The effect of repetitive spreading depression on neuronal damage in juvenile rat brain

Spreading depression (SD) is pronounced depolarization of neurons and glia that travels slowly across brain tissue followed by massive redistribution of ions between intra- and extracellular compartments. There is a relationship between SD and some neurological disorders. In the present study the effects of repetitive SD on neuronal damage in cortical and subcortical regions of juvenile rat brain were investigated. The animals were anesthetized and the electrodes as well as cannula were implanted over the brain. SD-like event was induced by KCl injection. The brains were removed after 2 or 4 weeks after induction of 2 or 4 SD-like waves (with interval of 1 week), respectively. Normal saline was injected instead of KCl in sham group. For stereological study, paraffin-embedded brains were cut in 5 μm sections. The sections were stained with Toluidine Blue to measure the volume-weighted mean volume of normal neurons and the numerical density of dark neurons. The volume-weighted mean volume of normal neurons in the granular layer of the dentate gyrus and layer V of the temporal cortex in SD group were significantly decreased after four repetitive SD. Furthermore, densities of dark neurons in the granular layer of the dentate gyrus (after 2 weeks), the caudate–putamen, and layer V of the temporal cortex (after 4 weeks) were significantly increased in SD group. Repetitive cortical SD in juvenile rats may cause neuronal damage in cortical and subcortical areas of the brain. This may important in pathophysiology of SD-related neurological disorders.     

川芎嗪对大鼠脑缺血再灌注损伤后大脑皮质Bc1-2表达的影响

目的:研究川芎嗪对大鼠脑缺血再灌注损伤后Bcl-2表达的影响.方法:以线栓法制作大鼠大脑中动脉阻塞的局灶性脑缺血再灌注模型,采用免疫印迹、2, 3, 5-氯化三苯四氮唑(TTC)、 H-E染色和神经行为相结合的方法,观测缺血再灌注侧大脑皮质内Bcl-2的表达、脑梗塞体积、脑组织结构及神经功能的变化.结果:与缺血再灌注组(I 2h/R24h)比较,川芎嗪组的Bcl-2表达明显增高,脑梗塞体明显缩小,脑组织的病理损伤和神经异常行为明显减轻.结论:川芎嗪可通过上调Bcl-2的表达,缩小脑梗塞的体积和减轻脑缺血区组织结构的损伤以及明显改善神经症状,对脑缺血再灌注损伤有保护作用.     

Enhanced visual spatial attention ipsilateral to rTMS-induced 'virtual lesions' of human parietal cortex

The breakdown of attentional mechanisms after brain damage can have drastic behavioral consequences, as in patients suffering from spatial neglect. While much research has concentrated on impaired attention to targets contralateral to sites of brain damage, here we report the ipsilateral enhancement of visual attention after repetitive transcranial magnetic stimulation (rTMS) of parietal cortex at parameters known to reduce cortical excitability. Normal healthy subjects received rTMS (1 Hz, 10 mins) over right or left parietal cortex. Subsequently, detection of visual stimuli contralateral to the stimulated hemisphere was consistently impaired when stimuli were also present in the opposite hemifield, mirroring the extinction phenomenon commonly observed in neglect patients. Additionally, subjects' attention to ipsilateral targets improved significantly over normal levels. These results underline the potential of focal brain dysfunction to produce behavioral improvement and give experimental support to models of interhemispheric competition in the distributed brain network for spatial attention.     

Twenty Questions Task and Frontal Lobe Dysfunction

Performance on the Twenty Questions task has been assumed to be deficient in those with frontal lobe damage, although few studies have specifically examined this. In the present study, 88 participants with frontal lobe epileptic dysfunction were assessed on this task, as were 57 participants with temporal lobe epileptic disturbance and 28 participants with no evidence of any neurological damage. Results indicated that those with either left or bifrontal lobe damage were more impaired on several indexes of test performance. Analysis also revealed that participants with orbitofrontal damage were impaired on the measure of “first guess” as compared to groups with damage to other regions of the prefrontal cortex (p < .05). Overall, the results support the utility of the Twenty Questions task in assessing frontal lobe damage and may suggest that qualitatively different deficits may be recorded depending on the region of frontal lobe dysfunction.     

