Assessment of EEG dynamical complexity in Alzheimer’s disease using multiscale entropy

ObjectiveMultiscale entropy (MSE) is a recently proposed entropy-based index of physiological complexity, evaluating signals at multiple temporal scales. To test this method as an aid to elucidating the pathophysiology of Alzheimer’s disease (AD), we examined MSE in resting state EEG activity in comparison with traditional EEG analysis.MethodsWe recorded EEG in medication-free 15 presenile AD patients and 18 age- and sex-matched healthy control (HC) subjects. MSE was calculated for continuous 60-s epochs for each group, concurrently with power analysis.ResultsThe MSE results from smaller and larger scales were associated with higher and lower frequencies of relative power, respectively. Group analysis demonstrated that the AD group had less complexity at smaller scales in more frontal areas, consistent with previous findings. In contrast, higher complexity at larger scales was observed across brain areas in AD group and this higher complexity was significantly correlated with cognitive decline.ConclusionsMSE measures identified an abnormal complexity profile across different temporal scales and their relation to the severity of AD.SignificanceThese findings indicate that entropy-based analytic methods with applied at temporal scales may serve as a complementary approach for characterizing and understanding abnormal cortical dynamics in AD.     

Multiple time scale complexity analysis of resting state FMRI

The present study explored multi-scale entropy (MSE) analysis to investigate the entropy of resting state fMRI signals across multiple time scales. MSE analysis was developed to distinguish random noise from complex signals since the entropy of the former decreases with longer time scales while the latter signal maintains its entropy due to a “self-resemblance” across time scales. A long resting state BOLD fMRI (rs-fMRI) scan with 1000 data points was performed on five healthy young volunteers to investigate the spatial and temporal characteristics of entropy across multiple time scales. A shorter rs-fMRI scan with 240 data points was performed on a cohort of subjects consisting of healthy young (age 23 ± 2 years, n = 8) and aged volunteers (age 66 ± 3 years, n = 8) to investigate the effect of healthy aging on the entropy of rs-fMRI. The results showed that MSE of gray matter, rather than white matter, resembles closely that of f ^?1 noise over multiple time scales. By filtering out high frequency random fluctuations, MSE analysis is able to reveal enhanced contrast in entropy between gray and white matter, as well as between age groups at longer time scales. Our data support the use of MSE analysis as a validation metric for quantifying the complexity of rs-fMRI signals.     

Changes in EEG multiscale entropy and power‐law frequency scaling during the human sleep cycle

We explored changes in multiscale brain signal complexity and power‐law scaling exponents of electroencephalogram (EEG) frequency spectra across several distinct global states of consciousness induced in the natural physiological context of the human sleep cycle. We specifically aimed to link EEG complexity to a statistically unified representation of the neural power spectrum. Further, by utilizing surrogate‐based tests of nonlinearity we also examined whether any of the sleep stage‐dependent changes in entropy were separable from the linear stochastic effects contained in the power spectrum. Our results indicate that changes of brain signal entropy throughout the sleep cycle are strongly time‐scale dependent. Slow wave sleep was characterized by reduced entropy at short time scales and increased entropy at long time scales. Temporal signal complexity (at short time scales) and the slope of EEG power spectra appear, to a large extent, to capture a common phenomenon of neuronal noise, putatively reflecting cortical balance between excitation and inhibition. Nonlinear dynamical properties of brain signals accounted for a smaller portion of entropy changes, especially in stage 2 sleep.     

Spectral pattern similarity analysis: Tutorial and application in developmental cognitive neuroscience

The human brain encodes information in neural activation patterns. While standard approaches to analyzing neural data focus on brain (de-)activation (e.g., regarding the location, timing, or magnitude of neural responses), multivariate neural pattern similarity analyses target the informational content represented by neural activity. In adults, a number of representational properties have been identified that are linked to cognitive performance, in particular the stability, distinctiveness, and specificity of neural patterns. However, although growing cognitive abilities across childhood suggest advancements in representational quality, developmental studies still rarely utilize information-based pattern similarity approaches, especially in electroencephalography (EEG) research. Here, we provide a comprehensive methodological introduction and step-by-step tutorial for pattern similarity analysis of spectral (frequency-resolved) EEG data including a publicly available pipeline and sample dataset with data from children and adults. We discuss computation of single-subject pattern similarities and their statistical comparison at the within-person to the between-group level as well as the illustration and interpretation of the results. This tutorial targets both novice and more experienced EEG researchers and aims to facilitate the usage of spectral pattern similarity analyses, making these methodologies more readily accessible for (developmental) cognitive neuroscientists.     

