Analysis of spontaneous MEG activity in mild cognitive impairment and Alzheimer's disease using spectral entropies and statistical complexity measures

Alzheimer's disease (AD) is the most common cause of dementia. Over the last few years, a considerable effort has been devoted to exploring new biomarkers. Nevertheless, a better understanding of brain dynamics is still required to optimize therapeutic strategies. In this regard, the characterization of mild cognitive impairment (MCI) is crucial, due to the high conversion rate from MCI to AD. However, only a few studies have focused on the analysis of magnetoencephalographic (MEG) rhythms to characterize AD and MCI. In this study, we assess the ability of several parameters derived from information theory to describe spontaneous MEG activity from 36 AD patients, 18 MCI subjects and 26 controls. Three entropies (Shannon, Tsallis and Rényi entropies), one disequilibrium measure (based on Euclidean distance ED) and three statistical complexities (based on Lopez Ruiz–Mancini–Calbet complexity LMC) were used to estimate the irregularity and statistical complexity of MEG activity. Statistically significant differences between AD patients and controls were obtained with all parameters (p < 0.01). In addition, statistically significant differences between MCI subjects and controls were achieved by ED and LMC (p < 0.05). In order to assess the diagnostic ability of the parameters, a linear discriminant analysis with a leave-one-out cross-validation procedure was applied. The accuracies reached 83.9% and 65.9% to discriminate AD and MCI subjects from controls, respectively. Our findings suggest that MCI subjects exhibit an intermediate pattern of abnormalities between normal aging and AD. Furthermore, the proposed parameters provide a new description of brain dynamics in AD and MCI

Analysis of Spontaneous EEG Activity in Alzheimer’s Disease Using Cross-Sample Entropy and Graph Theory

Producción CientíficaThe aim of this pilot study was to analyze spontaneous electroencephalography (EEG) activity in Alzheimer’s disease (AD) by means of Cross-Sample Entropy (Cross-SampEn) and two local measures derived from graph theory: clustering coefficient (CC) and characteristic path length (PL). Five minutes of EEG activity were recorded from 37 patients with dementia due to AD and 29 elderly controls. Our results showed that Cross-SampEn values were lower in the AD group than in the control one for all the interactions among EEG channels. This finding indicates that EEG activity in AD is characterized by a lower statistical dissimilarity among channels. Significant differences were found mainly for fronto-central interactions (p < 0.01, permutation test). Additionally, the application of graph theory measures revealed diverse neural network changes, i.e. lower CC and higher PL values in AD group, leading to a less efficient brain organization. This study suggests the usefulness of our approach to provide further insights into the underlying brain dynamics associated with AD.Ministerio de Economía y Competitividad (TEC2014-53196-R)Junta de Castilla y León (proyecto VA037U16 y BIO/VA08/15

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 (8-12Hz) and widespread delta (&lt;4Hz) and theta (4-8Hz) 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

Early diagnosis of Alzheimer's disease: the role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD

Physiological complexity of EEG as a proxy for dementia risk prediction: a review and preliminary cross-section analysis

The aim of this work is to give the readers a review (perspective) of prior work on this kind of complexity-based detection from resting-state EEG and present our preliminary cross-section analysis results on how EEG complexity of supposedly healthy senior persons can serve as an early warning to clinicians. Together with the use of wearables for health, this approach to early detection can be done out of clinical setting improving the chances of increasing the quality of life in seniors.Comment: 19 pages, 1 figure, 1 tabl

Inspection of Short-Time Resting-State Electroencephalogram Functional Networks in Alzheimer's Disease

Functional connectivity has proven useful to characterise electroencephalogram (EEG) activity in Alzheimer’s disease (AD). However, most current functional connectivity analyses have been static, disregarding any potential variability of the connectivity with time. In this pilot study, we compute short-time resting state EEG functional connectivity based on the imaginary part of coherency for 12 AD patients and 11 controls. We derive binary unweighted graphs using the cluster-span threshold, an objective binary threshold. For each short-time binary graph, we calculate its local clustering coefficient (Cloc), degree (K), and efficiency (E). The distribution of these graph metrics for each participant is then characterised with four statistical moments: mean, variance, skewness, and kurtosis. The results show significant differences between groups in the mean of K and E, and the kurtosis of Cloc and K. Although not significant when considered alone, the skewness of Cloc is the most frequently selected feature for the discrimination of subject groups. These results suggest that the variability of EEG functional connectivity may convey useful information about AD

Entropy and Complexity Analyses in Alzheimer’s Disease: An MEG Study

Alzheimer’s disease (AD) is one of the most frequent disorders among elderly population and it is considered the main cause of dementia in western countries. This irreversible brain disorder is characterized by neural loss and the appearance of neurofibrillary tangles and senile plaques. The aim of the present study was the analysis of the magnetoencephalogram (MEG) background activity from AD patients and elderly control subjects. MEG recordings from 36 AD patients and 26 controls were analyzed by means of six entropy and complexity measures: Shannon spectral entropy (SSE), approximate entropy (ApEn), sample entropy (SampEn), Higuchi’s fractal dimension (HFD), Maragos and Sun’s fractal dimension (MSFD), and Lempel-Ziv complexity (LZC). SSE is an irregularity estimator in terms of the flatness of the spectrum, whereas ApEn and SampEn are embbeding entropies that quantify the signal regularity. The complexity measures HFD and MSFD were applied to MEG signals to estimate their fractal dimension. Finally, LZC measures the number of different substrings and the rate of their recurrence along the original time series. Our results show that MEG recordings are less complex and more regular in AD patients than in control subjects. Significant differences between both groups were found in several brain regions using all these methods, with the exception of MSFD (p-value < 0.05, Welch’s t-test with Bonferroni’s correction). Using receiver operating characteristic curves with a leave-one-out cross-validation procedure, the highest accuracy was achieved with SSE: 77.42%. We conclude that entropy and complexity analyses from MEG background activity could be useful to help in AD diagnosis

