Monitoring of macrophage recruitment enhanced by Toll‐like receptor 4 activation with MR imaging in nerve injury

Introduction: Macrophage recruitment is critical for nerve regeneration after an injury. The aim of this study was to investigate whether ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle‐based MRI could be used to monitor the enhanced macrophage recruitment by Toll‐like receptor 4 (TLR4) activation in nerve injury. Methods: Rats received intraperitoneal injections of either lipopolysaccharide (LPS) or phosphate buffered saline (PBS) or no injection (controls) after a sciatic nerve crush injury. After intravenous injection of the USPIOs (LPS and PBS groups) or PBS (control group), MRI was performed and correlated with histological findings. Results: LPS group showed more remarkable hypointense signals on T2*‐weighted imaging and lower T2 values in the crushed nerves than PBS group. The hypointense signal areas were associated with an enhanced recruitment of iron‐loaded macrophages to the injured nerves. Discussion: USPIO‐enhanced MRI can be used to monitor the enhanced macrophage recruitment by means of TLR4 signal pathway activation in nerve injury. Muscle Nerve 58 : 123–132, 2018     

Lack of galectin‐3 speeds Wallerian degeneration by altering TLR and pro‐inflammatory cytokine expressions in injured sciatic nerve

Wallerian degeneration (WD) comprises a series of events that includes activation of non‐neuronal cells and recruitment of immune cells, creating an inflammatory milieu that leads to extensive nerve fragmentation and subsequent clearance of the myelin debris, both of which are necessary prerequisites for effective nerve regeneration. Previously, we documented accelerated axon regeneration in animals lacking galectin‐3 (Gal‐3), a molecule associated with myelin clearance. To clarify the mechanisms underlying this enhanced regeneration, we focus here on the early steps of WD following sciatic nerve crush in Gal‐3^?/? mice. Using an in vivo model of nerve degeneration, we observed that removal of myelin debris is more efficient in Gal‐3^?/? than in wild‐type (WT) mice; we next used an in vitro phagocytosis assay to document that the phagocytic potential of macrophages and Schwann cells was enhanced in the Gal‐3^?/? mice. Moreover, both RNA and protein levels for the pro‐inflammatory cytokines IL‐1β and TNF‐α, as well as for Toll‐like receptor (TLR)‐2 and ‐4, show robust increases in injured nerves from Gal‐3^?/?mice compared to those from WT mice. Collectively, these data indicate that the lack of Gal‐3 results in an augmented inflammatory profile that involves the TLR–cytokine pathway, and increases the phagocytic capacity of Schwann cells and macrophages, which ultimately contributes to speeding the course of WD.     

Schwann cells orchestrate peripheral nerve inflammation through the expression of CSF1, IL-34, and SCF in amyotrophic lateral sclerosis

Distal axonopathy is a recognized pathological feature of amyotrophic lateral sclerosis (ALS). In the peripheral nerves of ALS patients, motor axon loss elicits a Wallerian-like degeneration characterized by denervated Schwann cells (SCs) together with immune cell infiltration. However, the pathogenic significance of denervated SCs accumulating following impaired axonal growth in ALS remains unclear. Here, we analyze SC phenotypes in sciatic nerves of ALS patients and paralytic SOD1^G93A rats, and identify remarkably similar and specific reactive SC phenotypes based on the pattern of S100β, GFAP, isolectin and/or p75^NTR immunoreactivity. Different subsets of reactive SCs expressed colony-stimulating factor-1 (CSF1) and Interleukin-34 (IL-34) and closely interacted with numerous endoneurial CSF-1R-expressing monocyte/macrophages, suggesting a paracrine mechanism of myeloid cell expansion and activation. SCs bearing phagocytic phenotypes as well as endoneurial macrophages expressed stem cell factor (SCF), a trophic factor that attracts and activates mast cells through the c-Kit receptor. Notably, a subpopulation of Ki67+ SCs expressed c-Kit in the sciatic nerves of SOD1^G93A rats, suggesting a signaling pathway that fuels SC proliferation in ALS. c-Kit+ mast cells were also abundant in the sciatic nerve from ALS donors but not in controls. Pharmacological inhibition of CSF-1R and c-Kit with masitinib in SOD1^G93A rats potently reduced SC reactivity and immune cell infiltration in the sciatic nerve and ventral roots, suggesting a mechanism by which the drug ameliorates peripheral nerve pathology. These findings provide strong evidence for a previously unknown inflammatory mechanism triggered by SCs in ALS peripheral nerves that has broad application in developing novel therapies.     

