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.     

Cross-frequency and iso-frequency estimation of functional corticomuscular coupling after stroke

Functional corticomuscular coupling (FCMC) between the brain and muscles has been used for motor function assessment after stroke. Two types, iso-frequency coupling (IFC) and cross-frequency coupling (CFC), are existed in sensory-motor system for healthy people. However, in stroke, only a few studies focused on IFC between electroencephalogram (EEG) and electromyogram (EMG) signals, and no CFC studies have been found. Considering the intrinsic complexity and rhythmicity of the biological system, we first used the wavelet package transformation (WPT) to decompose the EEG and EMG signals into several subsignals with different frequency bands, and then applied transfer entropy (TE) to analyze the IFC and CFC relationship between each pair-wise subsignal. In this study, eight stroke patients and eight healthy people were enrolled. Results showed that both IFC and CFC still existed in stroke patients (EEG → EMG: 1:1, 3:2, 2:1; EMG → EEG: 1:1, 2:1, 2:3, 3:1). Compared with the stroke-unaffected side and healthy controls, the stroke-affected side yielded lower alpha, beta and gamma synchronization (IFC: beta; CFC: alpha, beta and gamma). Further analysis indicated that stroke patients yielded no significant difference of the FCMC between EEG → EMG and EMG → EEG directions. Our study indicated that alpha and beta bands were essential to concentrating and maintaining the motor capacities, and provided a new insight in understanding the propagation and function in the sensory-motor system.     

Task-Related Changes in Functional Properties of the Human Brain Network Underlying Attentional Control

Previous studies have demonstrated task-related changes in brain activation and inter-regional connectivity but the temporal dynamics of functional properties of the brain during task execution is still unclear. In the present study, we investigated task-related changes in functional properties of the human brain network by applying graph-theoretical analysis to magnetoencephalography (MEG). Subjects performed a cue-target attention task in which a visual cue informed them of the direction of focus for incoming auditory or tactile target stimuli, but not the sensory modality. We analyzed the MEG signal in the cue-target interval to examine network properties during attentional control. Cluster-based non-parametric permutation tests with the Monte-Carlo method showed that in the cue-target interval, beta activity was desynchronized in the sensori-motor region including premotor and posterior parietal regions in the hemisphere contralateral to the attended side. Graph-theoretical analysis revealed that, in beta frequency, global hubs were found around the sensori-motor and prefrontal regions, and functional segregation over the entire network was decreased during attentional control compared to the baseline. Thus, network measures revealed task-related temporal changes in functional properties of the human brain network, leading to the understanding of how the brain dynamically responds to task execution as a network.     

Hypofunction of directed brain network within alpha frequency band in depressive patients: a graph-theoretic analysis

Directed brain networks may provide new insights into exploring physiological mechanism and neuromarkers for depression. This study aims to investigate the abnormalities of directed brain networks in depressive patients. We constructed the directed brain network based on resting electroencephalogram for 19 depressive patients and 20 healthy controls with eyes closed and eyes open. The weighted directed brain connectivity was measured by partial directed coherence for α, β, γ frequency band. Furthermore, topological parameters (clustering coefficient, characteristic path length, and et al.) were computed based on graph theory. The correlation between network metrics and clinical symptom was also examined. Depressive patients had a significantly weaker value of partial directed coherence at alpha frequency band in eyes-closed state. Clustering coefficient and characteristic path length were significantly lower in depressive patients (both p < .01). More importantly, in depressive patients, disruption of directed connectivity was noted in left-to-left (p < .05), right-to-left (p < .01) hemispheres and frontal-to-central (p < .01), parietal-to-central (p < .05), occipital-to-central (p < .05) regions. Furthermore, connectivity in LL and RL hemispheres was negatively correlated with depression scale scores (both p < .05). Depressive patients showed a more randomized network structure, disturbed directed interaction of left-to-left, right-to-left hemispheric information and between different cerebral regions. Specifically, left-to-left, right-to-left hemispheric connectivity was negatively correlated with the severity of depression. Our analysis may serve as a potential neuromarker of depression.     

