Dissertations / Theses on the topic 'Brain variability'

The brain activities are characterized by spontaneous and persistent irregular fluctuations in space and time. Criticality theory from statistical physics has been proposed as a principle to explain the variability in normal brain spontaneous activity and has suggested the functional benefits of variability, such as maximized dynamic range of response to stimuli and information capacity. In parallel, the brains show variability in other aspects, such as the structural heterogeneity across brain regions, the intra-individual variability across experimental trials, and the behavior difference across groups and individuals. The associations between the variability of spontaneous activities and these different types of structural, intra and inter-individual variabilities remain elusive. My doctoral study thus aimed to bridge the brain variability and the above-mentioned variations based on criticality theory and analysis of empirical data. As a preparatory analysis, we first collected evidence to prove criticality in human functional magnetic resonance imaging (fMRI) data. The advanced statistical criteria were used to exclude potential artefacts that can induce power-law scaling without the mechanism of criticality. In the first part of the study, we addressed methodological issue and tested whether several measures of either spatial or temporal complexity due to experimental limitations could be reliable proxy of spatiotemporal variability (related to criticality) in vivo. The high spatiotemporal resolutions of whole-cortex optical voltage imaging in mice brain during the waking up from anesthesia enabled simultaneous investigation of functional connectivity (FC), Multi-Scale Entropy (MSE, measure of temporal variability), Regional Entropy (RE, quantity of spatiotemporal variability) and the interdependency among them under different brain states. The results suggested that MSE and FC could be effective measures to capture spatiotemporal variability under limitation of imaging modalities applicable to human subjects. This study also lays methodological basis for the third study in this thesis. In the second study, we explored the interaction between spontaneous activity and evoked activity from mice brain imaging under whisker stimulus. The whisker stimulus will first evoke the local activation in sensory cortex and then trigger whole-cortex activity with variable patterns in different experimental trials. This trial-to-trial variability in the cortical evoked component was then attributed to the changes of ongoing activity state at stimulus onset. The study links ongoing activity variability and evoked activity variability, which further consolidates the association between ongoing activity and brain functions. In the third study, we measured the signal variability of the whole brain from resting state fMRI, and developed the multivariate pattern of cortical entropy, called entropy profile, as reliable and interpretable biomarker of individual difference in cognitive ability. We showed that the whole cortical entropy profile from resting- state fMRI is a robust personalized measure. We tested the predictive power for general and specific cognitive abilities based on cortical entropy profiles with out- of-sample prediction. Furthermore, we revealed the anatomical features underlying cross-region and cross-individual variations in cortical entropy profiles. This study provides new potential biomarker based on brain spontaneous variability which could benefit the applications in psychology and psychiatry studies. The whole study laid a foundation for brain criticality-/variability-based studies and applications and broadened our understanding of the associations between neural structures, functional dynamics and cognitive ability

La même entrée sensorielle ne provoque pas toujours la même réaction. Dans les expériences en laboratoire, un stimulus donné peut engendrer une réponse différente à chaque nouvel essai, en particulier à proximité du seuil sensoriel. Ce phénomène est généralement attribué à une source de bruit non spécifique qui affecte la représentation sensorielle du stimulus ou le processus décisionnel. Dans cette thèse, nous examinons l'hypothèse selon laquelle cette variabilité des réponses peut être attribuée en partie à des fluctuations mesurables et spontanées de l'état cérébral. Dans ce but, nous développons et évaluons deux ensembles d'outils. L’un est un ensemble de modèles et de méthodes psychophysiques permettant de suivre les variations de la performance perceptive avec une bonne résolution temporelle et avec précision, sur différentes échelles de temps. Ces méthodes s’appuient sur des procédures adaptatives initialement développées pour mesurer efficacement les seuils de perception statiques et sont étendues ici dans le but de suivre des seuils qui varient au cours du temps. Le deuxième ensemble d'outils que nous développons comprend des méthodes d'analyse de données pour extraire de signaux d’électroencéphalographie (EEG) une quantité prédictive de la performance comportementale à diverses échelles de temps. Nous avons appliqué ces outils à des enregistrements conjoints d’EEG et de données comportementales collectées pendant que des auditeurs normo-entendants réalisaient une tâche de discrimination de fréquence sur des stimuli auditifs proche du seuil de discrimination. Contrairement à ce qui a été rapporté dans la littérature concernant des stimuli visuels, nous n'avons pas trouvé de preuve d’un quelconque effet des oscillations EEG spontanées de basse fréquence sur la performance auditive. En revanche, nous avons trouvé qu'une part importante de la variabilité des jugements peut s’expliquer par des effets de l'historique récent des stimuli et des réponses sur la décision prise à un moment donné
The same sensory input does not always trigger the same reaction. In laboratory experiments, a given stimulus may elicit a different response on each trial, particularly near the sensory threshold. This is usually attributed to an unspecific source of noise that affects the sensory representation of the stimulus or the decision process. In this thesis we explore the hypothesis that response variability can in part be attributed to measurable, spontaneous fluctuations of ongoing brain state. For this purpose, we develop and test two sets of tools. One is a set of models and psychophysical methods to follow variations of perceptual performance with good temporal resolution and accuracy on different time scales. These methods rely on the adaptive procedures that were developed for the efficient measurements of static sensory thresholds and are extended here for the purpose of tracking time-varying thresholds. The second set of tools we develop encompass data analysis methods to extract from electroencephalography (EEG) signals a quantity that is predictive of behavioral performance on various time scales. We applied these tools to joint recordings of EEG and behavioral data acquired while normal listeners performed a frequency-discrimination task on near-threshold auditory stimuli. Unlike what was reported in the literature for visual stimuli, we did not find evidence for any effects of ongoing low-frequency EEG oscillations on auditory performance. However, we found that a substantial part of judgment variability can be accounted for by effects of recent stimulus-response history on an ongoing decision

It is essential to characterize and quantify naturally occurring morphometric changes in the human brain when investigating the onset or progression of neurodegenerative disorders. The aim of this thesis is to characterize the properties and measure the performance of several popular automated magnetic resonance image analysis tools dedicated to brain morphometry. The thesis begins with an overview of morphometric analysis methods, followed by a literature review focusing on cortical parcellation protocols. Our work identified unanimous protocol weaknesses across all packages in particular issues when addressing cortical variability. The next chapters present a ground truth dataset and a dedicated software to analyse manually parcellated data. The dataset (https://datashare.is.ed.ac.uk/handle/10283/2936) includes 10 healthy middle-aged subjects, whose metrics we used as reference against automated tools. To develop the ground truth dataset, we also present a manual parcellation protocol (https://datashare.is.ed.ac.uk/handle/10283/3148) providing step-by-step instructions for outlining three cortical gyri known to vary with ageing and dementia: the superior frontal gyrus, the cingulate gyrus and the supramarginal gyrus. The software, Masks2Metrics (https://datashare.is.ed.ac.uk/handle/10283/3018), was built in Matlab to calculate cortical thickness, white matter surface area, and grey matter volume from 3D binary masks. Characterizing these metrics allowed further understanding of the assumptions made by software when creating and measuring anatomical parcels. Next, we present results from processing the raw T1-weighted volumes in the latest versions of several automated image analysis tools-FreeSurfer (versions 5.1 and 6.0), BrainGyrusMapping, and BrainSuite (version 13a)- against our ground truth. Tool repeatability for the same system was confirmed as multiple runs yielded identical results. Compared to our ground truth, the closest results were generated by BrainGyrusMapping for volume metrics and by FreeSurfer 6.0 for thickness and surface area metrics. In conclusion, our work sheds light on the significance of clearly detailed parcellation protocols and accurate morphometric tools due to the implications that they both will have. We therefore recommend extra caution when selecting image analysis tools for a study, and the use of independent publicly available ground truth datasets and metrics tools to assist with the selection process.

Models of whole-brain connectivity are valuable for understanding neurological function. This thesis seeks to develop an optimal framework for extracting models of whole-brain connectivity from clinically acquired diffusion data. We propose new approaches for studying these models. The aim is to develop techniques which can take models of brain connectivity and use them to identify biomarkers or phenotypes of disease. The models of connectivity are extracted using a standard probabilistic tractography algorithm, modified to assess the structural integrity of tracts, through estimates of white matter anisotropy. Connections are traced between 77 regions of interest, automatically extracted by label propagation from multiple brain atlases followed by classifier fusion. The estimates of tissue integrity for each tract are input as indices in 77x77 ”connectivity” matrices, extracted for large populations of clinical data. These are compared in subsequent studies. To date, most whole-brain connectivity studies have characterised population differences using graph theory techniques. However these can be limited in their ability to pinpoint the locations of differences in the underlying neural anatomy. Therefore, this thesis proposes new techniques. These include a spectral clustering approach for comparing population differences in the clustering properties of weighted brain networks. In addition, machine learning approaches are suggested for the first time. These are particularly advantageous as they allow classification of subjects and extraction of features which best represent the differences between groups. One limitation of the proposed approach is that errors propagate from segmentation and registration steps prior to tractography. This can cumulate in the assignment of false positive connections, where the contribution of these factors may vary across populations, causing the appearance of population differences where there are none. The final contribution of this thesis is therefore to develop a common co-ordinate space approach. This combines probabilistic models of voxel-wise diffusion for each subject into a single probabilistic model of diffusion for the population. This allows tractography to be performed only once, ensuring that there is one model of connectivity. Cross-subject differences can then be identified by mapping individual subjects’ anisotropy data to this model. The approach is used to compare populations separated by age and gender.

Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common psychiatric disorder of childhood and manifests as symptoms of developmentally inappropriate inattention, impulsivity and hyperactivity. Although numerous deficits have been identified in ADHD, one of the most consistent findings is that patients with ADHD are more variable in the speed of their reaction time (RT) responses on neuropsychological tasks than control children. In 2008, the default-mode interference hypothesis of ADHD was introduced by Sonuga-Barke and Castellanos as a biologically plausible account of this increased within-subject variability in ADHD. This hypothesis suggests that some patients with ADHD might not effectively attenuate low frequency resting brain activity from rest to task and that these low frequency oscillations may then intrude onto task performance and cause periodic attention lapses. These periodic attention lapses would manifest as increased variability in RT data. The present thesis provided the first test of this hypothesis using DC-EEG. We assessed the power in very low frequency EEG bands (< .1 Hz) during rest and during goal-directed task performance in two samples. First was a sample of adults who self-reported either high- or low-ADHD scores, and second was a clinic referred sample of adolescent boys with ADHD and age- and gender-matched controls. We found that in both samples, low frequency EEG was generally attenuated from rest to task, but the degree of this attenuation was lower in ADHD or inattentive participants compared to controls. We also found that periodicity was evident in RT data, and that there was synchrony between low frequency fluctuations in RT data and low frequency EEG. These findings provide some initial support for the default mode interference hypothesis. The findings also highlight the potential involvement of low frequency electrodynamics in attentional processes and in the pathophysiology of ADHD.

Motion capture technology and Magnetic Resonance Imaging with Diffusion Tensor Imaging (MRI-DTI) were used in this work to detect subtle abnormalities in patients with mild traumatic brain injury (MTBI). A new concept, termed dynamic variability, is introduced in this work to quantify and localize gait variability. Three chronic MTBI patients were recruited from the Veterans Affair Medical Center in Iowa City, IA, and three healthy controls with height, weight, and gender matched to the patients were recruited from the Reserve Officers' Training Corps in Iowa City, IA. Kinematic and kinetic data of the subjects were collected during the performance of three gait testing scenarios. The first test involved single-task walking and was used as a baseline. The second and third tests were dual tasks that involved walking while performing a cognitive or motor task and were designed to magnify gait abnormalities. The results showed that MTBI patients had reduced gait velocity, shortened stride length, and larger step width; findings that are consistent with those published in the literature. The new dynamic variability factor found that, as compared to controls, MTBI patients had more variability in their hip and ankle joint moments. MRI-DTI has been used to detect dysfunction of the major white matter tracts in chronic MTBI patients; although, the sample size of this study was too small to detect a difference between the MTBI and control subjects. The imaging and gait abnormalities are suggestive of frontal lobe-white matter tracts dysfunction.

