fMRI Studies of Pediatric Mood and Anxiety Disorders

儿科情绪和焦虑症的功能磁共振成像研究

• 批准号: 10012694
• 负责人: Daniel Pine
• 金额: $ 214.67万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10012694
• 关键词: Adolescent; Adult; Amygdaloid structure; Animal Model; Anxiety; Anxiety Disorders; Area; Attention; Behavior; Biology; Brain; Brain imaging; Brain region; Child; Child Welfare; Childhood; Clinical; Clinical Trials; Cognitive Therapy; Collaborations; Data; Development; Disease; Emotional; Exhibits; Extinction (Psychology); Extramural Activities; Functional Magnetic Resonance Imaging; Functional disorder; Grant; Impairment; Individual Differences; Measures; Memory; Mental disorders; Methods; Monitor; Mood Disorders; Moods; National Institute of Mental Health; Neurocognitive; Neuropsychology; Neurosciences; Paper; Parahippocampal Gyrus; Pathway interactions; Patient Care; Patients; Prefrontal Cortex; Protocols documentation; Psychopathology; Public Health; Publications; Publishing; Randomized; Randomized Controlled Trials; Reporting; Research; Series; Site; Specificity; Standardization; Stimulus; Syndrome; Techniques; Testing; Therapeutic; Time; Treatment outcome; United States National Institutes of Health; Universities; Wisconsin; Work; Youth; anxious; attentional bias; attentional modulation; base; childhood anxiety; cingulate gyrus; clinical practice; cognitive training; conditioned fear; effective therapy; imaging study; insight; interest; neural circuit; neural correlate; novel; novel therapeutics; patient response; recruit; relating to nervous system; response; success; treatment response

This work is conducted under protocol 01-M-0192, NCT00018057. We are using functional magnetic resonance imaging (fMRI) to examine neurocognitive correlates of pediatric anxiety disorders. Through ongoing collaborative studies, we also have increasingly compared findings in these syndromes with findings in adult anxiety disorders as well as findings in other pediatric mental disorders, particularly mood disorders. Through collaborative work, this allows us to examine the similarities and differences between pediatric and adult mood and anxiety disorders. From this vantage point, studies conducted at the NIH as part of this protocol focus most narrowly and deeply on pediatric anxiety disorders. On the other hand, studies conducted with collaborators focus most deeply on adult anxiety disorders and mood or other psychiatric disorders in children and adolescents. Finally, the current protocol also has generated key insights on novel treatments. Moreover, these new treatments are now being studied in the context of brain-imaging research. As a result, the protocol also focuses quite deeply on the manner in which effective treatment changes these neural correlates so that research on novel therapeutics might target such neural correlates. The work performed under this protocol and with the many associated collaborators holds the potential to dramatically impact public health, for various reasons. Mood and anxiety disorder dramatically alter the well-being of children and adolescents. Nevertheless, relatively little work has been conducted on the underlying pathophysiology of these conditions, using methods that allow direct extensions to work in basic neuroscience. fMRI research is vital for work in this area. Such research assesses brain function in children using methods that are directly comparable to the techniques used to study brain function in animal models. There is a particularly pressing need to use understandings from neuroscience to generate new ideas about treatment. Work in this protocol holds the hope of generating these insights, specifically in ways that will lead to novel treatment discovery. This hope has increased in recent years for various