High Frequential Resolution Networks: Considerations on a New Functional Brain Connectivity Framework.

Connectivity analyses are widely used to assess the interaction brain networks. This type of analyses is usually conducted considering the well-known classical frequency bands: delta, theta, alpha, beta, and gamma. However, this parcellation of the frequency content can bias the analyses, since it does not consider the between-subject variability or the particular idiosyncrasies of the connectivity patterns that occur within a band. In this study, we addressed these limitations by introducing the High Frequential Resolution Networks (HFRNs). HFRNs were constructed, using a narrow-bandwidth FIR bank filter of 1 Hz bandwidth, for two different connectivity metrics (Amplitude Envelope Correlation, AEC, and Phase Lag index, PLI) and for 3 different databases of MEG and EEG recordings. Results showed a noticeable similarity between the frequential evolution of PLI, AEC, and the Power Spectral Density (PSD) from MEG and EEG signals. Nonetheless, some technical remarks should be considered: (i) results at the gamma band should exclude the frequency range around 50 Hz due to abnormal connectivity patterns, consequence of the previously applied 50 Hz notch-filter; (ii) HFRNs patterns barely vary with the connection distance; and (iii) a low sampling frequency can exert a remarkable influence on HFRNs. To conclude, we proposed a new framework to perform connectivity analyses that allow to further analyze the frequency-based distribution of brain networks.

Characterization of the dynamic behavior of neural activity in Alzheimer's disease: exploring the non-stationarity and recurrence structure of EEG resting-state activity.

OBJECTIVE: Mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD) have been shown to induce perturbations to normal neuronal behavior and disrupt neuronal networks. Recent work suggests that the dynamic properties of resting-state neuronal activity could be affected by MCI and AD-induced neurodegeneration. The aim of the study was to characterize these properties from different perspectives: (i) using the Kullback-Leibler divergence (KLD), a measure of non-stationarity derived from the continuous wavelet transform; and (ii) using the entropy of the recurrence point density ([Formula: see text]) and the median of the recurrence point density ([Formula: see text]), two novel metrics based on recurrence quantification analysis. APPROACH: KLD, [Formula: see text] and [Formula: see text] were computed for 49 patients with dementia due to AD, 66 patients with MCI due to AD and 43 cognitively healthy controls from 60 s electroencephalographic (EEG) recordings with a 10 s sliding window with no overlap. Afterwards, we tested whether the measures reflected alterations to normal neuronal activity induced by MCI and AD. MAIN RESULTS: Our results showed that frequency-dependent alterations to normal dynamic behavior can be found in patients with MCI and AD, both in non-stationarity and recurrence structure. Patients with MCI showed signs of patterns of abnormal state recurrence in the theta (4-8 Hz) and beta (13-30 Hz) frequency bands that became more marked in AD. Moreover, abnormal non-stationarity patterns were found in MCI patients, but not in patients with AD in delta (1-4 Hz), alpha (8-13 Hz), and gamma (30-70 Hz). SIGNIFICANCE: The alterations in normal levels of non-stationarity in patients with MCI suggest an initial increase in cortical activity during the development of AD. This increase could possibly be due to an impairment in neuronal inhibition that is not present during later stages. MCI and AD induce alterations to the recurrence structure of cortical activity, suggesting that normal state switching during rest may be affected by these pathologies.

Encefalopatía inducida por metronidazol: descripción de un caso con hallazgos radiológicos y anatomopatológicos / Metronidazole-induced encephalopathy: description of a case with radiological and anatomopathological Findings

