Study of EEG microstates in Parkinson’s disease: a potential biomarker?

The spontaneous activity of the brain is dynamic even at rest and the deviation from this normal pattern of dynamics can lead to different pathological states. EEG microstate analysis of resting-state neuronal activity in Parkinson’s disease (PD) could provide insight into altered brain dynamics of patients exhibiting dementia. Resting-state EEG microstate maps were derived from 128 channel EEG data in 20 PD without dementia (PDND), 18 PD with dementia (PDD) and 20 Healthy controls (CON) using Cartool and sLORETA softwares. Microstate map parameters including global explained variance, mean duration, frequency of occurrence (TF) and time coverage were compared statistically among the groups. Eight maps that explained 72% of the topographic variance were identified and only three maps differed significantly across the groups. TF of Map1 was lower in both PDND and PDD (p < 0.001) and that of Map3 (p = 0.02) in PDND compared to control. Cortical sources showed higher activation in precuneus, cuneus and superior parietal lobe (Threshold: Log-F = 1.74, p < 0.05) with maximum activity in the precuneus region (MNI co-ordinates: − 25, − 75, − 40; Log-F = 1.9) in PDND compared to control only for Map1. Lower TF of Map1 (prototypical microstate D) may potentially serve as a biomarker for PD with or without dementia whereas higher activation of precuneus, cuneus and superior parietal lobe at resting-state could favour signal processing, lack of which could be associated with dementia in Parkinson’s disorder.     

Enhanced Functional Connectivity between Putamen and Supplementary Motor Area in Parkinson’s Disease Patients

Parkinson’s disease (PD) is a surprisingly heterogeneous disorder with symptoms including resting tremor, bradykinesia and rigidity. PD has been associated with abnormal task related brain activation in sensory and motor regions as well as reward related network. Although corticostriatal skeletomotor circuit dysfunction is implicated in the neurobiology of Parkinson’s disease, the functional connectivity within this circuit at the resting state is still unclear for PD. Here we utilized resting state functional magnetic resonance imaging to measure the functional connectivity of striatum and motor cortex in 19 patients with PD and 20 healthy controls. We found that the putamen, but not the caudate, exhibited enhanced connectivity with supplementary motor area (SMA), using either the putamen or the SMA as the “seed region”. Enhanced SMA-amygdala functional connectivity was also found in the PD group, compared with normal controls. Our findings highlight the key role of hyper-connected putamen-SMC circuit in the pathophysiology of PD.     

Reliability of Resting-State Microstate Features in Electroencephalography

Background

Electroencephalographic (EEG) microstate analysis is a method of identifying quasi-stable functional brain states (“microstates”) that are altered in a number of neuropsychiatric disorders, suggesting their potential use as biomarkers of neurophysiological health and disease. However, use of EEG microstates as neurophysiological biomarkers requires assessment of the test-retest reliability of microstate analysis.

Methods

We analyzed resting-state, eyes-closed, 30-channel EEG from 10 healthy subjects over 3 sessions spaced approximately 48 hours apart. We identified four microstate classes and calculated the average duration, frequency, and coverage fraction of these microstates. Using Cronbach''s α and the standard error of measurement (SEM) as indicators of reliability, we examined: (1) the test-retest reliability of microstate features using a variety of different approaches; (2) the consistency between TAAHC and k-means clustering algorithms; and (3) whether microstate analysis can be reliably conducted with 19 and 8 electrodes.

Results

The approach of identifying a single set of “global” microstate maps showed the highest reliability (mean Cronbach''s α>0.8, SEM ≈10% of mean values) compared to microstates derived by each session or each recording. There was notably low reliability in features calculated from maps extracted individually for each recording, suggesting that the analysis is most reliable when maps are held constant. Features were highly consistent across clustering methods (Cronbach''s α>0.9). All features had high test-retest reliability with 19 and 8 electrodes.

Conclusions

High test-retest reliability and cross-method consistency of microstate features suggests their potential as biomarkers for assessment of the brain''s neurophysiological health.     

