Neural Dimensions of Attention Bias Modification for Transdiagnostic Anxiety

描述(申请人提供)：目前临床焦虑症的一线治疗呈现50-70%的反应平台期，复发率高，缓解率低，几乎没有证据表明哪些患者可能从哪些治疗方案中受益。在更有效率和更有效的精神护理方法方面取得进展的障碍可能包括：对治疗结果的理论驱动的、机械性的预测不够重视；使用需要专家管理并具有多种可能机制的不同治疗方案；以及当前的精神病学诊断病因学可能模糊了生物行为功能的关键、跨诊断方面。候选人的长期抱负是通过更多地关注神经认知的跨诊断维度来改善临床焦虑治疗的结果。这项工作有可能1)指导改进和发展新的机械性的“神经行为”治疗方法，或通过行为方法针对大脑机制的治疗方法，以及2)微调特定方法的临床适应症，例如，通过表征特定神经行为治疗所针对(和不针对)的焦虑病理生理学的特定方面。候选人目前的重点是研究过度关注威胁的神经机制，并使用基于计算机的训练干预直接针对这些机制，注意力偏差修正(ABM)。对威胁的过度关注被认为是慢性焦虑症状和相关负面健康后果的关键因素。ABM直接针对这一机制，是一种成本效益很高的干预措施，其在临床焦虑人群中的有效性得到了迅速增长的经验支持。这位候选人试图通过研究焦虑中威胁处理的神经机制，并将这些神经维度与ABM结果联系起来，来连接基础研究和应用研究领域。目前的以患者为导向的导师职业发展奖将使候选人处于独特的地位，以推进她的长期研究议程。除了在临床心理学、统计学、研究方法和认知-情感神经科学方面的广泛培训外，她的背景还包括关于注意焦虑威胁的神经机制的专门培训、基本的fMRI方法和初步接触神经行为治疗研究。她寻求深化、扩展和整合她之前的培训，接受额外的培训，内容包括1)威胁处理的神经回路；2)高级功能磁共振方法；3)临床试验研究-包括测试有效性的基本方法和测试神经机制和结果预测的高级方法。匹兹堡大学是一个出色的环境，可以参与实现这些培训目标所需的跨学科培训。候选人的导师--匹兹堡大学的Greg Siegle、匹兹堡大学的David Brent和圣地亚哥州立大学的Nader Amir--拥有先进的功能磁共振成像方法、焦虑和威胁处理的神经和注意力机制、临床试验研究、神经行为治疗以及神经预测器和治疗结果机制方面的专业知识。团队对个人生产力的集体记录、强大的指导历史以及跨学科的协作使他们非常适合指导候选人的发展轨迹。这个 拟议的项目利用这一培训和专门知识来审查对威胁的关注的两个方面：初步警觉和对威胁的持续偏见。这项拟议的研究将使用个体差异、跨诊断的方法来检查每种形式的威胁处理的神经关联。65名患有临床致残特质焦虑的人将完成功能磁共振成像 旨在捕获这些可分离维度的任务，以及行为、自我报告和诊断措施。参与者将被随机分配接受ABM(n=45)，这是专门为提高对威胁的初始警觉而设计的，或者是假干预(n=20)。ABM完成者的一部分(n=20)将重复干预后的fMRI评估。数据将被用来测试反弹道导弹效能的神经机制模型，该模型假设反弹道导弹将专门针对最初的、但不是持续的威胁进行神经处理。因此，考生将考察1)与基线时对威胁的初始和持续注意的行为表现相关的神经机制；2)ABM对初始和持续威胁处理的症状水平、行为和神经维度的影响；3)基线神经维度和ABM结果之间的关联。这些分析将给予申请者宝贵的经验，使用个体差异的方法来理解焦虑的病理生理学和机械治疗后的结果。他们还将为程序性神经行为治疗研究的未来工作提供试点数据。未来的大规模R01研究将被设计成，例如，进一步验证已确定的威胁处理的神经维度作为治疗结果的调节和中介，将功能磁共振预测因子转换为临床可用的形式，并开发新的神经行为方法，旨在针对ABM无反应的预测因子。根据NIMH的战略计划战略1.4和建议的研究领域标准，这项工作的最终目标是促进基于神经认知过程的框架，以更有效地对患者进行分类和治疗。

DESCRIPTION (provided by applicant): Current first-line treatments for clinical anxiety exhibit a 50-70% response plateau, with high rates of relapse, low rates of remission, and little evidence to suggest which patients may benefit from which treatment options. Barriers to progress towards a more efficient and effective approach to psychiatric care may include inadequate focus on theory-driven, mechanistic predictors of treatment outcome; the use of heterogeneous treatment protocols that require expert administration and have multiple likely mechanisms; and the current diagnostic nosology of psychiatry, which may obscure critical, transdiagnostic dimensions of biobehavioral functioning. The candidate's long-term ambition is to improve outcomes in clinical anxiety treatment through an increased focus on transdiagnostic dimensions of neurocognition. Such work has the potential to 1) guide refinement and development of novel mechanistic, "neurobehavioral" treatment approaches, or treatments that target brain mechanisms through behavioral methods, and 2) fine-tune the clinical indications of specific approaches, e.g., by characterizing the specific aspects of anxiety pathophysiology that are (and are not) targeted by specific neurobehavioral treatments. The candidate's immediate focus is to study neural mechanisms of excessive attention to threat and target these mechanisms directly using a computer-based training intervention, attention bias modification (ABM). Excessive attention to threat is theorized to be a critical contributor to chronic anxiety symptoms and related negative health consequences. ABM, which directly targets this mechanism, is a highly cost-effective intervention with rapidly growing empirical support for its efficacy in clinically anxious populations. The candidate seeks to bridge basic and applied research domains by investigating neural mechanisms of threat processing in anxiety and relating these neural dimensions to