Energy Efficient Neural Stimulation: Coupling Circuit Design and Membrane Biophysics

The delivery of therapeutic levels of electrical current to neural tissue is a well-established treatment for numerous indications such as Parkinson’s disease and chronic pain. While the neuromodulation medical device industry has experienced steady clinical growth over the last two decades, much of the core technology underlying implanted pulse generators remain unchanged. In this study we propose some new methods for achieving increased energy-efficiency during neural stimulation. The first method exploits the biophysical features of excitable tissue through the use of a centered-triangular stimulation waveform. Neural activation with this waveform is achieved with a statistically significant reduction in energy compared to traditional rectangular waveforms. The second method demonstrates energy savings that could be achieved by advanced circuitry design. We show that the traditional practice of using a fixed compliance voltage for constant-current stimulation results in substantial energy loss. A portion of this energy can be recuperated by adjusting the compliance voltage to real-time requirements. Lastly, we demonstrate the potential impact of axon fiber diameter on defining the energy-optimal pulse-width for stimulation. When designing implantable pulse generators for energy efficiency, we propose that the future combination of a variable compliance system, a centered-triangular stimulus waveform, and an axon diameter specific stimulation pulse-width has great potential to reduce energy consumption and prolong battery life in neuromodulation devices.     

Designing the Charge Storage Properties of Li‐Exchanged Sodium Vanadium Fluorophosphate for Powering Implantable Biomedical Devices

The growing demand for bioelectronics has generated widespread interest in implantable energy storage. These implantable bioelectronic devices, powered by a complementary battery/capacitor system, have faced difficulty in miniaturization without compromising their functionality. This paper reports on the development of a promising high‐rate cathode material for implantable power sources based on Li‐exchanged Na_1.5VOPO₄F_0.5 anchored on reduced graphene oxide (LNVOPF‐rGO). LNVOPF is unique in that it offers dual charge storage mechanisms, which enable it to exhibit mixed battery/capacitor electrochemical behavior. In this work, electrochemical Li‐ion exchange of the LNVOPF structure is characterized by operando X‐ray diffraction. Through designed nanostructuring, the charge storage kinetics of LNVOPF are improved, as reflected in the stored capacity of 107 mAh g^?1 at 20C. A practical full cell device composed of LNVOPF and T‐Nb₂O₅, which serves as a pseudocapacitive anode, is fabricated to demonstrate not only high energy/power density storage (100 Wh kg^?1 at 4000 W kg^?1) but also reliable pulse capability and biocompatibility, a desirable combination for applications in biostimulating devices. This work underscores the potential of miniaturizing biomedical devices by replacing a conventional battery/capacitor couple with a single power source.     

The last frontier: transcatheter devices for percutaneous or minimally invasive treatment of chronic heart failure

Heart failure has a high prevalence in the general population. Morbidity and mortality of heart failure patients remain high, despite improvements in drug therapy, implantable cardioverter-defibrillators and cardiac resynchronisation therapy. New transcatheter implantable devices have been developed to improve the treatment of heart failure. There has been a rapid development of minimally invasive or transcatheter devices used in the treatment of heart failure associated with aortic and mitral valve disease and these devices are being incorporated into routine clinical practice at a fast rate. Several other new transcatheter structural heart interventions for chronic heart failure aimed at a variety of pathophysiologic approaches are currently being developed. In this review, we focus on devices used in the treatment of chronic heart failure by means of left ventricular remodelling, left atrial pressure reduction, tricuspid regurgitation reduction and neuromodulation. The clinical evaluations of these devices are early-stage evaluations of initial feasibility and safety studies and additional clinical evidence needs to be gathered in appropriately designed clinical trials.     

Ethics of the heart: ethical and policy challenges in the treatment of advanced heart failure

Heart failure is a major cause of morbidity and mortality in the United States and worldwide, accounting for immense health-care costs. Advanced therapies such as transplantation, ventricular assist devices, and implantable cardioverter defibrillators have had great success in significantly improving life expectancy and morbidity, however these advances have contributed substantially to the economic burden associated with this epidemic. Concomitantly, the accessibility of these advanced therapies is limited, due to a finite number of available organs for heart transplantation and, in the future, the economic costs associated with both transplant and device therapy. This article discusses ethical and policy challenges in the treatment of advanced heart failure, including decisions regarding procurement of hearts for transplant and allocation to recipients; and the complex issues surrounding the use of implantable cardioverter defibrillators and ventricular assist devices, including quality of life, advanced directive planning in the context of these devices, and resource utilization. Based on these challenges, we recommend that a discussion of these complex matters be incorporated into cardiovascular training programs.     

