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

Patient, interrupted: MEG oscillation dynamics reveal temporal dysconnectivity in schizophrenia

Current theories of schizophrenia emphasize the role of altered information integration as the core dysfunction of this illness. While ample neuroimaging evidence for such accounts comes from investigations of spatial connectivity, understanding temporal disruptions is important to fully capture the essence of dysconnectivity in schizophrenia. Recent electrophysiology studies suggest that long-range temporal correlation (LRTC) in the amplitude dynamics of neural oscillations captures the integrity of transferred information in the healthy brain. Thus, in this study, 25 schizophrenia patients and 25 controls (8 females/group) were recorded during two five-minutes of resting-state magnetoencephalography (once with eyes-open and once with eyes-closed). We used source-level analyses to investigate temporal dysconnectivity in patients by characterizing LRTCs across cortical and sub-cortical brain regions. In addition to standard statistical assessments, we applied a machine learning framework using support vector machine to evaluate the discriminative power of LRTCs in identifying patients from healthy controls. We found that neural oscillations in schizophrenia patients were characterized by reduced signal memory and higher variability across time, as evidenced by cortical and subcortical attenuations of LRTCs in the alpha and beta frequency bands. Support vector machine significantly classified participants using LRTCs in key limbic and paralimbic brain areas, with decoding accuracy reaching 82%. Importantly, these brain regions belong to networks that are highly relevant to the symptomology of schizophrenia. These findings thus posit temporal dysconnectivity as a hallmark of altered information processing in schizophrenia, and help advance our understanding of this pathology

Altered brain criticality in schizophrenia: new insights from magnetoencephalography

Schizophrenia has a complex etiology and symptomatology that is difficult to untangle. After decades of research, important advancements toward a central biomarker are still lacking. One of the missing pieces is a better understanding of how non-linear neural dynamics are altered in this patient population. In this study, the resting-state neuromagnetic signals of schizophrenia patients and healthy controls were analyzed in the framework of criticality. When biological systems like the brain are in a state of criticality, they are thought to be functioning at maximum efficiency (e.g., optimal communication and storage of information) and with maximum adaptability to incoming information. Here, we assessed the self-similarity and multifractality of resting-state brain signals recorded with magnetoencephalography in patients with schizophrenia patients and in matched controls. Schizophrenia patients had similar, although attenuated, patterns of self-similarity and multifractality values. Statistical tests showed that patients had higher values of self-similarity than controls in fronto-temporal regions, indicative of more regularity and memory in the signal. In contrast, patients had less multifractality than controls in the parietal and occipital regions, indicative of less diverse singularities and reduced variability in the signal. In addition, supervised machine-learning, based on logistic regression, successfully discriminated the two groups using measures of self-similarity and multifractality as features. Our results provide new insights into the baseline cognitive functioning of schizophrenia patients by identifying key alterations of criticality properties in their resting-state brain data

Intellectual functioning in first-episode schizophrenia, schizoaffective disorder and bipolar disorder

Intellectual functioning (IQ) prior to the onset of illness (premorbid IQ) and the pattern of its trajectory across illness onset can inform us of the early developmental pathology of mental disorders. The goals of this study were to 1) investigate these features in first-episode psychiatric patients with overlapping symptoms including schizophrenia (SZ), schizoaffective disorder (SA) and bipolar disorder (BD), as well as to 2) examine these features and the presence of psychosis, and the influence of mood-incongruent features, in BD patients. To address these objectives, SZ, SA, BD-I, and healthy controls, aged 17-37 years, were pooled from two early-intervention programs. The North American Adult Reading Test was used to estimate premorbid IQ, while the Kaufman Brief Intelligence Test was used to measure current IQ. Group differences in premorbid IQ and IQ trajectories were evaluated with ANOVA and repeated measure ANOVA. Both controls and BD patients had significantly higher premorbid IQ compared to SZ patients, BD patients had scores comparable to control, and there was a strong trend of premorbid IQ deficit in SA patients. Regarding IQ change, only subjects with SA and SZ experienced significant IQ deterioration through illness onset. Regarding psychosis, t-tests deciphered a strong, although insignificant, premorbid IQ difference across BD patients, with deficits seen in psychotic but not non-psychotic patients. Lastly, t-tests revealed a significant decline in IQ across psychotic BD patients with mood-congruent, and not –incongruent, features. Secondary post-hoc analyses revealed that this finding might be attributable to the type of antipsychotic that patients received. Taken together, these results suggest that early neurodevelopmental pathology, which most likely directly affects intellectual functioning, may be different in BD than in SA and SZ. Furthermore, low premorbid IQ could be a potential risk factor for psychosis. Assessment of IQ before and after illness onset could help facilitate early identification of psychopathology and assist with patient management and care.Medicine, Faculty ofGraduat

Acoustic correlates of allophonic versus phonemic dimensions in monolingual and bilingual infants’ input

A B S T R A C T Allophones are diverse phonetic instantiations of a single underlying sound category. As such, they pose a peculiar problem for infant language learners: These variants occur in the ambient language, but they are not used to encode lexical contrasts. Infants' sensitivity to sounds varying along allophonic dimensions declines by 11 months of age, suggesting that there must be information to phonological status available to pre-lexical infants. The present work tests one specific type of information: acoustic implementation. It was hypothesized that the acoustic distance between two vowel categories is smaller when the dimension along which the two vowels differ is allophonic (e.g., vowel nasality in American English, vowel tenseness in Quebec French) compared to when it is phonemic (e.g., vowel tenseness in American English, vowel nasality in Quebec French). Monolingual mothers speaking either English or French and bilingual mothers speaking both languages were recorded while they described objects to their 11-month-olds. Results provided weak support for the main hypothesis

