Locomotion induced by epidural stimulation in a decerebrated cat after spinal cord injury

The effect of partial and complete spinal cord transection (Th7–Th8) on locomotor activity evoked in decerebrated cats by electrical epidural stimulation (segment L5, 80–100 μA, 0.5 ms at 5 Hz) has been investigated. Transection of dorsal columns did not substantially influence the locomotion. Disruption of the ventral spinal quadrant resulted in deterioration and instability of the locomotor rhythm. Injury to lateral or medial descending motor systems led to redistribution of the tone in antagonist muscles. Locomotion could be evoked by epidural stimulation within 20 h after complete transection of the spinal cord. The restoration of polysynaptic components in EMG responses correlated with recovery of the stepping function. The data obtained confirm that initiation of locomotion under epidural stimulation is caused by direct action on intraspinal systems responsible for locomotor regulation. With intact or partially injured spinal cord, this effect is under the influence of supraspinal motor systems correcting and stabilizing the evoked locomotor pattern.     

The distribution of motoneurons supplying hind limb muscles in the clawed toad, Xenopus laevis

The distribution of motoneurons in the lumbar spinal cord (spinal segments 8-10) of the clawed toad, Xenopus laevis, was studied with the horseradish peroxidase technique. In a total of 13 different hind limb muscles this tracer was applied in a slow-release gel. Motoneurons innervating a particular hind limb muscle were clustered in longitudinally arranged motor pools. Motor pools of different muscles did show considerable overlap both in the rostrocaudal and transverse plane. But, the various motor pools clearly show a somatotopic organization of motoneurons even in such a condensed lumbar spinal cord as in Xenopus laevis. Motoneurons innervating more distally positioned muscles are generally found in more caudal segments, while proximal muscles (with the exception of the m. adductor magnus) are supplied by motoneurons more or less throughout the lumbar enlargement. Flexor muscles usually are innervated by motoneurons situated ventrolaterally in the ventral horn, extensor muscles by dorsomedially found motoneurons. This pattern is particularly apparent for proximal (thigh) muscles, less so for more distal (shank and foot) muscles. The present data are in keeping with those obtained with the retrograde cell degeneration technique in ranid frogs and are consistent with observations in other tetrapods, although a more clear separation of motor pools is evident in "higher" vertebrates such as birds and mammals.     

Mechanisms of stepping rhythm formation in decerebrated and chronic spinal cats under epidural stimulation

A study was made of the stepping pattern formation in decerebrated and in chronic spinal cats during epidural stimulation (ES). The hindlimb stepping performance depended on the parameters of ES and afferent input. At non-optimal ES parameters, no stepping was induced, only muscle reflexes followed the stimulation rhythm. Optimized ES (3–5 Hz, 50–100 μA for decerebrated and 20–30 Hz, 150–250 μA for spinal cats) evoked coordinated stepping movements at a natural rate (0.8–1 Hz) accompanied by electromyographic burst activity of the corresponding muscles. In decerebrated cats, the bursts are formed owing to modulation of early responses and the late polysynaptic activity. In chronic spinal cats, this process is mainly due to amplitude modulation of the early responses. Formation of the stepping pattern in decerebrated cats involves spinal interneurons responsible for the polysynaptic activity, which allows its correction based on processing the afferent signals. Activation of this system in chronic spinal cats can be realized by afferent stimulation alone, without ES.     

Antinociceptive effects of lacosamide on spinal neuronal and behavioural measures of pain in a rat model of osteoarthritis

Introduction

Alterations in voltage-gated sodium channel (VGSC) function have been linked to chronic pain and are good targets for analgesics. Lacosamide (LCM) is a novel anticonvulsant that enhances the slow inactivation state of VGSCs. This conformational state can be induced by repeated neuronal firing and/or under conditions of sustained membrane depolarisation, as is expected for hyperexcitable neurones in pathological conditions such as epilepsy and neuropathy, and probably osteoarthritis (OA). In this study, therefore, we examined the antinociceptive effect of LCM on spinal neuronal and behavioural measures of pain, in vivo, in a rat OA model.

