Greater repertoire and temporal variability of cross-frequency coupling (CFC) modes in resting-state neuromagnetic recordings among children with reading difficulties

Cross-frequency, phase-to-amplitude coupling (PAC) between neuronal oscillations at rest may serve as the substrate that supports information exchange between functionally specialized neuronal populations both within and between cortical regions. The study utilizes novel algorithms to identify prominent instantaneous modes of cross-frequency coupling and their temporal stability in resting state magnetoencephalography (MEG) data from 25 students experiencing severe reading difficulties (RD) and 27 age-matched non-impaired readers (NI). Phase coherence estimates were computed in order to identify the prominent mode of PAC interaction for each sensor, sensor pair, and pair of frequency bands (from δ to γ) at successive time windows of the continuous MEG record. The degree of variability in the characteristic frequency-pair PACf1−f2 modes over time was also estimated. Results revealed a wider repertoire of prominent PAC interactions in RD as compared to NI students, suggesting an altered functional substrate for information exchange between neuronal assemblies in the former group. Moreover, RD students showed significant variability in PAC modes over time. This temporal instability of PAC values was particularly prominent: (a) within and between right hemisphere temporo-parietal and occipito-temporal sensors and, (b) between left hemisphere frontal, temporal, and occipito-temporal sensors and corresponding right hemisphere sites. Altered modes of neuronal population coupling may help account for extant data revealing reduced, task-related neurophysiological and hemodynamic activation in left hemisphere regions involved in the reading network in RD. Moreover, the spatial distribution of pronounced instability of cross-frequency coupling modes in this group may provide an explanation for previous reports suggesting the presence of inefficient compensatory mechanisms to support reading

Altered cross-frequency coupling in resting-state MEG after mild traumatic brain injury

Cross-frequency coupling (CFC) is thought to represent a basic mechanism of functional integration of neural networks across distant brain regions. In this study, we analyzed CFC profiles from resting state Magnetoencephalographic (MEG) recordings obtained from 30 mild traumatic brain injury (mTBI) patients and 50 controls. We used mutual information (MI) to quantify the phase-to-amplitude coupling (PAC) of activity among the recording sensors in six nonoverlapping frequency bands. After forming the CFC-based functional connectivity graphs, we employed a tensor representation and tensor subspace analysis to identify the optimal set of features for subject classification as mTBI or control. Our results showed that controls formed a dense network of stronger local and global connections indicating higher functional integration compared to mTBI patients. Furthermore, mTBI patients could be separated from controls with more than 90% classification accuracy. These findings indicate that analysis of brain networks computed from resting-state MEG with PAC and tensorial representation of connectivity profiles may provide a valuable biomarker for the diagnosis of mTBI

Mining time-resolved functional brain graphs to an EEG-based chronnectomic brain aged index (CBAI)

The brain at rest consists of spatially and temporal distributed but functionally connected regions that called intrinsic connectivity networks (ICNs). Resting state electroencephalography (rs-EEG) is a way to characterize brain networks without confounds associated with task EEG such as task difficulty and performance. A novel framework of how to study dynamic functional connectivity under the notion of functional connectivity microstates (FCμstates) and symbolic dynamics is further discussed. Furthermore, we introduced a way to construct a single integrated dynamic functional connectivity graph (IDFCG) that preserves both the strength of the connections between every pair of sensors but also the type of dominant intrinsic coupling modes (DICM). The whole methodology is demonstrated in a significant and unexplored task for EEG which is the definition of an objective Chronnectomic Brain Aged index (CBAI) extracted from resting-state data (N = 94 subjects) with both eyes-open and eyes-closed conditions. Novel features have been defined based on symbolic dynamics and the notion of DICM and FCμstates. The transition rate of FCμstates, the symbolic dynamics based on the evolution of FCμstates (the Markovian Entropy, the complexity index), the probability distribution of DICM, the novel Flexibility Index that captures the dynamic reconfiguration of DICM per pair of EEG sensors and the relative signal power constitute a valuable pool of features that can build the proposed CBAI. Here we applied a feature selection technique and Extreme Learning Machine (ELM) classifier to discriminate young adults from middle-aged and a Support Vector Regressor to build a linear model of the actual age based on EEG-based spatio-temporal features. The most significant type of features for both prediction of age and discrimination of young vs. adults age groups was the dynamic reconfiguration of dominant coupling modes derived from a subset of EEG sensor pairs. Specifically, our results revealed a very high prediction of age for eyes-open (R2 = 0.60; y = 0.79x + 8.03) and lower for eyes-closed (R2 = 0.48; y = 0.71x + 10.91) while we succeeded to correctly classify young vs. middle-age group with 97.8% accuracy in eyes-open and 87.2% for eyes-closed. Our results were reproduced also in a second dataset for further external validation of the whole analysis. The proposed methodology proved valuable for the characterization of the intrinsic properties of dynamic functional connectivity through the age untangling developmental differences using EEG resting-state recordings

