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1.
Adv Exp Med Biol ; 1190: 65-83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760639

RESUMO

Propagation of action potentials along axons is optimized through interactions between neurons and myelinating glial cells. Myelination drives division of the axons into distinct molecular domains including nodes of Ranvier. The high density of voltage-gated sodium channels at nodes generates action potentials allowing for rapid and efficient saltatory nerve conduction. At paranodes flanking both sides of the nodes, myelinating glial cells interact with axons, forming junctions that are essential for node formation and maintenance. Recent studies indicate that the disruption of these specialized axonal domains is involved in the pathophysiology of various neurological diseases. Loss of paranodal axoglial junctions due to genetic mutations or autoimmune attack against the paranodal proteins leads to nerve conduction failure and neurological symptoms. Breakdown of nodal and paranodal proteins by calpains, the calcium-dependent cysteine proteases, may be a common mechanism involved in various nervous system diseases and injuries. This chapter reviews recent progress in neurobiology and pathophysiology of specialized axonal domains along myelinated nerve fibers.


Assuntos
Axônios/fisiologia , Fibras Nervosas Mielinizadas/fisiologia , Condução Nervosa , Axônios/patologia , Humanos , Fibras Nervosas Mielinizadas/patologia , Neuroglia/patologia , Neuroglia/fisiologia
2.
PLoS Comput Biol ; 15(10): e1007004, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31622338

RESUMO

With the advent of advanced MRI techniques it has become possible to study axonal white matter non-invasively and in great detail. Measuring the various parameters of the long-range connections of the brain opens up the possibility to build and refine detailed models of large-scale neuronal activity. One particular challenge is to find a mathematical description of action potential propagation that is sufficiently simple, yet still biologically plausible to model signal transmission across entire axonal fibre bundles. We develop a mathematical framework in which we replace the Hodgkin-Huxley dynamics by a spike-diffuse-spike model with passive sub-threshold dynamics and explicit, threshold-activated ion channel currents. This allows us to study in detail the influence of the various model parameters on the action potential velocity and on the entrainment of action potentials between ephaptically coupled fibres without having to recur to numerical simulations. Specifically, we recover known results regarding the influence of axon diameter, node of Ranvier length and internode length on the velocity of action potentials. Additionally, we find that the velocity depends more strongly on the thickness of the myelin sheath than was suggested by previous theoretical studies. We further explain the slowing down and synchronisation of action potentials in ephaptically coupled fibres by their dynamic interaction. In summary, this study presents a solution to incorporate detailed axonal parameters into a whole-brain modelling framework.


Assuntos
Mapeamento Encefálico/métodos , Sincronização Cortical/fisiologia , Fibras Nervosas Mielinizadas/fisiologia , Potenciais de Ação/fisiologia , Algoritmos , Animais , Axônios/fisiologia , Encefalopatias Metabólicas , Simulação por Computador , Humanos , Modelos Neurológicos , Bainha de Mielina/fisiologia , Condução Nervosa/fisiologia , Substância Branca
3.
Muscle Nerve ; 60(5): 575-579, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31443127

RESUMO

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting the peripheral nervous system. However, studies evaluating somatic small fiber sensory nerve function, which may contribute to pain in DM1, are lacking. METHODS: Using quantitative sensory testing of the hand and foot, we evaluated Aδ and C-fiber function. Of 20 adult DM1 patients recruited, 16 were analyzed. Their results were compared with those of 32 age- and sex-matched controls. RESULTS: No DM1 patient had diabetes mellitus or clinical evidence of small fiber neuropathy. In DM1, hand (P < .01) and foot (P = 0.02) warm detection thresholds were higher than those of controls. Cool detection thresholds were lower in the foot (P < .001). CONCLUSIONS: Subclinical small sensory fiber dysfunction occurs in DM1 patients without large fiber neuropathy. Further research with other modalities is required to characterize these disturbances as disease modifying therapies are developed.


