Brain health in diverse settings: How age, demographics and cognition shape brain function.

Diversity in brain health is influenced by individual differences in demographics and cognition. However, most studies on brain health and diseases have typically controlled for these factors rather than explored their potential to predict brain signals. Here, we assessed the role of individual differences in demographics (age, sex, and education; n = 1298) and cognition (n = 725) as predictors of different metrics usually used in case-control studies. These included power spectrum and aperiodic (1/f slope, knee, offset) metrics, as well as complexity (fractal dimension estimation, permutation entropy, Wiener entropy, spectral structure variability) and connectivity (graph-theoretic mutual information, conditional mutual information, organizational information) from the source space resting-state EEG activity in a diverse sample from the global south and north populations. Brain-phenotype models were computed using EEG metrics reflecting local activity (power spectrum and aperiodic components) and brain dynamics and interactions (complexity and graph-theoretic measures). Electrophysiological brain dynamics were modulated by individual differences despite the varied methods of data acquisition and assessments across multiple centers, indicating that results were unlikely to be accounted for by methodological discrepancies. Variations in brain signals were mainly influenced by age and cognition, while education and sex exhibited less importance. Power spectrum activity and graph-theoretic measures were the most sensitive in capturing individual differences. Older age, poorer cognition, and being male were associated with reduced alpha power, whereas older age and less education were associated with reduced network integration and segregation. Findings suggest that basic individual differences impact core metrics of brain function that are used in standard case-control studies. Considering individual variability and diversity in global settings would contribute to a more tailored understanding of brain function.

Prognostic implications of tumor-infiltrating T cells in early-stage endometrial cancer.

Patients with endometrial cancer differ in terms of the extent of T-cell infiltration; however, the association between T-cell subpopulations and patient outcomes remains unexplored. We characterized 285 early-stage endometrial carcinoma samples for T-cell infiltrates in a tissue microarray format using multiplex fluorescent immunohistochemistry. The proportion of T cells and their subpopulations were associated with clinicopathological features and relapse-free survival outcomes. CD3+ CD4+ infiltrates were more abundant in the patients with higher grade or non-endometrioid histology. Cytotoxic T cells (CD25+, PD-1+, and PD-L1+) were strongly associated with longer relapse-free survival. Moreover, CD3+ PD-1+ stromal cells were independent of other immune T-cell populations and clinicopathological factors in predicting relapses. Patients with high stromal T-cell fraction of CD3+ PD-1+ cells were associated with a 5-year relapse-free survival rate of 93.7% compared to 79.0% in patients with low CD3+ PD-1+ fraction. Moreover, in patients classically linked to a favorable outcome (such as endometrioid subtype and low-grade tumors), the stromal CD3+ PD-1+ T-cell fraction remained prognostically significant. This study supports that T-cell infiltrates play a significant prognostic role in early-stage endometrial carcinoma. Specifically, CD3+ PD-1+ stromal cells emerge as a promising novel prognostic biomarker.

Hierarchical Complexity of the Macro-Scale Neonatal Brain.

The human adult structural connectome has a rich nodal hierarchy, with highly diverse connectivity patterns aligned to the diverse range of functional specializations in the brain. The emergence of this hierarchical complexity in human development is unknown. Here, we substantiate the hierarchical tiers and hierarchical complexity of brain networks in the newborn period, assess correspondences with hierarchical complexity in adulthood, and investigate the effect of preterm birth, a leading cause of atypical brain development and later neurocognitive impairment, on hierarchical complexity. We report that neonatal and adult structural connectomes are both composed of distinct hierarchical tiers and that hierarchical complexity is greater in term born neonates than in preterms. This is due to diversity of connectivity patterns of regions within the intermediate tiers, which consist of regions that underlie sensorimotor processing and its integration with cognitive information. For neonates and adults, the highest tier (hub regions) is ordered, rather than complex, with more homogeneous connectivity patterns in structural hubs. This suggests that the brain develops first a more rigid structure in hub regions allowing for the development of greater and more diverse functional specialization in lower level regions, while connectivity underpinning this diversity is dysmature in infants born preterm.

