Fronto-limbic Connectivity in Adolescents with MDD

描述(申请人提供)：目的/假设：青春期是一个值得注意的时期，显著的大脑成熟和神经元连接的完善，也是严重抑郁障碍(MDD)患病率显著增加的时期。额叶-边缘神经网络介导情绪加工，并与MDD的病理生理学有关。我们最重要的假设是，MDD是额叶边缘神经回路异常发育的结果。神经成像方法的最新进展使测量神经连接或“连接”的强度成为可能。例如，扩散张量成像(DTI)可以用来测量“结构连通性”，而静息状态功能磁共振成像(RsfMRI)可以用来测量“功能连通性”。在使用这些方法对14名患有MDD的青少年和14名健康对照受试者进行的初步研究中，我们发现在抑郁症组中，亚膝前扣带回皮质和其他关键的额叶边缘区域之间的结构和功能连接都减少了。这些发现的结论是有限的，因为与抑郁症组的小样本量和药物暴露有关的混淆。为了更好地描述抑郁青少年额缘网络的发育异常，我们现在建议进行一项多模式的神经成像研究，在一个更大的、未接受治疗的样本中检查结构和功能的连接性。建议的方法：从明尼苏达大学和社区的临床环境中招募30名13-17岁的家族性、青春期起病、中至重度MDD的青少年和30名性别、利手、SES和IQ匹配的健康对照。评估将包括K-SADS-PL、BDI、CDRS和WASI。神经成像扫描将在UMN的研究专用西门子3T扫描仪上获得。将收集结构、扩散张量和静止状态的功能图像。结构连通性数据将使用体素比较和概率跟踪图进行分析。功能连接性将使用基于种子的方法进行分析。讨论/意义：抑郁症青少年额叶-边缘神经网络中的异常连接将有助于我们理解青少年MDD的神经发育机制。来自拟议项目的数据集将为未来的纵向调查提供基础，以(1)描绘MDD患者的神经发育轨迹，(2)确定治疗反应的预测因素，(3)检查治疗对神经回路的影响，以及(4)调查青少年MDD神经发育异常的遗传和环境基础。通过识别儿童抑郁症背后的神经发育异常，我们希望能为改变负面轨迹的干预措施的发展提供信息。 公共卫生相关性：迫切需要进行神经生物学研究，以解决严重抑郁障碍(MDD)造成的重大公共卫生负担。这种疾病通常始于青春期。由于早期干预有望影响可塑性系统和改变轨迹，因此在青春期MDD的神经发育生物学方面的进展尤为关键。

DESCRIPTION (provided by applicant): Objective/Hypothesis: Adolescence is a time period notable for significant brain maturation and refinement of neuronal connections, and also for a marked increase in prevalence of Major Depressive Disorder (MDD). Fronto-limbic neural networks mediate emotional processing and are implicated in the pathophysiology of MDD. Our over-arching hypothesis is that MDD results from abnormal development of fronto-limbic neural circuitry. Recent advances in neuroimaging methodology have allowed for measuring the strength of neural connections, or "connectivity". For instance, diffusion tensor imaging (DTI) can be used to measure "structural connectivity", and resting-state functional magnetic resonance imaging (rsfMRI) can be used to measure "functional connectivity". In a preliminary study using these methods in 14 adolescents with MDD and 14 healthy comparison subjects, we identified a reduction in both structural and functional connectivity between the subgenual anterior cingulate cortex and other key fronto-limbic areas in the depressed group. Conclusions from these findings are limited due to confounds related to small sample size and medication exposure in the depressed group. In order to better characterize the developmental abnormalities in fronto-limbic networks in depressed adolescents, we now propose to conduct a multi-modal neuroimaging investigation to examine structural and functional connectivity in a larger, treatment-naive sample. Proposed Methods: 30 adolescents aged 13-17 with familial, adolescent onset, moderate-severe MDD and 30 healthy comparisons matched for sex, handedness, SES and IQ will be recruited from clinical settings at the University of Minnesota and the community. Assessment will include the K-SADS-PL, BDI, CDRS, and WASI. Neuorimaging scans will be obtained at a research-dedicated Siemens 3T scanner at UMN. Structural, diffusion tensor, and resting-state functional images will be collected. Structural connectivity data will be analyzed using a voxel-wise comparison and also using probabilistic tractography. Functional connectivity will be analyzed using a seed-based approach. Discussion/Significance: Demonstration of abnormal connectivity within fronto-limbic neural networks in depressed teens will inform our understanding of the neurodevelopmental mechanisms of adolescent MDD. The dataset from the proposed project will provide the foundation for future longitudinal investigations to (1) delineate trajectories of neural development in individuals with MDD, (2) identify predictors for treatment response, (3) examine the impact of treatment on neural circuitry, and (4) investigate the genetic and environmental underpinnings of abnormal neural development in adolescent MDD. By identifying neurodevelopmental abnormalities that underlie the pediatric depression, our hope is to inform the development of interventions that will alter negative trajectories. PUBLIC HEALTH RELEVANCE: Neurobiological research is urgently needed to address the significant public health burden posed by Major Depressive Disorder (MDD). This illness frequently begins in adolescence. Since early interventions hold promise for impacting malleable systems and altering trajectories, advancement in the neurodevelopmental biology of MDD during adolescence is especially critical.