Examining longitudinal associations between prenatal exposure to infections and child brain morphology.

BACKGROUND: Maternal infection during pregnancy has been identified as a prenatal risk factor for the later development of psychopathology in exposed offspring. Neuroimaging data collected during childhood has suggested a link between prenatal exposure to maternal infection and child brain structure and function, potentially offering a neurobiological explanation for the emergence of psychopathology. Additionally, preclinical studies utilizing repeated measures of neuroimaging data suggest that effects of prenatal maternal infection on the offspring's brain may normalize over time (i.e., catch-up growth). However, it remains unclear whether exposure to prenatal maternal infection in humans is related to long-term differential neurodevelopmental trajectories. Hence, this study aimed to investigate the association between prenatal exposure to infections on child brain development over time using repeated measures MRI data. METHODS: We leveraged data from a population-based cohort, Generation R, in which we examined prospectively assessed self-reported infections at each trimester of pregnancy (N = 2,155). We further used three neuroimaging assessments (at mean ages 8, 10 and 14) to obtain cortical and subcortical measures of the offspring's brain morphology with MRI. Hereafter, we applied linear mixed-effects models, adjusting for several confounding factors, to estimate the association of prenatal maternal infection with child brain development over time. RESULTS: We found that prenatal exposure to infection in the third trimester was associated with a slower decrease in volumes of the pars orbitalis, rostral anterior cingulate and superior frontal gyrus, and a faster increase in the middle temporal gyrus. In the temporal pole we observed a divergent pattern, specifically showing an increase in volume in offspring exposed to more infections compared to a decrease in volume in offspring exposed to fewer infections. We further observed associations in other frontal and temporal lobe structures after exposure to infections in any trimester, though these did not survive multiple testing correction. CONCLUSIONS: Our results suggest that prenatal exposure to infections in the third trimester may be associated with slower age-related growth in the regions: pars orbitalis, rostral anterior cingulate and superior frontal gyrus, and faster age-related growth in the middle temporal gyrus across childhood, suggesting a potential sensitive period. Our results might be interpreted as an extension of longitudinal findings from preclinical studies, indicating that children exposed to prenatal infections could exhibit catch-up growth. However, given the lack of differences in brain volume between various infection groups at baseline, there may instead be either a longitudinal deviation or a subtle temporal deviation. Subsequent well-powered studies that extend into the period of full brain development (∼25 years) are needed to confirm whether the observed phenomenon is indeed catch-up growth, a longitudinal deviation, or a subtle temporal deviation.

Running in the FAMILY: understanding and predicting the intergenerational transmission of mental illness.

Over 50% of children with a parent with severe mental illness will develop mental illness by early adulthood. However, intergenerational transmission of risk for mental illness in one's children is insufficiently considered in clinical practice, nor is it sufficiently utilised into diagnostics and care for children of ill parents. This leads to delays in diagnosing young offspring and missed opportunities for protective actions and resilience strengthening. Prior twin, family, and adoption studies suggest that the aetiology of mental illness is governed by a complex interplay of genetic and environmental factors, potentially mediated by changes in epigenetic programming and brain development. However, how these factors ultimately materialise into mental disorders remains unclear. Here, we present the FAMILY consortium, an interdisciplinary, multimodal (e.g., (epi)genetics, neuroimaging, environment, behaviour), multilevel (e.g., individual-level, family-level), and multisite study funded by a European Union Horizon-Staying-Healthy-2021 grant. FAMILY focuses on understanding and prediction of intergenerational transmission of mental illness, using genetically informed causal inference, multimodal normative prediction, and animal modelling. Moreover, FAMILY applies methods from social sciences to map social and ethical consequences of risk prediction to prepare clinical practice for future implementation. FAMILY aims to deliver: (i) new discoveries clarifying the aetiology of mental illness and the process of resilience, thereby providing new targets for prevention and intervention studies; (ii) a risk prediction model within a normative modelling framework to predict who is at risk for developing mental illness; and (iii) insight into social and ethical issues related to risk prediction to inform clinical guidelines.

Attention-deficit hyperactivity disorder symptoms and brain morphology: Addressing potential selection bias with inverse probability weighting.