reasons. For example, work in this protocol and related studies has discovered replicable perturbations that might be targeted by novel treatments, identified through the confluence of findings in animal models and children. In the current protocol, such work has focused on extinction, as it relates to cognitive behavioral therapy, and attention bias, as it relates to both cognitive behavioral therapy and cognitive training. As such, this protocol defines a promising pathway for generating treatments that may alter clinical practice. In the past three years, we have published multiple papers that demonstrate such promise, by targeting aspects of attention, extending research completed in prior years; three randomized controlled trials were published in this area through work with collaborators; this follows from highly similar randomized controlled trials published in prior years. For work completed at the NIH, we target randomized controlled trials where data also are acquired using data from brain imaging. In this way, we are directly connecting a measure of brain function to a measure of treatment response, one very important potential breakthrough that is directly relevant to patient care. As such, this protocol demonstrates the potential importance of embedding a clinical trial within a brain imaging study. Finally, in the current year, we devoted considerable efforts to another randomized controlled trial that is heavily recruiting subjects. Currently, we have randomized more than 60 subjects in a study that will be completed after we have randomized 120 subjects. The central focus of the protocol is on individual differences in neural circuitry function, as they relate to individual differences in behavior and clinical response to treatment. Replicated findings from this project clearly implicate many such deficits in anxiety, moving research on developmental psychopathology into the domain of neuroscience. This shows that individual differences in behavior firmly relate to individual differences in brain function. In the past five years, our focus has been on extending attention-based and fear-conditioning work, in ways that most directly inform therapeutics. As noted above, this has led us to implement novel therapies. We have also devoted considerable time in the protocol to questions on disorder specificity, with a particular focus on comparing mood and anxiety-related problems in the past two years. Prior neuropsychological studies in children as well as in adults note that mood and anxiety disorders are associated with deficits in attention modulation and emotional memory. We have found consistent evidence of such deficits in the current protocol. Moreover, prior imaging studies in healthy adults show that tasks requiring attention modulation or emotional memory engage cortico-limbic brain regions previously implicated in adult mood and anxiety disorders. These regions include the amygdala, ventral prefrontal cortex, cingulate gyrus, and hippocampus. Once again, we also find such evidence in the current set of projects, with multiple, replicated reports of cortico-limbic dysfunction in both pediatric and adult anxiety disorders. This shows that fMRI attention modulation and emotional memory paradigms differentially engage cortico-limbic brain regions in psychiatrically healthy and anxious, impaired subjects. These studies are ongoing in more than 500 subjects. For these subjects, each received neurocognitive examinations, and a subset received fMRI examinations. Each also received standardized assessments of response to treatment. As part of our studies in healthy subjects, we also successfully developed each of the fMRI protocols that will be used in the current project. We have a particularly strong interest in