A four-dimensional computational model of dynamic contrast-enhanced magnetic resonance imaging measurement of subtle blood-brain barrier leakage.

Dynamic contrast-enhanced MRI (DCE-MRI) is increasingly used to quantify and map the spatial distribution of blood-brain barrier (BBB) leakage in neurodegenerative disease, including cerebral small vessel disease and dementia. However, the subtle nature of leakage and resulting small signal changes make quantification challenging. While simplified one-dimensional simulations have probed the impact of noise, scanner drift, and model assumptions, the impact of spatio-temporal effects such as gross motion, k-space sampling and motion artefacts on parametric leakage maps has been overlooked. Moreover, evidence on which to base the design of imaging protocols is lacking due to practical difficulties and the lack of a reference method. To address these problems, we present an open-source computational model of the DCE-MRI acquisition process for generating four dimensional Digital Reference Objects (DROs), using a high-resolution brain atlas and incorporating realistic patient motion, extra-cerebral signals, noise and k-space sampling. Simulations using the DROs demonstrated a dominant influence of spatio-temporal effects on both the visual appearance of parameter maps and on measured tissue leakage rates. The computational model permits greater understanding of the sensitivity and limitations of subtle BBB leakage measurement and provides a non-invasive means of testing and optimising imaging protocols for future studies.

Eribulin activity in soft tissue sarcoma monolayer and three-dimensional cell line models: could the combination with other drugs improve its antitumoral effect?

BACKGROUND: Eribulin has shown antitumour activity in some soft tissue sarcomas (STSs), but it has only been approved for advanced liposarcoma (LPS). METHODS: In this study, we evaluated the effect of eribulin on proliferation, migration and invasion capabilities in LPS, leiomyosarcoma (LMS) and fibrosarcoma (FS) models, using both monolayer (2D) and three-dimensional (3D) spheroid cell cultures. Additionally, we explored combinations of eribulin with other drugs commonly used in the treatment of STS with the aim of increasing its antitumour activity. RESULTS: Eribulin showed activity inhibiting proliferation, 2D and 3D migration and invasion in most of the cell line models. Furthermore, we provide data that suggest, for the first time, a synergistic effect with ifosfamide in all models, and with pazopanib in LMS as well as in myxoid and pleomorphic LPS. CONCLUSIONS: Our results support the effect of eribulin on LPS, LMS and FS cell line models. The combination of eribulin with ifosfamide or pazopanib has shown in vitro synergy, which warrants further clinical research.

Impact of Visual Design Elements and Principles in Human Electroencephalogram Brain Activity Assessed with Spectral Methods and Convolutional Neural Networks.

The visual design elements and principles (VDEPs) can trigger behavioural changes and emotions in the viewer, but their effects on brain activity are not clearly understood. In this paper, we explore the relationships between brain activity and colour (cold/warm), light (dark/bright), movement (fast/slow), and balance (symmetrical/asymmetrical) VDEPs. We used the public DEAP dataset with the electroencephalogram signals of 32 participants recorded while watching music videos. The characteristic VDEPs for each second of the videos were manually tagged for by a team of two visual communication experts. Results show that variations in the light/value, rhythm/movement, and balance in the music video sequences produce a statistically significant effect over the mean absolute power of the Delta, Theta, Alpha, Beta, and Gamma EEG bands (p < 0.05). Furthermore, we trained a Convolutional Neural Network that successfully predicts the VDEP of a video fragment solely by the EEG signal of the viewer with an accuracy ranging from 0.7447 for Colour VDEP to 0.9685 for Movement VDEP. Our work shows evidence that VDEPs affect brain activity in a variety of distinguishable ways and that a deep learning classifier can infer visual VDEP properties of the videos from EEG activity.

Measures of resting state EEG rhythms for clinical trials in Alzheimer's disease: Recommendations of an expert panel.

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12 Hz) and widespread delta (< 4 Hz) and theta (4-8 Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes.

Assessment of Outliers and Detection of Artifactual Network Segments Using Univariate and Multivariate Dispersion Entropy on Physiological Signals.

