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INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage of dementia. Understanding the mechanistic changes from healthy aging to MCI is critical for comprehending disease progression and enabling preventative intervention. METHODS: Patients with MCI and age-matched controls (CN) were administered cognitive tasks during functional near-infrared spectroscopy (fNIRS) recording, and changes in plasma levels of extracellular vesicles (EVs) were assessed using small-particle flow cytometry. RESULTS: Neurovascular coupling (NVC) and functional connectivity (FC) were decreased in MCI compared to CN, prominently in the left-dorsolateral prefrontal cortex (LDLPFC). We observed an increased ratio of cerebrovascular endothelial EVs (CEEVs) to total endothelial EVs in patients with MCI compared to CN, correlating with structural MRI small vessel ischemic damage in MCI. LDLPFC NVC, CEEV ratio, and LDLPFC FC had the highest feature importance in the random Forest group classification. DISCUSSION: NVC, CEEVs, and FC predict MCI diagnosis, indicating their potential as markers for MCI cerebrovascular pathology. HIGHLIGHTS: Neurovascular coupling (NVC) is impaired in mild cognitive impairment (MCI). Functional connectivity (FC) compensation mechanism is lost in MCI. Cerebrovascular endothelial extracellular vesicles (CEEVs) are increased in MCI. CEEV load strongly associates with cerebral small vessel ischemic lesions in MCI. NVC, CEEVs, and FC predict MCI diagnosis over demographic and comorbidity factors.
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Aging affects cognitive functions even in the absence of ongoing pathologies. The neurophysiological basis of age-related cognitive decline (CD), however, is not completely understood. Alterations in both functional brain connectivity and in the fractal scaling of neuronal dynamics have been linked to aging and cognitive performance. Recently, fractal connectivity (FrC) has been proposed - combining the two concepts - for capturing long-term interactions among brain regions. FrC was shown to be influenced by increased mental workload; however, no prior studies investigated how resting-state FrC relates to cognitive performance and plausible CD in healthy aging. We recruited 19 healthy elderly (HE) and 24 young control (YC) participants, who underwent resting-state electroencephalography (EEG) measurements and comprehensive cognitive evaluation using 7 tests of the Cambridge Neurophysiological Test Automated Battery. FrC networks were reconstructed from EEG data using the recently introduced multiple-resampling cross-spectral analysis (MRCSA). Elderly individuals could be characterized with increased response latency and reduced performance in 4-4 tasks, respectively, with both reaction time and accuracy being affected in two tasks. Auto- and cross-spectral exponents - characterizing regional fractal dynamics and FrC, respectively, - were found reduced in HE when compared to YC over most of the cortex. Additionally, fractal scaling of frontoparietal connections expressed an inverse relationship with task performance in visual memory and sustained attention domains in elderly, but not in young individuals. Our results confirm that the fractal nature of brain connectivity - as captured by MRCSA - is affected in healthy aging. Furthermore, FrC appears as a sensitive neurophysiological marker of age-related CD.
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Disfunção Cognitiva , Envelhecimento Saudável , Humanos , Idoso , Fractais , Encéfalo , Cognição/fisiologiaRESUMO
Analysis of brain functional connectivity (FC) could provide insight in how and why cognitive functions decline even in healthy aging (HA). Despite FC being established as fluctuating over time even in the resting state (RS), dynamic functional connectivity (DFC) studies involving healthy elderly individuals and assessing how these patterns relate to cognitive performance are yet scarce. In our recent study we showed that fractal temporal scaling of functional connections in RS is not only reduced in HA, but also predicts increased response latency and reduced task solving accuracy. However, in that work we did not address changes in the dynamics of fractal connectivity (FrC) strength itself and its plausible relationship with mental capabilities. Therefore, here we analyzed RS electroencephalography recordings of the same subject cohort as previously, consisting of 24 young and 19 healthy elderly individuals, who also completed 7 different cognitive tasks after data collection. Dynamic fractal connectivity (dFrC) analysis was carried out via sliding-window detrended cross-correlation analysis (DCCA). A machine learning method based on recursive feature elimination was employed to select the subset of connections most discriminative between the two age groups, identifying 56 connections that allowed for classifying participants with an accuracy surpassing 92%. Mean of DCCA was found generally increased, while temporal variability of FrC decreased in the elderly when compared to the young group. Finally, dFrC indices expressed an elaborate pattern of associations-assessed via Spearman correlation-with cognitive performance scores in both groups, linking fractal connectivity strength and variance to increased response latency and reduced accuracy in the elderly population. Our results provide further support for the relevance of FrC dynamics in understanding age-related cognitive decline and might help to identify potential targets for future intervention strategies.
