Human Nerve Research Articles

Antagonistic Effect and Mechanism of Gabapentin on Neuropathic Pain in Rats through P38 MAPK Signaling Pathway.

The etiology of neuropathic pain is complex, and the patients are distressed. In order to master more accurate information in the treatment of human nerve tissue and improve the efficiency of treatment, this paper discusses the antagonistic effect of gabapentin on neuropathic pain in rats through the p38 MAPK signal pathway. Thirty-six female Sprague Dawley (SD) rats were randomly divided into three groups, 12 in each group. One group was spinal nerve ligation group (SNL group), gabapentin Group (GBP group, spinal nerve ligation and intraperitoneal injection of gabapentin (50 mg/kg)) and sham operation group (sham group, no spinal nerve ligation, other surgical procedures were the same as SNL group), At 1, 3, 5 and 7 days after operation, the paw contraction latency (TWL) and mechanical paw contraction threshold (MWT) were detected. Then, the expression of Toll-like receptor 4 (TLR4) in dorsal root ganglia was detected by SPSS statistical analysis. Compared with the sham group, MWT and TWL in the SNL group and GBP group were lower at each time point after the operation (all P < 0.05). MWT and TWL in the GBP group were higher than those in the SNL group at 5 and 7 days after the operation (all P < 0.05). In addition, compared with the sham group, the expression of TLR4 in the dorsal root ganglia of the SNL group was significantly increased (P < 0.05), while the expression of TLR4 in the GBP group was not significantly increased (P > 0.05). Compared with the SNL group, the expression of TLR4 in the dorsal root ganglion of the GBP group was significantly decreased (P < 0.05). Thus, gabapentin combined therapy can effectively reduce the degree of pain in patients with significant efficacy, high safety and fewer adverse reactions.

LXR agonist improves peripheral neuropathy and modifies PNS immune cells in aged mice

BackgroundPeripheral neuropathy is a common and progressive disorder in the elderly that interferes with daily activities. It is of importance to find efficient treatments to treat or delay this age-related neurodegeneration. Silencing macrophages by reducing foamy macrophages showed significant improvement of age-related degenerative changes in peripheral nerves of aged mice. We previously demonstrated that activation of the cholesterol sensor Liver X receptor (LXR) with the potent agonist, GW3965, alleviates pain in a diet-induced obesity model. We sought to test whether LXR activation may improve neuropathy in aged mice.Methods21-month-old mice were treated with GW3965 (25 mg/Kg body weight) for 3 months while testing for mechanical allodynia and thermal hyperalgesia. At termination, flow cytometry was used to profile dorsal root ganglia and sciatic nerve cells. Immune cells were sorted and analyzed for cholesterol and gene expression. Nerve fibers of the skin from the paws were analyzed. Some human sural nerves were also evaluated. Comparisons were made using either t test or one-way ANOVA.ResultsTreatment with GW3965 prevented the development of mechanical hypersensitivity and thermal hyperalgesia over time in aged mice. We also observed change in polarization and cholesterol content of sciatic nerve macrophages accompanied by a significant increase in nerve fibers of the skin.ConclusionsThese results suggest that activation of the LXR may delay the PNS aging by modifying nerve-immune cell lipid content. Our study provides new potential targets to treat or delay neuropathy during aging.

Ventricular Infusion and Nanoprobes Identify Cerebrospinal Fluid and Glymphatic Circulation in Human Nerves.

