Unmyelinated Fibers Research Articles

Neuroplasticity and Content of Structural Elements in the Axoplasm of the Trigeminal Nerve During the Eruption of Permanent Teeth in Humans

The aim of the presented study was to identify the features of the quantitative formation of axoplasmic organelles with a primary analysis of the components of the axonal cytoskeleton (microtubules and neurofilaments) of myelinated and non-myelinated nerve fibers in the dental pulp during the eruption of permanent teeth in humans. Material and methods. The neurovascular bundle of dental pulp was studied in children aged 5, 10 and 14 years. On ultramicrographs of pulp sections at a magnification of ×40000, the diameters of myelin and non-myelin conductors were measured; per 1 µm2 of axoplasm of nerve conductors, the density of axoplasmic organelles, the number of microtubules and neurofilaments were calculated. The reliability of differences between groups was assessed using multivariate analysis of variance (MANOVA), the significance of average values was assessed using the Tukey test, correlation analysis was carried out using the Pearson criterion. Results. The process of eruption of permanent teeth was accompanied by a gradual increase in the number of organelles per unit cross-sectional area of the nerve, regardless of its characteristics (myelinated or nonmyelinated fiber type). The highest density of organelles was observed in large-diameter fibers of both myelinated and non-myelinated conductors throughout the indicated segment of ontogenetic development. The presence of myelin in the nerve sheath correlates positively with microtubule saturation in fibers of large (r=0.267, p=0.001) and small (r=0.314, p=0.000) diameters, and negatively in fibers with medium diameter (r=-0.246, p=0.002). The proportion of neurofilaments represented among the axoplasmic organelles of the neuroplasm as a whole was especially high in myelinated and unmyelinated nerve fibers of small diameter, averaging up to 70%. The presence of the myelin sheath and fiber diameter are not associated with neurofilament density with the exception of medium-diameter fibers (r=0.195, p=0.001). Conclusion. The process of eruption of permanent teeth is accompanied by an increase in the number of organelles, cytoskeletal elements in the axoplasm of nerve fibers innervating the dental pulp, providing the morphological substrate of neuroplasticity, which must be taken into account, for example, in the process of dental implantation and dental prosthetics.

Small Fibre Pathology in Fibromyalgia: A review.

Fibromyalgia syndrome (FMS) presents a complex and challenging disorder in both the diagnosis and treatment, with emerging evidence suggesting a role of small fibre pathology (SFP) in its pathophysiology. The significance of the role of SFP in FMS remains unclear; however, recent evidence suggests degeneration anddysfunction of the peripheral nervous system, particularly small unmyelinated fibres, which may influence pathophysiology and underlying phenotype. Both skin biopsy and corneal confocal microscopy (CCM) have consistently demonstrated that~50% of people with FMS have SFP. CCM, a non-invasive measure of small nerve fibres has detected small fibre loss, correlating with neuropathic pain descriptors. Additionally, quantitative sensory testing has shown abnormalities, primarily in pain pressure/mechanical pain thresholds. This narrative review provides a comprehensive understanding of the pathophysiological dimensions of FMS with a clear focus on small nerve fibres and the peripheral nervous system, offering a roadmap for future research.

A novel approach to completely alleviate peripheral neuropathic pain in human patients: insights from preclinical data.

Neuropathic pain is a pervasive health concern worldwide, posing significant challenges to both clinicians and neuroscientists. While acute pain serves as a warning signal for potential tissue damage, neuropathic pain represents a chronic pathological condition resulting from injury or disease affecting sensory pathways of the nervous system. Neuropathic pain is characterized by long-lasting ipsilateral hyperalgesia (increased sensitivity to pain), allodynia (pain sensation in response to stimuli that are not normally painful), and spontaneous unprovoked pain. Current treatments for neuropathic pain are generally inadequate, and prevention remains elusive. In this review, we provide an overview of current treatments, their limitations, and a discussion on the potential of capsaicin and its analog, resiniferatoxin (RTX), for complete alleviation of nerve injury-induced neuropathic pain. In an animal model of neuropathic pain where the fifth lumbar (L5) spinal nerve is unilaterally ligated and cut, resulting in ipsilateral hyperalgesia, allodynia, and spontaneous pain akin to human neuropathic pain. The application of capsaicin or RTX to the adjacent uninjured L3 and L4 nerves completely alleviated and prevented mechanical and thermal hyperalgesia following the L5 nerve injury. The effects of this treatment were specific to unmyelinated fibers (responsible for pain sensation), while thick myelinated nerve fibers (responsible for touch and mechanoreceptor sensations) remained intact. Here, we propose to translate these promising preclinical results into effective therapeutic interventions in humans by direct application of capsaicin or RTX to adjacent uninjured nerves in patients who suffer from neuropathic pain due to peripheral nerve injury, following surgical interventions, diabetic neuropathy, trauma, vertebral disc herniation, nerve entrapment, ischemia, postherpetic lesion, and spinal cord injury.

