Invasive Electrodes Research Articles

Cytoskeletal Remodeling and Gap Junction Translocation Mediates Blood-Brain Barrier Disruption by Non-invasive Low-Voltage Pulsed Electric Fields.

High-voltage pulsed electric fields (HV-PEF) delivered with invasive needle electrodes for electroporation applications is known to induce off-target blood-brain barrier (BBB) disruption. In this study, we sought to determine the feasibility of minimally invasive PEF application to produce BBB disruption in rat brain and identify the putative mechanisms mediating the effect. We observed dose-dependent presence of Evans Blue (EB) dye in rat brain when PEF were delivered with a skull mounted electrode used for neurostimulation application. Maximum region of dye uptake was observed while using 1500V, 100 pulses, 100µs and 10Hz. Results of computational models suggested that the region of BBB disruption was occurring at thresholds of 63V/cm or higher; well below intensity levels for electroporation. In vitro experiments recapitulating this effect with human umbilical vein endothelial cells (HUVEC) demonstrated cellular alterations that underlie BBB manifests at low-voltage high-pulse conditions without affecting cell viability or proliferation. Morphological changes in HUVECs due to PEF were accompanied by disruption of actin cytoskeleton, loss of tight junction protein-ZO-1 and VE-Cadherin at cell junctions and partial translocation into the cytoplasm. Uptake of propidium iodide (PI) in PEF treated conditions is less than 1% and 2.5% of total number of cells in high voltage (HV) and low-voltage (LV) groups, respectively, implying that BBB disruption to be independent of electroporation under these conditions. 3-D microfabricated blood vessel permeability was found to increase significantly following PEF treatment and confirmed with correlative cytoskeletal changes and loss of tight junction proteins. Finally, we show that the rat brain model can be scaled to human brains with a similar effect on BBB disruption characterized by electric field strength (EFS) threshold and using a combination of two bilateral HD electrode configurations.

Translational opportunities and challenges of invasive electrodes for neural interfaces.

Invasive brain-machine interfaces can restore motor, sensory and cognitive functions. However, their clinical adoption has been hindered by the surgical risk of implantation and by suboptimal long-term reliability. In this Review, we highlight the opportunities and challenges of invasive technology for clinically relevant electrophysiology. Specifically, we discuss the characteristics of neural probes that are most likely to facilitate the clinical translation of invasive neural interfaces, describe the neural signals that can be acquired or produced by intracranial electrodes, the abiotic and biotic factors that contribute to their failure, and emerging neural-interface architectures.

514 A Functional Ultrasound Brain-Machine Interface: Real-Time Decoding of Eight Movement Directions

INTRODUCTION: Brain-machine interfaces (BMIs) can be transformative for people living with chronic paralysis. By translating brain signals into computer commands, BMIs can bypass neurological impairments, enabling users to control computers, robots, and more. State-of-the-art BMIs have already made this future a reality in limited clinical trials. However, these BMIs requires inserting highly invasive electrodes into the brain. Device degradation limits longevity to 3-5 years and the field of view of brain activity is small. These factors limit BMI’s widespread adoption. The next generation of BMIs must be longer lasting, less invasive, and scalable. Functional ultrasound neuroimaging (fUSI) is a recently developed technique that meets these criteria. METHODS: We collected data from two nonhuman primates (NHPs). We used real-time fUSI to measure activity in the posterior parietal cortex, an important area for motor planning. We fed this fUSI data into real-time machine learning classifiers to predict the monkey’s intended movement direction and control a behavioral task in real-time. RESULTS: We could predict the monkey’s intended movement direction significantly above chance level (binomial test, p<0.001 for 2- and 8-directions) using the real-time fUSI-BMI. Most direction misclassifications were for neighboring directions (permutation test, p<0.001). The most important voxels for decoding eye movements were within small subpopulations of the lateral intraparietal area (LIP). We found that these LIP subpopulations had a stable encoding of movement direction and the NHPs could accurately control the task more than 40 days after training the decoder model. CONCLUSIONS: This work establishes, for the first time, the feasibility of a real-time ultrasound-based BMI and we have begun translating this work into human applications. This work contributes to the next generation of high-performing, yet minimally-invasive, BMIs that can restore function to patients with neurological impairments.