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Fractais , Envelhecimento Saudável , Humanos , Idoso , Imageamento por Ressonância Magnética/métodos , Encéfalo , Cognição/fisiologiaRESUMO
Riemannian geometry-based classification (RGBC) gained popularity in the field of brain-computer interfaces (BCIs) lately, due to its ability to deal with non-stationarities arising in electroencephalography (EEG) data. Domain adaptation, however, is most often performed on sample covariance matrices (SCMs) obtained from EEG data, and thus might not fully account for components affecting covariance estimation itself, such as regional trends. Detrended cross-correlation analysis (DCCA) can be utilized to estimate the covariance structure of such signals, yet it is computationally expensive in its original form. A recently proposed online implementation of DCCA, however, allows for its fast computation and thus makes it possible to employ DCCA in real-time applications. In this study we propose to replace the SCM with the DCCA matrix as input to RGBC and assess its effect on offline and online BCI performance. First we evaluated the proposed decoding pipeline offline on previously recorded EEG data from 18 individuals performing left and right hand motor imagery (MI), and benchmarked it against vanilla RGBC and popular MI-detection approaches. Subsequently, we recruited eight participants (with previous BCI experience) who operated an MI-based BCI (MI-BCI) online using the DCCA-enhanced Riemannian decoder. Finally, we tested the proposed method on a public, multi-class MI-BCI dataset. During offline evaluations the DCCA-based decoder consistently and significantly outperformed the other approaches. Online evaluation confirmed that the DCCA matrix could be computed in real-time even for 22-channel EEG, as well as subjects could control the MI-BCI with high command delivery (normalized Cohen's κ: 0.7409 ± 0.1515) and sample-wise MI detection (normalized Cohen's κ: 0.5200 ± 0.1610). Post-hoc analysis indicated characteristic connectivity patterns under both MI conditions, with stronger connectivity in the hemisphere contralateral to the MI task. Additionally, fractal scaling exponent of neural activity was found increased in the contralateral compared to the ipsilateral motor cortices (C4 and C3 for left and right MI, respectively) in both classes. Combining DCCA with Riemannian geometry-based decoding yields a robust and effective decoder, that not only improves upon the SCM-based approach but can also provide relevant information on the neurophysiological processes behind MI.
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Assessing power-law cross-correlations between a pair - or among a set - of processes is of great significance in diverse fields of analyses ranging from neuroscience to financial markets. In most cases such analyses are computationally expensive and thus carried out offline once the entire signal is obtained. However, many applications - such as mental state monitoring or financial forecasting - call for fast algorithms capable of estimating scale-free coupling in real time. Detrended cross-correlation analysis (DCCA), a generalization of the detrended fluctuation analysis (DFA) to the bivariate domain, has been introduced as a method designed to quantify power-law cross-correlations between a pair of non-stationary signals. Later, in analogy with the Pearson cross-correlation coefficient, DCCA was adapted to the detrended cross-correlation coefficient (DCCC), however as of now no online algorithms were provided for either of these analysis techniques. Here we introduce a new formula for obtaining the scaling functions in real time for DCCA. Moreover, the formula can be generalized via matrix notation to obtain the scaling relationship between not only a pair of signals, but also all possible pairs among a set of signals at the same time. This includes parallel estimation of the DFA scaling function of each individual process as well, thus allowing also for real-time acquisition of DCCC. The proposed algorithm matches its offline variants in precision, while being substantially more efficient in terms of execution time. We demonstrate that the method can be utilized for mental state monitoring on multi-channel electroencephalographic recordings obtained in eyes-closed and eyes-open resting conditions.