Age-related variation in EEG complexity to photic stimulation: A multiscale entropy analysis

ObjectiveThis study was intended to examine variations in electroencephalographic (EEG) complexity in response to photic stimulation (PS) during aging to test the hypothesis that the aging process reduces physiologic complexity and functional responsiveness.MethodsMultiscale entropy (MSE), an estimate of time-series signal complexity associated with long-range temporal correlation, is used as a recently proposed method for quantifying EEG complexity with multiple coarse-grained sequences. We recorded EEG in 13 healthy elderly subjects and 12 healthy young subjects during pre-PS and post-PS conditions and estimated their respective MSE values.ResultsFor the pre-PS condition, no significant complexity difference was found between the groups. However, a significant MSE change (complexity increase) was found post-PS only in young subjects, thereby revealing a power-law scaling property, which means long-range temporal correlation.ConclusionsEnhancement of long-range temporal correlation in young subjects after PS might reflect a cortical response to stimuli, which was absent in elderly subjects. These results are consistent with the general “loss of complexity/diminished functional response to stimuli” theory of aging.SignificanceOur findings demonstrate that application of MSE analysis to EEG is a powerful approach for studying age-related changes in brain function.     

Cortical maturation from childhood to adolescence is reflected in resting state EEG signal complexity

Endogenous cortical fluctuations captured by electroencephalograms (EEGs) reflect activity in large-scale brain networks that exhibit dynamic patterns over multiple time scales. Developmental changes in the coordination and integration of brain function leads to greater complexity in population level neural dynamics. In this study we examined multiscale entropy, a measure of signal complexity, in resting-state EEGs in a large (N = 405) cross-sectional sample of children and adolescents (9–16 years). Our findings showed consistent age-dependent increases in EEG complexity that are distributed across multiple temporal scales and spatial regions. Developmental changes were most robust as the age gap between groups increased, particularly between late childhood and adolescence, and were most prominent over fronto-central scalp regions. These results suggest that the transition from late childhood to adolescence is characterized by age-dependent changes in the underlying complexity of endogenous brain networks.     

Atypical EEG complexity in autism spectrum conditions: A multiscale entropy analysis

Objective

Intrinsic complexity subserves adaptability in biological systems. One recently developed measure of intrinsic complexity of biological systems is multiscale entropy (MSE). Autism spectrum conditions (ASC) have been described in terms of reduced adaptability at a behavioural level and by patterns of atypical connectivity at a neural level. Based on these observations we aimed to test the hypothesis that adults with ASC would show atypical intrinsic complexity of brain activity as indexed by MSE analysis of electroencephalographic (EEG) activity.

Methods

We used MSE to assess the complexity of EEG data recorded from 15 participants with ASC and 15 typical controls, during a face and chair matching task.

Results

Results demonstrate a reduction of EEG signal complexity in the ASC group, compared to typical controls, over temporo-parietal and occipital regions. No significant differences in EEG power spectra were observed between groups, indicating that changes in complexity values are not a reflection of changes in EEG power spectra.

Conclusions

The results are consistent with a model of atypical neural integrative capacity in people with ASC.

Significance

Results suggest that EEG complexity, as indexed by MSE measures, may also be a marker for disturbances in task-specific processing of information in people with autism.     

Cortical Source Analysis of Event-Related Potentials: A Developmental Approach

Cortical source analysis of electroencephalographic (EEG) signals has become an important tool in the analysis of brain activity. The aim of source analysis is to reconstruct the cortical generators (sources) of the EEG signal recorded on the scalp. The quality of the source reconstruction relies on the accuracy of the forward problem, and consequently the inverse problem. An accurate forward solution is obtained when an appropriate imaging modality (i.e., structural magnetic resonance imaging – MRI) is used to describe the head geometry, precise electrode locations are identified with 3D maps of the sensor positions on the scalp, and realistic conductivity values are determined for each tissue type of the head model. Together these parameters contribute to the definition of realistic head models. Here, we describe the steps necessary to reconstruct the cortical generators of the EEG signal recorded on the scalp. We provide an example of source reconstruction of event-related potentials (ERPs) during a face-processing task performed by a 6-month-old infant. We discuss the adjustments necessary to perform source analysis with measures different from the ERPs. The proposed pipeline can be applied to the investigation of different cognitive tasks in both younger and older participants.     