Methods

OA was induced in Sprague Dawley rats by intraarticular injection of 2 mg of monosodium iodoacetate (MIA). Sham rats received saline injections. Behavioural responses to mechanical and cooling stimulation of the ipsilateral hind paw and hindlimb weight-bearing were recorded. In vivo electrophysiology experiments were performed in anaesthetised MIA or sham rats, and we recorded the effects of spinal or systemic administration of LCM on the evoked responses of dorsal horn neurones to electrical, mechanical (brush, von Frey, 2 to 60 g) and heat (40°C to 50°C) stimulation of the peripheral receptive field. The effect of systemic LCM on nociceptive behaviours was assessed.

Results

Behavioural hypersensitivity ipsilateral to knee injury was seen as a reduced paw withdrawal threshold to mechanical stimulation, an increase in paw withdrawal frequency to cooling stimulation and hind limb weight-bearing asymmetry in MIA-treated rats only. Spinal and systemic administration of LCM produced significant reductions of the electrical Aβ- and C-fibre evoked neuronal responses and the mechanical and thermal evoked neuronal responses in the MIA group only. Systemic administration of LCM significantly reversed the behavioural hypersensitive responses to mechanical and cooling stimulation of the ipsilateral hind paw, but hind limb weight-bearing asymmetry was not corrected.

Conclusions

Our in vivo electrophysiological results show that the inhibitory effects of LCM were MIA-dependent. This suggests that, if used in OA patients, LCM may allow physiological transmission but suppress secondary hyperalgesia and allodynia. The inhibitory effect on spinal neuronal firing aligned with analgesic efficacy on nociceptive behaviours and suggests that LCM may still prove worthwhile for OA pain treatment and merits further clinical investigation.     

Behavioral and Electrophysiological Evidence for the Differential Functions of TRPV1 at Early and Late Stages of Chronic Inflammatory Nociception in Rats

We previously reported that vanilloid receptor type 1 (VR1, or TRPV1) was up-regulated in dorsal root ganglion (DRG) and the spinal dorsal horn after chronic inflammatory pain produced by complete Freund’s adjuvant (CFA) injection into the plantar of rat hind paw. In the present study, we found that subcutaneous or intrathecal application of capsazepine (CPZ), a TRPV1 competitive antagonist, could inhibit thermal hyperalgesia on day 1 and on day 14 but not on day 28 after CFA injection. With extracellular electrophysiological recording, the effect of CPZ on noxious electrical or heat stimulation evoked responses of wide dynamic range (WDR) neurons in the deep layers of the spinal dorsal horn was evaluated. Under noxious electrical stimulation to sciatic nerve, CPZ applied to the spinal cord produced an inhibition on Aδ- and C-fiber evoked responses of WDR neurons on day 1 and 14, but not on day 28. Under radiant heat stimulation to the receptive field skin, subcutaneous application of CPZ significantly inhibited the background activity and extended the response latency of WDR neurons on day 14. These results provide new evidence for the functional significance of TRPV1 at the early stage, but not the late stage, in the rat model of CFA-induced inflammatory pain. Special issue article in honor of Dr. Ji-Sheng Han. Hao Luo, Isabella Shi Xu, Yi Chen are Co-first authors.     

Control of the human and animal locomotor activity in the absence of supraspinal effects

In patients deprived of supraspinal effects, electrical epidural stimulation of the spinal cord's dorsal surface at the level of 2nd lumbar segment induces step-like movements accompanied by respective electromyographic activity of the leg's muscles. Triggering of the step-like movements occurs at certain parameters of the stimulation. The data obtained suggest that human spinal cord has networks of interneurons-generators of the step-like movements. A leading role of the spinal cord's propriospinal system in activation of spinal generators of stepping under epidural influences was shown in cats.     

