Neuroimaging study of risk factors for adolescent bipolar disorder

 描述（由申请人提供）：双相情感障碍的发作通常发生在青春期，此时眶额皮质（OFC）与边缘结构（包括杏仁核（AMY））的连接成熟。患有双相情感障碍和有发展风险的青少年和年轻人表现出OFC和AMY功能，化学和连接异常。具有发展双相情感障碍的家族风险的青少年通常最初表现为注意力缺陷，因此通常最初开精神兴奋剂药物（即，安非他明，AMPH）。虽然精神兴奋剂暴露对双相情感障碍相关的病理性大脑变化的影响尚不清楚，但越来越多的证据表明，长期精神兴奋剂暴露可能会引发情绪症状，并加速双相情感障碍的发作。此外，啮齿动物研究发现，反复暴露于刺激物会导致行为激活的进行性和持久性增加（即，致敏），这与OFC的树突萎缩和杏仁核活性的改变有关，表明兴奋剂可能有助于在双相青少年中观察到的OFC-AMY结构和功能连接的减少。转化证据还表明，在大脑发育过程中增加饮食中的ω-3脂肪酸可促进皮质成熟，并增加神经元对兴奋性毒性的恢复力以及AMPH诱导的啮齿动物行为敏化。临床研究发现，双相情感障碍与死后OFC中的ω-3脂肪酸缺乏和神经元萎缩以及在躁狂症最初发作之前和/或与躁狂症最初发作一致的红细胞膜ω-3脂肪酸缺乏相关。考虑到这些因素，指导这一建议的主要假设是，有家族性双相情感障碍风险的年轻人 当暴露于精神兴奋剂时，表现出ADHD症状的人对受损的OFC-AMY连接的脆弱性增加，最初表现为行为激活，最终表现为躁狂。此外，我们预测，在接受精神兴奋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结构和功能连接的更大程度降低相关。为了检验这些假设，我们建议进行第一次对照前瞻性监测试验，以检查候选风险因素的影响（即，具有双相情感障碍、DSM-5 ADHD、慢性精神兴奋剂暴露的一级亲属）和调节保护因素（即，ω-3脂肪酸生物状态）对OFC-AMY功能和结构连接的影响。为了实现这一目标，我们将招募总共240名无药物治疗的青少年（年龄13-17岁）ADHD患者（n=120名“高风险”和n=60名“低风险”）和60名健康对照受试者。高风险ADHD患者将随机接受安慰剂（n=60）或精神兴奋剂药物（MAS-XR）（n=60）治疗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周接受神经影像学扫描。

 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.