Fronto-Limbic Brain of Bipolar Children and Adolescents

在成人的神经成像研究中，涉及情绪调节的额叶边缘脑(FLB)区域的异常与双相情感障碍(BD)有关。这些FLB变化是随着BD的进展而发展的，还是在BD发展的早期出现的？后者提示：(1)大脑成熟过程中的发育异常可能导致了这些FLB值的变化。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。为了验证这些假设，我们将在患有BD(BD青少年)的青春期后青少年(年龄12-17岁)中进行一项联合的体内神经成像和临床干预试验，该试验将检查(A)FLB异常，(B)BD进展和严重程度，以及(C)对稳定情绪的药物(丙戊酸盐)的反应。我们将研究60例未经治疗的BD 青少年和60名匹配的健康对照组。30名BD患者不会同时患有注意力缺陷多动障碍(ADHD)、对立违抗障碍(ODD)和/或品行障碍(CD)，而另外30名患者将患有这些共病。除强迫症(OCD)和创伤后应激障碍(PTSD)外，两组患者还可能患有共病焦虑症。这60名患者将进入为期6周的公开试验，服用治疗量的丙戊酸盐(根据血清丙戊酸盐水平衡量)。将进行磁共振成像(MRI)和磁共振波谱(MRS)，以比较三组患者的大脑解剖(参与情绪调节的关键FLB区域的大小，重点是前额皮质和杏仁核)和神经化学(N-乙酰天冬氨酸(NAA)的水平，这是神经元存活或功能的非特异性标记物)以及治疗后的情况。还将进行神经心理测试，以评估特定的FLB功能。这将是第一次对BD青少年的FLB异常及其对治疗的反应进行体内评估。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，并有助于识别BD的新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.