Multimodal, longitudinal assessment of intracortical microstimulation

The fundamental obstacle to neuroprostheses based on penetrating microstimulation is the tissue’s response to the device insertion and to the application of the electrical stimulation. Our long-term goal is to develop multichannel microstimulation of central nervous tissue for clinical therapy. The overall objective of this research is to identify the optimal parameters for a chronically implanted microstimulation device. In particular, the work presented here focuses on the effects of repeated stimulation and the reactive tissue response on the efficacy of stimulation-driven behavior. To this end, psychophysical experiments were performed using multichannel cortical implants in the auditory cortex of rats. Further, we investigated the effect of the device–tissue interfacial quality on the psychophysical threshold. Here, we report the effects of cortical depth, days postimplant on the psychophysical threshold of auditory cortical microstimulation, along with correlated impedance spectral changes and post vivo histology. We expect that these data will further enable neuroprosthetic development

Voltage Biasing, Cyclic Voltammetry, & Electrical Impedance Spectroscopy for Neural Interfaces

Electrical impedance spectroscopy (EIS) and cyclic voltammetry (CV) measure properties of the electrode-tissue interface without additional invasive procedures, and can be used to monitor electrode performance over the long term. EIS measures electrical impedance at multiple frequencies, and increases in impedance indicate increased glial scar formation around the device, while cyclic voltammetry measures the charge carrying capacity of the electrode, and indicates how charge is transferred at different voltage levels. As implanted electrodes age, EIS and CV data change, and electrode sites that previously recorded spiking neurons often exhibit significantly lower efficacy for neural recording. The application of a brief voltage pulse to implanted electrode arrays, known as rejuvenation, can bring back spiking activity on otherwise silent electrode sites for a period of time. Rejuvenation alters EIS and CV, and can be monitored by these complementary methods. Typically, EIS is measured daily as an indication of the tissue response at the electrode site. If spikes are absent in a channel that previously had spikes, then CV is used to determine the charge carrying capacity of the electrode site, and rejuvenation can be applied to improve the interface efficacy. CV and EIS are then repeated to check the changes at the electrode-tissue interface, and neural recordings are collected. The overall goal of rejuvenation is to extend the functional lifetime of implanted arrays

Poly(3,4-ethylenedioxythiophene) as a Micro-Neural Interface Material for Electrostimulation

Chronic microstimulation-based devices are being investigated to treat conditions such as blindness, deafness, pain, paralysis, and epilepsy. Small-area electrodes are desired to achieve high selectivity. However, a major trade-off with electrode miniaturization is an increase in impedance and charge density requirements. Thus, the development of novel materials with lower interfacial impedance and enhanced charge storage capacity is essential for the development of micro-neural interface-based neuroprostheses. In this report, we study the use of conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) as a neural interface material for microstimulation of small-area iridium electrodes on silicon-substrate arrays. Characterized by electrochemical impedance spectroscopy, electrodeposition of PEDOT results in lower interfacial impedance at physiologically relevant frequencies, with the 1 kHz impedance magnitude being 23.3 ± 0.7 kΩ, compared to 113.6 ± 3.5 kΩ for iridium oxide (IrOx) on 177 μm2 sites. Further, PEDOT exhibits enhanced charge storage capacity at 75.6 ± 5.4 mC/cm2 compared to 28.8 ± 0.3 mC/cm2 for IrOx, characterized by cyclic voltammetry (50 mV/s). These improvements at the electrode interface were corroborated by observation of the voltage excursions that result from constant current pulsing. The PEDOT coatings provide both a lower amplitude voltage and a more ohmic representation of the applied current compared to IrOx. During repetitive pulsing, PEDOT-coated electrodes show stable performance and little change in electrical properties, even at relatively high current densities which cause IrOx instability. These findings support the potential of PEDOT coatings as a micro-neural interface material for electrostimulation

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI <18·5 kg/m2) and obesity (BMI ≥30 kg/m2). For schoolaged children and adolescents, we report thinness (BMI <2 SD below the median of the WHO growth reference) and obesity (BMI >2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining underweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesit

