Multimodal Neuroimaging of Treatment Effects in Adolescent Mania

描述（由申请人提供）：虽然青春期是双相情感障碍最常见的发病期，躁狂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经常经历几次不成功的药物试验，在此期间发生疾病进展。因此，了解这些青少年中药物干预的神经生理学作用，将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志物，从而促进合理的治疗分配。目前，双相情感障碍缺乏这样的标志物，并且在疾病的后期更难以检测。双相情感障碍的特点是情绪和注意力的破坏。前边缘网络，包括前额叶区域（例如，腹外侧前额叶皮层和前扣带皮层）、丘脑、杏仁核和纹状体似乎调节这些过程。因此，我们假设双相情感障碍的症状是由该网络内的功能障碍引起的。事实上，神经影像学研究表明，前额叶前部边缘区的异常激活和代谢可能是神经生理学变化的基础，这些变化产生了与双相情感障碍相关的进行性情绪不稳定。虽然目前尚不清楚双相情感障碍的治疗是否会中断这些变化，但该模型提供了潜在的靶点，以确定双相青少年药物治疗的神经生物学效应和治疗反应。考虑到这些因素，本建议的总体目标是将联合收割机新的神经影像学技术与早期躁狂青少年的系统治疗研究相结合，以1）确定与躁狂相关的神经生理学指标如何响应治疗而改变; 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相关;和3）鉴定与随后的治疗特异性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120名首次住院的躁狂青少年随机分为锂或奎替利双盲治疗6周，在此期间，我们将进行症状评级，以及fMRI和H-MRS扫描。我们还将招募60名健康受试者，以评估不同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。检查每个治疗组在研究过程中这些指标的变化，将确定有效的药物干预是否会中断躁狂相关变化的进展，并可能识别治疗特异性反应标志物。最终，这些发现可能会导致有针对性的治疗开发和分配，以及早期发现和干预策略，从而改善双相青少年的疾病结局。R 01申请的总体目标是进行一项研究，将新型神经影像学技术与早期躁狂青少年的系统治疗研究相结合，以阐明神经生理学效应和治疗反应的标志物。尽管与双相情感障碍相关的发病率和死亡率很高，但很少有研究探讨抗躁狂药物在这一人群中的神经生物学作用。拟议研究的结果将促进合理的治疗分配和潜在的早期干预策略和新型治疗药物的开发，最终改善青少年双相情感障碍的结局。

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.