Current Studies

Early Brain Development in 1 and 2 Year Olds
PI: Dr. John Gilmore

The first years of life are the most dynamic and perhaps the most critical phase of postnatal brain development. Abnormalities in early childhood brain development have been implicated in neurodevelopmental disorders, including autism and schizophrenia, though very little is known about this crucial time period. This project focuses on the continued study of a cohort of typically developing children using innovative image analysis tools.  Our previous studies have found rapid gray matter development and white matter maturation in the first 2 years of life, with marked regional differences in the cortex and in white matter tracts, consistent with temporal patterns of sensory/motor and higher integrative function development. We also found significant relationships between white matter maturation and working memory. These findings indicate that neonatal brain structure, reflective of prenatal brain development and the rapid growth trajectories of the first two years of life, likely play an important role in longer trm outcome. In our current study we will extend follow-up of our cohort to 6 years of age and focus on structure/function relationships and the predictive value of early brain structure for later childhood brain structure and cognitive function. We are collecting diffusion tensor imaging,  at ages 1, 2, 4, and 6 years and assessing cognitive development, including general cognitive function and working memory. Developmental trajectories of cortical gray matter (including cortical thickness and surface area) and white matter (including tract-based spatial statistics and quantitative tractography) will also be studied. New knowledge gained in this study will provide a framework for understanding abnormalities of early childhood brain development in neurodevelopmental disorders such as autism and schizophrenia and will provide the fundamental information critical for developing preventative strategies for these disorders. 

Early Brain Development in Twins
PI: Dr. John Gilmore

Twin studies have been critical in determining the contributions of genetic and environmental factors to normal brain structure and for understanding abnormalities of brain development that underlie neurodevelopmental and neuropsychiatric disorders. In adults and older children, twin studies indicate that genes play a significant role in the variability of global brain volumes, including total brain, total gray and total white matter volumes. Other than this current study, there have been no studies of twin brain development in early childhood, the period of brain development implicated in the pathogenesis of many psychiatric disorders. In our previous studies containing over 100 twin pairs, we used prenatal ultrasound and neonatal MRI to study discordance of early brain development, and to determine genetic and environmental contributions to neonatal brain structure. We found that discordance of prenatal brain size in MZ twins is similar to that in DZ twins, but that by 1 month after birth, discordance of overall brain volume in MZ twins is already less than in DZ twins. We also found that global tissue volumes are highly heritable, similar to that observed in older children and adults, though gray matter heritability may is somewhat less. Interestingly, while global white matter volumes are highly heritable, diffusion tensor properties of specific white matter tracts are not. In our current study, we will continue enlarging this unique cohort and follow them through age 6 years with structural MRI, diffusion tensor imaging (DTI), and developmental assessments to determine how genetic and environmental factors contribute to brain development in the first years of life.

Genome-Wide Identification of Variants Affecting Early Human Brain Development 
PI: Dr. Rebecca Knickmeyer 

Recent studies strongly suggest that there are common, genetically determined pathways to risk for psychiatric and neurodevelopmental disorders including autism, intellectual disability, attention deficit disorder, and schizophrenia, but no study has investigated the relationship between genetic variation and human brain development prior to the age at which clinical symptoms are first recognized. The primary objective of the current study is to use cutting-edge techniques in genomics to identify common and rare genetic variants which impact brain development in the early postnatal period, an extremely dynamic time which may be critical in the etiology of neurodevelopmental disorders. Intracranial volume (ICV), total white matter, total gray matter, lateral ventricle volume, and maturation of white matter tracts are heritable in neonates. The project will test several major genetic mechanisms which could explain this high heritability. This study will primarily focus on the neonatal period, but participants are also returning for follow-up scans and detailed developmental assessments at 1, 2, 4 and 6 yrs of age as part of our other studies. Thus, ultimately, the information generated in this grant can be used to study genetic determinates of the trajectories of structural and functional brain development across the critical transitional period of infancy and early childhood. This is an unprecedented opportunity to identify genetic variants which impact brain development, potentially mediating risk for psychiatric and neurodevelopmental disorders. A better understanding of such genetic mechanisms has the potential to inspire new approaches to prevention, diagnosis, and treatment which are urgently needed.

Gut Microbiota and Anxiety: A Mechanistic Study of Human Infants 
PI: Dr. Rebecca Knickmeyer 

Studies in rodents show that the gut microbiome influences neurodevelopment and subsequent anxiety-related behaviors which are relevant to a wide range of psychiatric illnesses. However, there is a fundamental gap in translating animal data into the clinic: no study has directly tested whether differences in microbial colonization impact anxiety-related behavior in humans. Furthermore, the mechanisms and pathways by which microbiota alter brain development are poorly understood. Our long-term goal is to determine how colonization of the gut microbiome impacts human brain development and later risk for psychiatric illness. The objective of this project is to determine how microbial colonization impacts anxious behavior at 1 year of age and to identify signaling mechanisms and neural circuits mediating this relationship using high resolution magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and resting state fMRI (rfcMRI). This study is innovative in that it will be the first to test if and how microbial compositin relates to anxious behavior in a human cohort. This research is significant in that it is an essential first-step in developing novel interventions to promote a healthy microbiome and reduce risk for psychiatric illness.
 

White Matter and Working Memory Development in Typical and High-Risk Children
PI: Dr. Sarah J. Short 

This study is focused on characterizing the development of white matter and working memory in children who are typically developing and in children who are at genetic high-risk for schizophrenia from 1 to 8 years of age. As part of this project, we will be conducting a pilot study with typical children to determine the feasibility of measuring experience-dependent structural plasticity in white matter, following training with a standardized adaptive working memory program. This program of training and research will improve current understanding of early brain development in typical and high-risk children in relation to an early emerging and formative cognitive skill, working memory. Results from this research will be used to identify early biomarkers of risk, which can be used to inform the design of targeted preventive intervention strategies for high-risk children. Our study will help identify white matter connections that are important for the development of working memory and will determine whether they are altered in children at risk for schizophrenia. In addition, the feasibility study of working memory training in typical children will provide valuable information about the capacity to measure experience-dependent structural changes in white matter tracts. Strengthening neural networks associated with early foundational cognitive processes may help to ameliorate later impairments in other cognitive, social and developmental capacities that depend on working memory.