Environmental effects on brain functional networks in a juvenile twin population

: The brain's intrinsic organization into large-scale functional networks, the resting state networks (RSN), shows complex inter-individual variability, consolidated during development. Nevertheless, the role of gene and environment on developmental brain functional connectivity (FC) remains largely unknown. Twin design represents an optimal platform to shed light on these effects acting on RSN characteristics. In this study, we applied statistical twin methods to resting-state functional magnetic resonance imaging (rs-fMRI) scans from 50 young twin pairs (aged 10-30 years) to preliminarily explore developmental determinants of brain FC. Multi-scale FC features were extracted and tested for applicability of classical ACE and ADE twin designs. Epistatic genetic effects were also assessed. In our sample, genetic and environmental effects on the brain functional connections largely varied between brain regions and FC features, showing good consistency at multiple spatial scales. Although we found selective contributions of common environment on temporo-occipital connections and of genetics on frontotemporal connections, the unique environment showed a predominant effect on FC link- and node-level features. Despite the lack of accurate genetic modeling, our preliminary results showed complex relationships between genes, environment, and functional brain connections during development. A predominant role of the unique environment on multi-scale RSN characteristics was suggested, which needs replications on independent samples. Future investigations should especially focus on nonadditive genetic effects, which remain largely unexplored

The adolescent brain : unraveling the neural mechanisms of cognitive and affective development

Adolescence is often characterized as a period of increased risk taking and impulsive behavior. Researchers have constructed brain-based models to explain the higher prevalence of risk taking during adolescence. It has been hypothesized that brain regions for cognitive control develop relatively slow compared to 'affective' brain regions. An imbalance between the maturity of these brain regions is thought to underlie the increased incidence of risk taking during adolescence. However, results on functional brain development remain contradictory and few studies have investigated the assumptions of imbalance models in large-scale longitudinal studies. In this PhD thesis both cognitive and affective aspects of development were investigated using a combination of functional and structural MRI data, hormonal measures and behavioral assessments, capturing the whole range of adolescence in a large sample of children, adolescents and adults between 8 and 27 years old. The results indicated that, contrary to predictions from imbalance models, brain regions for cognitive control could be recruited even by young children and adolescents, but in different situations than adults. The results have implications for the construction of new theoretical frameworks and may eventually contribute to educational interventions that are better tailored to both the challenges and possibilities of the adolescent brain.Pathways through Adolescenc

Changes in brain metabolic connectivity underlie autistic-like social deficits in a rat model of autism spectrum disorder

The neurobiological basis of social dysfunction and the high male prevalence in autism spectrum disorder (ASD) remain poorly understood. Although network alterations presumably underlie the development of autistic-like behaviors, a clear pattern of connectivity differences specific to ASD has not yet emerged. Because the heterogeneous nature of ASD hinders investigations in human subjects, we explored brain connectivity in an etiologically homogenous rat model of ASD induced by exposure to valproic acid (VPA) in utero. We performed partial correlation analysis of cross-sectional resting-state 18F-fluorodeoxyglucose positron emission tomography scans from VPA-exposed and control rats to estimate metabolic connectivity and conducted canonical correlation analysis of metabolic activity and behavior scores. VPA-treated rats exhibited impairments in social behaviors, and this difference was more pronounced in male than female rats. Similarly, current analyses revealed sex-specific changes in network connectivity and identified distinct alterations in the distributed metabolic activity patterns associated with autistic-like social deficits. Specifically, diminished activity in the salience network and enhanced activity in a cortico-cerebellar circuit correlated with the severity of social behavioral deficits. Such metabolic connectivity features may represent neurobiological substrates of autistic-like behavior, particularly in males, and may serve as a pathognomonic sign in the VPA rat model of ASD.ope