Laterality, sexual dimorphism, and human vagal projectome heterogeneity shape neuromodulation to vagus nerve stimulation

Neuromodulation by vagus nerve stimulation (VNS) provides therapeutic benefits in multiple medical conditions, including epilepsy and clinical depression, but underlying mechanisms of action are not well understood. Cervical vagus nerve biopsies were procured from transplant organ donors for high resolution light microscopy (LM) and transmission electron microscopy (TEM) to map the human fascicular and sub-fascicular organization. Cervical vagal segments show laterality with right sided dominance in fascicle numbers and cross-sectional areas as well as sexual dimorphism with female dominance in fascicle numbers. The novel and unprecedented detection of numerous small fascicles by high resolution LM and TEM expand the known fascicle size range and morphological diversity of the human vagus nerve. Ground truth TEM quantification of all myelinated and unmyelinated axons within individual nerve fascicles show marked sub-fascicular heterogeneity of nerve fiber numbers, size, and myelination. A heuristic action potential interpreter (HAPI) tool predicts VNS-evoked compound nerve action potentials (CNAPs) generated by myelinated and unmyelinated nerve fibers and validates functional dissimilarity between fascicles. Our findings of laterality, sexual dimorphism, and an expanded range of fascicle size heterogeneity provide mechanistic insights into the varied therapeutic responses and off-target effects to VNS and may guide new refinement strategies for neuromodulation.

Transarterial Embolization for Musculoskeletal Pain Management: AJR Expert Panel Narrative Review.

Musculoskeletal embolization has emerged in recent years as a treatment for chronic joint pain, as the inflammatory cascade responsible for such pain has become better understood. Studies have demonstrated a complex interplay between joint inflammation and synovial hypervascularity that causes growth of new unmyelinated nerve fibers responsible for pain. Embolization targets joint hypervascularity, to disrupt the inflammatory cycle and provide pain relief. The standard treatment algorithm for chronic joint pain is well-established and entails escalating therapeutic options that include exercise, self-management programs, analgesic medications, intra-articular injections, and finally surgical replacement or release. Genicular artery embolization (GAE), targeting abnormal vasculature around the knee joint, is the most heavily studied musucloskeletal embolization procedure, reflecting the high worldwide prevalence and increasing incidence of knee osteoarthritis. GAE is now supported by multiple prospective studies, including randomized control trials comparing GAE versus sham treatment. Embolization has also extended outside of the knee joint to include the shoulder (treatment of adhesive capsulitis or secondary stiff shoulder), elbow (medial/lateral epicondylitis), hip (osteoarthritis, great trochanteric pain syndrome), and ankle (plantar fasciitis). This AJR Expert Panel Narrative Review discusses the current status of transarterial embolization for musculoskeletal pain management, focusing on treatment of knee osteoarthritis and chronic shoulder pain.

First-in-human microelectrode recordings from the vagus nerve during clinical vagus nerve stimulation.

