Classifyber, a robust streamline-based linear classifier for white matter bundle segmentation.

Virtual delineation of white matter bundles in the human brain is of paramount importance for multiple applications, such as pre-surgical planning and connectomics. A substantial body of literature is related to methods that automatically segment bundles from diffusion Magnetic Resonance Imaging (dMRI) data indirectly, by exploiting either the idea of connectivity between regions or the geometry of fiber paths obtained with tractography techniques, or, directly, through the information in volumetric data. Despite the remarkable improvement in automatic segmentation methods over the years, their segmentation quality is not yet satisfactory, especially when dealing with datasets with very diverse characteristics, such as different tracking methods, bundle sizes or data quality. In this work, we propose a novel, supervised streamline-based segmentation method, called Classifyber, which combines information from atlases, connectivity patterns, and the geometry of fiber paths into a simple linear model. With a wide range of experiments on multiple datasets that span from research to clinical domains, we show that Classifyber substantially improves the quality of segmentation as compared to other state-of-the-art methods and, more importantly, that it is robust across very diverse settings. We provide an implementation of the proposed method as open source code, as well as web service.

Distribution pattern of dorsal root ganglion neurons synthesizing nitric oxide synthase in different animal species.

The main aim of the present review is to provide at first a short survey of the basic anatomical description of sensory ganglion neurons in relation to cell size, conduction velocity, thickness of myelin sheath, and functional classification of their processes. In addition, we have focused on discussing current knowledge about the distribution pattern of neuronal nitric oxide synthase containing sensory neurons especially in the dorsal root ganglia in different animal species; hence, there is a large controversy in relation to interpretation of the results dealing with this interesting field of research.

Statistical physics approach to quantifying differences in myelinated nerve fibers.

We present a new method to quantify differences in myelinated nerve fibers. These differences range from morphologic characteristics of individual fibers to differences in macroscopic properties of collections of fibers. Our method uses statistical physics tools to improve on traditional measures, such as fiber size and packing density. As a case study, we analyze cross-sectional electron micrographs from the fornix of young and old rhesus monkeys using a semi-automatic detection algorithm to identify and characterize myelinated axons. We then apply a feature selection approach to identify the features that best distinguish between the young and old age groups, achieving a maximum accuracy of 94% when assigning samples to their age groups. This analysis shows that the best discrimination is obtained using the combination of two features: the fraction of occupied axon area and the effective local density. The latter is a modified calculation of axon density, which reflects how closely axons are packed. Our feature analysis approach can be applied to characterize differences that result from biological processes such as aging, damage from trauma or disease or developmental differences, as well as differences between anatomical regions such as the fornix and the cingulum bundle or corpus callosum.

Mathematical model of nerve fiber activation during low back peripheral nerve field stimulation: analysis of electrode implant depth.

OBJECTIVES: 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 Aß 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 Aß-fiber stimulation is maximized, and Aδ-fiber minimized, which in turn should lead to therapy optimization. MATERIALS AND METHODS: 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 Aß- and Aδ-fiber types and were estimated using a passive cable model. RESULTS: The stimulus-response functions showed that the skin area covered by Aß-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 Aß-fiber activation was largest at lower depths. CONCLUSIONS: 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 Aß 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.

Development and validation of the QUT corneal nerve grading scale.

PURPOSE: The aim of this study was to develop and validate a grading scale to facilitate the estimation of the amount of nerve tissue in images of the corneal subbasal nerve plexus captured using in vivo laser scanning corneal confocal microscopy (LSCCM). METHODS: Images of the corneal subbasal nerve plexus obtained using a Heidelberg LSCCM were sourced from a large image bank at the Queensland University of Technology (QUT). These images were used to construct a grading scale for depicting the amount of nerve tissue, ranging from 0 (sparse) to 4 (extensive). Twenty-five observers graded 20 images of a known corneal nerve fiber length (defined as the total length of nerves per unit area) on 2 occasions, at least 2 weeks apart. An equivalent calculated grade was determined for each test image from known values of corneal nerve fiber length. RESULTS: The intraclass correlation coefficient for repeat gradings was 0.88 (P < 0.001). Intraobserver and interobserver repeatabilities were unrelated to the calculated grade (P = 0.467 and P = 0.530, respectively). Grading can be performed with average 95% confidence limits of ±1.2 grading units. Overall grading estimates did not differ between observers (P = 0.998). There was a strong agreement between the estimated and calculated grades (intraclass correlation coefficient = 0.92, P < 0.001). CONCLUSIONS: We have developed the QUT Corneal Nerve Grading Scale, which is demonstrated to be repeatable, reliable, precise, and accurate. This tool provides clinicians and researchers with a simple and convenient pictorial reference for assessing, comparing, and monitoring the corneal subbasal nerve plexus with reference to LSCCM images.

