Attention Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder of childhood that is characterized by symptoms of inattention, impulsivity/hyperactivity, or a combination of both. Intrinsic brain dysfunction in ADHD can be examined through various methods including resting state functional Magnetic Resonance Imaging (rs-fMRI), which investigates patients’ functional brain connections in the absence of an explicit task. To date, studies of group differences in resting brain connectivity between patients with ADHD and typically developing controls (TDCs) have revealed reduced connectivity within the Default Mode Network (DMN), a resting state network implicated in introspection, mind-wandering, and day-dreaming. However, few studies have addressed the use of resting state connectivity measures as a diagnostic aide for ADHD on the individual patient level. In the current work, we attempted first to characterize the differences in resting state networks, including the DMN and three attention networks (the salience network, the left executive network, and the right executive network), between a group of youth with ADHD and a group of TDCs matched for age, IQ, gender, and handedness. Significant over- and under-connections were found in the ADHD group in all of these networks compared with TDCs. We then attempted to use a support vector machine (SVM) based on the information extracted from resting state network connectivity to classify participants as “ADHD” or “TDC.” The IFGmiddle temporal network (66.8% accuracy), the parietal association network (86.6% specificity and 48.5% PPV), and a physiological noise component (sensitivity 39.7% and NPV 69.6%) performed the best classifications. Finally, we attempted to combine and utilize information from all the resting state networks that we identified to improve classification accuracy. Contrary to our hypothesis, classification accuracy decreased to 54-55% when this information was combined. Overall, the work presented here supports the theory that the ADHD brain is differently connected at rest than that of TDCs, and that this information may be useful for developing a diagnostic aid. However, because ADHD is such a heterogeneous disorder, each ADHD patient’s underlying brain deficits may be unique making it difficult to determine what connectivity information is diagnostically useful.

Moral injury (MI) is associated with severe blame-related emotion and the development of psychopathology including posttraumatic stress disorder (PTSD). Little is known about how MI events are neurally processed when PTSD is comorbid, limiting the development of tailored interventions. Thus, this thesis sought to provide a novel, multi-method examination of the biological underpinnings of moral injury and relevant behavioural correlates. Study one provides the first investigation into the neural activation patterns elicited during MI event recall in military members and public safety personnel with PTSD, relative to MI-exposed civilian controls. In PTSD, emotional processing is challenged by heightened sensory information. Here, we provide evidence of heightened viscerosensory information processing (i.e. internal gnawing or gastrointestinal constriction related to blame-based emotion) during MI event recall, which appears to exert a strong influence over cortical regions facilitating moral cognitive processes including emotion regulation, autobiographical memory integration, and social cognition. Overwhelming visceral sensations can elicit defensive behaviour including tonic immobility (TI), a defensive response that facilitates viscerosensory dampening. Interestingly, more severe negative alterations in cognition and mood were associated with viscerosensory dampening in our PTSD group, pointing towards a compensatory pattern of emotional numbing. Studies two and three explore two posttraumatic symptoms consistent with emotional numbing: alexithymia and posttraumatic TI. In study two, we explore posttraumatic TI as a survival-based dissociative response and test a new measure of posttraumatic TI. In study three, we provide evidence that alexithymia is associated with an altered (muted) pattern of emotion-specific bodily sensation. This thesis provides a framework for embodied MI event processing in PTSD and highlights the importance of assessing the somatic experience of MI and screening for TI responses and emotional numbing as part of PTSD symptomatology. The evidence presented here suggests sensorimotor-based approaches and bottom-up regulatory strategies may be useful adjuncts to MI event processing. / Dissertation / Doctor of Philosophy (PhD) / Moral injury (MI) is a psychosocial-spiritual injury that can occur when deeply held values are violated either by oneself or a trusted other; it produces considerable pain and social alienation. MI has been linked to suicide and the development of posttraumatic stress disorder (PTSD), a mental health condition associated with distressing symptoms and reduced functioning in important areas of life, including social relationships. This thesis focuses on how MI events are processed by military members and public safety personnel, who are both at risk for MI and PTSD. We investigate how shame is experienced in the brain and body, and explore how intensified visceral sensations may become overwhelming (e.g., pit in stomach, vomiting) prompting emotional numbing or difficulties remaining embodied in the present moment (e.g., zoning out, freezing up). By understanding MI event processing when PTSD is present, we hope to gain insight into more effective treatments for these individuals.