Vagus nerve stimulation (VNS) is an effective treatment for people with drug-resistant epilepsy. However, its mechanisms of action are poorly understood, including which nerve fibers are activated in humans during VNS in typical clinical settings and which are required for clinical efficacy. In particular, there have been no intraneural recordings of vagus nerve fiber activation in awake humans undergoing chronic VNS. In this study, for the first time, we report recordings from the vagus nerve in this setting. The recordings were performed using a sterile tungsten microelectrode inserted percutaneously into the cervical vagus nerve under ultrasound guidance. The clinical VNS systems were used to deliver stimulation while activity in the vagus nerve was recorded. In addition to activating myelinated axons at low currents, we provide evidence that VNS can also activate unmyelinated C fibers in the vagus nerve at currents <1 mA. These results add to our understanding of how VNS exerts its beneficial effects in drug-resistant epilepsy. Here we describe for the first time, electrical recordings from the vagus nerve in awake drug-resistant epilepsy patients with an implanted vagus nerve stimulation (VNS) device. We found that the VNS device was able to activate both myelinated and unmyelinated fibers within the vagus nerve, whichcontributes to our understanding of how VNS works in the context of drug-resistant epilepsy.

Reverse-engineered models reveal differential membrane properties of autonomic and cutaneous unmyelinated fibers.

Unmyelinated C-fibers constitute the vast majority of axons in peripheral nerves and play key roles in homeostasis and signaling pain. However, little is known about their ion channel expression, which controls their firing properties. Also, because of their small diameters (~ 1 μm), it has not been possible to characterize their membrane properties using voltage clamp. We developed a novel library of isoform-specific ion channel models to serve as the basis functions of our C-fiber models. We then developed a particle swarm optimization (PSO) framework that used the isoform-specific ion channel models to reverse engineer C-fiber membrane properties from measured autonomic and cutaneous C-fiber conduction responses. Our C-fiber models reproduced experimental conduction velocity, chronaxie, action potential duration, intracellular threshold, and paired pulse recovery cycle. The models also matched experimental activity-dependent slowing, a property not included in model optimization. We found that simple conduction responses, characterizing the action potential, were controlled by similar membrane properties in both the autonomic and cutaneous C-fiber models, but complicated conduction response, characterizing the afterpotenials, were controlled by differential membrane properties. The unmyelinated C-fiber models constitute important tools to study autonomic signaling, assess the mechanisms of pain, and design bioelectronic devices. Additionally, the novel reverse engineering approach can be applied to generate models of other neurons where voltage clamp data are not available.

Nonamyloidogenic TTR gene variants c.76G>A and c.337-18G>C are not associated with idiopathic small-fiber neuropathy.

Small-fiber neuropathy (SFN) affects only unmyelinated and thin myelinated fibers. It may be caused by amyloidogenic mutations of the transthyretin (TTR) gene, but not all TTR gene variants are pathogenic. The nonamyloidogenic c.76G>A (rs1800458) and c.337-18G>C (rs36204272) variants of TTR were recently reported to be associated with SFN. We investigated this putative association by analyzing TTR gene sequencing data retrospectively for two cohorts of patients, one with SFN and a control group. In this retrospective single-center study, we analyzed the frequency of the c.76G>A and c.337-18G>C TTR gene variants in a cohort of patients meeting a strict definition of SFN, with or without dysautonomia, a control cohort of patients investigated for nonneurological conditions, and the gnomAD international database. We included 55 SFN patients in this study, 17 of whom had dysautonomia. The allelic frequencies of the two variants in our cohort of 55 SFN patients were 7.27% for c.76G>A TTR and 5.25% for c.337-18G>C. The frequencies of both variants were statistically similar in the 337 control patients and the gnomAD database. The c.76G>A and c.337-18G>C TTR gene variants are not associated with SFN.

Maternal exposure to low-dose bisphenol A and its potential neurotoxic impact on male pups: A histological, immunohistochemical, and ultrastructural study