Assuntos
Distrofia Miotônica/fisiopatologia , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Limiar Sensorial , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Pé/inervação , Mãos/inervação , Humanos , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Sensação Térmica/fisiologia , Adulto Jovem
4.
Muscle Nerve ; 60(4): 367-375, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31107560

RESUMO

INTRODUCTION: Topical application of lidocaine-and-prilocaine (LP) cream attenuates the functionality of small cutaneous nerve fibers. The aim of this human study was to measure the underlying excitability modulation of small cutaneous nerve fibers using a novel and fast perception threshold tracking (PTT) technique. METHODS: Small sensory fibers were selectively blocked by 120-minute topical application of LP and confirmed by quantitative sensory testing. Excitability changes of small (activated by a specially designed pin electrode) and large (patch electrode) nerve fibers were assessed as the strength-duration relation and threshold electrotonus. RESULTS: The excitability assessed by the strength-duration relation and threshold electrotonus was significantly modulated for the small afferents (P < 0.05, Wilcoxon's test) but not the large afferents. DISCUSSION: This novel PTT technique was able to assess inhibition of membrane properties of small cutaneous fibers, suggesting the usefulness of the technique as a diagnostic method for assessing impairment of small fibers, as seen in many types of polyneuropathies.


Assuntos
Anestésicos Locais/farmacologia , Combinação Lidocaína e Prilocaína/farmacologia , Fibras Nervosas Mielinizadas/efeitos dos fármacos , Limiar Sensorial/efeitos dos fármacos , Neuropatia de Pequenas Fibras/diagnóstico , Administração Cutânea , Adulto , Estudos Cross-Over , Método Duplo-Cego , Estimulação Elétrica , Eletrodiagnóstico , Feminino , Voluntários Saudáveis , Humanos , Masculino , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/efeitos dos fármacos , Fibras Nervosas Amielínicas/fisiologia , Limiar Sensorial/fisiologia , Adulto Jovem
5.
BMJ ; 365: l1108, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068323

RESUMO

Sensory polyneuropathies, which are caused by dysfunction of peripheral sensory nerve fibers, are a heterogeneous group of disorders that range from the common diabetic neuropathy to the rare sensory neuronopathies. The presenting symptoms, acuity, time course, severity, and subsequent morbidity vary and depend on the type of fiber that is affected and the underlying cause. Damage to small thinly myelinated and unmyelinated nerve fibers results in neuropathic pain, whereas damage to large myelinated sensory afferents results in proprioceptive deficits and ataxia. The causes of these disorders are diverse and include metabolic, toxic, infectious, inflammatory, autoimmune, and genetic conditions. Idiopathic sensory polyneuropathies are common although they should be considered a diagnosis of exclusion. The diagnostic evaluation involves electrophysiologic testing including nerve conduction studies, histopathologic analysis of nerve tissue, serum studies, and sometimes autonomic testing and cerebrospinal fluid analysis. The treatment of these diseases depends on the underlying cause and may include immunotherapy, mitigation of risk factors, symptomatic treatment, and gene therapy, such as the recently developed RNA interference and antisense oligonucleotide therapies for transthyretin familial amyloid polyneuropathy. Many of these disorders have no directed treatment, in which case management remains symptomatic and supportive. More research is needed into the underlying pathophysiology of nerve damage in these polyneuropathies to guide advances in treatment.


Assuntos
Terapias Complementares/métodos , Terapia Genética/métodos , Imunoterapia/métodos , Exame Neurológico/métodos , Polineuropatias/diagnóstico , Humanos , Metanálise como Assunto , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Estudos Observacionais como Assunto , Polineuropatias/fisiopatologia , Polineuropatias/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Comportamento de Redução do Risco , Limiar Sensorial/fisiologia
6.
Front Neural Circuits ; 13: 34, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31133821

RESUMO

Histological studies of myelin-stained sectioned cadaver brain and in vivo myelin-weighted magnetic resonance imaging (MRI) show that the cerebral cortex is organized into cortical areas with generally well-defined boundaries, which have consistent internal patterns of myelination. The process of myelination is largely driven by neural experience, in which the axonal passage of action potentials stimulates neighboring oligodendrocytes to perform their task. This bootstrapping process, such that the traffic of action potentials facilitates increased traffic, suggests the hypothesis that the specific pattern of myelination (myeloarchitecture) in each cortical area reveals the principal cortical microcircuits required for the function of that area. If this idea is correct, the observable sequential maturation of specific brain areas can provide evidence for models of the stages of cognitive development.


Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Modelos Neurológicos , Bainha de Mielina , Fibras Nervosas Mielinizadas/fisiologia , Vias Neurais/crescimento & desenvolvimento , Animais , Humanos
7.
Exp Brain Res ; 237(7): 1735-1744, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31030281

RESUMO

BACKGROUND AND OBJECTIVES: Pain is a complex experience involving both nociceptive and affective-cognitive mechanisms. The present study evaluated whether modulation of pain perception, employing a conditioned pain modulation (CPM) paradigm, is paralleled by changes in contact heat-evoked potentials (CHEPs), a brain response to nociceptive stimuli. METHODS: Participants were 25 healthy, pain-free, college students (12 males, 13 females, mean age 19.24 ± 0.97 years). Twenty computer-controlled heat stimuli were delivered to the non-dominant forearm and CHEPs were recorded at Cz using a 32-channel EEG system. After each stimulus, participants rated the intensity of the heat pain using the 0-100 numerical rating scale. The latency and amplitude of N2, P2 components as well as single-sweep spectral analysis of individual CHEPs were measured offline. For CPM, participants had to submerge their dominant foot into a neutral (32 °C) or noxious (0 °C) water bath. CHEPs and heat pain ratings were recorded in 3 different conditions: without CPM, after neutral CPM (32 °C) and after noxious CPM (0 °C). RESULTS: The noxious CPM induced a facilitatory pain response (p = 0.001) with an increase in heat pain following noxious CPM compared to neutral CPM (p = 0.001) and no CPM (p = 0.001). Changes in CHEPs did not differ between conditions when measured as N2-P2 peak-to-peak amplitude (p = 0.33) but the CPM significantly suppressed the CHEPs-related delta power (p = 0.03). Changes in heat pain in the noxious CPM were predicted by trait catastrophizing variables (p = 0.04). CONCLUSION: The current study revealed that pain facilitatory CPM is related to suppression of CHEPs delta power which could be related to dissociation between brain responses to noxious heat and pain perception.


Assuntos
Encéfalo/fisiopatologia , Catastrofização/fisiopatologia , Medição da Dor/métodos , Percepção da Dor/fisiologia , Dor/fisiopatologia , Catastrofização/diagnóstico , Catastrofização/psicologia , Eletroencefalografia/métodos , Feminino , Temperatura Alta/efeitos adversos , Humanos , Masculino , Fibras Nervosas Mielinizadas/fisiologia , Dor/diagnóstico , Dor/psicologia , Medição da Dor/psicologia , Limiar da Dor/fisiologia , Adulto Jovem
8.
Neuroscience ; 404: 499-509, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30826524

RESUMO

Under pathological conditions, acupoint sensitization is the phenomenon of acupoints transforming from the stable state to the dynamic state. Evidences suggest that hyperpolarization-activated current (Ih), conducted by the hyperpolarization-activated/cyclic nucleotide-gated (HCN) channel, greatly contributes to the peripheral and central sensitization. However, the role of the Ih current in acupoint sensitization has not been explained. In the present study, changes in excitability, Ih density and the HCN channel of dorsal root ganglion (DRG) nociceptive neurons were examined in the later phase of knee osteoarthritis (KOA) rats. To investigate the neuronal specificity of acupoint sensitization, retrograde dyes were injected into the acupoints ST35 and GB37. The results showed that acupoint sensitization occurred in bilateral ST35 but not GB37 acupoints. The excitability and Ih density of C- but not Aδ-type neurons innervating ST35 acupoint increased in bilateral L5 DRG of acupoint sensitized rats than that of sham rats. No obvious changes were found in the excitability or Ih density of C- and Aδ-type neurons innervating the GB37 acupoint in the bilateral L5 DRG. HCN channel subtype 2 (HCN2) expression levels significantly increased after acupoint sensitization. Furthermore, ZD7288, an HCN current (Ih) blocker, attenuated the acupoint sensitization of the ST35 acupoint. Taken together, our findings suggest that the increased excitability of C- but not Aδ-type neurons and the upregulation of Ih/HCN2 channels contribute to the formation of acupoint sensitization.


Assuntos
Pontos de Acupuntura , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/fisiologia , Fibras Nervosas Mielinizadas/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Neurônios/fisiologia , Osteoartrite do Joelho/terapia , Animais , Masculino , Osteoartrite do Joelho/fisiopatologia , Ratos , Ratos Sprague-Dawley
9.
Glia ; 67(7): 1277-1295, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30761608