Spectrum of myelinated pulmonary afferents (II).

Recently, it has been recognized that a single airway sensory unit may contain multiple receptive fields and that each field houses at least one encoder. Since some units respond to both lung inflation and deflation, we hypothesized that these units contain heterogeneous encoders for sensing inflation and deflation, respectively. Single unit activities were recorded from the cervical vagus nerve in anesthetized, open chest, and mechanically ventilated rabbits. Fifty-two airway sensory units with multiple receptive fields that responded to both lung inflation and deflation were identified. Among them, 13 units had separate receptive fields for inflation and deflation, where one of the fields could be blocked by local injection of 2% lidocaine (10 µl). In 8 of the 13 units, the deflation response was blocked without affecting the unit's response to inflation, whereas in the remaining five units, the inflation response was blocked without affecting the deflation response. Our results support the hypothesis that a single mechanosensory unit may contain heterogeneous encoders that can respond to either inflation or deflation.

Why do axons differ in caliber?

CNS axons differ in diameter (d) by nearly 100-fold (∼0.1-10 µm); therefore, they differ in cross-sectional area (d(2)) and volume by nearly 10,000-fold. If, as found for optic nerve, mitochondrial volume fraction is constant with axon diameter, energy capacity would rise with axon volume, also as d(2). We asked, given constraints on space and energy, what functional requirements set an axon's diameter? Surveying 16 fiber groups spanning nearly the full range of diameters in five species (guinea pig, rat, monkey, locust, octopus), we found the following: (1) thin axons are most numerous; (2) mean firing frequencies, estimated for nine of the identified axon classes, are low for thin fibers and high for thick ones, ranging from ∼1 to >100 Hz; (3) a tract's distribution of fiber diameters, whether narrow or broad, and whether symmetric or skewed, reflects heterogeneity of information rates conveyed by its individual fibers; and (4) mitochondrial volume/axon length rises ≥d(2). To explain the pressure toward thin diameters, we note an established law of diminishing returns: an axon, to double its information rate, must more than double its firing rate. Since diameter is apparently linear with firing rate, doubling information rate would more than quadruple an axon's volume and energy use. Thicker axons may be needed to encode features that cannot be efficiently decoded if their information is spread over several low-rate channels. Thus, information rate may be the main variable that sets axon caliber, with axons constrained to deliver information at the lowest acceptable rate.

Similarities and differences of white matter connectivity and water diffusivity in bipolar I and II disorder.

Differences and similarities in microstructural white matter alterations between bipolar I and bipolar II disorder were investigated. Twelve patients with bipolar I disorder, 12 patients with bipolar II disorder and 22 healthy controls underwent diffusion tensor imaging. Fractional anisotropy (FA) and mean apparent diffusion coefficient (ADC) maps were compared between groups using voxel-based whole brain analyses. Both bipolar I and II groups had a FA decrease in the corpus callosum, cingulate and right prefrontal regions, and a ADC increase in the medial frontal, anterior cingulate, insular and temporal regions, compared to controls. The bipolar I group had a FA decrease in the right temporal white matter and a ADC increase in the frontal, temporal, parietal and thalamic regions, compared to the bipolar II group. The results suggest disrupted integrity of commissural fibers and white matter in the anterior paralimbic structures in bipolar disorder. Relative sparing of the dorsal system and long association fibers may differentiate bipolar II from I disorder.

Differential involvement of A-delta and A-beta fibres in neuropathic pain related to carpal tunnel syndrome.