Multivariate EEG spectral analysis evidences the functional link between motor and visual cortex during integrative sensorimotor tasks

The identification of the networks connecting brain areas and the understanding of their role in executing complex tasks is a crucial issue in cognitive neuroscience. In this study, specific visuomotor tasks were devised to reveal the functional network underlying the cooperation process between visual and motor regions. Electroencephalography (EEG) data were recorded from twelve healthy subjects during a combined visuomotor task, which integrated precise grip motor commands with sensory visual feedback (VM). This condition was compared with control tasks involving pure motor action (M), pure visual perception (V) and visuomotor performance without feedback (V + M). Multivariate parametric cross-spectral analysis was applied to ten EEG derivations in each subject to assess changes in the oscillatory activity of the involved cortical regions and quantify their coupling. Spectral decomposition was applied to precisely and objectively determine the power associated with each oscillatory component of the spectrum, while surrogate data analysis was performed to assess the statistical significance of estimated coherence values. A significant decrease of the alpha and/or beta power in EEG spectra with respect to rest values was assumed as indicative of specific cortical area activation during task execution. Indeed alpha band coherence increased in proximity of task-involved areas, while it was suppressed or remained unchanged in other regions, suggesting the activation of a specific network for each task. According to our coherence analysis, a direct link between visual and motor areas was activated during V + M and VM tasks. The effect of visual feedback was evident in the beta band, where the increase of coherence was observed only during the VM task. Multivariate analysis suggested the presence of a functional link between motor and visual cortex subserving sensorimotor integration. Furthermore, network activation was related to the sum of single task (M and V) local effects in the alpha band, and to the presence of visual feedback in the beta band.     

Genome-wide interaction of genotype by erythrocyte n-3 fatty acids contributes to phenotypic variance of diabetes-related traits

Background

Little is known about the interplay between n-3 fatty acids and genetic variants for diabetes-related traits at the genome-wide level. The present study aimed to examine variance contributions of genotype by environment (GxE) interactions for different erythrocyte n-3 fatty acids and genetic variants for diabetes-related traits at the genome-wide level in a non-Hispanic white population living in the U.S.A. (n = 820). A tool for Genome-wide Complex Trait Analysis (GCTA) was used to estimate the genome-wide GxE variance contribution of four diabetes-related traits: HOMA-Insulin Resistance (HOMA-IR), fasting plasma insulin, glucose and adiponectin. A GxE genome-wide association study (GWAS) was conducted to further elucidate the GCTA results. Replication was conducted in the participants of the Boston Puerto Rican Health Study (BPRHS) without diabetes (n = 716).

Results

In GOLDN, docosapentaenoic acid (DPA) contributed the most significant GxE variance to the total phenotypic variance of both HOMA-IR (26.5%, P-nominal = 0.034) and fasting insulin (24.3%, P-nominal = 0.042). The ratio of arachidonic acid to eicosapentaenoic acid + docosahexaenoic acid contributed the most significant GxE variance to the total variance of fasting glucose (27.0%, P-nominal = 0.023). GxE variance of the arachidonic acid/eicosapentaenoic acid ratio showed a marginally significant contribution to the adiponectin variance (16.0%, P-nominal = 0.058). None of the GCTA results were significant after Bonferroni correction (P < 0.001). For each trait, the GxE GWAS identified a far larger number of significant single-nucleotide polymorphisms (P-interaction ≤ 10E-5) for the significant E factor (significant GxE variance contributor) than a control E factor (non-significant GxE variance contributor). In the BPRHS, DPA contributed a marginally significant GxE variance to the phenotypic variance of HOMA-IR (12.9%, P-nominal = 0.068) and fasting insulin (18.0%, P-nominal = 0.033).

Conclusion

Erythrocyte n-3 fatty acids contributed a significant GxE variance to diabetes-related traits at the genome-wide level.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-781) contains supplementary material, which is available to authorized users.     

