The Pathophysiology and Treatment Of Children With Severe Mood Dysregulation

儿童严重情绪失调的病理生理学和治疗

• 批准号: 8342129
• 负责人: Ellen Leibenluft
• 金额: $ 155.7万
• 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/8342129
• 关键词: Address; Adopted; Adult; Adverse effects; Amygdaloid structure; Anger; Anterior; Antidepressive Agents; Anxiety; Anxiety Disorders; Attention; Attention deficit hyperactivity disorder; Behavior; Bipolar Disorder; Borderline Personality Disorder; Brain; Brain region; Bronchopulmonary Dysplasia; Characteristics; Child; Child Psychiatry; Chronic; Citalopram; Classification; Clinical; Clinical Trials; Clinical Trials Design; Data; Depressive disorder; Development; Diagnosis; Diagnostic; Double-Blind Method; Emotional; Emotions; Exhibits; Face; Face Processing; Failure; Family; Feedback; Fostering; Frontal gyrus; Frustration; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Hospitalization; Impairment; Inferior frontal gyrus; Intervention; Label; Lithium; Magnetoencephalography; Manic; Measures; Medial; Mediating; Mood Disorders; Moods; Names; National Institute of Mental Health; Nature; Outpatients; Parents; Patients; Pharmaceutical Preparations; Placebos; Play; Problem behavior; Process; Psychiatry; Public Health; Publications; Publishing; Randomized; Recording of previous events; Recruitment Activity; Relative (related person); Reporting; Research; Research Design; Resolution; Rewards; Risk; Role; Stimulus; Sum; Symptoms; Syndrome; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Training; Unipolar Depression; Visit; Work; Youth; atypical antipsychotic; behavior test; cingulate cortex; effective therapy; emotional stimulus; environmental change; experience; flexibility; inhibitor/antagonist; interest; meetings; neural circuit; neuroimaging; neuromechanism; novel; patient population; response; reuptake; standardize measure; treatment response

As noted above, in response to the concern about the appropriate diagnosis for children with chronic, severe irritability, we defined a group of children whom we described as having severe mood dysregulation (SMD). These children have extremely severe irritability and symptoms of hyperarousal (the latter being similar to those seen in attention deficit hyperactivity disorder (ADHD)) and, although they frequently receive the diagnosis of bipolar disorder (BD), they do not indeed meet diagnostic criteria for BD. Since the inception of this project, approximately 200 youth with SMD have been recruited into the project. Approximately 20 new patients were recruited this year. It is very important to note that these youth with SMD suffer very severe psychiatric impairment, and indeed are as ill as are youth with BD in terms of number of medications prescribed, number of psychiatric hospitalizations, and standardized measures of function. Also as noted above, in previous years we demonstrated differences between youth with SMD and those with BD in terms of clinical course, family history, and the brain mechanisms associated with behavioral problems. This year we gathered more data to support the conclusion that, while youth with SMD and those with BD both have severe mood disorders, the two groups differ in the nature of their brain dysfunction. In prior work, we demonstrated that youth with BD or SMD, but not those with other psychiatric illnesses, have deficits in face emotion labeling. This year we published data supporting previous findings indicating that, while BD and SMD have similar deficits in face labeling, the neural mechanisms mediating face emotion processing differ between groups. Specifically, when viewing angry faces, youth with BD showed decreased amygdala activation relative to youth with SMD or healthy subjects. This publication is in press. Consistent with this, in another study being prepared for publication, we found that, in healthy subjects, amygdala activity varied in response to increasing degrees of anger on a face, but that youth with BD and those with SMD both fail to show such brain modulation by the emotional content of the face. This failure to modulate brain activity in response to the level of emotion in a stimulus is consistent with the clinical presentation of these patient populations, which is characterized by an inability to modulate emotional responses. In addition to this work on face processing, this year we also compared the groups on brain activity during a task that requires subjects to respond flexibly to changes in which of their behaviors are rewarded. Both of our patient populations show deficits on such response flexibility tasks, and it is possible that these deficits contribute to the frustration experienced by youth with SMD. That is, youth with SMD may become frustrated and irritable because they are unable to respond appropriately to ever-changing environmental demands. Using fMRI in conjunction with a response reversal paradigm, we found that youth with SMD differed from healthy subjects and those with BD on activation in the inferior frontal gyrus, a brain region that is centrally involved in response flexibility. Given the central role that excessive responses to frustration play in the symptomatology of SMD, additional neuroimaging studies focus very directly on the brain dysfunction associated with frustration in SMD. Specifically, this year we published data comparing youth with SMD, those with BD, and healthy subjects on magnetoencephalography (MEG) measures obtained while the children played a frustrating game. Like fMRI, MEG is a noninvasive neuroimaging technique; the advantage of MEG is that it has exquisite temporal resolution. The results of this MEG study indicated that, during the game, youth with SMD reported more frustration than did BD or healthy subjects. In addition, in response to negative feedback, SMD experienced greater activation in the medial frontal gyrus and anterior cingulate cortex than did the other two groups. This indicates that negative feedback may be particularly salient to youths with SMD. Consistent with this, preliminary data from an fMRI study using the same task indicates that, when frustrated, youth with SMD experience considerable dysfunction in brain regions mediating attention (these data are currently being prepared for publication). This raises the possibility that a treatment aimed at training irritable youth to control their attention more effectively when frustrated might have therapeutic effects, although considerably more research needs to be conducted to confirm the feasibility and appropriateness of this approach. The fact that youth with SMD share many symptoms with youth with attention deficit hyperactivity disorder (ADHD), as well as an increasing emphasis on dimensional, rather than categorical, classification in psychiatry, is an important impetus for a new research approach that we began to adopt this year and will continue in the coming year. Consistent with the Research Domain Criteria initiative of the NIMH, this year we laid groundwork so that our research in the next year will adopt a dimensional approach to irritability, studying not just youth with SMD and healthy youth, but also youth with different levels of irritability. And, in doing so, we will control for the fact that SMD youth have ADHD symptoms. That is, we will recruit youth with ADHD and varying levels of irritability, as well as those with SMD, to participate in studies designed to further elucidate the brain mechanisms mediating frustration. Finally, from a public health perspective, it is essential to determine whether the distinction between SMD and BD, which is evident in terms of clinical course, family history, and neural circuitry, is also associated with between-group differences in treatment response. In previous work, we found that lithium was not effective in the treatment of SMD. Last year, we began a double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor antidepressant) plus stimulant is more effective than placebo plus stimulant in the treatment of SMD. Thus far, we have randomized approximately 20 children into the trial, and youth are tolerating the experimental treatment well.

