Large-Scale Brain Organization During Cognitive Control in ADHD

ADHD 认知控制期间的大规模大脑组织

• 批准号: 8765341
• 负责人: Jessica R Cohen
• 金额: $ 9.3万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8765341
• 关键词: Academic achievement; Adult; Affect; Anatomy; Attention; Attention deficit hyperactivity disorder; Base of the Brain; Behavior; Behavioral; Biological; Biological Markers; Brain; Brain Diseases; Brain region; California; Child; Childhood; Clinic; Clinical; Clinical Investigator; Cognitive; Commit; Communication; Complex; Data; Development; Developmental Therapeutics Program; Diagnosis; Diffuse; Disease; Dorsal; Early Diagnosis; Early treatment; Ensure; Exertion; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Graph; Health; Health Care Costs; Hyperactive behavior; Impaired cognition; Impulsivity; Individual; Institutes; Institutional Review Boards; Investigation; Knowledge; Laboratories; Lead; Location; Longitudinal Studies; Magnetic Resonance Imaging; Manuscripts; Mathematics; Mentors; Methodology; Methods; Metric; Neurologist; Outcome; Parietal; Participant; Patients; Pattern; Performance; Pharmaceutical Preparations; Phase; Population; Process; Property; Psychiatrist; Psychologist; Public Health; Records; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Rest; Risk; Schools; Solid; Substance abuse problem; Symptoms; System; Task Performances; Techniques; Testing; Thick; Time; Training; Translational Research; Tweens; Universities; Work; Writing; base; cognitive control; cognitive neuroscience; criminal behavior; developmental disease; effective therapy; experience; human subject; imaging modality; improved; innovation; knowledge base; neuroimaging; neuromechanism; relating to nervous system; response; skills; social; success; tool

DESCRIPTION (provided by applicant): Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed developmental disorder of childhood, affecting ~5% of children worldwide. ADHD is a great public health concern as its core symptoms, which include increased impulsivity/hyperactivity and difficulty in sustaining attention, increase the risk for por academic achievement, substance abuse, and criminal behavior. Research into the neural basis of ADHD is crucial to improve early detection and treatment of the disorder. ADHD is hypothesized to result from dysfunctional connectivity. However, there are two main limitations with extant research: 1) there is a large emphasis on studying intrinsic connectivity while participants are at rest, despite evidence from the primary mentor's lab that dysfunctional connectivity during impaired cognitive processes is more strongly related to behavioral deficits than intrinsic connectivity; and 2) most research is limited to probing specific networks or connections despite strong evidence that ADHD is associated with a distributed pattern of abnormality across much of the brain. The groundbreaking application of mathematical graph theoretical tools to functional neuroimaging data allows for the first time the quantification of complex properties of large-scale brain network organization that can be assessed during cognitive task performance, when children with ADHD display the greatest behavioral deficits. The candidate has successfully applied graph theoretical analyses to fMRI data in adults, and has conducted preliminary analyses in children with ADHD. This application tests the hypothesis that children with ADHD are impaired in the ability to flexibly adapt network organization to shifting cognitive demands during the exertion of cognitive control, leading to behavioral deficits and observed symptoms. This will be tested by employing innovative functional connectivity and graph theoretical tools to functional neuroimaging data in children with ADHD and typically developing (TD) children. The first aim (K99) will characterize large-scale neural organization during a response control task in children with ADHD. By the end of year 2 the data for aims 1 and 2 will be collected, the candidate will have received sufficient clinical and methodological training to execute the remaining aims independently, and a manuscript regarding aim 1 will have been submitted. The second aim (K99/R00) will quantify the change in organization from an intrinsic, resting state to different conditions of a response control task in children with ADHD. The data will be independently analyzed and a manuscript completed during year 3. The candidate will also set up her independent laboratory, submit an IRB application for human subjects testing, and create the infrastructure necessary to recruit ADHD and TD children for aim 3. The third, exploratory aim (R00) will assess the changes in network dynamics that result from stimulant administration in children with ADHD and how those changes relate to changes in behavior. In year 4 data will be collected and initial analyses conducted; aim 3 will be completed in year 5. Results from these studies will lead to the identification of biomarkers to improve early diagnosis of ADHD and treatments targeting the dysfunctional systems, and will form the basis of an R01 application written during the R00 phase. The candidate is trained in cognitive neuroscience and advanced functional MRI (fMRI) methodology and has conducted functional connectivity and graph theoretical analyses such as those she is proposing. She also has experience working with TD children and clinical populations. The proposed training will fill gaps in the candidate's current knowledge and provide a solid basis for her to independently conduct translational research in functional neuroimaging and developmental disorders. The candidate's clinical training will include formal coursework, seminars, clinics, and individual clinical training in the recruitment and assessment of children with ADHD, behavioral techniques to ensure compliance during behavioral and MRI testing, safe stimulant administration, and theoretical understanding of developmental disorders and therapeutic approaches. It will be led by her primary mentor, Dr. Stewart Mostofsky, a pediatric neurologist and clinical investigator at Kennedy Krieger Institute (KKI) and Johns Hopkins University (JHU) whose research focuses on neuroimaging and cognitive dysfunction in developmental brain disorders, and supplemented by KKI/JHU clinical psychologists Drs. Mark Mahone and Keith Slifer and child psychiatrist Dr. Roma Vasa (consultants). She will receive additional training to supplement her already strong knowledge base of advanced fMRI methodology, with a focus on functional connectivity and graph theoretical analyses, led by her co-mentor, Dr. Mark D'Esposito, a clinical neurologist and researcher at the University of California, Berkeley (UCB) whose research focuses on the effects of disruptions to brain circuitry and developing multivariate fMRI methodology, and supplemented by Dr. Brian Caffo, a biostatistician at JHU, and Dr. Fernando Perez, a physicist and applied mathematician at UCB (consultants). The candidate's training will also enhance her scientific writing and presentation skills. This training will ensure that the proposed R00 studies can be implemented independently. Both the candidate's mentors, who collaborate with each other, have strong track records supervising fellows into becoming independent investigators and are strongly committed to transitioning the candidate to independence. KKI, a world-renowned institute focusing on research of developmental disorders with close ties to JHU, is an ideal location in which the candidate can receive outstanding training in the clinical aspects of research on developmental disorders, as well as training to supplement her methodological skills. Completion of this research application and training plan will enable her to gain proficiency relevant to her goal of becoming an independent investigator in the fields of developmental disorders, cognitive neuroscience, and advanced neuroimaging methodologies.

