This work is conducted under protocol 89-M-0006 (NCT00001246). The Developmental Neurogenomics Unit (DNU) was established in October 2015, and work during the past year was focused on completion of basic infrastructural tasks including physical relocation and furnishing of the laboratory, recruitment of staff, and setting-up new standard operating procedures. We have also restructured our biosamples to distinguish material newly gathered under DNU projects from legacy samples that form a subset of the larger Child Psychiatry Branch collection. Our Unit has also embarked upon a large-scale process of re-annotation, collation and screening of all neuroimaging data gathered as part of the 30 year old longitudinal NIMH IRP study of structural brain maturation in typically developing humans ages 5-30 years old. These efforts are the first step in making these 1.5 Tesla structural neuroimaging data freely available for use by the wider research community. 1. Over the last year, our studies of brain development in healthy volunteers have involved the following activities and outputs: A) We have conducted a series of new analyses on existing longitudinal structural brain magnetic resonance imaging (MRI) scans and associated demographic information. First, given that we often study children - who tend to move more in the MRI scanner than adults - we carefully characterized the effects of in-scanner motion on the anatomical estimates we measure from MRI brain scans. This study showed that greater degrees of motion lead to greater underestimation of how thick the cerebral cortex is, and that this bias varies in magnitude between different cortical regions. These effects are largely reproducible across both main softwares for measuring cortical anatomy (CIVET and Freesurfer). Having defined these effects will help improve our future studies of structural brain development, and also provides the broader neuroimaging community with information that can ultimately help to promote reproducibility in research. Second, we harnessed naturally-occurring variation in gender, brain-size, age, and genetic status to study how different structural properties of the human brain hang-together, so that we can improve the biological utility of neuroimaging measures we use to study brain development in health and disease. For example, we showed that the classical method of focusing on brain volume within subcortical structures misses distinct region-specific anatomical changes within each subcortical nucleus. Moreover, the shape of subcortical structures varies with human brain size, and this new knowledge is critical for accurately defining disease-related changes in subcortical anatomy. We also completed a series of studies that focused on cortical folding - a prominent, but poorly understood aspect of brain anatomy, which is thought to carry special information about early development, and structure-function relationships within the central nervous system. These studies showed that folding patterns are stable during postnatal life, and that the pits and crests of cortical folds tend to mature in very different ways. These findings provide important new foundations for greater use of cortical folding to track brain development in health and illness. B) We have recruited, scanned and gathered detailed behavioral and cognitive measures on more than 150 adults who had previously been studied during childhood by our Branch an average of 20 years ago. Data collection is ongoing for this project, which represents the longest known neuroimaging follow-up study of human brain development, and will provide unique opportunities to study how childhood brain organization relates to later outcomes in adulthood. 2. Over the last year, our studies of brain development in clinical populations have involved the following activities and outputs: A) We have conducted a series of new analyses on existing structural brain magnetic resonance imaging (MRI) scans in participants with idiopathic and genetically-defined neurodevelopmental disorders. First, we studied children with idiopathic Autism Spectrum Disorder (ASD), and identified a set of brain regions that tend to show atypical structural maturation relative to the anatomical changes seen in typically developing children. Moreover, in a separate set of brain regions, inter-individual differences in brain maturation amongst children with ASD were correlated with inter-individual differences in language development. These studies emphasize that shifts in anatomical brain development are already detectible in ASD during preschool life, and point towards a set of brain regions that may mark compensatory processes in children with ASD who have more favorable language development. Second, we have analyzed existing structural neuroimaging data in children with a range of sex chromosome aneuploidy syndromes (SCAs) to provide new insights into the impact of changing X- and Y-chromosome dosage on diverse aspects of brain anatomy including cortical thickness, surface area and asymmetry as well as subcortical volume and shape. These studies have identified a set of brain regions that appear to be especially sensitive to SCA in terms of their anatomical development, and represent promising new candidates in the search for neural systems that underpin some of the cognitive and behavioral changes that can be associated with SCA. Third, we initiated a series of genomic studies designed to shed light on the way that SCA can alter cellular function. The cellular consequences of SCA represent a critical stepping-stone on the path between carriage of an atypical number of sex chromosomes and increased risk for neurodevelopmental disorders impacting cognition and behavior. B) We launched a new deep-phenotyping study of participants with SCA and their family members, which is ongoing, and expected to span several years. This study expands on past work in SCA by gathering more comprehensive measures of brain structure and function, as well as providing more fine-grained information regarding the cognitive and behavioral variations that can be seen in SCA. This new phase in our clinical research of participants with SCA is providing us with information that will ultimately help to better define the developmental risks and resiliencies associated with X- and Y-chromosome dosage variation in humans, and identify neurobiological systems that might underpin these associations. We hope these insights will (i) improve accurate public and professional awareness of SCAs, (Ii) help clinicians provide more targeted assessment and counseling to patient and families with SCA , and (iii) begin to identify biological markers with the potential to ultimately improve assessment, prediction and treatment of neurodevelopmental issues in SCA. C) We complemented our human studies with a series of neuroimaging studies in mouse models of ASD and SCA. These animal models provide new opportunities for investigating potential causes and consequences of the anatomical changes that are seen in genetically-determined alterations of brain development. Collectively, our studies in SCA also shape understanding of sex chromosome contributions to sex-differences seen in typically developing populations.
Showing the most recent 10 out of 36 publications