Enhancing the intracortical neural interface with poly(3,4-ethylenedioxythiophene) (PEDOT)

Intracortical neuroprostheses offer the prospect of bi-directional communication interfaces for treatment and scientific understanding of physical and mental neurological disorders; however, their long-term functionality is limited by our inability to compensate for the dynamics of the neural interface. The neural interface refers to the electrode-tissue interface formed by placing an electrode into neural tissue. The brain\u27s reactive tissue response electrically and mechanically isolates the device from healthy tissue, reducing recording quality as well as stimulation performance. Additionally, current intracortical microstimulation materials are either unable to safely deliver charge, or materials degrade during applied electrical stimulation. The objectives of the presented research were to enhance the long-term reliability of the intracortical neural interface by 1) improving the reliability and performance of micro-neural interface materials for electrical stimulation, and 2) forming an integrated neural interface after device implantation beyond the region of tissue affected by the reactive tissue response. Here we report the achievement of these objectives through the use of the conductive polymer poly(3,4-ethylenedioxythiophene) (PEDOT). The techniques presented here offer unique neural interfacing approaches to improve the long term functionality of intracortical neuroprostheses. In the first study, we evaluated the in vitro stability and in vivo performance of PEDOT coatings for microstimulation. Microelectrodes coated with PEDOT exhibited electrochemical properties superior to iridium oxide and remained stable after short-term repetitive pulsing at current densities damaging to iridium oxide. Further, chronically implanted PEDOT coated microelectrodes subjected to daily microstimulation displayed a more reliable, low-impedance interface which corresponded to safer, lower-amplitude voltage excursions. However, both electrode materials were equally effective in regards to behavioral thresholds suggesting similar amounts of tissue damage likely occurred with all implanted devices. In the second study, we evaluated in vivo PEDOT polymerization as a technique to grow the neural interface after implantation to interface with healthy tissue beyond the region influenced by the reactive tissue response and potentially improve the safety of stimulation levels. In vivo PEDOT polymerization in the rat cerebral cortex resulted in lower impedance and improved recording quality. Histological analysis by optical microscopy confirmed successful integration of a dense PEDOT network within the tissue extending approximately 100-200 µm adjacent to the electrode

Non-clinical and Pre-clinical Testing to Demonstrate Safety of the Barostim Neo Electrode for Activation of Carotid Baroreceptors in Chronic Human Implants

The Barostim neo™ electrode was developed by CVRx, Inc.to deliver baroreflex activation therapy (BAT)™ to treat hypertension and heart failure. The neo electrode concept was designed to deliver electrical stimulation to the baroreceptors within the carotid sinus bulb, while minimizing invasiveness of the implant procedure. This device is currently CE marked in Europe, and in a Pivotal (akin to Phase III) Trial in the United States. Here we present the in vitro and in vivo safety testing that was completed in order to obtain necessary regulatory approval prior to conducting human studies in Europe, as well as an FDA Investigational Device Exemption (IDE) to conduct a Pivotal Trial in the United States. Stimulated electrodes (10 mA, 500 μs, 100 Hz) were compared to unstimulated electrodes using optical microscopy and several electrochemical techniques over the course of 27 weeks. Electrode dissolution was evaluated by analyzing trace metal content of solutions in which electrodes were stimulated. Lastly, safety testing under Good Laboratory Practice guidelines was conducted in an ovine animal model over a 12 and 24 week time period, with results processed and evaluated by an independent histopathologist. Long-term stimulation testing indicated that the neo electrode with a sputtered iridium oxide coating can be stimulated at maximal levels for the lifetime of the implant without clinically significant dissolution of platinum or iridium, and without increasing the potential at the electrode interface to cause hydrolysis or significant tissue damage. Histological examination of tissue that was adjacent to the neo electrodes indicated no clinically significant signs of increased inflammation and no arterial stenosis as a result of 6 months of continuous stimulation. The work presented here involved rigorous characterization and evaluation testing of the neo electrode, which was used to support its safety for chronic implantation. The testing strategies discussed provide a starting point and proven framework for testing new neuromodulation electrode concepts to support regulatory approval for clinical studies