Cerebellar continuous theta‐burst stimulation affects motor learning of voluntary arm movements in humans

In this study we investigated in healthy subjects whether continuous theta‐burst stimulation (cTBS) over the lateral cerebellum alters motor practice and retention phases during ipsilateral index finger and arm reaching movements. In 12 healthy subjects we delivered cTBS before repeated index finger abductions or arm reaching movements differing in complexity (reaching‐to‐grasp and reaching‐to‐point). We evaluated kinematic variables for index finger and arm reaching movements and changes in primary motor cortex (M1) activity tested with transcranial magnetic stimulation. Peak acceleration increased during motor practice for index finger abductions and reaching‐to‐grasp movements and persisted during motor retention. Peak acceleration decreased during motor practice for reaching‐to‐point movements and the decrease remained during motor retention. Cerebellar cTBS left the changes in peak acceleration during motor practice for index finger abductions and reaching‐to‐grasp arm movements unchanged but reduced peak acceleration at motor retention. Cerebellar cTBS prevented the decrease in peak acceleration for reaching‐to‐point movements during motor practice and at motor retention. Index finger abductions and arm reaching movements increased M1 excitability. Cerebellar cTBS decreased the motor evoked potential (MEP) facilitation induced by index finger movements, but increased the MEP facilitation after reaching‐to‐grasp and reaching‐to‐point movements. Cerebellar stimulation prevents motor retention for index finger abductions, reaching‐to‐grasp and reaching‐to‐point movements and degrades motor practice only for reaching‐to‐point movements. Cerebellar cTBS alters practice‐related changes in M1 excitability depending on how intensely the cerebellum contributes to the task. Changes in M1 excitability reflect mechanisms of homeostatic plasticity elicited by the interaction of an ‘exogenous’ (cTBS‐induced) and an ‘endogenous’ (motor practice‐induced) plasticity‐inducing protocol.     

Critical role of glutamatergic and GABAergic neurotransmission in the central mechanisms of theta‐burst stimulation

Theta‐burst stimulation (TBS) is a varied form of repetitive transcranial magnetic stimulation (rTMS) and has more rapid and powerful effects than rTMS. Experiments on the human motor cortex have demonstrated that intermittent TBS has facilitatory effects, whereas continuous TBS has inhibitory effects. Huang's simplified model provides a solid basis for elucidating such after‐effects. However, evidence increasingly indicates that not all after‐effects of TBS are as expected, and high variability among individuals has been observed. Studies have suggested that the GABAergic and glutamatergic neurotransmission play a vital role in the aforementioned after‐effects, which might explain the interindividual differences in these after‐effects. Herein, we reviewed the latest findings on TBS from animal and human experiments on glutamatergic and GABAergic neurotransmissions in response to TBS. Furthermore, an updated theoretical model integrating glutamatergic and GABAergic neurotransmissions is proposed.     

Theta‐burst stimulation over primary motor cortex degrades early motor learning

Theta‐burst stimulation (TBS) is currently used for inducing long‐lasting changes in primary motor cortex (M1) excitability. More information is needed on how M1 is involved in early motor learning (practice‐related improvement in motor performance, motor retention and motor consolidation). We investigated whether inhibitory continuous TBS (cTBS) is an effective experimental approach for modulating early motor learning of a simple finger movement in healthy humans. In a short task, 11 subjects practised 160 movements, and in a longer task also testing motor consolidation ten subjects practised 600 movements. During both experiments subjects randomly received real or sham cTBS over the left M1. Motor evoked potentials were tested at baseline and 7 min after cTBS. In the 160‐movement experiment to test motor retention, 20 movements were repeated 30 min after motor practice ended. In the 600‐movement experiment motor retention was assessed 15 and 30 min after motor practice ended, motor consolidation was tested by performing 20 movements 24 h after motor practice ended. Kinematic variables – movement amplitude, peak velocity and peak acceleration – were measured. cTBS significantly reduced the practice‐related improvement in motor performance of finger movements in the experiment involving 160 movements and in the first part of the experiment involving 600 movements. After cTBS, peak velocity and peak acceleration of the 20 movements testing motor retention decreased whereas those testing motor consolidation remained unchanged. cTBS over M1 degrades practice‐related improvement in motor performance and motor retention, but not motor consolidation of a voluntary finger movement.     

