A new method to build multiplex networks using canonical correlation analysis for the characterization of the Alzheimer's disease continuum.

Objective. The aim of this study was to solve one of the current limitations for the characterization of the brain network in the Alzheimer's disease (AD) continuum. Nowadays, frequency-dependent approaches have reached contradictory results depending on the frequency band under study, tangling the possible clinical interpretations.Approach. To overcome this issue, we proposed a new method to build multiplex networks based on canonical correlation analysis (CCA). Our method determines two basis vectors using the source and electrode-level frequency-specific network parameters for a reference group, and then project the results for the rest of the groups into these hyperplanes to make them comparable. It was applied to: (i) synthetic signals generated with a Kuramoto-based model; and (ii) a resting-state electroencephalography (EEG) database formed by recordings from 51 cognitively healthy controls, 51 mild cognitive impairment subjects, 51 mild AD patients, 50 moderate AD patients, and 50 severe AD patients.Main results. Our results using synthetic signals showed that the interpretation of the proposed CCA-based multiplex parameters (multiplex strength, multiplex characteristic path length and multiplex clustering coefficient) can be analogous to their frequency-specific counterparts, as they displayed similar behaviors in terms of average connectivity, integration, and segregation. Findings using real EEG recordings revealed that dementia due to AD is characterized by a significant increase in average connectivity, and by a loss of integration and segregation.Significance. We can conclude that CCA can be used to build multiplex networks based from frequency-specific results, summarizing all the available information and avoiding the limitations of possible frequency-specific conflicts. Additionally, our method supposes a novel approach for the construction and analysis of multiplex networks during AD continuum.

Genome-Wide Scan for Five Brain Oscillatory Phenotypes Identifies a New QTL Associated with Theta EEG Band.

Brain waves, measured by electroencephalography (EEG), are a powerful tool in the investigation of neurophysiological traits and a noninvasive and cost-effective alternative in the diagnostic of some neurological diseases. In order to identify novel Quantitative Trait Loci (QTLs) for brain wave relative power (RP), we collected resting state EEG data in five frequency bands (δ, θ, α, ß1, and ß2) and genome-wide data in a cohort of 105 patients with late onset Alzheimer's disease (LOAD), 41 individuals with mild cognitive impairment and 45 controls from Iberia, correcting for disease status. One novel association was found with an interesting candidate for a role in brain wave biology, CLEC16A (C-type lectin domain family 16), with a variant at this locus passing the adjusted genome-wide significance threshold after Bonferroni correction. This finding reinforces the importance of immune regulation in brain function. Additionally, at a significance cutoff value of 5 × 10-6, 18 independent association signals were detected. These signals comprise brain expression Quantitative Loci (eQTLs) in caudate basal ganglia, spinal cord, anterior cingulate cortex and hypothalamus, as well as chromatin interactions in adult and fetal cortex, neural progenitor cells and hippocampus. Moreover, in the set of genes showing signals of association with brain wave RP in our dataset, there is an overrepresentation of loci previously associated with neurological traits and pathologies, evidencing the pleiotropy of the genetic variation modulating brain function.

Volume Conduction Effects on Connectivity Metrics: Application of Network Parameters to Characterize Alzheimer's Disease Continuum.

This study had two main objectives: (i) to study the effects of volume conduction on different connectivity metrics (Amplitude Envelope Correlation AEC, Phase Lag Index PLI, and Magnitude Squared Coherence MSCOH), comparing the coupling patterns at electrode- and sensor-level; and (ii) to characterize spontaneous EEG activity during different stages of Alzheimer's disease (AD) continuum by means of three complementary network parameters: node degree (k), characteristic path length (L), and clustering coefficient (C). Our results revealed that PLI and AEC are weakly influenced by volume conduction compared to MSCOH, but they are not immune to it. Furthermore, network parameters obtained from PLI showed that AD continuum is characterized by an increase in L and C in low frequency bands, suggesting lower integration and higher segregation as the disease progresses. These network changes reflect the abnormalities during AD continuum and are mainly due to neuronal alterations, because PLI is slightly affected by volume conduction effects.

Inter-band Bispectral Analysis of EEG Background Activity to Characterize Alzheimer's Disease Continuum.

The aim of this study was to characterize the EEG alterations in inter-band interactions along the Alzheimer's disease (AD) continuum. For this purpose, EEG background activity from 51 healthy control subjects, 51 mild cognitive impairment patients, 50 mild AD patients, 50 moderate AD patients, and 50 severe AD patients was analyzed by means of bispectrum. Three inter-band features were extracted from bispectrum matrices: bispectral relative power (BispRP), cubic bispectral entropy (BispEn), and bispectral median frequency (BispMF). BispRP results showed an increase of delta and theta interactions with other frequency bands and the opposite behavior for alpha, beta-1, and beta-2. Delta and theta interactions, along with the rest of the spectrum, also experimented a decrease of BispEn with disease progression, suggesting these bands interact with a reduced variety of components in advanced stages of dementia. Finally, BispMF showed a consistent reduction along the AD continuum in all bands, which is reflective of an interaction of the global spectrum with lower frequency bands as the disease develops. Our results indicate a progressive decrease in inter-band interactions with the severity of the disease, especially those involving high frequency components. Since inter-band coupling oscillations are related to complex and multi-scaled brain processes, these alterations likely reflect the neurodegeneration associated with the AD continuum.

