27 research outputs found

    Cortico-amygdalar connectivity and externalizing/internalizing behavior in children with neurodevelopmental disorders

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    Background: Externalizing and internalizing behaviors contribute to clinical impairment in children with neurodevelopmental disorders (NDDs). Although associations between externalizing or internalizing behaviors and cortico-amygdalar connectivity have been found in clinical and non-clinical pediatric samples, no previous study has examined whether similar shared associations are present across children with different NDDs. Methods: Multi-modal neuroimaging and behavioral data from the Province of Ontario Neurodevelopmental Disorders (POND) Network were used. POND participants aged 6–18 years with a primary diagnosis of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD) or obsessive–compulsive disorder (OCD), as well as typically developing children (TDC) with T1-weighted, resting-state fMRI or diffusion weighted imaging (DWI) and parent-report Child Behavioral Checklist (CBCL) data available, were analyzed (total n = 346). Associations between externalizing or internalizing behavior and cortico-amygdalar structural and functional connectivity indices were examined using linear regressions, controlling for age, gender, and image-modality specific covariates. Behavior-by-diagnosis interaction effects were also examined. Results: No significant linear associations (or diagnosis-by-behavior interaction effects) were found between CBCL-measured externalizing or internalizing behaviors and any of the connectivity indices examined. Post-hoc bootstrapping analyses indicated stability and reliability of these null results. Conclusions: The current study provides evidence towards an absence of a shared linear relationship between internalizing or externalizing behaviors and cortico-amygdalar connectivity properties across a transdiagnostic sample of children with different primary NDD diagnoses and TDC. Different methodological approaches, including incorporation of multi-dimensional behavioral data (e.g., task-based fMRI) or clustering approaches may be needed to clarify complex brain-behavior relationships relevant to externalizing/internalizing behaviors in heterogeneous clinical NDD populations

    The Multi-Dimensional Contributions of Prefrontal Circuits to Emotion Regulation during Adulthood and Critical Stages of Development

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    The prefrontal cortex (PFC) plays a pivotal role in regulating our emotions. The importance of ventromedial regions in emotion regulation, including the ventral sector of the medial PFC, the medial sector of the orbital cortex and subgenual cingulate cortex, have been recognized for a long time. However, it is increasingly apparent that lateral and dorsal regions of the PFC, as well as neighbouring dorsal anterior cingulate cortex, also play a role. Defining the underlying psychological mechanisms by which these functionally distinct regions modulate emotions and the nature and extent of their interactions is a critical step towards better stratification of the symptoms of mood and anxiety disorders. It is also important to extend our understanding of these prefrontal circuits in development. Specifically, it is important to determine whether they exhibit differential sensitivity to perturbations by known risk factors such as stress and inflammation at distinct developmental epochs. This Special Issue brings together the most recent research in humans and other animals that addresses these important issues, and in doing so, highlights the value of the translational approach

    Using novel imaging approaches in affective disorders : beyond current models

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    Depressie en angststoornissen, zoals major depressive disorder, paniekstoornis, sociale angststoornis en gegeneraliseerde angststoornis, vallen onder de meest voorkomende psychiatrische ziektebeelden. Door middel van neuroimaging onderzoek zoals structurele en functionele MRI (fMRI) is het mogelijk om op een non-invasieve manier de onderliggende neurobiologie van deze stoornissen in kaart te brengen. Op basis van dergelijk onderzoek werden ruim 15 jaar geleden enkele neurobiologische modellen opgesteld waarin werd voorgesteld dat het goed of juist niet goed hersengebieden een belangrijke bijdrage leverde aan het ontstaan en/of instandhouden van depressie en angst. In de loop der jaren zijn nieuwe MRI technieken ontwikkeld. Met behulp van structurele MRI en resting-state fMRI, waarmee connectiviteit tussen hersengebieden onderzocht kan worden, heb ik gekeken naar anatomische en functionele hersenafwijkingen bij volwassenen en jongeren met depressie en/of angststoornissen. Doel was te bepalen of de reeds bestaande neurobiologische modellen bevestigd danwel aangepast of aangevuld zouden kunnen worden met recent ontwikkelde onderzoeksmethoden. De resultaten van mijn studies bevestigden grotendeels de betrokkenheid van de hersengebieden in de modellen, maar wezen tevens op een rol voor uitgebreidere netwerken van hersengebieden dan in de modellen werd verondersteld.UBL - phd migration 201

    Sex Differences in Stress-Responsive Neural Substrates and the Development of Mood Disorder-Like Behavior Following a Rodent Model of Early-Life Adversity