Introducción. El metronidazol es un antibiótico ampliamente conocido y utilizado. En casos excepcionales puede producir como efecto adverso un cuadro de encefalopatía con unas lesiones características en la resonancia magnética, localizadas generalmente en el cerebelo y el esplenio del cuerpo calloso. La incidencia y la patogenia se desconocen. La suspensión del tratamiento habitualmente resuelve los síntomas y normaliza la resonancia magnética en pocas semanas. Debido al habitual buen pronóstico, los hallazgos anatomopatológicos son excepcionales. Se presenta un caso clínico con los hallazgos radiológicos sugestivos de la encefalopatía inducida por metronidazol y, de forma excepcional, se aportan los hallazgos anatomopatológicos. Caso clínico. Mujer de 72 años, con enfermedad de Crohn grave, que meses más tarde de iniciar tratamiento con metronidazol presentó de forma lentamente progresiva bradipsiquia y dificultad para caminar hasta llegar al coma. En la resonancia magnética mostraba características imágenes hiperintensas en T2 en el cuerpo calloso, y los núcleos rojos y dentados. Mejoró al suspender el metronidazol, pero posteriormente desarrolló una sepsis y falleció. En la autopsia se observó reblandecimiento del núcleo rojo y, microscópicamente, necrosis celular y desmielinización. Conclusión. Con la publicación de la información clínica, radiológica y anatomopatológica de este caso se pretende fomentar el conocimiento de esta infrecuente causa tratable de encefalopatía subaguda y aportar datos que ayuden a aclarar su patogenia

Introduction. Metronidazole is a widely known and used antibiotic. In exceptional cases, an encephalopathy with characteristic lesions on magnetic resonance imaging (MRI), usually located in the cerebellum and splenium of the corpus callosum, may be an adverse effect. The incidence and pathogenesis are unknown. The suspension of the treatment usually resolves the symptoms and normalizes the MRI in a few weeks. Due to the usual good prognosis, the anatomopathological findings are exceptional. We present a clinical case with the radiological findings suggestive of metronidazole-induced encephalopathy and, exceptionally, we provide the anatomopathological findings. Case report. A 72 years-old woman with severe Crohn’s disease who, months after starting treatment with metronidazole, presented a slowly progressing bradypsychia and difficulty walking until she came to coma. In MRI it showed hyperintense images in T2 in the corpus callosum, red and dentate nuclei. He improved by stopping metronidazole but later developed sepsis and died. At autopsy, softening of the red nucleus was observed and, microscopically, cell necrosis and demyelination. Conclusion. With the publication of the clinical, radiological and anatomopathological information of our case we intend to promote the knowledge of this infrequent treatable cause of subacute encephalopathy and provide data that help to clarify its pathogenesis

Characterizing the fluctuations of dynamic resting-state electrophysiological functional connectivity: reduced neuronal coupling variability in mild cognitive impairment and dementia due to Alzheimer's disease.

OBJECTIVE: The characterization of brain functional connectivity is a helpful tool in the study of the neuronal substrates and mechanisms that are altered in Azheimer's disease (AD) and mild cognitive impairment (MCI). Recently, there has been a shift towards the characterization of dynamic functional connectivity (dFC), discarding the assumption of connectivity stationarity during the resting-state. The majority of these studies have been performed with functional magnetic resonance imaging recordings, with only a small subset being based on magnetoencephalography/electroencephalography (MEG/EEG). However, only these modalities enable the characterization of potentially fast brain dynamics, which is mandatory for an accurate understanding of the transmission and processing of neuronal information. The aim of this study was to characterize the dFC of resting-state EEG activity in AD and MCI. APPROACH: Three measures: the phase lag index (PLI), leakage-corrected magnitude squared coherence (MSCOH) and leakage-corrected amplitude envelope correlation (AEC) were computed for 45 patients with dementia due to AD, 51 subjects with MCI due to AD and 36 cognitively healthy controls. All measures were estimated in epochs of 60 s using a sliding window approach. An epoch length of 15 s was used to provide reliable results. We tested whether the observed PLI, MSCOH and AEC fluctuations reflected actual variations in functional connectivity, as well as whether between-group differences could be found. MAIN RESULTS: We found dFC using PLI, MSCOH and AEC, with AEC having the highest number of statistically significant connections, followed by MSCOH and PLI. Furthermore, a significant reduction in AEC dFC for patients with AD compared to controls was found in the alpha (8-13 Hz) and beta-1 (13-30 Hz) bands. SIGNIFICANCE: Our results suggest that patients with AD (and MCI subjects to a lesser degree) show less variation in neuronal connectivity during resting-state, supporting the notion that dFC can be found at the EEG time scale and is abnormal in the MCI-AD continuum. Measures of dFC have the potential of being used as biomarkers of AD. Moreover, they could also suggest that AD resting-state networks may operate at a state of low firing activity induced by the observed reduction in coupling strength. Furthermore, the statistically significant correlation between dFC and relative power in the beta-1 band could be related to pathologically high levels of neural activity inducing a loss of dFC. These findings show that the stability of neuronal coupling is affected in AD and MCI.

