Pairwise interaction Markov model for 3D epidermal nerve fibre endings.

In this paper, the spatial arrangement and possible interactions between epidermal nerve fibre endings are investigated and modelled by using confocal microscopy data. We are especially interested in possible differences between patterns from healthy volunteers and patients suffering from mild diabetic neuropathy. The locations of the points, where nerves enter the epidermis, the first branching points and the points where the nerve fibres terminate, are regarded as realizations of spatial point processes. We propose an anisotropic point process model for the locations of the nerve fibre endings in three dimensions, where the points interact in cylindrical regions. First, the locations of end points in R 2 $\mathbb {R}^2$ are modelled as clusters around the branching points and then, the model is extended to three dimensions using a pairwise interaction Markov field model with cylindrical neighbourhood for the z-coordinates conditioned on the planar locations of the points. We fit the model to samples taken from healthy subjects and subjects suffering from diabetic neuropathy. In both groups, after a hardcore radius, there is some attraction between the end points. However, the range and strength of attraction are not the same in the two groups. Performance of the model is evaluated by using a cylindrical version of Ripley's K function due to the anisotropic nature of the data. Our findings suggest that the proposed model is able to capture the 3D spatial structure of the end points.

Neurophysiologic assessment of small fibre damage in chemotherapy-induced peripheral neuropathy.

OBJECTIVE: In patients with chemotherapy-induced peripheral neuropathy (CIPN), demonstration of small fibre (SF) damage is important to understand chronic late effects. METHODS: Thirty patients having complaints compatible with possible CIPN following treatment with oxaliplatin or docetaxel were compared with 27 healthy subjects. All subjects were evaluated with quantitative sensory testing (QST) assessing SF function and laser evoked potentials (LEP). In addition, SF-damage was assessed using cutaneous silent periods evoked with electrical (El-CSP) and laser (Ls-CSP) stimuli. RESULTS: For LEP, N2P2 amplitudes were significantly smaller in patients than controls in both upper (P = 0.007) and lower extremities (P = 0.002), and the N1 amplitude in upper extremities of patients were significantly smaller than in controls (P = 0.001). SF-QST, LEP, Ls-CSP, and El-CSP were abnormal in 10 (33.3%), 16 (53.3%), 19 (63.3%), and 24 (80%) of CIPN patients, respectively. CONCLUSIONS: In patients with possible CIPN, El-CSP and Ls-CSP were more often abnormal than LEP and QST. This is probably because El-CSP and Ls-CSP inform mainly about peripheral nociceptive fibres, while LEP and QST inform about peripheral and central nociceptive pathways together. SIGNIFICANCE: LEP and QST are established methods to detect SF-damage. El- and Ls-CSP might help clinicians in diagnosing SF-damage.

Behavioural, morphological and electrophysiological assessment of the effects of type 2 diabetes mellitus on large and small nerve fibres in Zucker diabetic fatty, Zucker lean and Wistar rats.

BACKGROUND: Peripheral neuropathy is a common complication in type 2 diabetes mellitus (T2DM). The most common presentation is in the form of a distal axonal sensory-motor polyneuropathy that involves large and small nerve fibres in variable proportion. METHODS: Zucker Diabetic Fatty (ZDF), Zucker Lean (ZL) and Wistar Han (WH) rats were used to assess the behavioural, morphological and electrophysiological effects that T2DM have on peripheral large and small nerve fibres of 6- to 40-week-old rats. RESULTS: ZDF rats presented mechanical hypersensitivity that initially worsened in parallel to the progression of diabetes and eventually reverted at later stages of the disease. The reversal from hypersensitivity to hyposensitivity paralleled a reduction in the number of intraepithelial skin nerve terminals and in the nerve fibre lengths. However, no increased levels of degeneration of dorsal root ganglion neurons were observed. Nerve conduction studies showed a reduction in sensory and motor nerve conduction velocity (CV) in hyperglycaemic ZDF rats. Microneurography showed significant alterations in several parameters of activity-dependent slowing (ADS) of mechano-insensitive C-nociceptors in ZDF rats. Surprisingly, some of these changes were also observed in ZL rats. Moreover, we found spontaneous activity in all three strains implying that C-nociceptors become hyperexcitable and spontaneously active not only in ageing hyperglycaemic ZDF rats but also in age-matched and apparently normoglycaemic ZL and WH rats fed with the same diet. CONCLUSIONS: ZDF rats presented a diabetic neuropathy involving large and small nerve fibres; additionally, ZL and WH rats also showed early small abnormalities in C-fibres, clearly detected by microneurography SIGNIFICANCE: This study provides a functional description of large and small nerve fibre function in a diabetic model that recapitulates many of the findings observed in patients suffering from type 2 diabetes mellitus.