Effects of passive flexion of the forepaw on the response gain of limb extensors to sinusoidal stimulation of labyrinth receptors

The main aim of the present study was to find out whether the dynamic characteristics of responses of limb extensor muscles to labyrinth stimulation were modified by the proprioceptive input elicited by appropriate displacements of the corresponding limb extremity. In cats decerebrated at precollicular or intercollicular level, the multiunit EMG activity of the medial head of the triceps brachii was recorded during roll tilt of the animal at the frequency of 0.15 Hz, +/- 10 degrees leading to selective stimulation of labyrinth receptors. This stimulation was then tested several times at regular intervals of 2 to 6 min for several hours while maintaining the ipsilateral forelimb in the horizontal extended position, i.e. with the plantar surface of the foot lying on the tilting table, or during passive flexion of the forepaw in plantar or dorsal direction. In all the experiments in which the forelimb was in the control position, the multiunit EMG responses of the triceps brachii were characterized by an increased activity during side-down tilt of the animal and a decreased activity during side up tilt. These responses were related to animal position and not to the velocity of animal displacement, thus being attributed to stimulation of macular, utricular receptors. Static displacement of limb extremities following plantar flexion of the forepaw greatly decreased the amplitude of the EMG modulation and thus the gain of the first harmonic component of the multiunit EMG responses of the ipsilateral triceps brachii to animal tilt. This reduced gain was due not only to a reduced number of motor units recruited during labyrinth stimulation, but also to a reduced modulation of firing rate of the active motor units, as shown by recording the activity of individual motor units. On the other hand, displacement of the same extremity in the opposite direction, i.e. following dorsiflexion of the forepaw, enhanced the amplitude of the EMG modulation and thus the gain of the multiunit EMG responses of the ipsilateral triceps brachii to animal tilt. This finding was mainly due to an increased recruitment of motor units during side-down tilt, although an increased modulation of the firing rate of individual motor units could not be excluded. In both instances, no changes in the phase angle to the responses were observed. The changes in response gain described above depended on the amount of passive displacement of the forepaw and persisted unmodified throughout the new maintained position.(ABSTRACT TRUNCATED AT 400 WORDS)     

Intraoperative motor evoked potentials monitoring in spinal neurosurgery.

Neurological damage may follow even a technically accurate spinal surgery. The intraoperative monitoring of neurological functions put at risk by the operation is a method utilized to correctly identify the topography of neural structures and to avoid surgical insults. SEPs monitoring is 20 year old, and only recently direct motor tract monitoring has become possible. Transcranial electrical motor cortex stimulation with single pulses or with short trains of stimuli and recording of the evoked responses from the spinal epidural space (D-waves) and from limb muscles is a reliable and safe technique for monitoring corticospinal tract activity even under general anesthesia. The method has a solid theoretical experimental background. Its clinical application has demonstrated high sensitivity and specificity. Intraoperative MEPs monitoring is nowadays considered indispensable during spinal neurosurgery.     

异丙酚对正常大鼠脊髓背角感觉神经元反应性的抑制作用

脊髓背角感觉神经元不仅在感觉信息的传递和调节中起到重要作用,也是各种内源性和外源性药物的作用靶位.为了解静脉麻醉剂异丙酚是否对背角感觉神经元的反应性具有调节作用,本实验采用在体单细胞胞外记录技术,观察了脊髓背表面直接滴注0.5 μmol异丙酚对戊巴比妥钠麻醉大鼠脊髓背角广动力域(WDR)神经元和低阈值机械感受型(LTM)神经元反应性的影响.实验发现,异丙酚能抑制背角WDR神经元由施加于外周感受野伤害性热刺激(45、47、49和53℃,15 s)和夹捏机械刺激(10 s)诱发的反应性,与DMSO对照组比较具有显著性统计学差异(P＜0.05);同样,异丙酚对非伤害性机械刺激诱发的WDR或LTM神经元的反应性也具有显著的抑制作用(P＜0.05).本结果提示,异丙酚可直接作用于正常大鼠脊髓背角神经元,对由非伤害性和伤害性纤维介导的神经元反应性均产生抑制作用,因此异丙酚的脊髓抗伤害作用可能不是特异性的.     