RESUMO

Multiple extracellular and intracellular signals regulate the functions of oligodendrocytes as they progress through the complex process of developmental myelination and then maintain a functionally intact myelin sheath throughout adult life, preserving the integrity of the axons. Recent studies suggest that Mek/ERK1/2-MAPK and PI3K/Akt/mTOR intracellular signaling pathways play important, often overlapping roles in the regulation of myelination. However, it remains poorly understood whether they function independently, sequentially, or converge using a common mechanism to facilitate oligodendrocyte differentiation, myelin growth, and maintenance. To address these questions, we analyzed multiple genetically modified mice and asked whether the deficits due to the conditional loss-of-function of ERK1/2 or mTOR could be abrogated by simultaneous constitutive activation of PI3K/Akt or Mek, respectively. From these studies, we concluded that while PI3K/Akt, not Mek/ERK1/2, plays a key role in promoting oligodendrocyte differentiation and timely initiation of myelination through mTORC1 signaling, Mek/ERK1/2-MAPK functions largely independently of mTORC1 to preserve the integrity of the myelinated axons during adulthood. However, to promote the efficient growth of the myelin sheath, these two pathways cooperate with each other converging at the level of mTORC1, both in the context of normal developmental myelination or following forced reactivation of the myelination program during adulthood. Thus, Mek/ERK1/2-MAPK and the PI3K/Akt/mTOR signaling pathways work both independently and cooperatively to maintain a finely tuned, temporally regulated balance as oligodendrocytes progress through different phases of developmental myelination into adulthood. Therapeutic strategies aimed at targeting remyelination in demyelinating diseases are expected to benefit from these findings.


Assuntos
MAP Quinase Quinase Quinases/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Bainha de Mielina/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Fatores Etários , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fibras Nervosas Mielinizadas/fisiologia , Transdução de Sinais/fisiologia
10.
Mol Psychiatry ; 24(2): 169-181, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29326435

RESUMO

Intelligence, or general cognitive function, is phenotypically and genetically correlated with many traits, including a wide range of physical, and mental health variables. Education is strongly genetically correlated with intelligence (rg = 0.70). We used these findings as foundations for our use of a novel approach-multi-trait analysis of genome-wide association studies (MTAG; Turley et al. 2017)-to combine two large genome-wide association studies (GWASs) of education and intelligence, increasing statistical power and resulting in the largest GWAS of intelligence yet reported. Our study had four goals: first, to facilitate the discovery of new genetic loci associated with intelligence; second, to add to our understanding of the biology of intelligence differences; third, to examine whether combining genetically correlated traits in this way produces results consistent with the primary phenotype of intelligence; and, finally, to test how well this new meta-analytic data sample on intelligence predicts phenotypic intelligence in an independent sample. By combining datasets using MTAG, our functional sample size increased from 199,242 participants to 248,482. We found 187 independent loci associated with intelligence, implicating 538 genes, using both SNP-based and gene-based GWAS. We found evidence that neurogenesis and myelination-as well as genes expressed in the synapse, and those involved in the regulation of the nervous system-may explain some of the biological differences in intelligence. The results of our combined analysis demonstrated the same pattern of genetic correlations as those from previous GWASs of intelligence, providing support for the meta-analysis of these genetically-related phenotypes.


Assuntos
Inteligência/genética , Neurogênese/genética , Cognição/fisiologia , Análise de Dados , Feminino , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Herança Multifatorial/genética , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/fisiologia , Neurogênese/fisiologia , Polimorfismo de Nucleotídeo Único/genética
11.
Brain Struct Funct ; 224(2): 891-905, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30539288

RESUMO

Microstructural properties of white matter pathways are associated with concurrent reading abilities in children. In this longitudinal study, we asked whether properties of white matter pathways at the onset of learning to read would be associated with reading abilities at older ages. Children (N = 37) with a wide range of reading abilities completed standardized measures of language and phonological awareness and diffusion MRI at age 6 years. Mean tract-fractional anisotropy (FA) was extracted from reading-related pathways. At age 8, the same children were re-assessed using a standardized reading measure. Using linear regressions, we examined the contribution of tract-FA at age 6 to reading outcome at age 8, beyond known demographic and pre-literacy predictors of reading. Tract-FA of the left arcuate, left and right superior longitudinal fasciculus (SLF), and left inferior cerebellar peduncle (ICP) made unique contributions to reading outcome after consideration of sex and family history of reading delays. Tract-FA of the left and right SLF and left ICP made unique contributions to reading outcome after the addition of pre-literacy skills. Thus, cerebellar and bilateral cortical pathways represented a network associated with subsequent reading abilities. Early white matter properties may be associated with other neuropsychological functions that predict reading or may influence reading development, independent of reading-related abilities. Tract FA at early stages of learning to read may serve as a biomarker of later reading abilities.