Nicotine and stimulant medications share similar neurotransmission-related effects in the pre-frontal cortex, but it is unclear if nicotine has a similar benefit on inhibitory control. Impulsivity resulting from deficits in inhibition and sustained attention have been posited as a unifying mechanism of adult ADHD psychopathology. These deficits were quantified in the present study using Go/No-Go task accuracy and intra-individual reaction time variability (RTV). The electro-cortical P3a amplitude indexes inhibitory cognitive processes and sustained attention-related frontal cortex activation in response to infrequent NOGO stimuli. However, little work has characterized the effects of nicotine on P3a or RTV in adult ADHD. Therefore, the effects of the nicotine patch on NOGO P3a amplitude, inhibitory accuracy, and RTV were assessed in non-medicated ADHD adults (12 smokers, 12 never-smokers) in a double-blind, placebo-controlled, repeated-measures design. Nicotine patch, relative to placebo patch, significantly increased NOGO inhibitory accuracy, significantly decreased GO RTV, and significantly increased NOGO P3a peak amplitude at four frontal electrode sites. These results suggest that the nicotine reduces impulsivity in adults with ADHD. The implications of these basic findings to the clinical assessment and treatment of ADHD are discussed. Additional reports at both the basic and clinical levels are needed to confirm and extend these findings.

Deep brain stimulation (DBS) is a neurosurgical intervention now established for the treatment of movement disorders. For the treatment of chronic pain refractory to medical therapies, several prospective case series have been reported, but few centres worldwide have published findings from patients treated during the last decade using current standards of technology. This thesis seeks to survey the current clinical status of DBS for pain, investigate its mechanisms and their interactions with autonomic function, its clinical limitations and ablative alternatives. Presented first is a review of the current status of analgesic DBS including contemporary clinical studies. The historical background, scientific rationale, patient selection and assessment methods, surgical techniques and results are described. The clinical outcomes of DBS of the sensory thalamus and periventricular / periaqueductal grey (PAVG) matter in two centres are presented including results from several pain and quality of life measures. A series of translational investigations in human subjects receiving DBS for pain elucidating mechanisms of analgesic DBS and its effects upon autonomic function are then presented. Single photon emission tomography comparing PAVG, VP thalamus and dual target stimulation is described. Somatosensory and local field potential (LFP) recordings suggesting PAVG somatotopy are shown. ABPM results demonstrating changes with PAVG DBS are given and Portapres studies into heart rate variability changes with ventral PAVG DBS are detailed. Investigations using naloxone are then shown to hypothesise separate dorsal opioidergic and ventral parasympathetic analgesic streams in the PAVG. Finally, cingulotomy in lung cancer to relieve pain and dyspnoea results are discussed in the context of altering pain and autonomic function by functional neurosurgery. Pain and autonomic interactions and mechanisms in deep brain surgery for pain are then discussed alongside its limitations with proposals made for optimising treatment and improving outcomes.

The connection between the heart and the brain was coined 150 years ago by Claude Bernard and has since then been an interesting topic of research. Scientists have for many years searched for biomarkers of stress and health to map the current status of the organism. Heart rate variability (HRV) has been presented as an emerging objective and promising marker to achieve just this. HRV refers to the beat-to-beat variations in heart rate (HR) and is thought to be a useful signal in understanding and providing valuable information of the autonomic nervous system (ANS). HRV has also been proposed as a marker of stress and health by sharing neural correlates and functions with several executive functions. This thesis identified several regions, including the ventromedial prefrontal cortex and the amygdala, in which significant associations across several studies were found between threat and safety perception, emotional regulation and HRV. This suggest that HRV may function as an index of the brain mechanism and structures that guide and govern adaptive functions and thus, provide researchers with valuable information regarding the stress and health of an organism. Two major theoretical frameworks, which articulate and explain the role of HRV as an indicator of individuals ability to adapt to environmental changes and cope under stress is presented. HRV can also be used in practice in several ways and a growing and promising field of application is HRV biofeedback.

Background Even though more than 600 stroke treatments have been shown effective in preclinical studies, clinically proven treatment alternatives for cerebral infarction remain scarce. Amongst the reasons for the discrepancy may be methodological shortcomings, such as high mortality and outcome variability, in the preclinical studies. A common approach in animal stroke experiments is that A) focal cerebral ischemia is inflicted, B) some type of treatment is administered and C) the infarct sizes are assessed. However, within this paradigm, the researcher has to make numerous methodological decisions, including choosing rat strain and type of surgical procedure. Even though a few studies have attempted to address the questions experimentally, a lack of consensus regarding the optimal methodology remains. Methods We therefore meta-analyzed data from 502 control groups described in 346 articles to find out how rat strain, procedure for causing focal cerebral ischemia and the type of filament coating affected mortality and infarct size variability. Results The Wistar strain and intraluminal filament procedure using a silicone coated filament was found optimal in lowering infarct size variability. The direct and endothelin methods rendered lower mortality rate, whereas the embolus method increased it compared to the filament method. Conclusions The current article provides means for researchers to adjust their middle cerebral artery occlusion (MCAo) protocols to minimize infarct size variability and mortality.

Funding Agencies|County Council of Ostergotland, Sweden||

La radiation adaptative des Equoidea est encore mal comprise en raison notamment de la méconnaissance de la phylogénie de cette super-famille. La principale irrésolution de ces relations de parenté porte sur les pachynolophes, Equoidea européens rapprochés des Equidae ou des Palaeotheriidae. Pendant une grande part de l'Éocène, l'Europe est isolée et subit à la fin de cette période de profonds changements climatiques. Lors de la Grande Coupure son isolement s'achève, tandis que l'aridité du climat s'installe, et des faunes migrantes provoquent l'extinction de nombreux groupes endémiques. Un Equoidea européen basal, richement représenté par un matériel bien préservé permet d'appuyer une des hypothèses phylogénétiques les plus récentes. Cependant, les caractères couramment utilisés pour débattre de cette question n'apportent pas de réponse claire et définitive. Aussi, cette étude se propose de mener des investigations sur des régions encore peu explorées de ces animaux comme le neurocrâne, grâce à la microtomographie (CT scan), qui permet un accès non destructif aux structures (encéphale, pétreux, labyrinthe osseux, sinus). Outre l'intérêt phylogénétique, ces organes peuvent, de par leurs fonctions, receler un intérêt paléoécologique. Jusqu'à présent, peu d'études à large échelle ont porté sur ces structures chez les Perissodactyla, s'agissant pour la plupart de mentions anecdotiques. Comme préalable indispensable, une étude modèle a été réalisée sur un Equidae sauvage actuel afin de mieux appréhender la variabilité de ces structures méconnues. Pour la première fois, un large échantillon d'Equoidea européens a été scanné et leurs structures neurocrâniennes reconstruites en trois dimensions virtuelles. Ce sont au total 20 espèces qui ont été échantillonnées, couvrant l'évolution de ces animaux de leur origine à leur extinction, pendant plus de 20 millions d'années. Leurs crânes ont été scannés, leurs structures internes reconstruites, comparées et analysées au moyen de la cladistique. Une nouvelle hypothèse phylogénétique propose des relations de parenté intra-Equoidea et montre la pertinence des caractères neurocrâniens, tout en conduisant à envisager une étude plus vaste. Les Palaeotheriidae apparaissent comme un groupe très diversifié, notamment au regard des Equidae éocènes d'Amérique du Nord, et caractérisé par une évolution en mosaïque. Ils connaissent une évolution cérébrale précoce par rapport aux faunes contemporaines (Equidae, Cetartiodactyla, Carnivora), ce qui, via le développement de nouvelles stratégies adaptatives, pourrait expliquer partiellement cette grande diversification familiale. Un parallèle est envisagé avec l'évolution endémique des Notoungulata, qui semblent eux aussi montrer une complexification cérébrale précoce. Cependant, face à un environnement biotique et abiotique bouleversé (fin de l'Éocène et lors de la Grande Coupure), ces structures complexes impliquant un coût métabolique important et une trop grande spécialisation, avec en conséquence, moins de potentiel adaptatif, auraient pu les désavantager et les conduire à l'extinction
The Equoidea adaptive radiation still remains badly known, especially due to the ignorance of their phylogeny. The main indecision of these relationships concerns the pachynolophs, European Equoidea either approached to the Equidae or to the Palaeotheriidae. During a great part of the Eocene times, Europe was isolated, and, at the end of this period, has undergone strong climatic changes. That isolation ended at the « Grande Coupure » event, whereas an arid climate moved, and migrant faunas caused the extinction of many endemic groups. A basal European Equoidea, richly represented by well-preserved material, can support one of the latest phylogenetic hypotheses. However, commonly used characters to discuss this issue do not provide a clear and definitive answer.Therefore, this study aims to investigate on unexplored regions of these animals as the neurocranium through microtomography (CT), which allows access to non-destructive structures (brain, petrosal, bony labyrinth, and sinus).Furthermore phylogenetic interest these bodies may, through their functions, harbor paleoecological interest. Until now, few large-scale studies have focused on those structures in the Perissodactyla, with regard to most were anecdotal reports. As a prerequisite, a model study was performed on a wild current Equidae to better understand the variability of these unknown structures. For the first time, a large sample of European Equoidea has been scanned and their neurocranium structures virtually reconstructed in three-dimensions. A total of 20 species were sampled, covering the evolution of these animals from their origin to their extinction, for over 20 million years. Their skulls were scanned; their internal structures reconstructed compared and analyzed using cladistics. A new phylogenetic hypothesis provides intra Equoidea relationships and shows the relevance of neurocranium characters, while driving to consider a larger study. The Palaeotheriidae appears as a highly diverse group, particularly with regard to Eocene Equidae in North America, and characterized by a mosaic evolution. Their brain evolved earlier than that of contemporary faunas (Equidae, Cetartiodactyla, Carnivora); which may partially explain the strong diversification of that family, through the development of new adaptive strategies

The focus of this project falls largely within the realm of investigating the development of brain-cognition relations from a developmental cognitive neuroscience perspective. There were two main goals of this study. First, this study focused on the regional differences in baseline-to-working memory task brain electrical activity and specifically investigated the hypothesis that there would be an increasing specificity of task EEG power between 3½ and 4½ years of age. The second goal of this study was to investigate the sources of variability in working memory function and to specifically examine the contributions of task-related EEG, the regulatory dimensions of temperament, and linguistic ability to the prediction of working memory performance. This second study objective included an investigation of the relation between working memory and each of these variables (1) separately, (2) in conjunction with age, and (3) collectively to examine any multivariate contributions to the explanation of variance in working memory function in early childhood. The results of this study provided some support to the increasing specificity of baseline-to-task EEG power hypothesis. Specifically, an increase in brain electrical activity was found for four scalp regions at age 4 and only two regions at age 4½. These findings coupled with previous work indicating an increase in task brain electrical activity for only one region at age 4½ suggest that cortical specialization is occurring during the early childhood years. With regard to the investigation of sources of variability working memory function, age, brain electrical activity, temperament, and linguistic functioning were all found to be meaningful variables in the explanation of variance in working memory. However, linguistic functioning " and specifically language receptivity " was found to be the strongest and most meaningful associate of working memory function. Additional findings of interest included the differential associations demonstrated between working memory and temperament for each age group and also an increase in the strength of the relation between working memory and language across the three ages.
Ph. D.

