黑龙江省齐齐哈尔医学院第三附属医院神经内科

脑卒中后运动功能恢复的机制尚未完全阐明。研究表明中风后功能的恢复与大脑可塑性有关,本文旨在阐述近年对一侧脑缺血后双侧大脑半球的活动的研究成果。     

Prediction of lower limb motor outcomes based on transcranial magnetic stimulation findings in patients with an infarct of the anterior cerebral artery

Abstract

The aim was to investigate the relationship between transcranial magnetic stimulation (TMS) at the early stage of stroke and 6-month motor outcome for patients with anterior cerebral artery territory infarct. Patients were classified into TMS(+) and TMS(?) groups. At the 6-month evaluation, lower limb motor function for the TMS(+) group was significantly better than those for the TMS(?) group. Thus, early TMS evaluation is useful for predicting recovery of lower limb motor function in patients experiencing this type of stroke.     

Hypoxic Preconditioning and Hypoxic-Ischemic Brain Damage in the Immature Rat: Pathologic and Metabolic Correlates

Abstract: It has been reported that immature rats subjected to cerebral hypoxia-ischemia sustain less brain damage if they are previously exposed to systemic hypoxia compared with animals not exposed to prior hypoxia. Accordingly, neuropathologic and metabolic experiments were conducted to confirm and extend the observation that hypoxic preconditioning protects the perinatal brain from subsequent hypoxic-ischemic brain damage. Six-day postnatal rats were subjected to systemic hypoxia with 8% oxygen at 37°C for 2.5 h. Twenty-four hours later, they were exposed to unilateral cerebral hypoxia-ischemia for 2.5 h, produced by unilateral common carotid artery ligation and systemic hypoxia with 8% oxygen. Neuropathologic analysis, conducted at 30 days of postnatal age, indicated a substantial reduction in the severity of brain damage in the preconditioned rats, such that only 6 of 14 such animals exhibited cystic infarction, but all 13 animals without prior preconditioning exhibited infarction ( p < 0.001). Measurement of cerebral glycolytic and tricarboxylic acid intermediates and high-energy phosphate reserves at the terminus of and at 4 and 24 h following hypoxia-ischemia showed no differences in the extent of alterations in the preconditioned and nonpreconditioned immature rats. A difference was seen in the restitution of high-energy stores during the first 24 h of recovery from hypoxia-ischemia, with a more optimal preservation of these metabolites in the preconditioned animals, reflecting the less severe ultimate brain damage. Accordingly, the neuroprotection afforded to the preconditioned animals was not the result of any differences in the extent of anaerobic glycolysis, tissue acidosis, or depletion in high-energy reserves during hypoxia-ischemia but rather the result of other mechanisms that improved the metabolic status of the immature brain during the early hours of reperfusion following hypoxia-ischemia.     

The Microstructural Status of the Corpus Callosum Is Associated with the Degree of Motor Function and Neurological Deficit in Stroke Patients

Human neuroimaging studies and animal models have suggested that white matter damage from ischemic stroke leads to the functional and structural reorganization of perilesional and remote brain regions. However, the quantitative relationship between the transcallosal tract integrity and clinical motor performance score after stroke remains unexplored. The current study employed a tract-based spatial statistics (TBSS) analysis on diffusion tensor imaging (DTI) to investigate the relationship between white matter diffusivity changes and the clinical scores in stroke patients. Probabilistic fiber tracking was also used to identify structural connectivity patterns in the patients. Thirteen ischemic stroke patients and fifteen healthy control subjects participated in this study. TBSS analyses showed that the corpus callosum (CC) and bilateral corticospinal tracts (CST) in the stroke patients exhibited significantly decreased fractional anisotropy and increased axial and radial diffusivity compared with those of the controls. Correlation analyses revealed that the motor and neurological deficit scores in the stroke patients were associated with the value of diffusivity indices in the CC. Compared with the healthy control group, probabilistic fiber tracking analyses revealed that significant changes in the inter-hemispheric fiber connections between the left and right motor cortex in the stroke patients were primarily located in the genu and body of the CC, left anterior thalamic radiation and inferior fronto-occipital fasciculus, bilateral CST, anterior/superior corona radiate, cingulum and superior longitudinal fasciculus, strongly suggesting that ischemic induces inter-hemispheric network disturbances and disrupts the white matter fibers connecting motor regions. In conclusion, the results of the present study show that DTI-derived measures in the CC can be used to predict the severity of motor skill and neurological deficit in stroke patients. Changes in structural connectivity pattern tracking between the left and right motor areas, particularly in the body of the CC, might reflect functional reorganization and behavioral deficit.     