Assuntos
Encéfalo/diagnóstico por imagem , Fibras Nervosas Mielinizadas/fisiologia , Leitura , Substância Branca/diagnóstico por imagem , Encéfalo/fisiologia , Criança , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Linguagem , Estudos Longitudinais , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologia , Substância Branca/fisiologia
12.
Neuromodulation ; 22(3): 269-279, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30586207

RESUMO

OBJECTIVE: Using computer simulation, we investigated the effect of electrode polarity on neural activation in spinal cord stimulation and propose a new strategy to maximize the activating area in the dorsal column (DC) and, thus, paresthesia coverage in clinical practice. MATERIALS AND METHODS: A new three-dimensional spinal cord model at the T10 vertebral level was developed to simulate neural activation induced by the electric field distribution produced by different typical four-contact electrode polarities in single- and dual-lead stimulation. Our approach consisted of the combination of a finite element model of the spinal cord developed in COMSOL Multiphysics and a nerve fiber model implemented in MATLAB. Five evaluation parameters were evaluated, namely, the recruitment ratio, the perception and discomfort thresholds, and the activating area and depth. The results were compared quantitatively. RESULTS: The dual-guarded cathode presents the maximum activating area and depth in single- and dual-lead stimulation. However, the lowest value of the ratio between the perception threshold in DC and the perception threshold in the dorsal root (DR) is achieved when the guarded cathode is programmed. Although the two versions of bipolar polarity (namely bipolar 1 and bipolar 2) produce higher activating area and depth than the guarded cathode, they are suitable for producing DR stimulation. Similarly, dual-lead stimulation is likely to activate DR fibers because the electrodes are closer to these fibers. CONCLUSIONS: The results suggest that the activating area in the DC is maximized by using the dual-guarded cathode both in single- and dual-lead stimulation modes. However, DC nerve fibers are preferentially stimulated when the guarded cathode is used. According to these results, the new electrode programming strategy that we propose for clinical practice first uses the dual-guarded cathode, but, if the DR nerve fibers are activated, it then uses guarded cathode polarity.


Assuntos
Simulação por Computador , Eletrodos Implantados , Imagem Tridimensional/métodos , Fibras Nervosas Mielinizadas/fisiologia , Parestesia/terapia , Estimulação da Medula Espinal/métodos , Adulto , Humanos , Parestesia/diagnóstico por imagem , Parestesia/fisiopatologia , Estimulação da Medula Espinal/instrumentação , Vértebras Torácicas/diagnóstico por imagem , Adulto Jovem
13.
Neuroscience ; 400: 17-32, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30553796

RESUMO

Despite advances in technology and rehabilitation, no effective therapies are available for patients with SCI, which remains a major medical challenge. This study compared the efficacy of 3 different doses of mesenchymal stem cells (MSCs) administered by intraperitoneal injection as a therapeutic strategy for compressive SCI. We used adult female C57BL/6 mice that underwent laminectomy at the T9 level, followed by spinal-cord compression for 1 min with a 30-g vascular clip. The animals received an intraperitoneal (i.p.) injection of MSCs (8 × 104, 8 × 105 or 8 × 106 in 500 µl) or DMEM (500 µl), one week after SCI. The cells of the three MSC doses administered i.p. were able to migrate to the injury site, increase local expression of trophic factors, and enhance fiber sparing and/or regeneration, accompanied by substantial improvement in locomotor performance. Cell transplantation at 8 × 105 density showed the best therapeutic potential, leading to significant tissue and functional improvements compared to the other two doses. These findings indicate that i.p. application of MSCs at the density of 8 × 105 yielded the best results, suggesting that this dose is a good choice for SCI treatment.


Assuntos
Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/fisiologia , Recuperação de Função Fisiológica , Compressão da Medula Espinal/fisiopatologia , Compressão da Medula Espinal/cirurgia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Gliose/etiologia , Locomoção , Camundongos Endogâmicos C57BL , Fibras Nervosas Mielinizadas/fisiologia , Neurotrofina 3/metabolismo , Compressão da Medula Espinal/complicações
14.
PLoS One ; 13(12): e0208985, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30540822

