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1.
J Neurosci ; 28(46): 11862-70, 2008 Nov 12.
Article in English | MEDLINE | ID: mdl-19005051

ABSTRACT

Paralysis is a major consequence of spinal cord injury (SCI). After cervical SCI, respiratory deficits can result through interruption of descending presynaptic inputs to respiratory motor neurons in the spinal cord. Expression of channelrhodopsin-2 (ChR2) and photostimulation in neurons affects neuronal excitability and produces action potentials without any kind of presynaptic inputs. We hypothesized that after transducing spinal neurons in and around the phrenic motor pool to express ChR2, photostimulation would restore respiratory motor function in cervical SCI adult animals. Here we show that light activation of ChR2-expressing animals was sufficient to bring about recovery of respiratory diaphragmatic motor activity. Furthermore, robust rhythmic activity persisted long after photostimulation had ceased. This recovery was accomplished through a form of respiratory plasticity and spinal adaptation which is NMDA receptor dependent. These data suggest a novel, minimally invasive therapeutic avenue to exercise denervated circuitry and/or restore motor function after SCI.


Subject(s)
Anterior Horn Cells/radiation effects , Phototherapy/methods , Respiration/radiation effects , Respiratory Insufficiency/therapy , Spinal Cord Injuries/therapy , Animals , Anterior Horn Cells/metabolism , Anterior Horn Cells/physiopathology , Diaphragm/innervation , Diaphragm/physiology , Disease Models, Animal , Female , Neural Pathways/metabolism , Neural Pathways/physiopathology , Neural Pathways/radiation effects , Neuronal Plasticity/physiology , Neuronal Plasticity/radiation effects , Paralysis/metabolism , Paralysis/physiopathology , Paralysis/therapy , Periodicity , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/metabolism , Respiratory Insufficiency/etiology , Respiratory Insufficiency/physiopathology , Rhodopsin/metabolism , Rhodopsin/radiation effects , Spinal Cord/metabolism , Spinal Cord/physiopathology , Spinal Cord/radiation effects , Spinal Cord Injuries/metabolism , Spinal Cord Injuries/physiopathology , Treatment Outcome
2.
Muscle Nerve ; 37(3): 343-9, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18061935

ABSTRACT

To test the hypothesis that the anterior horn cells become hypoexcitable in the absence of central drive, we recorded F waves simultaneously from the first dorsal interosseous (FDI) and the abductor digiti minimi (ADM) before and after volitionally inactivating one muscle (target) while periodically contracting the other muscle (control). In 14 healthy subjects, F waves recorded from the target muscle showed a progressive decrease in persistence and amplitude (whether counting all 100 trials or only detectable responses) after muscle relaxation for 1, 3, and 6 hours, followed by a quick recovery upon brief muscle contraction. We conclude that volitional inactivation suppresses the F waves of the target muscle without equally affecting the control muscle innervated by the same nerve. The history of activity of a muscle should therefore be taken into account in clinical testing, especially when the study of a paretic muscle shows abnormal F-wave excitability.


Subject(s)
Anterior Horn Cells/physiology , Evoked Potentials, Motor/physiology , Muscle Relaxation , Muscle, Skeletal/cytology , Adult , Analysis of Variance , Anterior Horn Cells/radiation effects , Electric Stimulation/methods , Electromyography , Evoked Potentials, Motor/radiation effects , Female , Humans , Male , Muscle Contraction/physiology , Muscle Contraction/radiation effects , Time Factors
3.
J Neurophysiol ; 97(5): 3166-80, 2007 May.
Article in English | MEDLINE | ID: mdl-17360828

ABSTRACT

The recovery of persistent inward currents (PICs) and motoneuron excitability after chronic spinal cord transection is mediated, in part, by the development of supersensitivity to residual serotonin (5HT) below the lesion. The purpose of this paper is to investigate if, like 5HT, endogenous sources of norepinephrine (NE) facilitate motoneuron PICs after chronic spinal transection. Cutaneous-evoked reflex responses in tail muscles of awake chronic spinal rats were measured after increasing presynaptic release of NE by administration of amphetamine. An increase in long-lasting reflexes, known to be mediated by the calcium component of the PIC (CaPIC), was observed even at low doses (0.1-0.2 mg/kg) of amphetamine. These findings were repeated in a reduced S2 in vitro preparation, demonstrating that the increased long-lasting reflexes by amphetamine were neural. Under intracellular voltage clamp, amphetamine application led to a large facilitation of the motoneuron CaPIC. This indicates that the increases in long-lasting reflexes induced by amphetamine in the awake animal were, in part, due to actions directly on the motoneuron. Reflex responses in acutely spinal animals were facilitated by amphetamine similar to chronic animals but only at doses that were ten times greater than that required in chronic animals (0.2 mg/kg chronic vs. 2.0 mg/kg acute), pointing to a development of supersensitivity to endogenous NE in chronic animals. In summary, the increases in long-lasting reflexes and associated motoneuron CaPICs by amphetamine are likely due to an increased release of endogenous NE, which motoneurons become supersensitive to in the chronic stages of spinal cord injury.