BackgroundBisphenol A (BPA) is a widely used chemical with a harmful effect on animal and human. The neonatal and juvenile period is a highly risky neurodevelopmental period. AimThis study aimed to determine how male albino rat pups’ cerebral cortex was altered by low doses of BPA given to mothers and the role of the oxidative stress. MethodsThirty pregnant rats were randomly split into three equal groups, negative control, and positive control: received 1 cc of corn oil once a day through gastric tube and BPA treated: a dose of 200 µg/kg/day (dissolved in 1 cc corn oil). The male rat pups of each group were sacrificed at 1 week, 3 weeks and 6 weeks. The cerebra were then separated from the brain for histological and biochemical studies. ResultsRats administered BPA had raised levels of lipid peroxidation marker (MDA), lower levels of enzymatic antioxidants (SOD and CAT) with decreased body, cerebral weights, and decreased levels of non-enzymatic antioxidant defense (GSH). Histo-pathologically, shrunken pyramidal cells with congested blood vessels appeared. GFAP displayed increased number of positive immune-reactive astrocytes with high statistically significant increase in the area % in BPA treated group when compared to the control groups, on contrary to MBP. Semi-thin and ultra-thin BPA-sections revealed degenerative changes in myelinated axons with tiny nucleus and broken nuclear membranes. Lysosomes, dilated endoplasmic reticulum cisternae with noticeable increase in unmyelinated nerve fibers were also observed. ConclusionThe structure of the developing cerebral cortex is negatively impacted by BPA due to oxidative stress.

Towards enhanced functionality of vagus neuroprostheses through in silico optimized stimulation

Bioelectronic therapies modulating the vagus nerve are promising for cardiovascular, inflammatory, and mental disorders. Clinical applications are however limited by side-effects such as breathing obstruction and headache caused by non-specific stimulation. To design selective and functional stimulation, we engineered VaStim, a realistic and efficient in-silico model. We developed a protocol to personalize VaStim in-vivo using simple muscle responses, successfully reproducing experimental observations, by combining models with trials conducted on five pigs. Through optimized algorithms, VaStim simulated the complete fiber population in minutes, including often omitted unmyelinated fibers which constitute 80% of the nerve. The model suggested that all Aα-fibers across the nerve affect laryngeal muscle, while heart rate changes were caused by B-efferents in specific fascicles. It predicted that tripolar paradigms could reduce laryngeal activity by 70% compared to typically used protocols. VaStim may serve as a model for developing neuromodulation therapies by maximizing efficacy and specificity, reducing animal experimentation.

Neuro-microcirculatory interrelationships in patients with kyphoscoliosis associated with neurological deficits

Background: The use of laser Doppler flowmetry with spectral wavelet analysis of blood flow fluctuations allows us to assess the functional state of thin unmyelinated nerve fibers and objectify the dynamics of recovery processes in patients with kyphoscoliotic spinal deformities associated with spinal cord compression. AIM: To study the features of neuromicrocirculatory relationships in patients with kyphoscoliosis associated with neurological deficits before and after surgical treatment. MATERIALS AND METHODS: 20 patients with spinal deformities associated with neurological deficits of varying severity were examined using the LDF method and operated on. Patients were examined before surgery, 1–2 weeks after surgery following regression of acute postoperative pain syndrome, 3–6 months, 6–12 months, and more than a year after surgery. The scope of the study included a general examination with a detailed assessment of the neurological status, radiation diagnostics (postural radiographs of the spine, computed tomography and magnetic resonance imaging of the spine with assessment of spinal canal stenosis). Patients with severe kyphoscoliotic deformities underwent CT myelography followed by the design of individual full-size 3D plastic models of the spine and myeloradicular structures. LDF with wavelet analysis was carried out at all periods of the survey. A perfusion study with determination of the average microcirculation was carried out at the level of the pad of the distal phalanx of the big toe using a two-channel LAKK-02 device with a semiconductor laser (sensing in the red Raman and infrared IR channels). The obtained LDF results were processed by spectral amplitude-frequency wavelet analysis to characterize microcirculation regulation factors in the ranges of sympathetic adrenergic regulation (0.02–0.046 Hz), sensory peptidergic influences (0.047–0.069 Hz), myogenic oscillations (0.07–0.145 Hz). RESULTS: After surgery, the activity of trophotropic sensory peptidergic nerve fibers, the values of perfusion of the microcirculatory channel increased and was maintained starting from the early postoperative period. Ergotropic sympathetic adrenergic activity was significantly decreased in the period of 6-12 months after surgery. Maximum mobilization of trophotropic neurogenic mechanisms of sanogenesis was observed in the period of 6-12 months after surgery. CONCLUSION: The obtained data indicate a significant participation of thin nerve fibers in the recovery processes after decompressive surgeries in the spinal canal zone and the creation of anatomical conditions for neurophysiological repair at the spinal cord level. The use of the LDF method with spectral wavelet analysis of blood flow fluctuations makes it possible to objectify the dynamics of thin unmyelinated nerve fibers and recovery processes in patients with kyphoscoliotic deformities of the spine associated with spinal cord compression.