Speech-brain synchronization: a possible cause for developmental dyslexia

152 p.Dyslexia is a neurological learning disability characterized by the difficulty in an individual¿s ability to read despite adequate intelligence and normal opportunities. The majority of dyslexic readers present phonological difficulties. The phonological difficulty most often associated with dyslexia is a deficit in phonological awareness, that is, the ability to hear and manipulate the sound structure of language. Some appealing theories of dyslexia attribute a causal role to auditory atypical oscillatory neural activity, suggesting it generates some of the phonological problems in dyslexia. These theories propose that auditory cortical oscillations of dyslexic individuals entrain less accurately to the spectral properties of auditory stimuli at distinct frequency bands (delta, theta and gamma) that are important for speech processing. Nevertheless, there are diverging hypotheses concerning the specific bands that would be disrupted in dyslexia, and which are the consequences of such difficulties on speech processing. The goal of the present PhD thesis was to portray the neural oscillatory basis underlying phonological difficulties in developmental dyslexia. We evaluated whether phonological deficits in developmental dyslexia are associated with impaired auditory entrainment to a specific frequency band. In that aim, we measured auditory neural synchronization to linguistic and non-linguistic auditory signals at different frequencies corresponding to key phonological units of speech (prosodic, syllabic and phonemic information). We found that dyslexic readers presented atypical neural entrainment to delta, theta and gamma frequency bands. Importantly, we showed that atypical entrainment to theta and gamma modulations in dyslexia could compromise perceptual computations during speech processing, while reduced delta entrainment in dyslexia could affect perceptual and attentional operations during speech processing. In addition, we characterized the links between the anatomy of the auditory cortex and its oscillatory responses, taking into account previous studies which have observed structural alterations in dyslexia. We observed that the cortical pruning in auditory regions was linked to a stronger sensitivity to gamma oscillation in skilled readers, but to stronger theta band sensitivity in dyslexic readers. Thus, we concluded that the left auditory regions might be specialized for processing phonological information at different time scales (phoneme vs. syllable) in skilled and dyslexic readers. Lastly, by assessing both children and adults on similar tasks, we provided the first evaluation of developmental modulations of typical and atypical auditory sampling (and their structural underpinnings). We found that atypical neural entrainment to delta, theta and gamma are present in dyslexia throughout the lifespan and is not modulated by reading experience

Aberrant resting-state functional brain networks in dyslexia: Symbolic mutual information analysis of neuromagnetic signals

Neuroimaging studies have identified a variety of structural and functional connectivity abnormalities in students experiencing reading difficulties. The present study adopted a novel approach to assess the dynamics of resting-state neuromagnetic recordings in the form of symbolic sequences (i.e., repeated patterns of neuromagnetic fluctuations within and/or between sensors). Participants were 25 students experiencing severe reading difficulties (RD) and 27 agematched non-impaired readers (NI) aged 7-14 years. Sensor-level data were first represented as symbolic sequences in eight conventional frequency bands. Next, dominant types of sensorto- sensor interactions in the form of intra and cross-frequency coupling were computed and subjected to graph modeling to assess group differences in global network characteristics. As a group RD students displayed predominantly within-frequency interactions between neighboring sensors which may reflect reduced overall global network efficiency and cost-efficiency of information transfer. In contrast, sensor networks among NI students featured a higher proportion of cross-frequency interactions. Brain-reading achievement associations highlighted the role of left hemisphere temporo-parietal functional networks, at rest, for reading acquisition and ability