Expression patterns of 5‐lipoxygenase in human brain with traumatic injury and astrocytoma

5‐Lipoxygenase (5‐LOX) is a key enzyme in the metabolism of arachidonic acid to leukotrienes. The levels of leukotrienes increase after brain injury and when tumors are present. It has been reported that 5‐LOX is widely expressed in the brain and that 5‐LOX inhibition provides neuroprotection. However, there is still no information available for the expression patterns of 5‐LOX in human brain following trauma or with astrocytomas. We investigated its expression patterns by immunohistochemistry. We found that 5‐LOX is normally expressed in neurons and glial cells. In neurons, it was expressed in two patterns: in the cytosol and nucleus or only in the cytosol. In traumatic brain injury, 5‐LOX expression increased in glial cells and neutrophils. Double‐labeling immunohistochemistry showed that part of the 5‐LOX‐positive glial cells were GFAP positive. No 5‐LOX expression was found in brain microvessel endothelia, except in the regenerated endothelia of a patient 8 days following brain trauma. Furthermore, 5‐LOX expression increased and showed a granular pattern in high‐grade (grade III/IV) astrocytoma. These results indicate that 5‐LOX has multiple expression patterns, and can be induced by brain injury, which implies that 5‐LOX might have pathophysiological roles in the human brain.     

Frequency‐specific noninvasive modulation of memory retrieval and its relationship with hippocampal network connectivity

Episodic memory is thought to rely on interactions of the hippocampus with other regions of the distributed hippocampal‐cortical network (HCN) via interregional activity synchrony in the theta frequency band. We sought to causally test this hypothesis using network‐targeted transcranial magnetic stimulation. Healthy human participants completed four experimental sessions, each involving a different stimulation pattern delivered to the same individualized parietal cortex location of the HCN for all sessions. There were three active stimulation conditions, including continuous theta‐burst stimulation, intermittent theta‐burst stimulation, and beta‐frequency (20‐Hz) repetitive stimulation, and one sham condition. Resting‐state fMRI and episodic memory testing were used to assess the impact of stimulation on hippocampal fMRI connectivity related to retrieval success. We hypothesized that theta‐burst stimulation conditions would most strongly influence hippocampal‐HCN fMRI connectivity and retrieval, given the hypothesized relevance of theta‐band activity for HCN memory function. Continuous theta‐burst stimulation improved item retrieval success relative to sham and relative to beta‐frequency stimulation, whereas intermittent theta‐burst stimulation led to numerical but nonsignificant item retrieval improvement. Mean hippocampal fMRI connectivity did not vary for any stimulation conditions, whereas individual differences in retrieval improvements due to continuous theta‐burst stimulation were associated with corresponding increases in fMRI connectivity between the hippocampus and other HCN locations. No such memory‐related connectivity effects were identified for the other stimulation conditions, indicating that only continuous theta‐burst stimulation affected memory‐related hippocampal‐HCN connectivity. Furthermore, these effects were specific to the targeted HCN, with no significant memory‐related fMRI connectivity effects for two distinct control brain networks. These findings support a causal role for fMRI connectivity of the hippocampus with the HCN in episodic memory retrieval and indicate that contributions of this network to retrieval are particularly sensitive to continuous theta‐burst noninvasive stimulation.     

The effect of traumatic brain injury on children with learning disability

The psychometric performance of 10 children with a history of learning disability (LD) who subsequently experienced a moderate to severe traumatic brain injury (TBI) was evaluated. Compared to premorbid data, children with LD experienced, after TBI, a statistically significant decline on a measure of psychometric intelligence, whereas their performance on measures of academic achievement remained stable. On specific neuropsychological measures, children with LD and TBI did not differ significantly post-injury from matched controls who also had TBI but no prior history of LD. It is concluded that moderate to severe TBI can cause significant additional cognitive impairment in children with LD, and that periodic modifications in the academic curriculum of these children are often needed after injury. Comparison of premorbid and postmorbid psychometric test data is crucial in this respect.     

