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; 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）：注意缺陷多动症（ADHD）是最常见的儿童发育障碍，影响了全球约5％的儿童。多动症是其核心症状，这是一个极大的公共卫生关注，包括增加冲动/多动和难以维持注意力，增加POR学术成就，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对疾病的早期检测和治疗至关重要。假设多动症是由功能失调的连通性引起的。但是，现有的研究有两个主要局限性：1）尽管参与者处于静止状态，但主要强调研究内在的连通性，尽管主要导师实验室的证据表明，在认知过程受损过程中连通性功能失调的连通性与行为缺陷相比，与内在连通性更密切相关； 2）大多数研究仅限于探测特定的网络或连接，尽管有充分的证据表明多动症与大脑的分布式异常有关。数学图理论工具在功能性神经成像数据中的开创性应用首次允许对大型大脑网络组织的复杂性质进行量化，当时患有多动症的儿童表现出最大的行为缺陷，可以在认知任务表现中进行评估。该候选人已成功地将理论分析应用于成人的fMRI数据，并在患有多动症儿童的儿童中进行了初步分析。该申请检验了以下假设：ADHD儿童在施加认知控制期间灵活地适应网络组织来转移认知需求的能力受损，从而导致行为缺陷 并观察到症状。这将通过使用创新的功能连接性和图理论工具来测试这一测试，以使ADHD和通常发育（TD）儿童的儿童的功能性神经影像学数据进行测试。第一个目标（K99）将在ADHD儿童的响应控制任务中表征大型神经组织。到2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培训来独立执行其余目标，并且将提交有关AIM 1的手稿。第二个目标（K99/R00）将量化组织从固有的，休息状态到ADHD儿童的反应控制任务的不同条件的变化。数据将进行独立分析，并在第3年完成的手稿完成。候选人还将建立她的独立实验室，向IRB提交人类受试者测试的申请，并创建招募AIM 3的基础架构。为AIM 3招募ADHD和TD儿童。第三个，探索性AIM（R00）将评估网络动态的变化，这些变化是由刺激儿童的变化和行为的变化，并在行为上进行了变化，并将这些变化的变化。在第4年的数据中，将收集并进行初步分析； AIM 3将在5年级完成。这些研究的结果将导致生物标志物的鉴定，以改善针对功能失调系统的ADHD的早期诊断和治疗方法，并将构成R00阶段编写的R01应用的基础。候选人接受了认知神经科学和高级功能MRI（fMRI）方法的培训，并进行了功能连通性和图理论分析，例如她提出的那些分析。她还拥有与TD儿童和临床人群合作的经验。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性神经影像学和发育障碍的转化研究提供了坚实的基础。候选人的临床培训将包括正式的课程，研讨会，诊所以及对ADHD儿童的招募和评估，行为技术的个人临床培训，以确保在行为和MRI测试期间合规，安全兴奋剂给药，以及对发育障碍的理论理解和治疗方法的理论理解。它将由她的主要导师斯图尔特·莫斯托夫斯基（Stewart Mostofsky）博士领导，斯图尔特·莫斯托夫斯基（Stewart Mostofsky）博士是肯尼迪·克里格研究所（KKI）和约翰·霍普金斯大学（JHU）的儿科神经科医生兼临床研究员，其研究重点介绍了神经影像学和认知功能障碍，并由KKI/JHU Clinical Clinical Clinical Clinical Clinical Clinical Clins Drss Drops Dress Dress Dress Dress Progents in Developmental Brain Disorders中。 Mark Mahone和Keith Slifer和儿童精神科医生Roma Vasa博士（顾问）。她将获得其他培训，以补充她本已强大的fMRI方法论知识基础，重点是功能连接性和图形理论分析，由她的同事Mark D'Esposito博士领导，Mark D'Esposito博士是加利福尼亚大学伯克利分校（UCB）的临床神经科医生和研究人员（UCB）的研究，其研究重点是脑电流和发展方法，以及脑电路的影响，以及脑电图的效果，以及脑电流的效果，FMRIID FRM的效果， JHU的生物统计学家Caffo和UCB的物理学家兼应用数学家Fernando Perez博士（顾问）。候选人的培训还将提高她的科学写作和演讲能力。该培训将确保拟议的R00研究 可以独立实施。互相合作的候选人的导师都有强大的往绩记录，使研究员成为独立调查员，并强烈致力于将候选人转变为独立。 KKI是一家世界知名的研究所，专注于与JHU紧密联系的发育障碍研究，是一个理想的地理位置，候选人可以在该研究方面接受有关发育障碍研究的临床方面的出色培训，并培训以补充其方法论技能。该研究申请和培训计划的完成将使她能够获得与她成为发育障碍，认知神经科学和先进神经影像学方法的独立研究者有关的目标。