Revealing a Brain Network Endophenotype in Families with Idiopathic Generalised Epilepsy

Idiopathic generalised epilepsy (IGE) has a genetic basis. The mechanism of seizure expression is not fully known, but is assumed to involve large-scale brain networks. We hypothesised that abnormal brain network properties would be detected using EEG in patients with IGE, and would be manifest as a familial endophenotype in their unaffected first-degree relatives. We studied 117 participants: 35 patients with IGE, 42 unaffected first-degree relatives, and 40 normal controls, using scalp EEG. Graph theory was used to describe brain network topology in five frequency bands for each subject. Frequency bands were chosen based on a published Spectral Factor Analysis study which demonstrated these bands to be optimally robust and independent. Groups were compared, using Bonferroni correction to account for nonindependent measures and multiple groups. Degree distribution variance was greater in patients and relatives than controls in the 6–9 Hz band (p = 0.0005, p = 0.0009 respectively). Mean degree was greater in patients than healthy controls in the 6–9 Hz band (p = 0.0064). Clustering coefficient was higher in patients and relatives than controls in the 6–9 Hz band (p = 0.0025, p = 0.0013). Characteristic path length did not differ between groups. No differences were found between patients and unaffected relatives. These findings suggest brain network topology differs between patients with IGE and normal controls, and that some of these network measures show similar deviations in patients and in unaffected relatives who do not have epilepsy. This suggests brain network topology may be an inherited endophenotype of IGE, present in unaffected relatives who do not have epilepsy, as well as in affected patients. We propose that abnormal brain network topology may be an endophenotype of IGE, though not in itself sufficient to cause epilepsy.     

Simultaneous EEG-fMRI during a Working Memory Task: Modulations in Low and High Frequency Bands

Background

EEG studies of working memory (WM) have demonstrated load dependent frequency band modulations. FMRI studies have localized load modulated activity to the dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), and posterior parietal cortex (PPC). Recently, an EEG-fMRI study found that low frequency band (theta and alpha) activity negatively correlated with the BOLD signal during the retention phase of a WM task. However, the coupling of higher (beta and gamma) frequencies with the BOLD signal during WM is unknown.

Methodology

In 16 healthy adult subjects, we first investigated EEG-BOLD signal correlations for theta (5–7 Hz), alpha1 (8–10), alpha2 (10–12 Hz), beta1 (13–20), beta2 (20–30 Hz), and gamma (30–40 Hz) during the retention period of a WM task with set size 2 and 5. Secondly, we investigated whether load sensitive brain regions are characterised by effects that relate frequency bands to BOLD signals effects.

Principal Findings

We found negative theta-BOLD signal correlations in the MPFC, PPC, and cingulate cortex (ACC and PCC). For alpha1 positive correlations with the BOLD signal were found in ACC, MPFC, and PCC; negative correlations were observed in DLPFC, PPC, and inferior frontal gyrus (IFG). Negative alpha2-BOLD signal correlations were observed in parieto-occipital regions. Beta1-BOLD signal correlations were positive in ACC and negative in precentral and superior temporal gyrus. Beta2 and gamma showed only positive correlations with BOLD, e.g., in DLPFC, MPFC (gamma) and IFG (beta2/gamma). The load analysis revealed that theta and—with one exception—beta and gamma demonstrated exclusively positive load effects, while alpha1 showed only negative effects.

Conclusions

We conclude that the directions of EEG-BOLD signal correlations vary across brain regions and EEG frequency bands. In addition, some brain regions show both load sensitive BOLD and frequency band effects. Our data indicate that lower as well as higher frequency brain oscillations are linked to neurovascular processes during WM.     

Individual Topographic Variability Is Inherent to Cortical Physiology but Task-Related Differences May Be Noise