The enduring impact of childhood maltreatment on grey matter development

Childhood maltreatment doubles an individual’s risk of developing a psychiatric disorder, yet the neurobiological nature of the enduring impact of childhood maltreatment remains elusive. This thesis explores the long-term effect of childhood maltreatment on grey matter. The primary aims of this thesis are to discern the spatial extent, temporal profile and physiological breadth of the developmental impact of childhood maltreatment amongst young people with emerging mental disorder. Chapter II comprises of a meta-analysis of thirty-eight published articles and demonstrates that adults with a history of childhood maltreatment most commonly exhibit reduced grey matter in the hippocampus, amygdala and right dorsolateral prefrontal cortex, compared to non-maltreated adults. Chapters III-V contain three original studies, involving a cohort of 123 young people, aged 14-26, with emerging mental illness. Chapter III bridges a gap between cross-sectional child and adult studies by longitudinally mapping the developmental trajectory of the hippocampus and amygdala following childhood maltreatment. This study provided the first direct evidence that childhood maltreatment stunts hippocampal development into young adulthood. Chapter IV assesses the utility of the cumulative stress and mismatch hypotheses in understanding the contribution of childhood abuse and recent stress to the structure and function of the limbic system. Chapter V extends on recent advances in connectome research to examine the effect of childhood maltreatment on structural covariance networks. Investigation of the correspondence of structural covariance with structural connectivity and functional connectivity revealed that reduced grey matter across the network is likely related to deceased functional coactivation following childhood maltreatment. Chapter VI discusses the significance of these studies in understanding how maltreatment shapes brain development and increases the risk of psychiatric illness

GENDER FEATURES OF THE COGNITIVE RESERVE

Background: The high risk of cognitive impairment in people of older age groups determines the relevance of the study of factors contributing to the preservation of cognitive potential at a young age, which is necessary to develop a cognitive reserve model aimed at preventi for the formation of a cognitive reserve. Materials and methods: The research material was scientific publications on the topic of work. The general scientific method was applied: analysis of modern scientific literature on the research problem, generalization, comparison, systematization of cognitive functions in the late period of life. The research material was scientific publications on the topic of the work. The General scientific method is applied: analysis of modern scientific literature on the problem of research, generalization, comparison, systematization of theoretical data in relation to factors that contribute to the preservation of normative parameters of cognitive functions in the later period of life. Results: The s of the cognitive reserve at a late age. Scientific novelty: for the first time, a systematic review of scientific literary sources was conducted, devoted to the analysis of the contribution tive reserve. the concept of cognitive reserve is usually used in relation to old age, but there is no doubt that it is the total result of various activities that a person has performed throughout life. Factors that determine the cognitive reserve, acquired factors that are implemented during the life of the individual and biological factors, one of which is the "gender" factor. The "gender" factor has a certain effect on the risk of developing late dementia. The proven Polo-specific differences in the structure of the brain, the dynamics of cognitive functions, which are implemented differently in men and women in ontogenesis, suggest the need for different approaches to the formation and maintenance of the cognitive reserve in men and women

Genetic and phylogenetic uncoupling of structure and function in human transmodal cortex

Brain structure scaffolds intrinsic function, supporting cognition and ultimately behavioral flexibility. However, it remains unclear how a static, genetically controlled architecture supports flexible cognition and behavior. Here, we synthesize genetic, phylogenetic and cognitive analyses to understand how the macroscale organization of structure-function coupling across the cortex can inform its role in cognition. In humans, structure-function coupling was highest in regions of unimodal cortex and lowest in transmodal cortex, a pattern that was mirrored by a reduced alignment with heritable connectivity profiles. Structure-function uncoupling in macaques had a similar spatial distribution, but we observed an increased coupling between structure and function in association cortices relative to humans. Meta-analysis suggested regions with the least genetic control (low heritable correspondence and different across primates) are linked to social-cognition and autobiographical memory. Our findings suggest that genetic and evolutionary uncoupling of structure and function in different transmodal systems may support the emergence of complex forms of cognition

