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1.
Nat Commun ; 12(1): 781, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536416

RESUMO

After complete spinal cord injuries (SCI), spinal segments below the lesion maintain inter-segmental communication via the intraspinal propriospinal network. However, it is unknown whether selective manipulation of these circuits can restore locomotor function in the absence of brain-derived inputs. By taking advantage of the compromised blood-spinal cord barrier following SCI, we optimized a set of procedures in which AAV9 vectors administered via the tail vein efficiently transduce neurons in lesion-adjacent spinal segments after a thoracic crush injury in adult mice. With this method, we used chemogenetic actuators to alter the excitability of propriospinal neurons in the thoracic cord of the adult mice with a complete thoracic crush injury. We showed that activating these thoracic neurons enables consistent and significant hindlimb stepping improvement, whereas direct manipulations of the neurons in the lumbar spinal cord led to muscle spasms without meaningful locomotion. Strikingly, manipulating either excitatory or inhibitory propriospinal neurons in the thoracic levels leads to distinct behavioural outcomes, with preferential effects on standing or stepping, two key elements of the locomotor function. These results demonstrate a strategy of engaging thoracic propriospinal neurons to improve hindlimb function and provide insights into optimizing neuromodulation-based strategies for treating SCI.


Assuntos
Dependovirus/genética , Membro Posterior/fisiopatologia , Locomoção/fisiologia , Neurônios/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Animais , Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Clozapina/análogos & derivados , Vetores Genéticos/genética , Membro Posterior/inervação , Locomoção/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia
2.
Nat Commun ; 12(1): 391, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452250

RESUMO

Spinal cord injury (SCI) often causes severe and permanent disabilities due to the regenerative failure of severed axons. Here we report significant locomotor recovery of both hindlimbs after a complete spinal cord crush. This is achieved by the unilateral transduction of cortical motoneurons with an AAV expressing hyper-IL-6 (hIL-6), a potent designer cytokine stimulating JAK/STAT3 signaling and axon regeneration. We find collaterals of these AAV-transduced motoneurons projecting to serotonergic neurons in both sides of the raphe nuclei. Hence, the transduction of cortical neurons facilitates the axonal transport and release of hIL-6 at innervated neurons in the brain stem. Therefore, this transneuronal delivery of hIL-6 promotes the regeneration of corticospinal and raphespinal fibers after injury, with the latter being essential for hIL-6-induced functional recovery. Thus, transneuronal delivery enables regenerative stimulation of neurons in the deep brain stem that are otherwise challenging to access, yet highly relevant for functional recovery after SCI.


Assuntos
Terapia Genética/métodos , Interleucina-6/genética , Locomoção/fisiologia , Regeneração Nervosa/fisiologia , Traumatismos da Medula Espinal/terapia , Animais , Axônios/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Janus Quinases/metabolismo , Masculino , Camundongos , Camundongos Knockout , Microinjeções , Neurônios Motores/fisiologia , PTEN Fosfo-Hidrolase/genética , Núcleos da Rafe/citologia , Núcleos da Rafe/fisiologia , Recuperação de Função Fisiológica , Fator de Transcrição STAT3/metabolismo , Neurônios Serotoninérgicos/fisiologia , Índice de Gravidade de Doença , Transdução de Sinais , Medula Espinal/citologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/diagnóstico , Traumatismos da Medula Espinal/fisiopatologia , Transdução Genética
3.
Anesth Analg ; 132(4): 1156-1163, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33323783

RESUMO

BACKGROUND: Pain is one of the first presenting symptoms in patients with head and neck cancer, who often develop chronic and debilitating pain as the disease progresses. Pain is also an important prognostic marker for survival. Unfortunately, patients rarely receive effective pain treatment due to our limited knowledge of the mechanisms underlying head and neck cancer pain (HNCP). Pain is often associated with neuroinflammation and particularly interleukin (IL)-1 signaling. The purpose of this study is to develop a novel syngeneic model of HNCP in immunocompetent mice to examine the contribution of IL-1 signaling. METHODS: Male C57BL/6 mice were injected with a murine model of human papillomavirus (HPV+)-induced oropharyngeal squamous cell carcinoma in their right hindlimb to induce tumor growth. Pain sensitivity was measured via von Frey filaments. Spontaneous pain was assessed via the facial grimace scale. IL-1ß was measured by quantifying gene expression via quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS: Pain hypersensitivity and spontaneous pain develop quickly after the implantation of tumor cells, a time when tumor volume is still insignificant. Spinal and circulating IL-1ß levels are significantly elevated in tumor-bearing mice. Blocking IL-1 signaling either by intrathecal administration of interleukin-1 receptor antagonist (IL-1ra) or by genetic deletion (interleukin-1 receptor knockout [Il1r1-/-]) does not alleviate HNCP. CONCLUSIONS: We established the first syngeneic model of HNCP in immunocompetent mice. Unlike inflammatory or nerve-injured pain, HNCP is independent of IL-1 signaling. These findings challenge the common belief that pain results from tissue compression or IL-1 signaling in patients with head and neck cancer.