Activity-dependent extracellular potassium changes in unmyelinated versus myelinated areas in olfactory regions of the isolated female guinea-pig brain

The potassium released in the extracellular space during neuronal activity is rapidly removed by glia and neurons to maintain tissue homeostasis. Oligodendrocyte-derived myelin axonal coating contributes to potassium buffering and is therefore crucial to control brain excitability.We studied activity-dependent extracellular potassium ([K+]o) changes in the piriform cortex (PC), a region that features highly segregated bundles of myelinated and unmyelinated fibers. Four-aminopyridine (4AP; 50 μM) treatment or patterned high-frequency stimulations (hfST) were utilized to generate [K+]o changes measured with potassium-sensitive electrodes in the myelinated lateral olfactory tract (LOT), in the unmyelinated PC layer I and in the myelinated deep PC layers in the ex vivo isolated guinea-pig brain.Seizure-like events induced by 4AP are initiated by the abrupt [K+]o rise in the layer I formed by unmyelinated fibers (Uva et al., 2017). Larger [K+]o shifts occurred in unmyelinated layers compared to the myelinated LOT. LOT hfST that mimicks pre-seizure discharges also generated higher [K+]o changes in unmyelinated PC layer I than in LOT and deep PC layers. The treatment with the Kir4.1 potassium channel blocker BaCl2 (100 μM) enhanced the [K+]o changes generated by hfST in myelinated structures.Our data show that activity-dependent [K+]o changes are intrinsically different in myelinated vs unmyelinated cortical regions. The larger [K+]o shifts generated in unmyelinated structures may represent a vehicle for seizure generation.

Gut microbiota depletion delays somatic peripheral nerve development and impairs neuromuscular junction maturation

ABSTRACT Gut microbiota is responsible for essential functions in human health. Several communication axes between gut microbiota and other organs via neural, endocrine, and immune pathways have been described, and perturbation of gut microbiota composition has been implicated in the onset and progression of an emerging number of diseases. Here, we analyzed peripheral nerves, dorsal root ganglia (DRG), and skeletal muscles of neonatal and young adult mice with the following gut microbiota status: a) germ-free (GF), b) gnotobiotic, selectively colonized with 12 specific gut bacterial strains (Oligo-Mouse-Microbiota, OMM12), or c) natural complex gut microbiota (CGM). Stereological and morphometric analyses revealed that the absence of gut microbiota impairs the development of somatic median nerves, resulting in smaller diameter and hypermyelinated axons, as well as in smaller unmyelinated fibers. Accordingly, DRG and sciatic nerve transcriptomic analyses highlighted a panel of differentially expressed developmental and myelination genes. Interestingly, the type III isoform of Neuregulin1 (NRG1), known to be a neuronal signal essential for Schwann cell myelination, was overexpressed in young adult GF mice, with consequent overexpression of the transcription factor Early Growth Response 2 (Egr2), a fundamental gene expressed by Schwann cells at the onset of myelination. Finally, GF status resulted in histologically atrophic skeletal muscles, impaired formation of neuromuscular junctions, and deregulated expression of related genes. In conclusion, we demonstrate for the first time a gut microbiota regulatory impact on proper development of the somatic peripheral nervous system and its functional connection to skeletal muscles, thus suggesting the existence of a novel ‘Gut Microbiota-Peripheral Nervous System-axis.’

Study on the relationship between peripheral nerve fiber types and levodopa usage in Parkinson's disease.