This dissertation is devoted to study of complex systems in human physiology particularly heartbeats and brain dynamics. We have studied the dynamics of heartbeats that has been a subject of investigation of two independent groups. The first group emphasized the multifractal nature of the heartbeat dynamics of healthy subjects, whereas the second group had established a close connection between healthy subjects and the occurrence of crucial events. We have analyzed the same set of data and established that in fact the heartbeats are characterized by the occurrence of crucial and Poisson events. An increase in the percentage of crucial events makes the multifractal spectrum broader, thereby bridging the results of the former group with the results of the latter group. The crucial events are characterized by a power index that signals the occurrence of 1/f noise for complex systems in the best physiological condition. These results led us to focus our analysis on the statistical properties of crucial events. We have adopted the same statistical analysis to study the statistical properties of the heartbeat dynamics of subjects practicing meditation. The heartbeats of people doing meditation are known to produce coherent fluctuations. In addition to this effect, we made the surprising discovery that meditation makes the heartbeat depart from the ideal condition of 1/f noise. We also discussed how to combine the wave-like nature of the dynamics of the brain with the existence of crucial events that are responsible for the 1/f noise. We showed that the anomalous scaling generated by the crucial events could be established by means of a direct analysis of raw data. The efficiency of the direct analysis procedure is made possible by the fact that periodicity and crucial events is the product of a spontaneous process of self-organization. We argue that the results of this study can be used to shed light into the nature of this process of self-organization.

Brain neural activity generates electrical discharges, which manifest as electrical and magnetic potentials around the scalp. Those potentials can be registered with magnetoencephalography (MEG) and electroencephalography (EEG) devices. Data acquired by M/EEG is extremely difficult to work with due to the inherent complexity of underlying brain processes and low signal-to-noise ratio (SNR). Machine learning techniques have to be employed in order to reveal the underlying structure of the signal and to understand the brain state. This thesis explores a diverse range of machine learning techniques which model the structure of M/EEG data in order to decode the mental state. It focuses on measuring a subject's variability and on modeling intrasubject variability. We propose to measure subject variability with a spectral clustering setup. Further, we extend this approach to a unified classification framework based on Laplacian regularized support vector machine (SVM). We solve the issue of intrasubject variability by employing a model with latent variables (based on a latent SVM). Latent variables describe transformations that map samples into a comparable state. We focus mainly on intrasubject experiments to model temporal misalignment.

L’étude de la complexité de l’anatomie du cerveau humain nécessite la caractérisation des paramètres multimodaux et multi-échelle obtenus par des techniques de neuroimagerie récentes. Pour ce travail de thèse nous avons tiré profit d’un logiciel automatique actuel d’analyse surfacique d’images cérébrales afin d’extraire les phénotypes structuraux du cortex cérébral humain, c’est-à-dire l’épaisseur corticale, l’aire de la surface, la profondeur sulcale, la courbure et le contenu en myéline intracorticale. L’objectif principal de ce travail a été de caractériser des variables structurales multimodales sur une large base de données de plus de 450 adultes sains âgés de 18 à 57 ans (base de données BIL&GIN) dans le but de décrire la variabilité interindividuelle de l’organisation structurale du cerveau et notamment la recherche de marqueurs de la maturation cérébrale et de la latéralisation. Nous avons tout d’abord pris l’exemple du gyrus de Heschl, support anatomique du cortex auditif primaire, qui possède une grande variabilité en lien avec l’existence de différents profils de duplication du gyrus couplée à de fortes différences interhémisphériques. Nous avons montré qu’une duplication partielle ou complète du gyrus de Heschl était associée à des modifications locorégionales d’épaisseur corticale, d’aire de la surface et de myéline localisée postérieurement à ce gyrus et dans le planum temporale, ces deux régions étant impliquées dans le traitement du langage. Dans une deuxième étude, nous avons recherché les modifications structurales du cortex associées à la maturation tardive (entre 18 et 30 ans) et à l’atrophie corticale liée au vieillissement. Nous avons montré que l’établissement d’un index de maturation basé sur l’intégration de l’épaisseur corticale et de la myéline intracorticale améliorait la discrimination entre les 2 profils de modifications de la substance grise pendant ces deux périodes de la vie. Finalement, nous avons caractérisé les asymétries corticales en utilisant un recalage surfacique des hémisphères qui s’affranchit des différences de morphologie sulcale et de position entre les deux hémisphères. Nous avons mis en évidence des régions pour lesquelles les asymétries d’épaisseur et de surface étaient concordantes (asymétrie gauche ou droite pour les deux variables anatomiques) et des régions pour lesquelles les asymétries étaient opposées (gauche pour l’une des variables et droite pour l’autre). Environ 20% des régions qui montraient une asymétrie d’épaisseur et d’aire présentaient des corrélations négatives entre ces variables. Il est frappant de constater que les deux régions ayant les asymétries les plus fortes, le planum temporale et le sillon temporal supérieur, ont des corrélations positives entre leurs asymétries d’épaisseur et d’aire. Le planum temporale possède une asymétrie gauche à la fois pour l’épaisseur et l’aire alors que le sillon temporal supérieur a une asymétrie droite pour les deux variables. Cette étude démontre qu’il existe des corrélations entre les asymétries d’épaisseur et d’aire qui sont caractéristiques de l’organisation du cortex. Ces régions sont des sites clé pour lesquels il reste maintenant à étudier la pertinence en tant que marqueurs de la latéralisation cérébrale et leurs corrélats fonctionnels
Studying the complexity of the human brain anatomy requires the characterization of multimodal and multiscale features obtained by recent in vivo neuroimaging techniques. In the present thesis, we benefited from up to date automated surface-based brain image analysis software to extract structural phenotypes of the human cerebral cortex, namely the cortical thickness, the surface area, the sulcal depth, the curvature and the intracortical myelin content. The principal aim of this work was to characterize multimodal structural variables on a large database of 450 healthy adults aged from 18 to 57 years (the BIL&GIN database) in order to describe the inter-individual variability of brain structural organization and notably the research of candidate markers for brain maturation and lateralization. We first took the example of the Heschl’s gyrus hosting the primary auditory cortex and having high variability due to the presence of different pattern of gyrus duplication coupled with strong interhemispheric differences. We showed that the partial or complete duplication of the Heschl’s gyrus was associated to loco-regional modifications in terms of cortical thickness, surface area and myelin located posteriorly to this gyrus and in the planum temporale, this two regions being implied in language processing. In a second study, we investigated the cortical structural modifications associated to late maturation (between 18 and 30 years) and cortical atrophy linked to aging. We revealed that the computation of a maturation index based on an integration of cortical thickness and intracortical myelin improved the discrimination of two different patterns of grey matter changes during these different stages of life. Finally, we characterized cortical asymmetries using a specific hemisphere surface matching which removed differences in sulcal morphology and position between both hemispheres. We highlighted regions where thickness and surface area asymmetries were concordant (leftward or rightward asymmetry for both anatomical variables) and regions of opposite asymmetries (leftward for one and rightward for the other). About 20% of regions that showed cortical thickness and surface area asymmetries presented negative correlation between these variables. It is striking that the two regions with the strongest anatomical asymmetries; the planum temporale and the superior temporal sulcus had rather positive asymmetry correlations. The planum temporale presented a leftward asymmetry of both cortical thickness and area while the superior temporal sulcus showed a right asymmetry of the two variables. This study demonstrated that there were correlations between thickness and surface area asymmetries, characteristics of the cortex organization. These areas are key sites for which it now remains to study the anatomical relevance as markers of brain lateralization and its functional correlates

Several studies reported training-induced improvements in executive function tasks and also observed transfer to untrained tasks. However, the results are mixed and there is a large interindividual variability within and across studies. Given that training-related performance changes would require modification, growth or differentiation at the cellular and synaptic level in the brain, research on critical moderators of brain plasticity potentially explaining such changes is needed. In the present study, a pre-post-follow-up design (N = 122) and a 3-weeks training of two response inhibition tasks (Go/NoGo and Stop-Signal) was employed and genetic variation (Val66Met) in the brain-derived neurotrophic factor (BDNF) promoting differentiation and activity-dependent synaptic plasticity was examined. Because Serotonin (5-HT) signaling and the interplay of BDNF and 5-HT are known to critically mediate brain plasticity, genetic variation in the 5-HTT gene-linked polymorphic region (5-HTTLPR) was also addressed. The overall results show that the kind of training (i.e., adaptive vs. non-adaptive) did not evoke genotype-dependent differences. However, in the Go/NoGo task, better inhibition performance (lower commission errors) were observed for BDNF Val/Val genotype carriers compared to Met-allele ones supporting similar findings from other cognitive tasks. Additionally, a gene-gene interaction suggests a more impulsive response pattern (faster responses accompanied by higher commission error rates) in homozygous l-allele carriers relative to those with the s-allele of 5-HTTLPR. This, however, is true only in the presence of the Met-allele of BDNF, while the Val/Val genotype seems to compensate for such non-adaptive responding. Intriguingly, similar results were obtained for the Stop-Signal task. Here, differences emerged at post-testing, while no differences were observed at T1. In sum, although no genotype-dependent differences between the relevant training groups emerged suggesting no changes in the trained inhibition function, the observed genotype-dependent performance changes from pre- to post measurement may reflect rapid learning or memory effects linked to BDNF and 5-HTTLPR. In line with ample evidence on BDNF and BDNF-5-HT system interactions to induce (rapid) plasticity especially in hippocampal regions and in response to environmental demands, the findings may reflect genotype-dependent differences in the acquisition and consolidation of task-relevant information, thereby facilitating a more adaptive responding to task-specific requirements.

Le comportement empathique d’autrui peut avoir un effet positif sur le ressenti douloureux. Dans le milieu médical, cette stratégie est encouragée par les soignants pour interagir et soutenir les patients. A l’inverse, la non-empathie c’est-à-dire une attitude négative envers la personne qui souffre est proscrite par crainte d’effets délétères. Comment l’empathie et la non-empathie d’autrui influencent-elles la perception douloureuse ? Investiguer cette problématique est l’objectif de ce travail de thèse. Dans la première partie de ce travail, nous avons construit et validé une manipulation expérimentale nous permettant de délivrer des feedbacks empathiques à des sujets recevant des stimulations nociceptives. Les commentaires empathiques ont réduit significativement l’intensité douloureuse des sujets (-12%). En revanche, les commentaires non-empathiques n’ont pas changé la cotation douloureuse, comparativement à une situation neutre. Ils sont néanmoins suffisants pour influencer la réponse autonomique à la douleur. Les analyses d’imagerie cérébrale (IRMf) ont montré que la modulation de l’intensité douloureuse par l’empathie passerait par des interactions entre les structures du réseau par défaut (vmPFC et CCP/Prec), le DLPFC et l’insula postérieure. Seule l’activité du CCP/Prec est capable d’intégrer le contenu des feedbacks empathiques. Cette structure en changeant sa connectivité fonctionnelle engagerait des mécanismes de contrôle (vmPFC) capables d’interagir avec l’insula postérieure et antérieure pour réduire la perception douloureuse. L’étude d’un tel système de modulation à l’échelle du réseau fonctionnel de la douleur a apporté des résultats concordants
Other’s empathetic behavior can have a positive effect on pain perception. In medical setting it is a known strategy from caregivers to support and interact with their patients. Conversely, unempathy, having a negative attitude towards the suffering person is outlawed out of fear of induce deleterious effects. How do empathy and unempathy from others influence pain perception? Investigating this issue is the aim of this thesis. First, we built and approved an experiment delivering different types of empathetic feedbacks to subjects who received nociceptive stimulations. The empathetic comments significantly alleviated subjects’ pain ratings (-12 %). The unempathetic comments did not influence the subjects’ pain ratings in comparison with neutral situation. However, they influenced autonomic response related to pain. Neuro-imaging studies shown that the pain intensity modulation related to empathetic feedbacks involved interactions between the core structures of the default network (vmPFC and PCC/Prec), the DLPFC and the posterior insula. Functional activations revealed that only the posterior cingulate cortex/precuneus activity was able to integrate the empathetic feedbacks’ content. Changing its functional connectivity, this structure would engage control mechanisms (vmPFC) able to interact with the posterior and anterior insula to reduce pain perception. The study of such modulation system at the level of the pain functional network provided consistent results