Subject(s)
Norepinephrine/metabolism , Spasm/etiology , Spasm/metabolism , Spinal Cord Injuries/complications , Adrenergic Uptake Inhibitors/pharmacology , Amphetamine/pharmacology , Anesthetics, Local/pharmacology , Animals , Anterior Horn Cells/drug effects , Anterior Horn Cells/physiology , Anterior Horn Cells/radiation effects , Chronic Disease , Disease Models, Animal , Dose-Response Relationship, Drug , Electric Stimulation/methods , Electromyography/methods , Female , In Vitro Techniques , Membrane Potentials/drug effects , Membrane Potentials/physiology , Membrane Potentials/radiation effects , Muscle Contraction/drug effects , Muscle Contraction/physiology , Patch-Clamp Techniques , Rats , Rats, Sprague-Dawley , Skin/innervation , Spinal Cord Injuries/pathology , Tetrodotoxin/pharmacology
4.
Spinal Cord ; 42(2): 99-105, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14765142

ABSTRACT

OBJECTIVE: To investigate the pathogenesis of the rare radiogenic lower motor neurone disease (LMND) on the basis of a meta-analysis of the published case histories. MATERIALS AND METHODS: The authors reviewed 47 well-documented radiogenic LMND cases from the English literature. RESULTS: The disease typically occurs following the irradiation of radiosensitive cancers situated near the spinal cord. It arises predominantly (46 cases) in the lower extremities; only one case involved the upper extremities. There is a male predominance (male:female ratio 7.8:1), and the patients are characteristically young (13-40 years, with four exceptions). An overdose does not seem to be a particular risk factor for the development of the disease, as total dose, fraction size and biologically effective dose are typically below 50 Gy, 2 Gy and 128 Gy2, respectively, which are regarded as safe doses. Other risk factors (chemotherapy, operations, etc) have been identified only rarely. Radiogenic LMND is manifested in an apparently random manner, 4-312 (mean 48.7) months after the completion of radiotherapy. DISCUSSION: The complete lack of a dose-effect relationship argues strongly against a pure radiogenic nature of the pathological process. The latency period is typically several years and it varies extremely, which excludes a direct and complete causal relationship between radiotherapy and LMND. As the interaction of ionizing radiation with living tissues is highly unspecific, thus a selective motor injury due to irradiation alone, without comparable effects on the sensory and vegetative fibers, seems improbable. CONCLUSIONS: On analogy with the viral motor neurone diseases, we suppose that radiogenic LMND may be preceded by viral (enterovirus/poliovirus) infection. Based on the meta-analysis, it is suggested that irradiation may be only a single component of the set of factors jointly resulting in the clinical state regarded as radiogenic LMND.


Subject(s)
Anterior Horn Cells/radiation effects , Anterior Horn Cells/virology , Central Nervous System Viral Diseases/complications , Motor Neuron Disease/virology , Radiotherapy/adverse effects , Adolescent , Adult , Age Factors , Anterior Horn Cells/physiopathology , Causality , Drug-Related Side Effects and Adverse Reactions , Enterovirus Infections/complications , Female , Humans , Male , Middle Aged , Motor Neuron Disease/epidemiology , Motor Neuron Disease/physiopathology , Neoplasms/radiotherapy , Poliomyelitis/complications , Radiation Dosage , Reaction Time/physiology , Reaction Time/radiation effects , Sex Factors
5.
Exp Neurol ; 177(2): 575-80, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12429203

ABSTRACT

Identification of long tracts responsible for spontaneous locomotion is critical for spinal cord injury (SCI) repair strategies. We recently demonstrated that extensive demyelination of adult rat thoracic ventral columns, ventromedial, and ventrolateral white matter produces persistent, significant open-field hindlimb locomotor deficits. Locomotor movements resulting from stimulation of the pontomedullary locomotor region are inhibited by dorsolateral funiculus (DLF) lesions suggesting that important pathways for locomotion may also exist in the dorsal white matter. However, dorsal hemisections that interrupt dorsal columns/dorsal corticospinal tract (DC/CST) and DLF pathways do not produce persistent, severe locomotor deficits in the adult rat. We studied the contributions of myelinated tracts in the DLF and DC/CST to overground locomotion following complete conduction blockade of axons in the ventrolateral funiculus (VLF), a region important for locomotor movements and for transcranial magnetic motor-evoked potentials (tcMMEP). Animals received ethidium bromide plus photon irradiation to produce discrete demyelinating lesions sufficient to stop axonal conduction in the VLF, combined VLF + DLF, or combined VLF + DC/CST. Open-field BBB scores and tcMMEPs were studied at 1, 2, 3, and 4 weeks postlesion. VLF lesions resulted in mean BBB scores of 17 at 4 weeks. VLF + DC/CST and VLF + DLF lesions resulted in mean BBB scores of 15.9 and 11.1, respectively. TcMMEPs were absent in all lesion types confirming VLF conduction blockade throughout the study. Our data indicate that significant contributions to locomotion from myelinated pathways within the rat DLF can be revealed when combined with simultaneous compromise of the VLF.


