Endocrine and Neurobiologic Events Accompanying Puberty

本项目涉及的协议是11-M-0251。本报告包括由以下议定书引起的工作：NCT01434368。 这项要求很高的纵向研究的招募工作还处于早期阶段，部分原因是核磁共振成像(MRI)测量这些儿童性腺体积所需的成像技术的成功开发，在这项纵向、重复测量研究中需要指定的功能性MRI来执行脑成像，以及几个大脑激活范例的成功试点，以测量儿童青春期特定的神经系统(例如，奖励系统)。我们目前有60名儿童参加了这项研究，有几名儿童已经回来重复访问。我们观察到了几个重要的方法学变量，这些变量可能会影响未来的研究：首先，年龄本身不足以决定青春期前的状态，因为我们已经确定了大约10%的女孩在8岁时出现了晚期黄褐色乳房。乳房发育是单侧的，反映了这些女孩早期的雌二醇分泌。其次，无论是实际年龄还是晒黑阶段，都不足以作为男孩和女孩性激素(即雌二醇)暴露的标志，因为我们已经发现，在参加这项研究的儿童中，有大约10%的儿童骨龄相对于他们的实际年龄异常超前，并控制了性别(通过左腕X光片测量)。最后，在这项研究中筛选的大约17%的正常健康儿童中，我们发现了BMI异常增加或减少(定义为正常BMI百分位数在15到85个百分位数之间)，并伴随着性类固醇分泌的变化，从而强调了在研究性类固醇分泌和大脑发育之间的关系时控制BMI的重要性。我们目前正在研究这些性腺活动的早期变化对大脑结构和功能的影响，这些变化反映在骨龄较高的情况下。 该项目的神经成像研究的初步结果表明，青春期阶段有助于衡量青少年大脑发育的几个指标，并解释了青少年和成人大脑发育的不同之处，这些差异是特定于大脑区域的。在3T扫描仪上对30例典型发育儿童(8~12岁，女性14例)进行了弥散张量成像(DTI)和髓鞘含水率(MWF)成像。测试DTI/MWF数据与激素和青春期测量的关系。在这个8-12岁的样本中，根据DTI和MWF的测量，骨龄和Tanner分期与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的微小变化有关。这些发现表明，在青春期早期，骨龄和棕褐色阶段可能与白质成熟有关，而性腺体积和类固醇激素可能与早期发育阶段更有限的变化有关。 此外，对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与早期生命创伤和未来精神疾病发病率相关的发育过程。钩状束是连接边缘和前额叶的主要白质束之一，有证据表明，在包括创伤后应激障碍在内的一些焦虑症中，杏仁核的激活预示着恐惧面孔的异常激活。然而，很少有研究研究杏仁核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的面孔时，钩状神经束的结构连通性和杏仁核功能激活之间的关系。在儿童中，钩状束的完整性增加预示着在观看厌恶的情绪面孔时杏仁核活动和与前扣带皮质的功能连接增加，而这种关系在成年人中不存在。这些结果表明，白质完整性对儿童额叶-杏仁核回路功能的影响可能不同于完全发育的成人大脑。

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.