Longitudinal study of cerebral surface morphology in youth with 22q11.2 deletion syndrome, and association with positive symptoms of psychosis.
ABSTRACT: BACKGROUND:22q11.2 deletion syndrome (22q11DS) is a genetic disorder that greatly increases risk of developing schizophrenia. We previously characterized cerebral surface morphology trajectories from late childhood to mid adolescence in a cohort of youth with 22q11DS. Herein, we extend the study period into early adulthood, and describe further the trajectories associated with severe psychiatric symptoms in this cohort. METHODS:Participants included 76 youth with 22q11DS and 30 unaffected siblings, assessed at three timepoints, during which high resolution, anatomic magnetic resonance images were acquired. High-dimensional, nonlinear warping algorithms were applied to images in order to derive characteristics of cerebral surface morphology for each participant at each timepoint. Repeated-measures, linear regressions using a mixed model were conducted, while covarying for age and sex. RESULTS:Alterations in cerebral surface morphology during late adolescence/early adulthood in individuals with 22q11DS were observed in the lateral frontal, orbitofrontal, temporal, parietal, occipital, and cerebellar regions. An Age x Diagnosis interaction revealed that relative to unaffected siblings, individuals with 22q11DS showed age-related surface protrusions in the prefrontal cortex (which remained stable or increased during early adulthood), and surface indentations in posterior regions (which seemed to level off during late adolescence). Symptoms of psychosis were associated with a trajectory of surface indentations in the orbitofrontal and parietal regions. CONCLUSIONS:These results advance our understanding of cerebral maturation in individuals with 22q11DS, and provide clinically relevant information about the psychiatric phenotype associated with the longitudinal trajectory of cortical surface morphology in youth with this genetic syndrome.
Project description:22q11.2 deletion syndrome (22q11DS) represents one of the largest known genetic risk factors for psychosis, yet the neurobiological mechanisms underlying symptom development are not well understood. Here we conducted a cross-sectional study of 22q11DS to decompose cortical volume into its constituent parts, cortical thickness (CT) and surface area (SA), which are believed to have distinct neurodevelopmental origins.High-resolution T1-weighted scans were collected on 65 participants (31 22q11DS, 34 demographically comparable typically developing controls, 10-25 years old). Measures of cortical volume, CT, and SA were extracted from regions of interest using the FreeSurfer image analysis suite. Group differences and age-related trajectories in these structures, as well as their association with psychotic symptomatology, were assessed.Relative to controls, 22q11DS participants showed bilateral volumetric reductions in the inferior temporal cortex, fusiform gyrus, anterior cingulate, superior parietal cortex, and cuneus, which were driven by decreased SA in these regions. 22q11DS participants also had increased volumes, driven by increased CT, in bilateral insula regions. 22q11DS youth had increased CT in frontal regions, particularly middle frontal and medial orbitofrontal cortices. A pattern of age-associated cortical thinning was observed in typically developing controls in brain regions associated with visual and sensory information-processing (i.e., left pericalcarine cortex and fusiform gyrus, right lingual and postcentral cortices). However, this relationship was disrupted in 22q11DS participants. Finally, correlational analyses revealed that increased CT in right medial orbitofrontal cortex was associated with increased positive symptom severity in 22q11DS.Differential disruptions of CT and SA in distinct cortical regions in 22q11DS may indicate abnormalities in distinct developmental neural processes. Further, neuroanatomic abnormalities in medial frontal brain structures disproportionately affected in idiopathic schizophrenia were associated with psychotic symptom severity in 22q11DS youth, suggesting that disrupted biological processes in these cortical regions may underlie development of psychotic symptoms, both in 22q11DS and in the broader population.
