Multimodal Neuroimaging of Treatment Effects in Adolescent Mania

描述(申请人提供)：虽然青春期是双相情感障碍最常见的发病时期，躁狂症是这种疾病的定义状态，但患有双相情感障碍的躁狂青少年在达到情绪稳定之前通常会经历几次不成功的药物试验，在此期间会发生疾病进展。因此，了解药物干预对这些青少年的神经生理学影响，将有助于阐明抗躁狂治疗对双相情感障碍神经发育的影响，并可能导致识别与治疗反应相关的神经生物学标记物，从而促进合理的治疗分配。目前，这种标记物缺乏双相情感障碍，在病程后期更难检测到。双相情感障碍的特征是情绪和注意力紊乱。前缘网络包括前额叶区域(如前额叶腹外侧区和前扣带回皮质)、丘脑、杏仁核和纹状体，似乎调节着这些过程。因此，我们假设双相情感障碍的症状是由这个网络中的功能障碍引起的。事实上，神经成像研究表明，前额叶前缘区的异常激活和代谢可能是导致与双相情感障碍相关的进行性情绪不稳定的神经生理变化的基础。尽管目前尚不清楚双相情感障碍的治疗是否会中断这些变化，但该模型为确定药物对双相情感障碍青少年的神经生物学效应和治疗反应提供了潜在的靶点。考虑到这些考虑，这项建议的总体目标是将新的神经成像技术与对早期躁狂青少年的系统治疗研究结合起来，以1)确定与躁狂相关的神经生理学指标如何对治疗做出反应；2)证明局部脑激活变化的正常化与局部代谢物水平的正常化有关；以及3)确定与随后的特定治疗反应相关的神经代谢和神经功能标记物。为了实现这些目标，我们将对120名首次住院的躁狂症青少年进行随机双盲治疗，用锂或奎硫平治疗6周，在此期间我们将进行症状评分，以及fMRI和H-MRS扫描。我们还将招募60名健康受试者，1评估两个时间点之间神经生理学测量的正常变异性，并解释双相青少年神经生物学变化的方向。在每个治疗组的研究过程中检查这些措施的变化，将确定有效的药物干预是否阻止与躁狂症相关的变化的进展，并可能确定特定于治疗的反应标记。最终，这些发现可能导致有针对性的治疗发展和分配，以及早期发现和干预战略，从而改善双相情感障碍青少年的疾病结局。这项R01应用的总体目标是进行一项研究，将新的神经成像技术与对早期躁狂青少年的系统治疗研究相结合，以澄清神经生理学效应和治疗反应的标记。尽管青春期发作的双相情感障碍的发病率和死亡率很高，但很少有研究检查抗躁狂药物对这一人群的神经生物学影响。拟议的研究结果将有助于合理的治疗分配和潜在的早期干预策略和新的治疗药物的发展；最终导致改善双相情感障碍青少年的结果。

DESCRIPTION (provided by applicant): Although adolescence is the most common period of onset of bipolar disorder and mania is the defining state of this illness, manic adolescents with bipolar disorder often undergo several unsuccessful medication trials prior to achieving mood stabilization, during which time illness progression occurs. Therefore, understanding the neurophysiologic effects of pharmacological interventions in these adolescents, will clarify the effects of anti-manic treatments on the neurodevelopment of bipolar disorder and may lead to the identification of neurobiological markers associated with treatment response, thereby facilitating rationale treatment assignment. Currently, such markers are lacking for bipolar disorder and are more difficult to detect later in the course of illness. Bipolar disorder is characterized by disruption of mood and attention. The anterior limbic network, which includes prefrontal regions (e.g., ventrolateral prefrontal cortex and anterior cingulate cortex), thalamus, amygdala, and striatum, appears to regulate these processes. Therefore, we hypothesize that the symptoms of bipolar disorder arise from dysfunction within this network. Indeed, neuroimaging studies suggest that abnormal activation and metabolism in prefrontal anterior limbic regions may underlie the neurophysiologic changes that produce the progressive emotional instability associated with bipolar disorder. Although it is unknown whether treatments for bipolar disorder interrupt these changes, this model provides potential targets to determine the neurobiological effects of medication and treatment response in bipolar adolescents. With these considerations, the overall goals of this proposal are to combine novel neuroimaging techniques with a systematic treatment study of early-course manic adolescents in order to 1) determine how neurophysiologic measures associated with mania change in response to treatment; 2) demonstrate that normalization of regional brain activation changes are associated with normalization of regional metabolite levels; and 3) identify neurometabolitic and neurofunctional markers that are associated with subsequent treatment-specific response. In order to accomplish these aims, we will randomize 120 first-hospitalization manic adolescents to double-blind treatment with lithium or quetiapine for 6 weeks, during which time we will perform symptom ratings, as well as fMRI and H-MRS scans. We will also recruit 60 healthy subjects to 1 assess normal variability in neurophysiologic measurements between time points and interpret the direction of the neurobiological changes in bipolar adolescents. Examining changes in these measures over the course of the study in each treatment group will determine whether effective pharmacological interventions interrupt the progression of the changes associated with mania and may identify treatment-specific markers of response. Ultimately, these findings may lead to targeted treatment development and assignment, as well as, early detection and intervention strategies, thereby improving illness outcome for bipolar adolescents. The overall goal of this R01 application is to conduct a study combining novel neuroimaging techniques with a systematic treatment study of early-course manic adolescents in order to clarify neurophysiologic effects and markers of treatment response. Despite the significant morbidity and mortality associated with adolescent-onset bipolar disorder, few studies have examined the neurobiological effects of anti-manic medications in this population. Findings of the proposed study will facilitate rationale treatment assignment and the development of potential early-intervention strategies and novel therapeutic agents; ultimately leading to improved outcomes of adolescents with bipolar disorder.