studying reliability of brain function, as assessed with fMRI. In recent years, we have been able to develop paradigms with acceptable levels of reliability. In the past year, we used such paradigms to focus our work in patients on brain functions that we have found to be reliable. Such work is highly important, since treatment-related brain imaging research benefits greatly from the ability to identify reliable perturbations in brain function among patients. As noted above, using these methods, many of our initial hypotheses have been confirmed, and our studies are now moving forward to examine issues of specificity and to consider how our findings might be used to inform advances in treatment. This focus has led to the publication of two notable brain-imaging papers in the past year that compare findings in anxiety and mood-related psychopathology among youth. Finally, within the past year, we have begun a large-scale collaboration. This collaboration is supported by an extramural grant that allows Vanderbilt University and the University of Wisconsin to work with our NIMH site to attempt to replicate findings across our three groups. This will generate data in approximately 500 young people on the biology of anxiety, as delineated in our work over the past 15 years. These efforts have already generated a series of important publications. During the coming year, we will devote most of our time to building on the successes of our past work. This includes continuing our recently initiated studies of novel treatments, monitoring ongoing efforts in our multi-site study, and implementing additional studies of disorder specificity.

这项工作是根据协议01-M-0192，NCT00018057进行的。 我们正在使用功能性磁共振成像（fMRI）来检查小儿焦虑症的神经认知相关性。通过正在进行的合作研究，我们还越来越多地将这些综合症的发现与成人焦虑症的发现以及其他儿科精神障碍（尤其是情绪障碍）的发现进行了比较。通过协作工作，这使我们能够研究儿科和成人情绪和焦虑症之间的相似性和差异。从这个有利的角度来看，作为该方案的一部分，在NIH进行的研究最狭义地关注小儿焦虑症。另一方面，与合作者进行的研究最重视儿童和青少年的成人焦虑症，情绪或其他精神疾病。最后，当前的方案还产生了对新型治疗方法的关键见解。 此外，现在正在研究这些新疗法在大脑成像研究的背景下进行研究。 结果，该方案还非常重视有效治疗改变这些神经相关的方式，因此对新型治疗剂的研究可能针对这种神经相关性。 由于各种原因，根据该协议进行的工作以及许多相关的合作者具有显着影响公共卫生的潜力。情绪和焦虑症极大地改变了儿童和青少年的幸福感。然而，使用允许直接扩展在基本神经科学中起作用的方法，对这些疾病的潜在病理生理学进行了相对较少的工作。 fMRI研究对于该领域的工作至关重要。此类研究使用与研究动物模型中用于研究大脑功能的技术直接相当的方法评估儿童的大脑功能。 特别需要利用神经科学的理解来产生有关治疗的新想法。 该协议中的工作希望能够产生这些见解，特别是以导致新的治疗发现的方式。近年来，由于各种原因，这种希望有所增加。例如，该方案和相关研究中的工作发现了可复制的扰动，这些扰动可能是通过新型治疗方法来瞄准的，这些疗法通过动物模型和儿童的发现汇合而识别。在当前的方案中，这种工作集中在灭绝上，因为它与认知行为疗法和注意力偏见有关，因为它与认知行为疗法和认知训练有关。因此，该协议定义了一种有希望的途径，用于生成可能改变临床实践的治疗方法。在过去的三年中，我们发表了多篇论文，通过针对关注的各个方面，扩展了前几年完成的研究，这些论文证明了这种诺言。通过与合作者的合作，在该领域发表了三项随机对照试验；这是从上几年发表的高度相似的随机对照试验中进行的。对于在NIH完成的工作，我们针对随机对照试验，其中还使用来自脑成像的数据获取数据。这样，我们将脑功能的度量与治疗反应的度量联系起来，这是与患者护理直接相关的一个非常重要的潜在突破。因此，该方案证明了将临床试验嵌入大脑成像研究中的潜在重要性。最后，在当年，我们为另一个正在招募主题的随机对照试验做出了相当大的努力。 目前，我们在一项研究中将完成120名受试者后将完成的60多名受试者。 该方案的主要重点是神经回路功能的个体差异，因为它们与行为和对治疗的临床反应有关。该项目的复制发现清楚地暗示了许多此类焦虑中的缺陷，将发育心理病理学的研究转移到神经科学领域。这表明行为的个体差异与大脑功能的个体差异牢固有关。在过去的五年中，我们的重点一直在以最直接为治疗疗法的方式扩展基于注意力的和恐惧条件的工作。如上所述，这使我们实施了新颖的疗法。我们还将大量时间用于有关疾病特异性的问题，特别着重于比较过去两年中与情绪和焦虑有关的问题。 先前在儿童以及成年人中的神经心理学研究指出，情绪和焦虑症与注意调节和情绪记忆的缺陷有关。我们发现了当前协议中此类缺陷的一致证据。此外，健康成年人的先前成像研究表明，需要注意调节或情绪记忆的任务与以前涉及成人情绪和焦虑症有关的皮质膜大脑区域。这些区域包括杏仁核，腹前额叶皮层，扣带回和海马。再次，我们在当前的一组项目中也发现了此类证据，并在儿科和成人焦虑症中都有多次复制的皮质 - 纤维膜功能障碍的报道。这表明fMRI注意力调节和情感记忆范式差异化使皮质膜脑区域与精神病健康和焦虑，受损的受试者参与。这些研究正在进行500多名受试者。对于这些受试者，每个受试者都接受了神经认知检查，并接受了fMRI检查。每个人还接受了对治疗反应的标准化评估。作为在健康受试者研究的一部分，我们还成功地开发了当前项目中将使用的每种fMRI方案。通过fMRI评估，我们对研究大脑功能的可靠性特别有兴趣。 近年来，我们已经能够开发具有可接受的可靠性水平的范例。 在过去的一年中，我们使用这样的范例将我们的工作集中在患者上，这是我们发现可靠的脑功能。 这种工作非常重要，因为与治疗相关的大脑成像研究从识别患者大脑功能的可靠扰动的能力受益匪浅。 如上所述，使用这些方法，我们的许多最初假设已得到证实，我们的研究现在正在前进，以研究特殊性问题，并考虑如何使用我们的发现来为治疗的进展提供信息。在过去的一年中，这一重点导致了两篇著名的大脑图像论文，这些论文比较了青年中焦虑和与情绪有关的心理病理学的发现。 最后，在过去的一年中，我们开始进行大规模合作。 这项合作得到了校外资助的支持，该赠款使范德比尔特大学和威斯康星大学可以与我们的NIMH网站合作，试图在我们的三个小组中复制发现。 这将在过去15年中的工作中描绘出大约500名年轻人的数据。 这些努力已经产生了一系列重要的出版物。 在来年，我们将大部分时间都花在过去工作的成功上。这包括继续我们最近开始对新型治疗方法的研究，监测我们多站点研究中的持续努力，以及对疾病特异性的其他研究。