Background:Growing evidence suggests that cerebrospinal fluid circulates in human nerves. Several conditions encountered by the plastic surgeon may be related to dysregulation of this system, including nerve transection, stretch injuries, and peripheral neuropathy. The purpose of this study was to show how ventricular infusion and nanoprobes identify CSF and glymphatic circulation in neural sheaths of human nerves.Methods:The technique of ventricular infusion using buffered saline was developed in 2017. The technique was used in a series of eight fresh cadavers before dissection of the median nerve, and combined with fluorescent imaging and nanoprobe injections in selected specimens.Results:Eight cadaver specimens underwent ventricular infusion. There were six female and two male specimens, ages 46–97 (mean 76.6). Ventricular cannulation was performed successfully using coordinates 2 cm anterior to coronal suture and 2.5 cm lateral to sagittal suture. Depth of cannulation ranged from 44 to 56 mm (mean 49.7). Ventricular saline infusion complemented by nanoprobe injection suggests CSF flows in neural sheaths, including pia meninges, epineurial channels, perineurium, and myelin sheaths (neurolemma).Conclusions:Ventricular infusion and nanoprobes identify CSF flow in neural sheaths of human nerves. CSF flow in nerves is an open circulatory system that occurs via channels, intracellular flow, and cell-to-cell transport associated with glial cells. Neural sheaths, including neurolemma, may participate in glucose and solute transport to axons. These techniques may be used in anatomic dissection and live animal models, and have been extended to the central nervous system to identify direct ventricle-to-pia meninges CSF pathways.

Circular RNA_0061587 is associated with the tumorigenesis of neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a kind of common neurogenetic disorder associated with various developmental deficits. Circular RNAs (circRNAs) have been frequently verified to be crucial modulators in human diseases. However, the functions of circRNAs on the occurrence of NF1 remain largely obscure. In our study, RT-qPCR was applied to analyze circ_0061,587 expression and we noticed that circ_0061,587 expression was overtly elevated in human NF1-associated malignant peripheral nerve sheath tumor (MPNST) cell lines. Meanwhile, the results of loss-of-function assays revealed that silencing of circ_0061,587 hampered the proliferation, migration, and invasion but stimulated the apoptosis of human NF1-associated MPNST cells. In addition, mechanism assays were implemented to unveil the possible regulatory mechanism behind circ_0061,587. As a result, circ_0061,587 sequestered microRNA-485–5p (miR-485–5p) to modulate the expression of RUNX family transcription factor 1 (RUNX1) and annexin A11 (ANXA11). Finally, rescue experiments confirmed that circ_0061,587 boosted the malignant behaviors of human NF1-associated MPNST cells through up-regulating RUNX1 and ANXA11. In conclusion, circ_0061,587 functioned as an oncogene in NF1-associated MPNST cells and this study might provide novel insights for the diagnosis and treatment of NF1.

Long-term clinical efficacy of topical treatment with recombinant human nerve growth factor in neurotrophic keratopathy: a novel cure for a rare degenerative corneal disease?

BackgroundNeurotrophic keratopathy (NK) is a rare, degenerative ocular disease characterized by reduction or loss of corneal sensitivity and development of non-healing corneal epithelial defects and ulcers. Cenegermin, a recombinant human nerve growth factor (rhNGF) eye drop solution, is the first drug approved for the treatment of NK. The aim of our study is to evaluate the long-term efficacy of this innovative topical treatment in patients with NK.MethodsRetrospective, consecutive, observational case series study from a single-center setting (Department of Sense Organs, University Sapienza of Rome, Rome, Italy). 18 patients with diagnosis of stage 2 or 3 NK, treated with Cenegermin 20 mcg/ml eye drops were followed for up to 48 months. Recurrence of lesion during follow-up was evaluated at 12, 24, 36, and 48 months. In addition, corneal sensitivity, Schirmer tear test, and visual acuity (VA) were recorded at baseline, end of treatment, and at 12, 24, 36, and 48 months.ResultsThree patients experienced recurrence of persistent epithelial defects (PEDs) within 12 months and one patient experienced recurrence of a corneal ulcer within 36 months. Corneal sensitivity was significantly improved at all timepoints (P < 0.05). Significant improvements in visual acuity and tear production were seen at the completion of treatment as well as at 12, 24, and 36 months (P < 0.05) when compared to baseline.ConclusionsA single 8-week treatment regimen of Cenegermin eye drops has clinical efficacy that can persist for up to 48 months. The long-term clinical utility of treatment with Cenegermin for NK was demonstrated through the low rate of lesion recurrence along with improvements in corneal sensitivity and tear production.