Post-explant profiling of subcellular-scale carbon fiber intracortical electrodes and surrounding neurons enables modeling of recorded electrophysiology

Objective. Characterizing the relationship between neuron spiking and the signals that electrodes record is vital to defining the neural circuits driving brain function and informing clinical brain-machine interface design. However, high electrode biocompatibility and precisely localizing neurons around the electrodes are critical to defining this relationship. Approach. Here, we demonstrate consistent localization of the recording site tips of subcellular-scale (6.8 µm diameter) carbon fiber electrodes and the positions of surrounding neurons. We implanted male rats with carbon fiber electrode arrays for 6 or 12+ weeks targeting layer V motor cortex. After explanting the arrays, we immunostained the implant site and localized putative recording site tips with subcellular-cellular resolution. We then 3D segmented neuron somata within a 50 µm radius from implanted tips to measure neuron positions and health and compare to healthy cortex with symmetric stereotaxic coordinates. Main results. Immunostaining of astrocyte, microglia, and neuron markers confirmed that overall tissue health was indicative of high biocompatibility near the tips. While neurons near implanted carbon fibers were stretched, their number and distribution were similar to hypothetical fibers placed in healthy contralateral brain. Such similar neuron distributions suggest that these minimally invasive electrodes demonstrate the potential to sample naturalistic neural populations. This motivated the prediction of spikes produced by nearby neurons using a simple point source model fit using recorded electrophysiology and the mean positions of the nearest neurons observed in histology. Comparing spike amplitudes suggests that the radius at which single units can be distinguished from others is near the fourth closest neuron (30.7 ± 4.6 µm, ± S) in layer V motor cortex. Significance. Collectively, these data and simulations provide the first direct evidence that neuron placement in the immediate vicinity of the recording site influences how many spike clusters can be reliably identified by spike sorting.

Immediate and Late Effects of Pulse Widths and Cycles on Bipolar, Gated Radiofrequency-Induced Tissue Reactions in in vivo Rat Skin.

Single to multiple pulse packs of bipolar, alternating current radiofrequency (RF) oscillations have been used for various medical purposes using invasive microneedle electrodes. This study was designed to evaluate the effects of pulse widths and cycles of RF pulse packs on immediate and delayed thermal tissue reactions in in vivo rat skin. RF energy at the frequency of 1 MHz and power of 70 W was delivered at each experimental setting into in vivo rat skin at 1.5-mm microneedle penetration, and then, tissue samples were obtained after 1 h and 3, 7, 14, and 21 days and histologically analyzed. A single-pulse-pack RF treatment generated coagulative necrosis zones in the dermal peri-electrode area and zones of non-necrotic thermal reactions in the dermal inter-electrode area. Multiple pulse-pack, RF-treated rat skin specimens revealed that the number and size of peri-electrode coagulative necrosis were markedly decreased by increasing the number of pulse packs and accordingly decreasing the conduction time of each pulse pack. The microscopic changes in RF-induced non-necrotic thermal reaction in the inter-electrode area were more remarkable in specimens treated with RF of 7 or 10 pulse packs than in specimens treated with RF of 1-4 pulse packs. The gated delivery of multiple RF pulse packs using a bipolar, alternating current, 1-MHz RF system using insulated microneedle electrodes efficiently generates non-necrotic thermal tissue reactions over the upper, mid, and deep dermis and subcutaneous fat in the inter-electrode areas.

Mechanism of Action of Peripheral Nerve Stimulation for Chronic Pain: A Narrative Review.

The use of stimulation of peripheral nerves to test or treat various medical disorders has been prevalent for a long time. Over the last few years, there has been growing evidence for the use of peripheral nerve stimulation (PNS) for treating a myriad of chronic pain conditions such as limb mononeuropathies, nerve entrapments, peripheral nerve injuries, phantom limb pain, complex regional pain syndrome, back pain, and even fibromyalgia. The ease of placement of a minimally invasive electrode via percutaneous approach in the close vicinity of the nerve and the ability to target various nerves have led to its widespread use and compliance. While most of the mechanism behind its role in neuromodulation is largely unknown, the gate control theory proposed by Melzack and Wall in the 1960s has been the mainstay for understanding its mechanism of action. In this review article, the authors performed a literature review to discuss the mechanism of action of PNS and discuss its safety and usefulness in treating chronic pain. The authors also discuss current PNS devices available in the market today.