Subject(s)
Efferent Pathways/physiology , Locomotion/physiology , Spinal Cord/physiology , Animals , Anterior Horn Cells/drug effects , Anterior Horn Cells/physiology , Anterior Horn Cells/radiation effects , Axons/physiology , Efferent Pathways/drug effects , Efferent Pathways/radiation effects , Electric Stimulation/instrumentation , Electromagnetic Fields , Ethidium/pharmacology , Evoked Potentials, Motor/physiology , Female , Hindlimb/innervation , Hindlimb/physiology , Locomotion/drug effects , Locomotion/radiation effects , Myelin Sheath/drug effects , Myelin Sheath/radiation effects , Nerve Fibers, Myelinated/drug effects , Nerve Fibers, Myelinated/physiology , Nerve Fibers, Myelinated/radiation effects , Neural Conduction/drug effects , Neural Conduction/radiation effects , Posterior Horn Cells/drug effects , Posterior Horn Cells/physiology , Posterior Horn Cells/radiation effects , Rats , Rats, Inbred F344 , Recovery of Function , Spinal Cord/drug effects , Spinal Cord/radiation effects
7.
J Neurol Sci ; 67(1): 1-14, 1985 Jan.
Article in English | MEDLINE | ID: mdl-2580059

ABSTRACT

The changes taking place in irradiated central nervous tissue prior to the onset of delayed radionecrosis are poorly understood, but functional abnormalities occurring during the latent interval after irradiation are likely to be of importance. In order to investigate functional disturbances in neurones during this period, unilateral sciatic nerve crush was performed in mice following sub-lethal X-irradiation of the lumbar spinal cord. Alterations in the axon reaction of anterior horn cells were studied using a monoclonal antibody to neurofilament protein. With irradiation immediately prior to crush, the normal, well-defined increase in perikaryal neurofilament protein was significantly diminished, although there was no concurrent radiation necrosis and no alterations were seen in contralateral neurones with intact distal axon processes. The effect was more marked in neurones irradiated one month prior to nerve crush, and in the non-irradiated nerve crush region regeneration was delayed, with diminished neurofilament protein in the regenerating axons. These observations indicate that ionising radiation can progressively impair the ability of neurones to synthesise neurofilament protein during distal axon regeneration. This may result from inadequate repair of radiation induced DNA strand-breaks, but may also follow more generalised damage to protein transcription enzymes and RNA metabolism.


Subject(s)
Anterior Horn Cells/radiation effects , Intermediate Filament Proteins/metabolism , Motor Neurons/radiation effects , Nerve Regeneration/radiation effects , Spinal Nerves/injuries , Animals , Anterior Horn Cells/metabolism , Anterior Horn Cells/pathology , Axons/radiation effects , DNA/metabolism , Immunoenzyme Techniques , Male , Mice , Mice, Inbred CBA , Neurofilament Proteins , RNA/metabolism , Spinal Nerves/metabolism
8.
Rev Neurol (Paris) ; 141(3): 222-7, 1985.
Article in French | MEDLINE | ID: mdl-4001710

ABSTRACT

Three patients developed a progressive flaccid paraparesis without sensory or sphincter disturbances, following radiotherapy for lymphoma in two cases and carcinoma of testis in one case. The course was progressive with stabilization between two and four years. Electrophysiological study suggested anterior horn cell damage the mechanism of which remains unclear.


Subject(s)
Anterior Horn Cells/radiation effects , Motor Neurons/radiation effects , Neuromuscular Diseases/etiology , Radiation Injuries/physiopathology , Radiotherapy/adverse effects , Adolescent , Adult , Electrophysiology , Hodgkin Disease/radiotherapy , Humans , Lymphoma/radiotherapy , Male , Middle Aged , Neuromuscular Diseases/physiopathology , Paralysis/etiology , Paralysis/physiopathology , Syndrome , Testicular Neoplasms/radiotherapy
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