The observation of highly variable sets of association neocortical areas across individuals, containing the estimated generators of Slow Potentials (SPs) and beta oscillations, lead to the persistence in individual analyses. This brought to notice an unexpected within individual topographic similarity between task conditions, despite our original interest in task-related differences. A recent related work explored the quantification of the similarity in beta topography between largely differing tasks. In this article, we used Independent Component Analysis (ICA) for the decomposition of beta activity from a visual attention task, and compared it with quiet resting, recorded by 128-channel EEG in 62 subjects. We statistically tested whether each ICA component obtained in one condition could be explained by a linear regression model based on the topographic patterns from the other condition, in each individual. Results were coherent with the previous report, showing a high topographic similarity between conditions. From an average of 12 beta component maps obtained for each task, over 80% were satisfactorily explained by the complementary task. Once more, the component maps including those considered unexplained, putatively “task-specific”, had their scalp distribution and estimated cortical sources highly variable across subjects. These findings are discussed along with other studies based on individual data and the present fMRI results, reinforcing the increasingly accepted view that individual variability in sets of active neocortical association areas is not noise, but intrinsic to cortical physiology. Actual ‘noise’, mainly stemming from group “brain averaging” and the emphasis on statistical differences as opposed to similarities, may explain the overall hardship in replication of the vast literature on supposed task-specific forms of activity, and the ever inconclusive status of a universal functional mapping of cortical association areas. A new hypothesis, that individuals may use the same idiosyncratic sets of areas, at least by their fraction of activity in the sub-delta and beta range, in various non-sensory-motor forms of conscious activities, is a corollary of the discussed variability.     

Associations between circulating endostatin levels and vascular organ damage in systemic sclerosis and mixed connective tissue disease: an observational study

IntroductionSystemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are chronic immune-mediated disorders complicated by vascular organ damage. The aim of this study was to examine the serum levels of the markers of neoangiogenesis: endostatin and vascular endothelial growth factor (VEGF), in our unselected cohorts of SSc and MCTD.MethodsSera of SSc patients (N = 298) and MCTD patients (N = 162) from two longitudinal Norwegian cohorts were included. Blood donors were included as controls (N = 100). Circulating VEGF and endostatin were analyzed by enzyme immunoassay.ResultsMean endostatin levels were increased in SSc patients 93.7 (37) ng/ml (P < .001) and MCTD patients 83.2 (25) ng/ml (P < .001) compared to controls 65.1 (12) ng/ml. Median VEGF levels were elevated in SSc patients 209.0 (202) pg/ml compared to MCTD patients 181.3 (175) pg/ml (P = .017) and controls 150.0 (145) pg/ml (P < .001). Multivariable analysis of SSc subsets showed that pulmonary arterial hypertension (coefficient 15.7, 95 % CI: 2.2–29.2, P = .023) and scleroderma renal crisis (coefficient 77.6, 95 % CI: 59.3–100.0, P < .001) were associated with elevated endostatin levels. Multivariable analyses of MCTD subsets showed that digital ulcers were associated with elevated endostatin levels (coefficient 10.5, 95 % CI: 3.2–17.8, P = .005). The risk of death increased by 1.6 per SD endostatin increase (95 % CI: 1.2–2.1, P = .001) in the SSc cohort and by 1.6 per SD endostatin increase (95 % CI: 1.0–2.4, P = .041) in the MCTD cohort after adjustments to known risk factors.ConclusionsEndostatin levels were elevated in patients with SSc and MCTD, particularly SSc patients with pulmonary arterial hypertension and scleroderma renal crisis, and MCTD patients with digital ulcers. Elevated endostatin levels were also associated with increased all-cause mortality during follow-up in both groups of patients. We propose that endostatin might indicate the degree of vascular injury in SSc and MCTD patients.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0756-5) contains supplementary material, which is available to authorized users.     

Cumulative inflammatory burden is independently associated with increased arterial stiffness in patients with psoriatic arthritis: a prospective study

