Peripheral Fibers Research Articles

Cortical responses to C-fiber stimulation by intra-epidermal electrical stimulation: An MEG study

Intra-epidermal electric stimulation (IES) is an alternative to laser stimulation for selective activation of cutaneous Aδ-fibers. IES is based on the fact that nociceptive fiber terminals are located in the epidermis, whereas receptors of other fibers end deep in the dermis. IES can selectively stimulate C-fibers if the electrode structure and stimulation parameters are carefully selected. However, stable selective stimulation of C-fibers using IES has proven difficult and cannot currently be used in clinical settings. The purpose of the present study was to determine if IES performed using a modified electrode reliably stimulates C-fibers. Magnetoencephalographic responses to IES to the foot were measured in seven healthy subjects. IES elicited somatosensory evoked fields in all subjects. The mean peak latency was 1327±116ms in the opercular region contralateral to the stimulated side, 1318±90ms in the opercular region ipsilateral to the stimulated side, and 1350±139ms in the primary somatosensory cortex. These results indicate that IES performed using the modified electrode can selectively stimulate C-fibers and may be a useful tool for pain research as well as clinical evaluation of peripheral small fiber function.

NGF-induced mechanical sensitization of the masseter muscle is mediated through peripheral NMDA receptors

Intramuscular injection of nerve growth factor (NGF) in healthy humans mimics some of the symptoms of myofascial temporomandibular disorders (M-TMD). We hypothesized that NGF induces a prolonged myofascial mechanical sensitization by increasing peripheral N-methyl-d-aspartate (NMDA) receptor expression, leading to an enhanced response of muscle nociceptors to endogenous glutamate. Behavioral experiments with an injection of NGF (25μg/ml, 10μl) into the masseter muscle reduced the mechanical withdrawal threshold for 1day in male rats and 5days in female rats. These results mirror the sex-related differences found in NGF-induced mechanical sensitization in humans. Intramuscular injection with the competitive NMDA receptor antagonist dl-2-amino-5-phosphonovaleric acid (APV, 0.020g/ml, 10μl) reversed the mechanical sensitization in male but not in female rats. NGF increased the number of NMDA receptor subtype 2B (NR2B)-expressing rat trigeminal masseter ganglion neurons in both sexes, which peaked at 3days post injection. There was an association between the levels of NR2B expression and NGF-induced mechanical sensitization. The average soma size of NR2B-expressing neurons increased significantly. Increased expression of neuropeptides (CGRP and SP) was observed in NR2B-expressing masseter ganglion neurons in female but not in male rats. In healthy men and women, comparable basal expression levels of NR2B and SP were found in peripheral fibers from masseter muscle microbiopsies. This study suggests that NGF-induced sensitization of masseter nociceptors is mediated, in part, by enhanced peripheral NMDA receptor expression. Measurement of peripheral NMDA receptor expression may be useful as a biomarker for M-TMD pain.

Mechanical principles of effects of botulinum toxin on muscle length–force characteristics: An assessment by finite element modeling

Recent experiments involving muscle force measurements over a range of muscle lengths show that effects of botulinum toxin (BTX) are complex e.g., force reduction varies as a function of muscle length. We hypothesized that altered conditions of sarcomeres within active parts of partially paralyzed muscle is responsible for this effect. Using finite element modeling, the aim was to test this hypothesis and to study principles of how partial activation as a consequence of BTX affects muscle mechanics. In order to model the paralyzing effect of BTX, only 50% of the fascicles (most proximal, or middle, or most distal) of the modeled muscle were activated. For all muscle lengths, a vast majority of sarcomeres of these BTX-cases were at higher lengths than identical sarcomeres of the BTX-free muscle. Due to such “longer sarcomere effect”, activated muscle parts show an enhanced potential of active force exertion (up to 14.5%). Therefore, a muscle force reduction originating exclusively from the paralyzed muscle fiber populations, is compromised by the changes of active sarcomeres leading to a smaller net force reduction. Moreover, such “compromise to force reduction” varies as a function of muscle length and is a key determinant of muscle length dependence of force reduction caused by BTX. Due to longer sarcomere effect, muscle optimum length tends to shift to a lower muscle length. Muscle fiber–extracellular matrix interactions occurring via their mutual connections along full peripheral fiber lengths (i.e., myofascial force transmission) are central to these effects. Our results may help improving our understanding of mechanisms of how the toxin secondarily affects the muscle mechanically.