ABM outcome. The current Mentored Patient Oriented Career Development Award will uniquely position the candidate to advance her long-term research agenda. Her background includes specialized training in neural mechanisms of attention to threat in anxiety, basic fMRI methods, and preliminary exposure to neurobehavioral treatment research, in addition to broad training in clinical psychology, statistics, research methods, and cognitive- affective neuroscience. She seeks to deepen, extend, and integrate across her previous training, receiving additional training in 1) neural circuitry of threat processing; 2) advanced fMRI methods; and 3) clinical trials research-including basic methods for testing efficacy and advanced methods for testing neural mechanisms and predictors of outcome. The University of Pittsburgh is an outstanding environment in which to engage in the interdisciplinary training required to achieve these training goals. The candidate's mentors-Greg Siegle (University of Pittsburgh), David Brent (University of Pittsburgh), and Nader Amir (San Diego State University)-have combined expertise in advanced fMRI methods, neural and attentional mechanisms of anxiety and threat processing, clinical trials research, neurobehavioral treatments, and neural predictors and mechanisms of treatment outcome. The team's collective record of individual productivity, strong mentorship histories, and interdisciplinary collaboration makes them ideally suited to guide the candidate's trajectory. The proposed project draws on this training and expertise to examine two dimensions of attention to threat: initial vigilance and sustained bias towards threat. The proposed study will examine the neural correlates of each form of threat processing using an individual differences, transdiagnostic approach. 65 individuals with clinically disabling trait anxiety will complete fMRI tasks designed to capture these dissociable dimensions, as well as behavioral, self-report, and diagnostic measures. Participants will be randomly allocated to receive ABM (n=45), which is specifically designed to ameliorate initial vigilance to threat, or a sham intervention (n=20). A subset of ABM completers (n=20) will repeat fMRI assessments post-intervention. Data will be used to test a neural mechanistic model of ABM efficacy which posits that initial, but not sustained, neural processing of threat will be specifically targeted by ABM. Accordingly, the candidate will examine 1) neural mechanisms correlated with behavioral manifestations of initial and sustained attention to threat at baseline; 2) ABM effects on symptom-level, behavioral, and neural dimensions of initial and sustained threat processing; and 3) associations between baseline neural dimensions and ABM outcomes. These analyses will give the applicant valuable experience using an individual differences approach to understand anxiety pathophysiology and outcomes following a mechanistic treatment. They will also provide pilot data for future work in programmatic neurobehavioral treatment research. Future large-scale R01 studies will be designed to, e.g., further validate identified neural dimensions of threat processing as moderators and mediators of treatment outcome, translate fMRI predictors into clinically available forms, and develop new neurobehavioral approaches designed to target predictors of ABM non-response. Consistent with NIMH's Strategic Plan Strategy 1.4 and proposed Research Domain Criteria, the ultimate goal of this work is to promote a neurocognitive process-based framework for more effective patient classification and treatment.