IntroductionThe aim of this study was to examine whether the cumulative inflammatory burden is associated with an increase in arterial stiffness in a prospective cohort of psoriatic arthritis (PsA) patients.MethodsIn total, 72 PsA patients were followed for a median of 6.5 years. Cumulative inflammatory burden was represented by the cumulative averages of repeated measures of erythrocyte sedimentation rate (ca-ESR) and C-reactive protein (ca-CRP). Brachial-ankle pulse wave velocity (PWV) was measured at the last visit. We also included 47 healthy controls for PWV assessment.ResultsPWV was significantly higher in PsA patients compared with healthy controls after adjustment for age, gender and body weight (1466 ± 29 cm/s versus 1323 ± 38 cm/s, P = 0.008). PsA patients were divided into two groups based on whether their PWV value is ≥1450 cm/s (High PWV group, N = 38) or <1450 cm/s (Low PWV group, N = 34). The High PWV group had a significantly higher ca-ESR (29 (19 to 44) versus 18 (10 to 32) mm/1st hour, P = 0.005) and ca-CRP (0.7 (0.3 to 1.4) versus 0.4 (0.2 to 0.7) mg/dl, P = 0.029). Using regression analysis, high ca-ESR (defined as ≥75th percentile: 37 mm/1st hour) was associated with a higher likelihood of being in the High PWV group (odds ratio (OR): 9.455 (1.939 to 46.093), P = 0.005, adjusted for baseline clinical and cardiovascular risk factors; and 9.111 (1.875 to 44.275), P = 0.006, adjusted for last visit parameters).ConclusionsCumulative inflammatory burden, as reflected by ca-ESR, was associated with increased arterial stiffness in PsA patients even after adjustment for cardiovascular risk factors, emphasizing the important role of chronic inflammation in accelerating the development of cardiovascular risks in PsA patients.     

Computer quantification of airway collapse on forced expiration to predict the presence of emphysema

Background

Spirometric parameters are the mainstay for diagnosis of COPD, but cannot distinguish airway obstruction from emphysema. We aimed to develop a computer model that quantifies airway collapse on forced expiratory flow–volume loops. We then explored and validated the relationship of airway collapse with computed tomography (CT) diagnosed emphysema in two large independent cohorts.

Methods

A computer model was developed in 513 Caucasian individuals with ≥15 pack-years who performed spirometry, diffusion capacity and CT scans to quantify emphysema presence. The model computed the two best fitting regression lines on the expiratory phase of the flow-volume loop and calculated the angle between them. The collapse was expressed as an Angle of collapse (AC) which was then correlated with the presence of emphysema. Findings were validated in an independent group of 340 individuals.

Results

AC in emphysema subjects (N = 251) was significantly lower (131° ± 14°) compared to AC in subjects without emphysema (N = 223), (152° ± 10°) (p < 0.0001). Multivariate regression analysis revealed AC as best indicator of visually scored emphysema (R² = 0.505, p < 0.0001) with little significant contribution of K_CO, %predicted and FEV_1, %predicted to the total model (total R² = 0.626, p < 0.0001). Similar associations were obtained when using CT-automated density scores for emphysema assessment. Receiver operating characteristic (ROC) curves pointed to 131° as the best cut-off for emphysema (95.5% positive predictive value, 97% specificity and 51% sensitivity). Validation in a second group confirmed the significant difference in mean AC between emphysema and non-emphysema subjects. When applying the 131° cut-off, a positive predictive value of 95.6%, a specificity of 96% and a sensitivity of 59% were demonstrated.

Conclusions

Airway collapse on forced expiration quantified by a computer model correlates with emphysema. An AC below 131° can be considered as a specific cut-off for predicting the presence of emphysema in heavy smokers.     

Gait mechanics in patients with chronic obstructive pulmonary disease

Background

Chronic obstructive pulmonary disease (COPD) is characterized by the frequent association of disease outside the lung. The objective of this study was to determine the presence of biomechanical gait abnormalities in COPD patients compared to healthy controls while well rested and without rest.

Methods

Patients with COPD (N = 17) and aged-matched, healthy controls (N = 21) walked at their self-selected pace down a 10-meter walkway while biomechanical gait variables were collected. A one-minute rest was given between each of the five collected trials to prevent tiredness (REST condition). Patients with COPD then walked at a self-selected pace on a treadmill until the onset of self-reported breathlessness or leg tiredness. Subjects immediately underwent gait analysis with no rest between each of the five collected trials (NO REST condition). Statistical models with and without covariates age, gender, and smoking history were used.

Results

After adjusting for covariates, COPD patients demonstrated more ankle power absorption in mid-stance (P = 0.006) than controls during both conditions. Both groups during NO REST demonstrated increased gait speed (P = 0.04), stride length (P = 0.03), and peak hip flexion (P = 0.04) with decreased plantarflexion moment (P = 0.04) and increased knee power absorption (P = 0.04) as compared to REST. A significant interaction revealed that peak ankle dorsiflexion moment was maintained from REST to NO REST for COPD but increased for controls (P < 0.01). Stratifying by disease severity did not alter these findings, except that step width decreased in NO REST as compared to REST (P = 0.01). Standardized effect sizes of significant effects varied from 0.5 to 0.98.

