Gamma神经振荡异常与决策认知损伤影响双相障碍自杀行为的机制研究

Decision-making impairment is one of the main causes of suicidal behavior in bipolar disorder (BD), and mechanism underlying the decision-making impairment is still unclear. Functional imaging studies indicate that decision-making engages a neural circuit that includes ventromedial prefrontal cortex (VMPFC), orbitofrontal cortex, amygdala, anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC). Our previous studies found that suicidal behavior in BD is associated with abnormal functional connectivity in cortico (frontal lobe)-basal ganglia-thalamocortical loop. And we also found that patients’ suicidal behavior is associated with the metabolic imbalance of γ-aminobutyric acid (GABA) / glutamic acid (Glu) and the abnormal gene expression of GABA and Glu receptor. Decision-making is mediated by Gamma neural oscillations through regulating GABA and Glu receptor signaling. Thus, we speculate that abnormal gene expression levels of Glu and GABA receptor may lead to the metabolic imbalance of Glu / GABA, then that will influence the gamma neural oscillations of decision-making neural circuit, leading to decision-making impairment. This might be a key mechanism of suicidal behavior in bipolar disorder. In this project, BD patients with attempted suicide performed the Iowa gambling task (IGT) during magnetic source imaging (MSI). We examine the gamma neural oscillation in the frontal lobe (VMPFC, DLPFC, orbitofrontal cortex, ACC)-basal ganglia-thalamocortical loop. We also evaluate the metabolic levels of Glu and GABA by using proton magnetic resonance spectroscopy (1H-MRS), and measure the gen expression levels of Glu and GABA by using fluorescence quantitative polymerase chain reaction (PCR). The aim of this project is to clarify the mechanism of gamma neural oscillation abnormality and decision-making impairment affecting suicidal behavior in BD. In addition, we compare the above observation indicators to BD patients with/without suicidal ideation, in order to find the biological prediction index of suicidal behavior in BD, and provide a theoretical basis for early recognition and intervention of their suicidal behavior.

决策认知损伤是双相障碍自杀的重要原因，具体机制未明。我们及前人研究发现双相障碍自杀与额叶-基底节-丘脑Gamma神经振荡、GABA/Glu代谢及受体基因表达异常相关。GABA和Glu受体信号系统介导Gamma振荡调节决策认知。因此推测Glu和GABA受体基因表达异常致Glu/GABA代谢失衡，影响决策认知神经环路Gamma神经振荡导致决策认知损伤，可能是双相障碍自杀行为产生的关键机制。项目拟采用MSI技术检测自杀未遂患者决策任务态额叶（VMPFC、DLPFC、眶额皮层、ACC）-基底节-丘脑环路Gamma振荡，1H-MRS检测Glu和GABA代谢，检测外周血Glu和GABA受体基因表达，明确Glu/GABA、Gamma振荡、决策认知与自杀的关系，阐明Gamma神经振荡异常与决策认知损伤影响双相障碍自杀行为的机制；与伴/不伴自杀意念双相抑郁和正常对照比较，发现双相障碍自杀的生物学预测指标。

双相障碍是第六位致残性最高的疾病，自杀发生率极高，远高于抑郁症，且绝大部分自杀发生在抑郁发作期患者（双相抑郁障碍患者）。然而，双相障碍的高自杀率与其发病机制不清、缺乏有效的早期诊断和预防手段密切相关。因此，深入研究双相障碍自杀行为的发生发展机制，发现与自杀有关的生物学预测指标，早期识别和心理干预有自杀意念的患者，能够有效提高双相障碍的治疗效果、降低自杀率。研究通过神经心理、影像学、分子生物学等多学科、多角度交叉，运用高空间、高时间分辨率的MSI联合1H-MRS、fMRI技术检测脑电反应和脑代谢、脑网络，联合神经认知功能评估，并检测外周血谷氨酸受体基因表达，揭示双相抑郁障碍及其自杀行为的分子影像机制，发现双相障碍自杀的生物学预测指标。目前结果发现，双相抑郁障碍自杀行为的发生与基底节神经环路、边缘系统、岛叶皮层环路的动态功能连接密切相关，可能是自杀行为潜在的神经标志物，结合基底节神经环路与岛叶皮层环路的动态功能连接能有效区分双相抑郁障碍自杀未遂患者与健康人群；进一步结合神经认知、内分泌和心理学特征探讨相关机制，发现双相抑郁障碍自杀未遂患者存在广泛的认知功能障碍，涉及信息处理速度、工作记忆等多个维度，与非自杀双相抑郁障碍患者和正常对照比较，自杀未遂患者还存在人格改变，可能受基底节神经环路与岛叶皮层环路的动态功能连接与内分泌激素水平异常的交互影响。此外，结合MSI分频带分析提示不同频带的动态脑功能连接可能不同，且影响不同的认知功能维度，后续研究将进一步明确。研究从一个新的角度探讨双相抑郁障碍及其自杀行为的分子生物学机制，为课题组下一步研究奠定基础，并为将来双相抑郁障碍及其自杀行为的发生发展机制和诊疗相关研究提供思路。