Corrigendum: Modeling the volume of tissue activated in deep brain stimulation and its clinical influence: a review.

[This corrects the article DOI: 10.3389/fnhum.2024.1333183.].

Modeling the volume of tissue activated in deep brain stimulation and its clinical influence: a review.

Deep brain stimulation (DBS) is a neuromodulatory therapy that has been FDA approved for the treatment of various disorders, including but not limited to, movement disorders (e.g., Parkinson's disease and essential tremor), epilepsy, and obsessive-compulsive disorder. Computational methods for estimating the volume of tissue activated (VTA), coupled with brain imaging techniques, form the basis of models that are being generated from retrospective clinical studies for predicting DBS patient outcomes. For instance, VTA models are used to generate target-and network-based probabilistic stimulation maps that play a crucial role in predicting DBS treatment outcomes. This review defines the methods for calculation of tissue activation (or modulation) including ones that use heuristic and clinically derived estimates and more computationally involved ones that rely on finite-element methods and biophysical axon models. We define model parameters and provide a comparison of commercial, open-source, and academic simulation platforms available for integrated neuroimaging and neural activation prediction. In addition, we review clinical studies that use these modeling methods as a function of disease. By describing the tissue-activation modeling methods and highlighting their application in clinical studies, we provide the neural engineering and clinical neuromodulation communities with perspectives that may influence the adoption of modeling methods for future DBS studies.

Using Compound Neural Action Potentials for Functional Validation of a High-Density Intraneural Interface: A Preliminary Study.

Compound nerve action potentials (CNAPs) were used as a metric to assess the stimulation performance of a novel high-density, transverse, intrafascicular electrode in rat models. We show characteristic CNAPs recorded from distally implanted cuff electrodes. Evaluation of the CNAPs as a function of stimulus current and calculation of recruitment plots were used to obtain a qualitative approximation of the neural interface's placement and orientation inside the nerve. This method avoids elaborate surgeries required for the implantation of EMG electrodes and thus minimizes surgical complications and may accelerate the healing process of the implanted subject.

Artificial neural network-based rapid predictor of biological nerve fiber activation for DBS applications.

Objective.Computational models are powerful tools that can enable the optimization of deep brain stimulation (DBS). To enhance the clinical practicality of these models, their computational expense and required technical expertise must be minimized. An important aspect of DBS models is the prediction of neural activation in response to electrical stimulation. Existing rapid predictors of activation simplify implementation and reduce prediction runtime, but at the expense of accuracy. We sought to address this issue by leveraging the speed and generalization abilities of artificial neural networks (ANNs) to create a novel predictor of neural fiber activation in response to DBS.Approach.We developed six variations of an ANN-based predictor to predict the response of individual, myelinated axons to extracellular electrical stimulation. ANNs were trained using datasets generated from a finite-element model of an implanted DBS system together with multi-compartment cable models of axons. We evaluated the ANN-based predictors using three white matter pathways derived from group-averaged connectome data within a patient-specific tissue conductivity field, comparing both predicted stimulus activation thresholds and pathway recruitment across a clinically relevant range of stimulus amplitudes and pulse widths.Main results.The top-performing ANN could predict the thresholds of axons with a mean absolute error (MAE) of 0.037 V, and pathway recruitment with an MAE of 0.079%, across all parameters. The ANNs reduced the time required to predict the thresholds of 288 axons by four to five orders of magnitude when compared to multi-compartment cable models.Significance.We demonstrated that ANNs can be fast, accurate, and robust predictors of neural activation in response to DBS.

Longitudinal surveillance and comparative characterization of Escherichia albertii in wild raccoons in the United States.