Project description:OBJECTIVE:To identify factors associated with nonadherence and unsuppressed viral load across adolescence among youth with perinatally acquired HIV. DESIGN:Longitudinal study at 15 US clinical sites. METHODS:Self-reported antiretroviral medication nonadherence (any missed dose, past week) and unsuppressed viral load (HIV RNA?>?400 copies/ml) were assessed annually. Individual, caregiver, social, and structural factors associated with nonadherence and unsuppressed viral load were identified by age (years): 8-11 (preadolescence), 12-14 (early adolescence), 15-17 (middle adolescence), and 18-22 (late adolescence/young adulthood), utilizing multivariable generalized linear mixed effects models. RESULTS:During a median 3.3-year follow-up, 381 youth with perinatally acquired HIV contributed viral load measurements and 379 completed 1190 adherence evaluations. From preadolescence to late adolescence/young adulthood, prevalence of nonadherence increased from 31 to 50% (P?<?0.001); prevalence of unsuppressed viral load increased from 16 to 40% (P?<?0.001). In adjusted analyses, in pre, middle, and late adolescence/young adulthood, perceived antiretroviral side effects were associated with nonadherence. Additional factors associated with nonadherence included: in preadolescence, using a buddy system (as an adherence reminder); in early adolescence, identifying as black, using buddy system; in middle adolescence, CD4% less than 15%, unmarried caregiver, indirect exposure to violence, stigma/fear of inadvertent disclosure, stressful life events. Associations with unsuppressed viral load included: in early adolescence, youth unawareness of HIV status, lower income; in middle adolescence, perceived antiretroviral side effects, lower income; in late adolescence/young adulthood, distressing physical symptoms, and perceived antiretroviral side effects. CONCLUSION:Prevalence of nonadherence and unsuppressed viral load increased with age. Associated factors varied across adolescence. Recognition of age-specific factors is important when considering strategies to support adherence.
Project description:BACKGROUND:Neighborhood deprivation adversely effects neurodevelopment and cognitive function; however, mechanisms remain unexplored. Neighborhood deprivation could be particularly impactful in late childhood/early adolescence, in neural regions with protracted developmental trajectories, e.g., prefrontal cortex (PFC). METHODS:The Adolescent Brain Cognitive Development (ABCD) study recruited 10,205 youth. Geocoded residential history was used to extract individual neighborhood characteristics. A general cognitive ability index and MRI scans were completed. Associations with neurocognition were examined. The relation of PFC surface area and cortical thickness to neighborhood deprivation was tested. PFC subregions and asymmetry, with putative differential environmental susceptibility during key developmental periods, were explored. Analyses tested PFC area as a possible mediating mechanism. RESULTS:Neighborhood deprivation predicted neurocognitive performance (? ?= ?-0.11), even after accounting for parental education and household income (? ?= ?-0.07). Higher neighborhood deprivation related to greater overall PFC surface area (?p2 ?= ?0.003), and differences in leftward asymmetry were observed for area (?p2 ?= ?0.001), and thickness (?p2 ?= ?0.003). Subregion analyses highlighted differences among critical areas that are actively developing in late childhood/early adolescence and are essential to modulating high order cognitive function. These included orbitofrontal, superior frontal, rostral middle frontal, and frontal pole regions (Cohen's d ?= ?0.03-0.09). PFC surface area partially mediated the relation between neighborhood deprivation and neurocognition. DISCUSSION:Neighborhood deprivation related to cognitive function (a foundational skill tied to a range of lifetime outcomes) and PFC morphology, with evidence found for partial mediation of PFC on neurocognitive function. Results inform public health conceptualizations of development and environmental vulnerability.
Project description:Background: Schizophrenia is currently considered a neurodevelopmental disorder of connectivity. Still few studies have investigated how brain networks develop in children and adolescents who are at risk for developing psychosis. 22q11.2 Deletion Syndrome (22q11DS) offers a unique opportunity to investigate the pathogenesis of schizophrenia from a neurodevelopmental perspective. Structural covariance (SC) is a powerful approach to explore morphometric relations between brain regions that can furthermore detect biomarkers of psychosis, both in 22q11DS and in the general population. Methods: Here we implement a state-of-the-art sliding-window approach to characterize maturation of SC network architecture in a large longitudinal cohort of patients with 22q11DS (110 with 221 visits) and healthy controls (117 with 211 visits). We furthermore propose a new clustering-based approach to group regions according to trajectories of structural connectivity maturation. We correlate measures of SC with development of working memory, a core executive function that is highly affected in both idiopathic psychosis and 22q11DS. Finally, in 22q11DS we explore correlations between SC dysconnectivity and severity of internalizing psychopathology. Results: In HCs network architecture underwent a quadratic developmental trajectory maturing up to mid-adolescence. Late-childhood maturation was particularly evident for fronto-parietal cortices, while Default-Mode-Network-related regions showed a more protracted linear development. Working memory performance was positively correlated with network segregation and fronto-parietal connectivity. In 22q11DS, we demonstrate aberrant maturation of SC with disturbed architecture selectively emerging during adolescence and correlating more severe internalizing psychopathology. Patients also presented a lack of typical network development during late-childhood, that was particularly prominent for frontal connectivity. Conclusions: Our results suggest that SC maturation may underlie critical cognitive development occurring during late-childhood in healthy controls. Aberrant trajectories of SC maturation may reflect core developmental features of 22q11DS, including disturbed cognitive maturation during childhood and predisposition to internalizing psychopathology and psychosis during adolescence.