Conclusions

Patients with COPD appear to demonstrate biomechanical gait changes at the ankle as compared to healthy controls. This was seen not only in increased peak ankle power absorption during no rest but was also demonstrated by a lack of increase in peak ankle dorsiflexion moment from the REST to the NO REST condition as compared to the healthy controls. Furthermore, a wider step width has been associated with fall risk and this could account for the increased incidence of falls in patients with COPD.     

Bone microarchitecture in ankylosing spondylitis and the association with bone mineral density,fractures, and syndesmophytes

Introduction

Osteoporosis of the axial skeleton is a known complication of ankylosing spondylitis (AS), but bone loss affecting the peripheral skeleton is less studied. This study on volumetric bone mineral density (vBMD) and bone microarchitecture in AS was conducted to compare peripheral vBMD in AS patients with that in healthy controls, to study vBMD in axial compared with peripheral bone, and to explore the relation between vertebral fractures, spinal osteoproliferation, and peripheral bone microarchitecture and density.

Methods

High-resolution peripheral quantitative computed tomography (HRpQCT) of ultradistal radius and tibia and QCT and dual-energy x-ray absorptiometry (DXA) of lumbar spine were performed in 69 male AS patients (NY criteria). Spinal radiographs were assessed for vertebral fractures and syndesmophyte formation (mSASSS). The HRpQCT measurements were compared with the measurements of healthy controls.

Results

The AS patients had lower cortical vBMD in radius (P = 0.004) and lower trabecular vBMD in tibia (P = 0.033), than did the controls. Strong correlations were found between trabecular vBMD in lumbar spine, radius (r_S = 0.762; P < 0.001), and tibia (r_S = 0.712; P < 0.001).When compared with age-matched AS controls, patients with vertebral fractures had lower lumbar cortical vBMD (-22%; P = 0.019), lower cortical cross-sectional area in radius (-28.3%; P = 0.001) and tibia (-24.0%; P = 0.013), and thinner cortical bone in radius (-28.3%; P = 0.001) and tibia (-26.9%; P = 0.016).mSASSS correlated negatively with trabecular vBMD in lumbar spine (r_S = -0.620; P < 0.001), radius (r_S = -0.400; p = 0.001) and tibia (r_S = -0.475; p < 0.001) and also with trabecular thickness in radius (r_S = -0.528; P < 0.001) and tibia (r_S = -0.488; P < 0.001).Adjusted for age, syndesmophytes were significantly associated with decreasing trabecular vBMD, but increasing cortical vBMD in lumbar spine, but not with increasing cortical thickness or density in peripheral bone. Estimated lumbar vBMD by DXA correlated with trabecular vBMD measured by QCT (r_S = 0.636; P < 0.001).

Conclusions

Lumbar osteoporosis, syndesmophytes, and vertebral fractures were associated with both lower vBMD and deteriorated microarchitecture in peripheral bone. The results indicate that trabecular bone loss is general, whereas osteoproliferation is local in AS.     

How Skill Expertise Shapes the Brain Functional Architecture: An fMRI Study of Visuo-Spatial and Motor Processing in Professional Racing-Car and Na?ve Drivers

The present study was designed to investigate the brain functional architecture that subserves visuo-spatial and motor processing in highly skilled individuals. By using functional magnetic resonance imaging (fMRI), we measured brain activity while eleven Formula racing-car drivers and eleven ‘naïve’ volunteers performed a motor reaction and a visuo-spatial task. Tasks were set at a relatively low level of difficulty such to ensure a similar performance in the two groups and thus avoid any potential confounding effects on brain activity due to discrepancies in task execution. The brain functional organization was analyzed in terms of regional brain response, inter-regional interactions and blood oxygen level dependent (BOLD) signal variability. While performance levels were equal in the two groups, as compared to naïve drivers, professional drivers showed a smaller volume recruitment of task-related regions, stronger connections among task-related areas, and an increased information integration as reflected by a higher signal temporal variability. In conclusion, our results demonstrate that, as compared to naïve subjects, the brain functional architecture sustaining visuo-motor processing in professional racing-car drivers, trained to perform at the highest levels under extremely demanding conditions, undergoes both ‘quantitative’ and ‘qualitative’ modifications that are evident even when the brain is engaged in relatively simple, non-demanding tasks. These results provide novel evidence in favor of an increased ‘neural efficiency’ in the brain of highly skilled individuals.     