A new penumbra: transitioning from injury into repair after stroke

The penumbra is an area of brain tissue that is damaged but not yet dead after focal ischemia. The existence of a penumbra implies that therapeutic salvage is theoretically possible after stroke. The first decade of penumbral science investigated the ischemic regulation of electrophysiology, cerebral blood flow and metabolism. The second decade advanced our understanding of molecular mechanisms that mediate penumbral cell death. And the third decade saw the rapid development of clinical neuroimaging tools that are now increasingly applied in stroke patients. But how can we look ahead as we move into the fourth decade of penumbra research? This author speculates that a paradigm shift is needed. Most molecular targets for therapy have biphasic roles in stroke pathophysiology. During the acute phase, these targets mediate injury. During the recovery phase, the same mediators contribute to neurovascular remodeling. It is this boundary zone that comprises the new penumbra, and future investigations should dissect where, when and how damaged brain makes the transition from injury into repair.     

The Ferrier Lecture 2004 what can transcranial magnetic stimulation tell us about how the brain works?

Transcranial magnetic stimulation (TMS) is a technique whereby parts of the cerebral cortex and underlying white matter can be excited by a brief electrical current induced by a similarly brief, rapidly fluctuating magnetic field which is itself produced by rapidly discharging a current through an insulated coil held against the scalp. When combined with magnetic resonance structural and functional images of the subject's brain, the stimulation can be directed at specific cortical areas. Over a period of only 15 years, TMS has revealed hitherto unsuspected aspects of brain function, such as the role of distant parts of the brain in recovery from stroke, and has helped to resolve several previously intractable disputes, such as the neuronal basis of conscious awareness. This article describes and discusses the origins and nature of TMS, its applications and limitations, and its especial usefulness in conjunction with other techniques of evaluating or imaging brain activity.     

Endogenous neurogenesis following ischaemic brain injury: Insights for therapeutic strategies

Ischaemic stroke is among the most common yet most intractable types of central nervous system (CNS) injury in the adult human population. In the acute stages of disease, neurons in the ischaemic lesion rapidly die and other neuronal populations in the ischaemic penumbra are vulnerable to secondary injury. Multiple parallel approaches are being investigated to develop neuroprotective, reparative and regenerative strategies for the treatment of stroke. Accumulating evidence indicates that cerebral ischaemia initiates an endogenous regenerative response within the adult brain that potentiates adult neurogenesis from populations of neural stem and progenitor cells. A major research focus has been to understand the cellular and molecular mechanisms that underlie the potentiation of adult neurogenesis and to appreciate how interventions designed to modulate these processes could enhance neural regeneration in the post-ischaemic brain. In this review, we highlight recent advances over the last 5 years that help unravel the cellular and molecular mechanisms that potentiate endogenous neurogenesis following cerebral ischaemia and are dissecting the functional importance of this regenerative mechanism following brain injury.This article is part of a Directed Issue entitled: Regenerative Medicine: the challenge of translation.     

The time course of action and action-word comprehension in the human brain as revealed by neurophysiology.

Numerous previous neuroimaging studies suggest an involvement of cortical motor areas not only in action execution but also in action recognition and understanding. Motor areas of the human brain have also been found to activate during the processing of written and spoken action-related words and sentences. Even more strikingly, stimuli referring to different bodily effectors produced specific somatotopic activation patterns in the motor areas. However, metabolic neuroimaging results can be ambiguous with respect to the processing stage they reflect. This is a serious limitation when hypotheses concerning linguistic processes are tested, since in this case it is usually crucial to distinguish early lexico-semantic processing from strategic effects or mental imagery that may follow lexico-semantic information access. Timing information is therefore pivotal to determine the functional significance of motor areas in action recognition and action-word comprehension. Here, we review attempts to reveal the time course of these processes using neurophysiological methods (EEG, MEG and TMS), in visual and auditory domains. We will highlight the importance of the choice of appropriate paradigms in combination with the corresponding method for the extraction of timing information. The findings will be discussed in the general context of putative brain mechanisms of word and object recognition.     

Increased cerebral activity in Parkinson’s disease patients carrying the DRD2 TaqIA A1 allele during a demanding motor task: a compensatory mechanism?