Battery-powered miniature implant for electrical nerve stimulation.

The range of application of implantable stimulators in functional electrical stimulation (FES) for therapeutic purposes and for the restoration of lost or damaged functions has steadily grown within the last 20 years. Each time a clinically used method is improved, a new field of FES application explored or basic research conducted, animal experiments are needed to check and evaluate the findings and results. It is precisely for this use that the stimulation system described in this paper was developed. The battery-powered single-channel stimulator can be used for the excitation of motor and sensory nerves with monophasic or biphasic impulses. All parameters and functions are programmable via the bidirectional telemetry circuit. Implant programming is achieved by a laptop computer, supported by a graphical user interface, instead of by a specially designed programmer. The maximum settings of the stimulation parameters are: frequency 100 Hz, monophasic pulse duration 0.8 ms, biphasic pulse duration 1.6 ms, stimulation current 3 mA. The implant volume was reduced to 2 cm3 (length 23 mm, width 13 mm, height 7.5 mm), lowering the weight to 3.6 g. Due to this small volume the implant can be used in small animals. The power supply via battery obviates the need for transcutaneous tunneling or permanent external high-frequency senders and facilitates the keeping of the animals.     

Evaluation of Intradural Stimulation Efficiency and Selectivity in a Computational Model of Spinal Cord Stimulation

Spinal cord stimulation (SCS) is an alternative or adjunct therapy to treat chronic pain, a prevalent and clinically challenging condition. Although SCS has substantial clinical success, the therapy is still prone to failures, including lead breakage, lead migration, and poor pain relief. The goal of this study was to develop a computational model of SCS and use the model to compare activation of neural elements during intradural and extradural electrode placement. We constructed five patient-specific models of SCS. Stimulation thresholds predicted by the model were compared to stimulation thresholds measured intraoperatively, and we used these models to quantify the efficiency and selectivity of intradural and extradural SCS. Intradural placement dramatically increased stimulation efficiency and reduced the power required to stimulate the dorsal columns by more than 90%. Intradural placement also increased selectivity, allowing activation of a greater proportion of dorsal column fibers before spread of activation to dorsal root fibers, as well as more selective activation of individual dermatomes at different lateral deviations from the midline. Further, the results suggest that current electrode designs used for extradural SCS are not optimal for intradural SCS, and a novel azimuthal tripolar design increased stimulation selectivity, even beyond that achieved with an intradural paddle array. Increased stimulation efficiency is expected to increase the battery life of implantable pulse generators, increase the recharge interval of rechargeable implantable pulse generators, and potentially reduce stimulator volume. The greater selectivity of intradural stimulation may improve the success rate of SCS by mitigating the sensitivity of pain relief to malpositioning of the electrode. The outcome of this effort is a better quantitative understanding of how intradural electrode placement can potentially increase the selectivity and efficiency of SCS, which, in turn, provides predictions that can be tested in future clinical studies assessing the potential therapeutic benefits of intradural SCS.     

Cardiac pacemaker battery discharge after external electrical cardioversion for broad QRS Complex Tachycardia

External electrical cardioversion or defibrillation may be necessary in patients with implanted cardiac pacemaker (PM) or implantable cardioverter defibrillator (ICD). Sudden discharge of high electrical energy employed in direct current (DC) transthoracic countershock may damage the PM/ICD system resulting in a series of possible device malfunctions. For this reason, when defibrillation or cardioversion must be attempted in a patient with a PM or ICD, some precautions should be taken, particularly in PM dependent patients, in order to prevent damage to the device. We report the case of a 76-year-old woman with a dual chamber PM implanted in the right subclavicular region, who received two consecutive transthoracic DC shocks to treat haemodynamically unstable broad QRS complex tachycardia after cardiac surgery performed with a standard sternotomic approach. Because of the sternal wound and thoracic drainage tubes together with the severe clinical compromise, the anterior paddle was positioned near the pulse generator. At the following PM test, a complete battery discharge was detected.     

An unusual cause of recurrent syncope in a patient with implantable cardioverter defibrillator

Electromagnetic interferences (EMI) deriving from electrical devices may affect implantable cardioverter defibrillators (ICD). Improved algorithms have been developed in order to minimize adverse effects. However, caution should be still recommended in ICD recipients when handling electrical devices. Here we describe the case of an ICD patient with recurrent syncopal episodes due to inhibition of pacing by oversensing of electrical noise from a not properly grounded washing machine.     