Network physiology has emerged as a promising paradigm for the extraction of clinically relevant information from physiological signals by moving from univariate to multivariate analysis, allowing for the inspection of interdependencies between organ systems. However, for its successful implementation, the disruptive effects of artifactual outliers, which are a common occurrence in physiological recordings, have to be studied, quantified, and addressed. Within the scope of this study, we utilize Dispersion Entropy (DisEn) to initially quantify the capacity of outlier samples to disrupt the values of univariate and multivariate features extracted with DisEn from physiological network segments consisting of synchronised, electroencephalogram, nasal respiratory, blood pressure, and electrocardiogram signals. The DisEn algorithm is selected due to its efficient computation and good performance in the detection of changes in signals for both univariate and multivariate time-series. The extracted features are then utilised for the training and testing of a logistic regression classifier in univariate and multivariate configurations in an effort to partially automate the detection of artifactual network segments. Our results indicate that outlier samples cause significant disruption in the values of extracted features with multivariate features displaying a certain level of robustness based on the number of signals formulating the network segments from which they are extracted. Furthermore, the deployed classifiers achieve noteworthy performance, where the percentage of correct network segment classification surpasses 95% in a number of experimental setups, with the effectiveness of each configuration being affected by the signal in which outliers are located. Finally, due to the increase in the number of features extracted within the framework of network physiology and the observed impact of artifactual samples in the accuracy of their values, the implementation of algorithmic steps capable of effective feature selection is highlighted as an important area for future research.

Augmentation of Dispersion Entropy for Handling Missing and Outlier Samples in Physiological Signal Monitoring.

Entropy quantification algorithms are becoming a prominent tool for the physiological monitoring of individuals through the effective measurement of irregularity in biological signals. However, to ensure their effective adaptation in monitoring applications, the performance of these algorithms needs to be robust when analysing time-series containing missing and outlier samples, which are common occurrence in physiological monitoring setups such as wearable devices and intensive care units. This paper focuses on augmenting Dispersion Entropy (DisEn) by introducing novel variations of the algorithm for improved performance in such applications. The original algorithm and its variations are tested under different experimental setups that are replicated across heart rate interval, electroencephalogram, and respiratory impedance time-series. Our results indicate that the algorithmic variations of DisEn achieve considerable improvements in performance while our analysis signifies that, in consensus with previous research, outlier samples can have a major impact in the performance of entropy quantification algorithms. Consequently, the presented variations can aid the implementation of DisEn to physiological monitoring applications through the mitigation of the disruptive effect of missing and outlier samples.

Hierarchical complexity of the adult human structural connectome.

The structural network of the human brain has a rich topology which many have sought to characterise using standard network science measures and concepts. However, this characterisation remains incomplete and the non-obvious features of this topology have largely confounded attempts towards comprehensive constructive modelling. This calls for new perspectives. Hierarchical complexity is an emerging paradigm of complex network topology based on the observation that complex systems are composed of hierarchies within which the roles of hierarchically equivalent nodes display highly variable connectivity patterns. Here we test the hierarchical complexity of the human structural connectomes of a group of seventy-nine healthy adults. Binary connectomes are found to be more hierarchically complex than three benchmark random network models. This provides a new key description of brain structure, revealing a rich diversity of connectivity patterns within hierarchically equivalent nodes. Dividing the connectomes into four tiers based on degree magnitudes indicates that the most complex nodes are neither those with the highest nor lowest degrees but are instead found in the middle tiers. Spatial mapping of the brain regions in each hierarchical tier reveals consistency with the current anatomical, functional and neuropsychological knowledge of the human brain. The most complex tier (Tier 3) involves regions believed to bridge high-order cognitive (Tier 1) and low-order sensorimotor processing (Tier 2). We then show that such diversity of connectivity patterns aligns with the diversity of functional roles played out across the brain, demonstrating that hierarchical complexity can characterise functional diversity strictly from the network topology.

Analysis of EEG networks and their correlation with cognitive impairment in preschool children with epilepsy.

