Human Nerve Research Articles

Blood-Nerve Barrier (BNB) Pathology in Diabetic Peripheral Neuropathy and In Vitro Human BNB Model.

In diabetic peripheral neuropathy (DPN), metabolic disorder by hyperglycemia progresses in peripheral nerves. In addition to the direct damage to peripheral neural axons, the homeostatic mechanism of peripheral nerves is disrupted by dysfunction of the blood–nerve barrier (BNB) and Schwann cells. The disruption of the BNB, which is a crucial factor in DPN development and exacerbation, causes axonal degeneration via various pathways. Although many reports revealed that hyperglycemia and other important factors, such as dyslipidemia-induced dysfunction of Schwann cells, contributed to DPN, the molecular mechanisms underlying BNB disruption have not been sufficiently elucidated, mainly because of the lack of in vitro studies owing to difficulties in establishing human cell lines from vascular endothelial cells and pericytes that form the BNB. We have developed, for the first time, temperature-sensitive immortalized cell lines of vascular endothelial cells and pericytes originating from the BNB of human sciatic nerves, and we have elucidated the disruption to the BNB mainly in response to advanced glycation end products in DPN. Recently, we succeeded in developing an in vitro BNB model to reflect the anatomical characteristics of the BNB using cell sheet engineering, and we established immortalized cell lines originating from the human BNB. In this article, we review the pathologic evidence of the pathology of DPN in terms of BNB disruption, and we introduce the current in vitro BNB models.

Development of local anesthetic drug delivery system by administration of organo-silica nanoformulations under ultrasound stimuli: in vitro and in vivo investigations

The development of local anesthetic (LA) system is the application of commercial drug for the pain management that indorses the reversible obstructive mechanism of neural transmission through preventing the innervation process in human peripheral nerves. Ropivacaine (RV) is one of the greatest frequently used LA s with the actions of long-lasting and low-toxicity for the post-operative pain management. In this work, we have approached novel design and development of glycosylated chitosan (GCS) encapsulated mesoporous silica nanoparticles (GCS-MONPs)-based nano-scaffold for sustainable distributions and controlled/supported arrival of stacked RV for targeting sites, which can be activated by either outer ultrasound activating to discharge the payload, foundation on-request and dependable analgesia. The structural and morphology analyses result established that prepared nano-formulations have successful molecular interactions and RV loaded spherical morphological structures. The drug release profile of developed nanostructure with ultrasound-activation has been achieved 50% of drug release in 2 h and 90% of drug release was achieved in 12 h, which displays more controlled release when compared to free RV solution. The in vitro cell compatibility analysis exhibited GCS-MONPs with RV has improved neuron cell survival rates when compared to other samples due to its porous surface and suitable biopolymer proportions. The analysis of ex vitro and in vivo pain relief analysis demonstrated treated animal models have high compatibility with GCS-MONPs@RV, which was confirmed by histomorphology. This developed MONPs based formulations with ultrasound-irradiation gives a prospective technique to clinical agony the board through on-request and dependable help with discomfort.

Recording of Electrically Evoked Neural Activity and Bladder Pressure Responses in Awake Rats Chronically Implanted With a Pelvic Nerve Array.

