Ryan L Muetzel

Erasmus MC | Erasmus MC · Department of Child and Adolescent Psychiatry

Cross-sectional and longitudinal volumetric studies suggest that the corpus callosum (CC) continues to mature structurally from infancy to adulthood. Diffusion tensor imaging (DTI) provides in vivo information about the directional organization of white matter microstructure and shows potential for elucidating even more subtle brain changes during...

Objective: Psychiatric symptomatology during childhood predicts persistent mental illness later in life. While neuroimaging methodologies are routinely applied cross-sectionally to the study of child and adolescent psychopathology, the nature of the relationship between childhood symptoms and the underlying neurodevelopmental processes remains unc...

Recent advances in neuroimaging techniques have provided significant insights into developmental trajectories of human brain function. Characterizations of typical neurodevelopment provide a framework for understanding altered neurodevelopment, including differences in brain function related to developmental disorders and psychopathology. Historica...

Objectives: Survivors of critical illness in early life are at risk of long-term-memory and attention impairments. However, their neurobiologic substrates remain largely unknown. Design: A prospective follow-up study. Setting: Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands. Patients: Thirty-eight school-age (8-12 yr) survi...

Objective: Specific modifiable factors (e.g., screen time [ST], sleep duration, physical activity, or social connections) are targets for reducing depression risk in adults. However, research in adolescents lacks causal inference implementations, as prevention trials are costly and often prohibitive. Emulating randomized trials with observational d...

Background Neuroaxonal loss occurs in the early stages of multiple sclerosis (MS), but whether it results from early inflammatory brain damage or an ongoing neurodegenerative process remains unclear. We hypothesise that genetic and childhood environmental risk factors for MS may already have an impact on neurodevelopment before the typical age of o...

Mapping differential brain structures for psychiatric problems has been challenging due to a lack of regional convergence and poor replicability in previous brain-behavior association studies. By leveraging two independent large cohorts of neurodevelopment, the ABCD and Generation R Studies (total N = 11271), we implemented an unsupervised machine...

Hostility often co-occurs in parents and associates with increased aggression and inattention problems in children. In this population-based cohort of 484 mother-father-child neuroimaging trios, we investigated the degree to which associations of prenatal and childhood parental hostility would be associated with maternal, paternal, and child brain...

Early threat-associated cortical thinning may be interpreted as accelerated cortical development. However, non-adaptive processes may show similar macrostructural changes. Examining cortical thickness (CT) together with grey/white-matter contrast (GWC), a proxy for intracortical myelination, may enhance the interpretation of CT findings. In this pr...

We aimed to determine the association of family history of dementia with structural brain measures and cognitive performance in childhood and mid-life adulthood. We studied 1,259 parents (mean age: 47.3 years, range 31.9–67.4) and 866 of their children (mean age [range] at brain MRI: 9.9 years [8.8–11.9], and for cognition: 13.5 years [12.6–15.8])...

Maternal immune activation (MIA) during pregnancy, as a result of infectious or inflammatory stimuli, has gained increasing attention for its potential role in adverse child neurodevelopment, with studies focusing on associations in children born preterm. This systematic review summarizes research on the link between several types of prenatal MIA a...

Background Low maternal urinary iodine concentration (UIC) during pregnancy is associated with adverse offspring neurodevelopment. Thyroglobulin (Tg) has been suggested as a more sensitive biomarker than UIC of long-term iodine status, but associations of Tg with neurodevelopment and the possible mediating role of thyroid function remain unknown....

Thanks to methodological advances, large-scale data collections, and longitudinal designs, psychiatric neuroimaging is better equipped than ever to identify the neurobiological underpinnings of youth mental health problems. However, the complexity of such endeavors has become increasingly evident, as the field has been confronted by limited clinica...

Adaptations of the immune system throughout gestation have been proposed as important mechanisms regulating successful pregnancy. Dysregulation of the maternal immune system has been associated with adverse maternal and fetal outcomes. To translate findings from mechanistic preclinical studies to human pregnancies, studies of serum immune markers a...