Mathematical Model of Nerve Fiber Activation During Low Back Peripheral Nerve Field Stimulation: Analysis of Electrode Implant Depth

The lower back is the most common location of pain experienced by one-fifth of the European population reporting chronic pain. A peripheral nerve field stimulation system, which involves electrodes implanted subcutaneously in the painful area, has been shown to be efficacious for low back pain. Moreover, the predominant analgesic mechanism of action is thought to be via activation of peripheral Aβ fibers. Unfortunately, electrical stimulation also might coactivate Aδ fibers, causing pain or unpleasantness itself. The aim of this study was to investigate at which implant depth Aβ-fiber stimulation is maximized, and Aδ-fiber minimized, which in turn should lead to therapy optimization. A finite element model was used to estimate the electrical potential generated by a bipolar single-lead electrode implanted in the subcutaneous adipose tissue at depths of 5 mm to 30 mm below the skin surface. The model includes low back tissue; the epidermis, dermis, adipose, and muscle layers, and nerve fibers, which were programmed to branch randomly in the model in a fiber type-specific manner. Likewise, activation thresholds were specific to Aβ- and Aδ-fiber types and were estimated using a passive cable model. The stimulus-response functions showed that the skin area covered by Aβ-fiber activation was larger than the area covered by Aδ-fiber activation at all depths and all intensities. The skin area covered by Aδ-fiber activation was largest when the electrode was modeled to have a superficial location (5 mm below the skin surface), while the skin area covered by Aβ-fiber activation was largest at lower depths. The present mathematical model predicts an optimal implantation depth of 10 to 15 mm below the skin surface to achieve activation of the greatest area of Aβ fibers and the smallest area of Aδ fibers. This finding may act as a guide for peripheral nerve field stimulation implant depth to treat low back pain.

Now is the Right Time to Establish a New Strategy for Managing Chronic Cough as a Neuropathic Disorder.

Now is the Right Time to Establish a New Strategy for Managing Chronic Cough as a Neuropathic Disorder.

Pain and discomfort management during central venous catheter insertion

Pain and discomfort management during central venous catheter insertion

Design of smart functional electric stimulator for physically challenged person

Paralysed muscles can regain their contraction by providing intact peripheral motor nerves, electrical stimulation. To elicit the muscle contraction of the peripheral nerves fibres may be achieved by activation of motor efferent or through reflex pathways by activation of sensory-afferent nerve fibres. The technique may also include activation of sensory nerve fibres for the purpose of eliciting a perceived response in the skin, which may be used to provide sensory clues to the non-sensory extremity. In more than 40 years of FES research, principles for safe stimulation of neuromuscular tissue have been established, and methods for modulating the strength of electrically induced muscle contractions have been discovered. The FES is a rehabilitation strategy which applies electrical current to the nerves that controls paralysed muscles in order to stimulate functional movement. Functional electrical stimulation includes both therapeutic applications and applications to obtain functional restoration of movement. Functional restoration of movement includes applications to enhance manipulation in the upper extremity or locomotion in the lower extremity.

TRPV1 antagonist attenuates postoperative hypersensitivity by central and peripheral mechanisms.

BackgroundAcute postoperative pain is one of the frequent reasons for pain treatment. However, the exact mechanisms of its development are still not completely clear. Transient receptor potential vanilloid 1 (TRPV1) receptors are involved in nociceptive signaling in various hypersensitive states. Here we have investigated the contribution of TRPV1 receptors expressed on cutaneous peripheral nociceptive fibers and in the spinal cord on the development and maintenance of hypersensitivity to thermal and mechanical stimuli following surgical incision. A rat plantar incision model was used to test paw withdrawal responses to thermal and mechanical stimuli. The effect of the TRPV1 receptor antagonist SB366791 was investigated 1) by intrathecal injection 15 min before incision and 2) intradermal injection before (30 min) and immediately after the surgery. Vehicle-injected rats and naïve animals treated identically were used as controls.ResultsPlantar incision induced mechanical allodynia and hyperalgesia and thermal hyperalgesia. A single intrathecal administration of SB366791 significantly reduced postincisional thermal hyperalgesia and also attenuated mechanical allodynia, while mechanical hyperalgesia remained unaffected. Local intradermal SB366791 treatment reduced thermal hyperalgesia and mechanical allodynia without affecting mechanical hyperalgesia.ConclusionsOur experiments suggest that both peripheral and spinal cord TRPV1 receptors are involved in increased cutaneous sensitivity following surgical incision. The analgesic effect of the TRPV1 receptor antagonist was especially evident in the reduction of thermal hyperalgesia. The activation of TRPV1 receptors represents an important mechanism in the development of postoperative hypersensitivity.