Assuntos
Dor do Câncer/etiologia , Interleucina-1beta/metabolismo , Neoplasias Orofaríngeas/complicações , Medula Espinal/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicações , Animais , Comportamento Animal , Dor do Câncer/metabolismo , Dor do Câncer/fisiopatologia , Linhagem Celular Tumoral , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/virologia , Limiar da Dor , Papillomaviridae/patogenicidade , Transdução de Sinais , Medula Espinal/fisiopatologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
4.
Phytomedicine ; 80: 153385, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33091854

RESUMO

BACKGROUND: Microglia-mediated neuroinflammation is one of the most prominent characteristics of multiple sclerosis (MS), a chronic demyelination disease. As one of the main active ingredients in Astragali radix, total flavonoids of Astragalus (TFA) has multiple pharmacological effects such as immunomodulation, anti-inflammation and and anti-tumor. However, little is known about whether TFA could inhibit microglia-mediated neuroinflammation in MS. PURPOSE: This study was aimed to elucidate whether TFA could inhibit microglia-mediated neuroinflammation in MS. STUDY DESIGN: In the present study, we explored the protective effect of TFA on experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in mice for the first time, and discussed its mechanism from the aspect of anti-microglia-mediated neuroinflammation. METHODS: The mice received oral administration of TFA (25 and 50 mg/kg) daily from two days before immunization and continued until day 21 post-immunization. The effect of TFA on EAE in mice and its mechanism were investigated by ELISA, Western blot, real-time PCR, luciferase reporter assay, histopathology and immunohistochemistry. RESULTS: TFA were shown to alleviate the severity of EAE in mice. It inhibited the excessive activation of microglia both in spinal cords of EAE mice and in LPS-stimulated BV-2 cells, evidenced by weakening the production of inflammatory mediators such as NO, TNF-α, IL-6, and IL-1ß markedly at either protein or mRNA level. Further study demonstrated that TFA repressed the phosphorylation, nuclear translocation and transcriptional activity of NFκB, and inhibited the activation of AKT and JNK signaling in BV-2 cells induced by LPS. The agonists of AKT and JNK, anisomycin and SC79, could partly abolish the inhibitory effect of TFA on the production of inflammatory mediators in BV-2 cells induced by LPS. CONCLUSIONS: Taken together, our results clarified that TFA inhibited microglia-mediated inflammation in EAE mice probably through deactivating JNK/AKT/NFκB signaling pathways. The novel findings may lay a theoretical foundation for the clinical application of TFA in the treatment of MS.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Astrágalo (Planta)/química , Encefalomielite Autoimune Experimental/tratamento farmacológico , Flavonoides/farmacologia , Microglia/efeitos dos fármacos , Animais , Linhagem Celular , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Flavonoides/química , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
5.
PLoS One ; 15(12): e0243723, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33315886

RESUMO

Studies of the neural basis of human pain processing present many challenges because of the subjective and variable nature of pain, and the inaccessibility of the central nervous system. Neuroimaging methods, such as functional magnetic resonance imaging (fMRI), have provided the ability to investigate these neural processes, and yet commonly used analysis methods may not be optimally adapted for studies of pain. Here we present a comparison of model-driven and data-driven analysis methods, specifically for the study of human pain processing. Methods are tested using data from healthy control participants in two previous studies, with separate data sets spanning the brain, and the brainstem and spinal cord. Data are analyzed by fitting time-series responses to predicted BOLD responses in order to identify significantly responding regions (model-driven), as well as with connectivity analyses (data-driven) based on temporal correlations between responses in spatially separated regions, and with connectivity analyses based on structural equation modeling, allowing for multiple source regions to explain the signal variations in each target region. The results are assessed in terms of the amount of signal variance that can be explained in each region, and in terms of the regions and connections that are identified as having BOLD responses of interest. The characteristics of BOLD responses in identified regions are also investigated. The results demonstrate that data-driven approaches are more effective than model-driven approaches for fMRI studies of pain.