<p>The aim of this study is to comprehensively determine the types of affected fibers in Parkinson&rsquo;s disease (PD) patients by employing nerve conduction studies (NCS), sympathetic skin response (SSR) examinations, and current perception threshold (CPT) testing and to analyze the correlation between levodopa use and nerve involvement.</p>. <p>This retrospective study included 36 clinically diagnosed PD patients who were recruited between January 2018 and April 2019. All patients underwent NCS, SSR testing, and CPT sensory examinations. Additionally, the PD patients were assessed for disease staging using the Hoehn and Yahr (H-Y) scale.&nbsp;</p>. <p>Fifteen patients were included in the tremor-dominant subtype, ten patients in the rigid-dominant subtype, and eleven patients in the mixed subtype. Eleven patients were using levodopa, while twenty-five patients had never used any anti-Parkinson&rsquo;s medication. Ten patients (28%) showed abnormal sympathetic skin responses (SSR). The CPT examination revealed sensory abnormalities in twenty-four patients (67%), with eighteen patients (75%) experiencing sensory hypersensitivity and six patients (25%) experiencing sensory hypoesthesia. Twelve patients (33%) had normal CPT results. Among the patients with abnormal CPT findings, seven cases (29%) involved large myelinated fiber damage, twenty-two cases (92%) involved small myelinated fiber damage, and nineteen cases (79%) involved unmyelinated fiber damage. The rate of sensory abnormalities was 64% (7/11) in the levodopa group and 68% (17/25) in the non-levodopa group, with no statistically significant difference between the two groups.&nbsp;</p>. <p>The incidence of abnormal CPT findings in PD patients was higher than that of abnormal SSR responses, suggesting that nerve fiber damage primarily affects small fiber nerves (SFN).</p>.

Selective intrafascicular stimulation of myelinated and unmyelinated nerve fibers through a longitudinal electrode: A computational study

Carbon nanotube (CNT) fiber electrodes have demonstrated exceptional spatial selectivity and sustained reliability in the context of intrafascicular electrical stimulation, as evidenced through rigorous animal experimentation. A significant presence of unmyelinated C fibers, known to induce uncomfortable somatosensory experiences, exists within peripheral nerves. This presence poses a considerable challenge to the excitation of myelinated Aβ fibers, which are crucial for tactile sensation. To achieve nuanced tactile sensory feedback utilizing CNT fiber electrodes, the selective stimulation of Aβ sensory afferents emerges as a critical factor.In confronting this challenge, the present investigation sought to refine and apply a rat sciatic-nerve model leveraging the capabilities of the COMSOL-NEURON framework. This approach enables a systematic evaluation of the influence exerted by stimulation parameters and electrode geometry on the activation dynamics of both myelinated Aβ and unmyelinated C fibers. The findings advocate for the utilization of current pulses featuring a pulse width of 600 μs, alongside the deployment of CNT fibers characterized by a diminutive diameter of 10 μm, with an exclusively exposed cross-sectional area, to facilitate reduced activation current thresholds. Comparative analysis under monopolar and bipolar electrical stimulation conditions revealed proximate activation thresholds, albeit with bipolar stimulation exhibiting superior fiber selectivity relative to its monopolar counterpart. Concerning pulse waveform characteristics, the adoption of an anodic-first biphasic stimulation modality is favored, taking into account the dual criteria of activation threshold and fiber selectivity optimization. Consequently, this investigation furnishes an efficacious stimulation paradigm for the selective activation of touch-related nerve fibers, alongside provisioning a comprehensive theoretical foundation for the realization of natural tactile feedback within the domain of prosthetic hand applications.

Mentalis nerve branches supplying the lower lip revisited: a study of human fetuses and donated elderly cadavers.