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 neurobiologic...

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 del...

The aim of this longitudinal cohort study, is to provide more insight into the pattern of brain abnormalities, and possible consequences for cognitive functioning, in patients with classic infantile Pompe disease. We included 19 classic infantile Pompe patients (median age last assessment 8.9 years, range 1.5–22.5 years; 5/19 CRIM negative), treate...

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 par...

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 Singap...

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 cer...

Objectives We aimed to determine the association of family history of dementia with structural brain measures and cognitive performance in childhood and mid-life adulthood. Methods We studied 1,259 parents (mean age: 47.3 years, standard deviation: 4.7) and 866 of their children (mean age 9.9 years standard deviation: 0.5) of the population-based G...

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. Here we aimed to delineate dimensions of brain functional connectivity that are associated with child psychiatric sy...

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 stud...

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 with offspring white matter development fr...

Background: Arterial wall thickness and stiffness and high blood pressure have been repeatedly associated with poorer brain health. However, previous studies largely focused on mid- or late-life stages. It is unknown whether any arterial health-related brain changes may be observable already in adolescence. Methods: We examined whether (i) carotid...

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 longi...

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...

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...

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 t...

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 large scale, population-wide neuroimaging data, we describe and provide detailed, openly available models of cerebellar de...

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 asso...

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...

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 b...

Physical activity has been suggested to project again brain atrophy, but also to be a determinant of physical activity in older adults. However, research is needed to confirm this bidirectional relationship. Therefore, this research aimed to study the bidirectional relationship between physical activity and brain structure in older adults from the...

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...

Background: Childhood internalizing and externalizing problems frequently co-occur. Many studies report neural correlates of either internalizing or externalizing problems, but few account for their co-occurrence. We aimed to assess specific cortical substrates of these psychiatric problems. Methods: We used data from 9635 children aged 9-11 yea...

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 healt...

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 betwe...

Background: Although it is well-established that both genetics and the environment influence brain development, they are typically examined separately. Here, we aimed to prospectively investigate the interactive effects of genetic variants-from a genome-wide approach-and early life stress (ELS) on child subcortical brain structures, and their asso...

Background: Associations between attention-deficit/hyperactivity disorder (ADHD) and brain morphology have been reported, although with several inconsistencies. These may partly stem from confounding bias, which could distort associations and limit generalizability. We examined how associations between brain morphology and ADHD symptoms change with...

Background Poor cardiovascular health during pregnancy has been associated with adverse neurocognitive outcomes in the offspring. We examined the associations of maternal cardiovascular health factors with brain structure in 10‐year‐old children. Methods and Results We included 2797 mother–offspring pairs from the Generation R Study. Maternal body...

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...

Objective Associations between psychiatric problems and white matter (WM) microstructure have been reported in childhood and adolescence. 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...

Importance: Maternal tobacco use during pregnancy has been associated with various health consequences, including suboptimal neurodevelopment in offspring. However, the effect of prenatal exposure to maternal smoking on child brain development has yet to be elucidated. Objective: To investigate the association between maternal smoking during pre...

Background Exposure to air pollution may impact neurodevelopment during childhood, but current evidence on the association with cognitive function and mental health is inconclusive and primarily focusses on young children. Therefore, we aim to study the association of exposure to air pollution during pregnancy and childhood, with cognitive function...

Background Peer connections in school classrooms play an important role in social–emotional development and mental health. However, research on the association between children's peer relationships and white matter connections in the brain is scarce. We studied associations between peer relationships in the classroom and white matter structural con...

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...

Background: Associations between attention-deficit/hyperactivity disorder (ADHD) and brain morphology have been reported, although with several inconsistencies. These may partly stem from confounding bias, which could distort associations and limit generalizability. We examined how associations between brain morphology and ADHD symptoms change with...

Background The amount of people affected by traffic-related air pollution and noise is continuously increasing, but limited research has been conducted on the association of these environmental exposures and functional brain connectivity in children. Objective This exploratory study aimed to analyze the associations between the exposure to traffic...