The goal of this study was to examine what happens to established associations between attention deficit hyperactivity disorder (ADHD) symptoms and cortical surface and thickness regions once we apply inverse probability of censoring weighting (IPCW) to address potential selection bias. Moreover, we illustrate how different factors that predict participation contribute to potential selection bias. Participants were 9- to 11-year-old children from the Generation R study (N = 2707). Cortical area and thickness were measured with magnetic resonance imaging (MRI) and ADHD symptoms with the Child Behavior Checklist. We examined how associations between ADHD symptoms and brain morphology change when we weight our sample back to either follow-up (ages 9-11), baseline (cohort at birth), or eligible (population of Rotterdam at time of recruitment). Weights were derived using IPCW or raking and missing predictors of participation used to estimate weights were imputed. Weighting analyses to baseline and eligible increased beta coefficients for the middle temporal gyrus surface area, as well as fusiform gyrus cortical thickness. Alternatively, the beta coefficient for the rostral anterior cingulate decreased. Removing one group of variables used for estimating weights resulted in the weighted regression coefficient moving closer to the unweighted regression coefficient. In addition, we found considerably different beta coefficients for most surface area regions and all thickness measures when we did not impute missing covariate data. Our findings highlight the importance of using inverse probability weighting (IPW) in the neuroimaging field, especially in the context of mental health-related research. We found that including all variables related to exposure-outcome in the IPW model and combining IPW with multiple imputations can help reduce bias. We encourage future psychiatric neuroimaging studies to define their target population, collect information on eligible but not included participants and use inverse probability of censoring weighting (IPCW) to reduce selection bias.

Population-wide cerebellar growth models of children and adolescents.

In the past, the cerebellum has been best known for its crucial role in motor function. However, increasingly more findings highlight the importance of cerebellar contributions in cognitive functions and neurodevelopment. Using a total of 7240 neuroimaging scans from 4862 individuals, we describe and provide detailed, openly available models of cerebellar development in childhood and adolescence (age range: 6-17 years), an important time period for brain development and onset of neuropsychiatric disorders. Next to a traditionally used anatomical parcellation of the cerebellum, we generated growth models based on a recently proposed functional parcellation. In both, we find an anterior-posterior growth gradient mirroring the age-related improvements of underlying behavior and function, which is analogous to cerebral maturation patterns and offers evidence for directly related cerebello-cortical developmental trajectories. Finally, we illustrate how the current approach can be used to detect cerebellar abnormalities in clinical samples.

Examining the interaction between prenatal stress and polygenic risk for attention-deficit/hyperactivity disorder on brain growth in childhood: Findings from the DREAM BIG consortium.

This study explored the interactions among prenatal stress, child sex, and polygenic risk scores (PGS) for attention-deficit/hyperactivity disorder (ADHD) on structural developmental changes of brain regions implicated in ADHD. We used data from two population-based birth cohorts: Growing Up in Singapore Towards healthy Outcomes (GUSTO) from Singapore (n = 113) and Generation R from Rotterdam, the Netherlands (n = 433). Prenatal stress was assessed using questionnaires. We obtained latent constructs of prenatal adversity and prenatal mood problems using confirmatory factor analyses. The participants were genotyped using genome-wide single nucleotide polymorphism arrays, and ADHD PGSs were computed. Magnetic resonance imaging scans were acquired at 4.5 and 6 years (GUSTO), and at 10 and 14 years (Generation R). We estimated the age-related rate of change for brain outcomes related to ADHD and performed (1) prenatal stress by sex interaction models, (2) prenatal stress by ADHD PGS interaction models, and (3) 3-way interaction models, including prenatal stress, sex, and ADHD PGS. We observed an interaction between prenatal stress and ADHD PGS on mean cortical thickness annual rate of change in Generation R (i.e., in individuals with higher ADHD PGS, higher prenatal stress was associated with a lower rate of cortical thinning, whereas in individuals with lower ADHD PGS, higher prenatal stress was associated with a higher rate of cortical thinning). None of the other tested interactions were statistically significant. Higher prenatal stress may promote a slower brain developmental rate during adolescence in individuals with higher ADHD genetic vulnerability, whereas it may promote a faster brain developmental rate in individuals with lower ADHD genetic vulnerability.

Adolescent substance use initiation and long-term neurobiological outcomes: insights, challenges and opportunities.