RESUMO

Elucidating whether there is a correlation between biomechanical functions and histomorphometric data in the rat sciatic nerve crush injury model would contribute to an accurate evaluation of the regeneration state without sacrificing animals. The gold standard for functional evaluation is the sciatic functional index (SFI) despite there being intrinsic shortcomings. Kinematic analysis is considered a reliable and sensitive approach for functional evaluation, most commonly assessed as ankle angle at various phases of a gait cycle. Studies utilizing the toe angle for functional evaluation are scarce, and changes in the toe angle following surgery remain unknown. The present study assessed correlations of ankle angle, toe angle and SFI with histomorphometric data, aiming to determine which parameters most accurately reflect changes in histomorphometric data over time. Six Lewis rats were designated as the control group. 30 animals received surgery, six of them were randomly selected on the first, second, third, fourth, and sixth week after surgery for measurements of ankle and toe angles in the "toe-off" phase, and for evaluation of SFI. Histomorphometric analysis were also performed, to determine the number of myelinated nerve fibers, diameters of myelinated nerve fibers, axon diameters, and myelin sheath thicknesses. Furthermore, we investigated changes in ankle angle, toe angle, SFI, and histomorphometric data over time, as well as correlations between ankle angle, toe angle, and SFI with histomorphometric data. The results revealed that changes in SFI, ankle angle, and toe angle highly correlate with histomorphometric data in the rat sciatic nerve crush injury model. Toe angle reflected changes in histomorphometric data with time more precisely than ankle angle or SFI did, and ankle angle was a better prognostic parameter than SFI.


Assuntos
Fenômenos Biomecânicos , Recuperação de Função Fisiológica , Nervo Isquiático/lesões , Animais , Axônios/fisiologia , Modelos Animais de Doenças , Masculino , Bainha de Mielina/patologia , Bainha de Mielina/fisiologia , Fibras Nervosas Mielinizadas/patologia , Fibras Nervosas Mielinizadas/fisiologia , Ratos , Ratos Endogâmicos Lew , Nervo Isquiático/patologia , Tarso Animal/patologia , Tarso Animal/fisiologia , Dedos do Pé/fisiologia
15.
J Comput Neurosci ; 45(3): 193-206, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30443813

RESUMO

Electrical stimulation of nerve fibers is used as a therapeutic tool to treat neurophysiological disorders. Despite efforts to model the effects of stimulation, its underlying mechanisms remain unclear. Current mechanistic models quantify the effects that the electrical field produces near the fiber but do not capture interactions between action potentials (APs) initiated by stimulus and APs initiated by underlying physiological activity. In this study, we aim to quantify the effects of stimulation frequency and fiber diameter on AP interactions involving collisions and loss of excitability. We constructed a mechanistic model of a myelinated nerve fiber receiving two inputs: the underlying physiological activity at the terminal end of the fiber, and an external stimulus applied to the middle of the fiber. We define conduction reliability as the percentage of physiological APs that make it to the somatic end of the nerve fiber. At low input frequencies, conduction reliability is greater than 95% and decreases with increasing frequency due to an increase in AP interactions. Conduction reliability is less sensitive to fiber diameter and only decreases slightly with increasing fiber diameter. Finally, both the number and type of AP interactions significantly vary with both input frequencies and fiber diameter. Modeling the interactions between APs initiated by stimulus and APs initiated by underlying physiological activity in a nerve fiber opens opportunities towards understanding mechanisms of electrical stimulation therapies.


Assuntos
Potenciais de Ação/fisiologia , Estimulação Elétrica , Modelos Neurológicos , Fibras Nervosas Mielinizadas/fisiologia , Condução Nervosa/fisiologia , Animais , Simulação por Computador , Humanos , Reprodutibilidade dos Testes
16.
Neuroradiology ; 60(12): 1343-1351, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30302499

RESUMO

PURPOSE: This study aims to provide a screening scoring method by assessing the age-related change of subcortical white matter (WM) myelination via T2-weighted imaging (T2WI). METHODS: This study retrospectively recruited 109 children aged 6-48 months without abnormalities on MRI. Based on Parazzini's study, we developed a modified T2WI-based method to assess subcortical WM myelination (frontal, temporal, parietal, occipital lobes, and insula) by scoring WM's signal changes. Inter- and intra-observer agreements were evaluated by Bland-Altman plot. Age-related changes of myelination score were explored by locally weighted scatterplot smoothing (LOESS), linear regression, and Spearman correlation coefficients (r). Relationships between diffusion tensor imaging (DTI) metrics and total myelination score were investigated to further validate practicability of the scoring method by tract-based spatial statistics (TBSS). RESULTS: This method showed good intra-observer (mean difference = 0.18, SD = 0.95) and inter-observer agreements (mean difference = - 0.06, SD = 1.01). The LOESS and linear regression results indicated that myelination proceeded in two phases: a period of rapid growth (6-20 months; slope = 0.561) and one of slower growth (21-48 months; slope = 0.097). Significant correlations between myelination score and age were observed in whole subcortical WM (r = 0.945; P < 0.001) and all regional subcortical WM (r_mean = 0.819, range, 0.664-0.928; P < 0.001). TBSS found significant correlations of WM-DTI metrics with myelination score during the range of 6-20 months, while no significant correlation was observed in 21-48 months. CONCLUSION: The modified T2WI-based screening scoring method is easily feasible to assess myelination progression of subcortical WM, especially suitable for children aged 6-20 months. It may show potential in identifying individual developmental abnormalities by scoring assessment in the future clinical practice.