The Brain-Gut Axis: From Pathophysiology to Possible Future Strategies of Treatment

The enteric nervous system (ENS) controls and modulates various functions of the digestive tract such as motility, exocrine and endocrine secretion, local microcirculation, inflammation and neuroimmunity. This system is autonomous from the central nervous system (CNS), although they share many neurons and neurotransmitters. The CNS may exert a modulatory role on ENS through brainstem and subcortical areas, peripheral and autonomic fibers. The brain-gut axis is the complex system regulating the interactions and mutual influences between the nervous system and the gut. This axis is divided into various levels through receptors, afferents, integration centers, efferents and effectors, and exploits multiple messengers belonging to the nervous, immune and endocrine systems. The proper functioning of this apparatus is essential in intestinal physiology, its involvement has been recognized as one of the leading pathophysiological basis of many digestive disorders and a target for current and future therapeutical approaches.

Animal Models of Peripheral Neuropathy: Modeling What We Feel, Understanding What They Feel

A lmost everyone has experienced the severe discomfort associated with hitting the “funny bone,” the pushing of the humerus distal medial epicondyle against the ulnar nerve. There is nothing amusing, however, about neuropathic pains and paresthesias that occur chronically, as with peripheral neuropathy. This issue of the Journal details the science of peripheral neuropathy as discovered through animal models. This introduction highlights the clinical description of peripheral neuropathy in order to center on the challenges of constructing animal models. Peripheral neuropathy (PN) is a pervasive and complex condition affecting approximately 20 million people in the United States and more than 10% of persons aged 40 years or older (Gregg et al. 2004). PN encompasses a variety of etiologies and manifestations. The majority are acquired consequences of other conditions or processes. Table 1 summarizes some of the causes or contributors to PN. About one third of cases are considered to be idiopathic (Dyck et al. 1981). Many patients diagnosed with idiopathic PN have abnormal glucose tolerance tests or elevated fasting glucose levels and are considered to be prediabetic (Smith and Singleton 2013). Hypertriglyceridemia and obesity without diabetes also may be important etiologic or contributing factors in humans (Tesfaye et al. 2010) and rodents (Vincent et al. 2009). Diabetes mellitus is the most common identified cause of PN, and 60–70% of the current 26 million diabetics (Centers for Disease Control and Prevention 2011) have some degree of neuropathy. The increasing worldwide prevalence of metabolic syndrome and its associated conditions, including diabetes, suggest that PN will continue to be an important clinical subject. Mitochondrial abnormalities related to oxidative stress from hyperglycemia or hyperlipidemia are hypothesized to play an important role in diabetic PN (Picard and Turnball 2013; Sleigh et al. 2011). The use of pharmaceuticals (nucleoside/nucleotide reverse transcriptase inhibitors and cancer chemotherapy compounds) that target mitochondria is also associated with development or worsening of PN (Leung 2012; Xiao and Bennett 2012). Whether mitochondrial damage is a common mechanism in all PN remains to be determined. Without question, animal models will continue to be important in unraveling the pathobiology of PN. The most common type of PN is distal symmetrical sensorimotor polyneuropathy, which occurs in diabetes, with diminished thermal and vibratory sensation leading to sensory loss and eventually involving pain and autonomic fibers (Tesfaye et al. 2010). With PN, clinical symptoms depend on the predilection of causative conditions to target particular peripheral fiber types (sensory, motor, autonomic, or different permutations of these three) and the type of stimulus that activates each nociceptor (e.g., thermal or mechanical). Assorted regions and functions of the peripheral neuron are affected, whether by direct injury or genetic predisposition, including dorsal root ganglion cation channel signaling (Staaf et al. 2009), axon transport (Holzbauer and Scherer 2011), and myelin sheath formation (Robinson et al. 2008). Clinically, a continuum of symptoms can occur, ranging from muscle weakness, spasticity, hyporeflexia, burning-type or aching pain, hyperalgesias, hypoalgesias, allodynia, dysesthesias, paresthesias, anesthesia in the hands and feet, poor proprioception, and hypotension to cardiac conduction abnormalities. Sensorimotor and sensory neuropathies occur more frequently than autonomic neuropathy, which may affect bowel function, bladder emptying, heart rate variation, and blood pressure controls. Human peripheral nervous system (PNS) perturbations lead to sensations that are episodic, paroxysmal, or constant, as well as evoked or spontaneous sensations, a spectrum of situations that render preclinical modeling problematic. Joanna Brell, MD, is Program Director in the Division of Cancer Prevention, National Cancer Institute, at the National Institutes of Health in Bethesda, MD. Address correspondence and reprint requests to Dr. Joanna Brell at 9609 Medical Center Drive 5E436, Bethesda, MD 2892-9785 or email brelljm@ mail.nih.gov