The influence of restricted posterior neodecortication on brightness preference and brightness discrimination performance of rats

Three experiments were conducted to measure the choice behavior and brightness discrimination performance of normal and neodecorticated rats which had sustained damage to striate and/or extrastriate areas of the posterior cortex. Choice of dark environments was reduced when lesions included the striate area, while extrastriate damage reduced repetitive positional responses in a Yerkes apparatus and enhanced choice of a brighter escape door. When tested for discrimination performance in a two-choice task where either bright or dim alternatives served as correct stimuli, differential preferences did not seem to determine the courses of acquisition. Rather, the task requiring dim choice revealed selective impairment in rats without striate cortices. The assessment of brightness discrimination as an indicator of lesion induced behavioral impairment was discussed.     

Electrophysiological correlates of visually processing subject's own name

The study aimed to test the modulation induced by 1 Hz repetitive Transcranial Magnetic Stimulation (rTMS) of the occipital cortex on the alpha phase synchronization under repetitive flash stimuli in 15 migraine without aura patients compared to 10 controls. The EEG was recorded by 7 channels, while flash stimuli were delivered at 9, 18, 21 and 24 Hz in basal, rTMS (15 min of 1 Hz stimulation of the occipital cortex) and sham conditions. Migraine patients displayed increased alpha-band phase synchronization under visual stimulation, while an overall desynchronizing effect was evident in controls. The rTMS resulted in a slight increase of synchronization index in migraine patients, which did not cause significant differences in respect to the basal and sham conditions. The synchronizing-desynchronizing changes of alpha rhythm under repetitive flash stimulation, seem independent from the state of occipital cortex excitability. Other mechanisms beyond cortical excitability may contribute to explain migraine pathogenesis.     

The role of human extra-striate visual areas V5/MT and V2/V3 in the perception of the direction of global motion: a transcranial magnetic stimulation study

Several published single case studies reveal a double dissociation between the effects of brain damage in separate extra-striate cortical visual areas on the perception of global visual motion defined by a difference in luminance (first-order motion) versus motion defined by a difference in contrast (second-order motion). In particular, the medial extrastriate cortical region V2/V3 seems to be crucial for the perception of first-order motion, but not for second-order, whereas a lateral and more anterior portion of the cortex close to the temporo–parieto–occipital junction (in the territory of the human motion area hV5/MT⁺) seems to be essential only for the perception of second-order motion. In order to test the hypothesis of a functional specialization of different visual areas for different types of motion, we applied repetitive transcranial magnetic stimulation (rTMS) unilaterally over areas V2/V3, V5/MT, or posterior parietal cortex (PPC) while subjects performed a 2AFC task with first- or second-order global motion displays in the contralateral visual field. Results showed a comparable disruption of the two types of motion, with both rTMS over V2/V3 or over MT/V5, and little or no effect with rTMS over PPC. The results suggest that either the previous psychophysical results with neurological patients are incorrect (highly unlikely) or that the lateral and medial regions are directly connected (as they are in macaque monkeys) such that stimulating one automatically affects the other, in this instance disruptively     

Pyramidal and non-pyramidal motor cortical effects on distal forelimb muscles of monkeys

Summary Monkeys with chronic unilateral lesions of the pyramidal tract were investigated with respect to motor cortical effects on distal forelimb muscles. The forelimb area of the pre-central gyrus was stimulated with long single pulses or with repetitive pulses at 50/sec on both sides, one cortex having an intact pyramidal projection (control) and the other cortex having a lesion in its pyramidal projection varying from 30–100%. Repetitive stimulation at 50/sec of the intact cortex elicited, after a summation period of variable length, synchronized discharges following each stimulus pulse. Long single pulses (3 msec, 1/sec) were likewise effective to activate the distal forelimb muscles. Stimulation of the motor cortex with a lesion in its pyramidal projection was no longer effective to elicit discharges in the distal muscles when single pulses of up to 6 mA were used, even in the animal with a 30% lesion. With repetitive stimuli (1 msec, 50/sec) some activity was evoked in all animals including the monkey with a 100% lesion. The pattern of activation tended to be diffuse, i.e. not time-locked to the individual stimulus pulses. In the animals with smaller lesions the mean latency of discharges following the repetitive stimuli was increased as compared with the control side. The motor cortical effects in a 10 month old monkey were the same as in the adult monkey with intact pyramidal projection. The results of motor cortex stimulation in a 7 week old monkey were, however, similar to those obtained in adult monkeys with pyramidal lesions.     