Complexity of resting-state EEG activity in the patients with early-stage Parkinson’s disease

To investigate the abnormal brain activities in the early stage of Parkinson’s disease (PD), the electroencephalogram (EEG) signals were recorded with 20 channels from non-dementia PD patients (18 patients, 8 females) and age matched healthy controls (18 subjects, 8 females) during the resting state. Two methods based on the ordinal patterns of the recorded series, i.e., permutation entropy (PE) and order index (OI), were introduced to characterize the complexity of the cortical activities for two groups. It was observed that the resting-state EEG of PD patients showed lower PE and higher OI than healthy controls, which indicated that the early-stage PD caused the reduced complexity of EEG. We further applied two methods to determine the complexity of EEG rhythms in five sub-bands. The results showed that the gamma, beta and alpha rhythms of PD patients were characterized by lower PE and higher OI, i.e., reduced complexity, than healthy subjects. No significant differences were observed in theta or delta rhythms between two groups. The findings suggested that PE and OI were promising methods to detect the abnormal changes in the dynamics of EEG signals associated with early-stage PD. Further, such changes in EEG complexity may be the early markers of the cortical or subcortical dysfunction caused by PD.     

Single molecule force spectroscopy reveals a weakly populated microstate of the FnIII domains of tenascin

The native states of proteins exist as an ensemble of conformationally similar microstates. The fluctuations among different microstates are of great importance for the functions and structural stability of proteins. Here, we demonstrate that single molecule atomic force microscopy (AFM) can be used to directly probe the existence of multiple folded microstates. We used the AFM to repeatedly stretch and relax a recombinant tenascin fragment TNfnALL to allow the fibronectin type III (FnIII) domains to undergo repeated unfolding/refolding cycles. In addition to the native state, we discovered that some FnIII domains can refold from the unfolded state into a previously unrecognized microstate, N* state. This novel state is conformationally similar to the native state, but mechanically less stable. The native state unfolds at approximately 120 pN, while the N* state unfolds at approximately 50 pN. These two distinct populations of microstates constitute the ensemble of the folded states for some FnIII domains. An unfolded FnIII domain can fold into either one of the two microstates via two distinct folding routes. These results reveal the dynamic and heterogeneous picture of the folded ensemble for some FnIII domains of tenascin, which may carry important implications for the mechanical functions of tenascins in vivo.     

Three-dimensional tomography of event-related potentials during response inhibition: evidence for phasic frontal lobe activation

Objectives: Spatial analysis of the evoked brain electrical fields during a cued revealed an extremely robust anteriorization of the positivity of a P300 microstate in the NoGo compared to the Go condition (NoGo-anteriorization in a prevailing study). To allow a neuroanatomical interpretation the NoGo-anteriorization was investigated with a new three-dimensional source tomography method (LORETA) was applied.Methods: The test contains subsets of stimuli requiring the execution (Go) or the inhibition (NoGo) of a cued motor response which can be considered as mutual control conditions for the study of inhibitory brain functions. 21-channel ERPs were obtained from 10 healthy subjects during a cued CPT, And analyzed with LORETA.Results: Topographic analyses revealed significantly different scalp distributions between the Go and the NoGo conditions in both P100 and P300 microstates, indicating that already at an early stage different neural assemblies are activated. LORETA disclosed a significant hyperactivity located in the right frontal lobe during the NoGo condition in the P300 microstate.Conclusions: The results indicate that right frontal sources are responsible for the NoGo-anteriorization of the scalp P300 which is consistent with animal and human lesion studies of inhibitory brain functions. Furthermore, it demonstrates that frontal activation is confined to a brief microstate and time-locked to phasic inhibitory motor control. This adds important functional and chronometric specificity to findings of frontal activation obtained with PET and Near-Infrared-Spectroscopy studies during the cued CPT, and suggests that these metabolic results are not due to general task demands.     

Altered Functional Connectivity and Small-World in Mesial Temporal Lobe Epilepsy

Background

The functional architecture of the human brain has been extensively described in terms of functional connectivity networks, detected from the low–frequency coherent neuronal fluctuations that can be observed in a resting state condition. Little is known, so far, about the changes in functional connectivity and in the topological properties of functional networks, associated with different brain diseases.