Little information is known about the mentalis nerve course from the lower lip approximation margin (free margin) to the upper lip. Likewise, no difference in nerve distribution has been observed between the cutaneous and mucosal parts of the lip. Therefore, this study reexamined mentalis nerve morphology. For macroscopic observations, three fresh cadavers were dissected (one male and two females; aged 78-93). We also evaluated histological sections obtained from five donated elderly cadavers (two males and three females, aged 82-96 years) and 15 human fetuses (11-40 weeks or crown-rump length 80-372mm). Immunohistochemical analysis for S100 protein and tyrosine hydroxylase was performed. In both fetuses and adult cadavers, one to three nerve branches ran upward in the submucosal tissue from the mental foramen. Near the free margin of the lip, some branches passed through the orbicularis oris muscle layer toward the lip skin, whereas others followed a reversed J-shaped course along the free margin. Nerve twigs ran in parallel beneath the mucosa, whereas wavy nerve twigs attached to the basal lamina of the lip epidermis. The difference in nerve endings abruptly occurred at the skin-mucosal junction. Tyrosine hydroxylase-positive sympathetic nerve twigs surrounded arteries and formed a branch composed of S100-negative unmyelinated fibers. The lower lip skin was innervated by a perforating branch passing through the orbicularis oris muscle, that was different from the lip mucosa. A sudden change in the nerve ending configuration at the mucocutaneous junction seemed to develop postnatally.

Evolutionarily conserved neural responses to affective touch in monkeys transcend consciousness and change with age

Affective touch-a slow, gentle, and pleasant form of touch-activates a different neural network than which is activated during discriminative touch in humans. Affective touch perception is enabled by specialized low-threshold mechanoreceptors in the skin with unmyelinated fibers called C tactile (CT) afferents. These CT afferents are conserved across mammalian species, including macaque monkeys. However, it is unknown whether the neural representation of affective touch is the same across species and whether affective touch's capacity to activate the hubs of the brain that compute socioaffective information requires conscious perception. Here, we used functional MRI to assess the preferential activation of neural hubs by slow (affective) vs. fast (discriminative) touch in anesthetized rhesus monkeys (Macaca mulatta). The insula, anterior cingulate cortex (ACC), amygdala, and secondary somatosensory cortex were all significantly more active during slow touch relative to fast touch, suggesting homologous activation of the interoceptive-allostatic network across primate species during affective touch. Further, we found that neural responses to affective vs. discriminative touch in the insula and ACC (the primary cortical hubs for interoceptive processing) changed significantly with age. Insula and ACC in younger animals differentiated between slow and fast touch, while activity was comparable between conditions for aged monkeys (equivalent to >70 y in humans). These results, together with prior studies establishing conserved peripheral nervous system mechanisms of affective touch transduction, suggest that neural responses to affective touch are evolutionarily conserved in monkeys, significantly impacted in old age, and do not necessitate conscious experience of touch.

AxoDetect: an automated nerve image segmentation and quantification workflow for computational nerve modeling

Objective. Bioelectronic treatments targeting near-organ innervation have unprecedented clinical applications. Particularly in the spleen, the inhibition of the cholinergic inflammatory response by near-organ nerve stimulation has potential to replace pharmacological treatments in chronic and autoimmune diseases. A caveat is that the optimization of therapeutic stimulation parameters relies on in vivo experimentation, which becomes challenging due to the small nerve diameters (2 μ m), complex anatomy, and mixed axon type composition of the autonomic nerves. Effective development of in silico models requires tools which allow for fast and efficient quantification of axonal composition of specific nerves. Current approaches to generate such information rely on manual image segmentation and quantification. Approach. We developed a combined image-segmentation and model-generation software called AxoDetect: a target- and format-agnostic computer vision algorithm which can segment myelin, endo/epineurium, and both myelinated and unmyelinated fibers from a nerve image without training. Main results. AxoDetect is over 10 times faster on average when compared with current automatic methods while maintaining flexibility through the use of tunable pixel threshold filters to detect different types of tissue. When compared to a distribution-based and a manually segmented model of the splenic nerve terminal branch 1, the model generated with AxoDetect had comparable threshold prediction and was able to accurately detect an increase in activation threshold caused by the addition of surrounding fat tissue to the modeled nerve. Significance. AxoDetect contributes to the acceleration of neuromodulation treatment development through faster model design and iteration without requiring training. Furthermore, the computer vision approach and tunable nature of the filters in our method allow for its use in a variety of histological applications. Our approach will impact not only the study of nerves but also the design of implantable neural interfaces to enhance bioelectronic therapeutic options.

Computational models of compound nerve action potentials: Efficient filter-based methods to quantify effects of tissue conductivities, conduction distance, and nerve fiber parameters.

