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Le cerveau endormi tend à se déconnecter dans sa progression vers le sommeil lent (SL) chez les jeunes adultes et se déconnecte moins chez les plus âgés. Les ondes lentes (OL) sont les caractéristiques principales du sommeil lent sur l’électroencéphalogramme (EEG). Notre groupe a récemment montré que deux types d’OL co-existent, les « slow switcher » (SlowS) et les « fast switcher » (FastS), caractérisées par leur vitesse de transition entre les maximums d’hyperpolarisation et de dépolarisation. Sur l’EEG, la connectivité globale pendant la transition des SlowS et des FastS diffère et diminue avec le vieillissement. Dans cette étude, nous utilisons des enregistrements de magnétoencéphalographie pour évaluer les changements relatifs à l’âge sur les générateurs des OL pendant la transition entre les maximums d’hyperpolarisation et de dépolarisation en termes de 1) topographie et 2) connectivité, avec l’indice de délais de phase pondéré basé sur le délai de phase moyen dans la transition des OL. Nous avons fait l’hypothèse que comparativement aux OL des individus jeunes, les OL des individus plus âgés vont 1) impliquer des régions corticales plus étendues et 2) montrer plus de connectivité, spécialement pour les SlowS. Nos résultats révèlent que comparativement aux jeunes participants, les plus vieux montrent 1) plus d’implication du précuneus droit pendant les SlowS et 2) une connectivité globale supérieure, surtout pour les SlowS. Finalement, les individus plus jeunes montrent plus de connectivité que les individus plus âgés entre des régions spécifiques, plus précisément dans le réseau antéropostérieur pour les SlowS que les FastS. Ensemble, nos résultats suggèrent une perte de flexibilité des réseaux pendant la transition des OL chez les individus plus âgés par rapport aux individus plus jeunes. / The sleeping brain tends to disconnect as it progresses toward slow wave sleep (SWS) in young adults and disconnects less in older adults. Slow waves (SW) are the main characteristics of slow wave sleep on the electroencephalogram (EEG). Our group recently showed that two types of SW co-exist, the “slow switcher” (SlowS) and the “fast switcher” (FastS), characterized by the transition speed between the hyperpolarized and depolarized peaks. On the EEG, the global connectivity during the transition of the SlowS and FastS differs and is reduced with aging. In this study, we used magnetoencephalography recordings to investigate age-related differences on the SW generators during the transition between the hyperpolarized and depolarized peaks in terms of 1) topography and 2) connectivity, using the weighted phase lag index based on the average phase lag during the SW transition. We hypothesised that as compared to younger individuals, SW of older participants would 1) involve broader cortical areas and 2) show higher connectivity than younger individuals, particularly for the SlowS. Our results revealed that as compared to younger participants, older individuals showed 1) more involvement of the right precuneus during the SlowS and 2) globally higher connectivity, more significantly for the SlowS. Finally, younger individuals showed higher connectivity than older individuals between specific regions, more precisely in the anteroposterior network for the SlowS than the FastS. Altogether, our results suggest an impaired flexibility of the network during the SW transition in older individuals as compared to younger individuals.