Projection from the thalamic intralaminar nuclei on the isocortex of the rat: a surface potential study

Summary Cortical surface potentials evoked from thalamic intralaminar nuclei have been studied in rats anaesthetized with chloralose. Stimulation with low current intensity in central lateral nucleus (CL), evoked potentials in large areas of the rat isocortex. In the posterior parietal cortex responses with a short latency negativity were evoked which followed high frequency repetitive stimulation. Its latency and ability to follow high frequency stimulation indicated a monosynaptic connection from CL to this part of the cortex. The short latency potential was followed by a second negativity with longer latency and varying amplitude. This second negativity did not follow repetitive stimulation exceeding 10 Hz, and was also reduced by supplementary doses of anaesthetics, indicating a polysynaptic origin. Stimulation at different CL sites elicited cortical potentials with short latency in a topographical pattern. Laminar analysis in the parietal and motor cortex suggested both a superficial and a deep layer termination of afferents from CL. Similar topografical relations and afferent layer distributions have previously been found in cats. The role of the thalamocortical projection from CL to parietal cortex in arousal, attention and pain mechanisms is discussed.     

The effects of selenium against cerebral ischemia-reperfusion injury in rats

It is known that the brain tissue is extremely sensitive to ischemia-reperfusion (IR) injury and therefore, brain ischemia and consecutive reperfusion result in neural damage and apoptosis. The proinflammatory cytokines such as tumor necrosis factor alfa (TNF-α) and interleukin-1 beta (IL-1β) are produced during neurological disorders including cerebral ischemia. On the other hand, nerve growth factor (NGF), which is essential for the differentiation, survival and functions of neuronal cells in the central nervous system, regulate neuronal development through cell survival and cell death signaling. In the present study, we aimed to investigate the effect of selenium (Se) on prefrontal cortex and hippocampal damage in rats subjected to cerebral IR injury. Selenium was injected intraperitoneally at the doses of 0.625 mg/(kg day) after induction of IR injury. Prefrontal cortex and hippocampal damage was examined by cresyl-violet staining. Apostain and caspase-3 immune staining were used to detect apoptosis. TNF-α, IL-1β and NGF levels were also evaluated. Histopathological evaluation showed that treatment with selenium after ischemia significantly attenuated IR-induced neuronal death in prefrontal cortex and hippocampal CA1 regions of rats. Apoptotic cells stained with apostain and caspase-3 were significantly decreased in treatment group when compared with the IR group. Additionally, treatment with selenium decreased the TNF-α and IL-1β levels and increased the NGF levels in prefrontal cortex and hippocampal tissue of animals subjected to IR. The present results suggest that selenium is potentially a beneficial agent in treating IR-induced brain injury in rats.     

重复磁刺激右侧大脑中动脉闭塞模型大鼠脑梗死区微环境及神经功能的变化

背景：国内外大量研究表明重复经颅磁刺激可使皮质兴奋性产生较刺激时间更加持久的改变,为磁刺激应用于脑梗死后康复治疗提供了一个新的研究方向,但其远期临床疗效与安全性尚需进一步研究。 目的：观察重复经颅磁刺激脑梗死大鼠对神经再生微环境及功能恢复的影响。 方法：将大鼠随机分为模型组、假刺激组及重复经颅磁刺激组(80%运动阈值(MT)组、100%MT组和120%MT组),采用线栓法制备大鼠右侧大脑中动脉闭塞模型。制模24 h后各重复经颅磁刺激亚组给予20 Hz相应强度磁刺激,假刺激组则给予假磁刺激,模型组制模后未给予特殊处理。 结果与结论：造模后7 d,重复经颅磁刺激组的脑梗死体积显著小于模型组及假刺激组(P < 0.05)。RT-PCR、Western blot检测显示,造模后72 h,重复经颅磁刺激组水通道蛋白4/9基因和蛋白表达均较模型组显著增高(P < 0.05)。与造模后第1天比较,造模后第15天重复经颅磁刺激组(100%MT)神经功能缺损评分得到明显改善(P < 0.05)。免疫组织化学检测结果显示,各重复经颅磁刺激亚组缺血半暗带区胶质纤维酸性蛋白表达与模型组比较均显著减少(P < 0.05)。结果证实,重复经颅磁刺激可减轻脑梗死模型大鼠神经功能缺损程度,通过诱导脑缺血耐受、减少神经细胞凋亡和降低水通道蛋白4/9基因和蛋白的表达,改善神经再生微环境。中国组织工程研究杂志出版内容重点：肾移植;肝移植;移植;心脏移植;组织移植;皮肤移植;皮瓣移植;血管移植;器官移植;组织工程     

