Complexity of Motor Sequences and Cortical Reorganization in Parkinson's Disease: A Functional MRI Study

Motor impairment is the most relevant clinical feature in Parkinson''s disease (PD). Functional imaging studies on motor impairment in PD have revealed changes in the cortical motor circuits, with particular involvement of the fronto-striatal network. The aim of this study was to assess brain activations during the performance of three different motor exercises, characterized by progressive complexity, using a functional fMRI multiple block paradigm, in PD patients and matched control subjects. Unlike from single-task comparisons, multi-task comparisons between similar exercises allowed to analyse brain areas involved in motor complexity planning and execution. Our results showed that in the single-task comparisons the involvement of primary and secondary motor areas was observed, consistent with previous findings based on similar paradigms. Most notably, in the multi-task comparisons a greater activation of supplementary motor area and posterior parietal cortex in PD patients, compared with controls, was observed. Furthermore, PD patients, compared with controls, had a lower activation of the basal ganglia and limbic structures, presumably leading to the impairment in the higher levels of motor control, including complexity planning and execution. The findings suggest that in PD patients occur both compensatory mechanisms and loss of efficiency and provide further insight into the pathophysiological role of distinct cortical and subcortical areas in motor dysfunction.     

6-OHDA帕金森病大鼠快动眼睡眠状态下皮层脑电及基底节场电位的异常变化

目的：了解帕金森病（PD）模型大鼠在快动眼睡眠状态下皮层脑电和基底节场电位的异常变化。方法：用6-羟基多巴胺（6-OHDA）脑内两点注射法建立PD大鼠模型,并经阿扑吗啡注射诱发旋转对模型进行评价。通过多导宏电极在体电生理记录技术结合视频录像,对正常大鼠和6-OHDA大鼠PD模型进行苍白球场电位和皮层M1、M2区脑电的多部位24小时同时记录。功率谱分析和相干分析用于揭示快动眼睡眠状态下各记录位点信号的频率成分以及不N记录位点神经元集群之间的变化。结果：与正常大鼠相比,6-OHDA帕金森病模型大鼠在REM期间的皮层脑电在臼和y频段上都有变化：初级运动皮质M1区的θ频段成分消失,辅助运动区M2的θ频段成分略有增加,患侧苍白球的θ频段成分增大显著;M1区的γ频段成分增大,而γ频段成分在苍白球基本没有变化。结论：6-OHDA对中脑多巴胺能神经元的损害可造成大鼠双侧皮层M1区θ节律的消失和γ节律的增强,以及对侧M1-M2区之间在γ节律上的同步被显著增强,而γ节律在苍白球没有变化。这些异常电活动可能是由于VTA受损引起从而与帕金森病的快动眼睡眠行为障碍有关。     

Assessment of brain interactivity in the motor cortex from the concept of functional connectivity and spectral analysis of fMRI data

Functional magnetic resonance imaging (fMRI) was used to assess the contributions of movement preparation and execution of a visuomotor task in a cerebral motor network. The functional connectivity of the voxel time series between brain regions in the frequency space was investigated by performing spectral analysis of fMRI time series. The regional interactivities between the two portions of the supplementary motor area (pre-SMA and SMA-proper) and the primary motor cortex (M1), defined as a seed region, were evaluated. The spectral parameter of coherence was used to describe a correlation structure in the frequency domain between two voxel-based time series and to infer the strength of the functional interaction within our presumed motor network of connections. The results showed meaningful differences of the functional interactions between the two portions of the SMA and the M1 area depending on the task conditions. This approach demonstrated the existence of a functional dissociation between the pre-SMA and SMA-proper subregions. We therefore conclude that spectral analysis is useful for identifying functional interactions of brain regions and might provide a powerful tool to quantify changes in connectivity profiles associated with various components of an experimental task.     

Systemic Blockade of Dopamine D2-Like Receptors Increases High-Voltage Spindles in the Globus Pallidus and Motor Cortex of Freely Moving Rats

High-voltage spindles (HVSs) have been reported to appear spontaneously and widely in the cortical–basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP) and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D₁-like receptors or D₂-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1) in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D₂-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D₂-like receptor antagonists. On the contrary, the selective dopamine D₁-like receptor antagonist, {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D₂-like receptors, but not D₁-like receptors, were involved in HVS regulation. This supports the important role of dopamine D₂-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion.     

