双相障碍父母的有前驱症状子女的神经认知及其神经环路机制研究

Bipolar disorder (BD) is one of the most common mental illnesses, with lifetime prevalence as high as 3.9% and high recurrence and comorbidity. Unfortunately, about 69% of BD patients are misdiagnosed often as unipolar depression because its mechanism is still unclear and there are lack of subjective biomarkers for the diagnosis. Neurocognitive deficits are observed in both acute and remission periods of BD, but the extent and neurocognitive profiles are different depending on the states.Many factors can contribute to the abnormalities, including recurrences, long duration, and medications. Some studies have shown that the unaffected relatives of the probands with BD may display deficits in some domains to a less extent, when compared to the probands with BD. A few studies suggested that there may be neurocognitive deficits in high-risk individuals with BD, but they may be different from that seen in BD patients and in the unaffected relatives. Research has shown abnormalities in some neural circuits such as fronto-temporal/limbic-either dysregulation or abnormal functional activities-in individuals with BD or even in the unaffected relatives of probands with BD. There are different in extents and levels of abnormal brain regions between diffenent states and diffenent stages in BD patients, and the unaffected relatives of probands with BD. Again, many factors can contribute to the abnormalities, including recurrences, long duration, and medications. Given the above considerations, we hypothesize that individuals who are at the prodromal stage of BD may have original neurocognitive deficits and related neural circuit abnormalities that are different from BD patients. This study will be a high-risk design, consisting of four groups. We will investigate the neuropsychological performance in 30 child or adolescent individuals with BD, 30 high-risk individuals with prodromal symptoms with one parent with BD, 30 high-risk individuals without prodromal symptoms with one parent with BD, and 30 healthy controls without parent with BD and without any psychiatric family history. We will administer MCCB( Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery）to assess neurocognitive function, including processing speed, attention, working memory, verbal learning, memory, visual learning, and executive function. We will apply a Philip Ingenia 3.0 T MRI Scanner to conduct a multimoding magnetic resonance imaging (MRI), including resting state, diffusion tensor imaging (DTI) , brain structural MRI as well as emotional and cognitive task MRI. The mains aim thus is to examine the initial impairment in neurocognitive function and its related neural circuit deficits in patients with BD. Such strategy will help understand the mechanisms of BD and thus assist the early diagnosis of and intervention on BD.

双相障碍（BD）是高患病率、高复发率的慢性终身性疾病，然69%BD患者曾被误诊或诊断延迟，主要原因是BD的发病机制不清楚。BD患者存在广泛的神经认知及其神经环路损害如额叶-颞叶(边缘系统)脑区的功能失调和激活不平衡，但心境发作期、心境稳定期、儿童期及患者一级亲属的损害都不同，BD患者的损害可能与反复发作、长期病程及药物治疗有关。假设BD患者前驱期存在某些不同于BD患者及其一级亲属的、最初的神经认知损害及其关联的、最初的神经环路损害。因此，我们拟对父母BD有前驱症状子女、父母BD无前驱症状子女、儿童青少年BD患者及年龄和受教育程度相当的健康对照各组30例，进行MCCB为主的神经认知测验，并进行结构态、弥散张量成像、静息态及在工作记忆和情绪序列任务激发下的磁共振检查，以探索BD患者前驱期、最初的神经认知损害及其相关联的神经环路机制，促进BD的早期诊断和早期治疗，减少患者、家属的痛苦和疾病负担。

双相障碍（BD）是高患病率的慢性疾病，误诊率与延迟诊断率高。BD患者存在广泛的神经认知及神经环路损害， 但可能与反复发作、长期病程及药物治疗有关。假设BD患者前驱期存在某些不同于BD患者的、最初的神经认知及其神经环路损害。为此，我们完成了父母BD有前驱症状子女（超高危个体，UHR）60例、父母BD无前驱症状子女（高危个体， HR）53例、儿童青少年BD患者（CBD）62例及健康对照组51例，进行MCCB为主的神经认知测验，并进行结构态、弥散张量成像、静息态及在任务激发下的磁共振检查。结果发现，与HC组比较，HR子女的言语学习和记忆显著较差，提示其神经认知损害可能是BD的神经认知内表型；UHR子女则表现出工作记忆、视空间记忆及认知计划损害，提示是发展为BD的风险。UHR子女表现的神经认知损害在无精神障碍家族史有BD阈下症状组中不存在。HR子女存在右侧眶额回（OFC）、右侧小脑叶缩小；与HR子女比较，UHR子女表现为右侧额上回(SFG）、右侧扣带回后部（PCC）、左侧枕回中下部、及顶上回皮质（SPC）4个脑区体积增大。HR和UHR子女都表现枕下回皮质异常，反映连接功能和区域集中程度的指标异常。与HR组比较，UHR子女表现出反映脑网络高聚集和效能的小世界网络拓扑结构上行趋势。体重指数（BMI）较高显著与大脑额叶及皮层下结构的体积较大相关。BMI与BD危险状态的交互效应与右侧额中回体积相关。BMI对脑容量的调节作用在14-19岁的受试者中最明显。双相障碍子女组状态与BDNF对神经影像学参数有显著交互作用的趋势，对小脑白质及额上回和额中回区域有显著影响。双侧小脑灰质体积减少成为潜在的内表型，而且(连同顶-枕叶灰质体积改变)将超高危个体（UHR）与健康对照及高危个体区分出来，分别增加临床分类特异性近10%和27%，高危个体中小脑灰质体积相对正常可能存在回复力。这些研究结果对进一步阐明BD的发病机制，BD的早期诊断生物学标记，以及BD的早期预防干预有重要的科学意义和临床意义。