Global Genetic Variations Predict Brain Response to Faces

Face expressions are a rich source of social signals. Here we estimated the proportion of phenotypic variance in the brain response to facial expressions explained by common genetic variance captured by ∼500,000 single nucleotide polymorphisms. Using genomic-relationship-matrix restricted maximum likelihood (GREML), we related this global genetic variance to that in the brain response to facial expressions, as assessed with functional magnetic resonance imaging (fMRI) in a community-based sample of adolescents (n = 1,620). Brain response to facial expressions was measured in 25 regions constituting a face network, as defined previously. In 9 out of these 25 regions, common genetic variance explained a significant proportion of phenotypic variance (40–50%) in their response to ambiguous facial expressions; this was not the case for angry facial expressions. Across the network, the strength of the genotype-phenotype relationship varied as a function of the inter-individual variability in the number of functional connections possessed by a given region (R² = 0.38, p<0.001). Furthermore, this variability showed an inverted U relationship with both the number of observed connections (R² = 0.48, p<0.001) and the magnitude of brain response (R² = 0.32, p<0.001). Thus, a significant proportion of the brain response to facial expressions is predicted by common genetic variance in a subset of regions constituting the face network. These regions show the highest inter-individual variability in the number of connections with other network nodes, suggesting that the genetic model captures variations across the adolescent brains in co-opting these regions into the face network.     

Characteristics of EEG reactivity changes during the performance of dual tasks in healthy subjects (voluntary postural control and calculation)

Comprehensive EEG and stabilography investigation with separate and simultaneous performance of motor (voluntary postural control) and cognitive (calculation) tasks has been performed in 20 healthy subjects (22 ± 0.7 years). Specific spatial and frequency reactive changes have been found during motor task performance. These included an increase in coherence in the EEG α band for distant derivation pairs in the right hemisphere, as well as in symmetric parietal-occipital areas in both hemispheres. Cognitive task performance was accompanied by an increase in coherence for the slow bands (δ and θ) with a higher activation in the left hemisphere and frontal cortex areas. In performing the dual task, one could observe activation of spatial and frequency changes including both motor and cognitive tasks. In the dual tasks where both components were performed worse as compared to the control, reactive reorganization of EEG coherence was less pronounced than during the performance of separate tasks. A decrease in the coherence of the α₁ band in the frontal areas appeared as a zone of “conflict of interest” or interference. In dual tasks with better performance of each component as compared to the control, EEG coherence increased in each specific area, as well as in the areas of “conflict of interests.”     

A Positively Selected MAGEE2 LoF Allele Is Associated with Sexual Dimorphism in Human Brain Size and Shows Similar Phenotypes in Magee2 Null Mice

A nonsense allele at rs1343879 in human MAGEE2 on chromosome X has previously been reported as a strong candidate for positive selection in East Asia. This premature stop codon causing ∼80% protein truncation is characterized by a striking geographical pattern of high population differentiation: common in Asia and the Americas (up to 84% in the 1000 Genomes Project East Asians) but rare elsewhere. Here, we generated a Magee2 mouse knockout mimicking the human loss-of-function mutation to study its functional consequences. The Magee2 null mice did not exhibit gross abnormalities apart from enlarged brain structures (13% increased total brain area, P = 0.0022) in hemizygous males. The area of the granular retrosplenial cortex responsible for memory, navigation, and spatial information processing was the most severely affected, exhibiting an enlargement of 34% (P = 3.4×10⁻⁶). The brain size in homozygous females showed the opposite trend of reduced brain size, although this did not reach statistical significance. With these insights, we performed human association analyses between brain size measurements and rs1343879 genotypes in 141 Chinese volunteers with brain MRI scans, replicating the sexual dimorphism seen in the knockout mouse model. The derived stop gain allele was significantly associated with a larger volume of gray matter in males (P = 0.00094), and smaller volumes of gray (P = 0.00021) and white (P = 0.0015) matter in females. It is unclear whether or not the observed neuroanatomical phenotypes affect behavior or cognition, but it might have been the driving force underlying the positive selection in humans.     