Neuroimaging Depression Risk in a Sample of Never-Depressed Children

Children of mothers with a history of depression are at significantly higher risk for developing depression themselves. Although numerous mechanisms explaining this relationship have been proposed (Goodman & Gotlib, 1999), relatively little is known about the neural substrates of never-depressed children’s depression risk. Of the few studies that have used neuroimaging techniques to characterize risk-based differences in children’s neural structure, function, and functional connectivity, most have used samples that include participants with a personal history of depression or older samples (i.e., past the typical age of onset for depressive disorders). These approaches limit what can be determined regarding whether findings are true markers of risk (and potential etiological mechanisms) or better reflect resilience to depression or brain-based sequelae of depression. There is a clear need to better characterize children’s neuroimaging-based markers of depression risk by focusing on samples with clear statistical risk (i.e., a maternal history of depression or early emerging depression symptoms) prior to their own onset of disorder. This dissertation addresses this gap in the literature by characterizing the association between a sample (Ns = 80-85) of never-depressed children’s risk for depression and magnetic resonance imaging (MRI) markers of children’s brain structure (Study 1), functional response to maternal feedback (Study 2), and resting-state functional connectivity (Study 3). Main findings included never-depressed children’s self-reported depression symptoms being negatively associated with grey matter volume in regions relevant to reward processing (i.e., orbitofrontal cortex; Study 1), functional activity in salience processing regions (i.e., anterior insula) and reward processing (i.e., putamen) during critical maternal feedback (Study 2), and resting-state functional connectivity within the Central Executive Network and Salience Network (Study 3). I also demonstrated that children with high maternal risk for depression (i.e., a maternal history of depression) had significantly increased resting-state functional connectivity within the default mode network. Results indicate that brain-based associates of depression risk (i.e., maternal history of depression and children’s depression symptoms) pre-exist the development of depression, potentially contributing to the etiology of depression. Future directions for the emerging field of neuroimaging children’s risk for depression are discussed

Resting-State Functional Connectivity in Youth With Gender Dysphoria

Current developmental models of gender identity and gender dysphoria (GD) lack sex-specific profiles of brain function that differentiate between typically-developing and cross-gender identified youth, as postulated by models like the unified theory of the origins of sex differences (Arnold, 2009) and the neurobiological theory of the origins of transsexuality (Swaab & Garcia-Falgueras, 2009). Previously, investigators have used brain imaging modalities such as Resting-State functional Magnetic Resonance Imaging (R-fMRI) to demonstrate differences in resting-state functional connectivity (RSFC) between typically-developing male and female youth, and between typically-developing and GID-diagnosed youth. In the present pilot study, I used R-fMRI to investigate differences in RSFC between typically-developing and cross-gender identified male and female youth subgroups, with the hypothesis that GID-diagnosed subgroups would demonstrate connectivity patterns in between those of typically-developing males and females. Eleven youth diagnosed with gender identity disorder (four males, ages 9 to 20 years; seven females, ages 12 to 20 years) were matched on age and assigned gender with 11 typically-developing youth. All participants completed written informed consent to undergo the IRB-approved research procedures. R-fMRI were collected while the participants were lying down and resting, with their eyes closed. Primary analyses focused on 14 brain regions selected because they showed sex differences most frequently or reliably in previous studies of R-fMRI in typically-developing youth. Statistical analysis used a 2 x 2 mixed effects analysis (assigned female versus assigned male x typically-developing versus GID-diagnosed), with-individual level connectivity maps as the dependent variable. Results showed that significant interaction effects of functional connectivity patterns were associated with 6 of the 14 selected brain regions. GID-diagnosed assigned females exhibited connectivity patterns similar to those of typically-developing males associated with the right medial superior frontal gyrus, right supplementary motor area, left lingual gyrus, right lingual gyrus, left middle frontal gyrus, left medial superior frontal gyrus, left cuneus, right thalamus, left dorsolateral superior frontal gyrus, and left inferior frontal gyrus, triangular part. GID-diagnosed assigned males exhibited functional connectivity patterns similar to those of typically-developing females associated with the right medial superior frontal gyrus and right supplementary motor area; in between those of typically-developing females and males associated with left lingual gyrus, right lingual gyrus, left middle frontal gyrus, left medial superior frontal gyrus, right medial superior frontal gyrus, left dorsolateral superior frontal gyrus, and left inferior frontal gyrus, triangular part; and similar to typically-developing males associated with the right lingual gyrus and left middle frontal gyrus. The right precuneus, hypothesized to show robust findings, did not reveal any effects. In the current study, GID-diagnosed assigned males tended toward demasculinized effects (quantitative interactions showing differences of magnitude), whereas GID-diagnosed assigned females tended toward masculinized effects (qualitative interactions showing differences in direction of correlation). The current findings support the view that brain development associated with gender dysphoria proceeds along separate but overlapping sex-related regions for GID-diagnosed assigned females and males and provide further evidence of greater cross-gender brain differentiation in assigned females at an earlier age than in assigned males (possibly due to earlier onset of puberty in females). These data suggest that any future use of patterns of brain function for diagnosing gender dysphoria may require separate criteria (e.g., different sets of brain regions) for assigned males and assigned females but will require replication on larger samples