Methodology/Principal Findings

In this study, we investigated alterations related to mesial temporal lobe epilepsy (mTLE), using resting state functional magnetic resonance imaging on 18 mTLE patients and 27 healthy controls. Functional connectivity among 90 cortical and subcortical regions was measured by temporal correlation. The related values were analyzed to construct a set of undirected graphs. Compared to controls, mTLE patients showed significantly increased connectivity within the medial temporal lobes, but also significantly decreased connectivity within the frontal and parietal lobes, and between frontal and parietal lobes. Our findings demonstrated that a large number of areas in the default-mode network of mTLE patients showed a significantly decreased number of connections to other regions. Furthermore, we observed altered small-world properties in patients, along with smaller degree of connectivity, increased n-to-1 connectivity, smaller absolute clustering coefficients and shorter absolute path length.

Conclusions/Significance

We suggest that the mTLE alterations observed in functional connectivity and topological properties may be used to define tentative disease markers.     

Alteration of Brain Functional Networks in Early-Stage Parkinson’s Disease: A Resting-State fMRI Study

Although alterations of topological organization have previously been reported in the brain functional network of Parkinson’s disease (PD) patients, the topological properties of the brain network in early-stage PD patients who received antiparkinson treatment are largely unknown. This study sought to determine the topological characteristics of the large-scale functional network in early-stage PD patients. First, 26early-stage PD patients (Hoehn and Yahr stage:1-2) and 30 age-matched normal controls were scanned using resting-state functional MRI. Subsequently, graph theoretical analysis was employed to investigate the abnormal topological configuration of the brain network in early-stage PD patients. We found that both the PD patient and control groups showed small-world properties in their functional brain networks. However, compared with the controls, the early-stage PD patients exhibited abnormal global properties, characterized by lower global efficiency. Moreover, the modular structure and the hub distribution were markedly altered in early-stage PD patients. Furthermore, PD patients exhibited increased nodal centrality, primarily in the bilateral pallidum, the inferior parietal lobule, and the medial superior frontal gyrus, and decreased nodal centrality in the caudate nucleus, the supplementary motor areas, the precentral gyrus, and the middle frontal gyrus. There were significant negative correlations between the Unified Parkinson Disease Rating Scale motor scores and nodal centralities of superior parietal gyrus. These results suggest that the topological organization of the brain functional network was altered in early-stage PD patients who received antiparkinson treatment, and we speculated that the antiparkinson treatment may affect the efficiency of the brain network to effectively relieve clinical symptoms of PD.     

Unstable Prefrontal Response to Emotional Conflict and Activation of Lower Limbic Structures and Brainstem in Remitted Panic Disorder

Background

The neural mechanisms of panic disorder (PD) are only incompletely understood. Higher sensitivity of patients to unspecific fear cues and similarities to conditioned fear suggest involvement of lower limbic and brainstem structures. We investigated if emotion perception is altered in remitted PD as a trait feature.

Methodology/Principal Findings

We used blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to study neural and behavioural responses of 18 remitted PD patients and 18 healthy subjects to the emotional conflict paradigm that is based on the presentation of emotionally congruent and incongruent face/word pairs. We observed that patients showed stronger behavioural interference and lower adaptation to interference conflict. Overall performance in patients was slower but not less accurate. In the context of preceding congruence, stronger dorsal anterior cingulate cortex (dACC) activation during conflict detection was found in patients. In the context of preceding incongruence, controls expanded dACC activity and succeeded in reducing behavioural interference. In contrast, patients demonstrated a dropout of dACC and dorsomedial prefrontal cortex (dmPFC) recruitment but activation of the lower limbic areas (including right amygdala) and brainstem.

Conclusions/Significance

This study provides evidence that stimulus order in the presentation of emotional stimuli has a markedly larger influence on the brain''s response in remitted PD than in controls, leading to abnormal responses of the dACC/dmPFC and lower limbic structures (including the amygdala) and brainstem. Processing of non-panic related emotional stimuli is disturbed in PD patients despite clinical remission.     