Working memory brain activation following severe traumatic brain injury

Functional magnetic resonance imaging (fMRI) has shown that brain activation during performance of working memory (WM) tasks under high memory loads is altered in adults with severe traumatic brain injury (TBI) relative to uninjured subjects (Perlstein et al., 2004; Scheibel et al., 2003). Our study attempted to equate TBI patients and orthopedically injured (OI) subjects on performance of an N-Back task that used faces as stimuli. To minimize confusion in TBI patients that was revealed in pilot work, we presented the memory conditions in two separate tasks, 0- versus 1-back and 0- versus 2-back. In the 0- versus 1-back task, OI subjects activated bilateral frontal areas more extensively than TBI patients, and TBI patients activated posterior regions more extensively than OI subjects. In the 0- versus 2-back task, there were no significant differences between the groups. Analysis of changes in activation over time on 1-back disclosed that OI subjects had decreases in bilateral anterior and posterior regions, while TBI patients showed activation increases in those and other areas over time. In the 2-back condition, both groups showed decreases over time in fusiform and parahippocampal gyri, although the OI group also showed increases over time in frontal, parietal, and temporal areas not seen in the TBI patients. The greatest group differences were found in the 1-back condition, which places low demand on WM. Although the extent of activation in the 2-back condition did not differ between the two groups, deactivation in the 2-back condition was seen in the OI patients only, and both groups' patterns of activation over time varied, suggesting a dissociation between the TBI and OI patients in recruitment of neural areas mediating WM.     

A meta-analysis of task-related influences in prospective memory in traumatic brain injury

Prospective memory is the ability to remember to do something in the future and it is essential to every-day functional independence. Traumatic brain injury is associated with frequent and persistent prospective memory deficits. This study presents a review and meta-analysis investigating the effects of task parameters on prospective memory performance of individuals with TBI. Individual studies using continuous behavioural measures of prospective memory with a sample of adults with TBI and matched controls were included. Consistent with previous research, a random effects meta-analysis indicated that TBI groups demonstrated lower prospective memory performance than control groups (d?=?1.10, SE?=?0.12, 95% CI?=?0.86–1.34). In addition, we found that type of prospective memory cue, saliency of cues, and complexity of the ongoing task significantly moderated the difference in prospective memory performance between TBI and control groups. These findings suggest that prospective memory task parameters should be considered in the assessment of prospective memory in individuals with cognitive impairment. In addition, considering the influence of these task parameters would be useful to develop effective compensatory strategies to reduce prospective memory failures.     

Endogenous adult neurogenesis and cognitive function recovery following traumatic brain injury in the rat hippocampus

BACKGROUND:Endogenous neural progenitor cells play a beneficial role for cognitive recovery following traumatic brain injury.However,there are few classification-control studies aimed at varying graded brain trauma.OBJECTIVE:To observe the effects of adult endogenous neurogenesis on cognitive function repair and regeneration of neural progenitor cells following varying graded traumatic hippocampal injury to determine the significance of endogenous neurogenesis in the repair of brain injury.DESIGN,TIME AND SETTING:A randomized,controlled,animal experiment was performed at the Key Laboratory of Injuries,Variations and Regeneration of Nervous System,Tianjin Medical University General Hospital,from February to October 2009.MATERIALS:Mouse anti-rat 5-bromodeoxyuridine (BrdU) and neuronal nuclei (NeuN) monoclonal antibodies were purchased from Millipore Corporation,USA.METHODS:A total of 45 Wistar rats were randomly assigned to three groups.Mild and severe injury groups were respectively subjected to (182 ± 2) kPa and (284 ± 4) kPa lateral fluid percussion to establish models of brain injury,and the control group was subjected to surgery with no lateral fluid percussion.MAIN OUTCOME MEASURES:Cognitive function was estimated using the Morris water maze.Proliferation,survival,and differentiation of newly generated cells in the injured hippocampus were observed through the use of immunofluorescent staining.RESULTS:At 7 days post-injury,the number of BrdU+ cells in the hippocampal dentate gyrus significantly increased in the mild and severe injury groups compared with the control group (P<0.01).At 61 days post-injury,the number of BrdU7NeuN+ cells in the hippocampal dentate gyrus was significantly greater in the mild injury group compared with the severe injury and control groups (P< 0.01).In addition,the control group exhibited the greatest proportion of surviving cells that differentiated into mature neurons compared with the injury groups (P< 0.01).Moreover,at 61 days post-injury,cognitive function in rats with mild injury recovered to normal levels,whereas the severe injury group exhibited cognitive deficits (P< 0.01).CONCLUSION:Traumatic brain injury may be a stimulation factor for proliferation of neural progenitor cells in the adult hippocampus but severe brain trauma does not lead to an increased number of newly generated cells.Endogenous adult neurogenesis repairs neurological functions to an extent.However,recovery of neurological function remains limited following severe traumatic brain injury.     

