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This book provides a full account of the concept of fiber and fiber theory in eighteenth-century British medicine. It explores the pivotal role fiber played as a defining, underlying concept in anatomy, physiology, pathology, therapeutics, psychology, and the life sciences. With the gradual demise of ancient humoralism, the solid fibers appeared on the medical scene both as the basic building unit of the body and as a dynamic agent of life. As such, fiber stands at the heart of eighteenth-century medicine, both iatromechanism and iatro-vitalism. Touching on the cultural aspects of fiber, the Baroque, and the culture of sensibility, this book also challenges the widely held assumption that the eighteenth century was the age of the nerve and instead offers an alternative model of fiber.

The human brain is a complex dynamic system capable of generating a multitude of oscillatory waves in support of brain function. Using fMRI, we examined the amplitude of spontaneous low-frequency oscillations (LFO) observed in the human resting brain and the test–retest reliability of relevant amplitude measures. We confirmed prior reports that gray matter exhibits higher LFO amplitude than white matter. Within gray matter, the largest amplitudes appeared along mid-brain structures associated with the “default-mode” network. Additionally, we found that high-amplitude LFO activity in specific brain regions was reliable across time. Furthermore, parcellation-based results revealed significant and highly reliable ranking orders of LFO amplitudes among anatomical parcellation units. Detailed examination of individual low frequency bands showed distinct spatial profiles. Intriguingly, LFO amplitudes in the slow-4 (0.027–0.073 Hz) band, as defined by Buzsáki et al., were most robust in the basal ganglia, as has been found in spontaneous electrophysiological recordings in the awake rat. These results suggest that amplitude measures of LFO can contribute to further between-group characterization of existing and future “resting-state” fMRI datasets.

Aims/Introduction Painful diabetic peripheral neuropathy (pDPN) is associated with small nerve fiber degeneration and regeneration. This study investigated whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control. Materials and Methods This exploratory substudy of an open‐label randomized controlled trial undertook the Douleur Neuropathique en 4 questionnaire and assessment of electrochemical skin conductance, vibration perception threshold and corneal nerve morphology using corneal confocal microscopy in participants with and without pDPN treated with exenatide and pioglitazone or basal–bolus insulin at baseline and 1‐year follow up, and 18 controls at baseline only. Results Participants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN had comparable corneal nerve fiber measures, electrochemical skin conductance and vibration perception threshold at baseline, and pDPN was not associated with the severity of DPN. There was a significant glycated hemoglobin reduction (P < 0.0001) and weight gain (P < 0.005), irrespective of therapy. Participants with pDPN showed a significant increase in corneal nerve fiber density (P < 0.05), length (P < 0.0001) and branch density (P < 0.005), and a decrease in the Douleur Neuropathique en 4 score (P < 0.01), but no change in electrochemical skin conductance or vibration perception threshold. Participants without pDPN showed a significant increase in corneal nerve branch density (P < 0.01) and no change in any other neuropathy measures. A change in the severity of painful symptoms was not associated with corneal nerve regeneration and medication for pain. Conclusions This study showed that intensive glycemic control is associated with greater corneal nerve regeneration and an improvement in the severity of pain in patients with painful diabetic neuropathy. There has been a resurgence of interest in identifying new drug targets or, predictive biomarkers of disease‐modifying therapies in diabetic neuropathy. We show that the presence of painful diabetic neuropathy was associated with greater corneal nerve regeneration and an improvement in painful neuropathic symptoms in patients with type 2 diabetes undergoing intensive glycemic control.

Many components of resting-state (RS) FMRI show non-random structure that has little to do with neural connectivity but can covary over multiple brain structures. Some of these signals originate in physiology and others are hardware-related. One artifact discussed herein may be caused by defects in the receive coil array or the RF amplifiers powering it. During a scan, this artifact results in small image intensity shifts in parts of the brain imaged by the affected array components. These shifts introduce artifactual correlations in RS time series on the spatial scale of the coil's sensitivity profile, and can markedly bias RS connectivity results. We show that such a transient artifact can be substantially removed from RS time series by using locally formed regressors from white matter tissue. This is particularly important in arrays with larger numbers of coils, which may generate smaller artifact zones. In such a case, brain-wide average noise estimates would fail to capture the artifact. We also examine the anatomical structure of artifactual variance in RS FMRI time series, by identifying sources that contribute to these signals and where in the brain are they manifested. We consider current methods for reducing confounding sources (or noises) and their effects on connectivity maps, and offer an improved approach (ANATICOR) that can also reduce hardware artifacts. The methods described herein are currently available with AFNI, in addition to tools for rapid, interactive generation of seed-based correlation maps at single-subject and group levels.