In vivo assessment of nervous fiber distribution in the intervertebral disc.

This present study aims to assess in vivo the nervous fibers distribution in the intervertebral disc using diffusion tensor imaging technique. Five healthy subjects participated into the data acquisition. Fiber extraction and tracking algorithms were used. The number of fibers in L4/5 disc ranges from 314 to 679 and the mean fiber length L4/5 in disc ranges from 8.22 ± 2.36 mm to 11.24 ± 5.17 mm. This study showed the feasibility of using diffusion tensor imaging technique to detect and assess the nervous fibers in the intervertebral discs. This could be of great clinical interest for the study of the correlations between these useful characteristics with pain levels on the low back pain patients.

Ophthalmoscopic assessment of the retinal nerve fiber layer. The Beijing Eye Study.

PURPOSE: To examine the retinal nerve fiber layer (RNFL) ophthalmoscopically, to search for localized RNFL defects, and to assess factors associated with RNFL visibility in a population-based setting. METHODS: The population-based cross-sectional Beijing Eye Study 2006 included 3251 subjects. Using color fundus photographs, RNFL visibility was assessed in grades from 0 to 8 in 8 fundus sectors. Localized RNFL defects were defined as wedge-shaped defects running towards the optic disc. RESULTS: After exclusion of subjects with optic media opacities, 2602 subjects (mean age: 58.1±9.0 years) were included. RNFL visibility score was highest (P<0.001) in the temporal inferior region, followed by the temporal superior region, nasal superior region, and nasal inferior region. In multivariate analysis, higher RNFL visibility score was associated with younger age (P<0.001; standardized coefficient beta: -0.44; regression coefficient B: -0.22; 95%CI: -0.24, -0.20), female gender (P<0.001; beta: 0.11; B: 1.00; 95%CI: 0.67, 1.32), higher blood concentration of low-density lipoproteins (P = 0.002; beta: 0.07; B: 0.34; 95%CI: 0.13, 0.56), absence of dyslipidemia (P = 0.001; beta: -0.07; B: -0.58; 95%CI: -0.93, -0.24), lower blood glucose concentration (P = 0.006; beta: -0.05; B: -0.14; 95%CI: -0.24, -0.04), hyperopic refractive error (P<0.001; beta: 0.15; B: 0.45; 95%CI: 0.34, 0.56), smaller optic disc size (P<0.001; beta: -0.08; B: -0.72; 95% CI: -1.04, -0.40), absence of glaucomatous optic neuropathy (P<0.001; beta: -0.06; B: -2.69; 95%CI: -4.18, -1.21) and absence of non-glaucomatous optic nerve damage (P = 0.001; beta: -0.06; B: -4.80; 95%CI: 0. -7.64, -1.96). Localized RNFL defects were detected in 96 subjects (prevalence:3.7±0.45% (95% confidence interval (CI): 3.0, 4.4). In multivariate analysis, prevalence of localized RNFL defects was associated with higher blood pressure (P<0.001; odds ratio (OR): 1.07; 95%CI: 1.03, 1.10), higher concentration of low-density lipoproteins (P = 0.01; OR: 1.42; 95%CI: 1.08, 1.85), higher prevalence of glaucomatous optic neuropathy (P<0.001; OR: 46.8; 95%CI: 19.4, 113) and diabetic retinopathy (P = 0.002; OR: 3.20; 95%CI: 1.53, 6.67), and lower total RNFL visibility (P<0.001; OR: 0.92; 95%CI: 0.88, 0.96). CONCLUSIONS: In Chinese aged 45+ years, a decreased RNFL visibility was associated with older age, male gender, dyslipidemia, hyperglycemia, myopia, larger optic disc, and glaucomatous or non-glaucomatous optic neuropathy. Localized RNFL defects (prevalence: 3.7±0.45%) were correlated mainly with higher blood pressure, higher concentration of low-density lipoproteins, glaucomatous optic neuropathy and diabetic retinopathy. These data are helpful for the routine ophthalmoscopic examination of the RNFL.

