Endocrine and Neurobiologic Events Accompanying Puberty

本项目涉及的方案为11-M-0251。本报告包括以下方案产生的工作：NCT 01434368。 这项要求严格的纵向研究的招募工作仍处于早期阶段，部分原因是成功开发了用磁共振成像（MRI）测量这些儿童性腺体积所需的成像技术，需要指定的功能性MRI来进行这项纵向重复测量研究中的脑成像，以及成功引导几种脑激活范例来测量特定的神经系统（例如，奖励系统）在儿童青春期的变化。 我们目前有60名儿童入组本研究，有几名儿童已返回进行重复访视。我们已经观察到几个重要的方法学变量，可能会为未来的研究提供信息：首先，年龄本身不足以确定青春期前的状态，因为我们已经确定了大约10%的女孩谁显示先进的坦纳乳房阶段在8岁。乳房发育是单侧的，反映了这些女孩的早期雌二醇分泌。其次，无论是年龄还是坦纳分期都不是性类固醇的充分标志物（即，雌二醇）暴露，因为我们已经确定了相对于他们的实足年龄的骨龄异常提前，并且在本研究中筛选的大约10%的儿童中控制了性别（通过左手腕X射线测量）。最后，我们已经确定了BMI的异常增加或减少（定义为BMI在15和85之间的正常值），这是伴随着性类固醇分泌的改变，在大约17%的其他正常的健康儿童筛选这项研究，从而强调控制BMI的重要性，在研究性类固醇分泌和大脑发育之间的关系。 我们目前正在研究这些早期的性腺活动的变化，反映了先进的骨龄对大脑结构和功能的影响。 在这个项目中的神经影像学研究的初步结果表明，青春期阶段有助于青少年大脑发育的几个措施，并占青少年和成人大脑发育的差异，大脑区域特异性。对30例正常发育儿童（8-12岁，女性14例）进行磁共振弥散张量成像（DTI）和髓鞘水分数（MWF）成像（mcDESPOT法）。DTI/MWF数据的关系，激素和青春期的措施进行了测试。在这个8-12岁的样本中，骨龄和坦纳分期与DTI和MWF测量的皮质脊髓束的成熟高度相关。相反，性腺体积和血浆类固醇激素水平与丘脑内侧MWF的最小变化相关。这些研究结果表明，骨龄和坦纳阶段可能与青春期早期的白色物质成熟协变，而性腺体积和类固醇激素可能与更有限的变化，在这个早期的发展阶段。 此外，这些儿童的研究的初步结果结合正在进行的成人研究揭示了一些发展过程相关的脆弱性，早期生活创伤和未来的精神疾病。有证据表明，钩束（连接边缘系统和前额叶区域的主要白色物质束之一）的结构完整性，预示着杏仁核对恐惧面孔的激活在某些焦虑状态（包括创伤后应激障碍）中是异常的。 然而，很少有研究探讨杏仁核的结构和功能连接的发展轨迹。 在儿童和成人中，我们研究了在观看厌恶情绪面孔时，钩状束的结构连接和杏仁核的功能激活之间的关系。 在儿童中，钩束的完整性增加预测杏仁核的活动和功能连接增加与前扣带皮层在观看厌恶情绪的面孔，而这种关系并不存在于成人。 这些结果表明，白色物质的完整性可能会影响功能的额杏仁核电路不同的儿童比在完全发达的成人大脑。

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.