Repair of ovine peripheral nerve injuries with xenogeneic human acellular sciatic nerves prerecellularized with allogeneic Schwann-like cells-an innovative and promising approach.

IntroductionThe iatrogenic effects of repairing peripheral nerve injuries (PNIs) with autografts (AGTs) encouraged the present study to involve a new approach consisting of grafting xenogeneic prerecellularized allogeneic cells instead of AGTs.MethodsWe compared sheep's AGT regenerative and functional capacity with decellularized human nerves prerecellularized with allogeneic Schwann-like cell xenografts (onwards called xenografts). Mesenchymal stem cells were isolated from ovine adipose tissue and induced in vitro to differentiate into Schwann-like cells (SLCs). Xenografts were grafted in ovine sciatic nerves. Left sciatic nerves (20 mm) were excised from 10 sheep. Then, five sheep were grafted with 20 mm xenografts, and five were reimplanted with their nerve segment rotated 180° (AGT).ResultsAll sheep treated with xenografts or AGT progressively recovered the strength, movement, and coordination of their intervened limb, which was still partial when the study was finished at sixth month postsurgery. At this time, numerous intrafascicular axons were observed in the distal and proximal graft extremes of both xenografts or AGTs, and submaximal nerve electrical conduction was observed. The xenografts and AGT-affected muscles appeared partially stunted.ConclusionsXenografts and AGT were equally efficacious in starting PNI repair and justified further studies using longer observation times. The hallmarks from this study are that human xenogeneic acellular scaffolds were recellularized with allogenic SCL and were not rejected by the nonhuman receptors but were also as functional as AGT within a relatively short time postsurgery. Thus, this innovative approach promises to be more practical and accessible than AGT or allogenic allografts and safer than AGT for PNI repair.

Impact of electrode position on the dynamic range of a human auditory nerve fiber

Objective. Electrodes of a cochlear implant generate spikes in auditory nerve fibers (ANFs). While the insertion depth of each of the electrodes is linked to a frequency section of the acoustic signal, the amplitude of the stimulating pulses controls the loudness of the related frequency band. However, in comparison to acoustic stimulation the dynamic range (DR) of an electrically stimulated ANF is quite small. Approach. The DR of an electrically stimulated ANF is defined as the interval of stimulus amplitudes that causes firing probabilities between 10% and 90%. A compartment model that includes sodium ion current fluctuations as the stochastic key component for spiking was evaluated for different electrode placements and fiber diameters. Main results. The DR is reversely related to ANF diameter. An increased DR is expected to improve the quality of auditory perception for CI users. Electrodes are often placed as close to the center axis of the cochlea as possible. The analysis of the simulated auditory nerve firing showed that this placement is disadvantageous for the DR of a selected ANF. Significance. Five times larger DRs are expected for electrodes close to the terminal of the dendrite or at mid-dendritic placement as opposed to electrodes close to the modiolus.

Disentangling glial diversity in peripheral nerves at single-nuclei resolution.

The peripheral nerve contains diverse cell types that support its proper function and maintenance. In this study, we analyzed multiple peripheral nerves using single-nuclei RNA sequencing, which allowed us to circumvent difficulties encountered in analyzing cells with complex morphologies via conventional single-cell methods. The resultant mouse peripheral nerve cell atlas highlights a diversity of cell types, including multiple subtypes of Schwann cells (SCs), immune cells and stromal cells. We identified a distinct myelinating SC subtype that expresses Cldn14, Adamtsl1 and Pmp2 and preferentially ensheathes motor axons. The number of these motor-associated Pmp2+ SCs is reduced in both an amyotrophic lateral sclerosis (ALS) SOD1G93A mouse model and human ALS nerve samples. Our findings reveal the diversity of SCs and other cell types in peripheral nerve and serve as a reference for future studies of nerve biology and disease.