There is dual tactile innervation of the human hairy skin: in addition to fast-conducting myelinated afferent fibers, there is a system of slow-conducting unmyelinated (C) afferents that respond to light touch. In a unique patient lacking large myelinated afferents, we found that activation of C tactile (CT) afferents produced a faint sensation of pleasant touch. Functional magnetic resonance imaging (fMRI) analysis during CT stimulation showed activation of the insular region, but not of somatosensory areas S1 and S2. These findings identify CT as a system for limbic touch that may underlie emotional, hormonal and affiliative responses to caress-like, skin-to-skin contact between individuals.

Elevated Triglycerides Correlate With Progression of Diabetic Neuropathy Timothy D. Wiggin 1 , Kelli A. Sullivan 1 , Rodica Pop-Busui 2 , Antonino Amato 3 , Anders A.F. Sima 4 and Eva L. Feldman 1 1 Department of Neurology, University of Michigan, Ann Arbor, Michigan; 2 Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, Michigan; 3 Sigma-Tau Research, Sigma-Tau Pharmaceuticals, Gaithersburg, Maryland; 4 Departments of Pathology and Neurology, Wayne State University, Detroit, Michigan. Corresponding author: Eva L. Feldman, efeldman{at}umich.edu . T.D.W. and K.A.S. are both first authors and contributed equally to this article. Abstract OBJECTIVE To evaluate mechanisms underlying diabetic neuropathy progression using indexes of sural nerve morphometry obtained from two identical randomized, placebo-controlled clinical trials. RESEARCH DESIGN AND METHODS Sural nerve myelinated fiber density (MFD), nerve conduction velocities (NCVs), vibration perception thresholds, clinical symptom scores, and a visual analog scale for pain were analyzed in participants with diabetic neuropathy. A loss of ≥500 fibers/mm 2 in sural nerve MFD over 52 weeks was defined as progressing diabetic neuropathy, and a MFD loss of ≤100 fibers/mm 2 during the same time interval as nonprogressing diabetic neuropathy. The progressing and nonprogressing cohorts were matched for baseline characteristics using an O'Brien rank-sum and baseline MFD. RESULTS At 52 weeks, the progressing cohort demonstrated a 25% decrease ( P < 0.0001) from baseline in MFD, while the nonprogressing cohort remained unchanged. MFD was not affected by active drug treatment ( P = 0.87), diabetes duration ( P = 0.48), age ( P = 0.11), or BMI ( P = 0.30). Among all variables tested, elevated triglycerides and decreased peroneal motor NCV at baseline significantly correlated with loss of MFD at 52 weeks ( P = 0.04). CONCLUSIONS In this cohort of participants with mild to moderate diabetic neuropathy, elevated triglycerides correlated with MFD loss independent of disease duration, age, diabetes control, or other variables. These data support the evolving concept that hyperlipidemia is instrumental in the progression of diabetic neuropathy. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received December 19, 2008. Accepted April 6, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.

As many causes can underlie small-fibre neuropathy (SFN)—a condition characterized by neuropathic pain symptoms and autonomic complaints—making a clinical diagnosis of this disorder is difficult. Hoeijmakers et al . review recent advances in the understanding of the pathophysiology of SFN, highlighting new diagnostic methods for this disorder and discussing how these advances will contribute to better patient management. Small-fibre neuropathy (SFN), a disorder of thinly myelinated Aδ-fibres and unmyelinated C-fibres, is clinically characterized by neuropathic pain symptoms and autonomic complaints. Diagnosis of SFN is challenging as the clinical picture can be difficult to interpret and results from nerve conduction studies are often normal. In cases of suspected SFN, measurement of intraepidermal nerve fibre density and/or analysis of quantitative sensory testing can enable diagnosis. New diagnostic techniques (including measurement of nerve fibre density using corneal confocal microscopy, and nociceptive evoked potentials) may contribute to the diagnostic work-up. SFN can be associated with systemic diseases such as immune-mediated disorders, but remains idiopathic in a substantial proportion of patients. Gain-of-function variants in the Na v 1.7 sodium channel have recently been found in nearly 30% of patients with idiopathic SFN, but the mechanisms of axonal degeneration in the disorder remain under investigation. Identification of the systemic diseases underlying SFN will enable development of drugs that target affected pathways to improve the management of neuropathic pain and autonomic dysfunction. In this Review, we discuss recent advances in the diagnosis and pathophysiology of SFN, highlighting how improved understanding of these aspects of the disorder will contribute to better patient management. Key Points Small-fibre neuropathy (SFN) is a disorder of thinly myelinated Aδ-fibres and unmyelinated C-fibres SFN is diagnosed on the basis of presence of typical SFN-related symptoms, normal nerve conduction studies, reduced intraepidermal nerve fibre density at the ankle, and/or abnormal quantitative sensory testing SFN can be associated with systemic diseases, with an immune-mediated basis proposed in some cases; however, the cause remains unclear in a substantial number of patients Mutations in SCN9A, which encodes the sodium channel Nav1.7, were found to underlie SFN in a subset of patients Therapy for SFN focuses mainly on pain relief, management of autonomic dysfunction, and disease modification where possible Future studies into therapies for SFN should address the efficacy of immunomodulating agents and selective sodium channel blockers