如上所述，为了应对对患有慢性，严重烦躁的儿童的适当诊断的关注，我们定义了一群孩子，我们描述的是严重的情绪失调（SMD）。 这些儿童具有极严重的烦躁和高伴症状（后者类似于注意力缺陷多动障碍（ADHD）），尽管他们经常接受双相情感障碍（BD）的诊断，但他们确实不符合BD的诊断标准。自该项目成立以来，已将大约200名SMD青年招募到该项目中。今年招募了大约20名新患者。非常重要的是要注意，这些患有SMD的年轻人遭受了非常严重的精神障碍，实际上，在规定的药物数量，精神病医院的数量和功能措施方面，BD的年轻人也像BD一样病。另外，如上所述，在往年，我们在临床过程，家族史以及与行为问题相关的大脑机制方面表现出了SMD青年与BD患者之间的差异。 今年，我们收集了更多数据，以支持以下结论：尽管SMD和BD患者都患有严重的情绪障碍，但两组的大脑功能障碍性质有所不同。 在先前的工作中，我们证明了患有BD或SMD的年轻人，但没有其他精神病患者的年轻人在面部情感标签中存在缺陷。今年，我们发布了支持先前发现的数据，表明尽管BD和SMD在面部标记中具有相似的缺陷，但介导的面部情感处理的神经机制在组之间有所不同。具体来说，当观看愤怒的面孔时，与SMD或健康受试者的年轻人相比，BD的青年激活杏仁核的激活下降。 该出版物在印刷中。与此一致，在另一项准备发表的研究中，我们发现，在健康的受试者中，杏仁核活动因脸部越来越多的愤怒而有所不同，但是BD和SMD的年轻人都无法通过面部的情感内容显示出这种大脑调节。这种未能根据刺激中的情绪水平调节大脑活动的失败与这些患者人群的临床表现一致，这的特征是无法调节情绪反应。 除了面对处理方面的这项工作外，今年我们还比较了在任务过程中大脑活动的组，该任务要求受试者对自己的行为的变化灵活地响应。我们的两个患者群体都表现出这种反应灵活性任务的缺陷，并且这些缺陷可能导致SMD青年遇到的挫败感。也就是说，患有SMD的青年可能会感到沮丧和烦躁，因为他们无法对不断变化的环境需求做出适当的反应。使用fMRI与响应逆转范式结合使用，我们发现，SMD的青年与健康受试者和BD激活的受试者有所不同，而在下额回中，这是一个大脑区域，这是一个集中参与响应灵活性的大脑区域。 鉴于对SMD症状中过度反应的核心作用，因此，其他神经影像学研究非常直接关注与SMD挫败感相关的脑功能障碍。具体来说，今年我们发布了数据，将年轻人与SMD，BD的年轻人，具有磁脑摄影（MEG）的健康受试者（MEG）措施进行了比较，而孩子们玩了令人沮丧的游戏。像fMRI一样，MEG是一种无创神经影像学技术。 MEG的优点是它具有精美的时间分辨率。这项MEG研究的结果表明，在游戏期间，SMD的青年比BD或健康受试者更加沮丧。此外，对于负反馈，SMD在内侧额叶和前扣带回皮层中的激活比其他两组更大。 这表明负面反馈可能对SMD的年轻人特别重要。与此相一致的是，来自功能磁共振成像研究的初步数据使用相同的任务表明，在沮丧时，SMD的年轻人在大脑区域中经历了相当大的功能障碍，从而介导了注意力（这些数据目前正在准备出版）。这增加了一种旨在训练烦躁的青年治疗的可能性，以便在沮丧时会更有效地控制他们的注意力，尽管需要进行更多的研究以确认这种方法的可行性和适当性。 SMD的青年与患有注意力缺陷多动障碍（ADHD）的年轻人共享许多症状，并且越来越强调精神病学的尺寸而不是绝对的分类，这是我们今年开始采用的新研究方法的重要动力，并将在今年继续进行。与NIMH的研究领域标准倡议一致，今年我们为明年的研究提供了基础，将采用一种维度方法来烦躁，不仅研究具有SMD和健康青年的青年，而且研究具有不同水平烦恼的青年。 而且，这样一来，我们将控制SMD青年患有多动症症状的事实。 也就是说，我们将招募患有多动症和不同水平的烦躁和SMD的青年，以参与旨在进一步阐明介导挫败感的大脑机制的研究。 最后，从公共卫生的角度来看，必须确定SMD和BD之间的区别是否与临床课程，家族史和神经电路相似，这也与治疗反应的组间差异有关。在先前的工作中，我们发现锂在治疗SMD方面无效。去年，我们开始了一项双盲试验，旨在确定Citalopram（血清素能抑制剂抗抑郁药）加上刺激剂是否比安慰剂加刺激剂在治疗SMD方面更有效。到目前为止，我们已经将大约20名儿童随机分为试验，而青年人却可以很好地容忍实验治疗。