Project description:The experience of parental divorce during childhood is associated with an increased risk of behavioral and physical health problems. Alterations in adrenocortical activity may be a mechanism in this relation. Parent-child relationships have been linked to cortisol regulation in children exposed to adversity, but prospective research is lacking. We examined maternal warmth in adolescence as a predictor of young adults' cortisol stress response 15 years after parental divorce.Participants included 240 youth from recently divorced families. Mother and child reports of maternal warmth were assessed at 6 time points across childhood, adolescence, and young adulthood. Offspring salivary cortisol was measured in young adulthood before and after a social stress task. Structural equation modeling was used to predict cortisol response from maternal warmth across early and late adolescence.Higher child-reported maternal warmth in early adolescence predicted higher child-reported maternal warmth in late adolescence (standardized regression = 0.45, standard error = 0.065, p < .01), which predicted lower cortisol response to a challenging interpersonal task in young adulthood (standardized regression = -0.20, standard error = 0.094, p = .031). Neither mother-reported warmth in early adolescence nor late adolescence was significantly related to offspring cortisol response in young adulthood.Results suggest that for children from divorced families, a warm mother-child relationship after divorce and across development, as perceived by the child, may promote efficient biological regulation later in life.ClinicalTrials.gov Identifier: NCT01407120.
Project description:Adolescence is a sensitive developmental period in which substance use can exert long-term effects on important biological systems. Emerging cross-sectional research indicates that problematic alcohol consumption may be associated with dysregulated neuroendocrine system functioning. The current study evaluated the prospective effects of binge drinking in adolescence on cortisol stress reactivity in young adulthood among individuals who had experienced parental divorce in childhood (N?=?160; Mean age?=?25.55, SD?=?1.22; 46.9% Female; 88.8% White Non-Hispanic). Youth completed validated measures of problematic drinking during adolescence (aged 15-19) and participated in a standardized social stress task nine years later in young adulthood. Latent growth modeling was conducted within a structural equation modeling framework. Greater binge drinking during adolescence was associated with a significantly lower cortisol stress response in young adulthood, controlling for young adult drinking, sex, childhood externalizing problems, and socioeconomic status. Findings suggest problematic alcohol consumption during mid-to-late adolescence may have important effects on the neuroendocrine stress response system at subsequent developmental stages.
Project description:OBJECTIVE:Adults with established diagnoses of serious mental illness (bipolar disorder and schizophrenia) exhibit structural brain abnormalities, yet less is known about how such abnormalities manifest earlier in development. METHOD:Cross-sectional data publicly available from the Philadelphia Neurodevelopmental Cohort (PNC) were analyzed. Structural magnetic resonance neuroimaging data were collected on a subset of the PNC (N = 989; 9-22 years old). Cortical thickness, surface area (SA), and subcortical volumes were calculated. Study participants were assessed for psychiatric symptomatology using a structured interview and the following groups were created: typically developing (n = 376), psychosis spectrum (PS; n = 113), bipolar spectrum (BP; n = 117), and BP + PS (n = 109). Group and developmental differences in structural magnetic resonance neuroimaging measures were examined. In addition, the extent to which any structural aberration was related to neurocognition, global functioning, and clinical symptomatology was examined. RESULTS:Compared with other groups, PS youth exhibited significantly decreased SA in the orbitofrontal, cingulate, precentral, and postcentral regions. PS youth also exhibited deceased thalamic volume compared with all other groups. The strongest effects for precentral and posterior cingulate SA decreases were seen during early adolescence (13-15 years old) in PS youth. The strongest effects for decreases in thalamic volume and orbitofrontal and postcentral SA were observed in mid-adolescence (16-18 years) in PS youth. Across groups, better overall functioning was associated with increased lateral orbitofrontal SA. Increased postcentral SA was associated with better executive cognition and less severe negative symptoms in the entire sample. CONCLUSION:In a community-based sample, decreased cortical SA and thalamic volume were present early in adolescent development in youth with PS symptoms, but not in youth with BP symptoms or with BP and PS symptoms. These findings point to potential biological distinctions between PS and BP conditions, which could suggest additional biomarkers relevant to early identification.