Central synapses release a resource-efficient amount of glutamate.

Why synapses release a certain amount of neurotransmitter is poorly understood. We combined patch-clamp electrophysiology with computer simulations to estimate how much glutamate is discharged at two distinct central synapses of the rat. We found that, regardless of some uncertainty over synaptic microenvironment, synapses generate the maximal current per released glutamate molecule while maximizing signal information content. Our result suggests that synapses operate on a principle of resource optimization.

Thermal record of the test tubes method used for small fibers assessment / Registro térmico do método dos tubos de ensaio aplicado na avaliação de fibras finas

In Brazil, the test that uses test tubes filled with cold water (25ºC) and tubes filled with water heated to a temperature of 45ºC is recommended by the Ministry of Health as a way of evaluate thermal sensitivity on the injured skin of leprosy patients. The purpose of this work was to quantify the thermal stimulation applied to the skin, as well as the temperature variation of the heated water and of the tube's outer surface during stimulation sessions. The experiment had the participation of 14 healthy volunteers (31.2±11.4 years-old), ten of which were male (33.1±13.5 years-old) and four were female (26.5±4.7 years-old). Three consecutive stimulation sessions were carried out, each of them with four stimuli. The maximum skin temperature at the end of the stimuli was measured at 35.8±0.6ºC. Such temperature values may be useful in the assessment of the loss of small fibers, which are responsible for the sensation of warmth.

No Brasil, o teste que utiliza tubos de ensaio preenchidos com água aquecida (45ºC) e resfriada (25ºC) é preconizado pelo Ministério da Saúde como forma de avaliar a sensibilidade térmica nas lesões de pele de pacientes com hanseníase. O objetivo deste trabalho foi quantificar o estímulo térmico na pele e a variação das temperaturas da água aquecida e da superfície externa do tubo, durante as sessões de estimulação. O experimento contou com 14 voluntários saudáveis (31,2±11,4 anos), sendo dez do gênero masculino (33,1±13,5 anos) e quatro do gênero feminino (26,5±4,7 anos). Realizaram-se três sessões seguidas de estimulação com quatro estímulos em cada sessão. A temperatura registrada na pele, ao final dos estímulos, apresentou diferenças entre as sessões, atingindo o máximo de 35,8±0,6ºC. Estes valores de temperatura podem ser úteis na avaliação da perda de fibras finas responsáveis pela sensação de aquecimento.

Direct segmentation of the major white matter tracts in diffusion tensor images.

Diffusion-weighted images of the human brain are acquired more and more routinely in clinical research settings, yet segmenting and labeling white matter tracts in these images is still challenging. We present in this paper a fully automated method to extract many anatomical tracts at once on diffusion tensor images, based on a Markov random field model and anatomical priors. The approach provides a direct voxel labeling, models explicitly fiber crossings and can handle white matter lesions. Experiments on simulations and repeatability studies show robustness to noise and reproducibility of the algorithm, which has been made publicly available.

Allopregnanolone prevents and suppresses oxaliplatin-evoked painful neuropathy: multi-parametric assessment and direct evidence.

Oxaliplatin (OXAL) is a platinum-based drug used for the treatment of colorectal, lung, breast and ovarian cancers. OXAL does not cause renal or hematologic toxicity. However, OXAL induces neuropathic pain which hampers the chemotherapy success. Attempts with neuroprotective agents including anticonvulsivants and antidepressants were made to prevent OXAL-induced painful neuropathy but the clinical data are controversial and the tested neuroprotectors are able to evoke themselves undesirable effects. Here, we demonstrated that the natural neurosteroid allopregnanolone (3α,5α-THP), known to be devoid of toxic side-effects in humans and experimental models, prevented and suppressed OXAL-induced painful neuropathic symptoms. Indeed, 3α,5α-THP repaired OXAL-evoked neurochemical and functional alterations in peripheral nerves and intra-epidermal nerve fibers (IENF). Behavioral analyses showed that prophylactic or corrective 3α,5α-THP treatment (4mg/kg/2days) respectively prevented or abolished OXAL-induced cold allodynia, mechanical allodynia and hyperalgesia by reversing to normal decreased thermal and mechanical pain thresholds of OXAL-treated rats. Electrophysiological investigations revealed that 3α,5α-THP restored control values of sciatic nerve conduction velocity and action potential peak amplitude drastically reduced by OXAL-treatment. Furthermore, immunohistochemistry and confocal microscopic quantifications demonstrated that 3α,5α-THP repaired OXAL-induced neurochemical/cellular alterations by restoring IENF control density and normal level of neurofilament 200kDa that was strongly repressed by OXAL in dorsal root ganglion neurons and sciatic nerve axons. OXAL showed no toxicity for the non-compact myelin protein 2',3'-cyclic-nucleotide-3'-phosphodiesterase whose expression level was similarly increased by 3α,5α-THP in controls and OXAL-treated rat nerves. Together, these results may be interesting for the development of natural or safe neurosteroid-based neuroprotective strategy against anticancer drug-evoked painful neuropathy.