Does bone perfusion/reperfusion initiate bone remodeling and the stress fracture syndrome?

Stress fractures have been proposed to arise from repetitive activity of training inducing an accumulation of microfractures in locations of peak strain. However, stress fractures most often occur long before accumulation of material damage could occur; they occur in cortical locations of low, not high, strain; and intracortical osteopenia precedes any evidence of micro-cracks. We propose that this lesion arises from a focal remodeling response to site-specific changes in bone perfusion during redundant axial loading of appendicular bones. Intramedullary pressures significantly exceeding peak arterial pressure are generated by strenuous exercise and, if the exercise is maintained, the bone tissue can suffer from ischemia caused by reduced blood flow into the medullary canal and hence to the inner two-thirds of the cortex. Site specificity is caused by the lack, in certain regions of the cortex, of compensating matrix-consolidation-driven fluid flow which brings nutrients from the periosteal surface to portions of the cortex. Upon cessation of the exercise, re-flow of fresh blood into the vasculature leads to reperfusion injury, causing an extended no-flow or reduced flow to that portion of the bone most strongly denied perfusion during the exercise. This leads to a cell-stress-initiated remodeling which ultimately weakens the bone, predisposing it to fracture.     

Exercise pre-conditioning reduces brain damage in ischemic rats that may be associated with regional angiogenesis and cellular overexpression of neurotrophin

There is increasing evidence that physical activity is associated with a decreased stroke risk. The purpose of this study was to determine if exercise could also reduce brain damage in rats subjected to transient middle cerebral artery (MCA) occlusion, and if the reduced brain injury is associated with angiogenesis as well as cellular expression of the nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in regions supplied by the MCA. Adult male Sprague Dawley rats (n=36) exercised 30 min each day for 3 weeks on a treadmill on which repetitive locomotor movement was required. Then, stroke was induced by a 2-h MCA occlusion using an intraluminal filament, followed by 48 h of reperfusion. In addition to the two exercised groups of animals with or without MCA occlusion, there were two other groups of animals, with or without MCA occlusion, housed for the same duration and used as non-exercised controls. Brain damage in ischemic rats was evaluated by neurologic deficits and infarct volume. Exercise preconditioned and non-exercised brains were processed for immunocytochemistry to quantify the number of microvessels or NGF- and BDNF-labeled cells. Pre-ischemic motor activity significantly (P<0.01) reduced neurologic deficits and infarct volume in the frontoparietal cortex and dorsolateral striatum. Cellular expressions of NGF and BDNF were significantly (P<0.01) increased in cortex (neuron) and striatum (glia) of rats under the exercise condition. Significant (P<0.01) increases in microvessel density were found in striatum. Physical activity reduced stroke damage. The reduced brain damage may be attributable to angiogenesis and neurotrophin overexpression in brain regions supplied by the MCA following exercise.     

Conditioning effects of repetitive mild neurotrauma on motor function in an animal model of focal brain injury