Cortico-Cortical White Matter Motor Pathway Microstructure Is Related to Psychomotor Retardation in Major Depressive Disorder

Alterations of brain structure and function have been associated with psychomotor retardation in major depressive disorder (MDD). However, the association of motor behaviour and white matter integrity of motor pathways in MDD is unclear. The aim of the present study was to first investigate structural connectivity of white matter motor pathways in MDD. Second, we explore the relation of objectively measured motor activity and white matter integrity of motor pathways in MDD. Therefore, 21 patients with MDD and 21 healthy controls matched for age, gender, education and body mass index underwent diffusion tensor imaging and 24 hour actigraphy (measure of the activity level) the same day. Applying a probabilistic fibre tracking approach we extracted connection pathways between the dorsolateral prefrontal cortex (dlPFC), the rostral anterior cingulate cortex (rACC), the pre-supplementary motor area (pre-SMA), the SMA-proper, the primary motor cortex (M1), the caudate nucleus, the putamen, the pallidum and the thalamus. Patients had lower activity levels and demonstrated increased mean diffusivity (MD) in pathways linking left pre-SMA and SMA-proper, and right SMA-proper and M1. Exploratory analyses point to a positive association of activity level and mean-fractional anisotropy in the right rACC-pre-SMA connection in MDD. Only MDD patients with low activity levels had a negative linear association of activity level and mean-MD in the left dlPFC-pre-SMA connection. Our results point to structural alterations of cortico-cortical white matter motor pathways in MDD. Altered white matter organisation of rACC-pre-SMA and dlPFC-pre-SMA pathways may contribute to movement initiation in MDD.     

Reduced noradrenaline,but not dopamine and serotonin in motor thalamus of the MPTP primate: relation to severity of Parkinsonism

We recently found severe noradrenaline deficits throughout the thalamus of patients with Parkinson's disease [C. Pifl, S. J. Kish and O. Hornykiewicz Mov Disord. 27, 2012, 1618.]. As this noradrenaline loss was especially severe in nuclei of the motor thalamus normally transmitting basal ganglia motor output to the cortex, we hypothesized that this noradrenaline loss aggravates the motor disorder of Parkinson's disease. Here, we analysed noradrenaline, dopamine and serotonin in motor (ventrolateral and ventroanterior) and non‐motor (mediodorsal, centromedian, ventroposterior lateral and reticular) thalamic nuclei in MPTP‐treated monkeys who were always asymptomatic; who recovered from mild parkinsonism; and monkeys with stable, either moderate or severe parkinsonism. We found that only the symptomatic parkinsonian animals had significant noradrenaline losses specifically in the motor thalamus, with the ventroanterior motor nucleus being affected only in the severe parkinsonian animals. In contrast, the striatal dopamine loss was identical in both the mild and severe symptom groups. MPTP‐treatment had no significant effect on noradrenaline in non‐motor thalamic nuclei or dopamine and serotonin in any thalamic subregion. We conclude that in the MPTP primate model, loss of noradrenaline in the motor thalamus may also contribute to the clinical expression of the parkinsonian motor disorder, corroborating experimentally our hypothesis on the role of thalamic noradrenaline deficit in Parkinson's disease.     

Neuronal activity in the primate supplementary motor area and the primary motor cortex in relation to spatio-temporal bimanual coordination

Single neuronal activity was recorded from the supplementary motor area (SMA-proper and pre-SMA) and primary motor cortex (M1) in two Macaca fascicularis trained to perform a delayed conditional sequence of coordinated bimanual pull and grasp movements. The behavioural paradigm was designed to distinguish neuronal activity associated with bimanual coordination from that related to a comparable motor sequence but executed unimanually (left or right arm only). The bimanual and unimanual trials were instructed in a random order by a visual cue. Following the cue, there was a waiting period until presentation of a "go-signal", signalling the monkey to perform the instructed movement. A total of 143 task-related neurons were recorded from the SMA (SMA-proper, 62; pre-SMA, 81). Most SMA units (87%) were active in both unimanual contralateral and unimanual ipsilateral trials (bilateral neurons), whereas 9% of units were active only in unimanual contralateral trials and 3% were active only in unimanual ipsilateral trials. Forty-eight per cent of SMA task-related units were classified as bimanual, defined as neurons in which the activity observed in bimanual trials could not be predicted from that associated with unimanual trials when comparing the same events related to the same arm. For direct comparison, 527 neurons were recorded from M1 in the same monkeys performing the same tasks. The comparison showed that M1 contains significantly less bilateral neurons (75%) than the SMA, whereas the reverse was observed for contralateral neurons (22% in M1). The proportion of M1 bimanual cells (53%) was not statistically different from that observed in the SMA. The results suggest that both the SMA and M1 may contribute to the control of sequential bimanual coordinated movements. Interlimb coordination may then take place in a distributed network including at least the SMA and M1, but the contribution of other cortical and subcortical areas such as cingulate motor cortex and basal ganglia remains to be investigated.     