The increased frequency of risk taking behavior combined with marked neuromaturation has positioned adolescence as a focal point of research into the neural causes and consequences of substance use. However, little work has provided a summary of the links between adolescent initiated substance use and longer-term brain outcomes. Here we review studies exploring the long-term effects of adolescent-initiated substance use with structural and microstructural neuroimaging. A quarter of all studies reviewed conducted repeated neuroimaging assessments. Long-term alcohol use, as well as tobacco use were consistently associated with smaller frontal cortices and altered white matter microstructure. This association was mostly observed in the ACC, insula and subcortical regions in alcohol users, and for the OFC in tobacco users. Long-term cannabis use was mostly related to altered frontal cortices and hippocampal volumes. Interestingly, cannabis users scanned more years after use initiation tended to show smaller measures of these regions, whereas those with fewer years since initiation showed larger measures. Long-term stimulant use tended to show a similar trend as cannabis in terms of years since initiation in measures of the putamen, insula and frontal cortex. Long-term opioid use was mostly associated with smaller subcortical and insular volumes. Of note, null findings were reported in all substance use categories, most often in cannabis use studies. In the context of the large variety in study designs, substance use assessment, methods, and sample characteristics, we provide recommendations on how to interpret these findings, and considerations for future studies.

Intrauterine Exposure to Antidepressants or Maternal Depressive Symptoms and Offspring Brain White Matter Trajectories From Late Childhood to Adolescence.

BACKGROUND: During pregnancy, both selective serotonin reuptake inhibitor (SSRI) exposure and maternal depression have been associated with poor offspring neurodevelopmental outcomes. In a population-based cohort, we investigated the association between intrauterine exposure to SSRIs and depressive symptoms and offspring white matter development from childhood to adolescence. METHODS: Self-reported SSRI use was verified by pharmacy records. In midpregnancy, women reported on depressive symptoms using the Brief Symptom Inventory. Using diffusion tensor imaging, offspring white matter microstructure, including whole-brain and tract-specific fractional anisotropy (FA) and mean diffusivity, was measured at 3 assessments between ages 7 to 15 years. The participants were divided into 4 groups: prenatal SSRI exposure (n = 37 with 60 scans), prenatal depression exposure (n = 229 with 367 scans), SSRI use before pregnancy (n = 72 with 95 scans), and reference (n = 2640 with 4030 scans). RESULTS: Intrauterine exposure to SSRIs and depressive symptoms were associated with lower FA in the whole-brain and the forceps minor at 7 years. Exposure to higher prenatal depressive symptom scores was associated with lower FA in the uncinate fasciculus, cingulum bundle, superior and inferior longitudinal fasciculi, and corticospinal tracts. From ages 7 to 15 years, children exposed to prenatal depressive symptoms showed a faster increase in FA in these white matter tracts. Prenatal SSRI exposure was not related to white matter microstructure growth over and above exposure to depressive symptoms. CONCLUSIONS: These results suggest that prenatal exposure to maternal depressive symptoms was negatively associated with white matter microstructure in childhood, but these differences attenuated during development, suggesting catch-up growth.

Levels of Physical Activity at Age 10 Years and Brain Morphology Changes From Ages 10 to 14 Years.

Importance: Physical activity may promote healthy brain development in children, but previous research was predominantly cross-sectional and included small samples, providing limited knowledge. Objective: To investigate the longitudinal associations of physical activity with brain morphology changes. Design, Setting, and Participants: A 4-year longitudinal population-based cohort study in Rotterdam, the Netherlands, embedded in Generation R, a cohort from fetal life onward. From the women enrolled during pregnancy, children who had repeated measures of brain structure at ages 10 (range 8 to 12) years and 14 (range 13 to 15) years were included. Data were collected from March 2013 to November 2015 (baseline) and from October 2016 to January 2020 (follow-up). Data were analyzed from April to December 2022. Exposure: At age 10 years, both the child and their primary caregiver reported the child's levels of physical activity with regard to sport participation, outdoor play, and total physical activity. Primary analyses were based on an average multi-informant report. Main outcomes and measures: Brain morphology was quantified by magnetic resonance imaging. Hypothesized regions of interest were the bilateral amygdala and hippocampal volumes. Global brain measures were studied to test the specificity of the hypothesis. Results: Data were available for 1088 children (566 girls [52%]; 693 [64%] Dutch). Their mean (SD) age at baseline was 10.1 (0.6) years. For amygdala volume change, positive associations with multi-informant reports of total physical activity (ß = 2.6; 95% CI, 0.3-4.9) were found. Total physical activity was associated with hippocampal volume increases only when reported by the child (ß = 3.1; 95% CI, 0.4-5.8). No robust associations with global brain measures were found. Conclusions and relevance: In this cohort study of 1088 children, more physical activity at 10 years was consistently associated with an increase in amygdala volume in children aged 10 to 14 years. Physical activity and increases in hippocampal volume were found using child reports of physical activity only. These findings suggest physical activity in late childhood was prospectively associated with volumetric changes in specific subcortical structures, but not to global brain development, from late childhood to early adolescence. These findings may inform the design of future public health interventions to best facilitate neurodevelopment with physical activity.

