PECASE: Using Control Systems to Quantify Limbic Dysregulation for Neurobiologically-Based Diagnoses of Psychiatric Disabilities

项目简介：智力优势：对于这个提案，我们将开发和测试计算方法，用于量化大脑中控制情绪唤醒的稳态调节的负反馈回路的兴奋性和抑制性成分之间的失调。这项工作在概念上将系统神经科学与最初为物理和工程开发的技术（功率谱尺度不变性，香农熵）集成在一起，这些技术已成功地应用于通过心率变异性分析来表征自主调节。从历史上看，神经成像的重点是测量某些特定任务中不同兴趣区域的激活水平的振幅。虽然在过去的几年里，新的连接方法，如结构方程建模、格兰杰因果关系和动态因果模型，在研究时间序列的时间成分方面取得了重要进展，但这些技术的目的是研究节点对之间的连接强度。相比之下，我们的方法建立在这项工作的基础上，以回答一个完全不同类型的问题：在维持稳态的过程中，系统作为一个整体对扰动的有效响应程度是多少？我们的研究方法显然是基于这样一个事实：从糖尿病到癌症再到库欣氏病，许多疾病本质上都是调节失调的。因此，一项在诊断方面取得很大成功的技术是“干扰”系统，然后测量其返回基线的动态特征。在本研究中，我们首先利用功能性MRI和近红外光谱获得的神经时间序列来测量边缘回路的失调，从而开发出一种基于神经生物学的仪器，用于客观和定量诊断精神疾病。我们将优化方法的三组患者包括广泛性焦虑障碍、重度抑郁症及其合并症。这些诊断选择为我们之前的边缘失调研究提供了合理的延伸，作为健康人群中特质焦虑个体差异的标志。此外，与焦虑和抑郁相关的症状在生理和行为唤醒方面具有明确定义的兴奋性和抑制性成分，因此将允许我们测试组间分离。帮助精神疾病患者的工程技术的发展使该提案有资格在RAPD类别中考虑，因为它推动了创新，超越了当前与残疾有关的精神疾病研究的前沿知识。鉴于目前精神疾病的诊断完全依靠临床医生对患者自我报告的情绪的评估，因此是高度主观的，完全依赖于患者的依从性，这项研究的广泛社会影响在于利用功能神经成像技术的潜在能力，这可能是精神健康障碍诊断的革命性应用，为评估前驱风险提供客观和可量化的标准。治疗效果，并确定干净的表型用于基因研究。这个职业奖将允许我在接下来的五年里收集必要的数据，并迭代地开发和调整必要的计算工程工具，以领导这个关键的不断发展的研究领域的发展。更广泛的影响：2007年，国会授权国家科学院、国家工程院和医学研究所组成一个委员会，以应对在日益全球化的经济中保持科学创新和经济竞争力的相关挑战。对于这个职业生涯奖，我将重点讨论委员会提出的两个具体建议。其中一个行动项目是通过加强科学教师自身的科学和工程教育，加强儿童K-12科学技术准备。第二个行动项目是增加有资格和有动力攻读科学和工程研究生学习的个人总数。该职业奖将直接解决这两个行动项目。第一项行动项目将分三部分解决：(1)通过使用STELLA软件开发一个有趣和智力参与的七年级实践课程，以“基于系统的思维”；(2)通过暑期研习班培训科学教师使用课程；(3)通过在我们的网站上发布课程和研讨会资料的方式进行传播，并进行后续评估，以衡量课程的有效性。第二个行动项目将通过与佐治亚理工学院生物医学工程系建立一个合作项目来解决，以招募少数民族生物医学工程师进入我们的生物医学工程博士项目：首先作为暑期研究本科生，然后作为全日制学生。通过在实验室中训练学生在他们自己的研究中利用系统思维的好处，然后训练他们在更基本的水平上教授教师和初中学生同样的概念工具，我们能够最大限度地整合我们的研究和教育目标。

PI: Mujica-Parodi, LilianneProposal Number: 0954643PROJECT SUMMARYIntellectual Merit: For this proposal, we will develop and test computational methods for quantifying dysregulation between the excitatory and inhibitory components of the negative feedback loops in the brain that control homeostatic regulation of emotional arousal. This work conceptually integrates systems neuroscience with techniques originally developed for physics and engineering (power spectrum scale invariance, Shannon entropy) that have been successfully applied towards characterizing autonomic regulation via heart-rate variability analysis. Historically, neuroimaging has focused on measuring the amplitude of activation-levels in different regions of interest for some specific task. While in the past few years newer connectivity methods such as structural equation modeling, Granger causality, and dynamic causal modeling are important advances in investigating the temporal components of the time-series, these techniques are designed to investigate the strength of connections between node pairs. In contrast, our approach builds upon this work to answer a completely different type of question: to what degree does the system as a whole respond efficiently to perturbation in its maintenance of homeostasis? Our approach is explicitly motivated by the fact that many diseases-from diabetes to cancer to Cushing's disease-are dysregulatory in nature. As such, one technique that has enjoyed much diagnostic success is to "perturb" the system and then measure dynamic features of its return to baseline. In this proposal, we measure dysregulation of the limbic circuit, with neural timeseries obtained first from functional MRI and then near-infrared spectroscopy, in developing a neurobiologically-based instrument for objective and quantitative diagnosis of mental illness. The three patient groups with whom we will optimize our methods will include