Assuntos
Tronco Encefálico/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Dor/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem , Adulto , Encéfalo/fisiopatologia , Mapeamento Encefálico/métodos , Tronco Encefálico/fisiopatologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Pessoa de Meia-Idade , Dor/fisiopatologia , Medição da Dor , Medula Espinal/fisiopatologia , Adulto Jovem
6.
BMJ Case Rep ; 13(12)2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33370945

RESUMO

Transient spinal shock is a previously unreported complication of intrathecal contrast. A 63-year-old man presented with the chief complaint of worsening back pain. Computed topography of lumbar spine without contrast showed a lytic lesion. After international normalized ratio (INR) correction, patient was sent for CT myelogram. After intrathecal contrast injection, the patient dropped his blood pressure profoundly and developed clinical manifestations of spinal shock. Emergent intravenous bolus fluids were initiated resulting in improvement in blood pressure. Patient's spinal shock resolved within hours. CT myelogram was normal except previously known lytic lesion. It was concluded that the transient shock was most likely due to contrast injection. We believe that this is the first reported case of transient spinal shock following CT myelogram using water-soluble iodinated non-ionic contrast agent administered intrathecally.


Assuntos
Dor nas Costas/diagnóstico , Meios de Contraste/efeitos adversos , Injeções Espinhais/efeitos adversos , Mielografia/efeitos adversos , Choque/induzido quimicamente , Medula Espinal/efeitos dos fármacos , Meios de Contraste/administração & dosagem , Humanos , Iohexol/administração & dosagem , Iohexol/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mielografia/métodos , Remissão Espontânea , Medula Espinal/fisiopatologia , Tomografia Computadorizada por Raios X
7.
Int J Nanomedicine ; 15: 10113-10125, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363370

RESUMO

Background: The excess production of reactive oxygen species (ROS) after traumatic spinal cord injury (TSCI) has been identified as a leading cause of secondary injury, which can significantly exacerbate acute damage in the injured spinal cord. Thus, scavenging of ROS has emerged as an effective route to ameliorate secondary spinal cord injury. Purpose: Selenium-doped carbon quantum dots (Se-CQDs) with the ability to scavenge reactive oxygen species were prepared and used for efficiently ameliorating secondary injury in TSCI. Methods: Water-soluble Se-CQDs were easily synthesized via hydrothermal treatment of l-selenocystine. The chemical structure, size, and morphology of the Se-CQDs were characterized in detail. The biocompatibility and protective effects of the Se-CQDs against H2O2-induced oxidative damage were investigated in vitro. Moreover, the behavioral test, bladder function, histological observation, Western blot were used to investigate the neuroprotective effect of Se-CQDs in a rat model of contusion TSCI. Results: The obtained Se-CQDs exhibited good biocompatibility and remarkable protective effect against H2O2-induced oxidative damage in astrocytes and PC12 cells. Moreover, Se-CQDs displayed marked anti-inflammatory and anti-apoptotic activities, which thereby reduced the formation of glial scars and increased the survival of neurons with unscathed myelin sheaths in vivo. As a result, Se-CQDs were capable of largely improving locomotor function of rats with TSCI. Conclusion: This study suggests that Se-CQDs can be used as a promising therapeutic platform for ameliorating secondary injury in TSCI.


Assuntos
Carbono/química , Pontos Quânticos/química , Espécies Reativas de Oxigênio/metabolismo , Selênio/farmacologia , Traumatismos da Medula Espinal/patologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Modelos Animais de Doenças , Feminino , Camundongos , Atividade Motora/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neuroglia/patologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Células PC12 , Pontos Quânticos/ultraestrutura , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/fisiopatologia
8.
Nat Commun ; 11(1): 5074, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033265

RESUMO

Touch and itch sensations are crucial for evoking defensive and emotional responses, and light tactile touch may induce unpleasant itch sensations (mechanical itch or alloknesis). The neural substrate for touch-to-itch conversion in the spinal cord remains elusive. We report that spinal interneurons expressing Tachykinin 2-Cre (Tac2Cre) receive direct Aß low threshold mechanoreceptor (LTMR) input and form monosynaptic connections with GRPR neurons. Ablation or inhibition markedly reduces mechanical but not acute chemical itch nor noxious touch information. Chemogenetic inhibition of Tac2Cre neurons also displays pronounced deficit in chronic dry skin itch, a type of chemical itch in mice. Consistently, ablation of gastrin-releasing peptide receptor (GRPR) neurons, which are essential for transmitting chemical itch, also abolishes mechanical itch. Together, these results suggest that innocuous touch and chemical itch information converge on GRPR neurons and thus map an exquisite spinal circuitry hard-wired for converting innocuous touch to irritating itch.