Enhanced brain signal variability in children with autism spectrum disorder during early childhood

Extensive evidence shows that a core neurobiological mechanism of autism spectrum disorder (ASD) involves aberrant neural connectivity. Recent advances in the investigation of brain signal variability have yielded important information about neural network mechanisms. That information has been applied fruitfully to the assessment of aging and mental disorders. Multiscale entropy (MSE) analysis can characterize the complexity inherent in brain signal dynamics over multiple temporal scales in the dynamics of neural networks. For this investigation, we sought to characterize the magnetoencephalography (MEG) signal variability during free watching of videos without sound using MSE in 43 children with ASD and 72 typically developing controls (TD), emphasizing early childhood to older childhood: a critical period of neural network maturation. Results revealed an age‐related increase of brain signal variability in a specific timescale in TD children, whereas atypical age‐related alteration was observed in the ASD group. Additionally, enhanced brain signal variability was observed in children with ASD, and was confirmed particularly for younger children. In the ASD group, symptom severity was associated region‐specifically and timescale‐specifically with reduced brain signal variability. These results agree well with a recently reported theory of increased brain signal variability during development and aberrant neural connectivity in ASD, especially during early childhood. Results of this study suggest that MSE analytic method might serve as a useful approach for characterizing neurophysiological mechanisms of typical‐developing and its alterations in ASD through the detection of MEG signal variability at multiple timescales. Hum Brain Mapp 37:1038–1050, 2016. © 2015 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc .     

Mobile EEG in research on neurodevelopmental disorders: Opportunities and challenges

Mobile electroencephalography (mobile EEG) represents a next-generation neuroscientific technology – to study real-time brain activity – that is relatively inexpensive, non-invasive and portable. Mobile EEG leverages state-of-the-art hardware alongside established advantages of traditional EEG and recent advances in signal processing. In this review, we propose that mobile EEG could open unprecedented possibilities for studying neurodevelopmental disorders. We first present a brief overview of recent developments in mobile EEG technologies, emphasising the proliferation of studies in several neuroscientific domains. As these developments have yet to be exploited by neurodevelopmentalists, we then identify three research opportunities: 1) increase in the ease and flexibility of brain data acquisition in neurodevelopmental populations; 2) integration into powerful developmentally-informative research designs; 3) development of innovative non-stationary EEG-based paradigms. Critically, we address key challenges that should be considered to fully realise the potential of mobile EEG for neurodevelopmental research and for understanding developmental psychopathology more broadly, and suggest future research directions.     

Discordant Occurrence of Cerebral Unilateral Heterotopia and Epilepsy in Monozygotic Twins

Summary: Cerebral developmental malformations are increasingly recognized as a cause of epilepsy. Magnetic resonance imaging (MRI) has advanced our understanding of these disorders and their relation to epilepsy. We report the occurrence of discordant unilateral heterotopia and epilepsy in monozygotic twins. The affected individual developed intractable focal seizures at age 16 years. Mild cognitive difficulties had been present in early life. Evaluation showed right hemisphere EEG epileptogenic abnormalities, and the MRI scan showed massive right hemisphere heterotopia. EEG and MRI examinations in the patient's twin brother were normal. These findings suggest that the development of some developmental brain malformations and epilepsy is strongly influenced by nongenetic factors such as anenvironmental insult.     

Wavelet entropy: a new tool for analysis of short duration brain electrical signals

Since traditional electrical brain signal analysis is mostly qualitative, the development of new quantitative methods is crucial for restricting the subjectivity in the study of brain signals. These methods are particularly fruitful when they are strongly correlated with intuitive physical concepts that allow a better understanding of brain dynamics. Here, new method based on orthogonal discrete wavelet transform (ODWT) is applied. It takes as a basic element the ODWT of the EEG signal, and defines the relative wavelet energy, the wavelet entropy (WE) and the relative wavelet entropy (RWE). The relative wavelet energy provides information about the relative energy associated with different frequency bands present in the EEG and their corresponding degree of importance. The WE carries information about the degree of order/disorder associated with a multi-frequency signal response, and the RWE measures the degree of similarity between different segments of the signal. In addition, the time evolution of the WE is calculated to give information about the dynamics in the EEG records. Within this framework, the major objective of the present work was to characterize in a quantitative way functional dynamics of order/disorder microstates in short duration EEG signals. For that aim, spontaneous EEG signals under different physiological conditions were analyzed. Further, specific quantifiers were derived to characterize how stimulus affects electrical events in terms of frequency synchronization (tuning) in the event related potentials.     

