The effect of changed visual feedback on intention tremor in multiple sclerosis

In patients with multiple sclerosis (MS), intention tremor amplitude is enhanced during the visually guided compared to the memory guided motor tasks. In the present study, the effect of visual feedback on intention tremor was investigated during visually guided wrist step-tracking tasks. Specifically, visual feedback of the hand was provided either instantly or averaged over different time windows. Thirteen MS patients with intention tremor and 14 healthy controls performed the wrist step-tracking task, while the visual representation of the actual hand position was displayed instantly or averaged over time windows of 150, 250 and 350 ms. It has been found in the patient group that, in association with a decreased initial error and decreased tremor amplitude on the screen, the amplitude of the actual performed tremor also decreased when visual feedback was changed. The tremor reduction was not different between conditions with manipulated feedback, although delays in presenting visual feedback of the hand position increased when the time window was larger. The reduction in overall tremor amplitude was unlikely related to other factors, such as eye fixation deficits or the speed of the primary hand movement. These results suggest that hand tremor severity is dependent on the visual feedback of position and movement errors.     

The relationship between physiological tremor and the performance of rapid alternating movements in healthy elderly subjects

The power distribution in the frequency spectrum of tremor is known to vary among individuals and its median power frequency declines with ageing. The purpose of the present study was to determine whether a reduction of the central component of physiological tremor would correlate with a reduction of motor performance. Then, the power distribution in the frequency spectrum of tremor from limb extremities might serve as an index of neural drive in healthy elderly subjects. Rest tremor, postural tremor from the finger, and pronation-supination at the wrist were recorded in 102 healthy nuns living in a convent (mean of 72±12 years). Results reveal that several elderly subjects possessed a power distribution of tremor very similar to that of much younger subjects (mean 27 years±3 SD), showing a preponderance of power within the 7.6- to 12.5-Hz band. Duration of pronation-supination cycles of these elderly subjects was, however, similar to that of other elderly subjects who had a preponderance of power within the 3.6- to 7.5-Hz band. Consequently, healthy elderly subjects who possessed a predominance of power within higher frequencies were not at an advantage over other healthy elderly subjects when performing a pronation-supination task. The age of subjects was, however, a better predictor or motor performance. In conclusion, the present findings suggest that, under normal physiological conditions, a reduction of the central component of physiological tremor does not induce a reduction of motor performance. Consequently, tremor recorded at limb extremities cannot be used as an index of neural drive. Electronic Publication     

Facilitation of transmission in the pathway of non-monosynaptic Ia excitation to wrist flexor motoneurones at the onset of voluntary movement in man

Summary Homonymous Ia facilitation of the flexor carpi radialis (FCR) motoneurones (MNs) was significantly larger at the onset of voluntary wrist flexion than at rest. Similarly, stimulation of the ulnar nerve, which was without effect at rest, evoked a significant heteronymous facilitation at the onset of movement. In both cases this extra facilitation occurred with a central latency 3–3.5 ms longer than the monosynaptic latency and had a short (2–5 ms) duration. This long central latency corresponds to that of the recently described non-monosynaptic Ia excitation of FCR MNs. This suggests that interneurones mediating non-monosynaptic Ia excitation to FCR MNs receive strong descending excitation at the onset of movement, and it is argued that they could mediate part of the descending command to MNs.     

多发性硬化症动物模型的研究进展

多发性硬化症(MS)是一种可在中枢神经系统引起髓鞘缺失的炎症性疾病,对该病的研究因其标本难以获取而备受限制.建立相应的动物疾病模型是研究MS病理过程、发病机制以及寻找药物靶点的重要途径.MS的动物模型包括自身免疫性脑脊髓炎模型、病毒模型和化学毒性模型.了解这几种MS动物模型的研究进展很有意义.     