Pragmatic ability is crucial in everyday interactions. In populations of neurotypical individuals, pragmatic skill varies greatly. The neural mechanisms behind the variety, and the neural development of pragmatics remain to be explained. The present study aims to deepen the understanding of pragmatics’ neural basis, by investigating the functional connectivity (FC) between two pragmatically interesting brain clusters during a pragmatic task. The investigated clusters, located in the bilateral, dorsal precuneus and in the left superior inferior parietal cortex were found by Bendtz et al. (2022) to have higher activity for young adults with high pragmatic skill compared to young adults with low pragmatic skill. Mahal (2022) found that the clusters were more functionally connected for the high skilled group during rest. In this study, fMRI data acquired during a pragmatic task was used to analyze the FC between the beforementioned clusters and compare two groups of young adults, one with high pragmatic skill (n = 25) and one with low pragmatic skill (n = 24). The groups of young adults were also compared with a group of 16 - 18 year old adolescents (n = 12). The results revealed higher FC for the high skilled group in both analyses, where the difference between the high skilled group and the adolescents was significant (p=.02). FC-values did not correlate with age in neither age group. The results are suggested to reflect (1) a neural development of pragmatics in adolescence towards a potential pragmatic network that involve increased functional connections between two clusters previously identified as possible neural markers of pragmatic individual variation, and (2) a possible window of opportunity for pragmatic development during adolescence. / Den pragmatiska förmågan är avgörande i vardags-interaktioner. I neurotypiska populationer varierar pragmatisk förmåga mycket, och det är ännu inte klarlagt hur de precisa mekanismerna bakom variationen och utvecklingen av pragmatisk förmåga fungerar. Denna studies syfte är att fördjupa förståelsen för pragmatikens neurala grunder, genom att undersöka funktionell konnektivitet (FC) mellan två pragmatiskt intressanta hjärnkluster. De undersökta klustren, ett i bilaterala dorsala precuneus och ett i vänstra superiora inferiora parietala cortex, var mer aktiva för unga vuxna med hög pragmatisk förmåga jämfört med unga vuxna med låg pragmatisk förmåga (Bendtz et el. 2022). Mahal (2022) noterade att klustrena var mer funktionellt kopplade i vila för gruppen med hög pragmatisk förmåga. I denna studie användes fMRI-data från en pragmatisk uppgift för att analysera FC mellan de tidigare nämnda klustren, och jämföra två grupper med unga vuxna, en med hög pragmatisk förmåga (n = 25) och en med låg pragmatisk förmåga (n = 24). Grupperna med unga vuxna jämfördes också med en grupp 16 – 18 år gamla tonåringar (n = 12). Resultaten visade på en högre FC för gruppen med hög pragmatisk förmåga i båda analyser, där skillnaden mellan gruppen med hög pragmatisk förmåga och tonåringarna var signifikant (p = .02). Värdena av FC korrelerade inte med ålder i någon av åldersgrupperna. Resultaten föreslås återspegla (1) en neural utveckling av pragmatik under tonåren mot ett potentiellt pragmatiskt nätverk som involverar ökade funktionella kopplingar mellan två kluster som tidigare identifierats som potentiella neurala markörer för individuell variation av pragmatik och (2) en eventuell kritisk period för pragmatisk utveckling under tonåren.

A leading theory for why we sleep focuses on memory consolidation - the process of stabilizing and strengthening newly acquired memories into long-term storage. Consolidation of memory for cognitive strategies and problem-solving skills is enhanced as compared to a period of daytime wakefulness. Importantly, sleep preferentially enhances memory for the cognitive strategy per se, over-and-above the motor skills that are used to execute the strategy. Although it has been known for some time that sleep benefits this type of memory, it is not known how this process unfolds during sleep, or how sleep transforms this memory trace in the brain. Sleep is classified into rapid eye movement (REM) sleep and non-REM (NREM) sleep. The role of REM sleep for consolidation of memory for problem-solving skills remains controversial. In addition, little attention has been paid to the possible distinct roles of phasic REM sleep (i.e., when bursts of eye movements occur) and tonic REM sleep (i.e., the presence of isolated eye movements and the absence of eye movement bursts). REM sleep might favour procedural memory consolidation for cognitive strategies and problem-solving skills, and the specific role of REM sleep in this process might be discernible only by differentiating between phasic and tonic REM states. In addition, fMRI studies have revealed that sleep-related consolidation of the memory trace for simple motor procedural skills is associated with strengthened activity of, and functional connectivity between, key memory-related brain areas (i.e., hippocampal, striatal, and neocortex). However, fMRI techniques have not yet been employed to investigate sleep-related consolidation of procedural memory for cognitive strategies and problem-solving skills. Participants (n=60) performed a procedural memory task involving a cognitive strategy while undergoing functional magnetic resonance imaging (fMRI) before and after a condition of Sleep, Nap, or Wake. Those in the Sleep and Nap condition underwent polysomnography (PSG) to further study the learning-related changes in sleep macrostructure and microstructure. This thesis not only shows that a period of sleep or a nap afford a greater benefit to memory consolidation of a procedural strategy than a period of wake, but more specifically: In Study 1, during sleep, phasic REM sleep theta power was directly associated with overnight improvement on the task, whereas tonic REM sleep sensorimotor rhythm power was greater following a night of learning compared to a non-learning control night. In Study 2, we show that distinct hippocampal, striatal, and cortical areas associated with strategy learning are preferentially enhanced. Study 3 reveals that the functional communication among these brain areas is greater following sleep compared to a daytime nap or day of wakefulness. Sleep-related changes in brain activation and functional connectivity were both correlated with improved performance from before to after a period of sleep. Overall, findings from this thesis support the benefit of sleep at the behavioural and systems level for consolidating procedural memory involving cognitive strategies used to solve problems. The findings suggest that the multifaceted nature of REM sleep must be examined separately by its phasic and tonic states, to identify the active role of REM sleep for consolidating memory. Further, the consolidation of the memory trace is reflected through activation of, and communication between hippocampal, striatal, and neocortical brain areas. In summary, this thesis shows that sleep actively consolidates memory for cognitive strategies and problem-solving skills.