Long-term effects of prenatal infection on the human brain: a prospective multimodal neuroimaging study.

There is convincing evidence from rodent studies suggesting that prenatal infections affect the offspring's brain, but evidence in humans is limited. Here, we assessed the occurrence of common infections during each trimester of pregnancy and examined associations with brain outcomes in adolescent offspring. Our study was embedded in the Generation R Study, a large-scale sociodemographically diverse prospective birth cohort. We included 1094 mother-child dyads and investigated brain morphology (structural MRI), white matter microstructure (DTI), and functional connectivity (functional MRI), as outcomes at the age of 14. We focused on both global and focal regions. To define prenatal infections, we composed a score based on the number and type of infections during each trimester of pregnancy. Models were adjusted for several confounders. We found that prenatal infection was negatively associated with cerebral white matter volume (B = -0.069, 95% CI -0.123 to -0.015, p = 0.011), and we found an association between higher prenatal infection scores and smaller volumes of several frontotemporal regions of the brain. After multiple testing correction, we only observed an association between prenatal infections and the caudal anterior cingulate volume (B = -0.104, 95% CI -0.164 to -0.045, p < 0.001). We did not observe effects of prenatal infection on other measures of adolescent brain morphology, white matter microstructure, or functional connectivity, which is reassuring. Our results show potential regions of interest in the brain for future studies; data on the effect of severe prenatal infections on the offspring's brain in humans are needed.

Prenatal Antidepressant Exposure and Offspring Brain Morphologic Trajectory.

Importance: Clinical decision-making on antidepressant treatment during pregnancy, particularly selective serotonin reuptake inhibitors (SSRIs), is challenging, as both prenatal SSRI exposure and maternal depressive symptoms may be associated with negative outcomes in offspring. Objective: To investigate the association between intrauterine SSRI exposure and maternal depressive symptoms and structural brain development in offspring from mid-childhood to early puberty. Design, Setting, and Participants: This prospective, population-based cohort study was embedded in the Generation R Study in Rotterdam, the Netherlands. All pregnant individuals with an expected delivery date between April 1, 2002, and January 31, 2006, were invited to participate. Data were analyzed from February 1 to September 30, 2022. Exposure: Maternal-reported SSRI use verified by pharmacy records. In mid-pregnancy and 2 and 6 months after delivery, participants reported depressive symptoms using the Brief Symptom Inventory and were divided into 5 groups: SSRI use during pregnancy (n = 41; 80 scans), SSRI use only before pregnancy (n = 77; 126 scans), prenatal depressive symptoms without prenatal SSRI use (n = 257; 477 scans), postnatal depressive symptoms only (n = 74; 128 scans), and nonexposed control individuals (n = 2749; 4813 scans). Main Outcomes and Measures: The main outcome was brain morphometry in offspring, including global and cortical brain volumes, measured at 3 magnetic resonance imaging assessments from 7 to 15 years of age. Results: The study included 3198 mother-child dyads. A total of 3198 mothers (100%) identified as women; mean (SD) age at intake was 31.1 (4.7) years. Children (1670 [52.2%] female) underwent brain imaging assessment from 7 to 15 years of age with 5624 total scans. Most brain gray matter volumes showed an inverted U-shaped trajectory. Compared with nonexposed controls, children prenatally exposed to SSRIs had less cerebral gray matter (ß [SE], -20 212.2 [7285.6] mm3; P = .006), particularly within the corticolimbic circuit, which persisted up to 15 years of age. Children exposed to SSRIs prenatally showed a steeper increase in volumes of the amygdala (age interaction: ß [SE], 43.3 [13.4] mm3; P = .006) and fusiform gyrus (age interaction: ß [SE], 168.3 [51.4] mm3; P = .003) from 7 to 15 years of age. These volumetric differences in the amygdala and fusiform observed in childhood did not persist until early adolescence. Prenatal depression was associated with a smaller volume in the rostral anterior cingulate gyrus (ß [SE], -166.3 [65.1] mm3; P = .006), and postnatal depression was associated with a reduced fusiform gyrus (ß [SE], -480.5 [189.2] mm3; P = .002). No association of SSRI use before pregnancy with brain outcomes was observed. Conclusions and Relevance: The results of this cohort study suggest that prenatal SSRI exposure may be associated with altered developmental trajectories of brain regions involved in emotional regulation in offspring. Further research on the functional implications of these findings is needed.