What changes in neural oscillations can reveal about developmental cognitive neuroscience: Language development as a case in point

EEG is a primary method for studying temporally precise neuronal processes across the lifespan. Most of this work focuses on event related potentials (ERPs); however, using time-locked time frequency analysis to decompose the EEG signal can identify and distinguish multiple changes in brain oscillations underlying cognition (Bastiaansen et al., 2010). Further this measure is thought to reflect changes in inter-neuronal communication more directly than ERPs (Nunez and Srinivasan, 2006). Although time frequency has elucidated cognitive processes in adults, applying it to cognitive development is still rare. Here, we review the basics of neuronal oscillations, some of what they reveal about adult cognitive function, and what little is known relating to children. We focus on language because it develops early and engages complex cortical networks. Additionally, because time frequency analysis of the EEG related to adult language comprehension has been incredibly informative, using similar methods with children will shed new light on current theories of language development and increase our understanding of how neural processes change over the lifespan. Our goal is to emphasize the power of this methodology and encourage its use throughout developmental cognitive neuroscience.     

Decreased resting‐state brain activity complexity in schizophrenia characterized by both increased regularity and randomness

Schizophrenia is characterized by heterogeneous pathophysiology. Using multiscale entropy (MSE) analysis, which enables capturing complex dynamics of time series, we characterized MSE patterns of blood‐oxygen‐level‐dependent (BOLD) signals across different time scales and determined whether BOLD activity in patients with schizophrenia exhibits increased complexity (increased entropy in all time scales), decreased complexity toward regularity (decreased entropy in all time scales), or decreased complexity toward uncorrelated randomness (high entropy in short time scales followed by decayed entropy as the time scale increases). We recruited 105 patients with schizophrenia with an age of onset between 18 and 35 years and 210 age‐ and sex‐matched healthy volunteers. Results showed that MSE of BOLD signals in patients with schizophrenia exhibited two routes of decreased BOLD complexity toward either regular or random patterns. Reduced BOLD complexity toward regular patterns was observed in the cerebellum and temporal, middle, and superior frontal regions, and reduced BOLD complexity toward randomness was observed extensively in the inferior frontal, occipital, and postcentral cortices as well as in the insula and middle cingulum. Furthermore, we determined that the two types of complexity change were associated differently with psychopathology; specifically, the regular type of BOLD complexity change was associated with positive symptoms of schizophrenia, whereas the randomness type of BOLD complexity was associated with negative symptoms of the illness. These results collectively suggested that resting‐state dynamics in schizophrenia exhibit two routes of pathologic change toward regular or random patterns, which contribute to the differences in syndrome domains of psychosis in patients with schizophrenia. Hum Brain Mapp 36:2174–2186, 2015. © 2015 Wiley Periodicals, Inc.     

LSD‐induced entropic brain activity predicts subsequent personality change

Personality is known to be relatively stable throughout adulthood. Nevertheless, it has been shown that major life events with high personal significance, including experiences engendered by psychedelic drugs, can have an enduring impact on some core facets of personality. In the present, balanced‐order, placebo‐controlled study, we investigated biological predictors of post‐lysergic acid diethylamide (LSD) changes in personality. Nineteen healthy adults underwent resting state functional MRI scans under LSD (75µg, I.V.) and placebo (saline I.V.). The Revised NEO Personality Inventory (NEO‐PI‐R) was completed at screening and 2 weeks after LSD/placebo. Scanning sessions consisted of three 7.5‐min eyes‐closed resting‐state scans, one of which involved music listening. A standardized preprocessing pipeline was used to extract measures of sample entropy, which characterizes the predictability of an fMRI time‐series. Mixed‐effects models were used to evaluate drug‐induced shifts in brain entropy and their relationship with the observed increases in the personality trait openness at the 2‐week follow‐up. Overall, LSD had a pronounced global effect on brain entropy, increasing it in both sensory and hierarchically higher networks across multiple time scales. These shifts predicted enduring increases in trait openness. Moreover, the predictive power of the entropy increases was greatest for the music‐listening scans and when “ego‐dissolution” was reported during the acute experience. These results shed new light on how LSD‐induced shifts in brain dynamics and concomitant subjective experience can be predictive of lasting changes in personality. Hum Brain Mapp 37:3203–3213, 2016. © 2016 Wiley Periodicals, Inc .     