Susceptibility to multiple sclerosis mediated by HLA-DRB1 is influenced by a second gene telomeric of the TNF cluster

Susceptibility to multiple sclerosis (MS) is clearly associated with human leukocyte antigen (HLA)-DRB1*1501, but some studies show associations with HLA-B7 and -B18. These are often co-expressed with DRB1*1501 in the ancestral haplotypes (AH) denoted 7.1 (HLA-A3, B7, tumor necrosis factor [TNF]a11b4, DRB1*1501) and 18.1 (HLA-A25, B18, TNFa10b4, DRB1*1501). Here we present a systematic study of 218 patients and 274 controls typed at all standard class II and TNF microsatellite loci, and a novel non-synonymous polymorphism in the central major histocompatibility complex gene, inhibitor of κ B-like protein (IKBL). The C allele at IKBL+738 is only found on the 7.1 haplotype. HLA-DRB1*1501 was associated with disease, as expected. When subjects expressing DRB1*1501 were analyzed separately, TNFa11b4 and IKBL+738C were less common in the patients and, hence, mark an allele that mediates resistance which lies telomeric of IKBL.

TNFa10b4 and TNFa1b5 were more common in DRB1*1501 patients than in controls. These alleles have been associated with the 18.1 and 18.2 AH, respectively. Since no component of these haplotypes was an independent risk factor in this study, it appears likely that a gene linked to TNFa10b4 and TNFa1b5 modifies the effect of the susceptibility locus marked by HLA-DRB1*1501. Potential candidate genes telomeric of the TNF cluster are discussed.     

诱发电位在多发性硬化诊断中的价值

目的：评价诱发电位在多发性硬化(MS)诊断中的价值，并为临床提供MS的诱发电位(EP)资料。方法：本课题采用临床病例分析统计方法，对164例MS患者的3项EP资料进行分析。结果：MS患者的3项EP中，视觉诱发电位(VEP)的异常率最高，其次为体感诱发电位(SEP)，脑干听觉诱发电位(BAEP)最低；这3项EP联合检查可使异常率提高，EP发现病灶的敏感性较临床检查高，其不仅可以发现中枢神经系统的病灶，而且还能够发现外周神经系统的病灶。结论：联合应用3项EP检查有助于MS诊断以及亚临床病灶的发现。     

Human herpesvirus 6 in the pathogenesis of multiple sclerosis

Multiple sclerosis (MS) is one of the most common disabling neurological diseases affecting young adults. It is a chronic disease characterised by inflammation and demyelination. The aetiology of MS is still unknown, but involvement of viruses has been suspected for many years. Recently much interest has focused on human herpesvirus 6 (HHV-6), since the virus has been detected in MS plaques in the brain and patients with MS have been shown to have an aberrant immune response to HHV-6. Results from different studies are, however, conflicting and in the light of the long list of previous claims to have found the viral aetiology of MS it is necessary to interpret the HHV-6 findings with great caution. Possible mechanisms for virally induced demyelination and autoimmunity are discussed in this review, and the evidence for and against a role for HHV-6 in MS is summarised.     

Targets of the humoral autoimmune response in multiple sclerosis

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system (CNS) with heterogeneous clinical, genetic and pathophysiological characteristics. The establishment of reliable biomarkers for diagnosis, prognosis and treatment of MS has therefore proven to be very difficult. During the last decades, mounting evidence has been collected for the involvement of B cells and antibodies in MS pathogenesis. A wide variety of autoantibodies has been described in MS and these autoantibodies could be useful biomarkers for MS.     

Delayed beta synchronization after movement of the more affected hand in essential tremor

To investigate the pathomechanism of parkinsonian tremor (PT) and essential tremor (ET) by studying the correlation between tremor asymmetry and post-movement beta synchronization (PMBS) of the human EEG. We recorded the EEG of 10 patients with ET, 10 patients with Parkinson's disease and 10 controls. Subjects pressed an on-off switch in a self-paced manner with the thumb of their less (T+) and more (T++) tremulous hand. After digitalization of the EEG from the Cz, C3, C4 electrodes the movement reactive beta frequency, its maximum peak power value and its latency triggered to movement offset were determined. In ET tremor intensity did not influence the power of PMBS, however it was significantly delayed after the movement of the more tremulous hand. In Parkinson's disease after the movement of the more tremulous hand PMBS power was decreased, but it was not delayed. In controls the side of movement had no effect on the power and latency of the PMBS. The neuronal mechanisms underlying PMBS generation are differently affected in essential tremor and Parkinson's disease. The increase of PMBS latency after movement of the more affected hand in ET indicates possible cortical mechanisms in essential tremor generation.     