A weight drop model of brain injury was used to determine the effects of repetitive mild brain injury on motor function, heat shock protein and glial fibrillary acidic protein expression in the anesthetized, adult male, Sprague-Dawley rat. Repetitive mild brain injury was produced when animals received a series of three mild injuries spaced three days apart. A separate group of repetitive mild injured animals also received a subsequent severe brain injury between three and five days after the last mild injury. All animals were trained on a beam-walking test prior to surgery. The mild, repetitive mild and repetitive mild plus severe brain injury groups showed no motor deficits in the beam-walking test, whereas the animals with only severe brain injury showed significant motor deficits (increase in number of footslips) in the beam-walking test that recovered within eight days after injury. Both repetitive mild plus severe injury and severe injury only animals had cortical necrotic cavities of similar size in the region of the hindlimb motor cortex. Both the repetitive mild and severe brain-injured animals had marked heat shock protein 27kDa and glial fibrillary acidic protein staining in the cerebral cortex. Fluoro-Jade, heat shock protein 27kDa and 72kDa labeling indicated that there were widespread effects on cortical, subcortical and spinal neurons and glial cells after repetitive mild brain injury. These results suggest that repetitive mild brain injury conditions the brain so that subsequent brain injury at the same site has no effect on motor function. Furthermore, repetitive mild injury-induced activation of processes distant to the primary injury site may have a role in activation of secondary sites involved in recovery of motor function.     

Neurological correlates of unilateral and bilateral "strokes" of the middle cerebral artery in the rat.

Rats with unilateral lesions of the middle cerebral artery (MCA) were tested for the ability to detect (touch) and remove a square of adhesive tape from each forepaw, and for performance on a number of neurological tests (e.g., placing and hopping reflexes, activity). Rats with MCA damage showed deficits in both touching and removing the tape from the paw contralateral to the damage, but not ipsilateral to the damage, while performing within normal limits on the other tests. After scores of the MCA rats dropped into the control group range on the adhesive tape test, they sustained damage to the opposite MCA. This did not reinstate the original deficit, suggesting that the recovery seen after the unilateral lesion was not mediated by the opposite cortex. The second lesion, however, caused a deficit in removing the adhesive tape from the limb opposite the new stroke. Some of the rats that originally had sham operations received bilateral MCA lesions at this time. These animals showed much more severe deficits on the adhesive tape test than the rats with sequential strokes. Rats with bilateral MCA damage (simultaneous or sequential) also slipped on a long narrow plank more often than control animals. Nimodipine did not enhance recovery on any of the behavioral measures.     

Development of speed of repetitive movements in children is determined by structural changes in corticospinal efferents.

This study was aimed to determine the relationship between the maturation of corticospinal efferents, determined by transcranial stimulation of motor cortex, and the development of fastest repetitive voluntary motor activity in children. The development of fastest repetitive voluntary motor activity was assessed for 3 different types of movements including fastest repetitive tapping movements, aiming movements and a pegboard transportation task. These 3 motor activities were chosen as they were different as to their dependence on detailed sensory guidance. Despite these differences the speed of all 3 movements showed a very similar developmental profile, which was matched, however, by the developmental slope of the fastest cortico-motoneuronal efferents. Hence the development of central conduction times determines the speed of repetitive movements in children. In contrast, we could not observe significant effects of repetitive training on speed of these movements. We show for the first time that the development of fastest voluntary movements is a structure-bound phenomenon, being independent from learning.     

Activation of leukocyte-endothelial interactions and reduction of selective neuronal death after global cerebral ischemia

The role of leukocyte-endothelial interactions (LEI) as part of the inflammatory response after global cerebral ischemia (GCI) is hardly understood and may be detrimental as well as beneficial. Objective of the current study was to investigate the cause-effect relationship of activated leukocytes for the development of ischemic brain damage. Mongolian gerbils were subjected to 15 min of global cerebral ischemia. A cranial window was implanted for quantitative analysis of the pial microcirculation focusing on leukocyte-endothelium interactions by intravital fluorescence microscopy up to 3 h of reperfusion. Subsequently the animals were daily screened for neurological deficits and the evolving brain damage was assessed histologically after 4 days. After global cerebral ischemia the number of rolling and adherent leukocytes increased 20- and >23-fold, respectively upon 3 h of reperfusion as compared to controls (P<0.05). Ischemic animals developed neurological deficits and showed a significant loss of neurons in selective vulnerable areas of the brain. The extent of leukocyte activation, i.e. the maximum number of rollers and stickers directly correlated to the number of viable neurons on day 4 in hippocampus, cortex, and striatum. We conclude that there is a relationship between activation of leukocyte-endothelium interactions and the reduction of ischemic brain damage after global cerebral ischemia. Activation of leukocytes may have neuroprotective potential or indicate regenerative processes.     