Carpal tunnel syndrome (CTS), a common entrapment neuropathy involving the median nerve at the wrist, frequently manifests with neuropathic pain. We sought information on pain mechanisms in CTS. We studied 70 patients with a diagnosis of CTS (117 CTS hands). We used the DN4 questionnaire to select patients with neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to assess the intensity of the various qualities of neuropathic pain. All patients underwent a standard nerve conduction study (NCS) to assess the function of non-nociceptive Abeta-fibres, and the cutaneous silent period (CSP) after stimulation of the IIIrd and Vth digits, to assess the function of nociceptive Adelta-fibres. In 40 patients (75 CTS hands) we also recorded laser-evoked potentials (LEPs) in response to stimuli delivered to the median nerve territory and mediated by nociceptive Adelta-fibres. We sought possible correlations between neurophysiological data and the various qualities of neuropathic pain as assessed by the NPSI. We found that the median nerve sensory conduction velocity correlated with paroxysmal pain and abnormal sensations, whereas LEP amplitude correlated with spontaneous constant pain. Our findings suggest that whereas paroxysmal pain and abnormal sensations reflect demyelination of non-nociceptive Abeta-fibres, spontaneous constant pain arises from damage to nociceptive Adelta-fibres.

Automated characterization of nerve fibers labeled fluorescently: determination of size, class and spatial distribution.

Morphological classification of nerve fibers could help interpret the assessment of neural regeneration and the understanding of selectivity of nerve stimulation. Specific populations of myelinated nerve fibers can be investigated by retrograde tracing from a muscle followed by microscopic measurements of the labeled fibers at different anatomical levels. Gastrocnemius muscles of adult rats were injected with the retrograde tracer Fluoro-Gold. After a survival period of 3 days, cross-sections of spinal cords, ventral roots, sciatic, and tibial nerves were collected and imaged on a fluorescence microscope. Nerve fibers were classified using a variation-based criterion acting on the distribution of their equivalent diameters. The same criterion was used to classify the labeled axons using the size of the fluorescent marker. Measurements of the axons were paired to those of the entire fibers (axons+myelin sheaths) in order to establish the correspondence between so-established axonal and fiber classifications. It was found that nerve fibers in L6 ventral roots could be classified into four populations comprising two classes of Aalpha (denoted Aalpha1 and Aalpha2), Agamma, and an additional class of Agammaalpha fibers. Cut-off borders between Agamma and Agammaalpha fiber classes were estimated to be 5.00+/-0.09 microm (SEM); between Agammaalpha and Aalpha1 fiber classes to be 6.86+/-0.11 microm (SEM); and between Aalpha1 and Aalpha2 fiber classes to be 8.66+/-0.16 microm (SEM). Topographical maps of the nerve fibers that innervate the gastrocnemius muscles were constructed per fiber class for the spinal root L6. The major advantage of the presented approach consists of the combined indirect classification of nerve fiber types and the construction of topographical maps of so-identified fiber classes.

A diffusion tensor imaging tractography atlas for virtual in vivo dissections.

Diffusion tensor imaging (DTI) tractography allows perform virtual dissections of white matter pathways in the living human brain. In 2002, Catani et al. published a method to reconstruct white matter pathways using a region of interest (ROI) approach. The method produced virtual representations of white matter tracts faithful to classical post-mortem descriptions but it required detailed a priori anatomical knowledge. Here, using the same approach, we provide a template to guide the delineation of ROIs for the reconstruction of the association, projection and commissural pathways of the living human brain. The template can be used for single case studies and case-control comparisons. An atlas of the 3D reconstructions of the single tracts is also provided as anatomical reference in the Montreal Neurological Institute (MNI) space.

Fiber composition of the rat sciatic nerve and its modification during regeneration through a sieve electrode.

Recovery after peripheral nerve transection is seldom complete, the outcome depending both on lesion and repair conditions, and on the type and neurochemical properties of axons. The interposition between the stumps of a perforated, or regenerative electrode (RE) is a promising avenue in the use of chronic nerve bioimplants, but represents an additional challenge to regeneration. We applied stereological methods to ultrathin and immunostained semithin sections to examine quantitatively the axon types that make up the sciatic nerve in control adult rats, and their changes 2 months after an RE implant. The number of myelinated axons (MAx) increased proximal to RE, but fell to 10% a few millimeters distal. This decrease affected more severely motor fibers, characterized by immunoreactivity to cholinacetyltransferase (ChAT+), than sensory (ChAT-) fibers. Regenerating MAx and myelin sheaths also changed notably in thickness. Unmyelinated axons (UAx) showed a moderate reduction in number distal to the implant. This reduction affected more tyrosine hydroxylase-immunoreactive axons (mostly vaso- and pilomotor fibers), than axons expressing ChAT and/or vasoactive intestinal peptide (mostly sudomotor fibers). Taken together with previous findings [Negredo, P., Castro, J., Lago, N., Navarro, X., Avendaño, C., 2004. Differential growth of axons from sensory and motor neurons through a regenerative electrode: a stereological, retrograde tracer, and functional study in the rat. Neuroscience 128, 605-615.], this study shows that regeneration through the RE is much less successful for MAx than UAx, that motor axons regenerate more poorly than sensory axons, and that some subclasses of sympathetic fibers regenerate better than others. The study also proves the value of the combined methodological approach presented here to assess the fiber composition of a nerve under normal, pathological or experimental conditions.