Assuntos
Rede Nervosa/fisiopatologia , Prurido/fisiopatologia , Tato/fisiologia , Animais , Comportamento Animal , Injeções Espinhais , Luz , Potenciais da Membrana , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Precursores de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores da Bombesina/metabolismo , Pele/patologia , Medula Espinal/fisiopatologia , Sinapses/metabolismo , Taquicininas/metabolismo
9.
Nat Commun ; 11(1): 5209, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060602

RESUMO

Chronic high-thoracic and cervical spinal cord injury (SCI) results in a complex phenotype of cardiovascular consequences, including impaired left ventricular (LV) contractility. Here, we aim to determine whether such dysfunction manifests immediately post-injury, and if so, whether correcting impaired contractility can improve spinal cord oxygenation (SCO2), blood flow (SCBF) and metabolism. Using a porcine model of T2 SCI, we assess LV end-systolic elastance (contractility) via invasive pressure-volume catheterization, monitor intraparenchymal SCO2 and SCBF with fiberoptic oxygen sensors and laser-Doppler flowmetry, respectively, and quantify spinal cord metabolites with microdialysis. We demonstrate that high-thoracic SCI acutely impairs cardiac contractility and substantially reduces SCO2 and SCBF within the first hours post-injury. Utilizing the same model, we next show that augmenting LV contractility with the ß-agonist dobutamine increases SCO2 and SCBF more effectively than vasopressor therapy, whilst also mitigating increased anaerobic metabolism and hemorrhage in the injured cord. Finally, in pigs with T2 SCI survived for 12 weeks post-injury, we confirm that acute hemodynamic management with dobutamine appears to preserve cardiac function and improve hemodynamic outcomes in the chronic setting. Our data support that cardio-centric hemodynamic management represents an advantageous alternative to the current clinical standard of vasopressor therapy for acute traumatic SCI.


Assuntos
Coração/fisiopatologia , Hemodinâmica/fisiologia , Hemorragia/fisiopatologia , Fenômenos Fisiológicos Respiratórios , Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/fisiopatologia , Animais , Modelos Animais de Doenças , Dobutamina/farmacologia , Feminino , Fluxometria por Laser-Doppler , Chaperonas Moleculares/metabolismo , Norepinefrina/farmacologia , Fluxo Sanguíneo Regional/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Suínos , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/fisiopatologia
10.
J Neurosci ; 40(27): 5314-5326, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32527981

RESUMO

An epileptic seizure can trigger a headache during (ictal) or after (postictal) the termination of the event. Little is known about the pathophysiology of seizure-induced headaches. In the current study, we determined whether a seizure can activate nociceptive pathways that carry pain signals from the meninges to the spinal cord, and if so, to what extent and through which classes of peripheral and central neurons. To achieve these goals, we used single-unit recording techniques and an established animal model of seizure (picrotoxin) to determine the effects of epileptic seizure on the activity of trigeminovascular Aδ-, C-, wide-dynamic range, and high-threshold neurons in male and female rats. Occurrence of seizure activated 54%, 50%, 68%, and 39% of the Aδ-, C-, wide-dynamic range, and high-threshold neurons, respectively. Regardless of their class, activated neurons exhibited a twofold to fourfold increase in their firing, which started immediately (1 min) or up to 90 min after seizure initiation, and lasted as short as 10 min or as long as 120 min. Administration of lidocaine to the dura prevented activation of all neuronal classes but not the initiation or maintenance of the seizure. These findings suggest that all neuronal classes may be involved in the initiation and maintenance of seizure-induced headache, and that their activation patterns can provide a neural substrate for explaining the timing and duration of ictal and possibly postictal headaches. By using seizure, which is evident in humans, this study bypasses controversies associated with cortical spreading depression, which is less readily observed in humans.SIGNIFICANCE STATEMENT This preclinical study provides a neural substrate for ictal and postictal headache. By studying seizure effects on the activity of peripheral (C and Aδ) and central (wide dynamic range and high-threshold) trigeminovascular neurons in intact and anesthetized dura, the findings help resolve two outstanding questions about the pathophysiology of headaches of intracranial origin. The first is that abnormal brain activity (i.e., seizure) that is evident in human (unlike cortical spreading depression) gives rise to specific and selective activation of the different components of the trigeminovascular system, and the second is that the activation of all components of the trigeminovascular pathway (i.e., peripheral and central neurons) depends on activation of the meningeal nociceptors from their receptors in the dura.