Dynamic Configuration of Large-Scale Cortical Networks: A Useful Framework for Clarifying the Heterogeneity Found in Attention-Deficit/Hyperactivity Disorder

The heterogeneity of attention-deficit/hyperactivity disorder(ADHD) traits (inattention vs. hyperactivity/impulsivity) complicates diagnosis and intervention. Identifying how the configuration of large-scale functional brain networks during cognitive processing correlate with this heterogeneity could help us understand the neural mechanisms altered across ADHD presentations. Here, we recorded high-density EEG while 62 non-clinical participants (ages 18-24; 32 male) underwent an inhibitory control task (Go/No-Go). Functional EEG networks were created using sensors as nodes and across-trial phase-lag index values as edges. Using cross-validated LASSO regression, we examined whether graph-theory metrics applied to both static networks (averaged across time-windows: -500–0ms, 0–500ms) and dynamic networks (temporally layered with 2ms intervals), were associated with hyperactive/impulsive and inattentive traits. Network configuration during response execution/inhibition was associated with hyperactive/impulsive (mean R2across test sets = .20, SE = .02), but not inattentive traits. Post-stimulus results at higher frequencies (Beta, 14-29Hz; Gamma, 30-90Hz) showed the strongest association with hyperactive/impulsive traits, and predominantly reflected less burst-like integration between modules in oscillatory beta networks during execution, and increased integration/small-worldness in oscillatory gamma networks during inhibition. We interpret the beta network results as reflecting weaker integration between specialized pre-frontal and motor systems during motor response preparation, and the gamma results as reflecting a compensatory mechanism used to integrate processing between less functionally specialized networks. This research demonstrates that the neural network mechanisms underlying response execution/inhibition might be associated with hyperactive/impulsive traits, and that dynamic, task-related changes in EEG functional networks may be useful in disentangling ADHD heterogeneity

Déconstruire l'hétérogénéité des systèmes neurocognitifs sous-jacents aux comportements antisociaux : de l'analyse développementale aux corrélats neurobiologiques