右正中神经电刺激对重型颅脑损伤患者脑血流灌注影响的SPECT-CT观察

目的研究SPECT-CT融合机检测重型颅脑损伤昏迷患者行右正中神经电刺激前后脑血流灌注变化情况。方法选择我院重型颅脑损伤患者50例作为研究对象,伤后2周持续昏迷,接受右正中神经电刺激治疗。治疗前后7 d均进行SPECT-CT检查,评价脑血流灌注变化的情况。利用MATLAB和SPM软件对检测结果进行分析处理,得到昏迷患者的脑皮层血流及健康成人的比较值,使用区域分析法进行脑皮层分析,丘脑及脑干部位的血流灌注增加特征变化,利用图形重建迭加技术获得脑表面血流灌注增加值.并测量GCS和GOS评分,伤后1年作GOS预后评估。结果电刺激治疗后,患者脑血流有明显改善,血流灌注增加表现,GOS评分较电刺激后评分升高。结论右正中神经电刺激技术可以改善脑干血流灌注状况。     

Novel‐graded traumatic brain injury model in rats induced by closed head impacts

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Due to the heterogeneity of human TBI, none of the available animal models can reproduce the entire spectrum of TBI. This study was designed to develop a novel‐graded TBI rat model which is induced by closed head impacts (CHI) with reproducible brain damage and neurological dysfunction. A total of 75 male Sprague–Dawley rats (200 ± 20 g) were randomly equally divided into five groups: the Sham, 0.5, 0.6, 0.7 and 0.8 MPa groups. A custom‐made, air‐driven injury apparatus was used to induce CHIs (from 0.5 to 0.8 MPa). The kinematic parameters during the procedure were recorded by a force sensor and a high‐speed camera. Mortality rate, duration of unconsciousness (latency period of righting reflex), modified neurological severity score (mNSS) and whole brain water content (BWC) were examined. Pathological changes were evaluated by hematoxylin‐eosin (HE) stain and immunohistochemical stain for amyloid precursor protein (APP). The impact force and speed were 785.3 ± 14.12 N and 5.71 m/s in the 0.5 MPa group, 837.72 ± 10.41 N and 6.06 m/s in the 0.6 MPa group, 857.65 ± 11.11 N and 6.25 m/s in the 0.7 MPa group, and 955.6 ± 16.35 N and 6.67 m/s in the 0.8 MPa group. The periods of loss of righting reflex in 0.6–0.8 MPa groups were significantly higher than that in the Sham group. The mNSS score and BWC of the 0.8 MPa group remained higher 24 h after injury than other groups. Brain damage was indicated by increased APP expression in TBI rats. In conclusion, the newly developed CHI rat model was a highly controlled and reproducible graded TBI model, and provided a useful tool to investigate the underlying mechanism and therapeutic effects of TBI with various injury severities.     

Impact of different intensities of intermittent theta burst stimulation on the cortical properties during TMS‐EEG and working memory performance

Intermittent theta burst stimulation (iTBS) is a noninvasive brain stimulation technique capable of increasing cortical excitability beyond the stimulation period. Due to the rapid induction of modulatory effects, prefrontal application of iTBS is gaining popularity as a therapeutic tool for psychiatric disorders such as depression. In an attempt to increase efficacy, higher than conventional intensities are currently being applied. The assumption that this increases neuromodulatory may be mechanistically false for iTBS. This study examined the influence of intensity on the neurophysiological and behavioural effects of iTBS in the prefrontal cortex. Sixteen healthy participants received iTBS over prefrontal cortex at either 50, 75 or 100% resting motor threshold in separate sessions. Single‐pulse TMS and concurrent electroencephalography (EEG) was used to assess changes in cortical reactivity measured as TMS‐evoked potentials and oscillations. The n‐back task was used to assess changes in working memory performance. The data can be summarised as an inverse U‐shape relationship between intensity and iTBS plastic effects, where 75% iTBS yielded the largest neurophysiological changes. Improvement in reaction time in the 3‐back task was supported by the change in alpha power, however, comparison between conditions revealed no significant differences. The assumption that higher intensity results in greater neuromodulatory effects may be false, at least in healthy individuals, and should be carefully considered for clinical populations. Neurophysiological changes associated with working memory following iTBS suggest functional relevance. However, the effects of different intensities on behavioural performance remain elusive in the present healthy sample.     