Background Psychotic disorders have been widely associated with structural brain abnormalities. However, it is unclear whether brain structure predicts psychotic experiences in youth from the general population, owing to an overall paucity of studies and predominantly cross-sectional designs. Here the authors investigated longitudinal associations...

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association...

Prenatal and childhood adverse events have been shown to be related to children’s cognitive and psychological development. However, the influence of early-life adversities on child brain morphology is not well understood, and most studies are based on small samples and often examine only one adversity. Thus, the goal of our study is to examine the...

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 inclu...

Objective: To investigate brain structure, cerebral vasculature and cognitive function in a cohort of patients with late-onset Pompe disease, with particular reference to the differences from those with the classic-infantile phenotype, where extensive white matter abnormalities and impaired cognition on long-term enzyme-treatment are reported in a...

Importance Preterm birth and low birth weight are associated with brain developmental and neurocognitive outcomes in childhood; however, not much is known about the specific critical periods in fetal life and infancy for these outcomes. Objective To examine the associations of fetal and infant growth patterns with brain morphology in children at s...

Background: Higher segregation of functional networks in the brain has been associated with better cognitive abilities in aging (Chan, PNAS, 2014) and higher cognitive resilience against Alzheimer's disease (Ewers, Brain, in press). Here, we elucidated for the first time the genetic and environmental (i.e. cardiovascular) determinants of system se...

The longitudinal study of typical neurodevelopment is key for understanding deviations due to specific factors, such as psychopathology. However, research utilizing repeated measurements remains scarce. Resting-state functional magnetic resonance imaging (MRI) studies have traditionally examined connectivity as ‘static’ during the measurement perio...

In adults, cardiovascular risk factors are known to be associated with brain health. We hypothesized that these associations are already present at school-age. We examined the associations of adverse body fat measures and cardiovascular risk factors with brain structure, including volumetric measures and white matter microstructure, in 10-year-old...

The functional architecture of the brain is composed of distinct networks, where higher system segregation, i.e. greater differentiation of such functional networks, is associated with better cognitive performance. Aging and many neurological diseases have been associated with reduced system segregation and thus cognitive impairment. The genetic ba...

Alcohol consumption is commonly initiated during adolescence but the effects on human brain development remain unknown. In this multi-site study, we investigated the longitudinal associations of adolescent alcohol use and brain morphology. Three longitudinal cohorts in the Netherlands (BrainScale n=200, BrainTime n=239, and a subsample of the Gener...

Autism spectrum disorders (ASD) are associated with widespread brain alterations. Previous research in our group linked autistic traits with altered gyrification, but without pronounced differences in cortical thickness. Herein, we aim to replicate and extend these findings using a larger and older sample. Additionally, we examined whether (a) brai...

Lateralization in brain function has been associated with age and sex in previous work, however, there has been less focus on lateralization of functional networks during development. A clearer understanding of how and to what extent functional brain networks are lateralized in typical development may eventually prove to hold predictive information...

Physical symptoms are defined as symptoms for which adequate examination does not reveal a sufficient underlying root cause, e.g., pain and fatigue. The extant literature of the neurobiological underpinnings of physical symptoms has been largely inconsistent and primarily consists of (clinical) case-control studies with relatively small samples siz...

The cerebral cortex is fundamental to the functioning of the mind and body. In vivo cortical morphology can be studied through magnetic resonance imaging in several ways, including reconstructing surface-based models of the cortex. However, existing software for surface-based statistical analyses cannot accommodate “big data” or commonly used stati...

Background Prenatal and childhood adverse events have been shown to be related to children’s cognitive and psychological development. However, the influence of early-life adversities on child brain morphology is not well understood and most studies are based on small samples and often examine only one adversity. Thus, the goal of our study is to ex...

(Abstracted from JAMA Pediatr 2020;e202991) Gestational age (GA) at birth is an important factor in child health and neurodevelopment. Yet, few studies have evaluated the associations between GA and brain morphometry.