Contexte. L’étiologie des comportements antisociaux est encore mal comprise. La population d’individus commettant ce type de comportements est hautement hétérogène, suggérant ainsi que plusieurs mécanismes biopsychosociaux pourraient augmenter ou réduire le risque de délinquance au cours du développement humain. Objectif. L’objectif principal de cette thèse est d’identifier ces mécanismes sous-jacents à la délinquance, par l’entremise de quatre méthodes scientifiques distinctes, mais complémentaires : les analyses de trajectoires développementales, l’activité cérébrale induite par une tâche, la connectivité cérébrale au repos ainsi que l’étude des lésions cérébrales. Méthodologie. Afin d’atteindre cet objectif, une première étude a été réalisée en réanalysant les données de l’Étude Longitudinale du Développement des Enfants du Québec (n=1309). Par l’entremise de modèles de trajectoires par classes latentes, cette étude visait à identifier des sous-groupes de jeunes présentant des trajectoires développementales de traits psychologiques (c.-à-d., l’insensibilité émotionnelle, les traits anxio-dépressifs, l’irritabilité et les traits d’hyperactivité/impulsivité) à risque de comportements antisociaux à l’enfance et l’adolescence. Par ailleurs, deux méta-analyses portant sur des études d’activation cérébrale (71 et 147 études) ont été réalisées afin d’identifier les principales altérations de l’activité cérébrale sous-jacent à différents domaines neurocognitifs, ainsi que leur similarité avec d’autres problématiques psychiatriques. De plus, une troisième méta-analyse (18 études) a été accomplie afin d’étudier si les individus antisociaux présentaient des déficits lors de la connectivité cérébrale au repos. De manière à combler les limites de la littérature sous-jacente à la connectivité cérébrale au repos des individus antisociaux, une étude transversale a été effectuée sur 1,416 enfants et adolescents issue Healthy Brain Network aux États-Unis. Outre l’objectif de valider les résultats de la méta-analyse précédente, cette étude a été conçue de manière à mieux comprendre le rôle de l’interaction entre des systèmes neurobiologiques dans l’explication des comportements antisociaux. Finalement, une récente revue de la littérature scientifique produite par des chercheurs américains a permis d’identifier 17 cas dans lesquels des lésions au cerveau étaient temporellement liés à l’émergence de comportements antisociaux. Grâce à une reconstruction des images de lesdites lésions, des analyses de coactivation méta- analytique ont été conduites afin de récréer les réseaux neurobiologiques altérés qui seraient possiblement à l’origine de de gestes délinquants. Résultats. Les résultats ont soutenu l’importance des traits d’insensibilité émotionnelle dans l’explication du risque de délinquance, et aussi montré que l’interaction développementale entre les traits psychologiques augmentait jusqu’à 10 fois le risque de comportements antisociaux à l’enfance. Sur une base neurobiologique, les résultats ont révélé que les personnes ayant commis des gestes délinquants rapporteraient d’importants déficits dans les régions cérébrales impliquées dans le contrôle cognitif, la réponse à une menace et les cognitions sociales. En comparaison avec le trouble du déficit de l’attention avec hyperactivité et les troubles anxieux et dépressifs, le trouble des conduites serait associé à un dysfonctionnement commun de régions cérébrales impliquées dans le contrôle des émotions et du système somato-moteur. Par ailleurs, les résultats indiquent que la population étudiée serait principalement caractérisée par une dysconnectivité fonctionnelle entre les réseaux socioaffectifse et attentionnels, mais aussi entre les systèmes somato-moteurs, attentionnels et ceux impliqués dans la détection de stimuli saillants. Finalement, les lésions cérébrales pourraient causer des comportements délinquants par l’entremise de trois mécanismes neurobiologiques, notamment par une défaillance du réseau de la récompense (lobe frontal), du réseau impliqué dans le traitement des émotions négatives (lobe temporal) ainsi que la reconnaissance émotionnelle faciale (amygdale). Conclusions. Les résultats des travaux présentés dans cette thèse soutiennent l’importance de mieux comprendre l’hétérogénéité de domaines neurocognitifs dans l’explication des comportements délinquants. D’une part, ceux-ci soulignent l’importance des systèmes neurobiologiques à valence négative (associés à l’anxiété et l’irritabilité), aux systèmes cognitifs (associés à l’hyperactivité/impulsivité et à l’inattention) ainsi qu’aux processus sociaux (associés à l’insensibilité émotionnelle). D’autre part, les résultats suggèrent un rôle limité des systèmes de récompense, mais un rôle prépondérant du système sensorimoteur (associé à