Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Introduction <s> Basic Concepts of Medical Instrumentation (W. Olson). Basic Sensors and Principles (R. Peura & J. Webster). Amplifiers and Signal Processing (J. Webster). The Origin of Biopotentials (J. Clark). Biopotential Electrodes (M. Neuman). Biopotential Amplifiers (M. Neuman). Blood Pressure and Sound (R. Peura). Measurement of Flow and Volume of Blood (J. Webster). Measurements of the Respiratory System (F. Primiano). Chemical Biosensors (R. Peura). Clinical Laboratory Instrumentation (L. Wheeler). Medical Imaging Systems (M. Siedband). Therapeutic and Prosthetic Devices (M. Neuman). Electrical Safety (W. Olson). Appendix. Index. <s> BIB001 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Introduction <s> A micropower signal-processor IC is the key component of an implantable telemetry system for neurophysiology. The bipolar/JFET/I/SUP 2/L chip uses digital and low-noise analog circuitry to amplify, filter, and multiplex eight channels of neutral, electrogram, and temperature data from unanesthetized and freely moving animals. Fully integrated continuous-time bandpass amplifiers incorporate a frequency-sensitive feedback network to prevent the amplification of input offset voltage. The system can telemeter data for over 500 h, permitting long-term neurophysiological investigations. <s> BIB002 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Introduction <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> BIB003 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Introduction <s> This paper describes some recent progress in the development of amplifiers and other signal acquisition and signal conditioning systems for biopotential recording. The discussion will be based on two contrasting applications. The first concerns the connection of implantable amplifiers to arrays of nerve cuff electrodes which requires very low noise design due to the inherently poor signal to noise ratio of the interface. The second example deals with the interface between cultured neurones and standard CMOS technology. In this case the interface impedance is difficult to quantify accurately and is potentially time varying, requiring a different approach to amplifier design, which is tolerant to these parameter uncertainties. <s> BIB004 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Introduction <s> Over the last five decades, progress in neural recording techniques has allowed the number of simultaneously recorded neurons to double approximately every 7 years, mimicking Moore's law. Such exponential growth motivates us to ask how data analysis techniques are affected by progressively larger numbers of recorded neurons. Traditionally, neurons are analyzed independently on the basis of their tuning to stimuli or movement. Although tuning curve approaches are unaffected by growing numbers of simultaneously recorded neurons, newly developed techniques that analyze interactions between neurons become more accurate and more complex as the number of recorded neurons increases. Emerging data analysis techniques should consider both the computational costs and the potential for more accurate models associated with this exponential growth of the number of recorded neurons. <s> BIB005 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Introduction <s> A functional electrical stimulation system in primates that is controlled by recordings made from microelectrodes permanently implanted in the brain can be used to control the intensity of stimulation of muscles that are temporarily paralysed by pharmacological motor nerve blockade, thereby restoring voluntary control of the affected muscles; this is a major advance towards similar restoration of hand function in human patients with spinal cord injury. <s> BIB006 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Introduction <s> Intracortical brain computer interfaces (iBCIs) are being developed to enable people to drive an output device, such as a computer cursor, directly from their neural activity. One goal of the technology is to help people with severe paralysis or limb loss. Key elements of an iBCI are the implanted sensor that records the neural signals and the software that decodes the user's intended movement from those signals. Here, we focus on recent advances in these two areas, placing special attention on contributions that are or may soon be adopted by the iBCI research community. We discuss how these innovations increase the technology's capability, accuracy, and longevity, all important steps that are expanding the range of possible future clinical applications. <s> BIB007 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Introduction <s> High-frequency deep brain stimulation is used to treat a wide range of brain disorders, like Parkinson's disease. The stimulated networks usually share common electrophysiological signatures, including hyperactivity and/or dysrhythmia. From a clinical perspective, HFS is expected to alleviate clinical signs without generating adverse effects. Here, we consider whether the classical open-loop HFS fulfills these criteria and outline current experimental or theoretical research on the different types of closed-loop DBS that could provide better clinical outcomes. In the first part of the review, the two routes followed by HFS-evoked axonal spikes are explored. In one direction, orthodromic spikes functionally de-afferent the stimulated nucleus