Bioelectronic medical devices are well established and widely used in the treatment of urological dysfunction. Approved targets include the sacral S3 spinal root and posterior tibial nerve, but an alternate target is the group of pelvic splanchnic nerves, as these contain sacral visceral sensory and autonomic motor pathways that coordinate storage and voiding functions of the bladder. Here, we developed a device suitable for long-term use in an awake rat model to study electrical neuromodulation of the pelvic nerve (homolog of the human pelvic splanchnic nerves). In male Sprague-Dawley rats, custom planar four-electrode arrays were implanted over the distal end of the pelvic nerve, close to the major pelvic ganglion. Electrically evoked compound action potentials (ECAPs) were reliably detected under anesthesia and in chronically implanted, awake rats up to 8 weeks post-surgery. ECAP waveforms showed three peaks, with latencies that suggested electrical stimulation activated several subpopulations of myelinated A-fiber and unmyelinated C-fiber axons. Chronic implantation of the array did not impact on voiding evoked in awake rats by continuous cystometry, where void parameters were comparable to those published in naïve rats. Electrical stimulation with chronically implanted arrays also induced two classes of bladder pressure responses detected by continuous flow cystometry in awake rats: voiding contractions and non-voiding contractions. No evidence of tissue pathology produced by chronically implanted arrays was detected by immunohistochemical visualization of markers for neuronal injury or noxious spinal cord activation. These results demonstrate a rat pelvic nerve electrode array that can be used for preclinical development of closed loop neuromodulation devices targeting the pelvic nerve as a therapy for neuro-urological dysfunction.

Analysis of Tembusu virus infection of human cell lines and human induced pluripotent stem cell derived hepatocytes

Tembusu virus (TMUV) causes disease in poultry, especially in ducks, resulting in abnormality in egg production and with high morbidity and mortality, resulting in great loss in duck farming industry in China and Southeast Asia. Previous studies on the pathogenesis of TMUV infection have been mostly conducted in poultry, with a few studies being undertaken in mice. While TMUV does not cause disease in humans, it has been reported that antibodies against TMUV have been found in serum samples from duck farmers, and thus data on TMUV infection in humans is limited, and the pathogenesis is unclear. In this study we investigated the cell tropism and potential susceptibility of humans to TMUV using several human cell lines. The results showed that human nerve and liver cell lines were both highly susceptible and permissive, while human kidney cells were susceptible and permissive, albeit to a lower degree. In addition, human muscle cells, lung epithelial cells, B-cells, T-cells and monocytic cells were largely refractory to TMUV infection. This data suggests that liver, neuron and kidney are potential target organs during TMUV infection in humans, consistent with what has been found in animal studies.

Limb-Specific Features and Asymmetry of Nerve Conduction Velocity and Nerve Trunk Size in Human.

This study aimed to simultaneously examine the differences of human nerve conduction velocity (NCV) and nerve cross-sectional area (nCSA) between the upper and lower limbs and between different regions of the upper and lower limbs. Thirty healthy subjects volunteered for the study. NCV and nCSA of the ulnar and tibial nerves were measured with the dominant and non-dominant arms and the supporting and reacting legs using supramaximal electric stimulation and peripheral nerve ultrasonography at three regions for ulnar and tibial nerves, respectively. Supramaximal electric stimulation was superficially applied to the ulnar and tibial nerves at each point. These action potentials were recorded from the digiti minimi and soleus muscles for the ulnar and tibial nerves, respectively. Our results clearly showed that the NCV, nCSA, and circumference of the ulnar and tibial nerves were higher and greater in the lower limbs than in the upper limbs. The greater the circumference, the greater the nCSA for both the upper and lower limbs. However, unlike the upper limbs, the supporting leg did not have higher NCV than the reacting leg despite its greater circumference. Therefore, nCSA can be related to the circumference but not necessarily function for NCV developments of the lower limbs. These various aspects between the upper and lower limbs suggest that NCV does not depend on the nCSA sizes or upper and lower limb circumference; the results indicate the existence of limb-specific NCV but not nCSA developments.

Comprehensive Assessment of Human Accessory Renal Artery Periarterial Renal Sympathetic Nerve Distribution.