Neural Bypasses: Literature Review and Future Directions in Developing Artificial Neural Connections.

Reported neuro-modulation schemes in the literature are typically classified as closed-loop or open-loop. A novel group of recently developed neuro-modulation devices may be better described as a neural bypass, which attempts to transmit neural data from one location of the nervous system to another. The most common form of neural bypasses in the literature utilize EEG recordings of cortical information paired with functional electrical stimulation for effector muscle output, most commonly for assistive applications and rehabilitation in spinal cord injury or stroke. Other neural bypass locations that have also been described, or may soon be in development, include cortical-spinal bypasses, cortical-cortical bypasses, autonomic bypasses, peripheral-central bypasses, and inter-subject bypasses. The most common recording devices include EEG, ECoG, and microelectrode arrays, while stimulation devices include both invasive and noninvasive electrodes. Several devices are in development to improve the temporal and spatial resolution and biocompatibility for neuronal recording and stimulation. A major barrier to entry includes neuroplasticity and current decoding mechanisms that regularly require retraining. Neural bypasses are a unique class of neuro-modulation. Continued advancement of neural recording and stimulating devices with high spatial and temporal resolution, combined with decoding mechanisms uninhibited by neuroplasticity, can expand the therapeutic capability of neural bypassing. Overall, neural bypasses are a promising modality to improve the treatment of common neurologic disorders, including stroke, spinal cord injury, peripheral nerve injury, brain injury and more.

Simulation and Experiment of Electric Field Distribution of Non-invasive Pelvic Floor Electric Stimulation Therapeutic Apparatus

This study analyzes the difference between non-invasive and invasive pelvic floor electric stimulation therapeutic apparatus. Through establishing the resistance network model of human pelvic floor muscle group, using circuit loop analysis and simulation, the current and voltage distribution are obtained, and the conclusions are listed as follows: Since invasive electrode has a central symmetry, pelvic floor muscles have equipotential areas and unable to form the current loop. Non-invasive electrodes don't have this problem. With the same stimulation conditions, non-invasive stimulation intensity of the superficial pelvic floor muscle is the highest, followed by the middle and the deep layer. While the invasive electrode stimulates the superficial and deep pelvic floor muscles moderately, the middle pelvic floor muscles some parts strongly, some parts weakly. The results of in vitro experiments show that the tissue impedance is very small, and the non-invasive electrical stimulation is well conducted into the tissue, which is consistent with the analysis and simulation results.

Consensus for experimental design in electromyography (CEDE) project: Single motor unit matrix.

The analysis of single motor unit (SMU) activity provides the foundation from which information about the neural strategies underlying the control of muscle force can be identified, due to the one-to-one association between the action potentials generated by an alpha motor neuron and those received by the innervated muscle fibers. Such a powerful assessment has been conventionally performed with invasive electrodes (i.e., intramuscular electromyography (EMG)), however, recent advances in signal processing techniques have enabled the identification of single motor unit (SMU) activity in high-density surface electromyography (HDsEMG) recordings. This matrix, developed by the Consensus for Experimental Design in Electromyography (CEDE) project, provides recommendations for the recording and analysis of SMU activity with both invasive (needle and fine-wire EMG) and non-invasive (HDsEMG) SMU identification methods, summarizing their advantages and disadvantages when used during different testing conditions. Recommendations for the analysis and reporting of discharge rate and peripheral (i.e., muscle fiber conduction velocity) SMU properties are also provided. The results of the Delphi process to reach consensus are contained in an appendix. This matrix is intended to help researchers to collect, report, and interpret SMU data in the context of both research and clinical applications.

Invasive and non-invasive electrodes for successful drug and gene delivery in electroporation-based treatments.

Electroporation is an effective physical method for irreversible or reversible permeabilization of plasma membranes of biological cells and is typically used for tissue ablation or targeted drug/DNA delivery into living cells. In the context of cancer treatment, full recovery from an electroporation-based procedure is frequently dependent on the spatial distribution/homogeneity of the electric field in the tissue; therefore, the structure of electrodes/applicators plays an important role. This review focuses on the analysis of electrodes and in silico models used for electroporation in cancer treatment and gene therapy. We have reviewed various invasive and non-invasive electrodes; analyzed the spatial electric field distribution using finite element method analysis; evaluated parametric compatibility, and the pros and cons of application; and summarized options for improvement. Additionally, this review highlights the importance of tissue bioimpedance for accurate treatment planning using numerical modeling and the effects of pulse frequency on tissue conductivity and relative permittivity values.