Although functional magnetic resonance imaging (fMRI) has gained increasing importance in investigating neural substrates of anxiety disorders, less is known about the stress eliciting properties of the scanner environment itself. The aim of the study was to investigate feasibility, self-reported distress and anxiety management strategies during an fMRI experiment in a comprehensive sample of patients with panic disorder and agoraphobia (PD/AG). Within the national research network PANIC-NET, n = 89 patients and n = 90 controls participated in a multicenter fMRI study. Subjects completed a retrospective questionnaire on self-reported distress, including a habituation profile and exploratory questions about helpful strategies. Drop-out rates and fMRI quality parameters were employed as markers of study feasibility. Different anxiety measures were used to identify patients particularly vulnerable to increased scanner anxiety and impaired data quality. Three (3.5%) patients terminated the session prematurely. While drop-out rates were comparable for patients and controls, data quality was moderately impaired in patients. Distress was significantly elevated in patients compared to controls; claustrophobic anxiety was furthermore associated with pronounced distress and lower fMRI data quality in patients. Patients reported helpful strategies, including motivational factors and cognitive coping strategies. The feasibility of large-scale fMRI studies on PD/AG patients could be proved. Study designs should nevertheless acknowledge that the MRI setting may enhance stress reactions. Future studies are needed to investigate the relationship between self-reported distress and fMRI data in patient groups that are subject to neuroimaging research.

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)

A number of studies have concluded that cognitive control is not fully established until late adolescence. The precise differences in brain function between adults and adolescents with respect to cognitive control, however, remain unclear. To address this issue, we conducted a study in which 185 adolescents (mean age (SD) 14.6 (0.3) years) and 28 adults (mean age (SD) 25.2 (6.3) years) performed a single task that included both a stimulus-response (S-R) interference component and a task-switching component. Behavioural responses (i.e. reaction time, RT; error rate, ER) and brain activity during correct, error and post-error trials, detected by functional magnetic resonance imaging (fMRI), were measured. Behaviourally, RT and ER were significantly higher in incongruent than in congruent trials and in switch than in repeat trials. The two groups did not differ in RT during correct trials, but adolescents had a significantly higher ER than adults. In line with similar RTs, brain responses during correct trials did not differ between groups, indicating that adolescents and adults engage the same cognitive control network to successfully overcome S-R interference or task switches. Interestingly, adolescents with stronger brain activation in the bilateral insulae during error trials and in fronto-parietal regions of the cognitive control network during post-error trials did have lower ERs. This indicates that those mid-adolescents who commit fewer errors are better at monitoring their performance, and after detecting errors are more capable of flexibly allocating further cognitive control resources. Although we did not detect a convincing neural correlate of the observed behavioural differences between adolescents and adults, the revealed interindividual differences in adolescents might at least in part be due to brain development.

