Neuroimaging study of risk factors for adolescent bipolar disorder

 患有双相情感障碍的青少年和有发展成双相情感障碍风险的年轻人在OFC和AMY功能、化学和连接性方面表现出异常。尽管精神刺激剂暴露对与双相情感障碍相关的大脑病理变化的影响尚不清楚，但越来越多的证据表明，长期暴露于精神刺激剂可能会引发情绪症状，并加速双相情感疾病的发生。此外，啮齿动物研究发现，反复接触刺激剂会导致行为激活(即敏化)逐渐和持久地增加，这与OFC的树突萎缩和杏仁核活动的改变有关，这表明刺激剂可能有助于在双相青少年中观察到OFC-AMY结构和功能连接的减少。临床研究发现，双相情感障碍与omega-3脂肪酸缺乏和死后OFC的神经元萎缩，以及红细胞膜omega-3脂肪酸缺乏有关，这些缺陷发生在躁狂发作之前和/或恰好发生在最初的躁狂发作之前。考虑到这些因素，指导这项提议的主要假设是，有患双相情感障碍家族风险的年轻人 那些表现出ADHD症状的人在暴露于精神刺激剂时，OFC-AMY连接受损的易感性增加，这最初表现为行为激活，最终表现为躁狂。此外，我们预测，在接受精神刺激剂治疗的高危青少年中，较低的omega-3脂肪酸生物状态将与OFC-AMY结构和功能连接性的更大下降相关。为了验证这些假设，我们建议进行第一个前瞻性对照监测试验，利用多模式神经成像技术(fMRI、DTI、1HMRS)来检验候选RIS因素(即与双相情感障碍、DSM-5 ADHD、慢性精神刺激暴露有一级亲属)和调节保护因素(即omega-3脂肪酸生物状态)对OFC-AMY功能和结构连接性的影响。为了实现这一目标，我们将招募240名未服用药物的青少年(年龄13-17岁)ADHD患者(n=120名‘高风险’和n=60名‘低风险’)和60名健康对照对象。高危ADHD患者将被随机分为安慰剂(n=60)或精神刺激药物(MAS-XR)(n=60)，为期12周，低风险ADHD患者将接受开放标签MAS-XR治疗12周。所有受试者将在基线和第12周接受神经成像扫描。

 DESCRIPTION (provided by applicant): The onset of bipolar disorder typically occurs during adolescence, the age when maturation of orbitofrontal cortical (OFC) connectivity with limbic structures including the amygdala (AMY) typically becomes established. Adolescents and young adults with and at risk for developing bipolar disorder exhibit abnormalities in OFC and AMY function, chemistry, and connectivity. Adolescents with a familial risk for developing bipolar disorder commonly initially present with deficits in attention, and are thus often initially prescribed a psychostimulant medication (i.e., amphetamine, AMPH). Although the effects of psychostimulant exposure on pathological brain changes associated with bipolar disorder are not known, a growing body of evidence suggests that long-term psychostimulant exposure may precipitate mood symptoms, and accelerate the onset of bipolar illness. Moreover, rodent studies have found that repeated stimulant exposure leads to a progressive and enduring increase in behavioral activation (i.e., sensitization) which is associated with dendritic atrophy n the OFC and alterations in amygdala activity, suggesting that stimulants may contribute to reductions in OFC- AMY structural and functional connectivity observed in bipolar adolescents. Translational evidence also suggests that increasing dietary omega-3 fatty acids during brain development promotes cortical maturation and increases neuronal resilience to excitoxicity as well as AMPH-induced behavioral sensitization in rodents. Clinical studies have found that bipolar disorder is associated with omega-3 fatty acid deficits and neuronal atrophy in postmortem OFC, and red blood cell membrane omega-3 fatty acid deficits which precede and/or coincide with the initial onset of mania. With these considerations in mind, the primary hypothesis guiding this proposal is that youth with a familial risk for developing bipolar disorder and who are expressing symptoms of ADHD have an increased vulnerability for impaired OFC-AMY connectivity when exposed to psychostimulants, which initially manifests as behavioral activation, and ultimately, mania. Moreover, we predict that lower omega-3 fatty acid biostatus will be associated with greater decreases in OFC-AMY structural and functional connectivity in psychostimulant-treated high-risk adolescents. To test these hypotheses, we propose to conduct the first controlled prospective surveillance trial to examine the effects of candidate ris factors (i.e., having a first-degree relative with bipolar disorder, DSM-5 ADHD, chronic psychostimulant exposure) and moderating protective factors (i.e., omega-3 fatty acid biostatus) on OFC-AMY functional and structural connectivity using multimodal neuroimaging techniques (fMRI, DTI,1H MRS). To achieve this objective, we will recruit a total of 240 medication-free adolescent (ages 13-17 years old) ADHD patients (n=120 `high-risk' and n=60 `low-risk') and 60 healthy comparison subjects. High-risk ADHD patients will be randomized to placebo (n=60) or psychostimulant medication (MAS-XR)(n=60) for 12 weeks, and low-risk ADHD patients will receive open-label MAS-XR for 12 weeks. All subjects will receive neuroimaging scans at baseline and Week 12.