Speech decoding from a small set of spatially segregated minimally invasive intracranial EEG electrodes with a compact and interpretable neural network

Objective. Speech decoding, one of the most intriguing brain-computer interface applications, opens up plentiful opportunities from rehabilitation of patients to direct and seamless communication between human species. Typical solutions rely on invasive recordings with a large number of distributed electrodes implanted through craniotomy. Here we explored the possibility of creating speech prosthesis in a minimally invasive setting with a small number of spatially segregated intracranial electrodes. Approach. We collected one hour of data (from two sessions) in two patients implanted with invasive electrodes. We then used only the contacts that pertained to a single stereotactic electroencephalographic (sEEG) shaft or an electrocorticographic (ECoG) stripe to decode neural activity into 26 words and one silence class. We employed a compact convolutional network-based architecture whose spatial and temporal filter weights allow for a physiologically plausible interpretation. Main results. We achieved on average 55% accuracy using only six channels of data recorded with a single minimally invasive sEEG electrode in the first patient and 70% accuracy using only eight channels of data recorded for a single ECoG strip in the second patient in classifying 26+1 overtly pronounced words. Our compact architecture did not require the use of pre-engineered features, learned fast and resulted in a stable, interpretable and physiologically meaningful decision rule successfully operating over a contiguous dataset collected during a different time interval than that used for training. Spatial characteristics of the pivotal neuronal populations corroborate with active and passive speech mapping results and exhibit the inverse space-frequency relationship characteristic of neural activity. Compared to other architectures our compact solution performed on par or better than those recently featured in neural speech decoding literature. Significance. We showcase the possibility of building a speech prosthesis with a small number of electrodes and based on a compact feature engineering free decoder derived from a small amount of training data.

PSUN272 Opportunity for Inpatient Use of Continuous Glucose Monitoring: A Case Report of Acute Pancreatitis Secondary to Hypertriglyceridemia

Abstract Background Continuous glucose monitoring (CGM) is a convenient method of estimating blood glucose (BG) levels through a minimally invasive subcutaneous electrode that senses interstitial fluid glucose readings. With recent advancements, this technology has the potential to transmit interstitial fluid glucose readings to electronic health records (EHR) in real-time. While some benefits of CGM have been studied in outpatient settings, current CGM research is beginning to explore the use and benefits of CGM in inpatient settings. The following case of acute pancreatitis (AP) secondary to hypertriglyceridemia (HTG) presents a novel opportunity for inpatient use of CGM. Clinical Case A 33-year-old-man with anxiety, alcohol use disorder, and without insulin resistance, presents as a transfer to a tertiary-care-center for consideration of plasmapheresis in the setting of AP secondary to HTG. He initially presented to outside hospital with acute onset diffuse abdominal pain. Family history of father with controlled HTG and hyperlipidemia on statins. Hemodynamically stable. Examination revealed diffuse abdominal tenderness. Labs revealed triglyceride (TG) level 3550 mg/dL (n<150 mg/dL), lipase 1423 U/L (n 0-160 U/L), TSH normal, A1c 5.2% (n<5.7%). CT abdomen pelvis with contrast revealed moderate acute interstitial edematous pancreatitis without necrosis, pseudocyst, or mass. He was volume resuscitated with intravenous (IV) fluids, then started on a non-titratable regular insulin infusion (N-TII) at 2 U/hr and continuous IV fluids with dextrose. Upon arrival, his BG was 101 mg/dL. The N-TII rate was decreased to 1 U/hr and managed with hourly finger-stick BG checks and continuous IV fluids with dextrose plus KCl. Arrival TG was 954 mg/dL. The case was discussed with Transfusion Medicine—given the down-trending TG level, plasmapheresis was not initiated. The next morning, repeat TG level was <500 mg/dL, thus, the N-TII was discontinued. During admission, BG ranged from 86-179 mg/dL and IV fluids with dextrose required titration of rate and concentration to avoid hypoglycemia while severe HTG resolved. Conclusion This case presents a novel scenario in which there is an opportunity for inpatient use of CGM. In addition to point-of-care finger-stick BG checks, the implementation of inpatient CGM may be beneficial in tracking glucose trends when N-TII are required for management of severe HTG, but risk iatrogenic hypoglycemia. Not only does this highlight an area in need of further research and technological developments that link CGM data to EHR in real-time, but also, by continuing to identify new opportunities for inpatient CGM use, we can better understand its nuances and implications, thus, thoughtfully advocate for policies and protocols that optimize benefits and justify cost of inpatient CGM. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Patient-specific solution of the electrocorticography forward problem in deforming brain