Cx46 hemichannels contribute to the sodium leak conductance in lens fiber cells

The lens is proposed to have an internal microcirculation system consisting of continuously circulating ionic fluxes that play an essential role in maintaining lens transparency. One of the key components of this system is the sodium leak conductance. Here we investigate the contribution of Cx46 hemichannels to the basal membrane permeability of peripheral fiber cells isolated from transgenic mouse lenses lacking Cx50 or both Cx50 and Cx46 (dKO) using the whole cell patch-clamp technique. Our results show that Cx46 hemichannels were largely closed at a resting voltage of -60 mV in the presence of millimolar divalent cation concentrations. However, even though the vast majority of these channels were closed at -60 mV, a small, persistent, inward current could still be detected. This current could be mostly blocked by exposure to 1 mM La(3+) and was not observed in fiber cells isolated from dKO mouse lenses suggesting that it was due to Cx46 hemichannels. In addition, Cx50(-/-) fiber cells showed increased open channel noise and a depolarized resting potential compared with dKO fiber cells. Exposure of Cx50(-/-) fiber cells to La(3+) hyperpolarized the resting potential to -58 mV, which is similar to the value of resting potential measured in dKO fiber and significantly reduced the open channel noise. In conclusion, these results suggest that Cx46 hemichannels may contribute to the sodium leak conductance in lens fiber cells.

Artemin induced functional recovery and reinnervation after partial nerve injury

Systemic artemin promotes regeneration of dorsal roots to the spinal cord after crush injury. However, it is unclear whether systemic artemin can also promote peripheral nerve regeneration, and functional recovery after partial lesions distal to the dorsal root ganglion (DRG) remains unknown. In the present investigation, male Sprague Dawley rats received axotomy, ligation, or crush of the L5 spinal nerve or sham surgery. Starting the day of injury, animals received intermittent subcutaneous artemin or vehicle across 2weeks. Sensory thresholds to tactile or thermal stimuli were monitored for 6weeks after injury. Immunohistochemical analyses of the DRG and nerve regeneration were performed at the 6-week time point. Artemin transiently reversed tactile and thermal hypersensitivity after axotomy, ligation, or crush injury. Thermal and tactile hypersensitivity reemerged within 1week of treatment termination. However, artemin-treated rats with nerve crush, but not axotomy or ligation, subsequently showed gradual return of sensory thresholds to preinjury baseline levels by 6weeks after injury. Artemin normalized labeling for NF200, IB4, and CGRP in nerve fibers distal to the crush injury, suggesting persistent normalization of nerve crush-induced neurochemical changes. Sciatic and intradermal administration of dextran or cholera toxin B distal to the crush injury site resulted in labeling of neuronal profiles in the L5 DRG, suggesting regeneration functional restoration of nonmyelinated and myelinated fibers across the injury site into cutaneous tissue. Artemin also diminished ATF3 and caspase 3 expression in the L5 DRG, suggesting persistent neuroprotective actions. A limited period of artemin treatment elicits disease modification by promoting sensory reinnervation of distal territories and restoring preinjury sensory thresholds.