Assuntos
Mapeamento Encefálico/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Imagem por Ressonância Magnética/métodos , Fibras Nervosas Mielinizadas/fisiologia , Fatores Etários , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
17.
Proc Natl Acad Sci U S A ; 115(46): 11832-11837, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30373833

RESUMO

The speed of impulse transmission is critical for optimal neural circuit function, but it is unclear how the appropriate conduction velocity is established in individual axons. The velocity of impulse transmission is influenced by the thickness of the myelin sheath and the morphology of electrogenic nodes of Ranvier along axons. Here we show that myelin thickness and nodal gap length are reversibly altered by astrocytes, glial cells that contact nodes of Ranvier. Thrombin-dependent proteolysis of a cell adhesion molecule that attaches myelin to the axon (neurofascin 155) is inhibited by vesicular release of thrombin protease inhibitors from perinodal astrocytes. Transgenic mice expressing a dominant-negative fragment of VAMP2 in astrocytes, to reduce exocytosis by 50%, exhibited detachment of adjacent paranodal loops of myelin from the axon, increased nodal gap length, and thinning of the myelin sheath in the optic nerve. These morphological changes alter the passive cable properties of axons to reduce conduction velocity and spike-time arrival in the CNS in parallel with a decrease in visual acuity. All effects were reversed by the thrombin inhibitor Fondaparinux. Similar results were obtained by viral transfection of tetanus toxin into astrocytes of rat corpus callosum. Previously, it was unknown how the myelin sheath could be thinned and the functions of perinodal astrocytes were not well understood. These findings describe a form of nervous system plasticity in which myelin structure and conduction velocity are adjusted by astrocytes. The thrombin-dependent cleavage of neurofascin 155 may also have relevance to myelin disruption and repair.


Assuntos
Astrócitos/fisiologia , Bainha de Mielina/fisiologia , Animais , Axônios/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Bainha de Mielina/metabolismo , Fibras Nervosas Mielinizadas/fisiologia , Condução Nervosa/fisiologia , Neuroglia/metabolismo , Nervo Óptico/metabolismo , Nós Neurofibrosos/metabolismo , Relação Estrutura-Atividade , Trombina , Proteína 2 Associada à Membrana da Vesícula
18.
Eur J Neurosci ; 48(10): 3186-3198, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30203624

RESUMO

Intra-epidermal electrical stimulation (IEES) has been shown to activate selectively Aδ fibers subserving spinothalamic-mediated sensations. Owing to electrically induced highly synchronous afferent volleys, IEES induces Aδ-mediated evoked potentials at nonpainful intensities, contrasting with thermo-nociceptive laser pulses which entail painful pricking sensations. Here, we recorded intracortical responses from sensory and limbic-cognitive regions of human subjects in response to IEE and laser stimuli, in order to test the hypothesis that IEES could dissociate the sensory from nonsensory networks of nociceptive processing. Intracortical evoked potentials were obtained in 11 epileptic patients with stereotactically implanted electrodes in sensory regions receiving spinothalamic afferents (posterior insula), limbic regions receiving spino-parabrachial input (amygdalar nucleus), and high-order affective-cognitive regions (anteromedial frontal cortex, including perigenual anterior cingulate and rostromedial prefrontal areas). Responses in the sensory posterior insula were of similar amplitude and latency to IEE and laser stimuli (after accounting for heat-transduction time of laser), and consistent in both cases with spinothalamic activation. However, responses to IEES in the amygdala and the anteromedial frontal regions were inconsistent and significantly smaller compared to those evoked to the laser stimulation. Thus, IEES can effectively activate the spinothalamic-sensory system with little recruitment of affective-motivational networks, including those triggered by spino-parabrachio-amygdalar projections. The fact that identical sensory responses were associated to either painful or nonpainful percepts underscores that subjective pain perception is not solely dependent on the sensory recruitment, but rather on the combined activation of sensory, limbic and cognitive areas with precise spatiotemporal relations.