The aim of this study was to understand the anatomy of periarterial nerve distribution in human accessory renal arteries (ARAs). Renal denervation is a promising technique for blood pressure control. Despite the high prevalence of ARAs, the anatomic distribution of periarterial nerves around ARAs remains unknown. Kidneys with surrounding tissues were collected from human autopsy subjects, and histological evaluation was performed using morphometric software. An ARA was defined as an artery arising from the aorta above or below the dominant renal artery (DRA) or an artery that bifurcated within 20mm of the takeoff of the DRA from the aorta. The DRA was defined as an artery that perfused >50% of the kidney. A total of 7,287 nerves from 14 ARAs and 9 DRAs were evaluated. The number of nerves was smaller in the ARA than DRA (median: 30 [interquartile range: 17.5 to 48.5] vs. 49 [interquartile range: 36 to 76]; p<0.0001). In both ARAs and DRAs, the distance from the arterial lumen to nerve was shortest in the distal, followed by the middle and proximal segments. On the basis of the post-mortem angiography, ARAs were divided into large (≥3 mm diameter) and small (<3mm) groups. The number of nerves was greatest in the DRA, followed by the large and small ARA groups (53 [41 to 97], 38 [25 to 53], and 24.5 [10.5 to 36.3], respectively; p=0.001). ARAs showed a smaller number of nerves than DRAs, but these results were dependent on the size of the ARA. Ablation, especially in large ARAs, may allow more complete denervation with the potential to further reduce blood pressure.

Dendritic Degeneration of Human Auditory Nerve Fibers and Its Impact on the Spiking Pattern Under Regular Conditions and During Cochlear Implant Stimulation.

Due to limitations of human in vivo studies, detailed computational models enable understanding the neural signaling in the degenerated auditory system and cochlear implants (CIs). Four human cochleae were used to quantify hearing levels depending on dendritic changes in diameter and myelination thickness from type I of the auditory nerve fibers (ANFs). Type I neurons transmit the auditory information as spiking pattern from the inner hair cells (IHCs) to the cochlear nucleus. The impact of dendrite diameter and degree of myelination on neural signal transmission was simulated for (1) synaptic excitation via IHCs and (2) stimulation from CI electrodes. An accurate three-dimensional human cochlear geometry, along with 30 auditory pathways, mimicked the CI environment. The excitation properties of electrical potential distribution induced by two CI were analyzed. Main findings: (1) The unimodal distribution of control dendrite diameters becomes multimodal for hearing loss cases; a group of thin dendrites with diameters between 0.3 and 1 μm with a peak at 0.5 μm appeared. (2) Postsynaptic currents from IHCs excite such thin dendrites easier and earlier than under control conditions. However, this advantage is lost as their conduction velocity decreases proportionally with the diameter and causes increased spike latency and jitter in soma and axon. Firing probability reduces through the soma passage due to the low intracellular current flow in thin dendrites during spiking. (3) Compared with dendrite diameter, variations in myelin thickness have a small impact on spiking performance. (4) Contrary to synaptic excitation, CIs cause several spike initiation sites in dendrite, soma region, and axon; moreover, fiber excitability reduces with fiber diameter. In a few cases, where weak stimuli elicit spikes of a target neuron (TN) in the axon, dendrite diameter reduction has no effect. However, in many cases, a spike in a TN is first initiated in the dendrite, and consequently, dendrite degeneration demands an increase in threshold currents. (5) Threshold currents of a TN and co-stimulation of degenerated ANFs in other frequency regions depend on the electrode position, including its distance to the outer wall, the cochlear turn, and the three-dimensional pathway of the TN.

Quantified Morphology of the Cervical and Subdiaphragmatic Vagus Nerves of Human, Pig, and Rat.