Assuntos
Cefaleia/etiologia , Cefaleia/fisiopatologia , Neurônios , Convulsões/complicações , Convulsões/fisiopatologia , Nervo Trigêmeo/fisiopatologia , Anestésicos Locais/farmacologia , Animais , Sistema Nervoso Central/fisiopatologia , Eletroencefalografia , Feminino , Lidocaína/farmacologia , Masculino , Meninges/fisiopatologia , Fibras Nervosas Mielinizadas , Fibras Nervosas Amielínicas , Vias Neurais/fisiopatologia , Nociceptores , Sistema Nervoso Periférico/fisiopatologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/fisiopatologia
11.
J Clin Neurosci ; 77: 142-147, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32386864

RESUMO

One of the major problems with walking encountered by patients with spastic hemiplegia is diminished toe clearance due to spasticity of their leg muscles. To improve their walking, a specialized robot assist for ankle movements (RE-Gait) has been utilized. The present study examined the neurophysiological effects whether spinal cord reciprocal Ia inhibition (RI) in the leg was altered by using RE-Gait. Sixteen patients with a clinical diagnosis of stroke were divided into the two groups, RE-Gait walking group (Group R) and normal (controlled) walking group (Group C). In each group, they walked on a flat floor for 15 min with or without RE-Gait. The depression of soleus (Sol) H-reflexes conditioned by common peroneal nerve stimuli with the conditioning-test (C-T) intervals of 1, 2, 3, and 4 ms were assessed before and immediately after each walking session. After the intervention, the LSM (SE) of Sol H-reflex amplitude with 1, 2 and 3 ms C-T interval conditions were significantly decreased in group R (1 ms: 88.15 (4.60), 2 ms: 86.37 (4.60), 3 ms: 89.68 (4.62)) compared to group C (1 ms: 105.57 (4.56), 2 ms: 100.89 (4.58), 3 ms: 107.72 (4.58)) [1 ms: p = 0.012, 2 ms: p = 0.035, 3 ms: p = 0.011]. Walking assistive robot that targets ankle movements might be a new rehabilitation tool for regulating spinal cord excitability.


Assuntos
Terapia por Exercício/métodos , Exoesqueleto Energizado , Marcha , Hemiplegia/terapia , Equipamentos Ortopédicos , Medula Espinal/fisiopatologia , Adulto , Tornozelo/fisiopatologia , Terapia por Exercício/instrumentação , Feminino , Reflexo H , Hemiplegia/reabilitação , Humanos , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular , Músculo Esquelético/fisiopatologia , Inibição Neural , Nervo Fibular/fisiopatologia
12.
Expert Opin Pharmacother ; 21(12): 1449-1454, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32452702

RESUMO

INTRODUCTION: Multiple Sclerosis (MS) manifests with a plethora of signs and symptoms affecting brain structures and spinal pathways. The multitude of lesions in MS patients makes difficult to establish the relative role of each of them to lower urinary tract symptoms (LUTS). Generally, the subcortical white-matter lesions result in detrusor overactivity, whilst lesions of the spinal cord result in the combined occurrence of detrusor overactivity and detrusor-sphincter dyssynergia (DSD). It has been estimated that 80-90% of patients with MS will suffer from some form of LUTS over the course of the disease. Among LUTS, the most reported is detrusor overactivity which includes urinary urgency, frequent urination, nocturia, and urge urinary incontinence. AREAS COVERED: The authors review the management of lower urinary tract symptoms in MS patients providing their expert opinions on the subject matter. EXPERT OPINION: LUTS affect the quality of life substantially and are associated with a significantly increased mortality. The adequate management is an important challenge for both patients and caregivers with a multidisciplinary approach likely necessary.


Assuntos
Toxinas Botulínicas Tipo A/uso terapêutico , Canabinoides/uso terapêutico , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Antagonistas Muscarínicos/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Toxinas Botulínicas Tipo A/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Canabinoides/administração & dosagem , Cateteres de Demora , Feminino , Humanos , Sintomas do Trato Urinário Inferior/diagnóstico , Sintomas do Trato Urinário Inferior/etiologia , Esclerose Múltipla/complicações , Esclerose Múltipla/patologia , Antagonistas Muscarínicos/administração & dosagem , Qualidade de Vida , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Estimulação Elétrica Nervosa Transcutânea , Infecções Urinárias/diagnóstico , Infecções Urinárias/etiologia , Urodinâmica
13.
J Neurosci ; 40(20): 3882-3895, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32291327

