Computerized Cognitive Remediation in Geriatric Depression

描述(由申请者提供)：这个K23指导的以患者为导向的研究职业发展奖的目标是获得必要的指导、培训和研究经验，以确立我作为一名独立调查者的地位，专注于为老年性抑郁症开发神经生物学知识的认知补救干预措施。我目前是韦尔-康奈尔老年抑郁症干预和服务研究高级中心(ACISR)的研究员。我的短期目标是完善我与导师共同开发的计算机化认知补救(CCR)干预，并进行初步研究以测试其有效性。除了作为一种培训工具， 改进的CCR方法将对我职业生涯的下一步至关重要，即由R01拨款支持的精简版干预的RCT。这些目标将在威尔-康奈尔ACISR的医学博士George Alexopoulos、耶鲁大学医学院的Bruce Wexler医学博士以及威尔-康奈尔医学院、耶鲁大学医学院和哥伦比亚大学医学中心的顾问团队的指导下完成。在老年性抑郁症中，执行功能缺陷是常见的，并使人丧失能力。我们和其他人已经证明，一些执行功能障碍及其潜在的大脑网络异常与抗抑郁药物反应不良有关。我自己的研究表明，抗抑郁药物抵抗的一个特定决定因素是语义策略障碍。这种损害在语言流畅性和语言记忆测试中都很明显。识别这种特定的和临床相关的神经认知缺陷是设计拟议的计算机化认知补救(CCR)干预的关键步骤。拟议的培训计划包括正式课程、研讨会、有针对性的教程、协作研究和手稿准备，所有这些都是为了传授正常衰老中的神经生物学和神经可塑性、CCR方法开发和临床试验方法学方面的知识和技能。培训体验的流程和内容将使我有机会从与导师、合作者和顾问的互动中最大限度地受益，并为我提交未来的R01申请做好准备。除了上述培训外，我还计划进行一个研究项目，作为实现我的教育目标的培训基础。在我的研究计划中，我提议调查老年抑郁症的计算机化认知补救(CCR-GD)是否可以通过针对特定的执行缺陷及其潜在的神经生物学异常来提高老年抑郁症的抗抑郁治疗的疗效。该项目的第一个目标是对CCR-GD进行预试和修订，以实现挑战、绩效和参与者可接受性之间的最佳平衡。由此产生的CCR-GD版本将在我的研究计划中进行试验。我假设，接受CCR-GD治疗剂量至少8周的患有严重抑郁症的老年人将比接受抗抑郁药物加对照条件的参与者在4周内表现出更大的抑郁症状(MADR)的减少和语义策略的增加。其他探索性分析将考察CCR-GD的益处是否会转移到干预目标之外的执行功能上，基线时的言语语义策略损伤是否会削弱CCR-GD在减轻抑郁症状方面的优势，以及语义策略的变化是否与抑郁评分的变化相关。最后，ACISR后续研究计划可能提供机会来检查CCR-GD(相对于对照条件)在抑郁症状和语义策略方面的益处是否在治疗完成12周后保留。

DESCRIPTION (provided by applicant): The goal of this K23 Mentored Patient-Oriented Research Career Development Award is to gain the mentorship, training, and research experiences necessary to establish myself as an independent investigator focused on developing neurobiologically informed cognitive remediation interventions for geriatric depression. I am currently a research fellow at the Weill-Cornell Advanced Center for Interventions and Services Research (ACISR) for Late-Life Depression. My short-term goals are to refine the computerized cognitive remediation (CCR) intervention I developed with my mentors and to conduct a preliminary study to test its efficacy. Beyond serving as a training tool, the improved CCR methods will be critical for the next step in my career, an RCT of a streamlined version of my intervention supported by an R01 grant. These goals will be completed under the mentorship of George Alexopoulos, M.D. of the Weill-Cornell ACISR, Bruce Wexler, M.D., of Yale University School of Medicine, and a team of consultants at Weill-Cornell Medical College, Yale University School of Medicine, and Columbia University Medical Center. In geriatric depression, deficits in executive functions are common and disabling. We and others have documented that some executive dysfunctions and their underlying brain network abnormalities are associated with poor response to antidepressants. My own work suggests that a specific determinant of resistance to antidepressants is semantic strategy impairment. This impairment is evident on both verbal fluency and verbal memory tests. The identification of this specific and clinically relevant neurocognitive deficit was an essential ste in designing the proposed computerized cognitive remediation (CCR) intervention. The proposed training plan consists of formal coursework, seminars, targeted tutorials, collaborative studies, and manuscript preparation, all of which are planned with the goal of imparting knowledge and skills in the neurobiology and neural plasticity in normal aging, CCR method development, and clinical trials methodology. The process and content of the training experiences are designed in a way that it will provide the opportunity for me to benefit maximally from interaction with mentors, collaborators, and consultants, and prepare me to submit a future R01 application. In addition to the above training, I plan to conduct a research project that will function as the training ground for accomplishing my educational objectives. In my Research Plan, I propose to investigate whether computerized cognitive remediation for geriatric depression (CCR-GD) can improve the efficacy of antidepressant treatment in geriatric depression by targeting specific executive deficits and (by inference) their underlying neurobiologic abnormalities. The first aim of the project is to pre-pilot and revise CCR-GD to achieve an optimal balance of challenge, performance, and acceptability to participants. The resultant version of CCR-GD will be piloted in my Research Plan. I hypothesize that older adults with major depression who have received therapeutic dosages of antidepressants for at least 8 weeks who receive CCR-GD will show greater reduction in depressive symptoms (MADRS), and greater increases in semantic strategy than participants on antidepressants plus a control condition over 4 weeks. Additional exploratory analyses will examine whether benefits of CCR-GD will transfer to executive functions other than those targeted by the intervention, whether verbal semantic strategy impairment at baseline moderates the advantage of CCR-GD in reducing depressive symptoms, and whether change in semantic strategy is associated with change in depression scores. Finally, the ACISR follow-up research program may offer the opportunity to examine whether benefits of CCR-GD (over the control condition) in depressive symptoms and in semantic strategy are retained 12-weeks after treatment completion.