Complexity of brain activity and connectivity in functional neuroimaging

Understanding the complexity of human brain dynamics and brain connectivity across the repertoire of functional neuroimaging and various conditions, is of paramount importance. Novel measures should be designed tailored to the input focusing on multichannel activity and dynamic functional brain connectivity (DFBC). Here, we defined a novel complexity index (CI) from the field of symbolic dynamics that quantifies patterns of different words up to a length from a symbolic sequence. The CI characterizes the complexity of the brain activity. We analysed dynamic functional brain connectivity by adopting the sliding window approach using imaginary part of phase locking value (iPLV) for EEG/ECoG/MEG and wavelet coherence (WC) for fMRI. Both intra and cross-frequency couplings (CFC) namely phase-to-amplitude were estimated using iPLV/WC at every snapshot of the DFBC. Using proper surrogate analysis, we defined the dominant intrinsic coupling mode (DICM) per pair of regions-of-interest (ROI). The spatio-temporal probability distribution of DICM were reported to reveal the most prominent coupling modes per condition and modality. Finally, a novel flexibility index is defined that quantifies the transition of DICM per pair of ROIs between consecutive time-windows. The whole methodology was demonstrated using four neuroimaging datasets (EEG/ECoG/MEG/fMRI). Finally, we succeeded to totally discriminate healthy controls from schizophrenic using FI and dynamic reconfiguration of DICM. Anesthesia independently of the drug caused a global decreased of complexity in all frequency bands with the exception in δ and alters the dynamic reconfiguration of DICM. CI and DICM of MEG/fMRI resting-state recordings in two spatial scales were high reliable

Dynamics of large-scale electrophysiological networks: a technical review

For several years it has been argued that neural synchronisation is crucial for cognition. The idea that synchronised temporal patterns between different neural groups carries information above and beyond the isolated activity of these groups has inspired a shift in focus in the field of functional neuroimaging. Specifically, investigation into the activation elicited within certain regions by some stimulus or task has, in part, given way to analysis of patterns of co-activation or functional connectivity between distal regions. Recently, the functional connectivity community has been looking beyond the assumptions of stationarity that earlier work was based on, and has introduced methods to incorporate temporal dynamics into the analysis of connectivity. In particular, non-invasive electrophysiological data (magnetoencephalography / electroencephalography (MEG/EEG)), which provides direct measurement of whole-brain activity and rich temporal information, offers an exceptional window into such (potentially fast) brain dynamics. In this review, we discuss challenges, solutions, and a collection of analysis tools that have been developed in recent years to facilitate the investigation of dynamic functional connectivity using these imaging modalities. Further, we discuss the applications of these approaches in the study of cognition and neuropsychiatric disorders. Finally, we review some existing developments that, by using realistic computational models, pursue a deeper understanding of the underlying causes of non-stationary connectivity

Speech-brain synchronization: a possible cause for developmental dyslexia

152 p.Dyslexia is a neurological learning disability characterized by the difficulty in an individual¿s ability to read despite adequate intelligence and normal opportunities. The majority of dyslexic readers present phonological difficulties. The phonological difficulty most often associated with dyslexia is a deficit in phonological awareness, that is, the ability to hear and manipulate the sound structure of language. Some appealing theories of dyslexia attribute a causal role to auditory atypical oscillatory neural activity, suggesting it generates some of the phonological problems in dyslexia. These theories propose that auditory cortical oscillations of dyslexic individuals entrain less accurately to the spectral properties of auditory stimuli at distinct frequency bands (delta, theta and gamma) that are important for speech processing. Nevertheless, there are diverging hypotheses concerning the specific bands that would be disrupted in dyslexia, and which are the consequences of such difficulties on speech processing. The goal of the present PhD thesis was to portray the neural oscillatory basis underlying phonological difficulties in developmental dyslexia. We evaluated whether phonological deficits in developmental dyslexia are associated with impaired auditory entrainment to a specific frequency band. In that aim, we measured auditory neural synchronization to linguistic and non-linguistic auditory signals at different frequencies corresponding to key phonological units of speech (prosodic, syllabic and phonemic information). We found that dyslexic readers presented atypical neural entrainment to delta, theta and gamma frequency bands. Importantly, we showed that atypical entrainment to theta and gamma modulations in dyslexia could compromise perceptual computations during speech processing, while reduced delta entrainment in dyslexia could affect perceptual and attentional operations during speech processing. In addition, we characterized the links between the anatomy of the auditory cortex and its oscillatory responses, taking into account previous studies which have observed structural alterations in dyslexia. We observed that the cortical pruning in auditory regions was linked to a stronger sensitivity to gamma oscillation in skilled readers, but to stronger theta band sensitivity in dyslexic readers. Thus, we concluded that the left auditory regions might be specialized for processing phonological information at different time scales (phoneme vs. syllable) in skilled and dyslexic readers. Lastly, by assessing both children and adults on similar tasks, we provided the first evaluation of developmental modulations of typical and atypical auditory sampling (and their structural underpinnings). We found that atypical neural entrainment to delta, theta and gamma are present in dyslexia throughout the lifespan and is not modulated by reading experience