OBJECTIVE: Cognitive impairment (CI) is common in children with epilepsy and can have devastating effects on their quality of life. Early identification of CI is a priority to improve outcomes, but the current gold standard of detection with psychometric assessment is resource intensive and not always available. This paper proposes exploiting network analysis techniques to characterize routine clinical electroencephalography (EEG) to help identify CI in children with early-onset epilepsy (CWEOE) (0-5 years old). METHODS: Functional networks from routinely acquired EEGs of 51 newly diagnosed CWEOE were analyzed. Combinations of connectivity metrics with subnetwork analysis identified significant correlations between network properties and cognition scores via rank correlation analysis (Kendall's τ). Predictive properties were investigated using a cross-validated classification model with healthy cognition, mild/moderate CI, and severe CI classes. RESULTS: Network analysis revealed phase-dependent connectivity having higher sensitivity to CI and significant functional network changes across EEG frequencies. Nearly 70.5% of CWEOE were aptly classified as having healthy cognition, mild/moderate CI, or severe CI using network features. These features predicted CI classes 55% better than chance and halved misclassification penalties. CONCLUSIONS: Cognitive impairment in CWEOE can be detected with sensitivity at 85% (in identifying mild/moderate or severe CI) and specificity of 84%, by network analysis. SIGNIFICANCE: This study outlines a data-driven methodology for identifying candidate biomarkers of CI in CWEOE from network features. Following additional replication, the proposed method and its use of routinely acquired EEG forms an attractive proposition for supporting clinical assessment of CI.

Complexity analysis of spontaneous brain activity in mood disorders: A magnetoencephalography study of bipolar disorder and major depression.

BACKGROUND AND PURPOSE: The lack of a biomarker for Bipolar Disorder (BD) causes problems in the differential diagnosis with other mood disorders such as major depression (MD), and misdiagnosis frequently occurs. Bearing this in mind, we investigated non-linear magnetoencephalography (MEG) patterns in BD and MD. METHODS: Lempel-Ziv Complexity (LZC) was used to evaluate the resting-state MEG activity in a cross-sectional sample of 60 subjects, including 20 patients with MD, 16 patients with BD type-I, and 24 control (CON) subjects. Particular attention was paid to the role of age. The results were aggregated by scalp region. RESULTS: Overall, MD patients showed significantly higher LZC scores than BD patients and CONs. Linear regression analyses demonstrated distinct tendencies of complexity progression as a function of age, with BD patients showing a divergent tendency as compared with MD and CON groups. Logistic regressions confirmed such distinct relationship with age, which allowed the classification of diagnostic groups. CONCLUSIONS: The patterns of neural complexity in BD and MD showed not only quantitative differences in their non-linear MEG characteristics but also divergent trajectories of progression as a function of age. Moreover, neural complexity patterns in BD patients resembled those previously observed in schizophrenia, thus supporting preceding evidence of common neuropathological processes.

Adaptive Windowing Framework for Surface Electromyogram-Based Pattern Recognition System for Transradial Amputees.

Electromyogram (EMG)-based Pattern Recognition (PR) systems for upper-limb prosthesis control provide promising ways to enable an intuitive control of the prostheses with multiple degrees of freedom and fast reaction times. However, the lack of robustness of the PR systems may limit their usability. In this paper, a novel adaptive time windowing framework is proposed to enhance the performance of the PR systems by focusing on their windowing and classification steps. The proposed framework estimates the output probabilities of each class and outputs a movement only if a decision with a probability above a certain threshold is achieved. Otherwise (i.e., all probability values are below the threshold), the window size of the EMG signal increases. We demonstrate our framework utilizing EMG datasets collected from nine transradial amputees who performed nine movement classes with Time Domain Power Spectral Descriptors (TD-PSD), Wavelet and Time Domain (TD) feature extraction (FE) methods and a Linear Discriminant Analysis (LDA) classifier. Nonetheless, the concept can be applied to other types of features and classifiers. In addition, the proposed framework is validated with different movement and EMG channel combinations. The results indicate that the proposed framework works well with different FE methods and movement/channel combinations with classification error rates of approximately 13% with TD-PSD FE. Thus, we expect our proposed framework to be a straightforward, yet important, step towards the improvement of the control methods for upper-limb prostheses.