Project description:INTRODUCTION:Adolescence and emergent adulthood are periods of peak prevalence for substance use that pose risks for short- and long-term health harm, particularly for youth with chronic medical conditions (YCMC) who are transitioning from adolescence to adulthood. As there have been no nationally representative studies of substance use during this period for these medically vulnerable youth, the authors sought to examine onset and intensification of these behaviors for a national sample of youth with and without chronic conditions. METHODS:Longitudinal data are from 2,719 youth between the ages of 12 and 26 years interviewed from 2002 to 2011 for the Panel Study of Income Dynamics, Child Development and Transition to Adulthood Supplements, a nationally representative, population-based survey. Multivariate generalized linear mixed models were used to estimate patterns of alcohol, tobacco, and marijuana use during adolescence and emergent adulthood for youth with and without chronic conditions, adjusting for potential confounders. RESULTS:Overall, 68.8%, 44.3%, and 47.8% of youth reported ever trying alcohol, tobacco, and marijuana, respectively. Among users, 42.2%, 73.4%, and 50.3% of youth reported binge drinking, regular cigarette use, and recent marijuana use, respectively. YCMC were more likely to engage in any and heavier substance use; transition years and early adulthood were periods of peak risk for YCMC compared with their healthy peers. CONCLUSIONS:Substance use among YCMC during adolescence and emergent adulthood is a substantial concern. Increased prevention and case detection are in order to address these behaviors and promote optimal health outcomes for medically vulnerable youth.
Project description:There is increased risk of developing psychosis in 22q11.2 deletion syndrome (22q11DS). Although this condition is associated with morphologic brain abnormalities, simultaneous examination of multiple high-resolution measures of cortical structure has not been performed.Fifty-three patients with 22q11DS, 30 with psychotic symptoms, were compared with demographically matched nondeleted youths: 53 typically developing and 53 with psychotic symptoms. High-resolution magnetic resonance imaging measures of cerebral volume, cortical thickness, surface area, and an index of local gyrification were obtained and compared between groups.Patients with 22q11DS demonstrated global increases in cortical thickness associated with reductions in surface area, reduced index of local gyrification, and lower cerebral volumes relative to typically developing controls. Findings were principally in the frontal lobe, superior parietal lobes, and in the paramedian cerebral cortex. Focally decreased thickness was seen in the superior temporal gyrus and posterior cingulate cortex in 22q11DS relative to nondeleted groups. Patterns between nondeleted participants with psychotic symptoms and 22q11DS were similar but with important differences in several regions implicated in schizophrenia. Post hoc analysis suggested that like the 22q11DS group, cortical thickness in nondeleted individuals with psychotic symptoms differed from typically developing controls in the superior frontal gyrus and superior temporal gyrus, regions previously linked to schizophrenia.Simultaneous examination of multiple measures of cerebral architecture demonstrates that differences in 22q11DS localize to regions of the frontal, superior parietal, superior temporal, and paramidline cerebral cortex. The overlapping patterns between nondeleted participants with psychotic symptoms and 22q11DS suggest partially shared neuroanatomic substrates.
Project description:Concentrated in adolescence, violent victimization is developmentally disruptive. It undermines physical, mental, and socioemotional well-being and compromises youths' transitions into and progression through key life course tasks. Youth violent victimization (YVV) has been linked to precocious exits from adolescence and premature entries into adulthood. This includes early entry into coresidential romantic unions, which is but one stage of a relationship sequence generally beginning via dating debut. Using data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) and Cox regression, we examine the effects of YVV on the timing of dating debut and progression to first coresidential unions during adolescence and the transition to adulthood. We pay particular attention to how these effects may be structured by age and gender. Overall, we find that victims begin dating sooner and progress more quickly from dating to first unions than do non-victims. However, youths victimized in early adolescence withdraw from dating and union formation, whereas late adolescent victims appear to overinvest in relationships-at least temporarily-displaying accelerated entry into dating and rapid progression to first unions. We conclude by discussing the implication of these age-graded patterns for intervention efforts and youth well-being more broadly.