Oxygen-Vacancy-Induced Synaptic Plasticity in an Electrospun InGdO Nanofiber Transistor for a Gas Sensory System with a Learning Function.

The perceptual learning function of a simulating human body is very important for constructing a neural computing system and a brainlike computer in the future. The sense of smell is an important part of the human sensory nervous system. However, current gas sensors simply convert gas concentrations into electrical signals and do not have the same learning and memory function as synapses. To solve this problem, we propose a new sensing idea to induce and activate the synaptic properties of transistors by adjusting the oxygen vacancy in the active layer. This sensor combines gas detection with synaptic memory and learning and overcomes the disadvantage of the separation of synaptic transistors and sensors, thus greatly reducing the cost of production. This work combines the detection of N,N-dimethylformamide (DMF) gas with the synaptic mechanism of human olfactory nerves. We successfully fabricated an InGdO nanofiber field-effect transistor by electrostatic spinning and simulated the response of human olfactory synapses to target gas by regulating the oxygen vacancy of the InGdO nanofiber. The synaptic transistor response under different concentrations of unmodulated pulses is tested, and the pavlovian conditioned reflex experiment is simulated successfully. This work provides a new idea of a gas sensor device, which is very important for the development of high-performance gas sensors and bionic electronic devices in the future.

Incompleteness of moral choice and evolution towards fully autonomous AI

Nowadays, it is fashionable to add the attribute “with artificial intelligence” to all possible devices, platforms and machines. The problem of ethical decision-making, viewed from the perspective of computer, technical and natural sciences, lies only in the complexity of the topic. AI scientists and developers basically proceed from the Turing machine model, assuming that a machine can be constructed to resolve any problems (including ethical decision-making issues) that can mechanically calculate a particular function if this function can be put into an algorithm. Thus, ethical decision-making is conceived as an abstract concept whose manifestation does not depend on the particular physical organism in which the algorithm takes place, nor on what it is made of. Whether from photons, mechanical relays, quantum fluctuations, artificial neurons or human nerve cells. If in practice, a sufficiently complex algorithm is built, it will also exhibit sufficiently complex behavior that can be characterized as ethical in the full sense of the word. This article reflects the main argument that if a task requires some form of moral authority when it is performed by humans, its full automation, transferring the same task to autonomous machines, platforms, and AI algorithms, necessarily implies the transfer of moral competence. The question of what this competence should include presupposes empirical research and reassessing purely normative approaches in AI ethics.

Validation of a Cleanroom Compliant Sonication-Based Decellularization Technique: A New Concept in Nerve Allograft Production.

Defects of the peripheral nervous system are extremely frequent in trauma and surgeries and have high socioeconomic costs. If the direct suture of a lesion is not possible, i.e., nerve gap > 2 cm, it is necessary to use grafts. While the gold standard is the autograft, it has disadvantages related to its harvesting, with an inevitable functional deficit and further morbidity. An alternative to autografting is represented by the acellular nerve allograft (ANA), which avoids disadvantages of autograft harvesting and fresh allograft rejection. In this research, the authors intend to transfer to human nerves a novel technique, previously implemented in animal models, to decellularize nerves. The new method is based on soaking the nerve tissues in decellularizing solutions while associating ultrasounds and freeze–thaw cycles. It is performed without interrupting the sterility chain, so that the new graft may not require post-production γ-ray irradiation, which is suspected to affect the structural and functional quality of tissues. The new method is rapid, safe, and inexpensive if compared with available commercial ANAs. Histology and immunohistochemistry have been adopted to evaluate the new decellularized nerves. The study shows that the new method can be applied to human nerve samples, obtaining similar, and, sometimes better, results compared with the chosen control method, the Hudson technique.

Peristimulus Time Responses Predict Adaptation and Spontaneous Firing of Auditory-Nerve Fibers: From Rodents Data to Humans.