Reliability of side‐to‐side ultrasound cross‐sectional area measurements of lower extremity nerves in healthy subjects

Introduction: In peripheral nerve ultrasound, the healthy contralateral side may be used as internal control. Therefore, inherent side‐to‐side differences must be minimal. The goal of this study was to assess intrastudy, intraobserver, and interobserver reproducibility of ultrasound in comparative side‐to‐side evaluation of lower limb nerves. Methods: Lower limb nerves of 60 normal subjects were evaluated by 3 radiologists. Bilateral sciatic, tibial, common fibular, sural, lateral femoral cutaneous, femoral, obturator, and saphenous nerves were evaluated. Results: Overall, side‐to‐side differences were not statistically significant at any level. In the lower limb nerves, in a between‐limb comparison, the minimum detectable difference of cross‐sectional area ranged from 16.4 mm² (sciatic nerve at the level of piriformis muscle) to 0.4 mm² (saphenous nerve). Conclusion: In general, the healthy contralateral side can be used as an internal control. Muscle Nerve 46: 717–722, 2012     

In vivo imaging of Α7 nicotinic receptors as a novel method to monitor neuroinflammation after cerebral ischemia

In vivo positron emission tomography (PET) imaging of nicotinic acetylcholine receptors (nAChRs) is a promising tool for the imaging evaluation of neurologic and neurodegenerative diseases. However, the role of α7 nAChRs after brain diseases such as cerebral ischemia and its involvement in inflammatory reaction is still largely unknown. In vivo and ex vivo evaluation of α7 nAChRs expression after transient middle cerebral artery occlusion (MCAO) was carried out using PET imaging with [¹¹C]NS14492 and immunohistochemistry (IHC). Pharmacological activation of α7 receptors was evaluated with magnetic resonance imaging (MRI), [¹⁸F]DPA‐714 PET, IHC, real time polymerase chain reaction (qPCR) and neurofunctional studies. In the ischemic territory, [¹¹C]NS14492 signal and IHC showed an expression increase of α7 receptors in microglia and astrocytes after cerebral ischemia. The role played by α7 receptors on neuroinflammation was supported by the decrease of [¹⁸F]DPA‐714 binding in ischemic rats treated with the α7 agonist PHA 568487 at day 7 after MCAO. Moreover, compared with non‐treated MCAO rats, PHA‐treated ischemic rats showed a significant reduction of the cerebral infarct volumes and an improvement of the neurologic outcome. PHA treatment significantly reduced the expression of leukocyte infiltration molecules in MCAO rats and in endothelial cells after in vitro ischemia. Despite that, the activation of α7 nAChR had no influence to the blood brain barrier (BBB) permeability measured by MRI. Taken together, these results suggest that the nicotinic α7 nAChRs play a key role in the inflammatory reaction and the leukocyte recruitment following cerebral ischemia in rats.     

Role of connexin 32 hemichannels in the release of ATP from peripheral nerves

Extracellular purines elicit strong signals in the nervous system. Adenosine‐5′‐triphosphate (ATP) does not spontaneously cross the plasma membrane, and nervous cells secrete ATP by exocytosis or through plasma membrane proteins such as connexin hemichannels. Using a combination of imaging, luminescence and electrophysiological techniques, we explored the possibility that Connexin 32 (Cx32), expressed in Schwann cells (SCs) myelinating the peripheral nervous system could be an important source of ATP in peripheral nerves. We triggered the release of ATP in vivo from mice sciatic nerves by electrical stimulation and from cultured SCs by high extracellular potassium concentration‐evoked depolarization. No ATP was detected in the extracellular media after treatment of the sciatic nerve with Octanol or Carbenoxolone, and ATP release was significantly inhibited after silencing Cx32 from SCs cultures. We investigated the permeability of Cx32 to ATP by expressing Cx32 hemichannels in Xenopus laevis oocytes. We found that ATP release is coupled to the inward tail current generated after the activation of Cx32 hemichannels by depolarization pulses, and it is sensitive to low extracellular calcium concentrations. Moreover, we found altered ATP release in mutated Cx32 hemichannels related to the X‐linked form of Charcot‐Marie‐Tooth disease, suggesting that purinergic‐mediated signaling in peripheral nerves could underlie the physiopathology of this neuropathy. GLIA 2013;61:1976–1989     

Fluorine‐19 magnetic resonance imaging probe for the detection of tau pathology in female rTg4510 mice