Background Although trainers and athletes consider ‘good timing skills’ to be critical for optimal sport performance, little is known in regard to how sport-specific skills may benefit from timing training. Thus, assuming that all motor performances are mediated by an internal timing mechanism, enhanced motor timing is expected to have positive effects on both planning and execution of movement performance, and consequently on complex sports actions as golf or soccer. Accordingly, in order to increase our knowledge of the importance of motor timing and possible effects of timing training, this thesis examines the effects of synchronized metronome training (SMT), thought to improve the execution of motor programs and to enhance motor skills in golf and soccer players. Methods Study I examined the effects of SMT on motor timing abilities and its potential effect on golf shot accuracy and consistency in 25 experienced male golfers. Additionally, Study II examined the effects of SMT on the spatiotemporal movement organisation and dynamics of the golf swing performance, as captured by kinematic measurements and analyses in thirteen male golfers. Study III examined the effect of SMT on accuracy and variability in a soccer specific, cross-pass task in elite and sub-elite female soccer players. Moreover, the underlying brain activity was assessed by means of functional magnetic resonance imaging (fMRI) to investigate the corresponding neural activity when passively observing the cross-pass task, and the possible pre- to post training effects. Results SMT was shown to improve motor timing ability, by means of less timing asynchrony and with associated changes in timing variability, in both golf- and soccer-players. Additionally, significant improvements in golf shot and soccer cross-pass performance, by means of significant increase in outcome accuracy combined with a decrease in outcome variability was found. From the kinematic investigation in Study II, results indicate that improved motor timing, as an effect of SMT, lead to a more coordinated and dynamic swing performance, and with decreased variability in the temporal structure of the swing motion. Finally, it was found that SMT induces changes in the activity of the action observation network (AON), underpinning action observation and action prediction, by means of decreased activation within bilateral cerebellum, fusiform gyrus and superior temporal gyrus. These findings hint at a more efficient pattern of neural recruitment during action observation, after SMT. Conclusion In summary, this thesis provides evidence that four weeks of SMT improved the participant’s motor timing and synchronization abilities, and showed influence on both behavioral and neurophysiological motor programs and skill performance in golf and soccer players. Thus, by improved outcome accuracy and decreased variability, affecting the coordinated movement pattern and organisation, as well as affecting the associated underlying brain activation.

Background: Children born very preterm are at an elevated risk of behavioural adjustment problems, particularly Attention-Deficit/Hyperactivity Disorder (ADHD) or inattention/hyperactivity difficulties. Importantly, these risks remain even after controlling for the effects of social risk factors correlated with very preterm birth. Behavioural outcomes in follow-up studies of children born very preterm are typically assessed using parent reports only. However, the extent to which behavioural problems are evident across multiple contexts (i.e., parent or teacher report) is not well known. Furthermore, the neonatal neuropathology underlying these behavioural difficulties in this population remains poorly understood. Aims: Three research studies are undertaken primarily to examine: (1) the degree of agreement between parent and teacher reports of child behaviour adjustment, and the extent of situational (parent- or teacher-identified) and pervasive (parent- and teacher-identified) inattention/hyperactivity problems at ages 4, 6, and 9 years among children born very preterm and full-term; (2) to cross-validate the classification of children with situational and pervasive inattention/hyperactivity problems across the ages of 4 to 9, for a clinical diagnosis of ADHD at age 9 years; (3) to document risk of persistent ADHD symptoms between ages 4 and 9 years in children born very preterm, and to examine associations between qualitative measures of neonatal cerebral white matter injury/abnormality and quantitative volumetric measures of cerebral structural development, identified using magnetic resonance imaging (MRI) at term equivalent age, and children’s later risks of persistent symptoms. Persistent ADHD symptoms were defined as behavioural inattention/hyperactivity problems shown at ages 4, 6, and 9, along with meeting the criteria for an ADHD clinical diagnosis at age 9 years. Methods: As part of a prospective longitudinal study, a regional cohort of 110 very preterm (≤ 33 weeks of gestation) and 113 full-term children born between 1998 and 2000 were studied from birth to age 9 years. At term equivalent age, all children born very preterm and 10 children born full-term underwent an MRI scan that was analysed using qualitative measures for cerebral white matter injury/abnormality, and quantitative volumetric techniques with tissue segmentation and regional parcellation for cortical and subcortical grey matter, myelinated and unmyelinated white matter, and cerebrospinal fluid. At ages 4, 6 (corrected for the extent of prematurity), and 9 years (uncorrected), children were screened for behavioural adjustment problems including inattention/hyperactivity symptoms using the parent and teacher rated Strengths and Difficulties Questionnaire (SDQ). At age 9, the Development and Well-Being Assessment (DAWBA) structured psychiatric interview was also completed with primary caregiver and an independent clinical diagnosis of ADHD determined by a child psychiatrist blinded to child’s perinatal history and group status. Results: Agreement between parent and teacher reports regarding child behaviour adjustment was lower for children born very preterm than full-term (mean alternative chance-correlated coefficient, AC₁ = 0.63 vs. 0.80). Across all assessment time-points, very preterm birth was associated with on average a 2-fold increased risk of behavioural inattention/hyperactivity problems. These elevated risks largely reflected high rates of situational symptoms (very preterm = 22.3% − 31.7%; full-term = 10.9% − 16.7%). In contrast, rates of pervasive symptoms were relatively modest (very preterm = 6.8% − 11.5%; full-term = 4.7% − 7.3%). Examination of the predictive validity of inattention/hyperactivity problems identified using parent and teacher reports showed that children exhibiting situational symptoms at ages 4 and 6 were much less likely than those exhibiting pervasive symptoms, for a subsequent clinical diagnosis of ADHD at age 9 years (very preterm = 29% − 47.8% vs. 66.7% − 75%; full-term = 13.3% − 22.2% vs. 33.3% − 40%). Furthermore, receiver operating characteristic curves fitted to the data showed that children born very preterm exhibiting inattention/hyperactivity problems at two or three time-points (area under curve, AUC = .909) have better predictive validity for later ADHD diagnosis, compared to those exhibiting symptoms at age 4 (AUC = .794) or 6 years (AUC = .813) only. Children born very preterm were also at an elevated risk of persistent ADHD symptoms across the ages of 4 to 9 years, with the risk being 5-fold higher than their full-term peers (13.1% vs. 2.8%). Results also revealed possible associations between neonatal neuropathology and later risk of persistent ADHD symptoms. There were no significant linear associations between increasing severity of qualitative neonatal MRI measures of white matter injury/abnormality and very preterm children’s later risk of persistent ADHD symptoms. However, reduction in total cerebral tissue volumes and corresponding increase of cerebrospinal fluid (adjusted for intracranial volume) were significantly associated with increased risk of persistent symptoms in children born very preterm (p = .001). In terms of regional tissue volumes, total cerebral tissues in the dorsal prefrontal region showed the largest volumetric reductions among all the subregions in children born very preterm exhibiting persistent ADHD symptoms, with 3.2 ml (7%) and 8.2 ml (16%) lower tissue volumes than children born very preterm and full-term without persistent symptoms, respectively. Conclusions: Reliance on a single informant to examine child behaviour outcomes at a single time-point may lead to an under- or over-estimation of later ADHD risks. Combining reports from multiple informants and repeated assessments over time may provide better clinical prognostic validity. Children born very preterm are at an increased risk of behavioural inattention/hyperactivity problems during their early school years; although risks of more severe, pervasive problems are relatively modest compared with situational problems. Behavioural adjustment difficulties recognised as early as during preschool age using standardised behaviour screening tools can be a reliable indicator for identifying children born very preterm at risk of subsequent ADHD diagnosis. Finally, study findings suggest that increased risk of ADHD symptoms in children born very preterm can at least in part be accounted for by disturbances to neonatal cerebral growth and maturation.

Parkinson’s disease (PD) affects patients voice characteristics, reducing pitch variability compared to normal controls (1,2). Previous reports have shown an increase in pitch variability due to deep brain stimulation (DBS) of the Subthalamic nucleus (STN) (3). For patients stimulated in caudal zona incerta (cZi), the results indicate no effect on pitch variability in a read speech task{Karlsson:2012jr}. The present study aimed at investigating the effects of speech task (spontaneous or read speech) and the lenght of the utterance on overall measures of pitch variability observed in DBS-treated patients. Ten patients treated with STN-DBS and ten patients treated with cZi-DBS were included in this prospective study. Utterances produced sponatenously and produced during readings of a standard passage were compared in terms of treatment effects in pitch variability due to STN-DBS and cZi-DBS (Stim OFF and Stim ON recordings made 1,5 hour apart, all in Med ON) 6 and 12 months after operation. The results indicate that pitch variability is affected differently by STN-DBS and cZi-DBS depending on speech task and utterance length. In short utterances (<10 words), an increase in pitch variability is observed for both treatment groups and both speech tasks. For longer utterances, however, a more diverse effect of treatment and speech task is observed. The results therefore suggest that spech task and characteristics of thate utterance should be carefully considered when drawing conclusions on the overall effect of DBS on pitch variability. 1. Jiménez-Jiménez FJ, Gamboa J, Nieto A, Guerrero J, Ortí-Pareja M, Molina JA, et al. Acoustic voice analysis in untreated patients with Parkinson's disease. Parkinsonism Relat. Disord. 1997 Apr;3(2):111–6.  2. Holmes RJ, Oates JM, Phyland DJ, Hughes AJ. Voice characteristics in the progression of Parkinson’s disease. International Journal of Language & Communication Disorders. 2000;35(3):407–18.  3. Dromey C, Kumar R, Lang AE, Lozano AM. An investigation of the effects of subthalamic nucleus stimulation on acoustic measures of voice. Mov. Disord. 2000;15(6):1132–8.
Intonation och rytm i talet hos personer med Parkinsons sjukdom - en longitudinell jämförelse mellan sjukdomens effekter och effekter av behandling

Several studies reported training-induced improvements in executive function tasks and also observed transfer to untrained tasks. However, the results are mixed and there is a large interindividual variability within and across studies. Given that training-related performance changes would require modification, growth or differentiation at the cellular and synaptic level in the brain, research on critical moderators of brain plasticity potentially explaining such changes is needed. In the present study, a pre-post-follow-up design (N = 122) and a 3-weeks training of two response inhibition tasks (Go/NoGo and Stop-Signal) was employed and genetic variation (Val66Met) in the brain-derived neurotrophic factor (BDNF) promoting differentiation and activity-dependent synaptic plasticity was examined. Because Serotonin (5-HT) signaling and the interplay of BDNF and 5-HT are known to critically mediate brain plasticity, genetic variation in the 5-HTT gene-linked polymorphic region (5-HTTLPR) was also addressed. The overall results show that the kind of training (i.e., adaptive vs. non-adaptive) did not evoke genotype-dependent differences. However, in the Go/NoGo task, better inhibition performance (lower commission errors) were observed for BDNF Val/Val genotype carriers compared to Met-allele ones supporting similar findings from other cognitive tasks. Additionally, a gene-gene interaction suggests a more impulsive response pattern (faster responses accompanied by higher commission error rates) in homozygous l-allele carriers relative to those with the s-allele of 5-HTTLPR. This, however, is true only in the presence of the Met-allele of BDNF, while the Val/Val genotype seems to compensate for such non-adaptive responding. Intriguingly, similar results were obtained for the Stop-Signal task. Here, differences emerged at post-testing, while no differences were observed at T1. In sum, although no genotype-dependent differences between the relevant training groups emerged suggesting no changes in the trained inhibition function, the observed genotype-dependent performance changes from pre- to post measurement may reflect rapid learning or memory effects linked to BDNF and 5-HTTLPR. In line with ample evidence on BDNF and BDNF-5-HT system interactions to induce (rapid) plasticity especially in hippocampal regions and in response to environmental demands, the findings may reflect genotype-dependent differences in the acquisition and consolidation of task-relevant information, thereby facilitating a more adaptive responding to task-specific requirements.