Influences of Chronic Mild Stress Exposure on Motor,Non-Motor Impairments and Neurochemical Variables in Specific Brain Areas of MPTP/Probenecid Induced Neurotoxicity in Mice

Parkinson''s disease (PD) is regarded as a movement disorder mainly affecting the elderly population and occurs due to progressive loss of dopaminergic (DAergic) neurons in nigrostriatal pathway. Patients suffer from non-motor symptoms (NMS) such as depression, anxiety, fatigue and sleep disorders, which are not well focussed in PD research. Depression in PD is a predominant /complex symptom and its pathology lies exterior to the nigrostriatal system. The main aim of this study is to explore the causative or progressive effect of chronic mild stress (CMS), a paradigm developed as an animal model of depression in1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg. body wt.) with probenecid (250 mg/kg, s.c.) (MPTP/p) induced mice model of PD. After ten i.p. injections (once in 3.5 days for 5 weeks) of MPTP/p or exposure to CMS for 4 weeks, the behavioural (motor and non-motor) impairments, levels and expressions of dopamine (DA), serotonin (5-HT), DAergic markers such as tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporters—2 (VMAT 2) and α-synuclein in nigrostriatal (striatum (ST) and substantia nigra (SN)) and extra-nigrostriatal (hippocampus, cortex and cerebellum) tissues were analysed. Significantly decreased DA and 5-HT levels, TH, DAT and VMAT 2 expressions and increased motor deficits, anhedonia-like behaviour and α-synuclein expression were found in MPTP/p treated mice. Pre and/or post exposure of CMS to MPTP/p mice further enhanced the MPTP/p induced DA and 5-HT depletion, behaviour abnormalities and protein expressions. Our results could strongly confirm that the exposure of stress after MPTP/p injections worsens the symptoms and neurochemicals status of PD.     

苍白球电毁损对帕金森病大鼠HVSs 振荡波的影响研究

目的:应用直流电核团毁损术毁损帕金森病(PD)大鼠模型的内侧苍白球(GPi),记录其手术前后脑电生理活动的变化,以探讨内苍白球射频毁损术治疗PD的可能机制。方法:成年SD大鼠随机分为GP毁损组、假手术组及正常组。对PD毁损组和假手术组大鼠采用6-羟基多巴胺(6-OHDA)右侧黑质致密部(SNc)、中脑腹侧被盖区(VTA)两点注射法建立PD大鼠模型,并经腹腔注射阿扑吗啡(APO)诱发旋转以对模型建立进行评价。通过多导联宏电极在体脑电生理记录技术对各组大鼠进行右侧(注射侧)大脑皮层M1、M2区脑电及纹状体场电位的连续24小时记录,同时进行视频录像。对GP毁损组大鼠行直流电GPi毁损术,术后4天对各组大鼠均行阿扑吗啡诱导旋转行为检验,继续记录脑电活动,记录数据经频率谱分析及相干分析以揭示各记录位点信号的频率成分以及不同位点神经元集群间的功能连接和同步性。结果:对GP毁损组大鼠毁损术前后在清醒静息状态下的皮层脑电和纹状体场电位有明显改变,术后HVSs(High Voltage Spindles)在持续时间上明显缩短发作次数明显减少;对各组大鼠术后在静息状态下的脑电信号进行对比,GP毁损组大鼠较假手术组的HVSs持续时间和发作频率均减少并接近正常组大鼠水平,相干性分析显示GP毁损组大鼠术后在HVSs频段(5-13Hz)上的相干程度显著小于假手术组。结论:在清醒静息状态下6-OHDA建立的PD大鼠皮层-基底节环路上HVSs持续时间延长发生频率增高,经GP毁损术后其时间缩短发作次数减少同步性降低并接近正常水平,从而改善PD症状,该现象可能解释临床采用苍白球射频毁损术治疗PD的治疗机制。     

Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation

Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase 3 family, is activated by oxidative stress. The death-signaling pathway mediated by ASK1 is inhibited by DJ-1, which is linked to recessively inherited Parkinson''s disease (PD). Considering that DJ-1 deficiency exacerbates the toxicity of the mitochondrial complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we sought to investigate the direct role and mechanism of ASK1 in MPTP-induced dopamine neuron toxicity. In the present study, we found that MPTP administration to wild-type mice activates ASK1 in the midbrain. In ASK1 null mice, MPTP-induced motor impairment was less profound, and striatal dopamine content and nigral dopamine neuron counts were relatively preserved compared to wild-type littermates. Further, microglia and astrocyte activation seen in wild-type mice challenged with MPTP was markedly attenuated in ASK1^−/− mice. These data suggest that ASK1 is a key player in MPTP-induced glial activation linking oxidative stress with neuroinflammation, two well recognized pathogenetic factors in PD. These findings demonstrate that ASK1 is an important effector of MPTP-induced toxicity and suggest that inhibiting this kinase is a plausible therapeutic strategy for protecting dopamine neurons in PD.     

The Subthalamic Microlesion Story in Parkinson's Disease: Electrode Insertion-Related Motor Improvement with Relative Cortico-Subcortical Hypoactivation in fMRI

Electrode implantation into the subthalamic nucleus for deep brain stimulation in Parkinson''s disease (PD) is associated with a temporary motor improvement occurring prior to neurostimulation. We studied this phenomenon by functional magnetic resonance imaging (fMRI) when considering the Unified Parkinson''s Disease Rating Scale (UPDRS-III) and collateral oedema. Twelve patients with PD (age 55.9± (SD)6.8 years, PD duration 9–15 years) underwent bilateral electrode implantation into the subthalamic nucleus. The fMRI was carried out after an overnight withdrawal of levodopa (OFF condition): (i) before and (ii) within three days after surgery in absence of neurostimulation. The motor task involved visually triggered finger tapping. The OFF/UPDRS-III score dropped from 33.8±8.7 before to 23.3±4.8 after the surgery (p<0.001), correlating with the postoperative oedema score (p<0.05). During the motor task, bilateral activation of the thalamus and basal ganglia, motor cortex and insula were preoperatively higher than after surgery (p<0.001). The results became more enhanced after compensation for the oedema and UPDRS-III scores. In addition, the rigidity and axial symptoms score correlated inversely with activation of the putamen and globus pallidus (p<0.0001). One month later, the OFF/UPDRS-III score had returned to the preoperative level (35.8±7.0, p = 0.4).In conclusion, motor improvement induced by insertion of an inactive electrode into the subthalamic nucleus caused an acute microlesion which was at least partially related to the collateral oedema and associated with extensive impact on the motor network. This was postoperatively manifested as lowered movement-related activation at the cortical and subcortical levels and differed from the known effects of neurostimulation or levodopa. The motor system finally adapted to the microlesion within one month as suggested by loss of motor improvement and good efficacy of deep brain stimulation.     

帕金森病的临床治疗概况

帕金森病(Parkinson's disease, PD),在医学上称为"原发性震颤麻痹",又称"震颤麻痹",是一种中枢神经系统变性疾病,主要是因位于中脑部位"黑质"中的多巴胺(DA)能神经元病理性改变后,多巴胺的合成减少,对与其功能相互拮抗的乙酰胆碱的抑制功能降低,则乙酰胆碱的兴奋作用相对增强。两者失衡的结果便出现了"震颤麻痹"。本综述先从PD发病机制方向总结归纳目前临床常用的西医药物(包括左旋多巴、DA降解酶抑制剂、DA受体激动剂、抗胆碱能药物)、基因治疗靶点、手术治疗(脑深部电刺激术)及物理疗法,又从中医角度整体介绍了目前中医中药治疗以及针灸治疗等。因PD对患者的日常生活及身心健康造成了严重影响,我们希望通过本综述为PD综合治疗提供更广阔的临床思路及更好的方案。     

Construction and Analysis of the Protein-Protein Interaction Networks Based on Gene Expression Profiles of Parkinson's Disease

Background

Parkinson''s Disease (PD) is one of the most prevailing neurodegenerative diseases. Improving diagnoses and treatments of this disease is essential, as currently there exists no cure for this disease. Microarray and proteomics data have revealed abnormal expression of several genes and proteins responsible for PD. Nevertheless, few studies have been reported involving PD-specific protein-protein interactions.