Peripheral nerve recordings can enhance the efficacy of neurostimulation therapies by providing a feedback signal to adjust stimulation settings for greater efficacy or reduced side effects. Computational models can accelerate the development of interfaces with high signal-to-noise ratio and selective recording. However, validation and tuning of model outputs against in vivo recordings remains computationally prohibitive due to the large number of fibers in a nerve. We designed and implemented highly efficient modeling methods for simulating electrically evoked compound nerve action potential (CNAP) signals. The method simulated a subset of fiber diameters present in the nerve using NEURON, interpolated action potential templates across fiber diameters, and filtered the templates with a weighting function derived from fiber-specific conduction velocity and electromagnetic reciprocity outputs of a volume conductor model. We applied the methods to simulate CNAPs from rat cervical vagus nerve. Brute force simulation of a rat vagal CNAP with all 1,759 myelinated and 13,283 unmyelinated fibers in NEURON required 286 and 15,860 CPU hours, respectively, while filtering interpolated templates required 30 and 38 seconds on a desktop computer while maintaining accuracy. Modeled CNAP amplitude could vary by over two orders of magnitude depending on tissue conductivities and cuff opening within experimentally relevant ranges. Conduction distance and fiber diameter distribution also strongly influenced the modeled CNAP amplitude, shape, and latency. Modeled and in vivo signals had comparable shape, amplitude, and latency for myelinated fibers but not for unmyelinated fibers. Highly efficient methods of modeling neural recordings quantified the large impact that tissue properties, conduction distance, and nerve fiber parameters have on CNAPs. These methods expand the computational accessibility of neural recording models, enable efficient model tuning for validation, and facilitate the design of novel recording interfaces for neurostimulation feedback and understanding physiological systems.

Characterizing Acute-Onset Small Fiber Neuropathy.

Immune-mediated small fiber neuropathy (SFN) is increasingly recognized. Acute-onset SFN (AOSFN) remains poorly described. Herein, we report a series of AOSFN cases in which immune origins are debatable. We included consecutive patients with probable or definite AOSFN. Diagnosis of SFN was based on the NEURODIAB criteria. Acute onset was considered when the maximum intensity and extension of both symptoms and signs were reached within 28 days. We performed the following investigations: clinical examination, neurophysiologic assessment encompassing a nerve conduction study to rule out large fiber neuropathy, laser-evoked potentials (LEPs), warm detection thresholds (WDTs), electrochemical skin conductance (ESC), epidermal nerve fiber density (ENF), and patient serum reactivity against mouse sciatic nerve teased fibers, mouse dorsal root ganglion (DRG) sections, and cultured DRG. The serum reactivity of healthy subjects (n = 10) and diseased controls (n = 12) was also analyzed. Data on baseline characteristics, biological investigations, and disease course were collected. Twenty patients presenting AOSFN were identified (60% women; median age: 44.2 years [interquartile range: 35.7-56.2]). SFN was definite in 18 patients (90%) and probable in 2 patients. A precipitating event was present in 16 patients (80%). The median duration of the progression phase was 14 days [5-28]. Pain was present in 17 patients (85%). Twelve patients (60%) reported autonomic involvement. The clinical pattern was predominantly non-length-dependent (85%). Diagnosis was confirmed by abnormal LEPs (60%), ENF (55%), WDT (39%), or ESC (31%). CSF analysis was normal in 5 of 5 patients. Antifibroblast growth factor 3 antibodies were positive in 4 of 18 patients (22%) and anticontactin-associated protein-2 antibodies in one patient. In vitro studies showed IgG immunoreactivity against nerve tissue in 14 patients (70%), but not in healthy subjects or diseased controls. Patient serum antibodies bound to unmyelinated fibers, Schwann cells, juxtaparanodes, paranodes, or DRG. Patients' condition improved after a short course of oral corticosteroids (3/3). Thirteen patients (65%) showed partial or complete recovery. Others displayed relapses or a chronic course. AOSFN primarily presents as an acute, non-length-dependent, symmetric painful neuropathy with a variable disease course. An immune-mediated origin has been suggested based on in vitro immunohistochemical studies.