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，使用功能性神经成像评估抑郁症神经机制的基础研究蓬勃发展。拟议中的研究将结合联合收割机神经影像学，行为/心理生理学评估和临床试验，以允许这一基础科学的严格翻译到临床。这项工作将有助于指导患者专门针对其特定机制的治疗，并可能导致新的神经科学干预措施的发展。这种转化研究几乎完全是在中年人中进行的。然而，注意力越来越集中在解决中年人相关大脑机制的干预措施的程度上（例如，认知行为疗法（SSRI）可能对脆弱或抑郁的青年和老年抑郁症患者有用。越来越多的研究表明，在中年抑郁症中被破坏的相同机制，以及治疗中的目标，如对情绪刺激的边缘系统反应增加，存在于易患抑郁症的焦虑青年中（Easter et al 2005），并且可能进一步预测这些个体的治疗反应（麦克卢尔et al in press-a）。类似地，抑郁症中情绪失调的标志，其预测中年个体的治疗反应，如前额叶功能下降，存在于高比例的老年抑郁症成年人中（例如，Alexopoulos等人，2000），因此在该人群中计划治疗时可能同样重要或更重要。因此，终身发展的观点将是一个关键的概括正在进行的翻译神经影像学研究。Siegle博士是唯一准备在这种类型的转化研究取得重大进展。在接受临床心理学家和认知神经科学家的培训后，他的K 01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。西方精神病研究所和诊所提供了一个高度合作的临床试验环境，使他能够测试这些假设。他的R 01已经开始这项工作，在现有的临床试验中增加评估，并与已有的临床试验研究人员合作。为了继续他的临床翻译，以他的基础研究的高标准，Siegle博士建议接受额外的培训和监督，在设计，执行和评价临床试验的传统和新型干预措施。此外，Siegle博士的研究主要集中在中年抑郁症患者身上，但越来越多地被应用于了解青年和老年人的临床结果。获得与推广到整个生命周期相关的潜在问题的培训对于让他为此类翻译提供建议至关重要。

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.