O presente estudo consistiu-se na avaliação clínica e aplicação de testes cognitivos, além da realização de ressonância magnética (RM), de 3 tesla, do cérebro, processada com a técnica de \"Voxel-based Morphometry\" (VBM) e \"Skull Strip\", e 18F-FDG PET -CT processado com \"Statistical Parametric Mapping\" (SPM8) e correção de volume parcial (PVELab), em idosos sem déficits cognitivos (CDR=0), com comprometimento cognitivo leve amnéstico (CCL) (CDR=0,5) e com Doença de Alzheimer leve (DA leve)(CDR de 0,5 a 1). Os objetivos foram comparar os padrões de neuroimagem estrutural e metabólica entre os grupos, assim como correlacionar alterações estruturais volumétricas da RM e alterações metabólicas cerebrais do PET-CT, a um teste funcional, o \"Informant Questionnaire on Cognitive Decline in the Elderly\" (IQCODE), nessa mesma amostra. Cada um dos grupo 3 grupos, pareados por idade, contém 30 indivíduos, totalizando amostra de 90. Os resultados dos exames de Neuroimagens, divididos por comparações entre os grupos, e corrigidos pela escolaridade, foram considerados significativos todos os achados nos quais a significância corrigida for <= 0,05 (p-FWEcorr <= 0,05). No CCL x DA foi observado hipometabolismo Giro do Cíngulo à Direita. No grupo DA x CCL foram observados hipometabolismos no Giro do Cíngulo à Esquerda, no Precuneus Esquerdo, Precuneus Direito e na parte inferior do Lobo Parietal Esquerdo. Na DA x Controle, utilizando-se pesquisa de área a priori e filtros gaussiano de 8mm e 4mm, foi observada redução estatisticamente significante quanto ao volume de substância cinzenta na Amígdala Esquerda e na Amígdala Direita. No PET - CT, da DA, em relação ao grupo controle foram observadas áreas de hipometabolismos no Giro do Cíngulo à Esquerda, no Precuneus Direito e no Giro Temporal Medial Direito. Na correlação direta do IQCODE, na comparação DA x Controle, no PET - CT evidenciou-se hipometabolismo no Giro Fusiforme Direito. Em conclusão, os resultados das comparações entre os grupos foram semelhantes ao encontrado na literatura para fases iniciais (leves) da patologia e mostraram, ainda, uma tendência a um \"continuum\" do controle até a DA. Por outro lado à correlação do IQCODE no DA x Controle carece de comprovação por outros trabalhos e com outros constructos estatísticos / This study consisted in the clinical evaluation and application of cognitive tests, in addition to magnetic resonance imaging (MRI) of 3 Tesla, of brain, processed with the technique of \"Voxel-based Morphometry\" (VBM) and \"Skull Strip\", and 18F-FDG PET-CT processed by \"Statistical Parametric Mapping\" (SPM8) and partial volume correction (PVELab) in subjects without cognitive impairment (CDR = 0), with amnestic mild cognitive impairment (MCI)(CDR = 0.5) and with mild Alzheimer \'s disease (AD mild)(CDRs of 0.5 to 1). The objectives were to compare the patterns of structural and metabolic neuroimaging between groups, as well as correlate MRI\'s volumetric structural changes and PET-CT\'s metabolic brain with a functional test, the \"Informant Questionnaire on Cognitive Decline in the Elderly\" (IQCODE) in this same sample. Each one of three groups, matched by age, contains 30 subjects, totaling 90. The test results of neuroimaging, divided by comparisons between groups, and corrected by education, were considered significant the findings that corrected significance is <= 0.05 (p-FWEcorr <= 0.05). In CCL x DA was observed hypometabolism right cingulate gyrus. In DA x CCL hypometabolism were observed in the left cingulate gyrus, the left precuneus, right precuneus and left inferior parietal lobe. In DA x Control, using the \"a priori\" research area and gaussian filters 8mm and 4mm was observed statistically significant reduction on the volume of gray matter in the left and right amygdala. In PET - CT of DA relative to control group were observed areas of hypometabolisms in left cingulate, right precuneus and in the right medial temporal gyrus. In direct correlation of the IQCODE, compared DA x Control on PET - CT revealed a hypometabolism in the right fusiform gyrus. In conclusion, the results of the comparisons between groups were similar to those found in the literature for early (mild) pathology and showed a \"continuum\" of control to the DA. On the other hand the correlation of the IQCODE in DA x Control lacks confirmation by other studies and other statistical constructs

