Translational Neuroimaging in Unipolar Depression: Towards Personalized Treatment

描述(由申请人提供)：最好的一线治疗对大约40%-60%的单相抑郁症成年人有效，这可能是由于这种疾病的复杂性和异质性。在过去的十年里，利用功能神经成像对抑郁症的神经机制进行评估的基础研究取得了蓬勃发展。拟议的研究将结合神经成像、行为/心理生理学评估和临床试验，以允许将这一基础科学严格转化为临床。这项工作将有助于指导患者进行专门的治疗，以解决他们的特定机制，并可能导致基于神经科学的新干预措施的发展。这样的翻译研究几乎只在中年成年人中进行。然而，人们越来越关注针对中年个体相关大脑机制的干预措施(例如，认知行为疗法，SSRI‘s)对脆弱或抑郁的青年和老年抑郁症个体可能有用的程度。越来越多的研究表明，在中年抑郁症中被破坏并作为治疗目标的相同机制，如对情绪刺激的边缘反应增加，在易患抑郁症的焦虑青年中也存在(Easter等人，2005年)，并可能进一步预测这些人的治疗反应(McClure等人在Press-a中)。同样，抑郁症中情绪失调的特征可以预测中年个体的治疗反应，例如前额叶功能下降，在很高比例的老年抑郁症成年人中存在(例如Alexopoulos等人，2000年)，因此在计划治疗时可能作为或更重要地在该人群中解决。因此，终生发展观将是正在进行的转译神经成像研究的关键概括。西格尔博士是唯一准备在这类翻译研究方面取得重大进展的人。在他接受临床心理学家和认知神经学家的培训后，他的K01奖产生了计算建模和神经成像数据，这些数据导致了对抑郁症康复的具体预测。西方精神病学研究所和诊所提供了一个高度协作的临床试验环境，使他能够测试这些假设。他的R01已经开始了这项工作，为现有的临床试验增加评估，并与现有的临床试验研究人员合作。为了继续他的临床翻译到他的基础研究的高标准，Siegle博士建议在传统和新干预的临床试验的设计、执行和评估方面接受额外的培训和监督。此外，西格尔博士的研究侧重于中年抑郁症患者，但越来越多地被应用于了解青年和中老年患者的临床结果。获得与推广到整个生命周期相关的潜在问题的培训将是重要的，使他能够为此类翻译提供建议。

DESCRIPTION (provided by applicant): The best first-line treatments work for approximately 40-60% of unipolar depressed adults, potentially due to the disorder's complexity and heterogeneity. Basic research on the neural mechanisms of depression, assessed using functional neuroimaging has blossomed in the past decade. The proposed research will combine neuroimaging, behavioral/psychophysiological assessment, and clinical trials to allow rigorous translation of this basic science to the clinic. This work will help to direct patients specifically to treatments that will address their particular mechanisms and could lead to the development of novel neuroscience-based interventions. Such translational research has been done almost exclusively in mid-life adults. Yet, attention has increasingly focused on the extent to which interventions that address relevant brain mechanisms in mid-life individuals (e.g., Cognitive Behavioral Therapy, SSRI's) might be useful with vulnerable or depressed youth and elderly depressed individuals. Increasing research suggests that the same mechanisms which are disrupted in mid-life depression, and which are targeted in therapy, such as increased limbic response to emotional stimuli, are present in anxious youth (Easter et al 2005) who are vulnerable to depression, and may further predict treatment response in these individuals (McClure et al in press-a). Similarly, hallmarks of dysregulated emotion in depression which predict treatment response in mid-life individuals such as decreased prefrontal function are present in a high proportion of elderly depressed adults (e.g., Alexopoulos et al., 2000) and may thus be as, or more important to address in planning treatments in that population. Thus, a life-span developmental perspective will be a key generalization of ongoing translational neuroimaging research. Dr. Siegle is uniquely poised to make significant advances in this type of translational research. Following his training as a clinical psychologist and cognitive neuroscientist, his K01 award yielded computational modeling and neuroimaging data that lead to specific predictions about recovery from depression. Western Psychiatric Institute and Clinic provides a highly collaborative clinical trials environment, allowing him to test these hypotheses. His R01 has begun this work, adding assessments to existing clinical trials and collaborating with established clinical trials researchers. To continue his clinical translations to the high standards of his basic research, Dr. Siegle proposes to receive additional training and supervision in the design, execution, and evaluation of clinical trials for conventional and novel interventions. In addition, Dr. Siegle's research has focused on mid-life depressed individuals, but is increasingly being applied to understanding clinical outcomes in youth and late-life individuals. Obtaining training in potential issues associated with generalizing to the entire lifespan will be important for allowing him to advise such translations.