Measures of resting state EEG rhythms for clinical trials in alzheimer's disease patients : recommendations of an expert panel

Background and Aim: Eyes-closed resting state electroencephalographic (rsEEG) rhythms reflect neurophysiological oscillatory mechanisms of synchronization/desynchronization of activity within neural populations of ascending reticular activating brain systems and thalamus-cortical circuits involved in quite vigilance regulation. Currently, they are not considered as biomarkers of Alzheimer’s disease (AD) in the amyloid, tau and neurodegeneration (ATN) Framework of Alzheimer’s Association and National Institute of Aging (AA-NIA). The Electrophysiology Professional Interest Area (EPIA) of AA and Global Brain Consortium endorsed this article written by a multidisciplinary Expert Panel to provide recommendations on candidate rsEEG measures for AD clinical trials. Method: The Panel revised the field literature and reached consensus about the rsEEG measures consistently associated with clinical phenotypes and neuroimaging markers of AD in previous international multicentric clinical trials. Most consistent findings: AD patients with mild cognitive impairment and dementia displayed reduced peak frequency, power, and paired-electrode “interrelatedness” in posterior alpha (8-12 Hz) rhythms and topographically widespread increases in delta (< 4 Hz) and theta (4-8 Hz) rhythms. Recommendations: (i) Careful multi-center standardization of instructions to patients, rsEEG recordings, and selection of artifact-free rsEEG periods; (ii) extraction of rsEEG power density and paired-electrode “interrelatedness” (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) rsEEG measures computed at delta, theta, and alpha frequency bands by validated open-access software platforms for replicability; (iii) valid use of those measures in stratification of AD patients and monitoring of disease progression and intervention; and iv) international initiatives to cross-validate rsEEG measures (including nonlinear) for disease monitoring and intervention

Novel non-linear approaches to understanding the dynamic brain: knowledge from rsfMRI and EEG studies

Advances in neuroimaging techniques have been critical to identifying new biomarkers for brain diseases. Resting State Functional Magnetic Resonance Imaging (rsfMRI) non-invasively quantifies the Blood Oxygen Level Dependent (BOLD) signal across brain regions with high spatial resolution; whilst temporal resolution of Electroencephalography (EEG) in measuring the brain's electrical response is unsurpassed. Most of the statistical and machine learning methods used to analyze rsfMRI and EEG data, are static and linear, fail to capture the dynamics and complexity of the brain, and are prone to residual noise. The general goals of this thesis dissertation are i) to provide methodological insight by proposing a statistical method namely point process analysis (PPA) and a machine learning (ML) multiband non-linear EEG method. These methods are especially useful to investigate the brain configuration of older participants and individuals with neurodegenerative diseases, and to predict age and sleep quality; and ii) to share biological insights about synchronization between brain regions (i.e., functional connectivity and dynamic functional connectivity) in different stages of mild cognitive impairment and in Alzheimer's disease. The findings, reported and discussed in this thesis, open a path for new research ideas such as applying PPA to EEG data, adjusting the non-linear ML algorithm to apply it to rsfMRI and use these methods to better understand other neurological diseases. Los avances en las técnicas de neuroimagen han sido fundamentales para identificar nuevos biomarcadores de enfermedades cerebrales. La resonancia magnética funcional en estado de reposo (rsfMRI) cuantifica de forma no invasiva la señal dependiente del nivel de oxígeno en sangre (BOLD) en todas las regiones del cerebro con una alta resolución espacial, mientras que la resolución temporal de la electroencefalografía (EEG) para medir la respuesta eléctrica del cerebro es insuperable. La mayoría de los métodos estadísticos y de aprendizaje automático utilizados para analizar datos de rsfMRI y EEG son estáticos y lineales, no captan el dinamismo y la complejidad del cerebro y son propensos al ruido residual. Los objetivos generales de esta tesis doctoral son i) proporcionar una visión metodológica proponiendo un método estadístico, llamado análisis por proceso de puntos (PPA), y un método de aprendizaje automático (ML) multibanda no lineal de EEG. Estos métodos son especialmente útiles para investigar la configuración cerebral de participantes de edad avanzada y de individuos con enfermedades neurodegenerativas, y para predecir la edad y la calidad del sueño; y ii) compartir conocimientos biológicos sobre la sincronización entre regiones cerebrales (es decir, la conectividad funcional y la conectividad funcional dinámica) en diferentes etapas del deterioro cognitivo leve y en la enfermedad de Alzheimer. Los hallazgos, comunicados y discutidos en esta tesis, abren un camino para nuevas ideas de investigación, como la aplicación de PPA a datos de EEG, el ajuste del algoritmo ML no lineal para aplicarlo a rsfMRI y el uso de estos métodos para comprender mejor otras enfermedades neurológicas