Sound-level coding in the auditory nerve is achieved through the progressive recruitment of auditory nerve fibers (ANFs) that differ in threshold of activation and in the stimulus level at which the spike rate saturates. To investigate the functional state of the ANFs, the electrophysiological tests routinely used in clinics only capture the first action potentials firing in synchrony at the onset of the acoustic stimulation. Assessment of other properties (e.g., spontaneous rate and adaptation time constants) requires single-fiber recordings directly from the nerve, which for ethical reasons is not allowed in humans. By combining neuronal activity measurements at the round window and signal-processing algorithms, we constructed a peristimulus time response (PSTR), with a waveform similar to the peristimulus time histograms (PSTHs) derived from single-fiber recordings in young adult female gerbils. Simultaneous recordings of round-window PSTR and single-fiber PSTH provided models to predict the adaptation kinetics and spontaneous rate of the ANFs tuned at the PSTR probe frequency. The predictive model derived from gerbils was then validated in female mice and finally applied to humans by recording PSTRs from the auditory nerve in normal-hearing patients who underwent cerebellopontine angle surgeries. A rapid adaptation time constant of ∼3 ms and a mean spontaneous rate of ∼22 spikes/s in the 4 kHz frequency range were found. This study offers a promising diagnostic tool to map the human auditory nerve, thus opening new avenues to better understanding auditory neuropathies, tinnitus, and hyperacusis.SIGNIFICANCE STATEMENT Neural adaptation in auditory nerve fibers corresponds to the reduction in the neuronal activity to prolonged or repeated sound stimulation. For obvious ethical reasons, single-fiber recordings from the auditory nerve are not feasible in humans, creating a critical gap in extending data obtained using animal models to humans. Using electrocochleography in rodents, we inferred adaptation kinetics and spontaneous discharge rates of the auditory nerve fibers in humans. Routinely used in basic and clinical laboratories, this tool will provide a better understanding of auditory disorders such as neuropathies, tinnitus, and hyperacusis, and will help to improve hearing-aid fittings.

Tear proteomics reveals the molecular basis of the efficacy of human recombinant nerve growth factor treatment for Neurotrophic Keratopathy

Neurotrophic Keratopathy (NK), classified as an orphan disease (ORPHA137596), is a rare degenerative corneal disease characterized by epithelial instability and decreased corneal sensitivity caused by the damage to the corneal nerves. The administration of human recombinant nerve growth factor (rhNGF) eye drops, as a licensed-in-Europe specific medication for treatment of moderate and severe NK, has added promising perspectives to the management of this disorder by providing a valid alternative to the neurotization surgery. However, few studies have been conducted to the molecular mechanism underlying the response to the treatment. Here, we carried out tears proteomics to highlight the protein expression during pharmacological treatment of NK (Data are available via ProteomeXchange with identifier PXD025408).Our data emphasized a proteome modulation during rhNGF treatment related to an increase in DNA synthesis, an activation of both BDNF signal and IL6 receptor. Furthermore, the amount of neuronal Extracellular Vesicles EVs (CD171+) correlated with the EVs carrying IL6R (CD126+) together associated to the inflammatory EVs (CD45+) in tears. Such scenario determined drug response, confirmed by an in vivo confocal microscopy analysis, showing an increase in length, density and number of nerve fiber branches during treatment. In summary, rhNGF treatment seems to determine an inflammatory micro-environment, mediated by functionalized EVs, defining the drug response by stimulating protein synthesis and fiber regeneration.