Physical symptoms and brain morphology: a population neuroimaging study in 12,286 pre-adolescents.

Physical symptoms, also known as somatic symptoms, are those for which medical examinations do not reveal a sufficient underlying root cause (e.g., pain and fatigue). The extant literature of the neurobiological underpinnings of physical symptoms is largely inconsistent and primarily comprises of (clinical) case-control studies with small sample sizes. In this cross-sectional study, we studied the association between dimensionally measured physical symptoms and brain morphology in pre-adolescents from two population-based cohorts; the Generation R Study (n = 2649, 10.1 ± 0.6 years old) and ABCD Study (n = 9637, 9.9 ± 0.6 years old). Physical symptoms were evaluated using continuous scores from the somatic complaints syndrome scale from the parent-reported Child Behavior Checklist (CBCL). High-resolution structural magnetic resonance imaging (MRI) was collected using 3-Tesla MRI systems. Linear regression models were fitted for global brain metrics (cortical and subcortical grey matter and total white matter volume) and surface-based vertex-wise measures (surface area and cortical thickness). Results were meta-analysed. Symptoms of anxiety/depression were studied as a contrasting comorbidity. In the meta-analyses across cohorts, we found negative associations between physical symptoms and surface area in the (i) left hemisphere; in the lateral orbitofrontal cortex and pars triangularis and (ii) right hemisphere; in the pars triangularis, the pars orbitalis, insula, middle temporal gyrus and caudal anterior cingulate cortex. However, only a subset of regions (left lateral orbitofrontal cortex and right pars triangularis) were specifically associated with physical symptoms, while others were also related to symptoms of anxiety/depression. No significant associations were observed for cortical thickness. This study in preadolescents, the most representative and well-powered to date, showed that more physical symptoms are modestly related to less surface area of the prefrontal cortex mostly. While these effects are subtle, future prospective research is warranted to understand the longitudinal relationship of physical symptoms and brain changes over time. Particularly, to elucidate whether physical symptoms are a potential cause or consequence of distinct neurodevelopmental trajectories.

Longitudinal Associations Between White Matter Microstructure and Psychiatric Symptoms in Youth.

OBJECTIVE: Associations between psychiatric problems and white matter (WM) microstructure have been reported in youth. Yet, a deeper understanding of this relation has been hampered by a dearth of well-powered longitudinal studies and a lack of explicit examination of the bidirectional associations between brain and behavior. We investigated the temporal directionality of WM microstructure and psychiatric symptom associations in youth. METHOD: In this observational study, we leveraged the world's largest single- and multi-site cohorts of neurodevelopment: the Generation R (GenR) and Adolescent Brain Cognitive Development Studies (ABCD) (total n scans = 11,400; total N = 5,700). We assessed psychiatric symptoms with the Child Behavioral Checklist as broad-band internalizing and externalizing scales, and as syndrome scales (eg, Anxious/Depressed). We quantified WM with diffusion tensor imaging (DTI), globally and at a tract level. We used cross-lagged panel models to test bidirectional associations of global and specific measures of psychopathology and WM microstructure, meta-analyzed results across cohorts, and used linear mixed-effects models for validation. RESULTS: We did not identify any longitudinal associations of global WM microstructure with internalizing or externalizing problems across cohorts (confirmatory analyses) before, and after multiple testing corrections. We observed similar findings for longitudinal associations between tract-based microstructure with internalizing and externalizing symptoms, and for global WM microstructure with specific syndromes (exploratory analyses). Some cross-sectional associations surpassed multiple testing corrections in ABCD, but not in GenR. CONCLUSION: Uni- or bi-directionality of longitudinal associations between WM and psychiatric symptoms were not robustly identified. We have proposed several explanations for these findings, including interindividual differences, the use of longitudinal approaches, and smaller effects than expected. STUDY REGISTRATION INFORMATION: Bidirectionality Brain Function and Psychiatric Symptoms; https://doi.org/10.17605/OSF.IO/PNY92.