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.

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.

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.

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.

Bispectral analysis of spontaneous EEG activity from patients with moderate dementia due to Alzheimer's disease.

Dementia due to Alzheimer's disease (AD) is a common disorder with a great impact on the patients' quality of life. The aim of this pilot study was to characterize spontaneous electroencephalography (EEG) activity in dementia due to AD using bispectral analysis. Five minutes of EEG activity were recorded from 17 patients with moderate dementia due to AD and 19 age-matched controls. Bispectrum results revealed that AD patients are characterized by an increase of phase coupling at low frequencies in comparison with controls. Additionally, some bispectral features calculated from the bispectrum showed significant differences between both groups (p <; 0.05, Mann-Whitney U test with Bonferroni's correction). Finally, a stepwise logistic regression analysis with a leave-one-out cross-validation procedure was used for classification purposes. An accuracy of 86.11% (sensitivity = 88.24%; specificity =84.21%) was achieved. This study suggests the usefulness of bispectral analysis to provide further insights into the underlying brain dynamics associated with AD.

Phase-amplitude coupling analysis of spontaneous EEG activity in Alzheimer's disease.

This study was aimed at exploring phase-amplitude coupling (PAC) patterns of neural activity in dementia due to Alzheimer's disease (AD). For this task, five minutes of spontaneous electroencephalographic (EEG) activity from 22 patients with mild AD and 16 cognitively healthy controls were studied. To assess PAC patterns, phase-locking value was computed between the phase of low frequencies and the power of high frequencies within each sensor. Our results showed that high-frequency gamma power is phase-locked to the alpha peak in EEG signals. Furthermore, statistically significant differences (p<;0.05, permutation test) between patients with mild AD and elderly controls were observed at the lower left temporo-parietal area, suggesting that early stages of AD elicit a region-specific decrease of PAC in the neural activity.

Spatio-Temporal Fluctuations of Neural Dynamics in Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: An accurate characterization of neural dynamics in mild cognitive impairment (MCI) is of paramount importance to gain further insights into the underlying neural mechanisms in Alzheimer's disease (AD). Nevertheless, there has been relatively little research on brain dynamics in prodromal AD. As a consequence, its neural substrates remain unclear. METHODS: In the present research, electroencephalographic (EEG) recordings from patients with dementia due to AD, subjects with MCI due to AD and healthy controls (HC) were analyzed using relative power (RP) in conventional EEG frequency bands and a novel parameter useful to explore the spatio-temporal fluctuations of neural dynamics: the spectral flux (SF). RESULTS: Our results suggest that dementia due to AD is associated with a significant slowing of EEG activity and several significant alterations in spectral fluctuations at low (i.e. theta) and high (i.e. beta and gamma) frequency bands compared to HC (p < 0.05). Furthermore, subjects with MCI due to AD exhibited a specific frequency-dependent pattern of spatio-temporal abnormalities, which can help identify neural mechanisms involved in cognitive impairment preceding AD. Classification analyses using linear discriminant analysis with a leave-one-out cross-validation procedure showed that the combination of RP and within-electrode SF at the beta band was useful to obtain a 77.3 % of accuracy to discriminate between HC and AD patients. In the case of comparison between HC and MCI subjects, the classification accuracy reached a value of 79.2 %, combining within-electrode SF at beta and gamma bands. SF has proven to be a useful measure to obtain an original description of brain dynamics at different stages of AD. CONCLUSION: Consequently, SF may contribute to gain a more comprehensive understanding into neural substrates underlying MCI, as well as to develop potential early AD biomarkers.

Analysis of spontaneous EEG activity in Alzheimer's disease using cross-sample entropy and graph theory.

The 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.