Wavelet‐based regularity analysis reveals recurrent spatiotemporal behavior in resting‐state fMRI

One of the major findings from multimodal neuroimaging studies in the past decade is that the human brain is anatomically and functionally organized into large‐scale networks. In resting state fMRI (rs‐fMRI), spatial patterns emerge when temporal correlations between various brain regions are tallied, evidencing networks of ongoing intercortical cooperation. However, the dynamic structure governing the brain's spontaneous activity is far less understood due to the short and noisy nature of the rs‐fMRI signal. Here, we develop a wavelet‐based regularity analysis based on noise estimation capabilities of the wavelet transform to measure recurrent temporal pattern stability within the rs‐fMRI signal across multiple temporal scales. The method consists of performing a stationary wavelet transform to preserve signal structure, followed by construction of “lagged” subsequences to adjust for correlated features, and finally the calculation of sample entropy across wavelet scales based on an “objective” estimate of noise level at each scale. We found that the brain's default mode network (DMN) areas manifest a higher level of irregularity in rs‐fMRI time series than rest of the brain. In 25 aged subjects with mild cognitive impairment and 25 matched healthy controls, wavelet‐based regularity analysis showed improved sensitivity in detecting changes in the regularity of rs‐fMRI signals between the two groups within the DMN and executive control networks, compared with standard multiscale entropy analysis. Wavelet‐based regularity analysis based on noise estimation capabilities of the wavelet transform is a promising technique to characterize the dynamic structure of rs‐fMRI as well as other biological signals. Hum Brain Mapp 36:3603–3620, 2015. © 2015 Wiley Periodicals, Inc.     

Modulation of simultaneously collected hemodynamic and electrophysiological functional connectivity by ketamine and midazolam

The pharmacological modulation of functional connectivity in the brain may underlie therapeutic efficacy for several neurological and psychiatric disorders. Functional magnetic resonance imaging (fMRI) provides a noninvasive method of assessing this modulation, however, the indirect nature of the blood‐oxygen level dependent signal restricts the discrimination of neural from physiological contributions. Here we followed two approaches to assess the validity of fMRI functional connectivity in developing drug biomarkers, using simultaneous electroencephalography (EEG)/fMRI in a placebo‐controlled, three‐way crossover design with ketamine and midazolam. First, we compared seven different preprocessing pipelines to determine their impact on the connectivity of common resting‐state networks. Independent components analysis (ICA)‐denoising resulted in stronger reductions in connectivity after ketamine, and weaker increases after midazolam, than pipelines employing physiological noise modelling or averaged signals from cerebrospinal fluid or white matter. This suggests that pipeline decisions should reflect a drug's unique noise structure, and if this is unknown then accepting possible signal loss when choosing extensive ICA denoising pipelines could engender more confidence in the remaining results. We then compared the temporal correlation structure of fMRI to that derived from two connectivity metrics of EEG, which provides a direct measure of neural activity. While electrophysiological estimates based on the power envelope were more closely aligned to BOLD signal connectivity than those based on phase consistency, no significant relationship between the change in electrophysiological and hemodynamic correlation structures was found, implying caution should be used when making cross‐modal comparisons of pharmacologically‐modulated functional connectivity.     

EEG and MEG coherence: measures of functional connectivity at distinct spatial scales of neocortical dynamics

We contrasted coherence estimates obtained with EEG, Laplacian, and MEG measures of synaptic activity using simulations with head models and simultaneous recordings of EEG and MEG. EEG coherence is often used to assess functional connectivity in human cortex. However, moderate to large EEG coherence can also arise simply by the volume conduction of current through the tissues of the head. We estimated this effect using simulated brain sources and a model of head tissues (cerebrospinal fluid (CSF), skull, and scalp) derived from MRI. We found that volume conduction can elevate EEG coherence at all frequencies for moderately separated (<10 cm) electrodes; a smaller levation is observed with widely separated (>20 cm) electrodes. This volume conduction effect was readily observed in experimental EEG at high frequencies (40-50 Hz). Cortical sources generating spontaneous EEG in this band are apparently uncorrelated. In contrast, lower frequency EEG coherence appears to result from a mixture of volume conduction effects and genuine source coherence. Surface Laplacian EEG methods minimize the effect of volume conduction on coherence estimates by emphasizing sources at smaller spatial scales than unprocessed potentials (EEG). MEG coherence estimates are inflated at all frequencies by the field spread across the large distance between sources and sensors. This effect is most apparent at sensors separated by less than 15 cm in tangential directions along a surface passing through the sensors. In comparison to long-range (>20 cm) volume conduction effects in EEG, widely spaced MEG sensors show smaller field-spread effects, which is a potentially significant advantage. However, MEG coherence estimates reflect fewer sources at a smaller scale than EEG coherence and may only partially overlap EEG coherence. EEG, Laplacian, and MEG coherence emphasize different spatial scales and orientations of sources.