Decreased expression of the endothelial cell-derived factor EGFL7 in systemic sclerosis: potential contribution to impaired angiogenesis and vasculogenesis

Introduction

Microvascular damage and defective angiogenesis and vasculogenesis have a major role in the pathogenesis of systemic sclerosis (SSc). Epidermal growth factor-like domain 7 (EGFL7) is a proangiogenic molecule which is predominantly expressed and secreted by endothelial cells and their progenitors and controls vascular development and integrity. In this study, we investigated the possible involvement of EGFL7 in SSc.

Methods

Serum EGFL7 levels from 60 patients with SSc and 35 age- and sex-matched healthy controls were examined by colorimetric sandwich enzyme-linked immunosorbent assay. The expression of EGFL7 in forearm skin biopsies (n = 16 SSc, n = 10 controls), cultured dermal microvascular endothelial cells (MVECs) (n = 3 SSc, n = 3 controls) and late-outgrowth peripheral blood endothelial progenitor cell (EPC)-derived endothelial cells (n = 15 SSc, n = 8 controls) was investigated by immunofluorescence and Western blotting.

Results

Serum EGFL7 levels were detectable in 68.6% of healthy controls and 45% of SSc cases (P < 0.05). Circulating levels of EGFL7 were significantly decreased in SSc patients compared with healthy controls (P = 0.01). Serum levels of EGFL7 were significantly lower in both limited cutaneous SSc and diffuse cutaneous SSc patients than in controls (P = 0.02 and P = 0.04, respectively). In SSc, decreased serum EGFL7 levels were significantly correlated with the severity of nailfold capillary abnormalities. Patients with the most severe capillary changes and digital ulcers had serum EGFL7 levels significantly lower than healthy controls, while the EGFL7 levels did not differ significantly between controls and SSc patients with less capillary damage and lack of digital ulcers. Endothelial EGFL7 expression was strongly downregulated or even almost completely undetectable in SSc-affected dermis compared with controls (P < 0.001). In cultured SSc dermal MVECs and late-outgrowth peripheral blood EPC-derived endothelial cells, EGFL7 was significantly downregulated compared with cells obtained from healthy subjects (P < 0.01 and P < 0.001, respectively).

Conclusions

Our findings suggest that the loss of EGFL7 expression in endothelial cells and their progenitors might play a role in the development and progression of peripheral microvascular damage and the defective vascular repair process characteristic of SSc.     

Early Adolescent Cognitive Gains Are Marked by Increased Sleep EEG Coherence

Although the increases in cognitive capacities of adolescent humans are concurrent with significant cortical restructuring, functional associations between these phenomena are unclear. We examined the association between cortical development, as measured by the sleep EEG, and cognitive performance in a sample of 9/10 year olds followed up 1 to 3 years later. Our cognitive measures included a response inhibition task (Stroop), an executive control task (Trail Making), and a verbal fluency task (FAS). We correlated sleep EEG measures of power and intra-hemispheric coherence at the initial assessment with performance at that assessment. In addition we correlated the rate of change across assessments in sleep EEG measures with the rate of change in performance. We found no correlation between sleep EEG power and performance on cognitive tasks for the initial assessment. In contrast, we found a significant correlation of the rate of change in intra-hemispheric coherence for the sigma band (11 to 16 Hz) with rate of change in performance on the Stroop (r = 0.61; p<0.02) and Trail Making (r = −0.51; p<0.02) but no association for the FAS. Thus, plastic changes in connectivity (i.e., sleep EEG coherence) were associated with improvement in complex cognitive function.