The action of TH17 cells on blood brain barrier in multiple sclerosis and experimental autoimmune encephalomyelitis

Th17 cells, known as a highly pro-inflammatory subtype of Th cells, are involved very early in numerous aspects of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) neuropathology. A crucial event for the formation and accumulation of MS lesions is represented by the disruption of the blood brain barrier (BBB) in relapsing-remitting MS. Th17 cells also contribute to the progression of MS/EAE. These events will allow for the passage of inflammatory cells into the brain. Secondary to this, increased recruitment of neutrophils occurs, followed by increased protease activity that will continue to attract macrophages and monocytes, leading to brain inflammation with sustained myelin and axon damage.This review focuses mainly on the role of Th17 cells in penetrating the BBB and on their important effects on BBB disruption via their main secretion products, IL-17 and IL-22. We present the morphological aspects of Th17 cells that allow for intercellular contacts with BBB endothelial cells and the functional/secretory particularities of Th17 cells that allow for intercellular communications that enhance Th17 entry into the CNS. The cytokines and chemokines involved in these processes are described. In conclusion, Th17 cells can efficiently cross the BBB using pathways distinct from those used by Th1 cells, leading to BBB disruption, the activation of other inflammatory cells and neurodegeneration in MS patients.     

Loss of interhemispheric inhibition in patients with multiple sclerosis is related to corpus callosum atrophy

Axonal injury and loss in the corpus callosum (CC) is characteristic of the pathology of multiple sclerosis (MS). Functional magnetic resonance imaging (fMRI) potentially allows neurophysiological consequences of this interhemispheric axonal loss to be defined quantitatively. Here we have used 3T fMRI to study the activation in the contralateral primary sensorimotor cortex and deactivation (mediated by transcallosal tracts) in the homologous ipsilateral region in 14 patients with MS and in 14 matched healthy controls during a simple hand-tapping task. Both healthy controls and MS patients showed similar activation in the motor cortex contralateral to the hand moved, but the patients showed a significantly smaller relative deactivation in the ipsilateral motor cortex (P = 0.002). The difference was accounted for by the sub-group of MS patients who previously had impairment of motor function of the hand tested (MS-phd). The CC of the whole patient group was significantly thinner than for the controls (P = 0.001). Atrophy of the CC was correlated with loss of deactivation for the whole patient group (r = −0.50, P = 0.035), but particularly for MS-phd (r = −0.914, P = 0.004). Interhemispheric physiological inhibition thus is impaired in patients with MS, potentially contributing to impairment of motor control. This work suggests one way in which FMRI monitoring of the transcallosal interactions in motor cortex could become a tool for evaluation of therapies that may enhance function in reversibly impaired pathways.     

多发性硬化患者淋巴细胞激活的临床意义

目的：探讨多发性硬化(MS)患者淋巴细胞的激活状态及临床意义。方法：流式细胞仪测定28例缓解复发型MS患者(复发期20例，缓解期8例)外周血(PB)、12例复发期脑脊液(CSF)及11例复发期MS患者予糖皮质激素治疗后淋巴细胞CD69和HLA-DR表达的阳性百分率。结果：复发期MS患者阳淋巴细胞HLA-DR 和CD3 ／HAL-DR 的百分率高于对照组和缓解期MS，缓解期MS患者CD3 /HLA-DR 的百分率高于对照组3复发期MS患者CSF中CD69 、HLA-DR 和CD3 ／HLA-DR 的百分率均高于PB；复发期MS患者CSF中CD69 的百分率与血脑屏障受损呈正相关；激素治疗降低复发期MS PB淋巴细胞HLA-DR 的百分率。结论：MS患者淋巴细胞激活涉及MS的发病机制并可作为MS活动期的一个指标。     