描述（由申请人提供）：注意力缺陷多动障碍 (ADHD) 是最常见的儿童发育障碍，影响全球约 5% 的儿童。 ADHD 是一个重大的公共卫生问题，因为它的核心症状包括冲动/多动和难以持续注意力增加，增加学业成就、药物滥用和犯罪行为的风险。对 ADHD 神经基础的研究对于改善该疾病的早期发现和治疗至关重要。据推测，多动症是由连接功能失调引起的。然而，现有研究存在两个主要局限性：1）尽管主要导师实验室的证据表明，认知过程受损期间的功能障碍连接与行为缺陷的相关性比行为缺陷更密切，但仍然非常重视研究参与者休息时的内在连接。内在的连通性； 2）尽管有强有力的证据表明多动症与大脑大部分区域的分布异常模式有关，但大多数研究仅限于探索特定的网络或连接。数学图论工具在功能性神经影像数据中的突破性应用首次允许对大规模大脑网络组织的复杂特性进行量化，这些特性可以在认知任务执行过程中进行评估，此时多动症儿童表现出最大的行为缺陷。该候选人已成功将图论分析应用于成人的功能磁共振成像数据，并对患有多动症的儿童进行了初步分析。该应用程序测试了这样一个假设：患有多动症的儿童在认知控制过程中灵活调整网络组织以适应不断变化的认知需求的能力受到损害，从而导致行为缺陷 并观察症状。这将通过采用创新的功能连接和图论工具来测试多动症儿童和典型发育（TD）儿童的功能神经影像数据。第一个目标 (K99) 将描述 ADHD 儿童的反应控制任务期间的大规模神经组织特征。到第 2 年年底，将收集目标 1 和 2 的数据，候选人将接受足够的临床和方法学培训以独立执行其余目标，并且将提交有关目标 1 的手稿。第二个目标 (K99/R00) 将量化 ADHD 儿童从内在的静息状态到反应控制任务的不同条件的组织变化。数据将在第三年进行独立分析并完成手稿。候选人还将建立自己的独立实验室，提交人体受试者测试的 IRB 申请，并创建必要的基础设施来招募 ADHD 和 TD 儿童以实现目标 3。 ，探索性目标（R00）将评估 ADHD 儿童服用兴奋剂所导致的网络动态变化，以及这些变化与行为变化的关系。第 4 年将收集数据并进行初步分析；目标 3 将在第 5 年完成。这些研究的结果将导致生物标志物的识别，以改善 ADHD 的早期诊断和针对功能失调系统的治疗，并将构成 R00 阶段编写的 R01 应用程序的基础。该候选人接受过认知神经科学和高级功能磁共振成像 (fMRI) 方法方面的培训，并进行了功能连接和图论分析，例如她所提议的分析。她还拥有治疗 TD 儿童和临床人群的经验。拟议的培训将填补候选人当前知识的空白，并为她独立进行功能神经影像和发育障碍的转化研究提供坚实的基础。候选人的临床培训将包括在招募和评估 ADHD 儿童方面的正式课程、研讨会、诊所和个人临床培训、确保行为和 MRI 测试期间合规的行为技术、安全兴奋剂管理以及对发育障碍和治疗的理论理解。接近。该项目将由她的主要导师 Stewart Mostofsky 博士领导，他是肯尼迪克里格研究所 (KKI) 和约翰霍普金斯大学 (JHU) 的儿科神经学家和临床研究员，其研究重点是发育性脑疾病的神经影像学和认知功能障碍，并辅以KKI/JHU 临床心理学家 Drs.马克·马洪 (Mark Mahone) 和基思·斯莱弗 (Keith Slifer) 以及儿童精神病学家罗马·瓦萨 (Roma Vasa) 博士（顾问）。她将接受额外的培训，以补充她在先进功能磁共振成像方法方面已经很强大的知识基础，重点是功能连接和图论分析，由她的共同导师 Mark D'Esposito 博士领导，他是该大学的临床神经学家和研究员加州大学伯克利分校 (UCB) 的研究重点是大脑回路中断的影响和开发多变量功能磁共振成像方法，并得到约翰霍普金斯大学生物统计学家 Brian Caffo 博士和 Fernando 博士的补充Perez，UCB 的物理学家和应用数学家（顾问）。候选人的培训还将提高她的科学写作和演示技能。该培训将确保拟议的 R00 研究 可以独立实施。候选人的两位导师相互合作，在监督研究员成为独立调查员方面拥有良好的记录，并坚定致力于使候选人过渡到独立。 KKI 是一家与 JHU 关系密切的专注于发育障碍研究的世界知名机构，是一个理想的场所，候选人可以在其中接受发育障碍研究临床方面的出色培训，以及补充其方法技能的培训。完成这项研究应用和培训计划将使她能够熟练掌握与成为发育障碍、认知神经科学和先进神经影像方法学领域的独立研究者的目标相关的知识。