Fronto-Limbic Brain of Bipolar Children and Adolescents

在成人的神经影像学研究中，涉及情绪调节的额边缘脑（FLB）区域的缺失与双相情感障碍（BD）有关。这些FLB变化是随着BD的发展而发展的，还是在BD开发的早期就出现了？后者表明：（1）大脑成熟过程中的发育异常可能导致这些FLB变化。如果是这样，那么（2）在疾病过程早期减少或减轻这些大脑变化的治疗可能会降低BD的严重程度。为了检验这些假设，我们将在青春期后BD青少年（年龄12-17岁）（BD青少年）中进行一项联合体内神经影像学和临床干预试验，该试验将检查（a）FLB异常、（B）BD进展和严重程度以及（c）对情绪稳定药物（丙戊酸盐）的反应之间的关系。我们将研究60例未经治疗的BD 青少年和60名匹配的健康对照。30名BD患者将不患有共病的注意缺陷多动障碍（ADHD）、对立违抗性障碍（ODD）和/或行为障碍（CD），而另外30名患者将患有这些共病。除了强迫症（OCD）和创伤后应激障碍（PTSD）外，两组患者也可能患有共病焦虑症。60例患者将进入一项为期6周的开放试验，接受治疗剂量的丙戊酸盐治疗（通过血清丙戊酸盐水平测定）。将进行磁共振成像（MRI）和磁共振波谱（MRS），以比较3组之间以及治疗后的脑解剖学（涉及情绪调节的关键FLB区域的大小，重点是前额叶皮层和杏仁核）和神经化学（N-乙酰天冬氨酸（NAA）水平，神经元活力或功能的非特异性标志物）。还将进行神经心理学测试以评估特定的FLB功能。这将是首次在体内评价BD青少年的FLB异常及其对治疗的反应。这将有助于阐明BD的病理生理机制，了解情绪稳定剂的作用机制，并确定新的BD内表型或有助于诊断，监测或治疗的生物靶点。

Abnormalities in fronto-limbic brain (FLB) regions involved in mood regulation have been associated with bipolar disorder (BD) in neuroimaging studies on adults. Did these FLB changes develop as BD progressed, or did they emerge early during BD development? The latter would suggest that (1) developmental abnormalities in brain maturation processes may have led to these FLB changes. And, if so, then (2) treatments that reduced or alleviated these brain changes early in the disease process might reduce the severity of BD. To test these hypotheses, we will conduct a combined in vivo neuroimaging and clinical intervention trial in post-pubertal adolescents (ages 12-17 years old) who have BD (BD adolescents), that will examine the relationships between (a) FLB abnormalities, (b) BD progression and severity, and (c) response to a mood-stabilizing medication (valproate). We will study 60 untreated BD adolescents and 60 matched healthy controls. 30 BD patients will not have comorbid attention deficit hyperactive disorder (ADHD), oppositional defiant disorder (ODD), and/or conduct disorder (CD), while another 30 will have these comorbid conditions. Patients in both groups may also have comorbid anxiety disorders, with the exception of obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). The 60 patients will enter a 6-week open trial with valproate at therapeutic doses (as measured by serum valproate levels). Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) will be performed to compare brain anatomy (size of key FLB regions involved in mood regulation, with a focus on prefrontal cortex and amygdala) and neurochemistry (levels of N-acetyl aspartate (NAA), a non-specific marker of neuronal viability or function) across the 3 groups, as well as after treatment. Neuropsychological testing will also be conducted to evaluate specific FLB functions. This will be the first in vivo evaluation of FLB abnormalities in BD adolescents and in their response to treatment. It will contribute to elucidating the pathophysiologic mechanisms of BD, to understanding the mechanisms of action of mood stabilizers, and to identifying new endophenotypes of BD or biological targets that could aid in diagnosis, monitoring or treatment.