Approximately 20% of the body’s energy consumption is ongoingly consumed by the brain, where the main part is due to the neural activity, which is only increased slightly when doing a demanding task. This ongoingly neural activity are studied with the so called resting-state fMRI, which mean that the neural activity in the brain is measured for participants with no specific task. These studies have been useful to understand the neural function and how the neural networks are constructed and cooperate. This have also been helpful in several clinical research, for example have differences been identified between bipolar disorder and major depressive disorder. Recent research has focused on temporal properties of the ongoing activity and it is well known that neural activity occurs in bursts. In this study, resting-state fMRI data and temporal graph theory is used to develop a point based method (PBM) to quantify these bursts at a nodal level. By doing this, the bursty pattern can be further investigated and the nodes showing the most bursty pattern (i.e hubs) can be identified. The method developed shows a robustness regarding several different aspects. In the method is two different variance threshold algorithms suggested. One local variance threshold (LVT) based on the individual variance of the edge time-series and one global variance threshold (GVT) based on the variance of all edges time-series, where the GVT shows the highest robustness. However, the choice of threshold needs to be adapted for the aims of the current study. Finally, this method ends up in a new measure to quantify this bursty pattern named bursty centrality. The derived temporal graph theoretical measure was correlated with traditional static graph properties used in resting state and showed a low but significant correlation. By applying this method on resting-state fMRI data for 32 young adults was it possible to identify regions of the brain that showed the most dynamic properties, these regions differed between the two thresholding algorithms

Background: Learning by conditioning is a key ability of animals and humans for acquiring novel behavior necessary for survival in a changing environment. Aberrant conditioning has been considered a crucial factor in the etiology and maintenance of panic disorder with agoraphobia (PD/A). Cognitive-behavioral therapy (CBT) is an effective treatment for PD/A. However, the neural mechanisms underlying the effects of CBT on conditioning processes in PD/A are unknown. Methods: In a randomized, controlled, multicenter clinical trial in medication-free patients with PD/A who were treated with 12 sessions of manualized CBT, functional magnetic resonance imaging (fMRI) was used during fear conditioning before and after CBT. Quality-controlled fMRI data from 42 patients and 42 healthy subjects were obtained. Results: After CBT, patients compared to control subjects revealed reduced activation for the conditioned response (CS+ > CS–) in the left inferior frontal gyrus (IFG). This activation reduction was correlated with reduction in agoraphobic symptoms from t1 to t2. Patients compared to control subjects also demonstrated increased connectivity between the IFG and regions of the “fear network” (amygdalae, insulae, anterior cingulate cortex) across time. Conclusions: This study demonstrates the link between cerebral correlates of cognitive (IFG) and emotional (“fear network”) processing during symptom improvement across time in PD/A. Further research along this line has promising potential to support the development and further optimization of targeted treatments.

It is estimated that about 35-40% of adults in the U.S. suffer from insufficient sleep. Chronic sleep deprivation has become a prevalent phenomenon because of contemporary lifestyle and work-related factors. Sleep deprivation can reduce the capabilities and efficiency of attentional performance by impairing perception, increasing effort to maintain concentration, as well as introducing vision disturbance. Thus, it is important to understand the neural mechanisms behind how chronic sleep deprivation impairs sustained attention. In recent years, more attention has been paid to the study of the integration between anatomically distributed and functionally connected brain regions. Functional connectivity has been widely used to characterize brain functional integration, which measures the statistical dependency between neurophysiological events of the human brain. Further, evidence from recent studies has shown the non-stationary nature of brain functional connectivity, which may reveal more information about the human brain. Thus, the objective of this thesis is to investigate the effects of chronic sleep deprivation on sustained attention from the perspective of dynamic functional connectivity. A modified spatial cueing paradigm was used to assess human sustained attention in rested wakefulness and chronic sleep deprivation conditions. Partial least squares approach was applied to distinguish brain functional connectivity for the experimental conditions. With the integration of a sliding-window approach, dynamic patterns of brain functional connectivity were identified in two experimental conditions. The brain was modeled as a series of dynamic functional networks in each experimental condition. Graph theoretic analysis was performed to investigate the dynamic properties of brain functional networks, using network measures of clustering coefficient and characteristics path length. In the chronic sleep deprivation condition, a compensation mechanism between highly clustered organization and ineffective adaptability of brain functional networks was observed. Specifically, a highly clustered organization of brain functional networks was illustrated with a large clustering coefficient. This organization suggested that brain utilizes more connections to maintain attention in the chronic sleep deprivation condition. A smaller impact of clustering coefficient variation on characteristics path lengths indicated an ineffective adaptability of brain functional networks in the chronic sleep deprivation condition. In the rested wakefulness condition, brain functional networks showed the small-world topology in general, with the average small-world topology index larger than one. Small-world topology was identified as an optimal network structure with the balance between local information processing and global integration. Given the fluctuating values of the index over time, small-world brain networks were observed in most cases, indicating an effective adaptability of the human brain to maintain the dominance of small-world networks in the rested wakefulness condition. On the contrary, given that the average small-world topology index was smaller than one, brain functional networks generally exhibited random network structure. From the perspective of dynamic functional networks, even though there were few cases showing small-world brain networks, brain functional networks failed to maintain the dominance of small-world topology in the chronic sleep deprivation condition. In conclusion, to the best of our knowledge this thesis was the first to investigate the effects of chronic sleep deprivation on sustained attention from the perspective of dynamic brain functional connectivity. A compensation mechanism between highly clustered organization and ineffective adaptability of brain functional networks was observed in the chronic sleep deprivation condition. Furthermore, chronic sleep deprivation impaired sustained attention by reducing the effectiveness of brain functional networks' adaptability, resulting in the disrupted dominance of small-world brain networks.