Aggregation of tau into neurofibrillary tangles (NFTs) is characteristic of tauopathies, including Alzheimer's disease. Recent advances in tau imaging have attracted much attention because of its potential contributions to early diagnosis and monitoring of disease progress. Fluorine‐19 magnetic resonance imaging (¹⁹F‐MRI) may be extremely useful for tau imaging once a high‐quality probe has been formulated. In this investigation, a novel fluorine‐19–labeling compound has been developed as a probe for tau imaging using ¹⁹F‐MRI. This compound is a buta‐1,3‐diene derivative with a polyethylene glycol side chain bearing a CF₃ group and is known as Shiga‐X35. Female rTg4510 mice (a mouse model of tauopathy) and wild‐type mice were intravenously injected with Shiga‐X35, and magnetic resonance imaging of each mouse's head was conducted in a 7.0‐T horizontal‐bore magnetic resonance scanner. The ¹⁹F‐MRI in rTg4510 mice showed an intense signal in the forebrain region. Analysis of the signal intensity in the forebrain region revealed a significant accumulation of fluorine‐19 magnetic resonance signal in the rTg4510 mice compared with the wild‐type mice. Histological analysis showed fluorescent signals of Shiga‐X35 binding to the NFTs in the brain sections of rTg4510 mice. Data collected as part of this investigation indicate that ¹⁹F‐MRI using Shiga‐X35 could be a promising tool to evaluate tau pathology in the brain.     

Deficiency of the negative immune regulator B7-H1 enhances inflammation and neuropathic pain after chronic constriction injury of mouse sciatic nerve

Peripheral nerve injury induces a profound local inflammatory response that involves T cells and macrophages and augments the generation of neuropathic pain. The mechanisms underlying immune cell activation or inhibition in the peripheral nervous system, however, are unknown. The co-inhibitory molecule B7-H1 (PD-L1, CD274) attenuates immune cell proliferation and cytokine production and protects from inflammation-induced tissue damage. We analyzed the temporal gene expression profile of B7-H1 and different cytokines after chronic constriction injury (CCI) of the sciatic nerve, a lesion paradigm inducing neuropathic pain, by quantitative real-time polymerase chain reaction and immunohistochemistry in B7-H1^−/− mice and wild-type (WT) controls. B7-H1 mRNA was markedly induced in WT nerves after CCI, and macrophages could be identified as major B7-H1 source. The proinflammatory mediators tumor necrosis factor alpha (TNFα) and monocyte chemoattractant protein-1 (MCP-1) displayed a strong, but transient expression in degenerating nerves on day 1 after CCI in WT mice, while a biphasic expression peak on day 1 and day 28 was found in B7-H1^−/− mice. Overall, TNFα and MCP-1 levels in B7-H1-deficient nerves dramatically exceeded those in WT controls. In contrast, induction of the anti-inflammatory cytokine interleukin(IL)-10 was restricted to WT nerves. The observation that B7-H1 deficiency enhances inflammation upon CCI was further corroborated by immunohistochemistry showing increased numbers of T cells and macrophages in injured nerves from B7-H1^−/− mice. Interestingly, mechanical hyperalgesia was more pronounced in the absence of B7-H1. Our study identifies B7-H1 as an important suppressor of the inflammatory response and neuropathic pain occurring after peripheral nerve injury.     

Persistence in degenerating sciatic nerve of substances having a trophic influence upon cultured muscle

Citrate-soluble proteins were extracted from normal and degenerating chicken sciatic nerves and added to chick embryonic skeletal muscle cultures to determine the trophic influences of the soluble proteins upon muscle cells. The soluble protein from normal or degenerating nerves was equally effective in promoting the protein synthesis, maturation, and long-term maintenance of muscle cells. Normal or degenerating nerve protein stimulated [¹⁴C]leucine incorporation into muscle cell protein and enhanced the morphologic maturation of muscle cells in culture. Furthermore, matured, cross-striated myotubes survived longer in the presence of normal or degenerating nerve protein than in control cultures. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis on thin-layer gels revealed similar electrophoretic patterns for normal and degenerating nerve proteins. Electrophoretic gels also revealed the presence in these extracts of a protein with MW_R 84,000 which migrated in a manner identical to a neurotrophic protein which was recently purified from chicken sciatic nerves. The present results indicate that neural proteins having trophic influences upon muscle in vitro persist in degenerating sciatic nerve. We therefore conclude that the in vivo changes in muscle after denervation are not due to the depletion of trophic substances following nerve transection.     