Les progrès technologiques en imagerie médicale ont permis pour la première fois d'explorer in vivo le cerveau des êtres vivants. Cela a conduit à la création de grands projets et de grandes bases de données pour l'étude du cerveau humain comme le Human Connectome Project (HCP) ou le Human Brain Project (HBP), dont cette thèse est issue. La tractographie par IRM de diffussion (dMRI) a été la première technique pour explorer la substance blanche et les principales connexions du cerveau humain, mais il reste encore beaucoup à faire en ce qui concerne les connexions des fibres courtes. D’ailleurs, la frontière entre fibres longues et courtes reste ambiguë et sans consensus au sein de la communauté scientifique et il est impératif de poursuivre les études. Au cours des dernières années, des atlas de faisceaux courts ont été proposés, identifiant une centaine de faisceaux. Cependant, la principale faiblesse dans le développement de ces atlas est un alignement approximatif entre les sujets qui considèrent soit l’espace standard de Talairach ou une méthode fondée sur le recalage des images du tenseur de diffusion (DTI-tk). Aucune de ces approches ne gère correctement la variabilité des motif du plissement cortical qui est étroitement lié aux connexions courtes entourant les sillons, communément appelées faisceaux en U.Ce travail de thèse propose un nouveau cadre pour la création d'un atlas étendu de faisceaux de fibres entre 20mm et 85mm de longueur à partir de deux bases de données de tractographie massives fondées sur l’IRM de diffusion: la base de données ARCHI et la base de données HCP. 76 sujets de chacune ont été utilisés pour construire deux atlas de connexions courtes en utilisant exactement le même pipeline. Cette méthode utilise une procédure d'alignement inter-sujets difféomorphe en deux étapes qui combine les approches DISCO et DARTEL. Premièrement, DISCO inclut l'information du plissement cortical et force l'appariement précis des sillons majeurs qui doivent être contournés par les faisceaux en U. Ensuite, la méthode DARTEL bien connue est appliquée aux fibres pour affiner l'alignement. Le template MNI 152 est utilisé comme cible de la normalisation spatiale, afin de fournir nos résultats dans un espace commun pour faciliter son utilisation dans la communauté scientifique.Un clustering hiérarchique adaptatif et focalisé sur l'extraction des connexions de courte portée est ensuite réalisé pour extraire les faisceaux les plus reproductibles entre les sujets. Cette méthode n’impose pas de restriction sur la forme des clusters de faisceaux obtenus et permet de traiter des bases de données de tractographie massive dans un temps raisonnable et sans utiliser de ressources de calcul de haute performance. Les résultats montrent un nombre accru de faisceaux en U cartographiés de façon reproductible dans la population générale par rapport aux atlas précédents créés auparavant à partir de la même base de données ARCHI. Ce premier atlas contient plus de 400 faisceaux des deux hémisphères. En outre, plus de 600 faisceaux ont été obtenus avec l'énorme base de données HCP de meilleure résolution spatiale. Chacun de ces nouveaux atlas contient tous les faisceaux des atlas existants de connexions courtes et bien plus encore à explorer. Et même, pour certains faisceaux dans la même région et la même position, on observe différentes morphologies. Ces résultats ouvrent une nouvelle voie pour améliorer notre compréhension de la relation entre le plissement cortical et la variabilité des faisceaux en U mais ils visent également la possibilité de détecter des configurations anormales induites par des problèmes de développement qui peuvent conduire à des pathologies mentales telles que la dépression bipolaire ou la schizophrénie
Technological breakthroughs in medical imaging have allowed for first time in vivo exploration of the brain of living beings. This has prompted the creation of big projects and large databases for the study of the human brain such as the Human Connectome Project (HCP) or the Human Brain Project (HBP), of which this thesis is a part. Tractography by diffusion MRI (dMRI) has been the first technique to explore the white matter and the major connections of the human brain but there is still a long way to go regarding short-range connections. Even more, the boundary of the division between long and short fibers remains ambiguous and without consensus among the scientific community and further study is imperative. In recent years, some short bundle atlases have been proposed, identifying about a hundred short-range fascicles. However, the main weakness in the development of these atlases is the poor alignment between subjects which consider only the standard Talairach alignment or the diffusion tensor image registration method (DTI-tk). Neither of those approaches take into account correctly the variability of the cortical folding pattern which is closely related to the short-range connections surrounding sulci, commonly known as U-bundles.This thesis work proposes a new framework for the creation of an extended atlas of short-range fiber bundles between 20mm and 85mm length from two massive dMRI tractography datasets : the ARCHI database and the HCP database. 76 subjects of each one have been used to construct two atlases of short-range connections using exactly the same pipeline. This method uses a two-step diffeomorphic inter-subject alignment procedure that combines DISCO and DARTEL approaches. First, DISCO includes information on cortical folding and forces the accurate match of the main sulci that have to be circumvented by the U-bundles. Then, the well-known DARTEL method is applied to refine the registration. The MNI 152 template is also used, in order to provide our results in a common space to facilitate its use in the scientific community.An adaptative hierarchical clustering based on DBSCAN, focused in the extraction of short-range connections is performed then to extract the most reproducible bundles across subjects. This method does not impose restriction on the shape of the bundle clusters and allows the processing of massive tractography datasets in a reasonable time and without the need of high performance computational resources. The results show an increased number of short-range bundles consistently mapped in the general population compared with previous atlases created from the same ARCHI database. This first atlas contains more than 400 bundles. On the other hand, more than 600 bundles were obtained with the massive HCP database endowed with higher spatial resolution. Each of this new atlases contains all the bundles of the existent atlases of short-range connections and much more to explore. And even, for some bundles in the same region and position, different morphologies of them have been differentiated. Those results open a new path to improve our understanding of the relationship between the folding pattern and the U-bundle variability but also the possibility to detect abnormal configurations induced by developmental issues which may lead to mental pathologies such as bipolar depression or schizophrenia

Rayons ionisants, dessiccation, ou encore métabolites secondaires exogènes sont autant de facteurs qui peuvent engendrer des dommages à l’ADN chez les bactéries du sol, notamment en provoquant la formation de cassures double-brin (DSB), préjudice majeur pour une cellule. Chez les procaryotes, l’évolution a sélectionné deux principaux mécanismes de réparation des DSB, à savoir la recombinaison homologue (RH) et le non-homologous end joining (NHEJ). La RH est un mécanisme quasi-ubiquiste dans le monde bactérien qui repose sur l’utilisation d’une copie intacte de la molécule endommagée comme matrice pour la réparation de la DSB. Contrairement à la RH, le NHEJ n’est présent que chez 20 à 25% des bactéries et est considéré comme un mécanisme mutagène puisque la réparation de la DSB se fait sans matrice homologue et peut entrainer l’ajout ou la délétion de nucléotides au site de cassure. Chez la bactérie modèle Mycobacterium, seuls deux acteurs sont nécessaires pour la réparation par NHEJ. Ainsi, un dimère de protéine Ku se fixe sur la cassure puis recrute la protéine multifonctionnelle LigD, qui catalyse le traitement puis la ligation des extrémités grâce à ses domaines polymérase, nucléase et ligase. Les mécanismes de réparation des DSB chez les Streptomyces étaient peu connus à l’initiation de ce travail. Cette bactérie présente des caractéristiques génomiques remarquables avec notamment un chromosome linéaire de grande taille (6 à 12 Mb). En ce qui concerne la RH, nous avons focalisé nos recherches sur les étapes tardives (post-synaptiques) et étudié le rôle du complexe RuvABC et de RecG impliqués chez Escherichia coli dans la migration de la croix de Holliday et de sa résolution. La construction de mutants simples et multiples a montré que bien que les gènes codant ces protéines soient très conservés chez les Streptomyces, leur déficience ne se traduit chez Streptomyces ambofaciens que par une faible baisse de la recombinaison suite à un événement de conjugaison. Aucune baisse de l’efficacité de recombinaison intrachromosomique n’a en revanche été observée. Ces résultats suggèrent que des acteurs alternatifs majeurs sont encore à découvrir chez les Streptomyces. Le décryptage du mécanisme de NHEJ chez S. ambofaciens constitue une première dans ce genre bactérien. Une étude génomique exhaustive a permis de révéler la très grande diversité du nombre d’acteurs potentiels de ce mécanisme (Ku, LigDom, PolDom, NucDom) et de l’organisation des gènes qui les codent.. L’analyse fonctionnelle a révélé que l’ensemble des acteurs étaient impliqués dans la réponse à l’exposition à un faisceau d’électrons accélérés, connus pour induire, entre autre, la formation de DSB. La génération de DSB, par coupure endonucléasique I-SceI, a par ailleurs permis de mettre en évidence au niveau moléculaire des réparations de type NHEJ (délétions ou insertions de quelques nucléotides, intégration de fragments d’ADN). Les cassures dans les régions terminales du chromosome sont accompagnées de grandes délétions (jusqu’à 2,1 Mb) et de réarrangements de grande ampleur incluant circularisations du chromosome et amplifications d’ADN. Les conséquences de la réparation de DSB chez S. ambofaciens sont en tous points similaires aux réarrangements observés spontanément ou par comparaison des génomes des espèces types. Ainsi, il est possible de lier la plasticité du génome à la réparation de DSB. En outre, l’intégration de matériel génétique exogène serait favorisée au cours de la réparation NHEJ ce qui donnerait à ce système de réparation une place importante dans le processus de transfert horizontal, mécanisme d’évolution majeur chez les bactéries
Ionizing radiation, desiccation or exogenous secondary metabolites are all factors that can cause DNA damage in soil bacteria, especially by triggering double strand breaks (DSB), the most detrimental harm for the cell. In prokaryotes, evolution selected two main DSB repair pathways, namely homologous recombination (HR) and non-homologous end joining (NHEJ). HR is almost ubiquitous in bacteria and relies on an intact copy of the damaged DNA molecule as a template for DSB repair. In contrast to HR, NHEJ is only present in 20 to 25% of bacteria and is considered as a mutagenic pathway since DSB repair is performed without the need of any template and can lead to nucleotide addition or deletion at DSB site. In the bacterial model Mycobacterium, two partners are sufficient for a functional NHEJ pathway. Thus, Ku protein dimer recognizes and binds the DSB and then recruits the multifunctional LigD protein for extremities treatment and ligation thanks to its polymerase, nuclease and ligase domains. At the beginning of this work, few informations on DSB repair in Streptomyces were available. This bacteria exhibits remarkable genomic features including a large linear chromosome (6 to 12 Mb). Regarding HR, we focused on the late stage (post-synaptic step) in studying the role of RuvABC complex and RecG, involved in branch migration and Holliday junction resolution in E. coli. Construction of single and multiple mutants showed that although the genes encoding these proteins are highly conserved in Streptomyces, their deficiency in Streptomyces ambofaciens only results in a mild decrease of recombination after conjugation events. Besides, no decrease of intrachromosomal recombination efficiency could be observed. These results suggest that major alternative factors are still to be discovered in Streptomyces. This work was also the first occasion to decipher a NHEJ pathway in Streptomyces. An exhaustive genomic study revealed a great diversity in the number of factors potentially implicated in this pathway (Ku, LigDom, PolDom, NucDom) and in the organization of their encoding genes. Functional analyses revealed that all the factors, whatever they are conserved or not between species, were involved in the response to electron beam exposure, known to induce, amongst other things, DSB formation. Generation of DSB by I-SceI endonuclease cleavage was also used to evidence at a molecular level NHEJ type DSB repair (deletions or insertions of several nucleotides, integration of DNA fragments). Targeted breaks in the terminal regions of the chromosome were accompanied by large deletions (up to 2.1 Mb) and major rearrangements including chromosome circularizations and DNA amplifications. Consequences of DSB repair in S. ambofaciens are in all points similar to chromosome rearrangements observed spontaneously or by comparing genomes of different species. Thus, it is possible to link the genome plasticity to DSB repair. In addition, the integration of exogenous genetic material would be favoured during NHEJ repair which would give this repair system a major role in the horizontal transfer process, known to be a main evolution mechanism in bacteria