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    Stress-related mood disorders, such as anxiety and depression, are the most common psychiatric conditions, occurring with a lifetime risk of 15-20%. Women are twice as likely to develop anxiety and depression than men, and this sex difference emerges during puberty. Exposure to abuse or maltreatment during early life increases mood disorder susceptibility, suggesting that females may be especially sensitive to long-lasting, negative effects of early-life stress. While the female-bias in mood disorders is one of the most robust sex differences in psychiatry, the origin of this difference remains unknown. Sexually dimorphic processing of stressors by the adolescent brain, or the sex-specific expression of stress-related neural substrates, may be mechanisms by which stress-related mood disorders are more prominent in females. We developed a novel animal model of early-life adversity, Juvenile Social Subjugation (JSS), to test the effect of chronic adolescent social stress on mood disorder-like pathology in adulthood. This dissertation addressed the following research questions: (1) Does chronic JSS induce sex-specific anxiety and depression-like behaviors and HPA axis dysfunction in adulthood? (2) Is JSS differentially processed by the male and female adolescent brain? (3) Is the corticotropin-releasing factor receptor (CRF) system sex-specifically expressed across development? Together our data point to regional sex differences in neuronal activation and CRF receptor expression in the brain as potential mechanisms by which stressors such as JSS induce sex-specific mood disorder-like behavior in adulthood

    The obsessed brain

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    A number of neuropsychological studies have evaluated the conspicuous features of obsessivecompulsive disorder (OCD), a heavily impairing psychiatric illness. While the neuropsychological model seems to be well understood and therefore the diagnose well established, the therapy effects are rather short term and go along with high relapse rates. This is probably the consequence of the still undetected disorder causes and therefore therapy is mainly symptom alleviation treatment, with only rarely lasting long term effects. Advances in research tools such as brain imaging have enabled the exploration of the coredriving organ in which OCD related processes take place, namely the brain. Against the background of findings from various OCD neuroimaging studies, a neurobiological model of the disorder has evolved including disturbances in cortico-striato-thalamo-cortical (CSTC) Areas and their functional circuits. Nevertheless, as there is a high inconsistency between study results and the analysis tools for brain imaging data are advancing fast, more recent studies reinforced the need for a revision of the OCD model by including additional areas. Thus, the integration of multiple variables from neuro-psychology, -biology as well as genetics and basic research, shifted the Research approach from a region-focused thinking to concepts of Network disruption in OCD. To disentangle the recent inconsistent neuroimaging findings, the aim of the current thesis was to investigate the neural patterns of brain function (e.g. activation, connectivity) and structure (e.g. measures of gray and white matter GM/WM), their associations with each other and their link to clinical characteristics such as symptom severity and duration of illness. The aim was accomplished in form of three recently published studies, in which we compared a large sample of OCD patients with age-, and gender- matched healthy controls. We examined brain function and structure using a 3T MRI, the functional images were acquired during OCD-sensitive tasks. Overall, in the three studies, we provided evidence for an overactive circuit during symptom provocation associated with structural impairments of underlying WM tracts. Moreover, we observed a globally decreased GM in patients in various properties of the cortical mantle, one of which has been associated with early brain development. Our results are partly in agreement with previous studies, but bring also additional evidence on interconnections between several neuronal measures. They as well suggest that in order to elucidate the neurobiological substrates of OCD, research questions need to be addressed on the network level rather than on regional dysfunctions. Furthermore, these findings should encourage future studies to replicate and validate existing results, ideally in the form of metaanalyses or multi-center studies. Valid and reliable Information about the interrelations of all measurable properties of the brain, but also their links to OCD onset and progression, will help in furthering our understanding about the neural mechanism of the disorder, but also in the clinical conceptualisation and categorisation. Moreover, this would enable future studies to investigate whether there is a trait-like neurobiological pattern common to all patients, or if the various symptom spectra are characterized by unique and partly distinct neural patterns. Answers to these questions might improve treatment and clinical handling of OCD, potentially leading to more individualized therapeutic interventions. These could also be of relevance for OCD drug-treatment research in detecting more specialized medication, with less side effects and fewer relapse rates, to be used as an additional supportive factor in therapy

    New advances in the neurobiological mechanisms regulating fear extinction.

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    Developmental neurocognitive pathway of psychosis proneness and the impact of cannabis use