Gating of somatosensory evoked potentials during voluntary movement of the lower limb in man

Somatosensory evoked potentials (SEPs) evoked by stimulation of the tibial nerve (TN) in the popliteal fossa, the sural nerve (Sur) at the lateral malleole, and an Achilles tendon (Achilles) tap were recorded before and during voluntary plantarflexion, dorsiflexion, and cocontraction of the ipsi- and contralateral foot in normal subjects. Suppression (gating) of the TN-SEP began around 60 ms before the onset of electromyographic activity (EMG), and became maximal 50–100 ms after the onset of EMG. Similar gating was observed for the SEP evoked by activation of muscle afferents (Achilles) and cutaneous afferents (Sur). The TN-SEP was similarly depressed at the onset of a plantarflexion as at the onset of dorsiflexion. A depression, although much smaller, was also observed at the onset of movement of the contralateral limb. The depression of the TN-SEP after the onset of EMG decreased when fast-conducting afferents were blocked by ischemia below the knee joint. The TN-SEP was equally depressed during tonic dorsiflexion, plantarflexion, and cocontraction of dorsi- and plantarflexors. The TN-SEP was depressed for up to 300 ms when preceded by stimulation of Sur or a biceps femoris tendon tap. Gating of lower limb SEPs thus appears to have both central and peripheral components of which neither seems to be specific for the muscle being contracted or the sensory afferents being stimulated. We encourage that caution is taken when drawing functional conclusions regarding movement-specific modulation of afferent inflow to the somatosensory cortex based on observations of gating of lower limb SEP. Received: 25 March 1997 / Accepted: 20 October 1997     

The role of nitric oxide in multiple sclerosis

 During the past decade nitric oxide has emerged as an important mediator of physiological and pathophysiological processes. Elevated nitric oxide biosynthesis has been associated with nonspecific immune-mediated cellular cytotoxicity and the pathogenesis of chronic, inflammatory autoimmune diseases including rheumatoid arthritis, insulin-dependent diabetes, inflammatory bowel disease, and mutiple sclerosis. Recent evidence suggests, however, that nitric oxide is also immunoregulatory and suppresses the function of activated proinflammatory macrophages and T lymphocytes involved in these diseases. This article reviews the role of nitric oxide in the biology of central nervous system glial cells (astrocytes and microglia) as it pertains to the pathogenesis of multiple sclerosis in humans and experimental allergic encephalitis, the animal model of this disease. Although nitric oxide has been clearly implicated as a potential mediator of microglia-dependent primary demyelination, a hallmark of multiple sclerosis, studies with nitric oxide synthase inhibitors in the encephalitis model have been equivocal. These data are critically reviewed in the context of what is know from clinical research on the nitric oxide pathway in multiple sclerosis. Specific recommendations for future preclinical animal model research and clinical research on the nitric oxide pathway in patients are suggested. These studies are necessary to further define the role of nitric oxide in the pathology of multiple sclerosis and to fully explore the potential for nitric oxide synthase inhibitors as novel therapeutics for this disease. Received: 6 June 1996 / Accepted: 24 September 1996     

Activity of primate putamen neurons is selective to the mode of voluntary movement: visually guided,self-initiated or memory-guided

Summary The aim of this report was to investigate the neural processes of movement initiation and control in which the basal ganglia play an essential role. Single-neuron activity was recorded in the putamen of monkeys performing learned arm movements initiated in three different modes: sensorially guided, internally-timed self-initiated and memory guided. There were no significant differences in the magnitude and timing of both prime mover and supporting muscle activity between the three modes of movement. Over half of the task-related neurons showed strong activity in one of the three modes of movement initiation, but were only slightly activated in the other two modes. No clear preference for a particular movement mode was evident in the population of putamen neurons as a whole. These results are consistent with the hypothesis that there are heterogeneous groups of neurons in the putamen, and that each group of neurons participates in retrieving a different kind of information required for movement based on either external sensory events or on internally stored information.     