l’action et au contrôle des mouvements). La présente thèse offre une perspective novatrice et exhaustive sur l’hétérogénéité neurocognitive sous-jacente à la délinquance. Or, la variabilité interindividuelle des systèmes neurobiologiques étudiés dans cette thèse reste à être identifiée, de manière à découvrir des cibles thérapeutiques prometteuses pour réduire le risque de délinquance.Background. The etiology of antisocial behaviors remains largely misunderstood. Antisocial population is characterized as highly heterogeneous, therefore indicating that several biopsychosocial mechanisms may increase or reduce the risk for delinquency during human development. Aim. The principal aim of this thesis is to identify these mechanisms underlying delinquent behaviors through different yet complementary method: developmental trajectories, task-based brain activity, brain connectivity at rest as well as the study of brain lesions. Methodology. To do so, a first study was conducted by reanalyzing cohort data from the Quebec Longitudinal Study of Child Development (n=1,309). Latent growth curve models allowed to identify subgroups of children exhibiting developmental trajectories of psychological traits (i.e., callous-unemotional traits, anxio-depressive traits, irritability and hyperactivity/impulsivity) that are at risk for antisocial behaviors during childhood and adolescence. Also, two meta-analyses of neuroimaging studies (71 and 147 studies) were carried out to highlight main deficits in brain activity underlying distinct neurocognitive systems as well as their similarity with other psychiatric disorders. Moreover, a third meta-analysis (18 studies) is presented to better understand whether antisocial subjects may exhibit brain connectivity at rest. In order to overcome limitations of past studies examining resting-state functional connectivity, a cross-sectional study was performed on 1,416 children and adolescents derived from the Healthy Brain Network in the United States. Additionnally to examine reliability of meta-analytic findings, this study was conducted in order to better understand the role of the interaction between neurobiological systems in our understanding of antisocial behaviors. Finally, a recent literature review carried out by American researchers highlighted 17 cases during which focal brain lesions were temporally associated with emergence of antisocial behaviors. By reconstructing images of these brain lesions, meta-analytic coactivation modelling was conducted in order to recreate neurobiological systems which would possibly be the origins of delinquent acts. Results. The results observed in this thesis support the crucial role of callous- unemotional traits in our understanding of the risk for delinquency, but also suggest that the developmental interaction between psychological markers increases up to 10 times this risk. On a neurobiological ground, results revealed that individuals that have committed antisocial behaviors were mainly characterized by dysfunctions in brain regions involved in cognitive control, threat detection as well as social cognition. In comparison to attention-deficit/hyperactivity disorder and anxiety and depressive disorders, conduct disorder was similarly associated with dysfunction in regions related to emotion regulation and somatomotor functions. Moreover, the results suggest that antisocial population may be characterized by dysconnectivity between socio-affective and attentional processes and between somatomotor and attentional processes as well as those involved in salient detection mechanism. Finally, brain lesions may cause antisocial behaviors by three neurobiological mechanisms, notably by disrupting the reward network (frontal lesions), the network involved in negative emotion processing (temporal lesions) and the emotional face processing (amygdala lesions). Conclusions. The results of the work presented in this thesis support the importance of studying the heterogeneity in neurocognitive systems for our understanding of antisocial behaviors. On the one hand, these results highlight the role of neurobiological systems of negative valence (related to anxiety and irritability), cognitive systems (related to hyperactivity/impulsivity and inattention) and social cognition (related to callous-unemotional traits). On the other hand, the results underline the limited contribution of positive valence system, but a prominent role of sensorimotor system (related to action and motor control). The current thesis offers a novel and exhaustive perspective on the heterogeneity of neurocognitive systems underlying delinquent behaviors. The interindividual variability of these systems is yet to be unveiled in order to uncover promising targets for treatment in a hopeful aim to reduce risk for delinquency