Altered Resting State Brain Dynamics in Temporal Lobe Epilepsy Can Be Observed in Spectral Power,Functional Connectivity and Graph Theory Metrics

Despite a wealth of EEG epilepsy data that accumulated for over half a century, our ability to understand brain dynamics associated with epilepsy remains limited. Using EEG data from 15 controls and 9 left temporal lobe epilepsy (LTLE) patients, in this study we characterize how the dynamics of the healthy brain differ from the “dynamically balanced” state of the brain of epilepsy patients treated with anti-epileptic drugs in the context of resting state. We show that such differences can be observed in band power, synchronization and network measures, as well as deviations from the small world network (SWN) architecture of the healthy brain. The θ (4–7 Hz) and high α (10–13 Hz) bands showed the biggest deviations from healthy controls across various measures. In particular, patients demonstrated significantly higher power and synchronization than controls in the θ band, but lower synchronization and power in the high α band. Furthermore, differences between controls and patients in graph theory metrics revealed deviations from a SWN architecture. In the θ band epilepsy patients showed deviations toward an orderly network, while in the high α band they deviated toward a random network. These findings show that, despite the focal nature of LTLE, the epileptic brain differs in its global network characteristics from the healthy brain. To our knowledge, this is the only study to encompass power, connectivity and graph theory metrics to investigate the reorganization of resting state functional networks in LTLE patients.     

Deficits in a tricarboxylic acid cycle enzyme in brains from patients with Parkinson's disease

Parkinson's disease (PD) is associated with mitochondrial dysfunction, specifically a deficiency of complex I of the electron transport chain. Most, although not all, studies indicate that this deficiency is limited to brain regions with neurodegeneration. The current studies tested for deficiencies in other mitochondrial components in PD brain in a neuropathologically unaffected region where the abnormality cannot be attributed to secondary effects of neurodegeneration. The activity of a key (and arguably rate-limiting) tricarboxylic acid cycle enzyme, the alpha-ketoglutarate dehydrogenase complex (KGDHC), was measured in the cerebellum of patients with PD. Activity in 19 PD brains was 50.5% of that in 18 controls matched for age, sex, post-mortem interval, and method of preservation (P<0.0019). The protein subunits of KGDHC were present in normal amounts in PD brains, indicating a relatively discrete abnormality in the enzyme. The activities of another mitochondrial enzyme, glutamate dehydrogenase (GDH), were normal in PD brains. These results demonstrate that specific reductions in KGDHC occur even in pathologically unaffected areas in PD, where the decline is unlikely to be a non-specific result of neurodegeneration. Reductions in the activity of this enzyme, if widespread in the brain, may predispose vulnerable regions to further damage.     

Altered Regional Homogeneity in Pediatric Bipolar Disorder during Manic State: A Resting-State fMRI Study

Pediatric bipolar disorder (PBD) is a severely debilitating illness, which is characterized by episodes of mania and depression separated by periods of remission. Previous fMRI studies investigating PBD were mainly task-related. However, little is known about the abnormalities in PBD, especially during resting state. Resting state brain activity measured by fMRI might help to explore neurobiological biomarkers of the disorder. Methods: Regional homogeneity (ReHo) was examined with resting-state fMRI (RS-fMRI) on 15 patients with PBD in manic state, with 15 age-and sex-matched healthy youth subjects as controls. Results: Compared with the healthy controls, the patients with PBD showed altered ReHo in the cortical and subcortical structures. The ReHo measurement of the PBD group was negatively correlated with the score of Young Mania Rating Scale (YMRS) in the superior frontal gyrus. Positive correlations between the ReHo measurement and the score of YMRS were found in the hippocampus and the anterior cingulate cortex in the PBD group. Conclusions: Altered regional brain activity is present in patients with PBD during manic state. This study presents new evidence for abnormal ventral-affective and dorsal-cognitive circuits in PBD during resting state and may add fresh insights into the pathophysiological mechanisms underlying PBD.     