Invasive intracranial electroencephalography (iEEG), or electrocorticography (ECoG), measures electric potential directly on the surface of the brain and can be used to inform treatment planning for epilepsy surgery. Combined with numerical modeling it can further improve accuracy of epilepsy surgery planning. Accurate solution of the iEEG forward problem, which is a crucial prerequisite for solving the iEEG inverse problem in epilepsy seizure onset zone localization, requires accurate representation of the patient’s brain geometry and tissue electrical conductivity after implantation of electrodes. However, implantation of subdural grid electrodes causes the brain to deform, which invalidates preoperatively acquired image data. Moreover, postoperative magnetic resonance imaging (MRI) is incompatible with implanted electrodes and computed tomography (CT) has insufficient range of soft tissue contrast, which precludes both MRI and CT from being used to obtain the deformed postoperative geometry. In this paper, we present a biomechanics-based image warping procedure using preoperative MRI for tissue classification and postoperative CT for locating implanted electrodes to perform non-rigid registration of the preoperative image data to the postoperative configuration. We solve the iEEG forward problem on the predicted postoperative geometry using the finite element method (FEM) which accounts for patient-specific inhomogeneity and anisotropy of tissue conductivity. Results for the simulation of a current source in the brain show large differences in electric potential predicted by the models based on the original images and the deformed images corresponding to the brain geometry deformed by placement of invasive electrodes. Computation of the lead field matrix (useful for solution of the iEEG inverse problem) also showed significant differences between the different models. The results suggest that rapid and accurate solution of the forward problem in a deformed brain for a given patient is achievable.

TH-212. Broad coverage sub-scalp electroencephalography via minimally invasive electrode implantation

TH-212. Broad coverage sub-scalp electroencephalography via minimally invasive electrode implantation

Evidence-Based Clinical Guidelines from the American Society of Pain and Neuroscience for the Use of Implantable Peripheral Nerve Stimulation in the Treatment of Chronic Pain.

The objective of this peripheral nerve stimulation consensus guideline is to add to the current family of consensus practice guidelines and incorporate a systematic review process. The published literature was searched from relevant electronic databases, including PubMed, Scopus, Cochrane Central Register of Controlled Trials, and Web of Science from database inception to March 29, 2021. Inclusion criteria encompassed studies that described peripheral nerve stimulation in patients in terms of clinical outcomes for various pain conditions, physiological mechanism of action, surgical technique, technique of placement, and adverse events. Twenty randomized controlled trials and 33 prospective observational studies were included in the systematic review process. There is Level I evidence supporting the efficacy of PNS for treatment of chronic migraine headaches via occipital nerve stimulation; chronic hemiplegic shoulder pain via stimulation of nerves innervating the trapezius, supraspinatus, and deltoid muscles; failed back surgery syndrome via subcutaneous peripheral field stimulation; and lower extremity neuropathic and lower extremity post-amputation pain. Evidence from current Level I studies combined with newer technologies facilitating less invasive and easier electrode placement make peripheral nerve stimulation an attractive alternative for managing patients with complex pain disorders. Peripheral nerve stimulation should be used judiciously as an adjunct for chronic and acute postoperative pain following adequate patient screening and positive diagnostic nerve block or stimulation trial.