Multivariate brain-based dimensions of child psychiatric problems: degrees of generalizability.

Multivariate machine learning techniques are a promising set of tools for identifying complex brain-behavior associations. However, failure to replicate results from these methods across samples has hampered their clinical relevance. This study aimed to delineate dimensions of brain functional connectivity that are associated with child psychiatric symptoms in two large and independent cohorts: the Adolescent Brain Cognitive Development (ABCD) Study and the Generation R Study (total n =8,605). Using sparse canonical correlations analysis, we identified three brain-behavior dimensions in ABCD: attention problems, aggression and rule-breaking behaviors, and withdrawn behaviors. Importantly, out-of-sample generalizability of these dimensions was consistently observed in ABCD, suggesting robust multivariate brain-behavior associations. Despite this, out-of-study generalizability in Generation R was limited. These results highlight that the degree of generalizability can vary depending on the external validation methods employed as well as the datasets used, emphasizing that biomarkers will remain elusive until models generalize better in true external settings.

Neurobiological, Psychosocial, and Behavioral Mechanisms Mediating Associations Between Physical Activity and Psychiatric Symptoms in Youth in the Netherlands.

Importance: Understanding the mechanisms by which physical activity is associated with a lower risk of psychiatric symptoms may stimulate the identification of cost-efficient strategies for preventing and treating mental illness at early life stages. Objective: To examine neurobiological, psychosocial, and behavioral mechanisms that mediate associations of physical activity with psychiatric symptoms in youth by testing an integrated model. Design, setting, and participants: Generation R is an ongoing prospective population-based cohort study collecting data from fetal life until young adulthood in a multiethnic urban population in the Netherlands. Pregnant women living in Rotterdam with an expected delivery date between April 2002 and January 2006 were eligible for participation along with their children born during this time. Data were collected at a single research center in the Erasmus Medical Center Sophia Children's Hospital. For the current study, data were analyzed from 4216 children with complete data on both exposure and outcome at ages 6, 10, and 13 years. Data were analyzed from January 2021 to November 2022. Exposures: Physical activity was ascertained at age 6 years (visit 1) via parent report and included weekly frequency and duration of walking or cycling to or from school, physical education at school, outdoor play, swimming, and sports participation. Main Outcomes and Measures: Psychiatric symptoms (internalizing and externalizing symptoms) were assessed at age 6 years (visit 1) and at age 13 years (visit 3) using the Child Behavior Checklist. Several mechanisms were explored as mediators, measured at age 10 years (visit 2). Neurobiological mechanisms included total brain volume, white matter microstructure, and resting-state connectivity assessed using a 3-T magnetic resonance imaging scanner. Psychosocial mechanisms included self-esteem, body image, and friendship. Behavioral mechanisms included sleep quality, diet quality, and recreational screen time. Pearson correlations between physical activity measures and psychiatric symptoms were calculated, with false discovery rate correction applied to account for the number of tests performed. Mediation analyses were performed when a correlation (defined as false discovery rate P < .05) between exposure and outcome was observed and were adjusted for confounders. Results: Among the 4216 children included in this study, the mean (SD) age was 6.0 (0.4) years at visit 1, and 2115 participants (50.2%) were girls. More sports participation was associated with fewer internalizing symptoms (ß for direct effect, -0.025; SE, 0.078; P = .03) but not externalizing symptoms. Self-esteem mediated the association between sports participation and internalizing symptoms (ß for indirect effect, -0.009; SE, 0.018; P = .002). No evidence was found for associations between any other neurobiological, psychosocial, or behavioral variables. No association was found between other types of physical activity and psychiatric symptoms at these ages. Conclusions and Relevance: The integrated model presented in this cohort study evaluated potential mechanisms mediating associations between physical activity and psychiatric symptoms in youth. Self-esteem mediated an association between sports participation in childhood and internalizing symptoms in adolescence; other significant mediations were not observed. Further studies might explore whether larger effects are present in certain subgroups (eg, children at high risk of developing psychiatric symptoms), different ages, or structured sport-based physical activity interventions.

Exploring the longitudinal associations of functional network connectivity and psychiatric symptom changes in youth.