Le lithium est le traitement de référence du trouble bipolaire. Cependant, il peut être responsable d’intoxications dont trois profils différents sont décrits chez l’homme, caractérisés par une expression variable encore inexpliquée de la neurotoxicité. Les objectifs de cette thèse étaient d’étudier la distribution cérébrale du lithium dans trois modèles de rats Sprague-Dawley reproduisant les modes d’intoxication au lithium chez l’homme et de déterminer son implication dans la survenue des complications neurologiques au moyen de tests comportementaux et d’une analyse électroencéphalographique. Dans ce contexte, une étude des relations effet/concentrations du lithium suivant le modèle d’intoxication a été conduite. Enfin, un protocole d’imagerie ex vivo permettant d’explorer la distribution intracérébrale du lithium a été mis en place chez le rat par résonance magnétique nucléaire du lithium-7. Ainsi, nous avons montré que les trois formes d’intoxication au lithium chez le rat diffèrent en termes de pharmacocinétique sanguine et cérébrale, mais aussi en termes d’intensité et de durée des effets neurocomportementaux. Nous avons mis en évidence une accumulation cérébrale de lithium significativement plus élevée suite à un prétraitement répété par lithium et majorée après induction d’une insuffisance rénale. Le surdosage de lithium était constamment à l’origine d’une hypolocomotion chez le rat, dont la profondeur et l’étendue apparaissaient être liées à la durée de l’exposition au lithium, et d’une encéphalopathie dont la sévérité apparaissait plutôt dépendre de la quantité de lithium cérébral accumulée. Ainsi, l’accumulation cérébrale de lithium pourrait engendrer des effets neurotoxiques directs et/ou indirects par modification de l’expression de cibles cérébrales spécifiques du lithium. Enfin, nous avons démontré la faisabilité et la fiabilité de notre technique d’imagerie ex vivo pour explorer la distribution cérébrale du lithium chez le rat, ouvrant dès lors des perspectives à son utilisation future chez l’homme
Lithium is the cornerstone treatment of bipolar disorder. However, lithium may be responsible for poisoning with three various profiles reported in humans and characterized by unexplained variable resulting neurotoxicity. Our objectives were to investigate brain lithium distribution in three Sprague-Dawley rat models mimicking the human intoxication patterns and define its involvement in the occurrence of neurological disorders using behavioral tests and electroencephalographic analysis. The effect/concentration relationships were studied according to the poisoning model. Finally, an ex vivo imaging protocol was established in the rat to investigate brain lithium distribution using the nuclear magnetic resonance of lithium-7. We showed significant differences between the three lithium poisoning patterns in the rat regarding the blood and brain lithium pharmacokinetics as well as the intensity and duration of lithium-induced neurobehavioural effects. We found significantly more marked brain lithium accumulation after an overdose following repeated lithium administration, enhanced after the induction of renal failure. In the rat, lithium overdose consistently induced hypolocomotion whose intensity was related to the duration of lithium exposure and encephalopathy whose severity rather depended on the lithium amount accumulated in the brain. Brain lithium accumulation seems thus able to generate direct and/or indirect neurotoxic effects mediated by the alteration of specific brain lithium target expression. Finally, we demonstrated the feasibility and reliability of our ex vivo imaging technique to investigate brain lithium distribution in the rat, supporting a possible future use in humans

La bactérie Deinococcus radiodurans est connue pour sa capacité à résister à un grand nombre de traitements génotoxiques parmi lesquels on peut citer l’exposition aux rayons ionisants, aux ultra-violets, à la mitomycine C, à la dessication et au stress oxydant. Elle est capable lors d’une exposition à des doses extrêmes de rayons γ générant des centaines de cassures de l’ADN de reconstituer un génome intact en seulement 2 à 3 heures via un mécanisme original, l’ESDSA, impliquant une synthèse massive d’ADN pendant la phase de réparation des cassures de l’ADN. En plus de mécanismes efficaces de réparation de l’ADN, elle possède un kit de survie comprenant une compaction importante du nucléoïde, des mécanismes de protection des protéines contre l’oxydation, une réponse originale aux lésions de l’ADN et des protéines spécifiques induites après irradiation. Tous ces facteurs contribuent au maintien de l’intégrité du génome et à la survie de la cellule lors de l’exposition à différents agents génotoxiques. Souvent considéré comme un organisme ayant une stabilité génomique exceptionnelle, cette bactérie possède dans son génome un grand nombre de séquences répétées et des éléments mobiles et est par ailleurs naturellement compétente. Ce sont autant de facteurs pouvant participer à la variabilité génétique de cette espèce. Je me suis donc intéressée lors de ma thèse à deux processus pouvant participer à l’instabilité génétique chez D. radiodurans : la recombinaison entre séquences répétées et la transformation naturelle.L’introduction dans le génome de D. radiodurans de séquences répétées directes de 438 pb séparées par des régions d’ADN d’une longueur allant de 1479 pb à 10 500 pb m’a permis de mettre en évidence le rôle majeur joué par l’appariement simple brin (Single Strand Annealing ou SSA) impliquant la protéine DdrB, spécifique des Deinococcaceae, joue un rôle majeur dans la recombinaison « spontanée » entre les séquences répétées en absence de la recombinase RecA. L’absence de DdrB dans des souches déficientes pour la recombinaison augmente davantage la perte de viabilité observée dans ces souches ce qui suggère que le SSA participe à la prise en charge de fourches de réplication bloquées, source majeure d’instabilité génétique en absence de stress extérieur, si ces fourches ne peuvent être prise en charge par des voies impliquant des protéines de recombinaison. Je me suis également intéressée à la transformation naturelle et aux protéines impliquées dans ce processus chez D. radiodurans. J’ai pu démontrer que la protéine DprA impliquée dans la protection de l’ADN simple brin et le chargement de RecA sur l’ADN simple brin internalisé lors de la transformation de nombreuses espèces comme Streptococcus pneumoniae, Bacillus subtilis ou Helicobacter pylori, est également impliquée dans la transformation chez D. radiodurans. J’ai pu montrer également qu’en plus de jouer un rôle majeur dans la transformation par de l’ADN plasmidique, DdrB est impliquée dans la transformation par de l’ADN génomique si la protéine DprA est absente
The bacterium Deinococcus radiodurans is known for its ability to withstand a large number of genotoxic treatments, including exposure to ionizing or ultraviolet radiation, mitomycin C, desiccation, and oxidative stress. It is able, upon exposure to extreme doses of γ-radiation generating hundreds of DNA breaks, to reconstitute an intact genome in only 2 to 3 hours via an ESDSA mechanism, involving massive DNA synthesis during DNA double strand break repair. Together with efficient DNA repair mechanisms, D. radiodurans possesses a survival kit comprising significant compaction of its nucleoid, protection mechanisms against protein oxidation, an original response to DNA damage and specific proteins induced after irradiation. All of these contribute to the maintenance of genomic integrity and cell survival upon exposure to various genotoxic agents. In spite of the idea that D. radiodurans is an organism with outstanding genomic stability, this bacterium has in its genome a large number of repeat sequences and mobile elements and is also naturally competent. All these factors contribute to the genetic variability of species. I was interested in two processes that can play a role in genetic variability in D. radiodurans: recombination between repeated sequences and natural transformation.The introduction, into the genome of D. radiodurans, of 438 bp direct repeated sequences separated by DNA regions ranging from 1,479 bp to 10,500 bp in length allowed me to demonstrate the major role of Single Strand Annealing (SSA) involving the DdrB protein specific for Deinococcaceae, in the "spontaneous" recombination between the repeated sequences in the absence of the RecA recombinase. The absence of DdrB in strains deficient for recombination further increased the loss of viability observed in these strains, suggesting that SSA is required for the management of blocked replication forks, a major source of genetic instability in the absence of external stress when these forks cannot be rescued by pathways involving recombination proteins.I was also interested in the natural transformation and proteins involved in this process in D. radiodurans. I demonstrated that DprA protein involved in DNA single strand protection and loading of RecA on single-stranded DNA internalized during transformation of many species such as Streptococcus pneumoniae, Helicobacter pylori, or Bacillus subtilis, is also involved in this process in D. radiodurans. I also showed that, in addition to playing a major role in transformation by plasmid DNA, DdrB is also involved in transformation by genomic DNA of cells devoid of the DprA protein

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2008.
Title from title screen (site viewed Mar. 10, 2009). PDF text: xii, 73 p. : ill. ; 769 K. UMI publication number: AAT 3331384. Includes bibliographical references. Also available in microfilm and microfiche formats.