Computational modeling of the effects of EEG volume conduction on functional connectivity metrics. Application to Alzheimer's disease continuum.

OBJECTIVE: The aim of this study was to evaluate the effect of electroencephalographic (EEG) volume conduction in different measures of functional connectivity and to characterize the EEG coupling alterations at the different stages of dementia due to Alzheimer's disease (AD). APPROACH: Magnitude squared coherence (MSCOH), imaginary part of coherence (iCOH), lagged coherence (lagCOH), amplitude envelope correlation (AEC), synchronization likelihood (SL), phase lag index (PLI), phase locking value (PLV), and corrected imaginary PLV (ciPLV) were applied to: (i) synthetic signals generated with a Kuramoto-based model of several coupled oscillators; and (ii) a resting-state EEG database of real recordings from 51 cognitively healthy controls, 51 mild cognitive impairment (MCI) subjects, 51 mild AD (AD mil ) patients, 50 moderate AD (AD mod ) patients, and 50 severe AD (AD sev ) patients. MAIN RESULTS: Our results using synthetic signals showed that PLI was the least affected parameter by spurious influences in a simulated volume conduction environment. Results using real EEG recordings showed that spontaneous activity of MCI patients is characterized by a significant coupling increase in the [Formula: see text] band. As dementia progresses, this increase in the [Formula: see text] band became more pronounced, and a significant widespread decrease in [Formula: see text] band appeared at the last stage of dementia. SIGNIFICANCE: Our results revealed that the estimation of functional EEG connectivity using PLI could reduce the bias introduced by the spurious influence of volume conduction, and it could increase the insight into the underlying brain dynamics at different stages of the AD continuum.

Characterization of EEG Resting-state Activity in Alzheimer's Disease by Means of Recurrence Plot Analyses.

The main objective of this study was to characterize EEG resting-state activity in 55 Alzheimer's disease (AD) patients and 29 healthy controls by means of TREND, a measure based on recurrence quantification analysis. TREND was computed from 60-second recordings of consecutive EEG activity, divided into non-overlapping windows of length 1, 2, 3, 5, 10, 15, 20 and 60 seconds. This measure was computed in the conventional EEG frequency bands (delta, theta, alpha, beta-1, beta-2 and gamma). The parameters delay (τ) and embedding dimension (m) were first optimized for every window size and frequency band under study. These embedding parameters proved to be frequency-dependent. Furthermore, 10 s epochs were set as the minimum length required to avoid spurious results. Statistically significant differences between both groups were found (p <; 0.05, Mann-Whitney U-test). The groups showed differences in TREND in the theta (4-8 Hz), beta1 (13-19 Hz) and beta-2 (19-30 Hz) frequency bands. Our results using TREND suggest that AD disrupts resting-state neural dynamics. Furthermore, these findings indicate that AD induces a frequency-dependent pattern of alterations in the non-stationarity levels of resting-state neural activity.

Analysis of Volume Conduction Effects on Different Functional Connectivity Metrics: Application to Alzheimer's Disease EEG Signals.

The aim of this study was to evaluate the effect of volume conduction on different connectivity metrics: Amplitude Envelope Correlation (AEC), Phase Lag Index (PLI), and Magnitude Squared Coherence (MSCOH). These measures were applied to: (i) a synthetic model of 64 coupled oscillators; and (ii) a resting-state EEG database of 72 patients with dementia due to Alzheimer's disease (AD) and 37 cognitively healthy controls. Our results revealed that AEC and PLI are weakly influenced by the simulated volume conduction compared to MSCOH, although the three metrics are not immune to this effect. Furthermore, results with real EEG recordings showed that AD patients are characterized by an AEC increase in δ frequency band and widespread connectivity decreases in α and ß1 bands. These coupling changes reflect the abnormalities in spontaneous EEG activity of AD patients and might provide further insights into the underlying brain dynamics associated with this disorder.

Measuring Alterations of Spontaneous EEG Neural Coupling in Alzheimer's Disease and Mild Cognitive Impairment by Means of Cross-Entropy Metrics.