Results

Microarray based gene expression data and protein-protein interaction (PPI) databases were combined to construct the PPI networks of differentially expressed (DE) genes in post mortem brain tissue samples of patients with Parkinson''s disease. Samples were collected from the substantia nigra and the frontal cerebral cortex. From the microarray data, two sets of DE genes were selected by 2-tailed t-tests and Significance Analysis of Microarrays (SAM), run separately to construct two Query-Query PPI (QQPPI) networks. Several topological properties of these networks were studied. Nodes with High Connectivity (hubs) and High Betweenness Low Connectivity (bottlenecks) were identified to be the most significant nodes of the networks. Three and four-cliques were identified in the QQPPI networks. These cliques contain most of the topologically significant nodes of the networks which form core functional modules consisting of tightly knitted sub-networks. Hitherto unreported 37 PD disease markers were identified based on their topological significance in the networks. Of these 37 markers, eight were significantly involved in the core functional modules and showed significant change in co-expression levels. Four (ARRB2, STX1A, TFRC and MARCKS) out of the 37 markers were found to be associated with several neurotransmitters including dopamine.

Conclusion

This study represents a novel investigation of the PPI networks for PD, a complex disease. 37 proteins identified in our study can be considered as PD network biomarkers. These network biomarkers may provide as potential therapeutic targets for PD applications development.     

Distinguishing Patients with Parkinson's Disease Subtypes from Normal Controls Based on Functional Network Regional Efficiencies

Many studies have demonstrated that the pathophysiology and clinical symptoms of Parkinson''s disease (PD) are inhomogeneous. However, the symptom-specific intrinsic neural activities underlying the PD subtypes are still not well understood. Here, 15 tremor-dominant PD patients, 10 non-tremor-dominant PD patients, and 20 matched normal controls (NCs) were recruited and underwent resting-state functional magnetic resonance imaging (fMRI). Functional brain networks were constructed based on randomly generated anatomical templates with and without the cerebellum. The regional network efficiencies (i.e., the local and global efficiencies) were further measured and used to distinguish subgroups of PD patients (i.e., with tremor-dominant PD and non-tremor-dominant PD) from the NCs using linear discriminant analysis. The results demonstrate that the subtype-specific functional networks were small-world-organized and that the network regional efficiency could discriminate among the individual PD subgroups and the NCs. Brain regions involved in distinguishing between the study groups included the basal ganglia (i.e., the caudate and putamen), limbic regions (i.e., the hippocampus and thalamus), the cerebellum, and other cerebral regions (e.g., the insula, cingulum, and calcarine sulcus). In particular, the performances of the regional local efficiency in the functional network were better than those of the global efficiency, and the performances of global efficiency were dependent on the inclusion of the cerebellum in the analysis. These findings provide new evidence for the neurological basis of differences between PD subtypes and suggest that the cerebellum may play different roles in the pathologies of different PD subtypes. The present study demonstrated the power of the combination of graph-based network analysis and discrimination analysis in elucidating the neural basis of different PD subtypes.     

Diminished Activation of Motor Working-Memory Networks in Parkinson's Disease

Parkinson''s disease (PD) is characterized by typical extrapyramidal motor features and increasingly recognized non-motor symptoms such as working memory (WM) deficits. Using functional magnetic resonance imaging (fMRI), we investigated differences in neuronal activation during a motor WM task in 23 non-demented PD patients and 23 age- and gender-matched healthy controls. Participants had to memorize and retype variably long visuo-spatial stimulus sequences after short or long delays (immediate or delayed serial recall). PD patients showed deficient WM performance compared to controls, which was accompanied by reduced encoding-related activation in WM-related regions. Mirroring slower motor initiation and execution, reduced activation in motor structures such as the basal ganglia and superior parietal cortex was detected for both immediate and delayed recall. Increased activation in limbic, parietal and cerebellar regions was found during delayed recall only. Increased load-related activation for delayed recall was found in the posterior midline and the cerebellum. Overall, our results demonstrate that impairment of WM in PD is primarily associated with a widespread reduction of task-relevant activation, whereas additional parietal, limbic and cerebellar regions become more activated relative to matched controls. While the reduced WM-related activity mirrors the deficient WM performance, the additional recruitment may point to either dysfunctional compensatory strategies or detrimental crosstalk from “default-mode” regions, contributing to the observed impairment.     