Investigation of neural activity in Schizophrenia during resting-state MEG : using non-linear dynamics and machine-learning to shed light on information disruption in the brain

Environ 25% de la population mondiale est atteinte de troubles psychiatriques qui sont typiquement associés à des problèmes comportementaux, fonctionnels et/ou cognitifs et dont les corrélats neurophysiologiques sont encore très mal compris. Non seulement ces dysfonctionnements réduisent la qualité de vie des individus touchés, mais ils peuvent aussi devenir un fardeau pour les proches et peser lourd dans l’économie d’une société. Cibler les mécanismes responsables du fonctionnement atypique du cerveau en identifiant des biomarqueurs plus robustes permettrait le développement de traitements plus efficaces. Ainsi, le premier objectif de cette thèse est de contribuer à une meilleure caractérisation des changements dynamiques cérébraux impliqués dans les troubles mentaux, plus précisément dans la schizophrénie et les troubles d’humeur. Pour ce faire, les premiers chapitres de cette thèse présentent, en intégral, deux revues de littératures systématiques que nous avons menées sur les altérations de connectivité cérébrale, au repos, chez les patients schizophrènes, dépressifs et bipolaires. Ces revues révèlent que, malgré des avancées scientifiques considérables dans l’étude de l’altération de la connectivité cérébrale fonctionnelle, la dimension temporelle des mécanismes cérébraux à l’origine de l’atteinte de l’intégration de l’information dans ces maladies, particulièrement de la schizophrénie, est encore mal comprise. Par conséquent, le deuxième objectif de cette thèse est de caractériser les changements cérébraux associés à la schizophrénie dans le domaine temporel. Nous présentons deux études dans lesquelles nous testons l’hypothèse que la « disconnectivité temporelle » serait un biomarqueur important en schizophrénie. Ces études explorent les déficits d’intégration temporelle en schizophrénie, en quantifiant les changements de la dynamique neuronale dite invariante d’échelle à partir des données magnétoencéphalographiques (MEG) enregistrés au repos chez des patients et des sujets contrôles. En particulier, nous utilisons (1) la LRTCs (long-range temporal correlation, ou corrélation temporelle à longue-distance) calculée à partir des oscillations neuronales et (2) des analyses multifractales pour caractériser des modifications de l’activité cérébrale arythmique. Par ailleurs, nous développons des modèles de classification (en apprentissage-machine supervisé) pour mieux cerner les attributs corticaux et sous-corticaux permettant une distinction robuste entre les patients et les sujets sains. Vu que ces études se basent sur des données MEG spontanées enregistrées au repos soit avec les yeux ouvert, ou les yeux fermées, nous nous sommes par la suite intéressés à la possibilité de trouver un marqueur qui combinerait ces enregistrements. La troisième étude originale explore donc l’utilité des modulations de l’amplitude spectrale entre yeux ouverts et fermées comme prédicteur de schizophrénie. Les résultats de ces études démontrent des changements cérébraux importants chez les patients schizophrènes au niveau de la dynamique d’invariance d’échelle. Elles suggèrent une dégradation du traitement temporel de l’information chez les patients, qui pourrait être liée à leurs symptômes cognitifs et comportementaux. L’approche multimodale de cette thèse, combinant la magétoencéphalographie, analyses non-linéaires et apprentissage machine, permet de mieux caractériser l’organisation spatio-temporelle du signal cérébrale au repos chez les patients atteints de schizophrénie et chez des individus sains. Les résultats fournissent de nouvelles preuves supportant l’hypothèse d’une « disconnectivité temporelle » en schizophrénie, et étendent les recherches antérieures, en explorant la contribution des structures cérébrales profondes et en employant des mesures non-linéaires avancées encore sous-exploitées dans ce domaine. L’ensemble des résultats de cette thèse apporte une contribution significative à la quête de nouveaux biomarqueurs de la schizophrénie et démontre l’importance d’élucider les altérations des propriétés temporelles de l’activité cérébrales intrinsèque en psychiatrie. Les études présentées offrent également un cadre méthodologique pouvant être étendu à d’autres psychopathologie, telles que la dépression.Psychiatric