O presente estudo consistiu-se na avaliação clínica e aplicação de testes cognitivos, além da realização de ressonância magnética (RM), de 3 tesla, do cérebro, processada com a técnica de \"Voxel-based Morphometry\" (VBM) e \"Skull Strip\", e 18F-FDG PET -CT processado com \"Statistical Parametric Mapping\" (SPM8) e correção de volume parcial (PVELab), em idosos sem déficits cognitivos (CDR=0), com comprometimento cognitivo leve amnéstico (CCL) (CDR=0,5) e com Doença de Alzheimer leve (DA leve)(CDR de 0,5 a 1). Os objetivos foram comparar os padrões de neuroimagem estrutural e metabólica entre os grupos, assim como correlacionar alterações estruturais volumétricas da RM e alterações metabólicas cerebrais do PET-CT, a um teste funcional, o \"Informant Questionnaire on Cognitive Decline in the Elderly\" (IQCODE), nessa mesma amostra. Cada um dos grupo 3 grupos, pareados por idade, contém 30 indivíduos, totalizando amostra de 90. Os resultados dos exames de Neuroimagens, divididos por comparações entre os grupos, e corrigidos pela escolaridade, foram considerados significativos todos os achados nos quais a significância corrigida for <= 0,05 (p-FWEcorr <= 0,05). No CCL x DA foi observado hipometabolismo Giro do Cíngulo à Direita. No grupo DA x CCL foram observados hipometabolismos no Giro do Cíngulo à Esquerda, no Precuneus Esquerdo, Precuneus Direito e na parte inferior do Lobo Parietal Esquerdo. Na DA x Controle, utilizando-se pesquisa de área a priori e filtros gaussiano de 8mm e 4mm, foi observada redução estatisticamente significante quanto ao volume de substância cinzenta na Amígdala Esquerda e na Amígdala Direita. No PET - CT, da DA, em relação ao grupo controle foram observadas áreas de hipometabolismos no Giro do Cíngulo à Esquerda, no Precuneus Direito e no Giro Temporal Medial Direito. Na correlação direta do IQCODE, na comparação DA x Controle, no PET - CT evidenciou-se hipometabolismo no Giro Fusiforme Direito. Em conclusão, os resultados das comparações entre os grupos foram semelhantes ao encontrado na literatura para fases iniciais (leves) da patologia e mostraram, ainda, uma tendência a um \"continuum\" do controle até a DA. Por outro lado à correlação do IQCODE no DA x Controle carece de comprovação por outros trabalhos e com outros constructos estatísticos / This study consisted in the clinical evaluation and application of cognitive tests, in addition to magnetic resonance imaging (MRI) of 3 Tesla, of brain, processed with the technique of \"Voxel-based Morphometry\" (VBM) and \"Skull Strip\", and 18F-FDG PET-CT processed by \"Statistical Parametric Mapping\" (SPM8) and partial volume correction (PVELab) in subjects without cognitive impairment (CDR = 0), with amnestic mild cognitive impairment (MCI)(CDR = 0.5) and with mild Alzheimer \'s disease (AD mild)(CDRs of 0.5 to 1). The objectives were to compare the patterns of structural and metabolic neuroimaging between groups, as well as correlate MRI\'s volumetric structural changes and PET-CT\'s metabolic brain with a functional test, the \"Informant Questionnaire on Cognitive Decline in the Elderly\" (IQCODE) in this same sample. Each one of three groups, matched by age, contains 30 subjects, totaling 90. The test results of neuroimaging, divided by comparisons between groups, and corrected by education, were considered significant the findings that corrected significance is <= 0.05 (p-FWEcorr <= 0.05). In CCL x DA was observed hypometabolism right cingulate gyrus. In DA x CCL hypometabolism were observed in the left cingulate gyrus, the left precuneus, right precuneus and left inferior parietal lobe. In DA x Control, using the \"a priori\" research area and gaussian filters 8mm and 4mm was observed statistically significant reduction on the volume of gray matter in the left and right amygdala. In PET - CT of DA relative to control group were observed areas of hypometabolisms in left cingulate, right precuneus and in the right medial temporal gyrus. In direct correlation of the IQCODE, compared DA x Control on PET - CT revealed a hypometabolism in the right fusiform gyrus. In conclusion, the results of the comparisons between groups were similar to those found in the literature for early (mild) pathology and showed a \"continuum\" of control to the DA. On the other hand the correlation of the IQCODE in DA x Control lacks confirmation by other studies and other statistical constructs

A number of studies have concluded that cognitive control is not fully established until late adolescence. The precise differences in brain function between adults and adolescents with respect to cognitive control, however, remain unclear. To address this issue, we conducted a study in which 185 adolescents (mean age (SD) 14.6 (0.3) years) and 28 adults (mean age (SD) 25.2 (6.3) years) performed a single task that included both a stimulus-response (S-R) interference component and a task-switching component. Behavioural responses (i.e. reaction time, RT; error rate, ER) and brain activity during correct, error and post-error trials, detected by functional magnetic resonance imaging (fMRI), were measured. Behaviourally, RT and ER were significantly higher in incongruent than in congruent trials and in switch than in repeat trials. The two groups did not differ in RT during correct trials, but adolescents had a significantly higher ER than adults. In line with similar RTs, brain responses during correct trials did not differ between groups, indicating that adolescents and adults engage the same cognitive control network to successfully overcome S-R interference or task switches. Interestingly, adolescents with stronger brain activation in the bilateral insulae during error trials and in fronto-parietal regions of the cognitive control network during post-error trials did have lower ERs. This indicates that those mid-adolescents who commit fewer errors are better at monitoring their performance, and after detecting errors are more capable of flexibly allocating further cognitive control resources. Although we did not detect a convincing neural correlate of the observed behavioural differences between adolescents and adults, the revealed interindividual differences in adolescents might at least in part be due to brain development.