Postconcussional disorder and PTSD symptoms of military‐related traumatic brain injury associated with compromised neurocircuitry

Traumatic brain injury (TBI) is a common combat injury, often through explosive blast, and produces heterogeneous brain changes due to various mechanisms of injury. It is unclear whether the vulnerability of white matter differs between blast and impact injury, and the consequences of microstructural changes on neuropsychological function are poorly understood in military TBI patients. Diffusion tensor imaging (DTI) techniques were used to assess the neurocircuitry in 37 US service members (29 mild, 7 moderate, 1 severe; 17 blast and 20 nonblast), who sustained a TBI while deployed, compared to 14 nondeployed, military controls. High‐dimensional deformable registration of MRI diffusion tensor data was followed by fiber tracking and tract‐specific analysis along with region‐of‐interest analysis. DTI results were examined in relation to post‐concussion and post‐traumatic stress disorder (PTSD) symptoms. The most prominent white matter microstructural injury for both blast and nonblast patients was in the frontal fibers within the fronto‐striatal (corona radiata, internal capsule) and fronto‐limbic circuits (fornix, cingulum), the fronto‐parieto‐occipital association fibers, in brainstem fibers, and in callosal fibers. Subcortical superior‐inferiorly oriented tracts were more vulnerable to blast injury than nonblast injury, while direct impact force had more detrimental effects on anterior‐posteriorly oriented tracts, which tended to cause heterogeneous left and right hemispheric asymmetries of white matter connectivity. The tractography using diffusion anisotropy deficits revealed the cortico‐striatal‐thalamic‐cerebellar‐cortical (CSTCC) networks, where increased post‐concussion and PTSD symptoms were associated with low fractional anisotropy in the major nodes of compromised CSTCC neurocircuitry, and the consequences on cognitive function were explored as well. Hum Brain Mapp 35:2652–2673, 2014. © 2013 Wiley Periodicals, Inc .     

NMDA receptor antagonist MK-801 reduces neuronal damage and preserves learning and memory in a rat model of traumatic brain injury

Objective

NMDA receptor channel plays an important role in the pathophysiological process of traumatic brain injury (TBI). The present study aims to study the pathological mechanism of TBI and the impairment of learning and memory after TBI, and to investigate the mechanism of the protective effect of NMDA receptor antagonist MK-801 on learning and memory disorder after TBI.

Methods

Forty Sprague-Dawley rats (weighing approximately 200 g) were randomized into 5 groups (n = 8 in each group): control group, model group, low-dose group (MK-801 0.5 mg/kg), middle-dose group (MK-801 2 mg/kg), and high-dose group (MK-801 10 mg/kg). TBI model was established using a weight-drop head injury mode. After 2-month drug treatment, learning and memory ability was evaluated by using Morris water maze test. Then the animals were sacrificed, and brain tissues were taken out for morphological and immunohistochemical assays.

Results

The ability of learning and memory was significantly impaired in the TBI model animals. Besides, the neuronal caspase-3 expression, neuronal nitric oxide synthase (nNOS)-positive neurons and OX-42-positive microglia were all increased in TBI animals. Meanwhile, the number of neuron synapses was decreased, and vacuoles degeneration could be observed in mitochondria. After MK-801 treatment at 3 different dosages, the ability of learning and memory was markedly improved, as compared to that of the TBI model animals. Moreover, neuronal caspase-3 expression, OX-42-positive microglia and nNOS-positive neurons were all significantly decreased. Meanwhile, the mitochondria degeneration was greatly inhibited.