Fluorodopa is a Promising Fluorine‐19 MRI Probe for Evaluating Striatal Dopaminergic Function in a Rat Model of Parkinson's Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra projecting to the striatum. It has been estimated that approximately 80% of the striatal dopamine and 50% of nigral dopaminergic neurons are lost before the onset of typical motor symptoms, indicating that early diagnosis of PD using noninvasive imaging is feasible. Fluorine‐19 (¹⁹F) magnetic resonance imaging (MRI) represents a highly sensitive, easily available, low‐background, and cost‐effective approach to evaluate dopaminergic function using non‐radioactive fluorine‐containing dopaminergic agents. The aim of this study was to find a potent ¹⁹F MRI probe to evaluate dopaminergic presynaptic function in the striatum. To select candidates for ¹⁹F MRI probes, we investigated the following eight non‐radioactive fluorine‐containing dopaminergic agents: fluorodopa (F‐DOPA), F‐tyrosine, haloperidol, GBR13069 duhydrochloride, GBR12909 duhydrochloride, 3‐bis‐(4‐fluorophenyl) methoxytropane hydrochloride, flupenthixol, and fenfluramine. In ¹⁹F nuclear magnetic resonance measurements, F‐tyrosine and F‐DOPA displayed a relatively higher signal‐to‐noise ratio value in brain homogenates than in others. F‐DOPA, but not F‐tyrosine, induced the rotational behavior in a 6‐hydroxydopamine (6‐OHDA)‐induced hemiparkinsonian rat model. In addition, a significantly high amount of F‐DOPA accumulated in the ipsilateral striatum of hemiparkinsonian rats after the injection. We performed ¹⁹F MRI in PC12 cells and isolated rat brain using a 7T MR scanner. Our findings suggest that F‐DOPA is a promising ¹⁹F MRI probe for evaluating dopaminergic presynaptic function in the striatum of hemiparkinsonian rats. © 2016 Wiley Periodicals, Inc.     

Peripheral Neuropathy: Assessment of Proximal Nerve Integrity By Diffusion Tensor Imaging

Introduction: We investigated the utility of diffusion tensor imaging (DTI) for detecting neuropathic changes in proximal nerve segments in patients with peripheral neuropathy. Methods: Twenty‐one individuals with (n = 11) and without (n = 10) peripheral neuropathy underwent DTI of a defined sciatic nerve segment. Patients and controls were evaluated by clinical examination and nerve conduction studies at baseline and 6 months after the initial DTI scan. Results: The mean fractional anisotropy (FA) value was significantly lower in sciatic nerves from patients with peripheral neuropathy as compared with controls. Sciatic nerve FA values correlated with clinical disability scores and electrophysiological parameters of axonal damage at baseline and 6 months after MRI scan. Conclusions: DTI‐derived FA values are a sensitive measure to discriminate healthy from functionally impaired human sciatic nerve segments. DTI of proximal nerve segments may be useful for estimating the proximal axonal degeneration burden in patients with peripheral neuropathies. Muscle Nerve 48 : 889–896, 2013     

Differential effects of central and peripheral nerves on macrophages and microglia

The poor ability of injured central nervous system (CNS) axons to regenerate has been correlated, at least partially, with a limited and suppressed postinjury inflammatory response. A key cell type in the inflammatory process is the macrophage, which can respond in various ways, depending on the conditions of stimulation. The aim of this study is to compare the activities of macrophages or microglia when encountering CNS and peripheral nervous systems (PNS), on the assumption that nerve-related differences in the inflammatory response may have implications for tissue repair and thus for nerve regeneration. Phagocytic activity of macrophages or of isolated brain-derived microglia was enhanced upon their exposure to sciatic (PNS) nerve segments, but inhibited by exposure to optic (CNS) nerve segments. Similarly, nitric oxide production by macrophages or microglia was induced by sciatic nerve segments but not by optic nerve segments. The previously demonstrated presence of a resident inhibitory activity in CNS nerve, could account, at least in part, for the inhibited phagocytic activity of blood-borne macrophages in CNS nerve as well as of microglia resident in the brain. It seems that the CNS microglia are reversibly immunosuppressed by the CNS environment, at least with respect to the activities examined here. It also appears from this study that the weak induction of early healing-related activities of macrophages/microglia in the environment of CNS might explain the subsequent failure of this environment to acquire growth-supportive properties in temporal and spatial synchrony with the needs of regrowing axons. GLIA 23:181–190, 1998. © 1998 Wiley-Liss, Inc.     