Previous studies suggest that neuroimaging techniques are useful for detecting the effects of functional genetic polymorphisms on brain function in healthy subjects or in patients presenting with psychiatric or neurodegenerative conditions. Former evidence showed that individuals carrying risk alleles displayed broader patterns of brain activity during behavioural and cognitive tasks, despite being clinically comparable to non-carriers. This suggests the presence of compensatory brain mechanisms. In the present study, we investigated this effect in Parkinson's disease (PD) patients carrying the DRD2 TaqIA A1 allelic variant. This variant may confer an increased risk of developing the disease and/or influence the clinical presentation. During a complex sequential motor task, we evidenced by functional magnetic resonance imaging that A1 allele carriers activated a larger network of bilateral cerebral areas than non-carriers, including cerebellar and premotor regions. Both groups had similar clinical and demographic measures. In addition, their motor performance during the functional magnetic resonance experiment was comparable. Therefore, our conclusions, pending replication in a larger sample, seem to reflect the recruitment of compensatory cerebral resources during motor processing in PD patients carrying the A1 allele.     

Melatonin renders neuroprotection by protein kinase C mediated aquaporin-4 inhibition in animal model of focal cerebral ischemia

Aim

Aquaporin-4(AQP4) expression in the brain with relation to edema formation following focal cerebral ischemia was investigated. Studies have shown that brain edema is one of the significant factors in worsening stroke outcomes. While many mechanisms may aggravate brain injury, one such potential system may involve AQP4 up regulation in stroke patients that could result in increased edema formation. Post administration of melatonin following ischemic stroke reduces AQP4 mediated brain edema and confers neuroprotection.

Materials and methods

An in-silico approach was undertaken to confirm effective melatonin-AQP4 binding. Rats were treated with 5 mg/kg, i.p. melatonin or placebo at 30 min prior, 60 min post and 120 min post 60 min of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. Rats were evaluated for battery of neurological and motor function tests just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, apoptosis study and western blot experiments.

Key findings

Melatonin at 60 min post ischemia rendered neuroprotection as evident by reduction in cerebral infarct volume, improvement in motor and neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and malondialdehyde (MDA) were also found to be significantly reduced in ischemic brain regions in treated animals. Melatonin potentiated intrinsic antioxidant status, inhibited acid mediated rise in intracellular calcium levels, decreased apoptotic cell death and also markedly inhibited protein kinase C (PKC) influenced AQP4 expression in the cerebral cortex and dorsal striatum.

Significance

Melatonin confers neuroprotection by protein kinase C mediated AQP4 inhibition in ischemic stroke.     

功能磁共振和脑电神经成像技术与大脑刺激相结合的研究进展

随着对神经机制问题阐述水平的迅速提高,所应用的神经成像技术、方法及各种工具的复杂程度也在不断提高．一方面是神经成像技术本身的不断发展,另一方面则是大脑直接刺激与神经成像技术同步记录方法的发展．经颅磁刺激-功能磁共振成像同步技术(TMS-fMRI)和经颅磁刺激-脑电技术(TMS-EEG)能为研究大脑网络的功能和有效连通性提供技术手段,该技术在多种认知领域的发展和应用,为神经科学、认知心理学、神经信息学等学科的研究者对人脑的研究开启了多条通道,更加有利于深入地理解人类大脑的工作机制．     

急性缺血性脑卒中患者入院时血浆BNP水平与梗死部位关系

目的：分析急性缺血性脑卒中患者入院时血浆脑钠肽（BNP）水平与缺血性脑卒中梗死部位的关系。方法：随机入选88例急性缺血性脑卒中患者,按梗死部位,将其分为前循环病灶组（66名）和后循环病灶组（22名）两组进行比较。测定入院时血浆脑钠肽（BNP）水平进行比较。两组脑卒中病人的危险因素血糖、糖化血红蛋白、血脂全套,肝肾功能分析对比,并将急性缺血性脑卒中患者梗死部位相关的多个变量采用单因素logistic回归分析。结果：前循环病灶组血浆脑利钠肽水平的中位数是225.90 pg/mL,四分位数间距为596.00 pg/mL;后循环病灶组的中位数是750.95 pg/mL,四分位数间距为907.00 pg/mL。后循环病灶组血浆脑利钠肽水平要显著高于前循环病灶组血浆脑利钠肽水平,两个部位间入院时的脑利钠肽水平有统计学差异（P=0.004）。通过入院时脑利钠肽水平与缺血性脑卒中梗死部位的关系的ROC曲线,得出截点299.50 pg/mL。入院时血浆脑利钠肽水平≥299.50 pg/mL可以作为后循环病灶组的预测指标,其敏感性72.72%,特异性62.12%。结论：急性缺血性脑卒中患者入院时血浆BNP水平可作为急性期区别前后循环脑梗死的预测因子。     