Conclusion

MK-801 could significantly inhibit the degeneration and apoptosis of neurons in damaged brain areas. It could also inhibit TBI-induced increase in nNOS-positive neurons and OX-42-positive microglia. Impairment in learning and memory in TBI animals could be repaired by treatment with MK-801.     

创伤性闭合性中型颅脑损伤动物模型的建立

目的构建一种创伤性闭合性中型颅脑损伤（TBI）动物模型。 方法雄性SD大鼠80只,完全随机平均分为4组,每组20只,包括3组不同程度的TBI（A、B、C）组和假手术（N）组。参照Marmarou损伤模型,A、B、C组分别按拟定的打击高度（1.0、1.5、2.0 m）使重量为450 g的钢棒自由下落撞击大鼠头部建立TBI。观察各组大鼠伤后一般状况、神经行为学、脑组织形态学等改变。 结果伤后14 d内,N、A、B、C组死亡率分别为0%、5%、20%、60%,随着致伤量的增加,死亡率增加（P<0.05）,伤后各观察时间点神经功能缺损评分（mNSS）升高（P<0.05）,均高于N组,差异均具有统计学意义。HE染色结果提示,与N组比较,随着致伤量的增加,光镜下可见基质疏松、神经元细胞周围间隙和血管间隙增宽、神经元细胞排列紊乱且变性、神经胶质肿胀变性程度更加明显。免疫组织化学染色结果提示,与N组比较,A、B、C组大脑皮质β-APP、NF-L阳性表达程度增强。 结论以450 g的钢棒自1.5 m高处自由打击大鼠颅骨可成功建立创伤性闭合性中型颅脑损伤动物模型,其病理学特征明显,重复性和稳定性好。     

Hyperbaric oxygen therapy reduces neuroinflammation and expression of matrix metalloproteinase-9 in the rat model of traumatic brain injury

The acute inflammatory response plays an important role in secondary brain damage after traumatic brain injury (TBI). Neutrophils provide the main source of matrix metalloproteinases (MMPs) which also play a deleterious role in TBI. Numerous preclinical studies have suggested that hyperbaric oxygen therapy (HBOT) may by beneficial in various noncerebral and cerebral inflammatory diseases. The goal of this study was to evaluate the effects of HBOT on inflammatory infiltration and the expression of MMPs in correlation with secondary cell death in the rat model of dynamic cortical deformation (DCD). Twenty animals underwent DCD with subsequent HBOT (2.8 ATA, two sessions of 45 min each); 10 animals: DCD and normobaric oxygenation (1 ATA), 10 animals: not treated after DCD. Cell death was evaluated by TUNEL. Neutrophils were revealed by myeloperoxidase staining. Immunohistochemical staining for MMP-2 and -9 and tissue inhibitors of MMP-1 (TIMP-1) and -2 was also performed and the results were quantitatively evaluated by image analysis. In the animals treated by HBOT, a significant decrease in the number of TUNEL-positive cells and neutrophilic inflammatory infiltration was seen in comparison with nontreated animals and those treated by normobaric oxygen. The expression of MMP-9 was also significantly lower in the treated group. Staining for MMP-2 and TIMP-2 did not change significantly. Our results demonstrate that HBOT decreased the extent of secondary cell death and reactive neuroinflammation in the TBI model. The decline of MMP-9 expression after HBOT may also contribute to protection of brain tissue in the perilesional area. Further research should be centred on the evaluation of long-term functional and morphological results of HBOT.     

痴呆患者下丘脑/穹窿核的脑深部电刺激电极植入技术

目的：探讨重度痴呆患者行下丘脑/穹隆核脑深部电刺激(DBS)电极植入的技术及安全性。方法介绍接受下丘脑/穹隆核 DBS 治疗的3例重度原发性神经系统痴呆患者手术方法,观察电极植入的靶点位置、手术操作的不良反应和电极植入的安全性。结果电极植入位置准确,3例患者术后磁共振或 CT 扫描证实电极均位于术前设计靶点位置,术中及术后均无手术操作相关的不良反应,术后3个月随访电极植入安全,无感染、电极移位等并发症。结论严格按照电极植入技术流程进行操作,可保证下丘脑/穹窿核 DBS 电极植入位置准确,术中及术后患者安全。