RESUMO

Neonatal tissue damage induces long-term deficits in inhibitory synaptic transmission within the spinal superficial dorsal horn (SDH) that include a reduction in primary afferent-evoked, feedforward inhibition onto adult projection neurons. However, the subpopulations of mature GABAergic interneurons which are compromised by early-life injury have yet to be identified. The present research illuminates the persistent effects of neonatal surgical injury on the function of inhibitory SDH interneurons derived from the prodynorphin (DYN) lineage, a population that synapses directly onto lamina I spinoparabrachial neurons and is known to suppress mechanical pain and itch in adults. The results demonstrate that hindpaw incision at postnatal day 3 (P3) significantly decreased the strength of primary afferent-evoked glutamatergic drive onto DYN neurons within the adult mouse SDH while increasing the appearance of afferent-evoked inhibition onto the same population. Neonatal injury also dampened the intrinsic membrane excitability of mature DYN neurons, and reduced their action potential discharge in response to sensory input, compared with naive littermate controls. Furthermore, P3 incision decreased the efficacy of inhibitory DYN synapses onto adult spinoparabrachial neurons, which reflected a prolonged reduction in the probability of GABA release. Collectively, the data suggest that early-life tissue damage may persistently constrain the ability of spinal DYN interneurons to limit ascending nociceptive transmission to the adult brain. This is predicted to contribute to the loss of feedforward inhibition onto mature projection neurons, and the "priming" of nociceptive circuits in the developing spinal cord, following injuries during the neonatal period.SIGNIFICANCE STATEMENT Neonatal injury has lasting effects on pain processing in the adult CNS, including a reduction in feedforward inhibition onto ascending projection neurons in the spinal dorsal horn. While it is clear that spinal GABAergic interneurons are comprised of multiple subpopulations that play distinct roles in somatosensation, the identity of those interneurons which are compromised by tissue damage during early life remains unknown. Here we document persistent deficits in spinal inhibitory circuits involving dynorphin-lineage interneurons previously implicated in gating mechanical pain and itch. Notably, neonatal injury reduced the strength of dynorphin-lineage inhibitory synapses onto mature lamina I spinoparabrachial neurons, a major output of the spinal nociceptive network, which could contribute to the priming of pain pathways by early tissue damage.


Assuntos
Dinorfinas , Membro Posterior/lesões , Inibição Neural , Vias Neurais/fisiopatologia , Corno Dorsal da Medula Espinal/lesões , Potenciais de Ação , Animais , Animais Recém-Nascidos , Análise por Conglomerados , Feminino , Glutamatos/fisiologia , Membro Posterior/inervação , Membro Posterior/fisiopatologia , Interneurônios , Camundongos , Neurônios Aferentes , Nociceptividade , Técnicas de Patch-Clamp , Medula Espinal/fisiopatologia , Corno Dorsal da Medula Espinal/fisiopatologia
14.
PLoS One ; 15(4): e0226050, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240164

RESUMO

Autotaxin (ATX) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a growth factor-like signaling lysophospholipid. ATX and LPA signaling have been incriminated in the pathogenesis of different chronic inflammatory diseases and various types of cancer. In this report, deregulated ATX and LPA levels were detected in the spinal cord and plasma of mice during the development of experimental autoimmune encephalomyelitis (EAE). Among the different sources of ATX expression in the inflamed spinal cord, F4/80+ CD11b+ cells, mostly activated macrophages and microglia, were found to express ATX, further suggesting an autocrine role for ATX/LPA in their activation, an EAE hallmark. Accordingly, ATX genetic deletion from CD11b+ cells attenuated the severity of EAE, thus proposing a pathogenic role for the ATX/LPA axis in neuroinflammatory disorders.


Assuntos
Encefalomielite Autoimune Experimental/genética , Lisofosfolipídeos/genética , Esclerose Múltipla/genética , Diester Fosfórico Hidrolases/genética , Animais , Antígeno CD11b/genética , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/fisiopatologia , Deleção de Genes , Expressão Gênica/genética , Humanos , Lisofosfolipídeos/biossíntese , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Microglia/metabolismo , Microglia/patologia , Esclerose Múltipla/sangue , Esclerose Múltipla/fisiopatologia , Transdução de Sinais/genética , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
15.
Pain Pract ; 20(5): 510-521, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32124540