The role of afferent feedback in the control of hamstrings activity during human gait

In vertebrates, possibly also in man, the pattern of activation of muscles during locomotion can be generated by the spinal cord (locomotor CPG, central pattern generator). However, sensory feedback is crucial to adapt the functioning of the CPG to the external requirements during gait. It is postulated that afferent input from skin and muscles can contribute to the EMG activation patterns as observed in various limb muscles during gait. The activity of the hamstrings at end swing may be partially due to stretch reflexes of these muscles. At end stance the hamstring activity may be assisted by reflexes from natural skin activation from the dorsum of the foot. In addition, more specific actions are also incorporated. For example, sural nerve stimulation induces an activation of biceps femoris (BF) whereas a suppression is usually obtained for semitendinosus (ST), indicating that the induced activation is aimed at exorotation of the lower leg. Similarly, the preferential activation of medial versus lateral gastrocnemius (GM versus GL) in sural nerve induced reflexes could favor such exorotation. It is concluded that the present evidence points towards a possible contribution of various reflexes to the motor output seen during gait for movements both inside and outside the sagittal plane.     

Botox produces functional weakness in non-injected muscles adjacent to the target muscle

Botulinum type-A (BTX-A) neurotoxin exerts a paralytic effect on muscles and is used increasingly to treat a variety of muscle spasticity disorders. While its pathogenesis for muscle-induced weakness has been well elucidated, the functional effects of BTX-A administration are incomplete. Specifically, weakness as a function of muscle length and stimulation frequency has only been investigated qualitatively in a few muscles and the possible effect of the toxin on non-target muscles, although considered possible based on laboratory experiments, has not been studied widely and the functional implications remain unknown. Therefore, the purpose of this study was to measure the functional implications of BTX-A on force production and possible weakness of a target muscle and a non-injected neighbouring muscle. The cat soleus was chosen as the target muscle and was injected with 3.2-3.5U of BTX-A/kg in one hind limb, while the soleus of the other hind limb served as a non-injected control. Force-length properties within and exceeding the functional range of motion were determined at frequencies of stimulation of 10, 30 and 50Hz. Force-length properties of the adjacent non-injected plantaris were also determined in the experimental and contralateral hind limb. Four weeks following BTX-A injections, peak soleus forces were decreased by 30% (50Hz), 29% (30Hz) and 29% (10Hz) and peak plantaris forces were decreased by 11% (50Hz), 16% (30Hz) and 16% (10Hz), in the experimental compared to the contralateral hind limb. Absolute BTX-associated force loss was significantly different at all frequencies of stimulation and all lengths for the soleus, while in the plantaris there was a significant force loss across long (> or = -4mm) but not short muscle lengths. Decreases in peak force were independent of the stimulation frequency. We concluded from the results of this study that BTX-A injection in the target muscle caused a measurable effect on force production and that force production was decreased in non-target neighbouring muscles at and near lengths of peak force production. These results are of particular importance in therapeutic procedures where isolated muscles are targeted for treatment. They should also be considered in neurophysiological studies in which BTX-A injections are used to selectively diminish muscle function.     

Features of stepping pattern formation in decerebrated cats under epidural spinal cord stimulation

The mechanisms of stepping pattern formation initiated by epidural spinal cord stimulation in decerebrated cats, were investigated. It is shown that the ability to produce the stepping pattern involve the L3-L5 segments. In flexor muscle, the formation of stepping pattern under optimal stimulation frequency (5-10 Hz) of these segments is provided by polysynaptic activity with the latency 80-110 ms. In extensor muscle, this process is realized through interaction of monosynaptic reflex and polysynaptic activity. The stepping pattern under epidural stimulation is determined by spinal structures with modulation influence of the peripheral feedback.     