It is necessary to understand the morphology of the vagus nerve (VN) to design and deliver effective and selective vagus nerve stimulation (VNS) because nerve morphology influences fiber responses to electrical stimulation. Specifically, nerve diameter (and thus, electrode-fiber distance), fascicle diameter, fascicular organization, and perineurium thickness all significantly affect the responses of nerve fibers to electrical signals delivered through a cuff electrode. We quantified the morphology of cervical and subdiaphragmatic VNs in humans, pigs, and rats: effective nerve diameter, number of fascicles, effective fascicle diameters, proportions of endoneurial, perineurial, and epineurial tissues, and perineurium thickness. The human and pig VNs were comparable sizes (∼2 mm cervically; ∼1.6 mm subdiaphragmatically), while the rat nerves were ten times smaller. The pig nerves had ten times more fascicles—and the fascicles were smaller—than in human nerves (47 vs. 7 fascicles cervically; 38 vs. 5 fascicles subdiaphragmatically). Comparing the cervical to the subdiaphragmatic VNs, the nerves and fascicles were larger at the cervical level for all species and there were more fascicles for pigs. Human morphology generally exhibited greater variability across samples than pigs and rats. A prior study of human somatic nerves indicated that the ratio of perineurium thickness to fascicle diameter was approximately constant across fascicle diameters. However, our data found thicker human and pig VN perineurium than those prior data: the VNs had thicker perineurium for larger fascicles and thicker perineurium normalized by fascicle diameter for smaller fascicles. Understanding these differences in VN morphology between preclinical models and the clinical target, as well as the variability across individuals of a species, is essential for designing suitable cuff electrodes and stimulation parameters and for informing translation of preclinical results to clinical application to advance the therapeutic efficacy of VNS.

High-resolution combinatorial 3D printing of gelatin-based biomimetic triple-layered conduits for nerve tissue engineering

Peripheral nerve injury is a common clinical problem often requiring surgical nerve reconstruction. To this end, tissue-engineered conduit has been proved to be crucial for nerve reconstruction. Despite its progress in recent years, the design and fabrication of translational biomimetic nerve conduits is highly challenging. Therefore, this study aims to design and fabricate mechanically-tunable nerve conduits with biomimetic structural features of the human nerve suitable for nerve tissue engineering. Herein, we employed combinatorial approach comprising of electrohydrodynamic (EHD) jet printing, dip-coating, and electrospinning techniques for fabricating triple-layered conduits. The intricate structural details were achieved via high-resolution EHD jet printed PCL filaments with tunable directionality, as the innermost layer; followed by dip coating of gelatin hydrogels to form the middle layer, and lastly, wrapped with electrospun PCL nanofibers as an outer layer of the conduits. The mechanical properties, porosity, and biocompatibility of the fabricated conduits were studied and compared with control. The results of this study confirmed that the combinatorial approach has greater potential to fabricate mechanically-tunable triple-layered conduits with favorable neuronal precursor and vascular cell compatibility.

Green synthesis of porous carbon nanocubes accumulated microspheres for the simultaneous non-enzymatic sensing of uric acid and dopamine in the presence of ascorbic acid

Nanomaterials synthesis from biowastes is becoming one of the green strategies towards the production of toxic solvents- and pollution-free materials and in that view, we have prepared porous carbon nanocubes accumulated microspheres (PCMS) and tested its efficacy for the electrochemical sensing of both uric acid (UA) and dopamine (DA) simultaneously in the presence of ascorbic acid. The PCMS nanomaterial successfully synthesized by echo-free pyrolysis of neighborhood collected coconut shell at 450 °C under air atmospheric condition in a muffle furnace. From the physical characterization, we found that the formed product is crystalline in nature (powdered XRD) and the FTIR analysis provided the surface functionality and bonding, while the UV-Vis spectroscopy for the optical properties. The low-resolution SEM studies indicated for a uniform spherical like structure (1 µM size) and the high-resolution TEM image support for the formation of PCMS absolutely in cubic structure (20 nm size). Hence, it may be an accumulation of the cubic nanocrystal to a spherical microstructure which has played vital performance due to the high surface area spherical structure and porosity. On testing of PCMS’s sensing efficiency, the cyclic voltammetry (CV) and differential pulse voltammetry (DPV) techniques showed well-detached oxidation peaks both for UA and DA. The lowest detection limits were observed to be 10 nM and 1 nM for the UA and DA respectively, and based on such low values of detection, this signal to noise ratio of the sensor can be applicable for real-time detection of UA and DA efflux from human nerve cells.

A narrative review of the role of fibroblasts in the growth and development of neurogenic tumors.