Tese de mestrado integrado, Engenharia Biomédica e Biofísica (Engenharia Clínica e Instrumentação Médica) Universidade de Lisboa, Faculdade de Ciências, 2018
Todos os anos, mais de 95 mil recém-nascidos são admitidos nas Unidades de Cuidados Intensivos Neonatais (UCIN) do Reino Unido, devido principalmente a partos prematuros ou outras complicações que pudessem ter ocorrido, como é o caso da encefalopatia hipóxico-isquémica (EHI), que assume 3% de todas as admissões nas unidades referidas. EHI é o termo que define uma complicação inesperada durante o parto, que resulta em lesões neurológicas a longo prazo e até em morte neonatal, devido à privação de oxigénio e fluxo sanguíneo ao recém-nascido durante o nascimento. Estima-se que tenha uma incidência de um a seis casos por 1000 nascimentos. Nos países desenvolvidos, a hipotermia é utilizada como método preventivo-terapêutico para esta condição. No entanto, existem dois grandes obstáculos para a obtenção da neuroprotecção pretendida e totalmente benéfica, na prática clínica. Em primeiro lugar, esta técnica é eficaz se for iniciada dentro de seis horas após o parto. Visto que o estado clínico da encefalopatia neonatal evolui nos dias posteriores ao nascimento, a sua deteção precoce é um grande desafio. Tal situação pode levar a diversos erros nas UCIN, tal como indivíduos sujeitos à terapia de hipotermia desnecessariamente, ou ainda mais grave, casos em que recém-nascidos foram inicialmente considerados como saudáveis, não tendo sido submetidos à terapia referida, apresentarem sinais de EHI após seis horas de vida. A segunda questão prende-se com o facto de a neuroprotecção poder ser perdida se o bebé estiver stressado durante o tratamento. Para além disso, não existe nenhuma ferramenta válida para a avaliação da dor dos recém-nascidos submetidos a esta terapia. Os obstáculos frisados anteriormente demonstram duas necessidades ainda não correspondidas: a carência de um método não invasivo e largamente adaptável a diferentes cenários para uma correta identificação de recém-nascidos com maior probabilidade de HIE, dentro de uma margem de seis horas após o parto, mas também um método preciso de stress em tempo real, não invasivo, que possa orientar tanto pessoal médico, como pais, de modo a oferecer um tratamento mais responsável, célere e individualizado. Deste modo, a análise do ritmo cardíaco demostra um enorme potencial para ser um biomarcador de encefalopatia neonatal, bem como um medidor de stress, através da eletrocardiografia (ECG), visto que é um importante indicador de homeostase, mas também de possíveis condições que podem afetar o sistema nervoso autónomo e, consequentemente, o equilíbrio do corpo humano. É extremamente difícil a obtenção de um parâmetro fisiológico, sem a presença de artefactos, especialmente no caso de recém-nascidos admitidos nas UCIN. Tanto no caso da aquisição de ECGs, como de outros parâmetros, existe uma maior probabilidade de o sinal ser corrompido por artefactos, visto que são longas aquisições, normalmente dias, onde o bebé é submetido a diversas examinações médicas, está rodeado de equipamentos eletrónicos, entre outros. Artefactos são definidos como uma distorção do sinal, podendo ser causados por diversas fontes, fisiológicas ou não. A sua presença nos dados adquiridos influencia e dissimula as informações corretas e reais, podendo mesmo levar a diagnósticos e opções terapêuticas erradas e perigosas para o paciente. Apesar de existirem diversos algoritmos de identificação de artefactos adequados para o sinal cardíaco adulto, são poucos os que funcionam corretamente para o de recém-nascido. Para além disso, é necessário bastante tempo tanto para o staff clínico, como para os investigadores, para o processo de visualização e identificação de artefactos no eletrocardiograma manualmente. Deste modo, o projeto desenvolvido na presente dissertação propõe um novo algoritmo de identificação e marcação de artefactos no sinal cardíaco de recém-nascidos. Para tal, foi criado um modelo híbrido de um método que tem em consideração todas as relações matemáticas de batimento para batimento cardíaco, com outro que tem como objetivo a remoção de spikes no mesmo sinal. O algoritmo final para além de cumprir com o objetivo descrito acima, é também adaptável a diferentes tipos de artefactos presentes no sinal, permitindo ao utilizador, de uma forma bastante intuitiva, escolher o tipo de parâmetros e passos a aplicar, podendo ser facilmente utilizado por profissionais de diferentes áreas. Deste modo, este algoritmo é uma mais-valia quando aplicado no processamento de sinal pretendido, evitando assim uma avaliação visual demorada de todo o sinal. Para obter a melhor performance possível, durante o desenvolvimento do algoritmo foram sempre considerados os resultados de validação, tais como exatidão, sensibilidade, entre outros. Para tal, foram analisados e comparados eletrocardiogramas de 4 recém-nascidos saudáveis e 4 recém-nascidos com encefalopatia. Todos possuíam aproximadamente 5 horas de sinal cardíaco adquirido após o nascimento, com diferentes níveis de presença de artefactos. O algoritmo final, obteve uma taxa de sensibilidade de 96.2% (±2.4%) e uma taxa de exatidão de 92.6% (±3.2%). Como se pode verificar pelos valores obtidos, o algoritmo obteve percentagens altas nos vários parâmetros de classificação, o que significa uma deteção correta. A taxa de exatidão apresenta um valor mais baixo, comparativamente ao parâmetro da sensibilidade, pois em diversas situações, normalmente perto de artefactos, os batimentos normais são considerados como artefactos, pelo algoritmo. Contudo, essa taxa não é alarmante, tendo sido considerada uma taxa reduzida, pelo pessoal médico. Após o processamento do sinal cardíaco dos grupos mencionados acima, um estudo comparativo, utilizando parâmetros da variabilidade do ritmo cardíaco, foi realizado. Diferenças significativas foram encontradas entre os dois grupos, onde o saudável assumiu sempre valores maiores. SDNN e baixa frequência foram os parâmetros que traduziram uma diferença maior entre os dois grupos, com um p-value <0.01. De modo a corresponder ao segundo obstáculo referido nesta dissertação, outro objetivo desta tese foi a criação de um algoritmo que pudesse identificar e diferenciar uma situação de stress nesta faixa etária, com recurso ao ritmo cardíaco. Um estudo multidimensional foi aplicado aos diferentes métodos de entropia utilizados nesta tese (approximate entropy, sample entropy, multiscales entopy e fuzzy entropy) de modo a estudar como os diferentes métodos de entropia interagem entre si e quais são os resultados dessa relação, especialmente na distinção de estados normais e stressantes. Para tal, a utilização de clusters foi essencial. Dado que para todos os ECGs de bebés saudáveis analisados neste projeto foram registados todas as possíveis situações de stress, como é o caso de choro, examinações médicas, mudança de posição, entre outros, foram escolhidos 10 minutos do sinal do ritmo cardíaco adquirido, antes da situação, para análise. Infelizmente, associado a um evento stressante, na maioria dos casos encontra-se uma percentagem bastante alta do sinal corrompida por artefactos. No entanto, em alguns casos foi possível observar uma clara distinção de grupos de clusters, indicando que naquele período de tempo, houve uma mudança de estado. Foi também realizado um estudo intensivo de diversos métodos de entropia aplicados ao grupo de sujeitos apresentados nesta dissertação, onde foi provado que o método mais adequado a nível de diferenciação é a Fuzzy Entropy (p=0.0078). Ainda é possível sugerir alguns aspetos e apontar algumas limitações, no âmbito de poderem ser ultrapassadas no futuro. Em primeiro lugar, é necessária a aquisição de mais eletrocardiogramas, quer de recém-nascidos saudáveis, quer com encefalopatia hipóxico-isquémica, de modo a aumentar o tamanho da amostra e, deste modo diminuir os valores do desvio-padrão em todos os parâmetros calculados. Relativamente ao estudo do stress, seria interessante, com uma amostra maior, a definição de clusters, de modo a ter uma identificação precisa de situações stressantes. Para além disso, a transformação do software atualmente escrito em MATLAB para GUI (interface gráfica do utilizador), a fim de tornar mais acessível a sua utilização por profissionais de diversas áreas.
In Neonatal Intensive Care Unit (NICU), the heart rate (HR) offers significant insight into the autonomic function of sick newborns, especially with hypoxic ischemic encephalopathy condition (HIE). However, the intensity of clinical care and monitoring contributes to the electrocardiogram (ECG) to be often noisy and contaminated with artefacts from various sources. These artefacts, defined as any distortion of the signal caused by diverse sources, being physiological or non-physiological features, interfere with the characterization and subsequent evaluation of the heart rate, leading to grave consequences, both in diagnostic and therapeutic decisions. Besides, its manual inspection in the ECG trace is highly time-consuming, which is not feasible in clinical monitoring, especially in NICU. In this dissertation, it is proposed an algorithm capable of automatically detect and mark artefacts in neonatal ECG data, mainly dealing with mathematical aspects of the heart rate, starting from the raw signal. Also, it is proposed an adjacent algorithm, using complexity science applied to HR data, with the objective of identifying stress scenarios. Periods of 10-minute ECG were considered from 8 newborns (4 healthy and 4 HIE) to the identification of stress situations, whereas for the artefacts removal algorithm small portions varying in time length according to the amount of noise present in the originally 5 hours long samples were utilised. In this report it is also present several comparisons utilising heart rate parameters between healthy and HIE groups. Fuzzy Entropy was considered the best method to differentiate both groups (p=0.00078). In this report, substantial differences in heart rate variability were found between healthy and HIE groups, especially in SDNN and low frequency (p<0.01), confirming results of previous literature. For the final artefact removal algorithm, it is illustrated significant differences between raw and post-processed ECG signals. This method had a Recall rate of 96.2% (±2.4%) and a Precision Rate of 92.6% (±3.2%), demonstrating high efficiency in ECG noise removal. Regarding stress measures, associated with a stressful event, in most cases there is a high percentage of the signal corrupted by artefacts. However, in some cases it was possible to see a clear distinction between groups of clusters, indicating that in that period, there was a change of state. Not all the time segments from subjects demonstrated differences in stress stages, indicating that there is still room for improvement in the method developed.

碩士
國立雲林科技大學
工業工程與管理系
102
Bain injury can be divided into traumatic cranial hemorrhage and spontaneous intracranial hemorrhage. On the other hand, brain tissue damage is caused by brain injury that it often leads to some of serious complications happen. According to the research of brain injury that brain injury may cause autonomic dysfunction. The brain injury will trigger secondary brain injury indirectly and increase the prevalence and mortality. This research combines two areas of heart rate variability analysis and brain injury. The research object is brain injury patients in the ICU. In this study, we obtain and utilize electrocardiography data from the brain injury patients to perform the heart rate variability analysis. We utilize heart rate variability to evaluate the brain injury patients' severity and recovery status within the six months period. Moreover, we observe the relationship between the activity of ANS and clinical condition. The results indicate that a notable reduction of HRV is found in brain injury patients who have a bad prognosis and severe coma. Regarding the HRV indices, the SDNN, VLF, LF, HF and TP were significantly reduced in the subgroup which has a bad prognosis and severe coma. It means that the brain injury patients, who have a bad prognosis and severe coma, are predisposed to have cardiac autonomic dysfunction. HRV is a powerful tool to evaluate the autonomic functions in patients with brain damage of various degrees.

Neuroscientists have long known that brain function is inherently variable. Functional magnetic resonance imaging (fMRI) research often attributes blood oxygen level-dependent (BOLD) signal variance to measurement-related confounds. However, what is typically considered “noise” variance in data may be a vital feature of brain function that reflects development, cognitive adaptability, flexibility, and performance. In the present thesis, we examine how brain signal variability (measured with a modified BOLD time series standard deviation (SDBOLD)) relates to human aging and cognitive performance in a series of studies. In Study 1, we examined brain variability during fixation baseline periods. We found that not only was the SDBOLD pattern robust, its unique age-predictive power was more than five times that of meanBOLD (a common measure of BOLD activity), yet revealed a spatial pattern virtually orthogonal to meanBOLD. Contrary to typical conceptions of age-related neural noise, young adults exhibited greater brain variability overall. In Study 2, we found that younger, faster, and more consistent performers exhibited significantly higher brain variability across three cognitive tasks, and showed greater variability-based regional differentiation compared to older, poorer performing adults. SDBOLD and meanBOLD spatial patterns were again orthogonal across brain measures. Study 3 demonstrated experimental condition-based modulations in SDBOLD. SDBOLD was an effective discriminator between internal (lower variability) and external (higher variability) cognitive demands, particularly in younger, high performing adults. Finally, to gauge the extent that brain variability can be incrementally manipulated within a single cognitive domain, Study 4 examined parametric modulations in SDBOLD on a face processing task in a young-only sample. Results indicated that SDBOLD can be robustly manipulated through experimental control, and that this manipulation linearly follows performance trends across conditions. These studies help establish the age- and performance-relevance of BOLD variability. We thus argue that the precise nature of relations between aging, cognition, and brain function is incompletely characterized by using mean-based brain measures exclusively.

Decisions often require weighing the costs and benefits of available prospects. Value-based decision making depends on the coordination of multiple cognitive faculties, making it potentially susceptible to at least two forms of variability. First, there is heterogeneity in brain organization across individuals in areas of association cortex that exhibit decision-related activity. Second, a person’s preferences can fluctuate even for repetitive decision scenarios. Using functional magnetic resonance imaging (fMRI) and behavioral experiments in humans, this project explored how these distinct sources of variability impact choice evaluation, localization of valuation in the brain, and the links between valuation and other cognitive phenomena. Group-level findings suggest that valuation processes share a neural representation with the “default network” (DN) in medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC). Study 1 examined brain network variability in an open dataset of resting-state fMRI (n=100) by quantitatively testing the hypothesis that the spatial layout of the DN is unique to each person. Functional network topography was well-aligned across individuals in PCC, but highly idiosyncratic in mPFC. These results highlighted that the apparent overlap of cognitive functions in these areas should be evaluated within individuals. Study 2 examined variability in the integration of rewards with subjective costs of time and effort. Two computerized behavioral experiments (total n=132) tested how accept-or-reject foraging decisions were influenced by demands for physical effort, cognitive effort, and unfilled delay. The results showed that people’s willingness to incur the three types of costs differed when they experienced a single type of demand, but gradually converged when all three were interleaved. The results could be accounted for by a computational model in which contextual factors altered the perceived cost of temporal delay. Finally, Study 3 asked whether the apparent cortical overlap between valuation effects and the DN persisted after accounting for individual variability in brain topography and behavior. Using fMRI scans designed to evoke valuation and DN-like effects (n=18), we reproduced the idiosyncratic network topography from Study 1, and observed valuation-related effects in individually identified DN regions. Collectively, these findings advance our taxonomic understanding of higher-order cognitive processes, suggesting that seemingly dissimilar valuation and DN-related functions engage overlapping cortical mechanisms.