Neuregulin attenuated cerebral ischemia-Creperfusion injury via inhibiting apoptosis and upregulating aquaporin-4

It has been demonstrated that neuregulin-1beta (NRG-1beta) plays a neuroprotective role in cerebral ischemic injury, however, its defined mechanisms and the perfect treatment window are still elusive. Therefore, we established the animal model of MCAO/R to evaluate cerebral damage. As a result, neurological deficit scores were increased, and a small infarction focus could be seen in ischemic cortex in the control group at ischemic 0.5h/reperfusion 24h. With the duration of ischemia time, deficit scores and infarction sizes obviously elevated in the control group. A large number of positive-apoptotic cells were widespread in the ischemic cortex. Simultaneously, the expression of AQP-4 mRNA and its protein increased. NRG-1beta significantly improved neurological function, decreased the infarction volume, and elevated the expression levels of AQP-4 compared with that in the control group. The therapeutic effect of NRG-1beta was notable, especially at the ischemic 1.0h. These results demonstrate that NRG-1beta might play a neuroprotective effect on cerebral ischemia and reperfusion by inhibiting mitochondrial apoptosis pathway and regulating the activation of AQP-4. The perfect treatment window is at ischemic 1.0h after MCAO.     

Neurophysiological mechanisms of recovery from visual cortex damage in cats: Properties of lateral suprasylvian visual area neurons following behavioral recovery

Summary Damage to visual cortical areas 17, 18, and 19 in the cat produces severe and long-lasting deficits in performance of form and pattern discriminations. However, with extensive retraining the animals are able to recover their ability to discriminate form and pattern stimuli. Recent behavioral experiments from this laboratory have shown that a nearby region of cortex, the lateral suprasylvian visual area (LS area), plays an important role in this recovery (Wood et al., 1974; Baumann and Spear, 1977b). The present experiment investigated the underlying neurophysiological mechanisms of the recovery by recording from single neurons in the LS area of cats which had recovered from long-term visual cortex damage.Five adult cats received bilateral removal of areas 17, 18, and 19. They were then trained to criterion on two-choice brightness, form, and pattern discriminations. Recording from LS area neurons was carried out after the behavioral training, from 3 to 7 months after the visual cortex lesions. The properties of these neurons were compared to those of LS area neurons in normal cats (Spear and Baumann, 1975) and in cats with acute or short-term visual cortex damage and no behavioral recovery (Spear and Baumann, 1979). The results showed that all of the changes from normal which were produced by acute visual cortex damage were also present after the behavioral recovery. Moreover, all of the response properties of LS area neurons which remain after acute visual cortex damage were present in similar form after the behavioral recovery. There was no evidence for any functional reorganization in the LS area concomitant with its role in the behavioral recovery.These results suggest that functional reorganization plays little or no role in recovery from visual cortex damage in adult cats. Rather, the recovery of form and pattern discrimination ability appears to be based upon the functioning of residual neural processes in the LS area which remain after the visual cortex damage.     

Reorganization in the auditory cortex of the rat induced by intracortical microstimulation: a multiple single-unit study

Many manipulations are able to change or perturb various aspects of single neuron properties and interneuronal relationships. Changes of cerebral cortex organization have been observed in different cortical areas and at different time scales in relation to peripheral stimulation, peripheral damage, associative learning, and electrical stimulation. Here we describe studies on separable multineuron recordings in the rat's auditory cortex under two different anesthetics. Acoustic stimuli were used as a normal, physiological input, and weak electrical intracortical microstimulation (ICMS) as a perturbation that forces a rapid cortical reorganization. ICMS induced fast changes in the cortical map and in the receptive field properties of cells at the electrically stimulated and adjacent electrodes. In effect there was an enlargement of the cortical domain tuned to the acoustic frequency that had been represented at the stimulating electrode. ICMS also incremented afterdischarge responses; these consisted of an initial response to the auditory stimulus followed by less intense repetitive activity that was stimulus-time locked and had a period of 8–12 Hz, similar to that of the spontaneous synchronous activity. Cortical activity under ketamine differed from that under pentobarbital sodium, although in both situations we observed that cortical neurons were highly synchronous.