Neurogenic tumors, a group of tumors arising from neurogenic elements, could theoretically appear in every region of human bodies wherever nerves exist. Patients with these tumors suffer from both physical and psychological problems. However, as a relatively rare tumor type, therapies are relatively scarce for these tumors due to the limited understanding of the underlying mechanisms. Recently, a tailored tumor microenvironment containing multiple types of nonneoplastic cells has been considered to play an essential role in tumor survival, growth, and metastasis. Fibroblasts are a crucial constituent of the tumor microenvironment and have been found to promote tumor growth via multiple mechanisms. However, the understanding of the pivotal role of fibroblasts in the tumorigenesis and development of the neurogenic tumors is still incomplete, and studies in this area show differences in rates of progression among different neurogenic tumor subtypes. Nevertheless, all these neural crest-originated neoplasms show some similarities in the tumor microenvironment, indicating that studies of one subtype of neurogenic tumor might assist in clarifying the underlying mechanisms of other subtypes. This review aims to provide current studies showing the impacts of fibroblasts on major benign/malignant subtypes of neurogenic tumors, including neurofibromatosis type 1, neuroblastomas, pheochromocytomas, and malignant peripheral nerve sheath tumors. Multiple related mechanisms such as the fibroblasts regulating the tumor inflammation, angiogenesis, metabolism, and microenvironment establishment have been studied up to present. Consistently, we focus on how studies on various subtypes of these neurogenic tumors contribute to the establishment of potential future directions for further studies in this area. Clarifying the underlying mechanisms by which fibroblasts promote the growth and metastasis of neurogenic tumors will indicate new therapeutic targets for further clinical treatment.

The distribution of toxic metals in the human retina and optic nerve head: Implications for age-related macular degeneration

ObjectiveToxic metals are suspected to play a role in the pathogenesis of age-related macular degeneration. However, difficulties in detecting the presence of multiple toxic metals within the intact human retina, and in separating primary metal toxicity from the secondary uptake of metals in damaged tissue, have hindered progress in this field. We therefore looked for the presence of several toxic metals in the posterior segment of normal adult eyes using elemental bioimaging.MethodsParaffin sections of the posterior segment of the eye from seven tissue donors (age range 54–74 years) to an eye bank were examined for toxic metals in situ using laser ablation-inductively coupled plasma-mass spectrometry, a technique that detects multiple elements in tissues, as well as the histochemical technique of autometallography that demonstrates inorganic mercury, silver, and bismuth. No donor had a visual impairment, and no significant retinal abnormalities were seen on post mortem fundoscopy and histology.ResultsMetals found by laser ablation-inductively coupled plasma-mass spectrometry in the retinal pigment epithelium and choriocapillaris were lead (n = 7), nickel (n = 7), iron (n = 7), cadmium (n = 6), mercury (n = 6), bismuth (n = 5), aluminium (n = 3), and silver (n = 1). In the neural retina, mercury was present in six samples, and iron in one. Metals detected in the optic nerve head were iron (N = 7), mercury (N = 7), nickel (N = 4), and aluminium (N = 1). No gold or chromium was seen. Autometallography demonstrated probable inorganic mercury in the retinal pigment epithelium of one donor.ConclusionSeveral toxic metals are taken up by the human retina and optic nerve head. Injury to the retinal pigment epithelium from toxic metals could damage the neuroprotective functions of the retinal pigment epithelium and allow toxic metals to enter the outer neural retina. These findings support the hypothesis that accumulations of toxic metals in the retina could contribute to the pathogenesis of age-related macular degeneration.