BACKGROUND: Functional connectivity has been associated with psychiatric problems, both in children and adults, but inconsistencies are present across studies. Prior research has mostly focused on small clinical samples with cross-sectional designs. METHODS: We adopted a longitudinal design with repeated assessments to investigate associations between functional network connectivity (FNC) and psychiatric problems in youth (9- to 17-year-olds, two time points) from the general population. The largest single-site study of pediatric neurodevelopment was used: Generation R (N = 3,131 with data at either time point). Psychiatric symptoms were measured with the Child Behavioral Checklist as broadband internalizing and externalizing problems, and its eight specific syndrome scales (e.g., anxious-depressed). FNC was assessed with two complementary approaches. First, static FNC (sFNC) was measured with graph theory-based metrics. Second, dynamic FNC (dFNC), where connectivity is allowed to vary over time, was summarized into 5 states that participants spent time in. Cross-lagged panel models were used to investigate the longitudinal bidirectional relationships of sFNC with internalizing and externalizing problems. Similar cross-lagged panel models were run for dFNC. RESULTS: Small longitudinal relationships between dFNC and certain syndrome scales were observed, especially for baseline syndrome scales (i.e., rule-breaking, somatic complaints, thought problems, and attention problems) predicting connectivity changes. However, no association between any of the psychiatric problems (broadband and syndrome scales) with either measure of FNC survived correction for multiple testing. CONCLUSION: We found no or very modest evidence for longitudinal associations between psychiatric problems with dynamic and static FNC in this population-based sample. Differences in findings may stem from the population drawn, study design, developmental timing, and sample sizes.

Cognitive performance in children and adolescents with psychopathology traits: A cross-sectional multicohort study in the general population.

Psychopathology and cognitive development are closely related. Assessing the relationship between multiple domains of psychopathology and cognitive performance can elucidate which cognitive tasks are related to specific domains of psychopathology. This can help build theory and improve clinical decision-making in the future. In this study, we included 13,841 children and adolescents drawn from two large population-based samples (Generation R and ABCD studies). We assessed the cross-sectional relationship between three psychopathology domains (internalizing, externalizing, dysregulation profile (DP)) and four cognitive domains (vocabulary, fluid reasoning, working memory, and processing speed) and the full-scale intelligence quotient. Lastly, differential associations between symptoms of psychopathology and cognitive performance by sex were assessed. Results indicated that internalizing symptoms were related to worse performance in working memory and processing speed, but better performance in the verbal domain. Externalizing and DP symptoms were related to poorer global cognitive performance. Notably, those in the DP subgroup had a 5.0 point lower IQ than those without behavioral problems. Cognitive performance was more heavily affected in boys than in girls given comparable levels of psychopathology. Taken together, we provide evidence for globally worse cognitive performance in children and adolescents with externalizing and DP symptoms, with those in the DP subgroup being most heavily affected.

Long-term associations between early-life family functioning and preadolescent white matter microstructure.

BACKGROUND: Causes of childhood behavior problems remain poorly understood. Enriched family environments and corresponding brain development may reduce the risk of their onset, but research investigating white matter neurodevelopmental pathways explaining associations between the family environment and behavior remains limited. We hypothesized that more positive prenatal and mid-childhood family functioning - a measure of a family's problem solving and supportive capacity - would be associated with two markers of preadolescent white matter neurodevelopment related to reduced behavior problems: higher global fractional anisotropy (FA) and lower global mean diffusivity (MD). METHODS: Data are from 2727 families in the Generation R Study, the Netherlands. Mothers reported family functioning (McMaster Family Assessment Device, range 1-4, higher scores indicate healthier functioning) prenatally and in mid-childhood (mean age 6.1 years). In preadolescence (mean age 10.1), the study collected diffusion-weighted scans. We computed standardized global MD and FA values by averaging metrics from 27 white matter tracts, and we fit linear models adjusting for possible confounders to examine global and tract-specific outcomes. RESULTS: Prenatal and mid-childhood family functioning scores were moderately correlated, r = 0.38. However, only prenatal family functioning - and not mid-childhood functioning - was associated with higher global FA and lower global MD in preadolescence in fully adjusted models: ßglobal FA = 0.11 (95% CI 0.00, 0.21) and ßglobal MD = -0.15 (95% CI -0.28, -0.03) per one-unit increase in functioning score. Sensitivity and tract-specific analyses supported these global findings. CONCLUSIONS: These results suggest high-functioning prenatal or perinatal family environments may confer lasting white matter neurodevelopmental benefits into preadolescence.

Diffusion tensor imaging of the brain in Pompe disease.