The ultrastructural study of human cochlear nerve at different ages

Ultrastructural and molecular changes in the myelin of the cochlear nerve (CN) have been associated with decreased hearing-acuity with increasing age. But most of these are animal studies or with very few human samples. Hence, we studied the ultrastructure of the human CN at different ages.We obtained samples of CN from persons, who at the time of death belonged to young, middle or old age-groups; defined as ≤ 30, 31 to 50, and ≥ 51 years of age, respectively. These were processed for viewing under a transmission electron microscope (TEM). Morphology and morphometry were assessed after blinding the observer. Measurements of diameter (whole nerve fibre, axon), myelin thickness and calculation of G-ratio were made on calibrated images using ImageJ software. K-Means cluster analysis was performed based on total and inner nerve fibre area.Middle and old age CN showed degenerating axons, splitting of myelin sheath and myelin balloons. Between the middle and old age groups there was significant decrease in axon diameter (p<0.001), inner nerve fibre area (p<0.001), myelin thickness (p<0.001), nerve fibre diameter (p<0.001), and G-ratio (p<0.001). By clustering, we identified three distinct populations of myelinated nerve fibres: large, medium and small. The large fibres (by size), seen in the young, disappeared in the old age-group. We were unable to find any unmyelinated nerve fibres in this study.The morphological deterioration CN fibres may be a visible sign of molecular degeneration and contribute to decreased hearing-acuity.

Treatment of Non-Infectious Corneal Injury: Review of Diagnostic Agents, Therapeutic Medications, and Future Targets.

Corneal injuries can occur secondary to traumatic, chemical, inflammatory, metabolic, autoimmune, and iatrogenic causes. Ocular infection may frequently occur concurrent to corneal injury; however, antimicrobial agents are excluded from this present review. While practitioners may primarily rely on clinical examination techniques to assess these injuries, several pharmacological agents, such as fluorescein, lissamine green, and rose bengal, can be used to formulate a diagnosis and develop effective treatment strategies. Practitioners may choose from several analgesic medications to help with patient comfort without risking further injury or delaying ocular healing. Atropine, cyclopentolate, scopolamine, and homatropine are among the most frequently used medications for this purpose. Additional topical analgesic agents may be used judiciously to augment patient comfort to facilitate diagnosis. Steroidal anti-inflammatory agents are frequently used as part of the therapeutic regimen. A variety of commonly used agents, including prednisolone acetate, loteprednol, difluprednate, dexamethasone, fluorometholone, and methylprednisolone are discussed. While these medications are effective for controlling ocular inflammation, side effects, such as elevated intraocular pressure and cataract formation, must be monitored by clinicians. Non-steroidal medications, such as ketorolac, bromfenac, nepafenac, and diclofenac, are additionally used for their efficacy in controlling ocular inflammation without incurring side effects seen with steroids. However, these agents have their own respective side effects, warranting close monitoring by clinicians. Additionally, ophthalmologists routinely employ several agents in an off-label manner for supplementary control of inflammation and treatment of corneal injuries. Patients with corneal injuries not infrequently have significant ocular surface disease, either as a concurrent pathology or as an exacerbation of previously existing disease. Several agents used in the management of ocular surface disease have also been found to be useful as part of the therapeutic armamentarium for treatment of corneal injuries. For example, several antibiotics, such as doxycycline and macrolides, have been used for their anti-inflammatory effects on specific cytokines that are upregulated during acute injuries. There has been a recent wave of interest in amniotic membrane therapies (AMTs), including topical, cryopreserved and dehydrated variants. AMT is particularly effective in ocular injuries with violation of corneal surface integrity due to its ability to promote re-epithelialization of the corneal epithelium. Blood-based therapies, including autologous serum tears, plasma-enriched growth factor eyedrops and autologous blood drops, have additionally been explored in small case series for effectiveness in challenging and recalcitrant cases. Protection of the ocular surface is also a vital component in the treatment of corneal injuries. Temporary protective methods, such as bandage contact lenses and mechanical closure of the eyelids (tarsorrhaphy) can be particularly helpful in selective cases. Glue therapies, including biologic and non-biologic variants, can also be used in cases of severe injury and risk of corneal perforation. Finally, there are a variety of recently introduced and in-development agents that may be used as adjuvant therapies in challenging patient populations. Neurotrophic corneal disease may occur as a result of severe or chronic injury. In such cases, recombinant human nerve growth factor (cenegermin), topical insulin, and several other novel agents may be an alternate and effective option for clinicians to consider.