The functional anatomy of cerebral reorganisation after focal brain injury

Stroke is a major cause of disability in all age groups. Although the value of specific rehabilitative therapies is now acknowledged, the mechanisms of impairment and recovery are not well understood. There is growing interest in the role that central nervous system reorganisation might play in the recovery process, and in particular whether this reorganisation can be manipulated to provide clinical benefits for patients. The careful use of non-invasive techniques such as functional magnetic resonance imaging and transcranial magnetic stimulation allows the study of the working human brain, and studies in humans suggest that functionally relevant adaptive changes occur in cerebral networks following stroke. An understanding of how these changes influence the recovery process will facilitate the development of novel therapeutic techniques that are based on neurobiological principles and will allow the delivery of specific therapies to appropriately targeted patients suffering from stroke.     

Non-invasive NIR spectroscopy of human brain function during exercise

The assessment of physiological changes associated with brain activity has become possible by optical methods, such as near-infrared spectroscopy (NIRS). NIRS is a useful neuroimaging technique based on haemodynamic principles for the non-invasive investigation of brain in motion. Due to its properties, the near-infrared light can penetrate biological tissue reasonably well to assess brain activity and two types of measurements are possible according to the number of channels used: dynamic changes in a localized brain region or functional brain imaging. The theoretical and technological advances of the past 10–15 years have opened the door to a range of applications in the human movement sciences, including some that involve imaging of the adult brain during motor and cognitive tasks, which for many years had been inaccessible to NIRS. This article examines the perturbation methods for measuring cerebral haemodynamic responses within resting and exercise conditions in humans and how NIRS can be used to image the moving brain. Methodological challenges of NIRS technique are presented, while the advantages and pitfalls of NIRS compared to other neuroimaging methods are discussed. Actual and future uses for NIRS in the field of sport sciences are outlined for a better understanding of brain processes during movement.     

Precision grasping in humans: from motor control to cognition

In the past decade, functional neuroimaging has proved extremely useful in mapping the human motor circuits involved in skilled hand movements. However, one major drawback of this approach is the impossibility to determine the exact contribution of each individual cortical area to precision grasping. Because transcranial magnetic stimulation (TMS) makes it possible to induce a transient 'virtual' lesion of discrete brain regions in healthy subjects, it has been extensively used to provide direct insight into the causal role of a given area in human motor behaviour. Recent TMS studies have allowed us to determine the specific contribution, as well as the timing and the hemispheric lateralisation, of distinct parietal and frontal areas to the control of both the kinematics and dynamics of precision grasping. Moreover, recent researches have shown that the same cortical network may contribute to language and number processing, supporting the existence of tight interactions between processes involved in cognition and actions. The aim of this paper is to offer a concise overview of recent studies that have investigated the neural correlates of precision grasping and the possible contribution of the motor system to higher cognitive functions such as language and number processing.     

慢病毒载体介导Bdnf基因修饰的骨髓间质干细胞移植治疗脑梗死

为研究经Bdnf基因修饰的骨髓间质干细胞(Mesenchymal stem cells, MSCs)对脑梗死的协同治疗作用, 构建带有大鼠Bdnf基因之慢病毒载体, 并感染大鼠骨髓间质干细胞(Rat mesenchymal stem cells, rMSCs)。运用线栓法制备大鼠大脑中动脉栓塞模型, 经尾静脉注射移植, 对照组注射0.1 mol/L磷酸盐缓冲液(PBS)1 mL, Bdnf-rMSCs和Mock-rMSCs组分别注射Bdnf-rMSCs细胞悬液以及未插入目的基因的空病毒载体感染后的rMSCs细胞悬液各1 mL。各组大鼠分别于术后24 h、移植后2周及2月应用modified Neurological Severity Scores (mNSS)评价神经功能状况。结果显示, 与对照组相比, Mock-rMSCs及Bdnf-rMSCs移植组神经功能改善明显, mNSS评分差异有统计学意义(P<0.001), 而且Bdnf-rMSCs移植组明显优于Mock-rMSCs移植组(P<0.001)。移植后2周及2月, 与对照组相比两移植组梗死区脑组织结构恢复较好, 均可见EGFP阳性细胞在梗死区及其周边区聚集并存活, 并有部分细胞出现神经元样改变。Bdnf- rMSCs移植组中移植细胞大量表达BDNF, 两移植组中均有部分植入细胞表达神经细胞表面标志物。研究表明Bdnf基因修饰的rMSCs经静脉移植后可迁移至脑梗死灶周围, 向神经细胞分化并长期存活。移植后的干细胞可与其分泌的BDNF协同促进脑梗死后神经功能恢复, 这为将来基因工程干细胞移植治疗脑梗死提供了实验依据。     

Multiparametric,Longitudinal Optical Coherence Tomography Imaging Reveals Acute Injury and Chronic Recovery in Experimental Ischemic Stroke

Progress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi-parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties.     