RESUMO

OBJECTIVES: To assess the supraspinal working mechanisms of the burst spinal cord stimulation (SCS) mode, we used functional magnetic resonance imaging (fMRI) in chronic neuropathic rats. We hypothesized that active recharge burst SCS would induce a more profound blood oxygenation level-dependent (BOLD) signal increase in areas associated with cognitive-emotional aspects of pain, as compared to tonic SCS. METHODS: Sprague Dawley rats (n = 17) underwent a unilateral partial sciatic nerve ligation, which resulted in chronic neuropathic pain. Quadripolar SCS electrodes were epidurally positioned on top of the dorsal columns at Th13. Isoflurane-anesthetized (1.5%) rats received either tonic SCS (n = 8) or burst SCS (n = 9) at 66% of motor threshold. BOLD fMRI was conducted before, during, and after SCS using a 9.4-T horizontal bore scanner. RESULTS: Overall, both tonic and burst SCS induced a significant increase of BOLD signal levels in areas associated with the location and intensity of pain, and areas associated with cognitive-emotional aspects of pain. Additionally, burst SCS significantly increased BOLD signal levels in the raphe nuclei, nucleus accumbens, and caudate putamen. Tonic SCS did not induce a significant increase in BOLD signal levels in these areas. CONCLUSIONS: In conclusion, active recharge burst and tonic SCS have different effects on the intensity and localization of SCS-induced activation responses in the brain. This work demonstrates that active recharge burst is another waveform that can engage brain areas associated with cognitive-emotional aspects of pain as well as areas associated with location and intensity of pain. Previous studies showing similar engagement used only passive recharge burst.


Assuntos
Encéfalo/fisiopatologia , Neuralgia/fisiopatologia , Estimulação da Medula Espinal/métodos , Animais , Imagem por Ressonância Magnética , Masculino , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/lesões , Medula Espinal/fisiopatologia
16.
Spine Deform ; 8(4): 655-661, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32207058

RESUMO

STUDY DESIGN: Retrospective cohort. We present a simple classification system that is able to identify patients with increased odds of losing intraoperative neuromonitoring data during thoracic deformity correction. Type 3 spinal cords, with the cord deformed against the concave pedicle in the axial plane, have ×28 greater odds of losing monitoring data during surgery. OBJECTIVES: Assess preoperative morphology of the spinal cord across the thoracic concavity to predict intraoperative loss of neuromonitoring data. METHODS: 128 consecutive patients undergoing surgical correction of a thoracic deformity with pedicle screw/rod constructs were included. Spinal cords were classified into 3 types based on the appearance of the cord on the axial-T2 MRI at the apex of the curve. Type 1 is defined as a circular/symmetric cord with visible CSF between the cord and the apical concave pedicle/vertebral body. Type 2 is a circular/oval/symmetric cord with no visible CSF between the concave pedicle and the cord. Type 3 is a spinal cord that is flattened/deformed by the apical concave pedicle or vertebral body, with no intervening CSF (Fig. 1). RESULTS: 128 patients were reviewed: 81 (63%) Type 1; 32 (25%) Type 2; and 12 (11.7%) Type 3 spinal cords. Lower extremity trans-cranial motor-evoked Potentials (MEPs) and/or somatosensory evoked potentials (SSEPs) were lost intraoperatively in 21 (16%) cases, with full recovery of data in 20 of those cases. On regression analysis, a Type 1 cord was protective against intraoperative data loss (OR = 0.17, p = 0.0003). Type 2 cords had no association with data loss (OR = 0.66, p = 0.49). Type 3 cords had significantly higher odds of intraoperative data loss (OR = 28.3, p < 0.0001). CONCLUSIONS: We present a new spinal cord risk classification scheme to identify patients with increased odds of losing spinal cord monitoring data with thoracic deformity correction. The odds of losing intraoperative MEPs/SSEPs are greater in type 3 spinal cords. LEVEL OF EVIDENCE: III.


Assuntos
Imagem de Difusão por Ressonância Magnética , Monitorização Neurofisiológica Intraoperatória , Medula Espinal/fisiopatologia , Curvaturas da Coluna Vertebral/cirurgia , Vértebras Torácicas/cirurgia , Adulto , Líquido Cefalorraquidiano/diagnóstico por imagem , Estudos de Coortes , Potencial Evocado Motor , Feminino , Humanos , Fixadores Internos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Risco , Medição de Risco , Medula Espinal/diagnóstico por imagem , Fusão Vertebral/instrumentação , Adulto Jovem
17.
Phys Ther ; 100(6): 946-962, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32201890

RESUMO

BACKGROUND: Pain is one of the main symptoms associated with spinal cord injury (SCI) and can be associated with changes to the central nervous system (CNS). PURPOSE: This article provides an overview of the evidence relating to CNS changes (structural and functional) associated with pain in SCIs. DATA SOURCES: A systematic review was performed, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, on PubMed, Embase, and Web of Science in March 2018. STUDY SELECTION: Studies were selected if they concerned changes in the CNS of patients with SCI, regardless of the type of imagery. DATA EXTRACTION: Data were extracted by 2 blinded reviewers. DATA SYNTHESIS: There is moderate evidence for impaired electroencephalographic function and metabolic abnormalities in the anterior cingulate in patients experiencing pain. There is preliminary evidence that patients with pain have morphological and functional changes to the somatosensory cortex and alterations to thalamic metabolism. There are conflicting data regarding the relationships between lesion characteristics and pain. In contrast, patients without pain can display protective neuroplasticity. LIMITATIONS AND CONCLUSION: Further studies are required to elucidate fully the relationships between pain and neuroplasticity in patients with SCIs. However, current evidence might support the use of physical therapist treatments targeting CNS plasticity in patients with SCI pain.