A Brief Review of In Vitro Models for Injury and Regeneration in the Peripheral Nervous System.

Nerve axonal injury and associated cellular mechanisms leading to peripheral nerve damage are important topics of research necessary for reducing disability and enhancing quality of life. Model systems that mimic the biological changes that occur during human nerve injury are crucial for the identification of cellular responses, screening of novel therapeutic molecules, and design of neural regeneration strategies. In addition to in vivo and mathematical models, in vitro axonal injury models provide a simple, robust, and reductionist platform to partially understand nerve injury pathogenesis and regeneration. In recent years, there have been several advances related to in vitro techniques that focus on the utilization of custom-fabricated cell culture chambers, microfluidic chamber systems, and injury techniques such as laser ablation and axonal stretching. These developments seem to reflect a gradual and natural progression towards understanding molecular and signaling events at an individual axon and neuronal-soma level. In this review, we attempt to categorize and discuss various in vitro models of injury relevant to the peripheral nervous system and highlight their strengths, weaknesses, and opportunities. Such models will help to recreate the post-injury microenvironment and aid in the development of therapeutic strategies that can accelerate nerve repair.

Comparison of Collagen and Human Amniotic Membrane Nerve Wraps and Conduits for Peripheral Nerve Repair in Preclinical Models: A Systematic Review of the Literature.

Collagen and human amniotic membrane (hAM) are Food and Drug Administration (FDA)-approved biomaterials that can be used as nerve wraps or conduits for repair of peripheral nerve injuries. Both biomaterials have been shown to reduce scarring and fibrosis of injured peripheral nerves. However, comparative advantages and disadvantages have not been definitively shown in the literature. The purpose of this systematic review is to comprehensively evaluate the literature regarding the roles of hAM and collagen nerve wraps and conduits on peripheral nerve regeneration in preclinical models. The MEDLINE database was queried using the PubMed search engine on July 7, 2019, with the following search strategy: ("amniotic membrane" OR "amnion") OR ("collagen conduit" OR "nerve wrap")] AND "nerve." All resulting articles were screened by two independent reviewers. Nerve type, lesion type/injury model, repair type, treatment, and outcomes were assessed. Two hundred and fifty-eight articles were identified, and 44 studies remained after application of inclusion and exclusion criteria. Seventeen studies utilized hAM, whereas 27 studies utilized collagen wraps or conduits. Twenty-three (85%) of the collagen studies utilized conduits, and four (15%) utilized wraps. Six (35%) of the hAM studies utilized conduits and 11 (65%) utilized wraps. Two (9%) collagen studies involving a conduit and one (25%) involving a wrap demonstrated at least one significant improvement in outcomes compared with a control. While none of the hAM conduit studies showed significant improvements, eight (73%) of the studies investigating hAM wraps showed at least one significant improvement in outcomes. The majority of studies reported positive outcomes, indicating that collagen and hAM nerve wraps and conduits both have the potential to enhance peripheral nerve regeneration. However, relatively few studies reported significant findings, except for studies evaluating hAM wraps. Preclinical models may help guide clinical practice regarding applications of these biomaterials in peripheral nerve repair.

Direct Cochlear Recordings in Humans Show a Theta Rhythmic Modulation of Auditory Nerve Activity by Selective Attention.