Magnetic separation of peripheral nerve-resident cells underscores key molecular features of human Schwann cells and fibroblasts: an immunochemical and transcriptomics approach

Nerve-derived human Schwann cell (SC) cultures are irreplaceable models for basic and translational research but their use can be limited due to the risk of fibroblast overgrowth. Fibroblasts are an ill-defined population consisting of highly proliferative cells that, contrary to human SCs, do not undergo senescence in culture. We initiated this study by performing an exhaustive immunological and functional characterization of adult nerve-derived human SCs and fibroblasts to reveal their properties and optimize a protocol of magnetic-activated cell sorting (MACS) to separate them effectively both as viable and biologically competent cells. We next used immunofluorescence microscopy imaging, flow cytometry analysis and next generation RNA sequencing (RNA-seq) to unambiguously characterize the post-MACS cell products. High resolution transcriptome profiling revealed the identity of key lineage-specific transcripts and the clearly distinct neural crest and mesenchymal origin of human SCs and fibroblasts, respectively. Our analysis underscored a progenitor- or stem cell-like molecular phenotype in SCs and fibroblasts and the heterogeneity of the fibroblast populations. In addition, pathway analysis of RNA-seq data highlighted putative bidirectional networks of fibroblast-to-SC signaling that predict a complementary, yet seemingly independent contribution of SCs and fibroblasts to nerve regeneration. In sum, combining MACS with immunochemical and transcriptomics approaches provides an ideal workflow to exhaustively assess the identity, the stage of differentiation and functional features of highly purified cells from human peripheral nerve tissues.

Production of functional human nerve growth factor from the submandibular glands of mice using a CRISPR/Cas9 genome editing system.

Nerve growth factor (NGF) is an essential trophic factor for the growth and survival of neurons in the central and peripheral nervous systems. For many years, mouse NGF (mNGF) has been used to treat various neuronal and non-neuronal disorders. However, the biological activity of human NGF (hNGF) is significantly higher than that of mNGF in human cells. Using the CRISPR/Cas9 system, we constructed the transgenic mice expressing hNGF specifically in their submandibular glands. As demonstrated by fluorescence immunohistochemical staining, these mice produced hNGF successfully, with 0.8mg produced per gram of submandibular glands. hNGF with 99% purity was successfully extracted by two-step ion-exchange chromatography and one-step size-exclusion chromatography from the submandibular glands of these transgenic mice. Further, the purified hNGF was verified by LC-MS/MS. We analyzed the NH2-terminus of hNGF using both Edman degradation and LC-MS/MS-based methods. Both results showed that the obtained hNGF lost the NH2-terminal octapeptide (SSSHPIFH). Moreover, the produced hNGF demonstrated a strong promotion in the proliferation of TF1 cells.

Density of nerve fibres and expression of substance P, NR2B-receptors and nerve growth factor in healthy human masseter muscle: An immunohistochemical study.

BackgroundIn skeletal muscle, free nerve endings are mostly located within the connective tissue. However, the distribution of sensory afferent fibres in healthy human masseter muscle tissues has not been studied.ObjectivesPrimarily to investigate human masseter muscle nerve fibre densities as well as expression of NR2B receptors, substance P (SP) and nerve growth factor (NGF), and secondarily to compare this between a) nerve fibres associated with myocytes and within connective tissue; b) sexes; and c) ages.MethodsMicrobiopsies of the masseter muscle were obtained from 60 sex‐ and age‐matched healthy participants. Biopsy sections were analysed using immunohistochemistry and were visualised with a Leica TCS SPE confocal microscope. The Mann‐Whitney U test was used for statistical analyses.ResultsThe density of nerve fibres within connective tissue was significantly greater than in nerve fibres associated with myocytes (P < .001). Nerve fibres within connective tissue expressed SP alone or together with NR2B significantly more often than those associated with myocytes (P < .001). The frequency of nerve fibres, which expressed SP alone or in combination with NR2B or NGF, was significantly greater in women than in men (P < .050). Moreover, the co‐expression of the three markers together was inversely correlated with age in women (P < .002).ConclusionsThere is a higher density and greater expression of sensory nerve fibres within the connective tissue than associated with myocytes in healthy human masseter muscle. This suggests that nerve fibres within connective tissue are more involved in nociception than nerve fibres associated with myocytes.

Ultrasound Localization and Percutaneous Electrical Stimulation of the Hypoglossal Nerve and Ansa Cervicalis.