Developmental analysis of grandchildless (gs(1)N441) mutation in Drosophila melanogaster; abnormal formation of pole cells

A detailed examination of the developmental features of abnormal formation of pole cells and a functional analysis of the germ plasma of gs(1)N441 embryos were carried out. The germ plasma is morphologically normal. Embryos in which cleavage nuclei show retarded migration to the posterior pole do not form pole cells. Pole cells, following formation, are abnormally segregated and then intermingled between the blastoderm cell layer but retaining normal morphology and differentiating into functional germ cells. The results of cytoplasmic transplantation experiments indicate the autonomous segregation ability of the mutant polar plasma to form pole cells to possibly be affected.     

Electrotransformation of Clostridium thermocellum

Electrotransformation of several strains of Clostridium thermocellum was achieved using plasmid pIKm1 with selection based on resistance to erythromycin and lincomycin. A custom-built pulse generator was used to apply a square 10-ms pulse to an electrotransformation cuvette consisting of a modified centrifuge tube. Transformation was verified by recovery of the shuttle plasmid pIKm1 from presumptive transformants of C. thermocellum with subsequent PCR specific to the mls gene on the plasmid, as well as by retransformation of Escherichia coli. Optimization carried out with strain DSM 1313 increased transformation efficiencies from <1 to (2.2 +/- 0.5) x 10(5) transformants per micro g of plasmid DNA. Factors conducive to achieving high transformation efficiencies included optimized periods of incubation both before and after electric pulse application, chilling during cell collection and washing, subculture in the presence of isoniacin prior to electric pulse application, a custom-built cuvette embedded in an ice block during pulse application, use of a high (25-kV/cm) field strength, and induction of the mls gene before plating the cells on selective medium. The protocol and preferred conditions developed for strain DSM 1313 resulted in transformation efficiencies of (5.0 +/- 1.8) x 10(4) transformants per micro g of plasmid DNA for strain ATCC 27405 and approximately 1 x 10(3) transformants per micro g of plasmid DNA for strains DSM 4150 and 7072. Cell viability under optimal conditions was approximately 50% of that of controls not exposed to an electrical pulse. Dam methylation had a beneficial but modest (7-fold for strain ATCC 27405; 40-fold for strain DSM 1313) effect on transformation efficiency. The effect of isoniacin was also strain specific. The results reported here provide for the first time a gene transfer method functional in C. thermocellum that is suitable for molecular manipulations involving either the introduction of genes associated with foreign gene products or knockout of native genes.     

Rate and predictors of electrical failure in non-recalled defibrillator leads

BackgroundImplantable cardioverter defibrillator (ICD) leads are considered as the ‘weakest link’ in defibrillator systems due to FDA recalls and advisories involving popular lead models from major manufacturers. The rate of electrical failure of ICD leads not implicated in a recall is however not well determined.MethodsMedical records of patients implanted with ICDs at hospitals of the University of Pittsburgh Medical Center between 2002 and 2014 were analyzed. Leads were classified as having electrically failed if removed or replaced for reasons other than infection or heart transplantation. Patients were followed to endpoint of death or electrical lead failure.Results2410 consecutive ICD recipients (mean age 66 ± 13 years, women 22%, single/dual/biventricular-ICD 20%/44%/36%) were included. During a mean follow-up of 3.9 ± 3.3 years, 1272 patients (53%) died, 55 patients (2.3%) had ICD lead electrical failure, and 1052 (44%) patients were alive with functional leads at the time of last follow-up. Patients with failed leads had higher BMI (p = 0.07), better functional status (p = 0.04), higher serum creatinine (p = 0.004), wider QRS complex (p = 0.01), higher number of implanted leads (p = 0.06) and were more likely to have ischemic cardiomyopathy (p = 0.03). After adjusting for these variables in a binary logistic regression model, only a lower BMI, presence of non-ischemic cardiomyopathy, and a better functional status remained independently predictive of electrical failure.ConclusionsOnly 2.3% of non-recalled ICD leads experience electrical failure (annual failure rate of 0.6%). A higher patient functional status, lower BMI, and non-ischemic etiology of cardiomyopathy are independently associated with higher rates of ICD lead failure.     