Resolving the cellular specificity of TSPO imaging in a rat model of peripherally-induced neuroinflammation

The increased expression of 18 kDa Translocator protein (TSPO) is one of the few available biomarkers of neuroinflammation that can be assessed in humans in vivo by positron emission tomography (PET). TSPO PET imaging of the central nervous system (CNS) has been widely undertaken, but to date no clear consensus has been reached about its utility in brain disorders. One reason for this could be because the interpretation of TSPO PET signal remains challenging, given the cellular heterogeneity and ubiquity of TSPO in the brain.The aim of the current study was to ascertain if TSPO PET imaging can be used to detect neuroinflammation induced by a peripheral treatment with a low dose of the endotoxin, lipopolysaccharide (LPS), in a rat model (ip LPS), and investigate the origin of TSPO signal changes in terms of their cellular sources and regional distribution. An initial pilot study utilising both [¹⁸F]DPA-714 and [¹¹C]PK11195 TSPO radiotracers demonstrated [¹⁸F]DPA-714 to exhibit a significantly higher lesion-related signal in the intracerebral LPS rat model (ic LPS) than [¹¹C]PK11195. Subsequently, [¹⁸F]DPA-714 was selected for use in the ip LPS study.Twenty-four hours after ip LPS, there was an increased uptake of [¹⁸F]DPA-714 across the whole brain. Further analyses of regions of interest, using immunohistochemistry and RNAscope Multiplex fluorescence V2 in situ hybridization technology, showed TSPO expression in microglia, monocyte derived-macrophages, astrocytes, neurons and endothelial cells. The expression of TSPO was significantly increased after ip LPS in a region-dependent manner: with increased microglia, monocyte-derived macrophages and astrocytes in the substantia nigra, in contrast to the hippocampus where TSPO was mostly confined to microglia and astrocytes. In summary, our data demonstrate the robust detection of peripherally-induced neuroinflammation in the CNS utilising the TSPO PET radiotracer, [¹⁸F]DPA-714, and importantly, confirm that the resultant increase in TSPO signal increase arises mostly from a combination of microglia, astrocytes and monocyte-derived macrophages.     

Diffusion tensor imaging to assess axonal regeneration in peripheral nerves

Development of outcome measures to assess ongoing nerve regeneration in the living animal that can be translated to human can provide extremely useful tools for monitoring the effects of therapeutic interventions to promote nerve regeneration. Diffusion tensor imaging (DTI), a magnetic resonance based technique, provides image contrast for nerve tracts and can be applied serially on the same subject with potential to monitor nerve fiber content. In this study, we examined the use of ex vivo high-resolution DTI for imaging intact and regenerating peripheral nerves in mice and correlated the MRI findings with electrophysiology and histology. DTI was done on sciatic nerves with crush, without crush, and after complete transection in different mouse strains. DTI measures, including fractional anisotropy (FA), parallel diffusivity, and perpendicular diffusivity were acquired and compared in segments of uninjured and crushed/transected nerves and correlated with morphometry. A comparison of axon regeneration after sciatic nerve crush showed a comparable pattern of regeneration in different mice strains. FA values were significantly lower in completely denervated nerve segments compared to uninjured sciatic nerve and this signal was restored toward normal in regenerating nerve segments (crushed nerves). Histology data indicate that the FA values and the parallel diffusivity showed a positive correlation with the total number of regenerating axons. These studies suggest that DTI is a sensitive measure of axon regeneration in mouse models and provide basis for further development of imaging technology for application to living animals and humans.     

Effects of a high-caloric diet and physical exercise on brain metabolite levels: a combined proton MRS and histologic study

Excessive intake of high-caloric diets as well as subsequent development of obesity and diabetes mellitus may exert a wide range of unfavorable effects on the central nervous system (CNS). It has been suggested that one mechanism in this context is the promotion of neuroinflammation. The potentially harmful effects of such diets were suggested to be mitigated by physical exercise. Here, we conducted a study investigating the effects of physical exercise in a cafeteria-diet mouse model on CNS metabolites by means of in vivo proton magnetic resonance spectroscopy (¹HMRS). In addition postmortem histologic and real-time (RT)-PCR analyses for inflammatory markers were performed. Cafeteria diet induced obesity and hyperglycemia, which was only partially moderated by exercise. It also induced several changes in CNS metabolites such as reduced hippocampal glutamate (Glu), choline-containing compounds (tCho) and N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamic acid (NAAG) (tNAA) levels, whereas opposite effects were seen for running. No association of these effects with markers of central inflammation could be observed. These findings suggest that while voluntary wheel running alone is insufficient to prevent the unfavorable peripheral sequelae of the diet, it counteracted many changes in brain metabolites. The observed effects seem to be independent of neuroinflammation.     