Hypoglossal nerve stimulation for obstructive sleep apnea (OSA) can be effective for appropriately selected patients, but current patient selection criteria are complex and still result in a proportion of nonresponders. Ansa cervicalis stimulation of the infrahyoid cervical strap muscles has recently been proposed as a new form of respiratory neurostimulation (RNS) therapy for OSA treatment. We hypothesized that percutaneous stimulation of both nerves in humans with temporary electrodes would make testing of the physiologic response to different RNS strategies possible. Nonrandomized acute physiology study. Tertiary care hospital. Fifteen participants with OSA underwent ultrasonography and placement of percutaneous electrodes proximal to the medial division of the hypoglossal nerve and the branch of the ansa cervicalis innervating the sternothyroid muscle (ACST). Procedural success was documented in each participant, as were any failures or procedural complication. The hypoglossal nerve was successfully localized in 15 of 15 (100%) participants and successfully stimulated in 13 of 15 (86.7%). The ACST was successfully localized in 15 of 15 (100%) participants and successfully stimulated in 14 of 15 (93.3%). Stimulation failure of the hypoglossal nerve was due to suboptimal electrode placement in 1 participant and electrode displacement in the other 2 cases. No complications occurred. The hypoglossal nerve and ACST can be safely stimulated via percutaneous electrode placement. Larger trials of percutaneous stimulation may help to identify responders to different RNS therapies for OSA with temporary or permanent percutaneous electrodes. Techniques for electrode design, nerve localization, and electrode placement are described.

Quantification of clinically applicable stimulation parameters for precision near-organ neuromodulation of human splenic nerves

Neuromodulation is a new therapeutic pathway to treat inflammatory conditions by modulating the electrical signalling pattern of the autonomic connections to the spleen. However, targeting this sub-division of the nervous system presents specific challenges in translating nerve stimulation parameters. Firstly, autonomic nerves are typically embedded non-uniformly among visceral and connective tissues with complex interfacing requirements. Secondly, these nerves contain axons with populations of varying phenotypes leading to complexities for axon engagement and activation. Thirdly, clinical translational of methodologies attained using preclinical animal models are limited due to heterogeneity of the intra- and inter-species comparative anatomy and physiology. Here we demonstrate how this can be accomplished by the use of in silico modelling of target anatomy, and validation of these estimations through ex vivo human tissue electrophysiology studies. Neuroelectrical models are developed to address the challenges in translation of parameters, which provides strong input criteria for device design and dose selection prior to a first-in-human trial.

Analysis of the effects of finite element type within a 3D biomechanical model of a human optic nerve head and posterior pole

Background and objectiveBiomechanical stresses and strains can be simulated in the optic nerve head (ONH) using the finite element (FE) method, and various element types have been used. This study aims to investigate the effects of element type on the resulting ONH stresses and strains. MethodsA single eye-specific model was constructed using 3D delineations of anatomic surfaces in a high-resolution, fluorescent, 3D reconstruction of a human posterior eye, then meshed using our simple meshing algorithm at various densities using 4- and 10-noded tetrahedral elements, as well as 8- and 20-noded hexahedral elements. A mesh-free approach was used to assign heterogeneous, anisotropic, hyperelastic material properties to the lamina cribrosa, sclera and pia. The models were subjected to elevated IOP of 45 mmHg after pre-stressing from 0 to 10 mmHg, and solved in the open-source FE package Calculix; results were then interpreted in relation to computational time and simulation accuracy, using the quadratic hexahedral model as the reference standard. ResultsThe 10-noded tetrahedral and 20R-noded hexahedral elements exhibited similar scleral canal and laminar deformations, as well as laminar and scleral stress and strain distributions; the quadratic tetrahedral models ran significantly faster than the quadratic hexahedral models. The linear tetrahedral and hexahedral elements were stiffer compared to the quadratic element types, yielding much lower stresses and strains in the lamina cribrosa. ConclusionsPrior studies have shown that 20-noded hexahedral elements yield the most accurate results in complex models. Results show that 10-noded tetrahedral elements yield very similar results to 20-noded hexahedral elements and so they can be used interchangeably, with significantly lower computational time. Linear element types did not yield acceptable results.