Enzyme replacement therapy has drastically changed prospects of patients with Pompe disease, a progressive metabolic myopathy. As classic infantile patients survive due to treatment, they exhibit progressive white matter abnormalities, while brain involvement in late-onset patients is not fully elucidated. To study the underlying microstructure of white matter, we acquired structural (T1, T2, FLAIR) and diffusion tensor imaging (DTI) of the brain in 12 classic infantile patients (age 5-20 years) and 18 late-onset Pompe patients (age 11-56 years). Structural images were scored according to a rating scale for classic infantile patients. Fractional anisotropy (FA) and mean diffusivity (MD) from classic infantile patients were compared to a reference population, using a Wilcoxon signed-rank, one sample test. Effect sizes (Hedges' G) were used to compare DTI metrics across different tracts. For late-onset patients, results were compared to (reported) tractography data on normal aging. In classic infantile patients, we found a significant lower FA and higher MD (p < 0.01) compared to the reference population. Large-association fibers were most severely affected. Classic infantile patients with advanced white matter abnormalities on structural MRI showed the largest deviations from the reference population. FA and MD were similar for younger and older late-onset patients in large WM-association fibers. We conclude that, while no deviations from typical neurodevelopment were found in late-onset patients, classic infantile Pompe patients showed quantifiable, substantially altered white matter microstructure, which corresponded with disease stage on structural MRI. DTI holds promise to monitor therapy response in future therapies targeting the brain.

10-Year trajectories of depressive symptoms and subsequent brain health in middle-aged adults.

Depressive symptoms differ in severity and stability over time. Trajectories depicting these changes, particularly those with high late-life depressive symptoms, have been associated with poor brain health at old age. To better understand these associations across the lifespan, we examined depressive symptoms trajectories in relation to brain health in middle age. We included 1676 participants from the ORACLE Study, all were expecting a child at baseline (mean age 32.8, 66.6% women). Depressive symptoms were assessed at baseline, 3 years and 10 years after baseline. Brain health (global brain volume, subcortical structures volume, white matter lesions, cerebral microbleeds, cortical thickness, cortical surface area) was assessed 15 years after baseline. Using k-means clustering, four depressive symptoms trajectories were identified: low, low increasing, decreasing, and high increasing symptoms. The high increasing trajectory was associated with smaller brain volume compared to low symptoms, not surviving multiple testing correction. The low increasing trajectory was associated with more cortical thickness in a small region encompassing the right lateral occipital cortex compared to low symptoms. These findings show that longitudinal depressive symptoms trajectories are only minimally associated with brain health in middle age, suggesting that associations may only emerge later in life.

Physical activity levels and brain structure in middle-aged and older adults: a bidirectional longitudinal population-based study.

Physical activity has been suggested as modifiable factor that might contribute to improving cognitive and brain function during aging. However, previous studies were mainly of cross-sectional design and did not consider effects of time or potential reverse causality. We aimed to investigate the bidirectional associations of physical activity with brain structure in middle-aged and older adults. Overall, 4365 participants (64.01 ± 10.82 years; 56% women) from the Rotterdam Study had physical activity and brain structure assessed on at least one of 2 timepoints ('baseline': 2006-2012 or 'follow-up': 2012-2017, median duration between visits: 5 years). Physical activity was assessed through the LASA Physical Activity Questionnaire. T1-weighted MRI and diffusion tensor imaging were used to quantify brain volumes and white matter microstructure, respectively. Cross-lagged panel models were performed to estimate bidirectional associations, and linear mixed-effects models to investigate the consistency of findings. Larger total brain volume (ß = 0.067, 95%-confidence interval 0.035;0.099, pFDR = 0.001), gray matter volume (ß = 0.063, 0.031;0.096, pFDR = 0.002), and white matter volume (ß = 0.051, 0.020;0.083, pFDR = 0.013) at baseline were associated with higher levels of sports at follow-up. Lower global mean diffusivity at baseline was associated with higher levels of walking at follow-up (ß = -0.074, -0.111;-0.037, pFDR = 0.001). No associations were found between physical activity levels at baseline and brain metrics at follow-up. In conclusion, larger brain volumes and white matter microstructure at baseline were associated with individuals remaining more physically active at follow-up. Overall, this study identified older adults with potentially advanced brain aging status as being at higher risk of physical inactivity over time, and therefore as potential target group for prevention and novel intervention strategies.