Assuntos
Córtex Cerebral/fisiologia , Potenciais Somatossensoriais Evocados/fisiologia , Fibras Nervosas Mielinizadas/fisiologia , Nociceptividade/fisiologia , Córtex Periamigdalóideo/fisiologia , Adulto , Estimulação Elétrica , Eletrocorticografia , Epiderme/fisiologia , Epilepsia/fisiopatologia , Feminino , Giro do Cíngulo/fisiologia , Humanos , Lasers , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/fisiologia , Adulto Jovem
19.
Sci Rep ; 8(1): 14004, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30228335

RESUMO

Severe peripheral nerve injuries often result in partial repair and lifelong disabilities in patients. New surgical techniques and better graft tissues are being studied to accelerate regeneration and improve functional recovery. Currently, limited tools are available to provide in vivo monitoring of changes in nerve physiology such as myelination and vascularization, and this has impeded the development of new therapeutic options. We have developed a wide-field and label-free functional microscopy platform based on angiographic and vectorial birefringence methods in optical coherence tomography (OCT). By incorporating the directionality of the birefringence, which was neglected in the previously reported polarization-sensitive OCT techniques for nerve imaging, vectorial birefringence contrast reveals internal nerve microanatomy and allows for quantification of local myelination with superior sensitivity. Advanced OCT angiography is applied in parallel to image the three-dimensional vascular networks within the nerve over wide-fields. Furthermore, by combining vectorial birefringence and angiography, intraneural vessels can be discriminated from those of the surrounding tissues. The technique is used to provide longitudinal imaging of myelination and revascularization in the rodent sciatic nerve model, i.e. imaged at certain sequential time-points during regeneration. The animals were exposed to either crush or transection injuries, and in the case of transection, were repaired using an autologous nerve graft or acellular nerve allograft. Such label-free functional imaging by the platform can provide new insights into the mechanisms that limit regeneration and functional recovery, and may ultimately provide intraoperative assessment in human subjects.


Assuntos
Neovascularização Fisiológica , Fibras Nervosas Mielinizadas/fisiologia , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/fisiopatologia , Recuperação de Função Fisiológica , Nervo Isquiático/patologia , Animais , Microscopia , Nervo Isquiático/irrigação sanguínea , Nervo Isquiático/lesões , Tomografia de Coerência Óptica
20.
PLoS One ; 13(9): e0203365, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30188910

RESUMO

High frequency electrical stimulation (HFS) of the skin induces increased pinprick sensitivity in the surrounding unconditioned skin. The aim of the present study was to investigate the contribution of A-fiber nociceptors to this increased pinprick sensitivity. For this we assessed if the perception and brain responses elicited by low-intensity intra-epidermal electrical stimulation (IES), a method preferentially activating Aδ-fiber nociceptors, are increased in the area of HFS-induced increased pinprick sensitivity. HFS was delivered to one of the two forearms of seventeen healthy volunteers. Mechanical pinprick stimulation and IES were delivered at both arms before HFS (T0), 20 minutes after HFS (T1) and 45 minutes after HFS (T2). In all participants, HFS induced an increase in pinprick perception at the HFS-treated arm, adjacent to the site of HFS. This increase was significant at both T1 and T2. HFS did not affect the percept elicited by IES, but did enhance the magnitude of the N2 wave of IES-evoked brain potentials, both at T1 and at T2. Our results show that HFS induces a long-lasting enhancement of the N2 wave elicited by IES in the area of secondary hyperalgesia, indicating that HFS enhances the responsiveness of the central nervous system to nociceptive A-fiber input. However, we found no evidence that HFS affects the perception elicited by IES, which may suggest that the population of nociceptors that mediate the perception elicited by IES do not contribute to HFS-induced increased pinprick sensitivity.


Assuntos
Estimulação Elétrica/efeitos adversos , Potenciais Somatossensoriais Evocados/fisiologia , Pele/inervação , Adulto , Estimulação Elétrica/métodos , Eletroencefalografia , Feminino , Antebraço , Humanos , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Masculino , Fibras Nervosas Mielinizadas/fisiologia , Nociceptores/fisiologia , Limiar da Dor/fisiologia , Percepção/fisiologia , Estimulação Física , Tempo de Reação/fisiologia , Pele/fisiopatologia , Adulto Jovem
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