Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Expanding applications for IC neural recordings <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> BIB001 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Expanding applications for IC neural recordings <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> BIB002 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Expanding applications for IC neural recordings <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> BIB003 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Expanding applications for IC neural recordings <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> BIB004 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Expanding applications for IC neural recordings <s> Aim The neural cardiac therapy for heart failure (NECTAR-HF) was a randomized sham-controlled trial designed to evaluate whether a single dose of vagal nerve stimulation (VNS) would attenuate cardiac remodelling, improve cardiac function and increase exercise capacity in symptomatic heart failure patients with severe left ventricular (LV) systolic dysfunction despite guideline recommended medical therapy. ::: ::: Methods Patients were randomized in a 2 : 1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The primary endpoint was the change in LV end systolic diameter (LVESD) at 6 months for control vs. therapy, with secondary endpoints of other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-h Holter, and circulating biomarkers. ::: ::: Results Of the 96 implanted patients, 87 had paired datasets for the primary endpoint. Change in LVESD from baseline to 6 months was −0.04 ± 0.25 cm in the therapy group compared with −0.08 ± 0.32 cm in the control group ( P = 0.60). Additional echocardiographic parameters of LV end diastolic dimension, LV end systolic volume, left ventricular end diastolic volume, LV ejection fraction, peak V02, and N -terminal pro-hormone brain natriuretic peptide failed to show superiority compared to the control group. However, there were statistically significant improvements in quality of life for the Minnesota Living with Heart Failure Questionnaire ( P = 0.049), New York Heart Association class ( P = 0.032), and the SF-36 Physical Component ( P = 0.016) in the therapy group. ::: ::: Conclusion Vagal nerve stimulation as delivered in the NECTAR-HF trial failed to demonstrate a significant effect on primary and secondary endpoint measures of cardiac remodelling and functional capacity in symptomatic heart failure patients, but quality-of-life measures showed significant improvement. <s> BIB005 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Expanding applications for IC neural recordings <s> BACKGROUND ::: Baroreflex activation therapy (BAT) by electrical stimulation of baroreceptors at the carotid sinus is a promising therapeutic approach to reduce elevated blood pressure (BP). To assess the efficacy of long-term BAT, we investigated acute BP alterations after device deactivation and reactivation (on/off effects) in patients on chronic BAT, as well as chronic BP reductions. ::: ::: ::: METHOD ::: Resistant hypertension patients (n = 17) were enrolled in an open-label, single-arm evaluation of unilateral BAT after exclusion of secondary hypertension. Initial eligibility criteria were SBP≥ 140 mmHg, despite stable medical therapy with at least three antihypertensive drugs including at least one diuretic. For on/off testing, several office cuff BP measurements were performed: at rest with activated device, 4-6 min after deactivation, and 4-6 min after reactivation. ::: ::: ::: RESULTS ::: Before BAT, mean office cuff BP was 179 ± 25 over 98 ± 18 mmHg. At the time of on/off testing (15.1 ± 8.7 months after initial activation and before deactivation), BP was reduced to 147 ± 29 over 84 ± 20 mmHg. On deactivation, SBP increased to 158 ± 38 mmHg (P = 0.004) and DBP to 89 ± 23 mmHg (P = 0.04). After reactivation, SBP decreased to 144 ± 34 mmHg (P = 0.002 vs. deactivation) and DBP to 83 ± 23 mmHg (P = 0.009). There was no correlation between duration of chronic BAT and systolic or diastolic acute on/off response. ::: ::: ::: CONCLUSION ::: Unilateral BAT reduces BP in patients with resistant hypertension in the long term. There is a significant on/off effect on BP, supporting the efficacy of BAT. The acute on/off response to BAT does not depend on treatment duration. Thus, no evidence of tolerance over time to chronic BAT was found. <s> BIB006 </s> Implantable neurotechnologies: a review of integrated circuit neural amplifiers <s> Expanding applications for IC neural recordings <s> The inflammatory reflex is a neural circuit defined by action potentials transmitted in the vagus nerve that regulate cytokine production in the spleen. Detailed mechanistic studies implicate the vagus nerve, the splenic nerve, a T-cell subset that produces acetylcholine under the control of adrenergic signals, and alpha7 nicotinic acetylcholine receptors (α7nAChR). expressed on macrophages. This study defines the vagus nerve fibers that transmit the efferent signal in this pathway, a motor arc of the inflammatory reflex. Mice and rats were subjected to electrical cervical vagus nerve stimulation or sham surgery. Cytokine levels in serum were measured in endotoxemic animals or in endotoxin-exposed blood samples. Evoked potentials were measured in the vagus nerve and a portion of the vagus nerve was anesthetized using local application of lidocaine before stimulation. The lowest threshold subdiaphragmatic fibers in the rat vagus nerve have conduction velocities consistent with that of myelinated B fibers. The stimulation current threshold for significant suppression of serum TNF levels was similar in mice and rats (≤500 µA). Blockade of the fibers caudal to the site of vagus nerve stimulation impaired the inhibition of TNF release. A single suprathreshold pulse stimulation was sufficient to suppress TNF release in endotoxemia. These results indicate that single-pulse and unidirectional electrical activation of the cervical vagus nerve reduce TNF in endotoxemia. <s> BIB007
The role of neural recording ICs is likely to expand with the development of closed-loop neuromodulation therapies. As previously discussed, implanted neural recording ICs can acquire useful signals for closed-loop stimulation for DBS BIB002 BIB003 BIB001 , the treatment of epilepsy BIB004 and the restoration of bladder function BIB006 . Potential neuromodulation therapies are emerging for hypertension BIB006 , inflammatory disease BIB007 and heart failure BIB005 , and the ultimate success of these therapies may hinge on the ability to decode relevant biomarkers in real time. Hence, research on neural amplifiers is in a continual state of technological enhancement, promising improvements in the IC process as well as further reductions in power consumption and amplifier noise and increased channel densities.