Intracranial EEG in Episodic Memory Research: Possibilities, Limitations, Results

Stereoelectroencephalography (sEEG) and electrocorticography (ECoG) are methods of intracranial (invasive) EEG (iEEG). These methods record alterations of local field potential (LFP) using stereotaxically or subdurally implanted invasive electrodes. Nowadays, these methods are widely used for diagnostics and therapy of various neurological disorders. Moreover, they offer a valuable opportunity for fundamental research of cognitive and sensorimotor processes. Here, we address the possibilities and limitations of iEEG for human episodic memory research and review the main results obtained by this method, delineating the functional role of medial temporal lobes structures, the temporal dynamics of their activation, and the role of different frequency oscillations in local and global processing during episodic memory

Impact of high-density EEG in presurgical evaluation for refractory epilepsy patients

ObjectiveElectrical source localization (ESI) can help to identify the seizure onset zone or propagation zone, but it is unclear how dipole localization techniques influence surgical planning. MethodsPatients who received a high density (HD)-EEG from 7/2014–7/2019 at Stanford were included if they met the following inclusion criteria: (1) adequate epileptiform discharges were recorded for source localization analysis, (2) underwent surgical treatment, which was at least 6 months before the survey. Interictal ESI was performed with the LORETA method on age matched MRIs. Six neurophysiologists from the Stanford Epilepsy Program independently reviewed each case through an HIPPA-protected online survey. The same cases were presented again with additional data from the HD-EEG study. Ratings of how much the HD-EEG findings added value and in what way were recorded. ResultsFifty out of 202 patients met the inclusion criteria, providing a total of 276 h of HDEEG recordings. All patients had video EEG recordings and at least one brain MRI, 88 % had neuropsychological testing, 78 % had either a PET or SPECT scan. Additional HD-EEG information was rated as helpful in 83.8 %, not useful in 14.4 % and misleading in 1.8 % of cases. In 20.4 % of cases the HD-EEG information altered decision-making in a major way, such as choosing a different surgical procedure, avoidance of invasive recording or suggesting placement of invasive electrodes in a lobe not previously planned. In 21.5 % of cases, HD-EEG changed the plan in a minor way, e.g., extra invasive electrodes near the previously planned sites in the same sub-lobar region. In 42.3 % cases, HD-EEG did not change their plan but provided confirmation. In cases with normal MRI, additional HD-EEG information was more likely to change physicians’ decision making during presurgical process when compared to the cases with MRI-visible lesions (53.3 % vs. 34.3 %, p = 0.002). Among patients achieving Engel class I/II outcome, the concordance rate of HD-EEG and resection zone was 64.7 % versus 35.3 % with class III/IV (p = 0.028). ConclusionHD-EEG assists presurgical planning for refractory epilepsy patients, with a higher yield in patients with non-lesional MRIs. Concordance of HD-EEG dipole analysis localization and resection site is a favorable outcome indicator.

A Soft Zwitterionic Hydrogel as Potential Coating on a Polyimide Surface to Reduce Foreign Body Reaction to Intraneural Electrodes.

Invasive intraneural electrodes can control advanced neural-interfaced prostheses in human amputees. Nevertheless, in chronic implants, the progressive formation of a fibrotic capsule can gradually isolate the electrode surface from the surrounding tissue leading to loss of functionality. This is due to a nonspecific inflammatory response called foreign-body reaction (FBR). The commonly used poly(ethylene glycol) (PEG)-based low-fouling coatings of implantable devices can be easily encapsulated and are susceptible to oxidative damage in long-term in vivo applications. Recently, sulfobetaine-based zwitterionic hydrogels have emerged as an important class of robust ultra-low fouling biomaterials, holding great potential to mitigate FBR. The aim of this proof-of-principle in vitro work was to assess whether the organic zwitterionic—poly(sulfobetaine methacrylate) [poly(SBMA)]—hydrogel could be a suitable coating for Polyimide (PI)-based intraneural electrodes to reduce FBR. We first synthesized and analyzed the hydrogel through a mechanical characterization (i.e., Young’s modulus). Then, we demonstrated reduced adhesion and activation of fibrogenic and pro-inflammatory cells (i.e., human myofibroblasts and macrophages) on the hydrogel compared with PEG-coated and polystyrene surfaces using cell viability assays, confocal fluorescence microscopy and high-content analysis of oxidative stress production. Interestingly, we successfully coated PI surfaces with a thin film of the hydrogel through covalent bond and demonstrated its high hydrophilicity via water contact angle measurement. Importantly, we showed the long-term release of an anti-fibrotic drug (i.e., Everolimus) from the hydrogel. Because of the low stiffness, biocompatibility, high hydration and ultra-low fouling characteristics, our zwitterionic hydrogel could be envisioned as long-term diffusion-based delivery system for slow and controlled anti-inflammatory and anti-fibrotic drug release in vivo.