from its downstream target networks. In the opposite direction, antidromic spikes prevent this nucleus from being influenced by its afferent networks. As a result, the pathological synchronized activity no longer propagates from the cortical networks to the stimulated nucleus. The overall result can be described as a reversible functional de-afferentation of the stimulated nucleus from its upstream and downstream nuclei. In the second part of the review, the latest advances in closed-loop DBS are considered. Some of the proposed approaches are based on mathematical models, which emphasize different aspects of the parkinsonian basal ganglia: excessive synchronization, abnormal firing-rate rhythms, and a deficient thalamo-cortical relay. The stimulation strategies are classified depending on the control-theory techniques on which they are based: adaptive and on-demand stimulation schemes, delayed and multi-site approaches, stimulations based on proportional and/or derivative control actions, optimal control strategies. Some of these strategies have been validated experimentally, but there is still a large reservoir of theoretical work that may point to ways of improving practical treatment. <s> BIB008 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Introduction <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> BIB009 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Introduction <s> Abstract Deep brain stimulation (DBS) is usually performed to treat advanced Parkinson’s disease (PD) patients with electrodes permanently implanted in basal ganglia while the stimulator delivers electrical impulses continuously and independently of any feedback (open-loop stimulation). Conversely, in closed-loop stimulation, electrical stimulation is delivered as a function of neuronal activities recorded and analyzed online. There is an emerging development of closed-loop DBS in the treatment of PD and a growing discussion about proposing cortical stimulation rather than DBS for this purpose. Why does it make sense to “close the loop” to treat parkinsonian symptoms? Could closed-loop stimulation applied to the cortex become a valuable therapeutic strategy for PD? Can mathematical modeling contribute to the development of this technique? We review the various evidences in favor of the use of closed-loop cortical stimulation for the treatment of advanced PD, as an emerging technique which might offer substantial clinical benefits for PD patients. <s> BIB010 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Introduction <s> Brain–machine interfaces are being investigated for recovery of motor function after paralysis. Shanechi et al. present a neural prosthesis that decodes premotor neuronal activity in an alert monkey to activate spinal neurons and muscles that produce target-directed movements in a sedated monkey or avatar. <s> BIB011 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Introduction <s> 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. <s> BIB012
Microelectronic recording interfaces are widely used in neuroscience research as well as in diagnostic and therapeutic technologies. The high-quality amplification of Abstract 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 weak neural signals remains a challenge in both data acquisition and diagnostic devices. Important examples of neural recordings include electrocorticograms (ECoG) BIB010 BIB006  BIB011 BIB005 and electroneurograms BIB004 . In addition, neural recordings are essential for brain-machine interfaces BIB007 and closed-loop therapeutic devices that interface with the brain BIB010 BIB008 , nerves BIB009 BIB003 or visceral organs BIB012 . The key requirements in the above applications are to acquire, amplify and process neural signals using low-noise amplifiers and associated signal conditioning circuits BIB001  . The amplified and processed recordings may then be used in research, clinical diagnostics or, in the case of closedloop therapeutic devices, functional electrical stimulation. Neural recordings can be acquired using commercially available amplifier systems    137] . However, custom-designed neural recording ICs offer several prime advantages, including miniaturized form factor, low weight and low power consumption. These properties allow for portable and implantable neurodevices. The first neural amplifier IC was reported by Dorman et al. BIB002 . Continuous advancements in microelectronic fabrication technology and novel circuit design techniques have benefited IC neural amplifiers with steady and significant improvements, particularly regarding the noise-versus-power tradeoff. The area density of such IC chips has also increased in line with Moore's law  , which has thus far correctly predicted the continuing progress in shrinking transistor sizes with simultaneous improvements in IC performance. Despite the progress made in IC-based neural amplifiers, designing such amplifiers is still a non-trivial exercise, requiring expertise in circuit design and in-depth familiarity with the biological aspects of neural recording. This review includes the background design concepts and considerations of neural signal recording and discusses the state-of-the-art design technologies. A survey of applications in neural engineering and prosthetic systems that benefit from these technologies is also given. The review concludes with future outlooks and challenges in the evolution of neural amplifier design and applications.