Preferential conduction block of myelinated axons by nitric oxide

Conduction block by nitric oxide (NO) was examined in myelinated and unmyelinated axons from both the central nervous system and peripheral nervous system. In rat vagus nerves, mouse optic nerves at P12–P23, adult and developing mouse sciatic nerves, and mouse spinal cords, myelinated fibers were preferentially blocked reversibly by concentrations of NO similar to those encountered in inflammatory lesions. The possibility that these differences between myelinated and unmyelinated axons are due to the normal developmental substitution of Na⁺ channel subtype Na_v1.6 for Na_v1.2 at nodes of Ranvier was tested by repeating experiments on mice null for Na_v1.6. Results were unchanged in this mutant. In shiverer optic nerve, which has only scattered regions with nodes of Ranvier, only the fastest component of the compound action potential was reduced. NO was compared with three other methods of blocking conduction: low Na⁺, high K⁺, and tetrodotoxin (TTX). In each of these three cases, unmyelinated axons lost conduction simultaneously with myelinated fibers. From changes in conduction velocity in myelinated axons as they were blocked, it was ascertained that NO acted most similarly to TTX. It was concluded that NO likely interacts with axonal Na⁺ channels through an intermediate that is associated with myelin. © 2016 Wiley Periodicals, Inc.     

Lesional infiltration of receptor activator of nuclear factor-κB ligand+ cells in experimental autoimmune neuritis rats

Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune demyelinating inflammatory disease of the peripheral nervous system. Receptor activator of NF-κB ligand (RANKL), a member of the tumor necrosis factor family, regulates proliferation of mature T cells. Here, we have studied the expression of RANKL in sciatic nerves of EAN rats. EAN was induced in male Lewis rats. The spatiotemporal expression of RANKL in sciatic nerves of EAN rats was investigated using immunohistochemistry. In sciatic nerves of normal rats RANKL⁺ cells were rarely seen. EAN induced a significant accumulation of RANKL⁺ cells in sciatic nerves and there was a significant positive correlation of the time course of RANKL⁺ cell accumulations with neurological scores of EAN rats. The major cellular resources of RANKL in sciatic nerves were T cells and macrophages. The positive association of RANKL⁺ cell accumulations with neurological scores of EAN rats together with the known functions of RANKL indicated that RANKL might play a role in pathologic development of EAN and need further investigation.     

Nerve strain correlates with structural changes quantified by fourier analysis

Introduction: Nerve deformation affects physiological function. Bands of Fontana are an optical manifestation of axonal undulations and may provide a structural indicator of nerve strain. Methods: We developed an automated Fourier‐based image processing method to quantify the periodicity of bands of Fontana both in bright field images and in axonal undulations in immunolabeled longitudinal sections. Results: We found a strong linear relationship between applied strain and the frequency of bands of Fontana in rat sciatic nerves (?0.0056 μm^??%^?, r² = 0.829; P < 0.05). This relationship agreed with the observed trend between strain and axonal waviness, calculated from longitudinal sections of sciatic nerves immunolabeled against myelin basic protein. Conclusions: This accurate and objective approach has potential to increase our understanding of structure–function relationships in the nervous system and to guide preservation and enhancement of neural function. Muscle Nerve 48 : 433–435, 2013     

MR neurography for the evaluation of CIDP

Introduction: To visualize peripheral nerves in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), we used MR imaging. We also quantified the volumes of the brachial and lumbar plexus and their nerve roots. Methods: Thirteen patients with CIDP and 12 healthy volunteers were enrolled. Whole‐body MR neurography based on diffusion‐weighted whole‐body imaging with background body signal suppression (DWIBS) was performed. Peripheral nerve volumes were calculated from serial axial MR images. Results: The peripheral nervous system was visualized with 3‐dimensional reconstruction. Volumes ranged from 8.7 to 49.5 cm³/m² in the brachial plexus and nerve roots and from 10.2 to 53.5 cm³/m² in the lumbar plexus and nerve roots. Patients with CIDP had significantly larger volumes than controls (P < 0.05), and volume was positively correlated with disease duration. Conclusions: MR neurography and the measurement of peripheral nerve volume are useful for diagnosing and assessing CIDP. Muscle Nerve 55 : 483–489, 2017