generalized anxiety disorder, major depression, and their comorbidity. These diagnostic choices provide a rational extension of our previous research on limbic dysregulation as a marker for individual variability in trait anxiety within the healthy population. Moreover, the symptoms associated with anxiety and depression have clearly-defined excitatory and inhibitory components with respect to physiological and behavioral arousal, and therefore will allow us to test dissociation between groups. The development of engineering techniques to assist individuals with psychiatric illness qualifies this proposal for consideration in the RAPD category as it advances innovation beyond the frontiers of current knowledge in disability-related research of mental illness. Given that psychiatric illnesses are currently diagnosed solely by clinicians' assessment of patients' self-reported moods, and therefore are highly subjective and wholly dependent upon patient compliance, the broad societal impact of this research lies in the potential ability to harness the functional neuroimaging technologies for applications that could be revolutionary in the diagnosis of mental health disorders, providing objective and quantifiable criteria for assessing prodromal risk, treatment efficacy, and identifying clean phenotypes for genetic research. This CAREER award would permit me, over the next five years, to collect the necessary data and to iteratively develop and adapt the computational engineering tools necessary to lead development in this critical evolving area of research.Broader Impact: In 2007, the National Academy of Science, National Academy of Engineering, andInstitute of Medicine were charged by Congress to form a committee to address the challenges associated with maintaining scientific innovation and economic competitiveness within an increasingly global economy. For this CAREER award, I will focus on addressing two specific recommendations made by this committee. One action item was to strengthen children's K-12 preparation in science and technology by enhancing the science and engineering education of the science teachers themselves. A second action item was to increase the total number of individuals qualified and motivated to pursue postgraduate study in science and engineering. This CAREER award will directly address both of these action items. The first action item will be addressed in three parts: (1) through the development of a fun and intellectually engaging hands-on 7th grade curriculum in "systems-based thinking" using STELLA software; (2) through training science teachers to use the curriculum during summer workshops; and, (3) through dissemination of the curriculum and workshop materials by posting them on our website and follow-up assessment to measure the curriculum's efficacy. The second action item will be addressed by setting up a collaborative program with the Georgia Institute of Technology Department of Biomedical Engineering to recruit minority biomedical engineers into our Biomedical Engineering Ph.D. program: first as summer-research undergraduates, and then as full-time students. By training students in the lab to exploit the benefits of thinking in terms of systems in their own research, and then training them to teach teachers and by extension junior high school students the same conceptual tools at a more basic level, we are able to integrate our research and educational goals to the fullest extent possible.