Altered Spontaneous Brain Activity in Patients with Parkinson’s Disease Accompanied by Depressive Symptoms,as Revealed by Regional Homogeneity and Functional Connectivity in the Prefrontal-Limbic System

As patients with Parkinson’s disease (PD) are at high risk for comorbid depression, it is hypothesized that these two diseases are sharing common pathogenic pathways. Using regional homogeneity (ReHo) and functional connectivity approaches, we characterized human regional brain activity at resting state to examine specific brain networks in patients with PD and those with PD and depression (PDD). This study comprised 41 PD human patients and 25 normal human subjects. The patients completed the Hamilton Depression Rating Scale and were further divided into two groups: patients with depressive symptoms and non-depressed PD patients (nD-PD). Compared with the non-depressed patients, those with depressive symptoms exhibited significantly increased regional activity in the left middle frontal gyrus and right inferior frontal gyrus, and decreased ReHo in the left amygdala and bilateral lingual gyrus. Brain network connectivity analysis revealed decreased functional connectivity within the prefrontal-limbic system and increased functional connectivity in the prefrontal cortex and lingual gyrus in PDD compared with the nD-PD group. In summary, the findings showed regional brain activity alterations and disruption of the mood regulation network in PDD patients. The pathogenesis of PDD may be attributed to abnormal neural activity in multiple brain regions.     

Altered topological properties of functional network connectivity in schizophrenia during resting state: a small-world brain network study

Aberrant topological properties of small-world human brain networks in patients with schizophrenia (SZ) have been documented in previous neuroimaging studies. Aberrant functional network connectivity (FNC, temporal relationships among independent component time courses) has also been found in SZ by a previous resting state functional magnetic resonance imaging (fMRI) study. However, no study has yet determined if topological properties of FNC are also altered in SZ. In this study, small-world network metrics of FNC during the resting state were examined in both healthy controls (HCs) and SZ subjects. FMRI data were obtained from 19 HCs and 19 SZ. Brain images were decomposed into independent components (ICs) by group independent component analysis (ICA). FNC maps were constructed via a partial correlation analysis of ICA time courses. A set of undirected graphs were built by thresholding the FNC maps and the small-world network metrics of these maps were evaluated. Our results demonstrated significantly altered topological properties of FNC in SZ relative to controls. In addition, topological measures of many ICs involving frontal, parietal, occipital and cerebellar areas were altered in SZ relative to controls. Specifically, topological measures of whole network and specific components in SZ were correlated with scores on the negative symptom scale of the Positive and Negative Symptom Scale (PANSS). These findings suggest that aberrant architecture of small-world brain topology in SZ consists of ICA temporally coherent brain networks.     

颞叶癫痫脑“默认模式”的fMRI研究

功能磁共振成像(functional magnetic resonance imaging,fMRI)被用于检测静息时脑功能神经网络.作者运用静息fMRI检测海马硬化颞叶癫痫(temporal lobe epilepsy,TLE)脑"默认模式",采用感兴趣区域功能连接分析检测16例TLE患者和16名正常对照静息时脑的"默认模式",并进行组内和组间分析.研究发现,与正常对照相比,TLE静息时海马、颞极、额叶、颞叶、壳核及楔前叶等脑区与后扣带回的功能连接增强.研究结果表明TLE患者的固有脑功能组织模式有可能出现紊乱.这一研究将有助于从脑功能的角度了解癫痫患者某些临床症状的发病机理,为今后癫痫诊治的发展提供一定的帮助.     

Stress Impact on Resting State Brain Networks

Resting state brain networks (RSNs) are spatially distributed large-scale networks, evidenced by resting state functional magnetic resonance imaging (fMRI) studies. Importantly, RSNs are implicated in several relevant brain functions and present abnormal functional patterns in many neuropsychiatric disorders, for which stress exposure is an established risk factor. Yet, so far, little is known about the effect of stress in the architecture of RSNs, both in resting state conditions or during shift to task performance. Herein we assessed the architecture of the RSNs using functional magnetic resonance imaging (fMRI) in a cohort of participants exposed to prolonged stress (participants that had just finished their long period of preparation for the medical residence selection exam), and respective gender- and age-matched controls (medical students under normal academic activities). Analysis focused on the pattern of activity in resting state conditions and after deactivation. A volumetric estimation of the RSNs was also performed. Data shows that stressed participants displayed greater activation of the default mode (DMN), dorsal attention (DAN), ventral attention (VAN), sensorimotor (SMN), and primary visual (VN) networks than controls. Importantly, stressed participants also evidenced impairments in the deactivation of resting state-networks when compared to controls. These functional changes are paralleled by a constriction of the DMN that is in line with the pattern of brain atrophy observed after stress exposure. These results reveal that stress impacts on activation-deactivation pattern of RSNs, a finding that may underlie stress-induced changes in several dimensions of brain activity.     

