Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Neural amplifiers for therapeutic neuromodulation <s> Deep brain stimulation (DBS) has been used to treat various neurological and psychiatric disorders. Over the years, the most suitable surgical candidates and targets for some of these conditions have been characterized and the benefits of DBS well demonstrated in double-blinded randomized trials. This review will discuss some of the areas of current investigation and potential new applications of DBS. <s> BIB001 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Neural amplifiers for therapeutic neuromodulation <s> We present a fully differential 128-channel integrated neural interface. It consists of an array of 8 X 16 low-power low-noise signal-recording and generation circuits for electrical neural activity monitoring and stimulation, respectively. The recording channel has two stages of signal amplification and conditioning with and a fully differential 8-b column-parallel successive approximation (SAR) analog-to-digital converter (ADC). The total measured power consumption of each recording channel, including the SAR ADC, is 15.5 ?W. The measured input-referred noise is 6.08 ? Vrms over a 5-kHz bandwidth, resulting in a noise efficiency factor of 5.6. The stimulation channel performs monophasic or biphasic voltage-mode stimulation, with a maximum stimulation current of 5 mA and a quiescent power dissipation of 51.5 ?W. The design is implemented in 0.35-?m complementary metal-oxide semiconductor technology with the channel pitch of 200 ?m for a total die size of 3.4 mm × 2.5 mm and a total power consumption of 9.33 mW. The neural interface was validated in in vitro recording of a low-Mg2+/high-K+ epileptic seizure model in an intact hippocampus of a mouse. <s> BIB002 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Neural amplifiers for therapeutic neuromodulation <s> This paper describes a neurostimulation IC for use in advanced closed-loop neurostimulation applications, such as deep brain stimulation (DBS) for treatment and research of neurological disorders including Parkinson's disease. This system senses and filters neural activity with eight pre-amplifiers, a 200 kS/s 8-bit log ADC and digital filters and incorporates 64 programmable current-stimulation channels. The entire device, implemented in 0.18 μm CMOS, occupies 2.7 mm2 and consumes 89 μW in normal operation mode and 271 μW in configuration mode from a 1.8 V supply. <s> BIB003 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Neural amplifiers for therapeutic neuromodulation <s> High-frequency open-loop deep brain stimulation (DBS) has been used to alleviate Parkinson's symptoms for almost 20 years. In this issue of Neuron , Rosin et al. present a closed-loop real-time approach that improves DBS and shines light on the etiology of motor symptoms in Parkinson's disease. <s> BIB004 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Neural amplifiers for therapeutic neuromodulation <s> Deep brain stimulation (DBS) is an effective surgical treatment for medication-refractory hypokinetic and hyperkinetic movement disorders, and it is being explored for a variety of other neurological and psychiatric diseases. Deep brain stimulation has been Food and Drug Administration-approved for essential tremor and Parkinson disease and has a humanitarian device exemption for dystonia and obsessive-compulsive disorder. Neurostimulation is the fruit of decades of both technical and scientific advances in the field of basic neuroscience and functional neurosurgery. Despite the clinical success of DBS, the therapeutic mechanism of DBS remains under debate. Our objective is to provide a comprehensive review of DBS focusing on movement disorders, including the historical evolution of the technique, applications and outcomes with an overview of the most pertinent literature, current views on mechanisms of stimulation, and description of hardware and programming techniques. We conclude with a discussion of future developments in neurostimulation. <s> BIB005 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Neural amplifiers for therapeutic neuromodulation <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> BIB006 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Neural amplifiers for therapeutic neuromodulation <s> An ultra wideband (UWB) 64-channel responsive neural stimulator system-on-chip (SoC) is presented. It demonstrates the first on-chip neural vector analyzer capable of wirelessly monitoring magnitude, phase and phase synchronization of neural signals. In a closed-loop, abnormal phase synchrony triggers the programmable-waveform biphasic current-mode neural stimulator. To implement these functionalities, the SoC integrates 64 neural recording amplifiers with tunable switched-capacitor (SC) bandpass filters, 64 multiplying 8-bit SAR ADCs, 64 programmable 16-tap FIR filters, a tri-core CORDIC processor, 64 biphasic current stimulation channels, and a 3.1-10.6 GHz UWB wireless transmitter onto a 4 mm × 3 mm 0.13 μm CMOS die. To minimize both the area and power dissipation of the SoC, the SAR ADC is re-used as a multiplier for FIR filtering and as a DAC and duty cycle controller for the biphasic neural stimulator. The SoC has been validated in the early detection and abortion of seizures in freely moving rodents on-line and in early seizure detection in humans off-line. <s> BIB007 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Neural amplifiers for therapeutic neuromodulation <s> Although closed-loop deep brain stimulation (DBS) promises treatment of many neurological disorders, an implantable system-on-chip (SoC) implementing an effective closed-loop DBS algorithm has not been demonstrated. This work introduces a logarithmic, closed-loop DBS system that detects and processes low-frequency brain field signals to control and adapt stimulation currents. The system records and processes neural signals with four low-noise neural amplifier (LNA) channels, a multiplexed logarithmic ADC, and two high-pass and two low-pass digital logarithmic filters. Logarithmic processing saves power and achieves high dynamic range. A logarithmic domain digital signal processor (DSP) and PI-controller controls eight current stimulator channels and enables closed-loop stimulation. An RF transceiver, a clock generator, and a power harvester