碩士
元智大學
機械工程學系
94
The purpose of this research is to find the heart rate variability (HRV) of irreversible apneic coma (IAC) and brain death for the clinical correlation research. IAC, or the rather controversial term - brain death, is defined as the irreversible loss of function of the brain. Sympathetic storm, a cardiovascular hyperdynamic state occurring in the process of brain stem failure, has been well studied in animal models. Observations of hypertension and tachycardia due to intense vasoconstriction in IAC patients have been described in clinical settings. The phenomenon of sympathetic storm was also mentioned by researchers after introducing the HRV, suggesting its contributory potential to the diagnosis of IAC. The Poincare'' plots are one of the non-linear analysis of HRV. We calculate Poincare'' plot index (SD1, SD2 and area) and frequency index (HF/LF, HF/TF) in order to obtain the relationship between HRV and Autonomic nervous system. Observing the Poincare'' plots of three groups (IAC, normal coma and normal), We find the shapes of IAC and brain death patients are fan and area are smaller, but shapes of normal people are comet and area are bigger. Finally we use statistics to discuss the difference of Poincare'' plots with three groups.

In functional magnetic resonance imaging (fMRI) studies, inter-subject anatomical variability of the human brain has been a major challenge in finding reliable functional/anatomical correspondences. Assessment of brain-behavior relations involves a series of geometrical/statistical operations on brain images to minimize such inter-subject variability, so that group maps of brain activity relative to brain anatomy can be developed. Various methods of image registration, segmentation, and analysis have been proposed for mapping functional activity on to anatomical atlases of the brain. The two most common techniques that have been widely accepted and used by neuroimaging scientists are volume-based (VB) analysis using group registration methods and region-of-interest (ROI)-based methods using automated segmentation algorithms or macro/microanatomical probabilistic atlases for labeling. Nevertheless, the analysis results based on these techniques are significantly affected by the accuracy of the selected segmentation and/or registration methods. Furthermore, conventional fMRI data analysis techniques (VB, and ROI-based methods) mainly rely on the assumption that brain processes are common and universal among individual humans; however, besides anatomical differences, there also exist cognitive and behavioral variability among individuals due to differential engagement of brain networks even when performing an identical cognitive task. In this thesis, I have assessed the impact of anatomy-based alignment techniques (VB, and ROI-based methods) on sensitivity of fMRI data group analysis. I evaluated the effect of the type of inter-subject registration used and related factors on sensitivity of group-level fMRI data analysis. Furthermore, I have also assessed the goodness of fit of probabilistic maps by proposing an evidence-based framework for evaluation of probabilistic maps. As a test model, I have selected the human auditory cortex. Auditory cortex is an interesting yet challenging case with substantial inter-individual functional/anatomical variability. For the sake of ROI-based method of analysis, I have proposed a novel approach for automatic segmentation of Heschl's gyrus, which is the landmark for primary auditory cortex. Finally, in order to assess the impact of inter-subject variability in anatomy on functional organization, I analyze data from an fMRI study, which demonstrates that the degree to which anatomical registration compensates for functional variability depends on the brain region activated.
Thesis (Ph.D, Computing) -- Queen's University, 2010-04-29 07:07:55.77

Dissertação de mestrado integrado em Psicologia
This study aims to investigate associations between individual differences in empathy and structural variations in the insular cortex, particularly in the anterior insula (AI). A normative sample of 31 male subjects was selected from the community, ranging from the ages of 20 to 40 years old. Individual differences on empathy were assessed through the Questionnaire of Cognitive and affective Empathy (QCAE). Measures of grey matter volume, area, cortical thickness and white matter volume were extracted from T1-Wheighted structural MRI scans with FreeSurfer, and analysed in Statistical Package for the Social Sciences (SPSS). Hierarchical Regression analyses showed that variance in anterior insula grey matter area and insula white matter volume is positively significantly associated with individual differences in empathy.
Este estudo pretende investigar associações entre diferenças individuais ao nível da empatia e variações na estrutura da insula, particularmente ao nível da insula anterior (AI). Uma amostra normativa de 31 sujeitos do sexo masculino foi selecionada da comunidade, com idades compreendidas entre os 20 e 40 anos. Diferenças individuais ao nível da empatia foram medidas através do Questionnaire of Cognitive and affective Empathy (QCAE). Medidas de relativas ao volume, área e espessura cortical da substância cinzenta e medidas do volume da substância branca foram extraídas de scans de MRI estruturais, T1-Wheithed, com o programa FreeSurfer e analisadas no Statistical Package for the Social Sciences (SPSS). Análises de regressão Hierárquica revelaram variações significativas na área da substância cinzenta da insula anterior e volume da substância branca da insula, positivamente, associadas com diferenças individuais na empatia.

Mild Traumatic Brain Injury (mTBI), often called concussion, has become a growing public health concern, prevalent in both athletic and military settings. In response, many researchers have explored cognitive outcomes post-mTBI, with a plethora of meta-analyses summarizing these findings; however, these meta-analyses examine solely mean performances on cognitive tasks, ignoring intra-individual variability (IIV) in cognitive performance that may elucidate neuropsychological impairment following mTBI. The current thesis involved two studies, responding to both the growing meta-analytic research and limited IIV findings. Study 1: Many meta-analyses have amalgamated individual study results on post-mTBI neuropsychological outcomes. With the abundance of meta-analyses, a systematic review of meta-analyses stands as the next logical step. Method: A systematic literature search yielded 11 meta-analyses meeting inclusion criteria (i.e., English-language systematic reviews/meta-analyses covering post-mTBI observational cognitive research on late adolescents/adults), with their findings qualitatively synthesized based on moderator variables (i.e., cognitive domain, time since injury, past head injury, participant characteristics, comparison group, assessment technique, and persistent symptoms). Results: The overall effect sizes ranged for both general (range: .07-.61) and sports-related mTBI (range: .40-.81) and differed both between and within cognitive domains, with executive functions appearing most sensitive to multiple mTBI. Cognitive domains varied in recovery rates, but overall recovery occurred by 90 days post-injury for most individuals and by seven days post-injury for athletes. Greater age/education and male gender produced smaller effects sizes, while high school athletes suffered the largest deficits post-mTBI. Control-group comparisons yielded larger effects than within-person designs, while assessment techniques had limited moderating effects. Conclusions: Overall, meta-analytic review quality remained low with few studies assessing publication or study quality bias. Meta-analyses consistently identified adverse acute mTBI-related effects and fairly rapid symptom resolution. Study 2: The long-term outcomes of executive functions and IIV following mTBI are unclear due to inconsistent and limited research, respectively. Further, the relationship between physical activity (PA) and cognitive performance at young adulthood remains almost fully unexplored. In turn, the current study aimed to (a) assess the diagnostic utility of both executive functions and IIV at predicting mTBI history and (b) evaluate the interaction between PA levels and mTBI on both of these cognitive metrics. Method: Altogether 138 self-identified athletes (Mage = 19.9 ± 1.91 years, 60.8% female, 19.6% 1 mTBI, 18.1% 2+ mTBIs) completed three executive-related cognitive tasks (i.e., N-Back, Go/No-go, Local-Global). Ordinal logistic regression analyses examined the joint effect of person-mean and IIV as predictors of mTBI status. Multi-level models examined mTBI and PA levels as predictors of trial-to-trial changes in performance. Results: Only mean response time (RT) for the Local-Global task predicted mTBI status, while no IIV variables reached unique significance. PA levels predicted subtle within-task decreases in RT across Local-Global trials. Conclusions: IIV research on mTBI remains limited; however, the preliminary results do not indicate any additional predictive value of IIV indices above mean performances. For executive functions, shifting appeared most affected, with past researchers identifying post-mTBI impairment in attentional processing. Higher PA levels minutely benefited within-task shifting and mean inhibitory performance, although these finding require cautious interpretation.
Graduate
0622
jkarr@uvic.ca

The process of controlling executive and motor behaviours is central to one’s ability to self-regulate and accomplish day-to-day goals across the lifespan. Executive and motor control share a set of underlying neural substrates that support a common set of processes, including planning, sequencing and monitoring of behaviour. They share a bidirectional relationship, such that gains or deficits in one area can have profound effects on the other. This doctoral dissertation examines the interplay between executive and motor control at three distinct stages of life and in the context of neurological conditions whose clinical manifestations shed additional light on the nature of the constructs. Central to each investigation is the methodological theme of intraindividual variability, as a means of leveraging valuable data within-persons. Chapter 2 examines executive and motor control in typically developing children and children with attention-deficit/hyperactivity disorder (ADHD). Findings suggest that dysregulation of motor processes accounts for hyperactive symptoms in ADHD and detracts from higher-order executive control. Chapter 3 examines the impact of mild traumatic brain injury (mTBI) in young adult varsity athletes, who routinely practice executive motor control by virtue of their level of play. Findings suggest that the impacts of mTBI are discernible through a dampened electrophysiological response during computerized tests of higher order executive functioning, and may not outweigh the otherwise myriad health benefits of athletic engagement. Chapter 4 examines the impact of dementia on executive motor control during gait dual-tasking in older adults. Findings suggest that the consistency of performance across multiple indicators of gait is sensitive to dementia, and that engagement in cognitive and social lifestyle behaviours is protective against likelihood of both dementia and mild cognitive impairment (MCI) classification. On mass, these findings highlight the importance of assessing executive motor control to understand the pathophysiology of neurological conditions. The potential benefits that may generalize from one area to the other offer unique opportunities for preventative and rehabilitative efforts.
Graduate

La plupart des études portant sur les commotions cérébrales se sont principalement intéressées aux conséquences de ces dernières sur le cerveau lui-même. Or, le cerveau assure de nombreuses fonctions, étant notamment impliqué dans la régulation du rythme cardiaque. Récemment, des chercheurs ont donc étudié les conséquences de ces commotions cérébrales sur la régulation de la fréquence cardiaque par le cerveau durant un effort physique. Cependant, la majorité des athlètes qui subissent une commotion cérébrale doivent non seulement planifier leur retour au jeu, mais également prévoir un retour au travail ou aux études. Ainsi, l’objectif de ce projet de recherche est d’étudier les conséquences des commotions cérébrales sur la régulation de la fréquence cardiaque par le cerveau durant un effort cognitif. Onze athlètes universitaires ayant subi une commotion cérébrale ainsi que 14 athlètes n’ayant aucun historique de commotion cérébrale ont pris part à l’étude. Les athlètes du groupe commotion ont été évalués en moyenne 14,6 jours (± 7,4 jours) après leur blessure. La fréquence cardiaque des participants a été enregistrée au repos ainsi que durant un effort cognitif qui consistait en une tâche d’alternance (« switch task »). De courts segments de la fréquence cardiaque d’une durée de deux minutes, au repos et durant la tâche cognitive, ont été analysés. Les résultats montrent une augmentation significative de l’entropie approximative chez les athlètes du groupe contrôle durant la tâche cognitive (ρ < 0,05), tandis qu’aucune différence n’a été observée entre l’entropie approximative au repos et celle durant la tâche cognitive chez les athlètes du groupe commotion. Ces résultats suggèrent que des déficits neurologiques liés à la régulation de la fréquence cardiaque peuvent être observés durant une tâche cognitive chez des athlètes ayant récemment subi une commotion cérébrale.
Most studies have focused on the consequences of concussions on the brain itself. However, the brain performs many functions, including regulating heart rate. Therefore, researchers have begun studying the consequences of these concussions on the brain’s heart rate regulation during physical exertion. Most athletes who sustain a concussion need to plan for their return to play as well as a return to work or school. The purpose of this research project was to study the consequences of concussions on the brain’s regulation of heart rate during cognitive effort. This study involved 11 university athletes who sustained a concussion, as well as 14 athletes with no history of concussion. Concussed athletes were assessed an average of 14.6 days (± 7.4 days) after their injury. The participants’ heart rate was recorded at rest and during cognitive effort, which consisted of a switch task. Short segments lasting two minutes at rest and during cognitive task were analyzed. The results show a significant increase in the approximate entropy in the control group during the cognitive task (ρ <0.05), while no difference was observed between the approximate entropy at rest and during the cognitive task in the concussed athletes. These results suggest that neurological deficits related to heart rate regulation may be observed during cognitive task in athletes who recently sustained a concussion.