Objective:To describe the clinical and laboratory features of a painful non-length dependent, small fibre ganglionopathy (SFG).Background:The syndrome of generalised SFG with early involvement of the face, trunk or proximal limbs is not well recognised and contrasts with the burning feet syndrome of small fibre neuropathy (SFN) and classical large fibre features of sensory ganglionopathy.Methods:Retrospective case review including skin biopsies from four neuromuscular centres. Patients with pre-existing diseases associated with ganglionopathies were excluded.Results:12 men and 11 women, with an average age of 50 years, were studied. Neuropathic pain developed over days in eight and over months in the other patients. The face (n = 12), scalp (n = 10), tongue (n = 6), trunk (n = 15) and acral extremities (n = 21) were involved. Symptoms began in the hands or face before the legs in 10. The pain was characterised as burning (n = 22), prickling (n = 13), shooting (n = 13) or allodynic (n = 11). There was loss of pinprick sensation in affected regions in 19, with minimal or no loss of large fibre sensibility. Laboratory findings included abnormal glucose metabolism in six patients, Sjögren syndrome in three and monoclonal gammopathy, sprue and hepatitis C infection in one each, with the remainder idiopathic. Sensory nerve action potentials were normal in 12 and were reduced in the hands but normal in the legs in six. Skin biopsy in 14 of 17 showed reduced nerve fibre density in the thigh equal to or more prominent than in the calf. Two of seven patients improved with immune therapies, 13 symptomatically with analgesic medications and the remainder had little improvement. Ten considered the pain disabling at the last follow-up (mean 2 years).Conclusion:The pattern of symmetric, non-length dependent neuropathic pain with face and trunk involvement suggests a selective disorder of the dorsal ganglia cells subserving small nerve fibres. It can be distinguished from distal SFN. A potential metabolic or immune process was detected in half of the cases and the disorder was often refractory to treatment.

Brief high-power laser pulses applied onto the hairy skin of the distal end of a limb generate a double sensation related to the activation of Aδ- and C-fibres, referred to as first and second pain. However, neurophysiological and behavioural responses related to the activation of C-fibres can be studied reliably only if the concomitant activation of Aδ-fibres is avoided. Here, using a novel CO(2) laser stimulator able to deliver constant-temperature heat pulses through a feedback regulation of laser power by an online measurement of skin temperature at target site, combined with an adaptive staircase algorithm using reaction-time to distinguish between responses triggered by Aδ- and C-fibre input, we show that it is possible to estimate robustly and independently the thermal detection thresholds of Aδ-fibres (46.9±1.7°C) and C-fibres (39.8±1.7°C). Furthermore, we show that both thresholds are dependent on the skin temperature preceding and/or surrounding the test stimulus, indicating that the Aδ- and C-fibre afferents triggering the behavioural responses to brief laser pulses behave, at least partially, as detectors of a change in skin temperature rather than as pure level detectors. Most importantly, our results show that the difference in threshold between Aδ- and C-fibre afferents activated by brief laser pulses can be exploited to activate C-fibres selectively and reliably, provided that the rise in skin temperature generated by the laser stimulator is well-controlled. Our approach could constitute a tool to explore, in humans, the physiological and pathophysiological mechanisms involved in processing C- and Aδ-fibre input, respectively.

Functional MRI (fMRI) most commonly employs 2D echo-planar imaging (EPI). The advantages for fMRI brought about by the increasingly popular ultra-high field strengths are best exploited in high-resolution acquisitions, but here 2D EPI becomes unpractical for several reasons, including the very long volume acquisitions times. In this study at 7 T, a 3D EPI sequence with full parallel and partial Fourier imaging capability along both phase encoding axes was implemented and used to evaluate the sensitivity of 3D and corresponding 2D EPI acquisitions at four different spatial resolutions ranging from small to typical voxel sizes (1.5–3.0 mm isotropic). Whole-brain resting state measurements (N=4) revealed a better, or at least comparable sensitivity of the 3D method for gray and white matter. The larger vulnerability of 3D to physiological effects was outweighed by the much shorter volume TR, which moreover allows whole-brain coverage at high resolution within fully acceptable limits for event-related fMRI: TR was only 3.07 s for 1.5 mm, 1.88 s for 2.0 mm, 1.38 s for 2.5 mm and 1.07 s for 3.0 mm isotropic resolution. In order to investigate the ability to detect and spatially resolve BOLD activation in the visual cortex, functional 3D EPI experiments (N=8) were performed at 1 mm isotropic resolution with parallel imaging acceleration of 3 × 3, resulting in a TR of only 3.2 s for whole-brain coverage. From our results, and several other practical advantages of 3D over 2D EPI found in the present study, we conclude that 3D EPI provides a useful alternative for whole-brain fMRI at 7 T, not only when high-resolution data are required.