Cardiac sympathetic activity in chronic heart failure: cardiac <Superscript>123</Superscript>I-<Emphasis Type="Italic">m</Emphasis>IBG scintigraphy to improve patient selection for ICD implantation

Heart failure is a life-threatening disease with a growing incidence in the Netherlands. This growing incidence is related to increased life expectancy, improvement of survival after myocardial infarction and better treatment options for heart failure. As a consequence, the costs related to heart failure care will increase. Despite huge improvements in treatment, the prognosis remains unfavourable with high one-year mortality rates. The introduction of implantable devices such as implantable cardioverter defibrillators (ICD) and cardiac resynchronisation therapy (CRT) has improved the overall survival of patients with chronic heart failure. However, after ICD implantation for primary prevention in heart failure a high percentage of patients never have appropriate ICD discharges. In addition 25–50?% of CRT patients have no therapeutic effect. Moreover, both ICDs and CRTs are associated with malfunction and complications (e.?g. inappropriate shocks, infection). Last but not least is the relatively high cost of these devices. Therefore, it is essential, not only from a clinical but also from a socioeconomic point of view, to optimise the current selection criteria for ICD and CRT. This review focusses on the role of cardiac sympathetic hyperactivity in optimising ICD selection criteria. Cardiac sympathetic hyperactivity is related to fatal arrhythmias and can be non-invasively assessed with ¹²³I-meta-iodobenzylguanide (¹²³I-mIBG) scintigraphy. We conclude that cardiac sympathetic activity assessed with ¹²³I-mIBG scintigraphy is a promising tool to better identify patients who will benefit from ICD implantation.     

Proteomic analysis of metabolic, cytoskeletal and stress response proteins in human heart failure

Human heart failure is a complex syndrome and a primary cause of morbidity and mortality in the world. However, the molecular pathways involved in the remodelling process are poorly understood. In this study, we performed exhaustive global proteomic surveys of cardiac ventricle isolated from failing and non-failing human hearts, and determined the regulatory pathway to uncover the mechanism underlying heart failure. Two-dimensional gel electrophoresis (2-DE) coupled with tandem mass spectrometry was used to identify differentially expressed proteins in specimens from failing (n = 9) and non-failing (n = 6) human hearts. A total of 25 proteins with at least 1.5-fold change in the failing heart were identified; 15 proteins were up-regulated and 10 proteins were down-regulated. The altered proteins belong to three broad functional categories: (i) metabolic [e.g. NADH dehydrogenase (ubiquinone), dihydrolipoamide dehydrogenase, and the cytochrome c oxidase subunit]; (ii) cytoskeletal (e.g. myosin light chain proteins, troponin I type 3 and transthyretin) and (iii) stress response (e.g. αB-crystallin, HSP27 and HSP20). The marked differences in the expression of selected proteins, including HSP27 and HSP20, were further confirmed by Western blot. Thus, we carried out full-scale screening of the protein changes in human heart failure and profiled proteins that may be critical in cardiac dysfunction for future mapping.     

Effect of stimulating the auricular branch of the vagus nerve on the heart rate in patients with severe chronic heart failure

A study was made to evaluate the prospects of improving the cardiac function by electrical stimulation of the auricular branch of the vagus nerve in patients with severe chronic heart failure (CHF). Sympathetic hyperactivity and the cardiac function were evaluated by 24-hour ECG monitoring, echocardiography, and a 6-min walk test. At the time of enrollment into the study, patients had a heart rate (HR) of more than 60 bpm, a left ventricular (LV) ejection fraction (EF) of less than 40%, and CHF NYHA functional class (FC) III or IV even with well tolerated medications. Control-group patients (n = 7) did not show significant changes in the functional state of the heart after sham treatment. In the test group (n = 44), a significant increase in LV EF and a decrease in end-systolic volume were induced by electrical pulse stimulation of the auricular branch. A decrease in HR was documented in 34 patients; CHF FC decreased by one or two grades in 40 patients. The changes were assumed to reflect new balance achieved in the autonomic regulation of the heart to contribute to sustaining competence of the myocardium. Electrical pulse stimulation of the auricular branch of the vagus nerve was concluded to provide a safe and efficacious addition to drug therapy in patients with severe CHF.     

Designing molecular devices by altering bond lengths

The work focuses on a theoretical approach to investigating the electric field (EF) dependence of bond-length alternation, the geometric and electronic structures of molecular wires used in the design of molecular electronic devices, the EF dependence of SCF energy, and the spatial distribution of the frontier orbitals of the molecular wires. Just as the bond length is an important influence on the conductance of the molecular wire, the dependence of the conductance on the chain length was also studied. We have also investigated how the current–voltage (I-V) characteristics change with bond length, as the bond length plays an important role in determining the conductance of molecular wires.     