Long-term performance of Utah slanted electrode arrays and intramuscular electromyographic leads implanted chronically in human arm nerves and muscles

Objective. We explore the long-term performance and stability of seven percutaneous Utah Slanted Electrode Arrays (USEAs) and intramuscular recording leads (iEMGs) implanted chronically in the residual arm nerves and muscles of three human participants as a means to permanently restore sensorimotor function after transradial amputations. Approach. We quantify the number of functional recording and functional stimulating electrodes over time. We also calculate the signal-to-noise ratio (SNR) of USEA and iEMG recordings and quantify the stimulation current necessary to evoke detectable sensory percepts. Furthermore, we quantify the consistency of the sensory modality, receptive field location, and receptive field size of USEA-evoked percepts. Main results. In the most recent subject, involving USEAs with technical improvements, neural recordings persisted for 502 d (entire implant duration) and the number of functional recording electrodes for one USEA increased over time. However, for six out of seven USEAs across the three participants, the number of functional recording electrodes decreased within the first 2 months after implantation. The SNR of neural recordings and electromyographic recordings stayed relatively consistent over time. Sensory percepts were consistently evoked over the span of 14 months, were not significantly different in size, and highlighted the nerves’ fascicular organization. The percentage of percepts with consistent modality or consistent receptive field location between sessions (∼1 month apart) varied between 0%–86.2% and 9.1%–100%, respectively. Stimulation thresholds and electrode impedances increased initially but then remained relatively stable over time. Significance. This work demonstrates improved performance of USEAs, and provides a basis for comparing the longevity and stability of USEAs to that of other neural interfaces. USEAs provide a rich repertoire of neural recordings and sensory percepts. Although their performance still generally declines over time, functionality can persist long-term. Future work should leverage the results presented here to further improve USEA design or to develop adaptive algorithms that can maintain a high level of performance.

Aprepitant for Cough in Lung Cancer. A Randomized Placebo-controlled Trial and Mechanistic Insights.

Rationale: Effective cough treatments are a significant unmet need in patients with lung cancer. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of NK-1 (neurokinin 1) receptors, a mechanism also implicated in cough.Objectives: To assess aprepitant in patients with lung cancer with cough and evaluate mechanisms in vagal nerve tissue.Methods: Randomized double-blind crossover trial of patients with lung cancer and bothersome cough. They received 3 days of aprepitant or matched placebo; after a 3-day washout, patients crossed to the alternative treatment. The primary endpoint was awake cough frequency measured at screening and Day 3 of each treatment; secondary endpoints included patient-reported outcomes. In vitro, the depolarization of isolated guinea pig and human vagus nerve sections in grease-gap recording chambers, indicative of sensory nerve activation, was measured to evaluate the mechanism.Measurements and Main Results: Twenty patients with lung cancer enrolled, with a mean age 66 years (±7.7); 60% were female and 80% had non-small cell cancer, 50% had advanced stage, and 55% had World Health Organization performance status 1. Cough frequency improved with aprepitant, reducing by 22.2% (95% confidence interval [CI], 2.8-37.7%) over placebo while awake (P = 0.03), 30.3% (95% CI, 12.7-44.3) over 24 hours (P = 0.002), and 59.8% (95% CI, 15.1-86.0) during sleep (P = 0.081). Patient-reported outcomes all significantly improved. Substance P depolarized both guinea pig and human vagus nerve. Aprepitant significantly inhibited substance P-induced depolarization by 78% in guinea pig (P = 0.0145) and 94% in human vagus (P = 0.0145).Conclusions: Substance P activation of NK-1 receptors appears to be an important mechanism driving cough in lung cancer, and NK-1 antagonists show promise as antitussive therapies.