Impaired resting-state functional integrations within default mode network of generalized tonic-clonic seizures epilepsy

Generalized tonic-clonic seizures (GTCS) are characterized by unresponsiveness and convulsions, which cause complete loss of consciousness. Many recent studies have found that the ictal alterations in brain activity of the GTCS epilepsy patients are focally involved in some brain regions, including thalamus, upper brainstem, medial prefrontal cortex, posterior midbrain regions, and lateral parietal cortex. Notably, many of these affected brain regions are the same and overlap considerably with the components of the so-called default mode network (DMN). Here, we hypothesize that the brain activity of the DMN of the GTCS epilepsy patients are different from normal controls, even in the resting state. To test this hypothesis, we compared the DMN of the GTCS epilepsy patients and the controls using the resting state functional magnetic resonance imaging. Thirteen brain areas in the DMN were extracted, and a complete undirected weighted graph was used to model the DMN for each participant. When directly comparing the edges of the graph, we found significant decreased functional connectivities within the DMN of the GTCS epilepsy patients comparing to the controls. As for the nodes of the graph, we found that the degree of some brain areas within the DMN was significantly reduced in the GTCS epilepsy patients, including the anterior medial prefrontal cortex, the bilateral superior frontal cortex, and the posterior cingulate cortex. Then we investigated into possible mechanisms of how GTCS epilepsy could cause the reduction of the functional integrations of DMN. We suggested the damaged functional integrations of the DMN in the GTCS epilepsy patients even during the resting state, which could help to understand the neural correlations of the impaired consciousness of GTCS epilepsy patients.     

Investigation of EEG abnormalities in the early stage of Parkinson’s disease

The objective of the present study was to investigate brain activity abnormalities in the early stage of Parkinson’s disease (PD). To achieve this goal, eyes-closed resting state electroencephalography (EEG) signals were recorded from 15 early-stage PD patients and 15 age-matched healthy controls. The AR Burg method and the wavelet packet entropy (WPE) method were used to characterize EEG signals in different frequency bands between the groups, respectively. In the case of the AR Burg method, an increase of relative powers in the δ- and θ-band, and a decrease of relative powers in the α- and β-band were observed for patients compared with controls. For the WPE method, EEG signals from patients showed significant higher entropy over the global frequency domain. Furthermore, WPE in the γ-band of patients was higher than that of controls, while WPE in the δ-, θ-, α- and β-band were all lower. All of these changes in EEG dynamics may represent early signs of cortical dysfunction, which have potential use as biomarkers of PD in the early stage. Our findings may be further used for early intervention and early diagnosis of PD.     

Pondering the mechanism of receptor tyrosine kinase activation: The case for ligand-specific dimer microstate ensembles

Receptor tyrosine kinases (RTKs) are single-pass membrane proteins that regulate cell growth, differentiation, motility, and metabolism. Here, we review recent advancements in RTK structure determination and in the understanding of RTK activation. We argue that further progress in the field will necessitate new ways of thinking, and we introduce the concept that RTK dimers explore ensembles of microstates, each characterized by different kinase domain dimer conformations, but the same extracellular domain dimer structure. Many microstates are phosphorylation-competent and ensure the phosphorylation of one specific tyrosine. The prevalence of each microstate correlates with its stability. A switch in ligand will lead to a switch in the extracellular domain configuration and to a subsequent switch in the ensemble of microstates. This model can explain how different ligands produce specific phosphorylation patterns, how receptor overexpression leads to enhanced signaling even in the absence of activating ligands, and why RTK kinase domain structures have remained unresolved in cryogenic electron microscopy studies.