The acoustic properties of bilingual infant-directed speech

Abstract: Does the acoustic input for bilingual infants equal the conjunction of the input heard by monolinguals of each separate language? The present letter tackles this question, focusing on maternal speech addressed to 11-month-old infants, on the cusp of perceptual attunement. The acoustic characteristics of the point vowels /a,i,u/ were measured in the spontaneous infant-directed speech of French-English bilingual mothers, as well as in the speech of French and English monolingual mothers. Bilingual caregivers produced their two languages with acoustic prosodic separation equal to that of the monolinguals, while also conveying distinct spectral characteristics of the point vowels in their two languages

From intentions to actions: Neural oscillations encode motor processes through phase, amplitude and phase-amplitude coupling.

International audienceGoal-directed motor behavior is associated with changes in patterns of rhythmic neuronal activity across widely distributed brain areas. In particular, movement initiation and execution are mediated by patterns of synchronization and desynchronization that occur concurrently across distinct frequency bands and across multiple motor cortical areas. To date, motor-related local oscillatory modulations have been predominantly examined by quantifying increases or suppressions in spectral power. However, beyond signal power, spectral properties such as phase and phase-amplitude coupling (PAC) have also been shown to carry information with regards to the oscillatory dynamics underlying motor processes. Yet, the distinct functional roles of phase, amplitude and PAC across the planning and execution of goal-directed motor behavior remain largely elusive. Here, we address this question with unprecedented resolution thanks to multi-site intracerebral EEG recordings in human subjects while they performed a delayed motor task. To compare the roles of phase, amplitude and PAC, we monitored intracranial brain signals from 748 sites across six medically intractable epilepsy patients at movement execution, and during the delay period where motor intention is present but execution is withheld. In particular, we used a machine-learning framework to identify the key contributions of various neuronal responses. We found a high degree of overlap between brain network patterns observed during planning and those present during execution. Prominent amplitude increases in the delta (2-4Hz) and high gamma (60-200Hz) bands were observed during both planning and execution. In contrast, motor alpha (8-13Hz) and beta (13-30Hz) power were suppressed during execution, but enhanced during the delay period. Interestingly, single-trial classification revealed that low-frequency phase information, rather than spectral power change, was the most discriminant feature in dissociating action from intention. Additionally, despite providing weaker decoding, PAC features led to statistically significant classification of motor states, particularly in anterior cingulate cortex and premotor brain areas. These results advance our understanding of the distinct and partly overlapping involvement of phase, amplitude and the coupling between them, in the neuronal mechanisms underlying motor intentions and executions

NeuroPycon: An open-source python toolbox for fast multi-modal and reproducible brain connectivity pipelines

International audienceKeywords: Magnetoencephalography (MEG) Electroencephalography (EEG) Electrophysiology MRI Functional connectivity Graph theory Multi-modality Python MNE Source reconstruction Brain networks Nipype Brain imaging Reproducible science Pipelines A B S T R A C T Recent years have witnessed a massive push towards reproducible research in neuroscience. Unfortunately, this endeavor is often challenged by the large diversity of tools used, project-specific custom code and the difficulty to track all user-defined parameters. NeuroPycon is an open-source multi-modal brain data analysis toolkit which provides Python-based template pipelines for advanced multi-processing of MEG, EEG, functional and anatomical MRI data, with a focus on connectivity and graph theoretical analyses. Importantly, it provides shareable parameter files to facilitate replication of all analysis steps. NeuroPycon is based on the NiPype framework which facilitates data analyses by wrapping many commonly-used neuroimaging software tools into a common Python environment. In other words, rather than being a brain imaging software with is own implementation of standard algorithms for brain signal processing, NeuroPycon seamlessly integrates existing packages (coded in python, Matlab or other languages) into a unified python framework. Importantly, thanks to the multi-threaded processing and computational efficiency afforded by NiPype, NeuroPycon provides an easy option for fast parallel processing, which critical when handling large sets of multi-dimensional brain data. Moreover, its flexible design allows users to easily configure analysis pipelines by connecting distinct nodes to each other. Each node can be a Python-wrapped module, a user-defined function or a well-established tool (e.g. MNE-Python for MEG analysis, Rada-tools for graph theoretical metrics, etc.). Last but not least, the ability to use NeuroPycon parameter files to fully describe any pipeline is an important feature for reproducibility, as they can be shared and used for easy repli-cation by others. The current implementation of NeuroPycon contains two complementary packages: The first, called ephypype, includes pipelines for electrophysiology analysis and a command-line interface for on the fly pipeline creation. Current implementations allow for MEG/EEG data import, pre-processing and cleaning by automatic removal of ocular and cardiac artefacts, in addition to sensor or source-level connectivity analyses. The second package, called graphpype, is designed to investigate functional connectivity via a wide range of graph-theoretical metrics, including modular partitions. The present article describes the philosophy, architecture, and functionalities of the toolkit and provides illustrative examples through interactive notebooks. NeuroPycon is available for download via github (https://github.com/neuropycon) and the two principal packages are documented online (https://neuropycon.github.io/ephypype/index.html, and https://neuropycon.github.io/graph pype/index.html). Future developments include fusion of multi-modal data (eg. MEG and fMRI or intracranial EEG and fMRI). We hope that the release of NeuroPycon will attract many users and new contributors, an