Alzheimer's Disease (AD) represents the most prevalent form of dementia and is considered a major health problem due to its high prevalence and its economic costs. An accurate characterization of the underlying neural dynamics in AD is crucial in order to adopt effective treatments. In this regard, mild cognitive impairment (MCI) is an important clinical entity, since it is a risk-state for developing dementia. In the present study, coupling patterns of 111 resting-state electroencephalography (EEG) recordings were analyzed. Specifically, we computed Cross-Approximate Entropy (Cross-ApEn) and Cross-Sample Entropy (Cross-SampEn) of 37 patients with dementia due to AD, 37 subjects with MCI, and 37 healthy control (HC) subjects. Our results showed that Cross-SampEn outperformed Cross-ApEn, revealing higher number of significant connections among the three groups (Kruskal-Wallis test, FDR-corrected p-values < 0.05). AD patients exhibited statistically significant lower similarity values at θ and ß1 frequency bands compared to HC. MCI is also characterized by a global decrease of similarity in all bands, being only significant at ß1. These differences shows that ß band might play a significant role in the identification of early stages of AD. Our results suggest that Cross-SampEn could increase the insight into brain dynamics at different AD stages. Consequently, it may contribute to develop early AD biomarkers, potentially useful as diagnostic information.

Assessment of EEG Connectivity Patterns in Mild Cognitive Impairment Using Phase Slope Index.

Mild cognitive impairment (MCI) is a pathology characterized by an abnormal cognitive state. MCI patients are considered to be at high risk for developing dementia. The aim of this study is to characterize the changes that MCI causes in the patterns of brain information flow. For this purpose, spontaneous EEG activity from 41 MCI patients and 37 healthy controls was analyzed by means of an effective connectivity measure: the phase slope index (PSl). Our results showed statistically significant decreases in PSI values mainly at delta and alpha frequency bands for MCI patients, compared to the control group. These abnormal patterns may be due to the structural changes in the brain suffered by patients: decreased hippocampal volume, atrophy of the medial temporal lobe, or loss of gray matter volume. This study suggests the usefulness of PSI to provide further insights into the underlying brain dynamics associated with MCI.

Automated Multiclass Classification of Spontaneous EEG Activity in Alzheimer's Disease and Mild Cognitive Impairment.

The discrimination of early Alzheimer's disease (AD) and its prodromal form (i.e., mild cognitive impairment, MCI) from cognitively healthy control (HC) subjects is crucial since the treatment is more effective in the first stages of the dementia. The aim of our study is to evaluate the usefulness of a methodology based on electroencephalography (EEG) to detect AD and MCI. EEG rhythms were recorded from 37 AD patients, 37 MCI subjects and 37 HC subjects. Artifact-free trials were analyzed by means of several spectral and nonlinear features: relative power in the conventional frequency bands, median frequency, individual alpha frequency, spectral entropy, Lempel-Ziv complexity, central tendency measure, sample entropy, fuzzy entropy, and auto-mutual information. Relevance and redundancy analyses were also conducted through the fast correlation-based filter (FCBF) to derive an optimal set of them. The selected features were used to train three different models aimed at classifying the trials: linear discriminant analysis (LDA), quadratic discriminant analysis (QDA) and multi-layer perceptron artificial neural network (MLP). Afterwards, each subject was automatically allocated in a particular group by applying a trial-based majority vote procedure. After feature extraction, the FCBF method selected the optimal set of features: individual alpha frequency, relative power at delta frequency band, and sample entropy. Using the aforementioned set of features, MLP showed the highest diagnostic performance in determining whether a subject is not healthy (sensitivity of 82.35% and positive predictive value of 84.85% for HC vs. all classification task) and whether a subject does not suffer from AD (specificity of 79.41% and negative predictive value of 84.38% for AD vs. all comparison). Our findings suggest that our methodology can help physicians to discriminate AD, MCI and HC.

Alterations of Effective Connectivity Patterns in Mild Cognitive Impairment: An MEG Study.

Neuroimaging techniques have demonstrated over the years their ability to characterize the brain abnormalities associated with different neurodegenerative diseases. Among all these techniques, magnetoencephalography (MEG) stands out by its high temporal resolution and noninvasiveness. The aim of the present study is to explore the coupling patterns of resting-state MEG activity in subjects with mild cognitive impairment (MCI). To achieve this goal, five minutes of spontaneous MEG activity were acquired with a 148-channel whole-head magnetometer from 18 MCI patients and 26 healthy controls. Inter-channel relationships were investigated by means of two complementary coupling measures: coherence and Granger causality. Coherence is a classical method of functional connectivity, while Granger causality quantifies effective (or causal) connectivity. Both measures were calculated in the five conventional frequency bands: delta (δ, 1-4 Hz), theta (θ, 4-8 Hz), alpha (α, 8-13 Hz), beta (ß, 13-30 Hz), and gamma (γ, 30-45 Hz). Our results showed that connectivity values were lower for MCI patients than for controls in all frequency bands. However, only Granger causality revealed statistically significant differences between groups (p-values < 0.05, FDR corrected Mann-Whitney U-test), mainly in the beta band. Our results support the role of MCI as a disconnection syndrome, which elicits early alterations in effective connectivity patterns. These findings can be helpful to identify the neural substrates involved in prodromal stages of dementia.