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Investigating scale-free (i.e., fractal) functional connectivity in the brain has recently attracted increasing attention. Although numerous methods have been developed to assess the fractal nature of functional coupling, these typically ignore that neurophysiological signals are assemblies of broadband, arrhythmic activities as well as oscillatory activities at characteristic frequencies such as the alpha waves. While contribution of such rhythmic components may bias estimates of fractal connectivity, they are also likely to represent neural activity and coupling emerging from distinct mechanisms. Irregular-resampling auto-spectral analysis (IRASA) was recently introduced as a tool to separate fractal and oscillatory components in the power spectrum of neurophysiological signals by statistically summarizing the power spectra obtained when resampling the original signal by several non-integer factors. Here we introduce multiple-resampling cross-spectral analysis (MRCSA) as an extension of IRASA from the univariate to the bivariate case, namely, to separate the fractal component of the cross-spectrum between two simultaneously recorded neural signals by applying the same principle. MRCSA does not only provide a theoretically unbiased estimate of the fractal cross-spectrum (and thus its spectral exponent) but also allows for computing the proportion of scale-free coupling between brain regions. As a demonstration, we apply MRCSA to human electroencephalographic recordings obtained in a word generation paradigm. We show that the cross-spectral exponent as well as the proportion of fractal coupling increases almost uniformly over the cortex during the rest-task transition, likely reflecting neural desynchronization. Our results indicate that MRCSA can be a valuable tool for scale-free connectivity studies in characterizing various cognitive states, while it also can be generalized to other applications outside the field of neuroscience.
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Dopaminergic treatment (DT), the standard therapy for Parkinson's disease (PD), alters the dynamics of functional brain networks at specific time scales. Here, we explore the scale-free functional connectivity (FC) in the PD population and how it is affected by DT. We analyzed the electroencephalogram of: (i) 15 PD patients during DT (ON) and after DT washout (OFF) and (ii) 16 healthy control individuals (HC). We estimated FC using bivariate focus-based multifractal analysis, which evaluated the long-term memory (H(2)) and multifractal strength (ΔH15) of the connections. Subsequent analysis yielded network metrics (node degree, clustering coefficient and path length) based on FC estimated by H(2) or ΔH15. Cognitive performance was assessed by the Mini Mental State Examination (MMSE) and the North American Adult Reading Test (NAART). The node degrees of the ΔH15 networks were significantly higher in ON, compared to OFF and HC, while clustering coefficient and path length significantly decreased. No alterations were observed in the H(2) networks. Significant positive correlations were also found between the metrics of H(2) networks and NAART scores in the HC group. These results demonstrate that DT alters the multifractal coupled dynamics in the brain, warranting the investigation of scale-free FC in clinical and pharmacological studies.
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INTRODUCTION: Investigating how the brain adapts to increased mental workload through large-scale functional reorganization appears as an important research question. Functional connectivity (FC) aims at capturing how disparate regions of the brain dynamically interact, while graph theory provides tools for the topological characterization of the reconstructed functional networks. Although numerous studies investigated how FC is altered in response to increased working memory (WM) demand, current results are still contradictory as few studies confirmed the robustness of these findings in a low-density setting. METHODS: In this study, we utilized the n-back WM paradigm, in which subjects were presented stimuli (single digits) sequentially, and their task was to decide for each given stimulus if it matched the one presented n-times earlier. Electroencephalography recordings were performed under a control (0-back) and two task conditions of varying difficulty (2- and 3-back). We captured the characteristic connectivity patterns for each difficulty level by performing FC analysis and described the reconstructed functional networks with various graph theoretical measures. RESULTS: We found a substantial decrease in FC when transitioning from the 0- to the 2- or 3-back conditions, however, no differences relating to task difficulty were identified. The observed changes in brain network topology could be attributed to the dissociation of two (frontal and occipitotemporal) functional modules that were only present during the control condition. Furthermore, behavioral and performance measures showed both positive and negative correlations to connectivity indices, although only in the higher frequency bands. CONCLUSION: The marked decrease in FC may be due to temporarily abandoned connections that are redundant or irrelevant in solving the specific task. Our results indicate that FC analysis is a robust tool for investigating the response of the brain to increased cognitive workload.