The architecture of the efferent auditory system enables prioritization of strongly overlapping spatiotemporal cochlear activation patterns elicited by relevant and irrelevant inputs. So far, attempts at finding such attentional modulations of cochlear activity delivered indirect insights in humans or required direct recordings in animals. The extent to which spiral ganglion cells forming the human auditory nerve are sensitive to selective attention remains largely unknown. We investigated this question by testing the effects of attending to either the auditory or visual modality in human cochlear implant (CI) users (3 female, 13 male). Auditory nerve activity was directly recorded with standard CIs during a silent (anticipatory) cue-target interval. When attending the upcoming auditory input, ongoing auditory nerve activity within the theta range (5-8 Hz) was enhanced. Crucially, using the broadband signal (4-25 Hz), a classifier was even able to decode the attended modality from single-trial data. Follow-up analysis showed that the effect was not driven by a narrow frequency in particular. Using direct cochlear recordings from deaf individuals, our findings suggest that cochlear spiral ganglion cells are sensitive to top-down attentional modulations. Given the putatively broad hair-cell degeneration of these individuals, the effects are likely mediated by alternative efferent pathways compared with previous studies using otoacoustic emissions. Successful classification of single-trial data could additionally have a significant impact on future closed-loop CI developments that incorporate real-time optimization of CI parameters based on the current mental state of the user.SIGNIFICANCE STATEMENT The efferent auditory system in principle allows top-down modulation of auditory nerve activity; however, evidence for this is lacking in humans. Using cochlear recordings in participants performing an audiovisual attention task, we show that ongoing auditory nerve activity in the silent cue-target period is directly modulated by selective attention. Specifically, ongoing auditory nerve activity is enhanced within the theta range when attending upcoming auditory input. Furthermore, over a broader frequency range, the attended modality can be decoded from single-trial data. Demonstrating this direct top-down influence on auditory nerve activity substantially extends previous works that focus on outer hair cell activity. Generally, our work could promote the use of standard cochlear implant electrodes to study cognitive neuroscientific questions.

Research in the Treatment of Essential Oil of Traditional Chinese Medicine through Gut Microbiota to Related Diseases

Gut Microbiota, as a major bacterial barrier in organisms, regulates a variety of important functions of the digestive system. Researches have shown that Gut Microbiota is also closely related to human metabolism, immunity, nerve conduction and other physiological activities, and is involved in maintaining people's life and health. At the same time, the imbalance of Gut Microbiota is also significantly related to the occurrence of multi system diseases in the human body, which can directly or indirectly affect the normal metabolism and biological barrier, and then lead to the disease of the body. As an extract of traditional Chinese medicine, it uses different properties, tastes, meridian tropism and pharmacological effects to realize the regulation of Gut Microbiota imbalance, so as to affect and regulate the related diseases caused by Gut Microbiota imbalance. After searching a large number of literatures, this review summarizes the regulatory relationship between Gut Microbiota and related diseases, and the treatment of related diseases by using Gut Microbiota with traditional Chinese medicine essential oil.

Using a Transection Paradigm to Enhance the Repair Mechanisms of an Investigational Human Cell Therapy

One promising strategy in cell therapies for Parkinson’s disease (PD) is to harness a patient’s own cells to provide neuroprotection in areas of the brain affected by neurodegeneration. No treatment exists to replace cells in the brain. Thus, our goal has been to support sick neurons and slow neurodegeneration by transplanting living repair tissue from the peripheral nervous system into the substantia nigra of those with PD. Our group has pioneered the transplantation of transection-activated sural nerve fascicles into the brain of human subjects with PD. Our experience in sural nerve transplantation has supported the safety and feasibility of this approach. As part of a paradigm to assess the reparative properties of human sural nerve following a transection injury, we collected nerve tissue approximately 2 weeks after sural nerve transection for immunoassays from 15 participants, and collected samples from two additional participants for single nuclei RNA sequencing. We quantified the expression of key neuroprotective and select anti-apoptotic genes along with their corresponding protein levels using immunoassays. The single nuclei data clustered into 10 distinctive groups defined on the basis of previously published cell type-specific genes. Transection-induced reparative peripheral nerve tissue showed RNA expression of neuroprotective factors and anti-apoptotic factors across multiple cell types after nerve injury induction. Key proteins of interest (BDNF, GDNF, beta-NGF, PDGFB, and VEGF) were upregulated in reparative tissue. These results provide insight on this repair tissue’s utility as a neuroprotective cell therapy.