Escherichia albertii is an emerging enteric bacterial pathogen causing watery diarrhea, abdominal distension, vomiting and fever in humans. E. albertii has caused many foodborne outbreaks in Japan and was also reported in other countries worldwide. However, the important animal reservoirs of this pathogen are still largely unknown, impeding us to combat this emerging pathogen. Recently, we reported that wild raccoons (Procyon lotor) and broiler chickens are significant reservoirs of E. albertii in Japan and the U.S., respectively. Here, we performed a longitudinal surveillance to monitor prevalence of E. albertii in wild raccoons in the U.S. and conducted comprehensive comparative analyses of the E. albertii of different origins. A total of 289 fecal swab samples were collected from wild raccoons in Tennessee and Kentucky in the U.S. (2018-2020). Approximately 26% (74/289) of the raccoons examined were PCR-positive for E. albertii and eventually 22 E. albertii isolates were obtained. PFGE analysis showed the U.S. raccoon E. albertii were phylogenetically distant even though the corresponding raccoons were captured from a small area. Unlike the high prevalence of multidrug resistance (83%) observed in previous chicken E. albertii survey, antibiotic resistance was rarely observed in all the U.S. raccoon and 22 Japan raccoon strains with only one Japan strain displaying multidrug resistance (2%). Whole genome sequencing of 54 diverse E. albertii strains and subsequent comparative genomics analysis revealed unique clusters that displayed close evolutionary relationships and similar virulence gene profiles among the strains of different origins in terms of geographical locations (e.g., U.S. and Japan) and hosts (raccoon, chicken, swine, and human). Challenge experiment demonstrated raccoon E. albertii strains could successfully colonize in the chicken intestine at 3 and 8 days postinfection. A pilot environmental survey further showed all the four tested water samples from Tennessee river were E. albertii-positive; two different E. albertii strains, isolated from a single water sample, showed close relationships to those of human origin. Together, the findings from this study provide new insights into the ecology, evolution, and pathobiology of E. albertii, and underscore the need to control the emerging E. albertii in a complex ecosystem using One Health approach.

Effects of nanostructuration on the electrochemical performance of metallic bioelectrodes.

The use of metallic nanostructures in the fabrication of bioelectrodes (e.g., neural implants) is gaining attention nowadays. Nanostructures provide increased surface area that might benefit the performance of bioelectrodes. However, there is a need for comprehensive studies that assess electrochemical performance of nanostructured surfaces in physiological and relevant working conditions. Here, we introduce a versatile scalable fabrication method based on magnetron sputtering to develop analogous metallic nanocolumnar structures (NCs) and thin films (TFs) from Ti, Au, and Pt. We show that NCs contribute significantly to reduce the impedance of metallic surfaces. Charge storage capacity of Pt NCs is remarkably higher than that of Pt TFs and that of the other metals in both morphologies. Circuit simulations of the electrode/electrolyte interface show that the signal delivered in voltage-controlled systems is less filtered when nanocolumns are used. In a current-controlled system, simulation shows that NCs provide safer stimulation conditions compared to TFs. We have assessed the durability of NCs and TFs for potential use in vivo by reactive accelerated aging test, mimicking one-year in vivo implantation. Although each metal/morphology reveals a unique response to aging, NCs show overall more stable electrochemical properties compared to TFs in spite of their porous structure.

Gender-Based Violence Risk Mitigation by Non-GBV Specialists Prior to and during COVID-19: A Global Survey of Knowledge, Attitudes and Practices of Humanitarian Practitioners.

Available evidence indicates that the COVID-19 pandemic and response measures may lead to increased risk of gender-based violence (GBV), including in humanitarian contexts. This study examined the knowledge, attitudes, and practices of humanitarian practitioners related to GBV risk mitigation approaches during COVID-19 in order to refine current guidance and inform future materials. A global, online cross-sectional survey of humanitarian practitioners was conducted between November 2020 and April 2021. We calculated descriptive statistics and used Chi-square or Fisher's exact tests to compare knowledge, attitudes, and practices among GBV specialists and non-specialists. Of 170 respondents, 58% were female and 44% were GBV specialists. Almost all (95%) of the respondents agreed or strongly agreed that they have a role to play in GBV risk mitigation. Compared to GBV specialists, a higher proportion of non-specialists reported little to no knowledge on GBV risk mitigation global guidance (38% vs. 7%, p < 0.001) and on how to respond to a disclosure of GBV (18% vs. 3%, p < 0.001). Respondents reported several barriers to integrating GBV risk mitigation into their work during COVID-19, including insufficient funding, capacity, knowledge, and guidance. Efforts to mainstream GBV risk mitigation actions should continue and intensify, leveraging the lessons and experiences generated thus far.

Effects of Varied Stimulation Parameters on Adipose-Derived Stem Cell Response to Low-Level Electrical Fields.