经颅磁刺激在大脑皮质研究中的应用和进展

经颅磁刺激（TMS）是一种能够在脑中感应聚焦电流,瞬间调制大脑皮质的无创方法,在临床研究、基础神经学和诊治疾病等方面有许多应用。通过记录运动皮质诱发电位（MEPs),TMS已经或将成为探测脑下运动路径传导、评价皮质兴奋性、皮质映射和研究皮质塑性的常规工具。TMS能够主动干预脑功能,这种特性使它成为研究正常人脑－行为关系的独特技术,可以建立脑活动与任务完成之间的因果关系,探索脑功能连接。近年来的许多实验又表明,TMS在运动紊乱和精神疾病方面有潜在的治疗作用,但达到临床应用还有一定距离。     

Alterations in Spontaneous Brain Oscillations during Stroke Recovery

Amplitude or frequency alterations of spontaneous brain oscillations may reveal pathological phenomena in the brain or predict recovery from brain lesions, but the temporal evolution and the functional significance of these changes is not well known. We performed follow-up recordings of spontaneous brain oscillations with whole-head MEG in 16 patients with first-ever stroke in the middle cerebral artery territory, affecting upper limb motor function, 1–7 days (T₀), 1 month (T₁), and 3 months (T₂) after stroke, with concomitant clinical examination. Clinical test results improved significantly from T₀ to T₁ or T₂. During recovery (at T₁ and T₂), the strength of temporo–parietal ∼10-Hz oscillations in the affected hemisphere (AH) was increased as compared with the unaffected hemisphere. Abnormal low-frequency magnetic activity (ALFMA) at ∼1 Hz in the AH was detected in the perilesional cortex in seven patients at T₀. In four of these, ALFMA persisted at T₂. In patients with ALFMA, the lesion size was significantly larger than in the rest of the patients, and worse clinical outcome was observed in patients with persisting ALFMA. Our results indicate that temporo–parietal ∼10-Hz oscillations are enhanced in the AH during recovery from stroke. Moreover, stroke causes ALFMA, which seems to persist in patients with worse clinical outcome.     

The effects of voluntary, involuntary, and forced exercises on brain-derived neurotrophic factor and motor function recovery: a rat brain ischemia model

Background

Stroke rehabilitation with different exercise paradigms has been investigated, but which one is more effective in facilitating motor recovery and up-regulating brain neurotrophic factor (BDNF) after brain ischemia would be interesting to clinicians and patients. Voluntary exercise, forced exercise, and involuntary muscle movement caused by functional electrical stimulation (FES) have been individually demonstrated effective as stroke rehabilitation intervention. The aim of this study was to investigate the effects of these three common interventions on brain BDNF changes and motor recovery levels using a rat ischemic stroke model.

Methodology/Principal Findings

One hundred and seventeen Sprague-Dawley rats were randomly distributed into four groups: Control (Con), Voluntary exercise of wheel running (V-Ex), Forced exercise of treadmill running (F-Ex), and Involuntary exercise of FES (I-Ex) with implanted electrodes placed in two hind limb muscles on the affected side to mimic gait-like walking pattern during stimulation. Ischemic stroke was induced in all rats with the middle cerebral artery occlusion/reperfusion model and fifty-seven rats had motor deficits after stroke. Twenty-four hours after reperfusion, rats were arranged to their intervention programs. De Ryck''s behavioral test was conducted daily during the 7-day intervention as an evaluation tool of motor recovery. Serum corticosterone concentration and BDNF levels in the hippocampus, striatum, and cortex were measured after the rats were sacrificed. V-Ex had significantly better motor recovery in the behavioral test. V-Ex also had significantly higher hippocampal BDNF concentration than F-Ex and Con. F-Ex had significantly higher serum corticosterone level than other groups.

Conclusion/Significance

Voluntary exercise is the most effective intervention in upregulating the hippocampal BDNF level, and facilitating motor recovery. Rats that exercised voluntarily also showed less corticosterone stress response than other groups. The results also suggested that the forced exercise group was the least preferred intervention with high stress, low brain BDNF levels and less motor recovery.