Flexible polyimide probes with microelectrodes and embedded microfluidic channels for simultaneous drug delivery and multi-channel monitoring of bioelectric activity

The study of intracellular communication requires devices that can not only monitor the bioelectric activity, but also control and observe the biochemical environment at the cellular level. This paper reports on the development and characterisation of implantable polyimide microprobes that allow simultaneous, selective chemical delivery/probing and multi-channel recording/stimulation of bioelectric activity. The key component of the system is a flexible polyimide substrate with embedded microchannels that is batch-fabricated combining polyimide micromachining and a lamination technique. The devices provide platinum microelectrodes on both sides of the polyimide substrate with an active surface between 20 microm x 20 microm and 50 microm x 50 microm. The embedded microchannels permit highly localised drug delivery or probing at the tip of the device via channel outlets adjacent to the microelectrodes. The microelectrodes were characterised by electrical impedance spectroscopy and the microchannels were studied in microflow experiments. Two different fluid delivery schemes were explored in two different designs. The first device type consists of a simple combination of microchannels and microelectrodes on one substrate. Liquids are ejected at the tip of the device by pressure injection techniques. The second device was inspired by the so-called U-tube concept allowing for highly localised delivery of controlled amounts of liquids in the picoliters range. Thus, the influence of chemical compounds on the electrical activity of cells can be studied with high temporal and spatial resolution. The flexible, implantable devices can be used for studying the chemical and electrical information exchange and communication of cells in in vivo and in vitro experiments.     

Comparative Reliability Studies and Analysis of Au,Pd-Coated Cu and Pd-Doped Cu Wire in Microelectronics Packaging

This paper compares and discusses the wearout reliability and analysis of Gold (Au), Palladium (Pd) coated Cu and Pd-doped Cu wires used in fineline Ball Grid Array (BGA) package. Intermetallic compound (IMC) thickness measurement has been carried out to estimate the coefficient of diffusion (D_o) under various aging conditions of different bonding wires. Wire pull and ball bond shear strengths have been analyzed and we found smaller variation in Pd-doped Cu wire compared to Au and Pd-doped Cu wire. Au bonds were identified to have faster IMC formation, compared to slower IMC growth of Cu. The obtained weibull slope, β of three bonding wires are greater than 1.0 and belong to wearout reliability data point. Pd-doped Cu wire exhibits larger time-to-failure and cycles-to-failure in both wearout reliability tests in Highly Accelerated Temperature and Humidity (HAST) and Temperature Cycling (TC) tests. This proves Pd-doped Cu wire has a greater potential and higher reliability margin compared to Au and Pd-coated Cu wires.     

A Wireless Multi-Channel Recording System for Freely Behaving Mice and Rats

To understand the neural basis of behavior, it is necessary to record brain activity in freely moving animals. Advances in implantable multi-electrode array technology have enabled researchers to record the activity of neuronal ensembles from multiple brain regions. The full potential of this approach is currently limited by reliance on cable tethers, with bundles of wires connecting the implanted electrodes to the data acquisition system while impeding the natural behavior of the animal. To overcome these limitations, here we introduce a multi-channel wireless headstage system designed for small animals such as rats and mice. A variety of single unit and local field potential signals were recorded from the dorsal striatum and substantia nigra in mice and the ventral striatum and prefrontal cortex simultaneously in rats. This wireless system could be interfaced with commercially available data acquisition systems, and the signals obtained were comparable in quality to those acquired using cable tethers. On account of its small size, light weight, and rechargeable battery, this wireless headstage system is suitable for studying the neural basis of natural behavior, eliminating the need for wires, commutators, and other limitations associated with traditional tethered recording systems.     

Multiplexed, high density electrophysiology with nanofabricated neural probes

Extracellular electrode arrays can reveal the neuronal network correlates of behavior with single-cell, single-spike, and sub-millisecond resolution. However, implantable electrodes are inherently invasive, and efforts to scale up the number and density of recording sites must compromise on device size in order to connect the electrodes. Here, we report on silicon-based neural probes employing nanofabricated, high-density electrical leads. Furthermore, we address the challenge of reading out multichannel data with an application-specific integrated circuit (ASIC) performing signal amplification, band-pass filtering, and multiplexing functions. We demonstrate high spatial resolution extracellular measurements with a fully integrated, low noise 64-channel system weighing just 330 mg. The on-chip multiplexers make possible recordings with substantially fewer external wires than the number of input channels. By combining nanofabricated probes with ASICs we have implemented a system for performing large-scale, high-density electrophysiology in small, freely behaving animals that is both minimally invasive and highly scalable.