The protocol involved in this project is 11-M-0251. This report includes work arising from the following protocol: NCT01434368. Recruitment for this demanding longitudinal study is in its early stages due in part to the successful development of imaging techniques required to measure gonadal volume in these children with Magnetic Resonance Imaging (MRI), the need for a designated functional MRI to be in place for the performance of brain imaging in this longitudinal, repeated measures study, and the successful piloting of several brain-activation paradigms to measure specific neural systems (e.g., the reward system) across puberty in children. We currently have sixty children enrolled in this study and several children have returned for repeat visits. We have observed several important methodologic variables that potentially will inform future studies: First, age alone is not sufficient to determine prepubertal status since we have identified approximately 10% of girls who show advanced Tanner breast stage at age 8. Breast development was unilateral and reflected early estradiol secretion in these girls. Second, neither chronologic age nor Tanner stage are sufficient markers of sex steroid (i.e., estradiol) exposure in boys and girls, since we have identified abnormally advanced bone age relative to their chronologic age and controlled for sex (as measured by left wrist x-rays) in approximately 10% of children screened for enrollment in this study. Finally, we have identified abnormally increased or decreased BMI (defined by normal BMI percentiles between 15 and 85th percentiles) which is accompanied by alterations in sex steroid secretion in approximately 17% of otherwise normal healthy children screened for this study thus emphasizing the importance of controlling for BMI in studies of the relationship between sex steroid secretion and brain development. We are currently investigating the effects of these early changes in gonadal activity as reflected by advanced bone age on brain structure and function. Preliminary results of neuroimaging studies in this project suggest that pubertal stage contributes to several measures of adolescent brain development and accounts for differences between adolescent and adult brain development that were brain region-specific. Diffusion tensor imaging (DTI), and myelin water fraction (MWF) imaging (mcDESPOT method) were acquired on a 3T scanner in 30 typically developing children (8-12 year-olds, 14 females). The relationship of DTI/MWF data to hormone and pubertal measures was tested. In this sample of 8-12 year-olds, bone age and Tanner stage were highly correlated with maturation of the corticospinal tracts as measured by both DTI and MWF. In contrast, gonadal volume and plasma steroid hormone levels were associated with minimal changes in MWF medial to the thalamus. These findings suggest that bone age and Tanner stage may covary with white matter maturation during the early pubertal phase, while gonadal volume and steroid hormones may be associated with more restricted changes in this early phase of development. Additionally, preliminary results from the study of these children combined with ongoing studies in adults shed light on some developmental processes relevant for vulnerability to early life trauma and future psychiatric morbidity. There is evidence that the structural integrity of the uncinate fasciculus, one of the major white matter tracts connecting limbic and prefrontal regions, predicts amygdala activation to fearful faces abnormal in some anxiety conditions including PTSD. However, few studies have investigated the developmental trajectory of the amygdalas structural and functional connectivity. In both children and adults, we examined the relationship between structural connectivity of the uncinated fasciculus and functional activation of the amygdala during viewing of aversive emotional faces. In children, increased integrity of the uncinate fasciculus predicted increased amygdala activity and functional connectivity with the anterior cingulate cortex during viewing of aversive emotional faces, while this relationship was not present in adults. These results suggest that white matter integrity may impact the functioning of the fronto-amygdalar circuitry differently in children than in the fully developed adult brain.