Learning with slight forgetting optimizes sensorimotor transformation in redundant motor systems

Recent theoretical studies have proposed that the redundant motor system in humans achieves well-organized stereotypical movements by minimizing motor effort cost and motor error. However, it is unclear how this optimization process is implemented in the brain, presumably because conventional schemes have assumed a priori that the brain somehow constructs the optimal motor command, and largely ignored the underlying trial-by-trial learning process. In contrast, recent studies focusing on the trial-by-trial modification of motor commands based on error information suggested that forgetting (i.e., memory decay), which is usually considered as an inconvenient factor in motor learning, plays an important role in minimizing the motor effort cost. Here, we examine whether trial-by-trial error-feedback learning with slight forgetting could minimize the motor effort and error in a highly redundant neural network for sensorimotor transformation and whether it could predict the stereotypical activation patterns observed in primary motor cortex (M1) neurons. First, using a simple linear neural network model, we theoretically demonstrated that: 1) this algorithm consistently leads the neural network to converge at a unique optimal state; 2) the biomechanical properties of the musculoskeletal system necessarily determine the distribution of the preferred directions (PD; the direction in which the neuron is maximally active) of M1 neurons; and 3) the bias of the PDs is steadily formed during the minimization of the motor effort. Furthermore, using a non-linear network model with realistic musculoskeletal data, we demonstrated numerically that this algorithm could consistently reproduce the PD distribution observed in various motor tasks, including two-dimensional isometric torque production, two-dimensional reaching, and even three-dimensional reaching tasks. These results may suggest that slight forgetting in the sensorimotor transformation network is responsible for solving the redundancy problem in motor control.     

Role of basal ganglia circuits in resisting interference by distracters: a swLORETA study

Background

The selection of task-relevant information requires both the focalization of attention on the task and resistance to interference from irrelevant stimuli. Both mechanisms rely on a dorsal frontoparietal network, while focalization additionally involves a ventral frontoparietal network. The role of subcortical structures in attention is less clear, despite the fact that the striatum interacts significantly with the frontal cortex via frontostriatal loops. One means of investigating the basal ganglia''s contributions to attention is to examine the features of P300 components (i.e. amplitude, latency, and generators) in patients with basal ganglia damage (such as in Parkinson''s disease (PD), in which attention is often impaired). Three-stimulus oddball paradigms can be used to study distracter-elicited and target-elicited P300 subcomponents.

Methodology/Principal Findings

In order to compare distracter- and target-elicited P300 components, high-density (128-channel) electroencephalograms were recorded during a three-stimulus visual oddball paradigm in 15 patients with early PD and 15 matched healthy controls. For each subject, the P300 sources were localized using standardized weighted low-resolution electromagnetic tomography (swLORETA). Comparative analyses (one-sample and two-sample t-tests) were performed using SPM5® software. The swLORETA analyses showed that PD patients displayed fewer dorsolateral prefrontal (DLPF) distracter-P300 generators but no significant differences in target-elicited P300 sources; this suggests dysfunction of the DLPF cortex when the executive frontostriatal loop is disrupted by basal ganglia damage.

Conclusions/Significance

Our results suggest that the cortical attention frontoparietal networks (mainly the dorsal one) are modulated by the basal ganglia. Disruption of this network in PD impairs resistance to distracters, which results in attention disorders.     