Characterization of Electrodes to Record Neural Signals in the Periphery

Appropriately designed electrodes to make in vivo recordings of neural activity have been essential to understanding the nervous system. Recording electrode design has been extensively explored for use in measurement of naturally occurring neural activity in the brain. Recently, recordings of evoked compound action potentials (ECAPs) in the periphery have garnered interest due to their relevance in neuromodulation therapies for determining target engagement and enabling closed‐loop operation. Here, we compare three types of recording electrodes – microelectrodes, cuff electrodes, and intrafascicular electrodes – and their ability to make in vivo recordings of electrically ECAPs, naturally occurring neural activity, and sensory evoked neural activity in the peripheral nerves of a human‐relevant large animal model.The great auricular nerve, innervating the auricle, and cervical vagus nerve of domestic pigs were instrumented with the three recording electrodes. Naturally occurring neural activity, sensory evoked neural activity induced by gentle brushing of the auricle, and electrically ECAPs initiated by non‐invasive and invasive stimulation electrodes were recorded. The study was pre‐registered (https://osf.io/y9k6j).We showed that the recording cuff had superior performance in measuring invasive electrically ECAPs (p < 0.05) while the tungsten microelectrode, routinely used for microneurography in humans, had superior performance in measuring naturally occurring action potentials (p < 0.05). The microelectrode was still able to record electrically ECAPs. Further, we show how choice of reference electrode position may be optimized per application.Microneurography recordings paired with the deployment of a non‐invasive neuromodulation therapy can be used to functionally map sensory innervation areas in patients, allowing individualized placement of stimulation electrodes to achieve on‐target neural fiber activation. These findings provide a basis to select recording electrode type and configuration for measurement of neural signals in the development and deployment of neuromodulation therapies.

First Food and Drug Administration Cleared Thin-Film Electrode for Intracranial Stimulation, Recording, and Monitoring of Brain Activity-Part 1: Biocompatibility Testing.

Subdural strip and grid invasive electroencephalography electrodes are routinely used for surgical evaluation of patients with drug-resistant epilepsy (DRE). Although these electrodes have been in the United States market for decades (first FDA clearance 1985), their fabrication, materials, and properties have hardly changed. Existing commercially available electrodes are made of silicone, are thick (>0.5 mm), and do not optimally conform to brain convolutions. New thin-film polyimide electrodes (0.08 mm) have been manufactured to address these issues. While different thin-film electrodes are available for research use, to date, only one electrode is cleared by Food and Drug Administration (FDA) for use in clinical practice. This study describes the biocompatibility tests that led to this clearance. Biocompatibility was tested using standard methods according to International Organization for Standardization (ISO) 10993. Electrodes and appropriate control materials were bent, folded, and placed in the appropriate extraction vehicles, or implanted. The extracts were used for in vitro and in vivo tests, to assess the effects of any potential extractable and leachable materials that may be toxic to the body. In vitro studies included cytotoxicity tested in L929 cell line, genotoxicity tested using mouse lymphoma assay (MLA) and Ames assay, and hemolysis tested in rabbit whole blood samples. The results indicated that the electrodes were non-cytotoxic, non-mutagenic, non-clastogenic, and non-hemolytic. In vivo studies included sensitization tested in guinea pigs, irritation tested in rabbits, acute systemic toxicity testing in mice, pyrogenicity tested in rabbits, and a prolonged 28-day subdural implant in sheep. The results indicated that the electrodes induced no sensitization and irritation, no weight loss, and no temperature increase. Histological examination of the sheep brain tissue showed no or minimal immune cell accumulation, necrosis, neovascularization, fibrosis, and astrocyte infiltration, with no differences from the control material. In summary, biocompatibility studies indicated that these new thin-film electrodes are appropriate for human use. As a result, the electrodes were cleared by the FDA for use in clinical practice [510(k) K192764], making it the first thin-film subdural electrode to progress from research to clinic. Its readiness as a commercial product ensures availability to all patients undergoing surgical evaluation for DRE.