disorders affect nearly a quarter of the world’s population. These typically bring about debilitating behavioural, functional and/or cognitive problems, for which the underlying neural mechanisms are poorly understood. These symptoms can significantly reduce the quality of life of affected individuals, impact those close to them, and bring on an economic burden on society. Hence, targeting the baseline neurophysiology associated with psychopathologies, by identifying more robust biomarkers, would improve the development of effective treatments. The first goal of this thesis is thus to contribute to a better characterization of neural dynamic alterations in mental health illnesses, specifically in schizophrenia and mood disorders. Accordingly, the first chapter of this thesis presents two systematic literature reviews, which investigate the resting-state changes in brain connectivity in schizophrenia, depression and bipolar disorder patients. Great strides have been made in neuroimaging research in identifying alterations in functional connectivity. However, these two reviews reveal a gap in the knowledge about the temporal basis of the neural mechanisms involved in the disruption of information integration in these pathologies, particularly in schizophrenia. Therefore, the second goal of this thesis is to characterize the baseline temporal neural alterations of schizophrenia. We present two studies for which we hypothesize that the resting temporal dysconnectivity could serve as a key biomarker in schizophrenia. These studies explore temporal integration deficits in schizophrenia by quantifying neural alterations of scale-free dynamics using resting-state magnetoencephalography (MEG) data. Specifically, we use (1) long-range temporal correlation (LRTC) analysis on oscillatory activity and (2) multifractal analysis on arrhythmic brain activity. In addition, we develop classification models (based on supervised machine-learning) to detect the cortical and sub-cortical features that allow for a robust division of patients and healthy controls. Given that these studies are based on MEG spontaneous brain activity, recorded at rest with either eyes-open or eyes-closed, we then explored the possibility of finding a distinctive feature that would combine both types of resting-state recordings. Thus, the third study investigates whether alterations in spectral amplitude between eyes-open and eyes-closed conditions can be used as a possible marker for schizophrenia. Overall, the three studies show changes in the scale-free dynamics of schizophrenia patients at rest that suggest a deterioration of the temporal processing of information in patients, which might relate to their cognitive and behavioural symptoms. The multimodal approach of this thesis, combining MEG, non-linear analyses and machine-learning, improves the characterization of the resting spatiotemporal neural organization of schizophrenia patients and healthy controls. Our findings provide new evidence for the temporal dysconnectivity hypothesis in schizophrenia. The results extend on previous studies by characterizing scale-free properties of deep brain structures and applying advanced non-linear metrics that are underused in the field of psychiatry. The results of this thesis contribute significantly to the identification of novel biomarkers in schizophrenia and show the importance of clarifying the temporal properties of altered intrinsic neural dynamics. Moreover, the presented studies offer a methodological framework that can be extended to other psychopathologies, such as depression

Magnetoencephalography

This is a practical book on MEG that covers a wide range of topics. The book begins with a series of reviews on the use of MEG for clinical applications, the study of cognitive functions in various diseases, and one chapter focusing specifically on studies of memory with MEG. There are sections with chapters that describe source localization issues, the use of beamformers and dipole source methods, as well as phase-based analyses, and a step-by-step guide to using dipoles for epilepsy spike analyses. The book ends with a section describing new innovations in MEG systems, namely an on-line real-time MEG data acquisition system, novel applications for MEG research, and a proposal for a helium re-circulation system. With such breadth of topics, there will be a chapter that is of interest to every MEG researcher or clinician