Obsessive-compulsive disorder (OCD) is heterogeneous. Clinical presentation of OCD differs by sex and age-of-onset and evidence supports classification based on these subtypes. The prevalence of OCD in the general population is 2%. However, it has been established that women tend to experience onset and exacerbation of OCD during reproductive milestones. In particular, the prevalence of postpartum OCD is between 4 to 9%. This study seeks to examine the effects of past childhood maltreatment and S/Lg-allele status of the 5-HTTLPR polymorphism on perinatal obsessive-compulsive symptoms and aberrant resting state functional connectivity in the postpartum period. Forty women participated in the first visit and sixteen women have been followed up with in the postpartum period. 5-HTTLPR genotype was determined from whole blood samples via polymerase chain reaction and a restriction fragment length digest. We used the Yale-Brown Obsessive-Compulsive Scale and Perinatal Obsessive-Compulsive scale to measure symptom severity. Resting state functional connectivity was determined from functional magnetic resonance imaging data. Obsessive-compulsive symptoms during late pregnancy are significantly predicted by 5-HTTLPR genotype, past history of total childhood maltreatment or childhood emotional neglect and trait anxiety symptoms. Whereas obsessive-compulsive symptoms during the postpartum period are predicted by poor sleep quality and childhood emotional maltreatment or 5-HTTLPR genotype, childhood emotional maltreatment and trait anxiety symptoms. Seed to region-of-interest analysis was employed to evaluate resting state functional connectivity differences between OCD patients and healthy controls in the postpartum period. Compared to healthy controls, OCD patients show greater connectivity between the caudate nucleus with the orbitofrontal cortex, the pars triangularis and the cingulate area. The insular cortex shows decreased connectivity between the right and left, the dorsal anterior cingulate area and the pars opercularis. The amygdala has increased connectivity with the cingulate area, the calcarine fissure, the supramarginal gyrus and decreased connectivity with the gyrus rectus. The above clinical and neuroimaging findings are in line with past work. However, this is the first study to show both 5-HTTLPR genotype and history of childhood maltreatment predict obsessive-compulsive symptoms in a perinatal population. Further, the resting state data replicates findings in the OCD literature but the study is the first to show this in postpartum women. This study serves as a platform for future work to further investigate both gene-environment interactions and distinct neuroimaging correlates in perinatal OCD. / Thesis / Master of Science (MSc)

The present dissertation details a sequence of studies in mild traumatic brain injury, the progression of its effects on the human brain as recorded by event-related electroencephalography, and potential applications of machine learning algorithms in detecting such effects. The work investigated data collected from two populations (in addition to healthy controls): 1) a recently-concussed adolescent group, and 2) a group of retired football athletes who sustained head trauma a number of years prior to testing. Neurophysiological effects of concussion were assessed across both groups with the same experimental design using a multi-deviant auditory oddball paradigm designed to elicit the P300 and other earlier components. Explainable machine learning models were trained to classify concussed individuals from healthy controls. Cross-validation performance accuracies on the recently-concussed (chapter 4) and retired athletes (chapter 3) were 80% and 85%, respectively. Features showed to be most useful in the two studies were different, motivating a study of potential differences between the different injury-stage/age groups (chapter 5). Results showed event-related functional connectivity to modulate differentially between the two groups compared to healthy controls. Leveraging results from the presented work a theoretical model of mild traumatic brain injury progression was proposed to form a framework for synthesizing hypotheses in future research. / Dissertation / Doctor of Philosophy (PhD)