Exogenous electrical fields have been explored in regenerative medicine to increase cellular expression of pro-regenerative growth factors. Adipose-derived stem cells (ASCs) are attractive for regenerative applications, specifically for neural repair. Little is known about the relationship between low-level electrical stimulation (ES) and ASC regenerative potentiation. In this work, patterns of ASC expression and secretion of growth factors (i.e., secretome) were explored across a range of ES parameters. ASCs were stimulated with low-level stimulation (20 mV/mm) at varied pulse frequencies, durations, and with alternating versus direct current. Frequency and duration had the most significant effects on growth factor expression. While a range of stimulation frequencies (1, 20, 1000 Hz) applied intermittently (1 h × 3 days) induced upregulation of general wound healing factors, neural-specific factors were only increased at 1 Hz. Moreover, the most optimal expression of neural growth factors was achieved when ASCs were exposed to 1 Hz pulses continuously for 24 h. In evaluation of secretome, apparent inconsistencies were observed across biological replications. Nonetheless, ASC secretome (from 1 Hz, 24 h ES) caused significant increase in neurite extension compared to non-stimulated control. Overall, ASCs are sensitive to ES parameters at low field strengths, notably pulse frequency and stimulation duration.

A multi-channel peripheral nerve stimulator with integrate-and-fire encoding.

Activation of peripheral nervous system (PNS) fibres to produce variable tactile and proprioceptive sensations in advanced bidirectional prosthetic limbs relies on neural stimulators with high spatial selectivity, dynamic range and resolution. A multi-channel application-specific integrated circuit (ASIC) is developed for PNS fibre activation using a wide dynamic range (10 nA-5 mA), high-resolution (30 nA step, 100 ns pulse accuracy) current stimulator, dissipating 0.73-2.75 mW at 3 V. The ASIC also enables encoding of external pressure signals via an integrate-and-fire methodology. Electrophysiological data of compound nerve action potentials were recorded for a range of stimulus amplitudes and pulse widths. This data was used to benchmark the performance of the ASIC with a known neural stimulator.

Deep brain stimulation in essential tremor: targets, technology, and a comprehensive review of clinical outcomes.

Introduction: Essential tremor (ET) is a common movement disorder with an estimated prevalence of 0.9% worldwide. Deep brain stimulation (DBS) is an established therapy for medication refractory and debilitating tremor. With the arrival of next generation technology, the implementation and delivery of DBS has been rapidly evolving. This review will highlight the current applications and constraints for DBS in ET.Areas covered: The mechanism of action, targets for neuromodulation, next generation guidance techniques, symptom-specific applications, and long-term efficacy will be reviewed.Expert opinion: The posterior subthalamic area and zona incerta are alternative targets to thalamic DBS in ET. However, they may be associated with additional stimulation-induced side effects. Novel stimulation paradigms and segmented electrodes provide innovative approaches to DBS programming and stimulation-induced side effects.

Enhanced Rabies Surveillance Using a Direct Rapid Immunohistochemical Test.

Laboratory-based surveillance is integral for rabies prevention, control and management efforts. While the DFA is the gold standard for rabies diagnosis, there is a need to validate additional diagnostic techniques to improve rabies surveillance, particularly in developing countries. Here, we present a standard protocol for the DRIT as an alternative, laboratory or field-based testing option that uses light microscopy as compared to the DFA. Touch impressions of brain tissue collected from suspect animals are fixed in 10% buffered formalin. The DRIT uses rabies virus-specific monoclonal or polyclonal antibodies (conjugated to biotin), a streptavidin-peroxidase enzyme, and a chromogen reporter (such as acetyl 3-amino-9-ethylcarbazole) to detect viral inclusions within infected tissue. In approximately 1 h, a brain tissue sample can be tested and interpreted by the DRIT. Evaluation of suspect animal brains tested from a variety of species in North America, Asia, Africa, and Europe have illustrated high sensitivity and specificity by the DRIT approaching 100% with results compared to DFA. Since 2005, the United States Department of Agriculture's Wildlife Services (USDA WS) program has conducted large-scale enhanced rabies surveillance efforts using the DRIT to test >94,000 samples collected from wildlife in strategic rabies management areas. The DRIT provides a powerful, economical tool for rabies diagnosis that can be used by laboratorians and field biologists to improve current rabies surveillance, prevention and control programs globally.

Electrode impedance analysis of chronic tungsten microwire neural implants: understanding abiotic vs. biotic contributions.