Assuntos
Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Dor Crônica/etiologia , Neuralgia/etiologia , Traumatismos da Medula Espinal/complicações , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/metabolismo , Dor Crônica/fisiopatologia , Eletroencefalografia/métodos , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Imagem por Ressonância Magnética/métodos , Neuralgia/fisiopatologia , Neuroimagem/métodos , Plasticidade Neuronal/fisiologia , Viés de Seleção , Córtex Somatossensorial/diagnóstico por imagem , Córtex Somatossensorial/patologia , Córtex Somatossensorial/fisiopatologia , Medula Espinal/diagnóstico por imagem , Medula Espinal/metabolismo , Medula Espinal/patologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/diagnóstico por imagem , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Tálamo/diagnóstico por imagem , Tálamo/metabolismo
18.
Exp Neurol ; 327: 113246, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32057795

RESUMO

Epidural electrical spinal stimulation can facilitate recovery of volitional motor control in individuals that have been completely paralyzed for more than a year. We recently reported a novel neuromodulation method named Dynamic Stimulation (DS), which short-lastingly increased spinal excitability and generated a robust modulation of locomotor networks in fully-anesthetized intact adult rats. In the present study, we applied repetitive DS patterns to four lumbosacral segments acutely after a contusive injury at lumbar level. Repetitive DS delivery restored the spinally-evoked motor EMG responses that were previously suppressed by a calibrated spinal cord contusion. Sham experiments without DS delivery did not allow any spontaneous recovery. Thus, DS uniquely provides the potential for a greater long-term functional recovery after paralysis.


Assuntos
Potencial Evocado Motor/fisiologia , Traumatismos da Medula Espinal/terapia , Estimulação da Medula Espinal/métodos , Medula Espinal/fisiopatologia , Animais , Eletromiografia , Feminino , Vértebras Lombares , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/fisiopatologia
20.
World Neurosurg ; 137: e106-e117, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31954908

RESUMO

BACKGROUND AND OBJECTIVE: Complex regional pain syndrome (CRPS) is a multifaceted disorder resulting in an abnormal pain response to tissue injury. Among key CRPS features are neurogenic inflammation, maladaptive plasticity, and vasomotor dysfunction, which can result in severe pain and disability. Spinal cord stimulation (SCS) is an efficacious treatment for several chronic pain conditions and may improve pain and life quality in CRPS patients with CRPS. However, little information exists regarding perioperative outcomes of patients with CRPS undergoing surgical implantation of an SCS device. METHODS: Patients were included if they underwent an SCS procedure at our institution between 2008 and 2016 for chronic pain. Cases were excluded if the procedure involved stimulator removal or if it was an outpatient procedure. Multivariate regression assessed the effect of CRPS and other clinical variables on perioperative outcomes. RESULTS: Eighty-one inpatient SCS implantation cases for chronic pain were included, with 9 patients (11.1%) having a CRPS diagnosis. The CRPS cohort received higher mean quantities of intraoperative opioids and had a lower proportion of patients reporting meaningful pain reduction (16.7%) in the 24-hour postoperative setting compared with patients without CRPS (35.9%), although this was not statistically significant. Multivariate regression modeling suggested that CRPS was a significant predictor of increased odds of extended time to the postanesthesia care unit discharge (P = 0.0406) and higher direct costs of hospitalization (P = 0.0326). CONCLUSIONS: Our data suggest that CRPS may pose several unique risks in the perioperative period after inpatient SCS implantation. These findings support the need for future prospective investigations examining risks and outcomes for SCS procedures in this population.


Assuntos
Síndromes da Dor Regional Complexa/fisiopatologia , Manejo da Dor , Distrofia Simpática Reflexa/fisiopatologia , Medula Espinal/fisiopatologia , Adulto , Síndromes da Dor Regional Complexa/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Manejo da Dor/métodos , Medição da Dor/métodos , Estimulação da Medula Espinal/métodos
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