Inhibition of repulsive guidance molecule, RGMa, increases afferent synapse formation with auditory hair cells

The peripheral fibers that extend from auditory neurons to hair cells are sensitive to damage, and replacement of the fibers and their afferent synapse with hair cells would be of therapeutic interest. Here, we show that RGMa, a repulsive guidance molecule previously shown to play a role in the development of the chick visual system, is expressed in the developing, newborn, and mature mouse inner ear. The effect of RGMa on synaptogenesis between afferent neurons and hair cells, from which afferent connections had been removed, was assessed. Contact of neural processes with hair cells and elaboration of postsynaptic densities at sites of the ribbon synapse were increased by treatment with a blocking antibody to RGMa, and pruning of auditory fibers to achieve the mature branching pattern of afferent neurons was accelerated. Inhibition by RGMa could thus explain why auditory neurons have a low capacity to regenerate peripheral processes: postnatal spiral ganglion neurons retain the capacity to send out processes that respond to signals for synapse formation, but expression of RGMa postnatally appears to be detrimental to regeneration of afferent hair cell innervation and antagonizes synaptogenesis. Increased synaptogenesis after inhibition of RGMa suggests that manipulation of guidance or inhibitory factors may provide a route to increase formation of new synapses at deafferented hair cells.

Amyotrophic Lateral Sclerosis and Skeletal Muscle: An Update

Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease characterized by degeneration of upper and lower motor neurons (MNs), generalized weakness and muscle atrophy. The "neurocentric" view of ALS assumes that the disease primarily affects motor neurons, while muscle alterations only represent a consequence, in the periphery, of motor neuron loss. However, this outlook was recently challenged by evidence suggesting that non-neural cells such as microglia, astrocytes, peripheral blood mononuclear cells (PBMCs) and skeletal muscle fibres participate in triggering motor neuron degeneration, and this stressed the concept that alterations in different cell types may act together to exacerbate the disease. In this review, we will summarize the most recent findings on the alterations of skeletal muscle fibres found in ALS, with particular attention to the relationship between mutant SOD1 and skeletal muscle. We will analyze changes in muscle function, in the expression of myogenic regulatory factors, and also mitochondrial dysfunction, SOD1 aggregation and proteasome activity.

Potassium channels in peripheral pain pathways: expression, function and therapeutic potential.

Electrical excitation of peripheral somatosensory nerves is a first step in generation of most pain signals in mammalian nervous system. Such excitation is controlled by an intricate set of ion channels that are coordinated to produce a degree of excitation that is proportional to the strength of the external stimulation. However, in many disease states this coordination is disrupted resulting in deregulated peripheral excitability which, in turn, may underpin pathological pain states (i.e. migraine, neuralgia, neuropathic and inflammatory pains). One of the major groups of ion channels that are essential for controlling neuronal excitability is potassium channel family and, hereby, the focus of this review is on the K+ channels in peripheral pain pathways. The aim of the review is threefold. First, we will discuss current evidence for the expression and functional role of various K+ channels in peripheral nociceptive fibres. Second, we will consider a hypothesis suggesting that reduced functional activity of K+ channels within peripheral nociceptive pathways is a general feature of many types of pain. Third, we will evaluate the perspectives of pharmacological enhancement of K+ channels in nociceptive pathways as a strategy for new analgesic drug design.

Relationships between electrochemical skin conductance and kidney disease in Type 2 diabetes