Increase in tissue concentrations of histamine and 5-hydroxytryptamine following capsaicin treatment of newborn rats

Treatment of newborn rats with capsaicin is known to result in a permanent deficit of unmyelinated afferent neurones. The present study was concerned with the effect of neonatal capsaicin (50 mg kg^?1 s.c.) on tissue concentrations of histamine and 5-hydroxytryptamine (5-HT) in the adult rat. The amines were determined at the age of 5 to 6 months using high performance liquid chromatography. Histamine and 5-HT concentrations were significantly increased in the dorsal skin of the hind paw and the dorsal spinal cord. Histamine concentrations were also increased in lungs and ventral spinal cord while 5-HT concentrations were unaltered in these tissues. Both histamine and 5-HT concentrations were unchanged in the ventral skin of the hind paw, gastrointestinal tract and brain. It is proposed that the changes in the amine concentrations reflect a secondary response of histamine and 5-HT containing mast cells and neurones to the irreversible degeneration of unmyelinated afferent neurones caused by neonatal capsaicin treatment.     

脊髓细胞外调节激酶1/2在大鼠后足切割痛中的表达和作用

目的：探讨大鼠后足切割后脊髓ERK的表达情况。方法：以大鼠右后足切割作为急性疼痛模型;用免疫组织化学法测试脊髓磷酸化ERK（pERK）表达情况。ERK抑制剂U0126（1μg）在切割前20min或切割后20min鞘内注射。用von Frey纤维测试大鼠机械性痛敏。结果：大鼠后足切割后1min,在切割侧L4-L5脊髓浅层背侧角（板层Ⅰ和板层Ⅱ）ERK被迅速地激活,并在5min达到峰值,随后恢复到基础值。切割前鞘内给予U0126能显著减轻机械性痛敏,然而,切割后鞘内给予U0126对机械性痛敏的作用并不明显。结论：脊髓ERK在大鼠后足切割痛中产生机械性痛敏发挥了重要的作用。     

BOLD signals correlate with ensemble unit activities in rat's somatosensory cortex

Evoked neural activity (ensemble single-unit activity and evoked field potential) and functional magnetic resonance imaging (fMRI) changes of the primary somatosensory cortex in response to electrical stimulation of the hind paw were studied in rats under anesthesia. The effects of stimulation frequency (ranging from 0.3 to 10 Hz) and types of anesthetics (alpha-chloralose and sodium pentobarbital) on blood oxygen level dependent (BOLD) activation and neural activation were compared. Both ensemble single-unit activity and BOLD signal changes achieved maximal activation at 3 Hz of stimulation and responses were significantly stronger under alpha-chloralose anesthesia. The maximal activation of the integral evoked potential (sigmaEP), in contrast, was the highest at 10 Hz; and the values were similar for alpha-chloralose and pentobarbital. These analyses revealed that fMRI image changes were better correlated with ensemble single-unit activity than with sigmaEP during somatosensory stimulations.     

L'augmentation de la contraction du muscle soléaire du membre d'appui chez l'homme ne retarde pas la phase pendulaire au cours de pas déclenchés par la chute en avant

In this study it was examined in man whether tension increase in the extensor muscles of the stance foot delays the stance to swing transition, as suggested by some observations made in cats. Steps reproducibly elicited by forward fall were studied. Increase in muscle tension was obtained by electrical stimulation of the tibial nerve during the last third of the first step stance phase with trains of five rectangular pulses, 1 ms in duration, at 20 Hz, whose intensity was sufficient for eliciting maximal responses in the stance Soleus muscle (e.m.g. M responses). Trials with and without electrical stimulation were randomly carried out in five healthy subjects who had consented to take part in the experimentation. The stance to swing transition was characterized by the time of activation of the Tibialis anterior muscle of the stance foot and by the time of clearance of this foot from the ground. It was found that maximal contractions of the stance Soleus muscle did not change these times. Thus, in contradiction to some observations made in spinal and decerebrated cats, tension increase in the stance Soleus in man during steps elicited by a forward fall does not delay the transition to the swing phase.     