Thermal record of the test tubes method used for small fibers assessment.

In Brazil, the test that uses test tubes filled with cold water (25ºC) and tubes filled with water heated to a temperature of 45ºC is recommended by the Ministry of Health as a way of evaluate thermal sensitivity on the injured skin of leprosy patients. The purpose of this work was to quantify the thermal stimulation applied to the skin, as well as the temperature variation of the heated water and of the tube's outer surface during stimulation sessions. The experiment had the participation of 14 healthy volunteers (31.2 ± 11.4 years-old), ten of which were male (33.1 ± 13.5 years-old) and four were female (26.5 ± 4.7 years-old). Three consecutive stimulation sessions were carried out, each of them with four stimuli. The maximum skin temperature at the end of the stimuli was measured at 35.8 ± 0.6ºC. Such temperature values may be useful in the assessment of the loss of small fibers, which are responsible for the sensation of warmth.

Estimation of diffusion properties in crossing fiber bundles.

There is an ongoing debate on how to model diffusivity in fiber crossings. We propose an optimization framework for the selection of a dual tensor model and the set of diffusion weighting parameters b, such that both the diffusion shape and orientation parameters can be precisely as well as accurately estimated. For that, we have adopted the Cramér-Rao lower bound (CRLB) on the variance of the model parameters, and performed Monte Carlo simulations. We have found that the axial diffusion lambda(parallel) needs to be constrained, while an isotropic fraction can be modeled by a single parameter f(iso). Under these circumstances, the Fractional Anisotropy (FA) of both tensors can theoretically be independently estimated with a precision of 9% (at SNR = 25). Levenberg-Marquardt optimization of the Maximum Likelihood function with a Rician noise model approached this precision while the bias was insignificant. A two-element b-vector b = [1.0 3.5] x 10(3) mm(-2)s was found to be sufficient for estimating parameters of heterogeneous tissue with low error. This has allowed us to estimate consistent FA-profiles along crossing tracts. This work defines fundamental limits for comparative studies to correctly analyze crossing white matter structures.

Physical neurosensory testing versus current perception threshold assessment in trigeminal nerve injuries related to dental treatment: a retrospective study.

OBJECTIVE: To provide a preliminary comparison of traditional clinical neurosensory examination (CNE) and current perception threshold (CPT). METHOD AND MATERIALS: This is a retrospective chart audit of patients with trigeminal nerve injuries related to dental treatment who were evaluated with both CNE and CPT assessments (electrical stimulus tests) after presenting with altered sensation involving either the inferior alveolar nerve (IAN) or lingual nerve (LN) distributions. The tests were performed on the anterior two-thirds of the tongue for LN injuries and the lower lip and chin for IAN injuries. Results were defined as hyper-, hypo-, or normal sensory response. RESULTS: Twelve charts were reviewed; 10 of the 12 nerve injuries occurred secondary to mandibular third molar extraction affecting 7 LN and 5 IAN branches. Following LN injuries, the C, and A-delta fibers assessment demonstrated hyposensitivity in the affected nerve territory in CPT and the CNE tests with the exception of 1 normal nerve response in 5-Hz CPT. Within the LN injury group, good correlation was observed between the CNE and CPT tests with the exception of brush stroke and 250-Hz CPT stimuli. Following IAN injuries, sensory testing results were more varied. A-beta fiber evaluation demonstrated hyposensitivity to VF in all patients and in 4 of 5 for brush test. One patient was hypersensitive for the brush test. The response to 2,000-Hz electrical stimulus demonstrated hyposensitivity in 3 patients, hypersensitivity in 1 (the same patient that was hypersensitive for brush), and normal sensitivity in 1 patient. Good correlations were found only between the CPT 5-Hz and heat and cold tests. Only 1 patient (IAN injury) reported pain that was hypersensitive for heat, cold, pinprick, brush, and 250-Hz and 2,000-Hz stimuli. CONCLUSION: Following LN injuries, CNE and CPT tests provided similar findings. More disparity was observed between the CNE and CPT methods in the IAN injury evaluation. For LN injury assessments, CNE alone appears to be adequate for assessing nerve injuries.

Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse.

BACKGROUND: Psychiatric sequelae of exposure to parental verbal abuse (PVA) appear to be comparable with that of nonfamilial sexual abuse and witnessing domestic violence. Diffusion tensor imaging (DTI) was used to ascertain whether PVA was associated with abnormalities in white matter (WM) tract integrity. METHODS: 1271 healthy young adults were screened for exposure to childhood adversity. Diffusion tensor imaging was collected on 16 unmedicated subjects with history of high-level exposure to PVA but no other form of maltreatment (4 male/12 female subjects, mean age 21.9 +/- 2.4 years) and 16 healthy control subjects (5 male/11 female subjects, 21.0 +/- 1.6 years). Group differences in fractional anisotropy (FA), covaried by parental education and income, were assessed using tract-based spatial statistics (TBSS). RESULTS: Three WM tract regions had significantly reduced FA: 1) arcuate fasciculus in left superior temporal gyrus, 2) cingulum bundle by the posterior tail of the left hippocampus, and 3) the left body of the fornix. Fractional anisotropy in these areas was strongly associated with average PVA scores (r(s) = -.701, -.801, -.524, respectively) and levels of maternal verbal abuse. Across groups, FA in region 1 correlated with verbal IQ and verbal comprehension index. Fractional anisotropy in region 2 was inversely associated with ratings of depression, dissociation, and limbic irritability. Fractional anisotropy in region 3 was inversely correlated with ratings of somatization and anxiety. CONCLUSIONS: Exposure to PVA may be associated with alteration in the integrity of neural pathways with implications for language development and psychopathology.

In vitro assessment of the effects of cadmium and zinc on mammalian nerve fibres.

Zinc and cadmium are environmental contaminants that have a wide range of effects on the nervous system, but zinc is also considered to be an important metal in the human body. In this study the effect of CdCl(2) and ZnCl(2), at concentrations of 50,150, 250 and 500 microM, on the nerve fibres of the sciatic nerve of the rat isolated in a three-chamber recording bath were studied. At the same concentrations, CdCl(2) and ZnCl(2) were found to have almost the same inhibitory effect on the compound action potential (CAP) of the nerve fibres. Their concentration-effect curves almost overlap and there was no significant difference in their EC(50) which for CdCl(2) is 250.1+/-18 microM (n=5) and for ZnCl(2) is 282.2+/-25 microM (n=5) correspondingly (P>0.05). The no-observed-effect concentration (NOEC) was estimated to be 50-100 microM for both metals. The identical inhibitory effect of both metals on the sciatic nerve fibres indicates a common mode of action which is related to their potential to generate reactive oxygen species (ROS).

Use of the novel Contact Heat Evoked Potential Stimulator (CHEPS) for the assessment of small fibre neuropathy: correlations with skin flare responses and intra-epidermal nerve fibre counts.