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Mapeamento Encefálico , Memória de Curto Prazo , Encéfalo , Eletroencefalografia , Humanos , Imageamento por Ressonância Magnética , Rede NervosaRESUMO
The human brain consists of anatomically distant neuronal assemblies that are interconnected via a myriad of synapses. This anatomical network provides the neurophysiological wiring framework for functional connectivity (FC), which is essential for higher-order brain functions. While several studies have explored the scale-specific FC, the scale-free (i.e., multifractal) aspect of brain connectivity remains largely neglected. Here we examined the brain reorganization during a visual pattern recognition paradigm, using bivariate focus-based multifractal (BFMF) analysis. For this study, 58 young, healthy volunteers were recruited. Before the task, 3-3 min of resting EEG was recorded in eyes-closed (EC) and eyes-open (EO) states, respectively. The subsequent part of the measurement protocol consisted of 30 visual pattern recognition trials of 3 difficulty levels graded as Easy, Medium, and Hard. Multifractal FC was estimated with BFMF analysis of preprocessed EEG signals yielding two generalized Hurst exponent-based multifractal connectivity endpoint parameters, H(2) and ΔH 15; with the former indicating the long-term cross-correlation between two brain regions, while the latter captures the degree of multifractality of their functional coupling. Accordingly, H(2) and ΔH 15 networks were constructed for every participant and state, and they were characterized by their weighted local and global node degrees. Then, we investigated the between- and within-state variability of multifractal FC, as well as the relationship between global node degree and task performance captured in average success rate and reaction time. Multifractal FC increased when visual pattern recognition was administered with no differences regarding difficulty level. The observed regional heterogeneity was greater for ΔH 15 networks compared to H(2) networks. These results show that reorganization of scale-free coupled dynamics takes place during visual pattern recognition independent of difficulty level. Additionally, the observed regional variability illustrates that multifractal FC is region-specific both during rest and task. Our findings indicate that investigating multifractal FC under various conditions - such as mental workload in healthy and potentially in diseased populations - is a promising direction for future research.
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INTRODUCTION: Alterations in narrow-band spectral power of electroencephalography (EEG) recordings are commonly reported in patients with schizophrenia (SZ). It is well established however that electrophysiological signals comprise a broadband scale-free (or fractal) component generated by mechanisms different from those producing oscillatory neural activity. Despite this known feature, it has not yet been investigated if spectral abnormalities found in SZ could be attributed to scale-free or oscillatory brain function. METHODS: In this study, we analyzed resting-state EEG recordings of 14 SZ patients and 14 healthy controls. Scale-free and oscillatory components of the power spectral density (PSD) were separated, and band-limited power (BLP) of the original (mixed) PSD, as well as its fractal and oscillatory components, was estimated in five frequency bands. The scaling property of the fractal component was characterized by its spectral exponent in two distinct frequency ranges (1-13 and 13-30 Hz). RESULTS: Analysis of the mixed PSD revealed a decrease of BLP in the delta band in SZ over the central regions; however, this difference could be attributed almost exclusively to a shift of power toward higher frequencies in the fractal component. Broadband neural activity expressed a true bimodal nature in all except frontal regions. Furthermore, both low- and high-range spectral exponents exhibited a characteristic topology over the cortex in both groups. CONCLUSION: Our results imply strong functional significance of scale-free neural activity in SZ and suggest that abnormalities in PSD may emerge from alterations of the fractal and not only the oscillatory components of neural activity.