BackgroundSUDOSCAN® non-invasively measures peripheral small fiber and autonomic nerve activity using electrochemical skin conductance. Since neuropathy and nephropathy are microvascular Type 2 diabetes (T2D) complications, relationships between skin conductance, estimated glomerular filtration rate (eGFR), and urine albumin:creatinine ratio (UACR) were assessed. MethodsTwo hundred five African Americans (AA) with T2D, 93 AA non-diabetic controls, 185 European Americans (EA) with T2D, and 73 EA non-diabetic controls were evaluated. Linear models were fitted stratified by population ancestry and T2D, adjusted for covariates. ResultsRelative to EA, AA had lower skin conductance (T2D cases p<0.0001; controls p<0.0001). Skin conductance was also lower in T2D cases vs. controls in each population (p<0.0001, AA and EA). Global skin conductance was significantly associated with eGFR in AA and EA with T2D; adjusting for age, gender, BMI, and HbA1c, positive association was detected between skin conductance and eGFR in AA T2D cases (parameter estimate 3.38, standard error 1.2; p=5.2E−3), without association in EA T2D cases (p=0.22). ConclusionsNoninvasive measurement of skin conductance strongly associated with eGFR in AA with T2D, replicating results in Hong Kong Chinese. SUDOSCAN® may prove useful as a low cost, non-invasive screening tool to detect undiagnosed diabetic kidney disease in populations of African ancestry.

PL.04.01 Autoimmune processes in encephalopathy: a promise for treatment of psychiatric disorders

with somatoform pain disorders and with depression. We hypothesized that patients with fibromyalgia syndrome have disturbed processing of painful stimuli in the peripheral as well as in the central nervous system. Using near infrared spectroscopy (NIRS) we investigated cerebral activation upon painful stimuli. The main finding was that in spite of lower pressure pain thresholds FMS patients had increased bilateral cortical activation compared to controls. They also had a stronger contralateral activity over the dorsolateral prefrontal cortex in comparison with depressive patients. In a second study [2], we investigated the peripheral nervous system and afferent fiber tracts using three methods: quantitative sensory testing (QST), A-delta fiber evoked potentials, and intraepidermal nerve fiber density in skin biopsies. Patients with FMS but not patients with depression had impaired small fiber function in QST. A-delta evoked potentials had increased N1 latencies upon stimulation at the feet and reduced amplitudes upon stimulation at face, hands, and feet in fibromyalgia patients compared to patients with depression and to controls, indicating abnormalities of small fibers or their central afferents. In skin biopsies intraepidermal nerve fibers at the leg were reduced in patients with fibromyalgia syndrome. All three methods used support the concept of impaired small fiber function in patients with FMS, pointing towards a neuropathic component of their pain that may dynamically evoke and maintain central sensitization.

Peripheral neuropathy (PN) and small fiber (autonomic) dysfunction in patients with Parkinson's disease (PD) and parkinsonism

Peripheral neuropathy (PN) and small fiber (autonomic) dysfunction in patients with Parkinson's disease (PD) and parkinsonism

Differences in age‐related effects on myelinated and unmyelinated peripheral fibres: A sensitivity and evoked potentials study

Experimental data regarding age effects on sensitivity and pain thresholds are not always consistent, with the type of stimulus being a major source of variability. This could suggest that some types of peripheral sensory fibres undergo more important modifications with age than others. We investigated whether ageing affects differently myelinated and unmyelinated fibres. Somatosensitivity and pain perception and recorded somatosensory evoked potentials (SEPs) were assessed in younger and older adults during the selective activation of either myelinated Aδ- or unmyelinated C-fibres. Somatosensitivity for information transmitted and SEPs elicited by stimulation of C-fibres did not differ between both groups. In contrast, pain perception was lower in older than in younger adults, and older adults showed longer SEP latencies and reduced peak-to-peak amplitude, during selective stimulation of Aδ-fibres. These findings suggest that myelinated Aδ-fibres are compromised by the normal ageing process, whereas unmyelinated C-fibres seem to remain unaltered or, at least, less affected.

All-optical controlled switching in centrally coupled circular array of nonlinear optical fibers

We show that, in a nonlinear centrally coupled circular array of evanescently coupled fibers, the coupling dynamics of a weak signal beam can be efficiently influenced by a high-power control beam that induces nonlinear defects. When the intense control beam is launched into the central core and one core in the periphery, then localized solitons are formed and cause the fibers with induced defects (defected fibers) to decouple from the other array elements. In the presence of a high-intensity control beam, the propagation of weak signal is restricted to the defected optical fibers. The weak signal periodically couples between the induced defects. This oscillatory behavior depends on the sign of the (Kerr-type) nonlinearity and the initial phase difference between the control fields injected to the central and one of the peripheral fibers. This all-optical network has the advantage of routing and switching the weak signal field in a controlled way by adjusting the parameters of intense control field.