BACKGROUND: The Contact Heat Evoked Potential Stimulator (CHEPS) rapidly stimulates cutaneous small nerve fibres, and resulting evoked potentials can be recorded from the scalp. We have studied patients with symptoms of sensory neuropathy and controls using CHEPS, and validated the findings using other objective measures of small nerve fibres i.e. the histamine-induced skin flare response and intra-epidermal fibres (IEF), and also quantitative sensory testing (QST), a subjective measure. METHODS: In patients with symptoms of sensory neuropathy (n = 41) and healthy controls (n = 9) we performed clinical examination, QST (monofilament, vibration and thermal perception thresholds), nerve conduction studies, histamine-induced skin flares and CHEPS. Skin punch biopsies were immunostained using standard ABC immunoperoxidase for the nerve marker PGP 9.5 or the heat and capsaicin receptor TRPV1. Immunoreactive IEF were counted per length of tissue section and epidermal thickness recorded. RESULTS: Amplitudes of Adelta evoked potentials (muV) following face, arm or leg stimulation were reduced in patients (e.g. for the leg: mean +/- SEM - controls 11.7 +/- 1.95, patients 3.63 +/- 0.85, p = 0.0032). Patients showed reduced leg skin flare responses, which correlated with Adelta amplitudes (rs = 0.40, p = 0.010). In patient leg skin biopsies, PGP 9.5- and TRPV1-immunoreactive IEF were reduced and correlated with Adelta amplitudes (PGP 9.5, rs = 0.51, p = 0.0006; TRPV1, rs = 0.48, p = 0.0012). CONCLUSION: CHEPS appears a sensitive measure, with abnormalities observed in some symptomatic patients who did not have significant IEF loss and/or QST abnormalities. Some of the latter patients may have early small fibre dysfunction or ion channelopathy. CHEPS provides a clinically practical, non-invasive and objective measure, and can be a useful additional tool for the assessment of sensory small fibre neuropathy. Although further evaluation is required, the technique shows potential clinical utility to differentiate neuropathy from other chronic pain states, and provide a biomarker for analgesic development.

Bayesian regularization of diffusion tensor images.

Diffusion tensor imaging (DTI) is a powerful tool in the study of the course of nerve fiber bundles in the human brain. Using DTI, the local fiber orientation in each image voxel can be described by a diffusion tensor which is constructed from local measurements of diffusion coefficients along several directions. The measured diffusion coefficients and thereby the diffusion tensors are subject to noise, leading to possibly flawed representations of the 3-dimensional (3D) fiber bundles. In this paper, we develop a Bayesian procedure for regularizing the diffusion tensor field, fully utilizing the available 3D information of fiber orientation. The use of the procedure is exemplified on synthetic and in vivo data.

Modelo experimental comportamental e histológico da regeneração do nervo facial em ratos / Behavioral and histologic experimental model of facial nerve regeneration in rats

O estabelecimento de modelos experimentais é o passo inicial para estudos de regeneração neural. OBJETIVO: Estabelecer modelo experimental de regeneração do nervo facial. MATERIAIS E MÉTODOS: Ratos Wistar com secção completa e sutura do tronco do nervo facial extratemporal, com análise comportamental e histológica até 9 semanas. FORMA DE ESTUDO: Estudo prospectivo experimental. RESULTADOS: Progressiva recuperação clínica e histológica dos animais. CONCLUSÃO: Estabelecemos um método aceitável para o estudo de regeneração do nervo facial em ratos.

To setup an experimental model is the first step to study neural regeneration. AIM: Setting up an experimental model on facial nerve regeneration. MATERIAL AND METHODS Wistar rats with complete sectioning and suturing of the extratemporal facial nerve trunk; with a behavioral and histological analysis for 9 weeks. STUD DESIGN: Experimental prospective study. RESULTS: Progressive clinical and histological recovery of the animals. CONCLUSION: Our method is acceptable to study facial nerve regeneration in rats.

The ulnar test: a method for the quantitative functional assessment of posttraumatic ulnar nerve recovery in the rat.

The assessment of recovery of the neuromuscular function following nerve lesion and repair is one of the main goals of peripheral nerve researchers. The forelimb model has recently seen an increase in its employment for experimental nerve repair studies especially because of the availability of the grasping test for assessing the functional recovery of one of its major nerves, the median nerve. Nerve repair studies sometimes require the use of more than one nerve to simulate severe clinical situations and, in this case, the ulnar nerve is often used together with the median nerve. However, a test for assessing ulnar nerve functional recovery is yet not available. To fill this gap, we have developed and experimentally tested a method for the functional assessment of posttraumatic ulnar nerve recovery in the rat. Animal testing using this method is simple, quick and provides the animal with minimal distress. The method proved to be effective in detecting the date on which recovery starts after ulnar nerve impairment and in following its improvement, over time. The availability of this new test is expected to further increase the employment of forelimb experimental nerve models instead of the more disabling hindlimb models.