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    Cette thèse fait la promotion d’une nouvelle approche ciblant le risque de psychose qui consiste à identifier les enfants et les jeunes adolescents de la communauté appartenant à différentes trajectoires développementales d’expériences psychotiques. Une identification très précoce du risque de psychose chez des jeunes de la communauté pourrait ainsi diminuer la période où les symptômes cliniques ne sont pas traités, mais aurait également le potentiel de prévenir efficacement l’émergence de symptômes avérés, et ce, si les facteurs de risque sont identifiés. Étant donné que la consommation de cannabis s’avère un important facteur de risque de la psychose et le contexte actuel où les états en sont à réviser leurs politiques de réglementation du cannabis, il s’avère primordial de mieux comprendre comment la consommation peut mener à la psychose chez les individus vulnérables. Tout d’abord, j’ai investigué la séquence temporelle entre la consommation de cannabis et les expériences psychotiques chez une population de 4000 adolescents, suivis pendant 4 ans, au moment de l’adolescence où les deux phénomènes s’initient. Ensuite, j’ai examiné, chez des adolescents suivant une trajectoire de vulnérabilité, le rôle d’un moins bon fonctionnement cognitif ainsi que celui d’une exacerbation des symptômes anxieux et dépressifs comme médiateurs du lien entre cannabis et risque de psychose. Enfin, j’ai investigué la présence de marqueurs neurocognitifs précoces (fonctionnels et structurels) qui seraient associés à l’émergence de symptômes psychotiques chez des adolescents, et exploré si la consommation de cannabis pourrait modérer l’ampleur de ces marqueurs. Les données proviennent de deux cohortes longitudinales suivant des adolescents de la population générale, l’étude Co-Venture (n=4000, âgés de 12 ans, suivis annuellement pendant 4 ans) et l’étude de neuroimagerie IMAGEN (n=2200, âgés de 14 ans, suivis pendant 2 ans), ainsi qu’un sous-échantillon de l’étude Co-Venture ayant complété des mesures de neuroimagerie (n=151, âgés de 12 ans, suivis annuellement pendant 4 ans). Les résultats ont montré que la consommation de cannabis précédait systématiquement l’augmentation des expériences psychotiques, et non l’inverse. Chez les jeunes suivant une trajectoire de vulnérabilité, la relation entre la consommation de cannabis et le risque de psychose était davantage expliquée par une augmentation des symptômes de dépression et d’anxiété. Une réduction du volume de l’hippocampe et de l’amygdale en combinaison avec une hyperactivité de ces mêmes régions en réponse à des expressions neutres étaient tous associés à l’émergence de symptômes psychotiques. Or, la consommation de cannabis n’a pas exacerbé les altérations structurelles observées chez les adolescents rapportant des expériences psychotiques. Ces résultats ont mis en évidence le rôle primordial d’un hyperfonctionnement du système limbique pouvant mener à l’attribution aberrante d’une importance émotionnelle aux stimuli de l’environnement, et ce, chez des adolescents vulnérables. Il semble que le mécanisme par lequel la consommation de cannabis mène à l’émergence de symptômes cliniques passe par son influence sur les symptômes de dépression et d’anxiété ainsi que leurs mécanismes neuronaux sous-jacents d’une hypersensibilité au stress. Enfin, de par ces résultats, cette thèse permet de contribuer au développement de nouvelles interventions visant à réduire la demande de cannabis chez des adolescents vulnérables.Following the worldwide initiative on intervening early in clinical high-risk individuals for psychosis, this thesis promotes a novel approach to identify those at risk for psychosis by studying children and adolescents from the community who report different trajectories of subclinical psychosis symptoms (i.e., psychotic-like experiences) without the confounds of iatrogenic effects such as major social and cognitive impairments. Early identification from this approach may not only reduce harm by shortening the duration of untreated symptoms, but may also have the capacity to prevent the emergence of clinically validated symptoms, particularly if early risk factors can be identified. Considering the long-standing notion that cannabis misuse is an important risk factor for psychosis and that jurisdictions around the world are currently revising their cannabis regulatory policies, there is a need to better understand how cannabis use may lead to psychosis in vulnerable youths. This thesis examined different mechanisms that may explain the complex relationship between cannabis use and psychosis risk. I first explored the temporal sequence between cannabis use and self-reported psychotic-like experiences in a population-based sample of 4000 adolescents, over a 4-year period when both phenomena have their onset. Second, in vulnerable youths, I investigated the role of impaired cognitive functioning as well as increased affective and anxious symptoms as mediators of the cannabis-to-psychosis relationship. And third, I explored the presence of early neurocognitive markers (both functional and structural) associated with the emergence of psychotic symptoms, and how cannabis use moderates these markers. Two longitudinal cohorts from the general population, the Co-Venture Study (n=4000, aged 12 years old, followed annually for 4 years) and the neuroimaging IMAGEN Study (n=2200, aged 14 years old, followed for 2 years), as well as the neuroimaging subsample from the Co-Venture Study (n=151, aged 12 years old, followed annually for 4 years) were used. It was found that an increase in cannabis use always preceded an increase in reported psychotic-like experiences throughout adolescence, but an increase in psychotic-like experiences rarely predicted an increase in cannabis use. Then, in vulnerable adolescents, the cannabis-to-psychosis risk relationship was better explained by increases in depression and anxiety symptoms relative to changes in cognitive functioning. It was demonstrated that reduced hippocampus and amygdala volumes, combined with hyperactivity of the same regions during neutral cues processing were associated with the emergence of psychotic symptoms in young adolescents reporting psychotic-like experiences. However, cannabis use did not exacerbate the structural alterations observed in youths with psychotic-like experiences. These findings have improved our understanding of the relationship between cannabis use and vulnerability to psychosis. They have also highlighted the important role of an impaired limbic network leading to an aberrant emotional salience attribution in vulnerable adolescents. Although cannabis use did not exacerbate brain structural alterations observed in vulnerable youths, it appears that cannabis will more likely interfere with depression and/or anxiety symptoms and their associated brain mechanisms underlying vulnerability to stress in the path towards psychosis risk. This thesis may inform the development of new evidence-based interventions that reduce demand for cannabis among vulnerable youths
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