Changes in biotic and abiotic factors can be reflected in the complex impedance spectrum of the microelectrodes chronically implanted into the neural tissue. The recording surface of the tungsten electrode in vivo undergoes abiotic changes due to recording site corrosion and insulation delamination as well as biotic changes due to tissue encapsulation as a result of the foreign body immune response. We reported earlier that large changes in electrode impedance measured at 1 kHz were correlated with poor electrode functional performance, quantified through electrophysiological recordings during the chronic lifetime of the electrode. There is a need to identity the factors that contribute to the chronic impedance variation. In this work, we use numerical simulation and regression to equivalent circuit models to evaluate both the abiotic and biotic contributions to the impedance response over chronic implant duration. COMSOL® simulation of abiotic electrode morphology changes provide a possible explanation for the decrease in the electrode impedance at long implant duration while biotic changes play an important role in the large increase in impedance observed initially.

Corrosion of tungsten microelectrodes used in neural recording applications.

In neuroprosthetic applications, long-term electrode viability is necessary for robust recording of the activity of neural populations used for generating communication and control signals. The corrosion of tungsten microwire electrodes used for intracortical recording applications was analyzed in a controlled bench-top study and compared to the corrosion of tungsten microwires used in an in vivo study. Two electrolytes were investigated for the bench-top electrochemical analysis: 0.9% phosphate buffered saline (PBS) and 0.9% PBS containing 30 mM of hydrogen peroxide. The oxidation and reduction reactions responsible for corrosion were found by measurement of the open circuit potential and analysis of Pourbaix diagrams. Dissolution of tungsten to form the tungstic ion was found to be the corrosion mechanism. The corrosion rate was estimated from the polarization resistance, which was extrapolated from the electrochemical impedance spectroscopy data. The results show that tungsten microwires in an electrolyte of PBS have a corrosion rate of 300-700 µm/yr. The corrosion rate for tungsten microwires in an electrolyte containing PBS and 30 mM H2O2 is accelerated to 10,000-20,000 µm/yr. The corrosion rate was found to be controlled by the concentration of the reacting species in the cathodic reaction (e.g. O2 and H2O2). The in vivo corrosion rate, averaged over the duration of implantation, was estimated to be 100 µm/yr. The reduced in vivo corrosion rate as compared to the bench-top rate is attributed to decreased rate of oxygen diffusion caused by the presence of a biological film and a reduced concentration of available oxygen in the brain.

An implantable integrated low-power amplifier-microelectrode array for Brain-Machine Interfaces.

One of the important challenges in designing Brain-Machine Interfaces (BMI) is to build implantable systems that have the ability to reliably process the activity of large ensembles of cortical neurons. In this paper, we report the design, fabrication, and testing of a polyimide-based microelectrode array integrated with a low-power amplifier as part of the Florida Wireless Integrated Recording Electrode (FWIRE) project at the University of Florida developing a fully implantable neural recording system for BMI applications. The electrode array was fabricated using planar micromachining MEMS processes and hybrid packaged with the amplifier die using a flip-chip bonding technique. The system was tested both on bench and in-vivo. Acute and chronic neural recordings were obtained from a rodent for a period of 42 days. The electrode-amplifier performance was analyzed over the chronic recording period with the observation of a noise floor of 4.5 microVrms, and an average signal-to-noise ratio of 3.8.

Flexible polymer substrate and tungsten microelectrode array for an implantable neural recording system.

This paper describes the process flow and testing of a substrate for a fully implantable neural recording system. Tungsten microwires are hybrid-packaged on a micromachined flexible polymer substrate forming an intracortical microelectrode array for brain machine interfaces. The microelectrode array is characterized on the bench top and tested in vivo. The microelectrode noise floor is less than 2 microV and acute recording results show a signal to noise ratio of 9.9-17.3 dB. The technique of hybrid fabrication of the electrodes on a flexible substrate provides a general platform for the development of an implantable neural recording system.

Design and fabrication of a flexible substrate microelectrode array for brain machine interfaces.

We report a neural microelectrode array design that leverages the recording properties of conventional microwire electrode arrays with the additional features of precise control of the electrode geometries. Using microfabrication techniques, a neural probe array is fabricated that possesses a flexible polyimide-based cable. The performance of the design was tested with electrochemical impedance spectroscopy and in vivo studies. The gold-plated electrode site has an impedance value of 0.9 M Omega at 1 kHz. Acute neural recording provided high neuronal yields, peak-to-peak amplitudes (as high as 100 microV), and signal-to-noise ratios (27 dB).