L’atrophie corticale postérieure (ACP) est un syndrome clinique assez rare d’apparition insidieuse et d’évolution progressive amenant des difficultés visuelles complexes, associées à une atrophie prédominant dans les régions corticales postérieures, en dépit d’une relative préservation des autres sphères de la cognition. Cependant, cette forme atypique de démence demeure encore mal caractérisée en début d’évolution. L’objectif principal de ce projet est de mieux caractériser sur le plan neuropsychologique l’ACP en début d’évolution. Une étude de cas neuropsychologique approfondie a été réalisée chez un patient de 63 ans atteint d’une ACP débutante (M.T.) présentant initialement des plaintes au niveau de la perception visuelle. Une batterie exhaustive de tests neuropsychologiques a été administrée afin d’évaluer l’ensemble des fonctions cognitives. Une évaluation fonctionnelle en ergothérapie a également été réalisée afin d’évaluer l’ampleur des difficultés dans les activités de la vie quotidienne, ainsi qu’une IRM anatomique haute résolution (3 Teslas). Les résultats de l’évaluation neuropsychologique ont mis en évidence des difficultés relativement sélectives à traiter de l’information visuelle spatiale tridimensionnelle, suggérant sur le plan clinique une atteinte de la voie dorsale. Les résultats de l’imagerie par résonance magnétique (IRM) ont mis en évidence une atrophie prédominant dans la région pariétale, surtout dans l’hémisphère droit, corroborant ainsi les atteintes sur le plan neuropsychologique. Cette étude dans son ensemble contribue à mieux documenter la nature des atteintes cognitives, fonctionnelles et cérébrales dans un syndrome progressif rare. / Posterior cortical atrophy (PCA) is an insidious, rare and progressive clinic syndrome which causes complex visual difficulties, associated with atrophy predominating in posterior cortical areas, despite a relative preservation in other cognitive domains. This unusual type of dementia has been poorly characterized in the very early stage of the disease from a neuropsychological standpoint. The main goal of this project is to better characterize PCA from a neuropsychological and functional perspective in the very early stage of the disease, through a very detailed single case study of a 63 years old patient who presented with slowly progressive difficulties in visual perception. A detailed neuropsychological assessment of patient M.T. was carried out in order to assess his abilities in different cognitive domains. A functional evaluation of his activities of daily living was also carried out. The results of the neuropsychological assessment revealed specific difficulties in processing three-dimensional, visuospatial information, suggesting lesions to the occipitoparietal pathway (dorsal stream). M.T. carried out a high-resolution 3T anatomical MRI, which revealed bi-parietal atrophy, predominating in the right hemisphere. This study helps better documenting the nature of neuropsychological, functional, and neuroanatomical deficits in the very early stage of PCA.

The blood oxygen level dependent functional MRI (BOLD-fMRI) signal is an indirect measure of the neuronal activity that most BOLD studies are interested in. This thesis uses generative embedding algorithms to investigate some of the challenges and opportunities that this presents for BOLD imaging. It is standard practice to analyse BOLD signals using general linear models (GLMs) that assume fixed neurovascular coupling. However, this assumption may cause false positive or negative neural activations to be detected if the biological manifestations of brain diseases, disorders and pharmaceutical drugs (termed "neuromodulations") alter this coupling. Generative embedding can help overcome this problem by identifying when a neuromodulation confounds the standard GLM. When applied to anaesthetic neuromodulations found in preclinical imaging data, Fentanyl has the smallest confounding effect and Pentobarbital has the largest, causing extremely significant neural activations to go undetected. Half of the anaesthetics tested caused overestimation of the neuronal activity but the other half caused underestimation. The variability in biological action between anaesthetic modulations in identical brain regions of genetically similar animals highlights the complexity required to comprehensively account for factors confounding neurovascular coupling in GLMs generally. Generative embedding has the potential to augment established algorithms used to compensate for these variations in GLMs without complicating the standard (ANOVA) way of reporting BOLD results. Neuromodulation of neurovascular coupling can also present opportunities, such as improved diagnosis, monitoring and understanding of brain diseases accompanied by neurovascular uncoupling. Information theory is used to show that the discriminabilities of neurodegenerative-diseased and healthy generative posterior parameter spaces make generative embedding a viable tool for these commercial applications, boasting sensitivity to neurovascular coupling nonlinearities and biological interpretability. The value of hybrid neuroimaging systems over separate neuroimaging technologies is found to be greatest for early-stage neurodegenerative disease.