Coarse-Graining Approaches in Univariate Multiscale Sample and Dispersion Entropy.

The evaluation of complexity in univariate signals has attracted considerable attention in recent years. This is often done using the framework of Multiscale Entropy, which entails two basic steps: coarse-graining to consider multiple temporal scales, and evaluation of irregularity for each of those scales with entropy estimators. Recent developments in the field have proposed modifications to this approach to facilitate the analysis of short-time series. However, the role of the downsampling in the classical coarse-graining process and its relationships with alternative filtering techniques has not been systematically explored yet. Here, we assess the impact of coarse-graining in multiscale entropy estimations based on both Sample Entropy and Dispersion Entropy. We compare the classical moving average approach with low-pass Butterworth filtering, both with and without downsampling, and empirical mode decomposition in Intrinsic Multiscale Entropy, in selected synthetic data and two real physiological datasets. The results show that when the sampling frequency is low or high, downsampling respectively decreases or increases the entropy values. Our results suggest that, when dealing with long signals and relatively low levels of noise, the refine composite method makes little difference in the quality of the entropy estimation at the expense of considerable additional computational cost. It is also found that downsampling within the coarse-graining procedure may not be required to quantify the complexity of signals, especially for short ones. Overall, we expect these results to contribute to the ongoing discussion about the development of stable, fast and robust-to-noise multiscale entropy techniques suited for either short or long recordings.

Amplitude- and Fluctuation-Based Dispersion Entropy.

Dispersion entropy (DispEn) is a recently introduced entropy metric to quantify the uncertainty of time series. It is fast and, so far, it has demonstrated very good performance in the characterisation of time series. It includes a mapping step, but the effect of different mappings has not been studied yet. Here, we investigate the effect of linear and nonlinear mapping approaches in DispEn. We also inspect the sensitivity of different parameters of DispEn to noise. Moreover, we develop fluctuation-based DispEn (FDispEn) as a measure to deal with only the fluctuations of time series. Furthermore, the original and fluctuation-based forbidden dispersion patterns are introduced to discriminate deterministic from stochastic time series. Finally, we compare the performance of DispEn, FDispEn, permutation entropy, sample entropy, and Lempel-Ziv complexity on two physiological datasets. The results show that DispEn is the most consistent technique to distinguish various dynamics of the biomedical signals. Due to their advantages over existing entropy methods, DispEn and FDispEn are expected to be broadly used for the characterization of a wide variety of real-world time series. The MATLAB codes used in this paper are freely available at http://dx.doi.org/10.7488/ds/2326.

Automatic Artifact Removal in EEG of Normal and Demented Individuals Using ICA-WT during Working Memory Tasks.

Characterizing dementia is a global challenge in supporting personalized health care. The electroencephalogram (EEG) is a promising tool to support the diagnosis and evaluation of abnormalities in the human brain. The EEG sensors record the brain activity directly with excellent time resolution. In this study, EEG sensor with 19 electrodes were used to test the background activities of the brains of five vascular dementia (VaD), 15 stroke-related patients with mild cognitive impairment (MCI), and 15 healthy subjects during a working memory (WM) task. The objective of this study is twofold. First, it aims to enhance the recorded EEG signals using a novel technique that combines automatic independent component analysis (AICA) and wavelet transform (WT), that is, the AICA-WT technique; second, it aims to extract and investigate the spectral features that characterize the post-stroke dementia patients compared to the control subjects. The proposed AICA-WT technique is a four-stage approach. In the first stage, the independent components (ICs) were estimated. In the second stage, three-step artifact identification metrics were applied to detect the artifactual components. The components identified as artifacts were marked as critical and denoised through DWT in the third stage. In the fourth stage, the corrected ICs were reconstructed to obtain artifact-free EEG signals. The performance of the proposed AICA-WT technique was compared with those of two other techniques based on AICA and WT denoising methods using cross-correlation X C o r r and peak signal to noise ratio ( P S N R ) (ANOVA, p ˂ 0.05). The AICA-WT technique exhibited the best artifact removal performance. The assumption that there would be a deceleration of EEG dominant frequencies in VaD and MCI patients compared with control subjects was assessed with AICA-WT (ANOVA, p ˂ 0.05). Therefore, this study may provide information on post-stroke dementia particularly VaD and stroke-related MCI patients through spectral analysis of EEG background activities that can help to provide useful diagnostic indexes by using EEG signal processing.