Morphometric analysis of the inferior alveolar nerve fails to demonstrate sexual dimorphism.

PURPOSE: With regard to the incidence of inferior alveolar nerve (IAN) damage after an IAN block or following oral and maxillofacial surgical procedures, there are reports of sexual dimorphism, no sexual dimorphism, and little sexual dimorphism. However, details of the morphology and sexual dimorphism in the characteristics of the IAN have not been available in textbooks. We morphometrically analyzed the human IAN and clarified these issues. MATERIALS AND METHODS: The materials were obtained from 22 cadavers (11 female and 11 male), aged 59 to 84 years (average age: 74.1 yr), and dentulous. The causes of death did not influence the nervous system, so the IANs were considered to be normal. Human IANs were resected at the mandibular foramen. We counted the myelinated axons and measured the transverse area, perimeter, and circularity ratio of the myelinated axons. RESULTS: We estimated the average total number of myelinated axons in the female IAN to be 25,230, with an average transverse area of 34.1 microm(2), an average perimeter of 21.8 microm, and an average circularity ratio of 0.86, with the same measurements in the male IAN being 20,278, 31.7 microm(2), 20.7 microm, and 0.87, respectively. Our data showed no significant difference between the female and male specimens in any measured item (P < .05). CONCLUSIONS: We assumed that the sex difference in the incidence of IAN damage was not affected by the morphometric findings. Our findings might partly explain why there is no significant sex difference in the incidence of IAN damage.

Modification of classical neurochemical markers in identified primary afferent neurons with Abeta-, Adelta-, and C-fibers after chronic constriction injury in mice.

It is functionally important to differentiate between primary afferent neurons with A-fibers, which are nociceptive or nonnociceptive, and C-fibers, which are mainly nociceptive. Neurochemical markers such as neurofilament 200 (NF200), substance P (SP), and isolectin B4 (IB4) have been useful to distinguish between A- and C-fiber neurons. However, the expression patterns of these markers change after peripheral nerve injury, so that it is not clear whether they still distinguish between fiber types in models of neuropathic pain. We identified neurons with Abeta-, Adelta-, and C-fibers by their conduction velocity (corrected for utilization time) in dorsal root ganglia taken from mice after a chronic constriction injury (CCI) of the sciatic nerve and control mice, and later stained them for IB4, SP, calcitonin gene-related peptide (CGRP), NF200, and neuropeptide Y (NPY). NF200 remained a good marker for A-fiber neurons, and IB4 and SP remained good markers for C-fiber neurons after CCI. NPY was absent in controls but was expressed in A-fiber neurons after CCI. After CCI, a group of C-fiber neurons emerged that expressed none of the tested markers. The size distribution of the markers was investigated in larger samples of unidentified dorsal root ganglion neurons and, together with the results from the identified neurons, provided only limited evidence for the expression of SP in Abeta-fiber neurons after CCI. The extent of up-regulation of NPY showed a strong inverse correlation with the degree of heat hyperalgesia.

Enzyme replacement therapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy.