are also included in the system to achieve a complete implantable SoC. The 4 mm ::: 2 ::: 180 nm CMOS prototype consumes a total of 468 μW for recording and processing neural signals, for stimulation, and for two-way wireless communication. <s> BIB008 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Neural amplifiers for therapeutic neuromodulation <s> An 8-channel closed-loop neural-prosthetic SoC is presented for real-time intracranial EEG (iEEG) acquisition, seizure detection, and electrical stimulation in order to suppress epileptic seizures. The SoC is composed of eight energy-efficient analog front-end amplifiers (AFEAs), a 10-b delta-modulated SAR ADC (DMSAR ADC), a configurable bio-signal processor (BSP), and an adaptive high-voltage-tolerant stimulator. A wireless power-and-data transmission system is also embedded. By leveraging T-connected pseudo-resistors, the high-pass (low-pass) cutoff frequency of the AFEAs can be adjusted from 0.1 to 10 Hz (0.8 to 7 kHz). The noise-efficiency factor (NEF) of the AFEA is 1.77, and the DMSAR ADC achieves an ENOB of 9.57 bits. The BSP extracts the epileptic features from time-domain entropy and frequency spectrum for seizure detection. A constant 30- μA stimulus current is delivered by closed-loop control. The acquired signals are transmitted with on-off keying (OOK) modulation at 4 Mbps over the MedRadio band for monitoring. A multi-LDO topology is adopted to mitigate the interferences across different power domains. The proposed SoC is fabricated in 0.18- μm CMOS and occupies 13.47 mm2. Verified on Long Evans rats, the proposed SoC dissipates 2.8 mW and achieves high detection accuracy (> 92%) within 0.8 s. <s> BIB009 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Neural amplifiers for therapeutic neuromodulation <s> Neural stimulation using injected electrical charge is widely used both in functional therapies and as an experimental tool for neuroscience applications. Electrical pulses can induce excitation of targeted neural pathways that aid in the treatment of neural disorders or dysfunction of the central and peripheral nervous system. In this review, we summarize the recent trends in the field of electrical stimulation for therapeutic interventions of nervous system disorders, such as for the restoration of brain, eye, ear, spinal cord, nerve and muscle function. Neural prosthetic applications are discussed, and functional electrical stimulation parameters for treating such disorders are reviewed. Important considerations for implantable packaging and enhancing device reliability are also discussed. Neural stimulators are expected to play a profound role in implantable neural devices that treat disorders and help restore functions in injured or disabled nervous system. <s> BIB010 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Neural amplifiers for therapeutic neuromodulation <s> Objective:The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures. Methods:All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy. Results:The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%). Conclusions:The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures. Classification of evidence:This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years. <s> BIB011
The information gleaned from the acquisition of neural electrical activity can be used to augment therapeutic stimulation of the nervous system BIB010 . Neural stimulation can be used to treat neurological diseases of the brain, restore the functions of the limbs, interface and restore functions provided by peripheral or visceral nerves, restore bladder function or relieve chronic pain. For example, deep brain stimulation (DBS) is particularly successful in treating movement disorders, such as Parkinson's Disease, dystonia and essential tremor BIB001  BIB005 . DBS is also an alternative treatment for pharmaco-resistant epilepsy, pain control and psychiatric disorders BIB001 . However, current DBS therapies are conducted in open-loop configurations and require periodic visits with a clinician to make adjustments for optimal stimulation efficacy. Closed-loop DBS has been proposed to provide synchronous adaptive neuromodulation based on real-time pathological brain states in each patient BIB006 BIB005 BIB004 . In this paradigm, neural activities are amplified and analyzed to detect disease-state biomarkers; this information is then used to either augment ongoing stimulation or initiate new stimulation. This process is dynamically repeated until the desired therapeutic efficacy is achieved. For example, the Neuropace system (California, USA) [91] is a commercially available device that performs closedloop neurostimulation for the treatment of epilepsy. Recent studies on patients implanted with this device have exhibited significant reductions in seizures over a sustained period of time, and hence, the patients experience an improved quality of life BIB011 . Neural amplifier systems can be coupled with a microcomputer module and discrete electrical stimulators to form a complete closed-loop neuromodulation device. However, integration of these modules onto a single neuromodulation chip significantly decreases the form factor and simplifies the packaging required for implantation. Shahrokhi et al. reported a prototype 128-channel neurorecording and stimulator chip BIB002 with off-chip signal processing for a proposed closed-loop neuromodulation system. Recently, Abdelhalim et al. BIB007 reported a neuromodulation system-on-chip (SoC) that detects and suppresses imminent epileptic seizures based on fluctuations in phase synchrony within the narrow frequency bands of recorded neural signals. This chip was tested on rat models and off-line human trials. Similarly, Flynn et al. first reported a 64-channel neurorecording and stimulator chip BIB003 that relied on off-chip signal processing. Subsequently, they developed a closed-loop DBS SoC that contained an integrated power harvester, 4 neural amplifiers, a digital signal processor (DSP), 8 neurostimulators and a two-way wireless transceiver BIB008 . The on-chip DSP analyzed neural signal frequency content and set stimulation parameters. Another recent work by Wu et al. BIB009 reported a neuromodulation chip comprising 8 neural recording amplifiers, a bio-signal processor with 92 % seizure detection accuracy and a high-voltage stimulator.