Selection of Mother Wavelet Functions for Multi-Channel EEG Signal Analysis during a Working Memory Task.

We performed a comparative study to select the efficient mother wavelet (MWT) basis functions that optimally represent the signal characteristics of the electrical activity of the human brain during a working memory (WM) task recorded through electro-encephalography (EEG). Nineteen EEG electrodes were placed on the scalp following the 10-20 system. These electrodes were then grouped into five recording regions corresponding to the scalp area of the cerebral cortex. Sixty-second WM task data were recorded from ten control subjects. Forty-five MWT basis functions from orthogonal families were investigated. These functions included Daubechies (db1-db20), Symlets (sym1-sym20), and Coiflets (coif1-coif5). Using ANOVA, we determined the MWT basis functions with the most significant differences in the ability of the five scalp regions to maximize their cross-correlation with the EEG signals. The best results were obtained using "sym9" across the five scalp regions. Therefore, the most compatible MWT with the EEG signals should be selected to achieve wavelet denoising, decomposition, reconstruction, and sub-band feature extraction. This study provides a reference of the selection of efficient MWT basis functions.

Role of EEG as biomarker in the early detection and classification of dementia.

The early detection and classification of dementia are important clinical support tasks for medical practitioners in customizing patient treatment programs to better manage the development and progression of these diseases. Efforts are being made to diagnose these neurodegenerative disorders in the early stages. Indeed, early diagnosis helps patients to obtain the maximum treatment benefit before significant mental decline occurs. The use of electroencephalogram as a tool for the detection of changes in brain activities and clinical diagnosis is becoming increasingly popular for its capabilities in quantifying changes in brain degeneration in dementia. This paper reviews the role of electroencephalogram as a biomarker based on signal processing to detect dementia in early stages and classify its severity. The review starts with a discussion of dementia types and cognitive spectrum followed by the presentation of the effective preprocessing denoising to eliminate possible artifacts. It continues with a description of feature extraction by using linear and nonlinear techniques, and it ends with a brief explanation of vast variety of separation techniques to classify EEG signals. This paper also provides an idea from the most popular studies that may help in diagnosing dementia in early stages and classifying through electroencephalogram signal processing and analysis.

Stratified Multivariate Multiscale Dispersion Entropy for Physiological Signal Analysis.

Multivariate entropy quantification algorithms are becoming a prominent tool for the extraction of information from multi-channel physiological time-series. However, in the analysis of physiological signals from heterogeneous organ systems, certain channels may overshadow the patterns of others, resulting in information loss. Here, we introduce the framework of Stratified Entropy to prioritize each channels' dynamics based on their allocation to respective strata, leading to a richer description of the multi-channel time-series. As an implementation of the framework, three algorithmic variations of the Stratified Multivariate Multiscale Dispersion Entropy are introduced. These variations and the original algorithm are applied to synthetic time-series, waveform physiological time-series, and derivative physiological data. Based on the synthetic time-series experiments, the variations successfully prioritize channels following their strata allocation while maintaining the low computation time of the original algorithm. In experiments on waveform physiological time-series and derivative physiological data, increased discrimination capacity was noted for multiple strata allocations in the variations when benchmarked to the original algorithm. This suggests improved physiological state monitoring by the variations. Furthermore, our variations can be modified to utilize a priori knowledge for the stratification of channels. Thus, our research provides a novel approach for the extraction of previously inaccessible information from multi-channel time series acquired from heterogeneous systems.