BACKGROUND: Peripheral neuropathy in Fabry disease predominantly involves small nerve fibers. Recently, enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase A has become available. OBJECTIVE: To evaluate whether ERT improves Fabry neuropathy. METHODS: In 22 Fabry patients (age 27.9 +/- 8.0 years) undergoing ERT with recombinant human alpha-galactosidase A (agalsidase beta) for 18 (n = 11) or 23 (n = 11) months and in 25 control subjects (age 29.0 +/- 10.4 years), the authors performed quantitative sensory testing using the 4, 2, and 1 stepping algorithm (CASE IV). Detection thresholds of vibration (VDT) on the first toe were assessed; cold detection thresholds (CDT), heat-pain onset (HP 0.5), and intermediate heat-pain (HP 5.0) assessments were made on the dorsum of the feet. Patient values above mean + 2.5 SD of control values were considered abnormal. RESULTS: Before ERT, VDT, CDT, HP 0.5, and HP 5.0 were higher in patients than control subjects (p < 0.05). Following ERT, patients developed lower thresholds than prior to ERT for VDT (15.5 +/- 3.5 vs 14.3 +/- 4.1; p < 0.05), HP 0.5 (22.3 +/- 6.7 vs 19.4 +/- 1.3; p < 0.01), and HP 5.0 (27.3 +/- 5.6 vs 22.5 +/- 2.3; p < 0.01). Moreover, fewer patients had abnormal results of VDT (2 vs 4), CDT (7 vs 12), HP 0.5 (0 vs 9), and HP 5.0 (4 vs 20) after than before ERT. CONCLUSIONS: ERT therapy with agalsidase beta significantly improves function of C-, Adelta-, and Abeta-nerve fibers and intradermal vibration receptors in Fabry neuropathy. Lack of recovery in some patients with abnormal cold or heat-pain perception suggests the need for early ERT, prior to irreversible nerve fiber loss.

A myelo-architectonic method for the structural classification of cortical areas.

We describe an automatic and reproducible method to analyze the histological design of the cerebral cortex as applied to brain sections stained to reveal myelinated fibers. The technique provides an evaluation of the distribution of myelination across the width of the cortical mantle in accordance with a model of its curvature and its intrinsic geometry. The profile lines along which the density of staining is measured are generated from the solution of a partial differential equation (PDE) that models the intermediate layers of the cortex. Cortical profiles are classified according to significant components that emerge from wavelet analysis. Intensity profiles belonging to each distinct class are normalized and averaged to produce area-specific templates of cortical myelo-architecture.

Capsaicin responses in heat-sensitive and heat-insensitive A-fiber nociceptors.

The recently cloned vanilloid receptor (VR1) is postulated to account for heat and capsaicin sensitivity in unmyelinated afferents. We sought to determine whether heat and capsaicin sensitivity also coexist in myelinated nociceptive afferents. Action potential (AP) activity was recorded from single A-fiber nociceptors that innervated the hairy skin in monkey. Before intradermal injection of capsaicin (10 microg/10 microl) into the receptive field, nociceptors were classified as heat-sensitive (threshold,

The classification and properties of nociceptive afferent units from the skin of the anaesthetized pig.

The afferent properties of nerve fibres innervating the hairy skin of the pig hind limb were investigated by recording from 142 single units from the saphenous nerve. Identified single units were isolated using maximal electrical stimulation of the nerve trunk. Afferent units were classified on the basis of their responses to a range of stimuli, both thermal (heating to 60 degrees C and cooling to 10 degrees C) and mechanical (air jet, von Frey type filaments with forces of 0.1-250 mN, and strong pressure with a blunt needle). A-fibre units (conduction velocity 6.3-64 m/s, n = 60) fell into categories that have been described in hairy skin in other mammalian species. Most were mechanoreceptors, although seven typical A-fibre mechanical nociceptors with large, multipoint fields were also isolated. No cutaneous receptive field could be found for 15% of A-fibre units. Out of 62 C-fibre units (conduction velocity 0.49-2 m/s) 40% had no cutaneous field for pressure, heat or cold. Of the C-fibre units with cutaneous fields, 42% were polymodal nociceptors, 38% were mechanoreceptors with a variety of properties, including some excited by noxious heat, and 19% were heat-only nociceptors. C-polymodal nociceptors had large receptive fields up to 12.5 mm across and did not sensitize following strong heating. Twenty units conducted at 2-6.3 m/s, between the main C- and A-fibre bands, and were varied in their responses. Some had properties identical to C-fibre mechanoreceptors whilst four were sensitive cold thermoreceptors and one was a polymodal nociceptor. Two units were mechanical nociceptors with small receptive fields.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral neuropathy in myotonic dystrophy: a nerve biopsy study.

Sural nerve biopsies from 13 unselected myotonic dystrophy patients and 6 normal controls were studied morphometrically. The myelinated fiber density was reduced in 11 of the 13 myotonic dystrophy patients, with preferential loss of large myelinated fibers. Unmyelinated fiber densities and diameters were normal. Teased fiber studies commonly revealed focal areas of remyelination and abnormal wrinkling of the myelin sheath. Measurement of internodal length disclosed features of both axonal regeneration and focal demyelination-remyelination. These findings are consistent with a chronic axonopathy of moderate severity, possibly due to axonal atrophy.