arm by a human amputee using signals recorded from an intrafascicular electrode interface while also incorporating sensory feedback. Similarly, Jia et al.  demonstrated the ability of a human amputee to control a finger extension. Most recently, Micera et al. used peripheral nerve stimulation to evoke graded [82] . Reproduced with kind permission from Professor Silvestro Micera, EPFL sensory perceptions in a human amputee subject while using the subject's residual muscle activity to decode movement intention and actuate a robotic arm (Fig. 10) [82, BIB005 . Neural recording IC technology has not been widely adopted in PNS-based research or neuromodulation systems. Although neural recording ICs targeted for PNS-based neural prostheses have been proposed BIB004 BIB003 82, BIB007 BIB005  BIB008 , demonstrating a fully implanted system, analogous to the works of BIB009 BIB008 and BIB012 , is lacking. Hence, the opportunity to utilize implantable IC neural amplification systems for PNS interfacing remains largely unexplored. The use of neural recording amplifiers in the PNS continues to be an active area of development. For example, Rozman et al. BIB002 demonstrated neural recording from the nerves innervating the pancreas and proposed using such recordings to achieve closed-loop controlled secretion of pancreatic hormones. As discussed in the last section, there are no reported applications of neural recording ICs for any chronically implantable PNS neuroprosthesis.