大鼠脊髓诱发电位与脊髓损伤的关系——Ⅲ.脊髓局部损毁后电位的变化及电位来源分析

本文描述了大鼠脊髓L_1节段后柱、后索、侧索和前角的诱发电位及其损伤后的变化,并观察了切断L_4、L_5脊神经背、腹根与横断高位颈髓对电位的影响,以进行行电位来源分析。结果可见,上述四个区域的诱发电位基本由早反应三相波和晚反应组成。分别电解损毁这些部位后,电位波幅均普遍降低,晚期反应较早反应降低明显。后柱或后索受损对电位影响最大。局部损毁后可见L_1及T_(13)水平的硬膜上电位改变明显,尤其晚反应减弱、波峰平坦。反应时值与潜伏时未见明显改变。切断L_4脊神经背、腹根后、电位基本消失。去大脑对电位未见明显影响。结果表明,刺激坐骨神经诱发的脊髓电位起源于低位腰段传入神经和脊髓内多通路的兴奋传导,在一定程度上受腹根逆行活动的影响,与大脑及脊髓下行传导束活动无直接联系。脊髓诱发电位的幅度与波形改变可作为脊髓损伤的判断指标之一。     

Significance of peripheral feedback in stepping movement generation under epideral spinal cord stimulation

In acute experiments on decerebrated and spinalized cats, the role of peripheral afferent input from hindlimbs in stepping patterns formation under epidural spinal cord stimulation (ESCS), was investigated. The hindlimb muscles' electromyographic activity and kinematic parameters of evoked stepping were analyzed. It has been shown that epidural stimulation (20-100 microA, 5 Hz) of L4-L5 spine segments induced coordinated stepping on the treadmill belt. In conditions of weight-bearing support (stopped treadmill, hindlimbs lifted above the treadmill), the stepping rhythmic was unstable, stepping cycle period and its internal structure having changed as well. With increased speed of locomotion the stepping frequency increased due to the duration of the support phase decreasing. Forward stepping could be reversed to backward stepping by changing the direction of the treadmill belt movement. In 2-4 hours after complete spinal transection (T8-T9), the epidural stimulation elicited stepping movements on a moving treadmill only. It was found that the influence of peripheral feedback on initiation of the stepping after spinalization increased. Peripheral feedback seems to play a major role in determining the fundamental features of motor output during the ESCS.     

Tonic facilitatory influences of dorsal pontine reticular structures on the response gain of limb extensors to sinusoidal labyrinth and neck stimulations

Experiments were performed to find out whether changes in resting discharge of the inhibitory reticulospinal (RS) neurons of the medulla, produced either by selective destruction or by cholinergic activation of a pontine tegmental reticular system, may modify the response gain of limb extensor muscles to given parameters of roll tilt of the animal or neck rotation. In precollicular decerebrate cats, an electrolytic lesion of the dorsal aspect of the pontine tegmentum, which slightly increased the tonic contraction of limb extensors, greatly decreased the amplitude of the multiunit EMG response of forelimb extensor muscles, i.e. of the medial head of the triceps brachii, to roll tilt of the animal and neck rotation (at 0.15 Hz, +/- 10 degrees), leading to selective stimulation of labyrinth or neck receptors. Correspondingly, the response gain of the forelimb extensors to labyrinth and neck stimulation decreased, but no change in the phase angle of the responses was observed. These findings did not depend on the increased postural activity, since they were still observed in the absence of any change in spontaneous EMG activity of the triceps brachii following the lesion. The changes in posture as well as in response gain of the forelimb extensors to labyrinth and neck stimulation produced by the pontine lesion appeared suddenly, and persisted for several hours throughout the survival period. Moreover, these changes involved mainly, but not exclusively, the limbs ipsilateral to the side of the lesion. Histological controls indicated that the structure responsible for the postural and reflex changes described above corresponded to the dorsal aspect of the pontine tegmentum located immediately ventral to the locus coeruleus (LC); this area corresponded to the peri-LC region as well as the surrounding pontine reticular formation (RF), including the dorsal aspect of the central tegmental field. This region closely corresponds to the area from which a tegmentoreticular tract, ending on the medullary inhibitory area, originates. It was previously shown that unilateral or bilateral lesion of the LC, which decreased the extensor tonus in the ipsilateral limbs, greatly enhanced the response gain of the triceps brachii to sinusoidal stimulation of labyrinth and neck receptors. These findings were attributed to suppression of an inhibitory influence that the LC exerts on the dorsal pontine reticular structures described above.(ABSTRACT TRUNCATED AT 400 WORDS)