The control of rapid limb movement in the cat

Summary Electromyographic (EMG) activity associated with rapid voluntary limb movements exhibits a characteristic three burst pattern. The first burst is in the agonist muscle (AG1), the second is in the antagonist (ANT) and the third is again in the agonist (AG2). The present study was undertaken to determine whether ANT and AG2 reflect preprogrammed commands or responses to stretch consequent upon limb displacement. To answer this question EMG activity of agonist and antagonist muscles was examined in cats performing a tracking task. To dissociate centrally programmed muscular events from their intended mechanical consequences, isometric and anisometric conditions were presented in either a predictable or unpredictable sequence. A torque motor was used to control limb trajectory and to impose passive angular displacements.Whereas AG1 was present under both isometric and anisometric conditions, ANT and AG2 required limb displacement and were time locked to movement parameters. ANT occurred within 15 ms following the onset of acceleration. Its magnitude varied linearly with this parameter and inversely with AG1. Passive displacements stretching the antagonist elicited responses with similar latencies and greatest magnitude for a given acceleration. AG2 was only present in underdamped movements with terminal oscillations and typically occurred when the position reached its peak and the velocity recrossed zero. Its magnitude was a function of both limb deceleration and of intended force.The data indicate that both ANT and AG2 represent responses to muscles stretch whose amplitudes are modulated by descending commands. Reciprocal mechanisms operating at a spinal level could account for the reduction of the antagonist response as a function of intended force. The increased sensitivity of late stretch responses in the agonist with higher intended forces is compatible with motoneuron facilitation by tonic descending commands. It is proposed that the stretch evoked responses function to dampen terminal oscillations which ensue from rapid displacement of the mass of the limb against elastic forces of muscle and soft tissue.Supported by NIH Grant NS 15750     

基质金属蛋白酶在多发性硬化发病中的作用机制及治疗现状

多发性硬化（MS）是中枢神经系统炎性脱髓鞘疾病,基质金属蛋白酶是一组蛋白水解酶,有重要的病理和生理作用,近年的研究表明它在（MS）的发生和疾病进展中都具有重要作用,参与主要的发病过程,具有多种发病机制,抑制其活性具有有效的治疗意义。     

视觉、脑干听觉诱发电位对多发性硬化的诊断价值

目的 :探讨视觉诱发电位 (VEP)、听觉诱发电位 (BAEP)对多发性硬化 (MS)的诊断价值。方法 :对 30例临床诊断为MS的患者进行VEP、BAEP检测 ,并与正常对照组进行比较分析。结果 :MS患者VEP和BAEP的异常率分别为 73%和 6 0 %。异常中VEP有 6 8% ,BAEP有 78%的患者 ,临床有相应的症状 ;VEP 32 % ,BAEP 2 2 %的患者临床无相应症状。 5例MS患者在临床缓解期复查VEP、BAEP ,1例VEP、BAEP恢复正常 ,4例仍异常。结论 :VEP、BAEP检测对MS的诊断具有重要意义。     

Regeneration and repair in multiple sclerosis: The role of cell transplantation

Physiological (spontaneous) and reactive (reparative) regenerative processes are fundamental part of life and greatly differ among the different animals and tissues. While spontaneous regeneration naturally occurs upon cell attrition, reparative regeneration occurs as a consequence of tissue damage. Both spontaneous and reparative regeneration play an important role in maintaining the normal equilibrium of the central nervous system (CNS) as well as in promoting its repair upon injury. Cells play a critical role in reparative regeneration as regenerating structures (cells or tissues) depend on the proliferation without (de)differentiation of parenchymal cells surviving to the injury, proliferation of stem (progenitor) cells resident in the injured tissue, dedifferentiation of mature cells in the remaining tissue, or by the influx of stem cells originating outside the damaged tissue. Considering the central role of stem and progenitor cells in regeneration, a spur of experimental stem cell-based transplantation approaches for tissue (e.g. CNS) repair has been recently generated. This review will focus on the therapeutic efficacy of different sources of somatic stem cells – and in particular on those of neural origin – in promoting CNS repair in a chronic (auto)immune-mediated inflammatory disorder such as multiple sclerosis.