Lifestyle Regularity Measured by The Social Rhythm Metric in Parkinson's Disease

Parkinson's disease (PD) is a chronic progressive motor disorder that may present with a spectrum of symptoms and disease severity. Therapy is frequently associated with motor fluctuations and dyskinesias; therefore, monitoring of motor fluctuations and daily abilities is important for adequate management. The Social Rhythm Metric (SRM) is a diary‐like questionnaire that quantifies the extent to which a person's life is regular vs. irregular on a daily basis with respect to event timing. Lifestyle regularity has been assessed by the SRM in other clinical situations. The aim of this study was to evaluate lifestyle regularity in a population with PD using the SRM and its relationship to clinical and therapeutic factors. Twenty‐eight consecutive patients with PD and 14 control subjects were studied. Severity of motor dysfunction was evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS). Depressive symptoms were assessed with the Montgomery Asberg Depressive Rating Scale (MADRS), sleep quality with the Pittsburgh Sleep Quality Index (PSQI), and subjective daytime sleepiness with the Epworth sleepiness scale. Daily lifestyle regularity was assessed by the SRM for 2 weeks. Patients with PD had lower SRM scores than controls, and those with motor fluctuations had even lower scores (p=0.04). Patients with motor fluctuations showed more clinical disability (p=0.01), a worse quality of sleep (p=0.02), and more depressive symptoms (p=0.02). SRM results were correlated with PSQI values (p=0.016). Our findings show that the regularity of daily activities as measured by the SRM is disorganized in patients with PD and that this irregularity is related to sleep quality.     

Theta-burst stimulation-induced plasticity over primary somatosensory cortex changes somatosensory temporal discrimination in healthy humans

Background

The somatosensory temporal discrimination threshold (STDT) measures the ability to perceive two stimuli as being sequential. Precisely how the single cerebral structures contribute in controlling the STDT is partially known and no information is available about whether STDT can be modulated by plasticity-inducing protocols.

Methodology/Principal Findings

To investigate how the cortical and cerebellar areas contribute to the STDT we used transcranial magnetic stimulation and a neuronavigation system. We enrolled 18 healthy volunteers and 10 of these completed all the experimental sessions, including the control experiments. STDT was measured on the left hand before and after applying continuous theta-burst stimulation (cTBS) on the right primary somatosensory area (S1), pre-supplementary motor area (pre-SMA), right dorsolateral prefrontal cortex (DLPFC) and left cerebellar hemisphere. We then investigated whether intermittent theta-burst stimulation (iTBS) on the right S1 improved the STDT. After right S1 cTBS, STDT values increased whereas after iTBS to the same cortical site they decreased. cTBS over the DLPFC and left lateral cerebellum left the STDT statistically unchanged. cTBS over the pre-SMA also left the STDT statistically unchanged, but it increased the number of errors subjects made in distinguishing trials testing a single stimulus and those testing paired stimuli.

Conclusions/Significance

Our findings obtained by applying TBS to the cortical areas involved in processing sensory discrimination show that the STDT is encoded in S1, possibly depends on intrinsic S1 neural circuit properties, and can be modulated by plasticity-inducing TBS protocols delivered over S1. Our findings, giving further insight into mechanisms involved in somatosensory temporal discrimination, help interpret STDT abnormalities in movement disorders including dystonia and Parkinson''s disease.     

Spike Firing and IPSPs in Layer V Pyramidal Neurons during Beta Oscillations in Rat Primary Motor Cortex (M1) In Vitro

Beta frequency oscillations (10–35 Hz) in motor regions of cerebral cortex play an important role in stabilising and suppressing unwanted movements, and become intensified during the pathological akinesia of Parkinson''s Disease. We have used a cortical slice preparation of rat brain, combined with concurrent intracellular and field recordings from the primary motor cortex (M1), to explore the cellular basis of the persistent beta frequency (27–30 Hz) oscillations manifest in local field potentials (LFP) in layers II and V of M1 produced by continuous perfusion of kainic acid (100 nM) and carbachol (5 µM). Spontaneous depolarizing GABA-ergic IPSPs in layer V cells, intracellularly dialyzed with KCl and IEM1460 (to block glutamatergic EPSCs), were recorded at −80 mV. IPSPs showed a highly significant (P< 0.01) beta frequency component, which was highly significantly coherent with both the Layer II and V LFP oscillation (which were in antiphase to each other). Both IPSPs and the LFP beta oscillations were abolished by the GABA_A antagonist bicuculline. Layer V cells at rest fired spontaneous action potentials at sub-beta frequencies (mean of 7.1+1.2 Hz; n = 27) which were phase-locked to the layer V LFP beta oscillation, preceding the peak of the LFP beta oscillation by some 20 ms. We propose that M1 beta oscillations, in common with other oscillations in other brain regions, can arise from synchronous hyperpolarization of pyramidal cells driven by synaptic inputs from a GABA-ergic interneuronal network (or networks) entrained by recurrent excitation derived from pyramidal cells. This mechanism plays an important role in both the physiology and pathophysiology of control of voluntary movement generation.