Positive and Negative Valence Systems Underlying Suicide in Youth

项目摘要/摘要 自杀是青少年的主要公共卫生问题，也是这个年龄段的第二大死亡原因， 强调了调查青少年自杀的必要性。完成的两个最突出的风险因素 青年自杀是过去的自杀未遂和抑郁发作的诊断，两者都是独立的 意味着完全自杀的风险增加了10到30倍。然而，虽然超过80%的自杀青年 在尝试时出现抑郁症状的年轻人中，只有30%的人会尝试 自杀。这些数据表明，有自杀企图的抑郁青少年代表着一种独特的 神经生物学亚群。然而，目前我们还没有生物标志物来识别那些患有抑郁症的青年 会有自杀行为。这项建议解决了这一关切。我们提出的模型是：(1)快感缺乏症 与抑郁青年自杀风险增加有关；(2)正价(PVS)缺陷(奖赏 预期、达到、正向预测误差)和负价(NVS)多动(负向预测 错误、痛苦回避)导致了抑郁青年的快感缺失和自杀行为； 缰核(Hb)是一个小的边缘中枢，通过抑制奖赏信号在PVS/NVS过程中发挥关键作用。 对疼痛和失落的反应；以及(4)高分辨率磁共振成像的最新进展解决了先前在 研究像HB这样的小结构。这些进展现在使我们能够研究潜在的神经回路。 PVS和NVS在神经解剖学严格的框架内。在支持方面，我们记录了青少年的情况 抑郁症的核心症状，只有快感缺乏，而不是易怒，与抑郁症患者的自杀行为有关 青春年华。类似地，我们发现快感缺乏和诱捕都与自杀独立相关。 在有自杀倾向的住院患者中。我们还开发了奖励侧翼(RFT)和奖励预测 错误(RPET)fMRI任务和在奖励预期、实现和积极期间识别的脑功能 负预测误差。值得注意的是，RPET和热痛任务都引起了可测量的Hb激活。 此外，利用一种优化的分割和种子方法，我们映射了HB的本征函数 有精神症状的成年人和青少年的连接性。在我们工作的基础上，我们提出了一个紧密的 对PVS缺乏症和NVS多动共同导致自杀的总体假设进行综合研究 抑郁青年的行为。我们将研究30名有自杀倾向和30名非自杀倾向的抑郁症青少年，年龄在12-17岁之间， 在年龄、性别和惯用手方面相匹配的一组。所有这些都将进行全面的临床评估(诊断、 行为测量、计算机化奖励任务)。神经成像研究将包括结构磁共振、静息状态 任务功能磁共振(RFT、RPET、热痛)。机器学习算法将用于检查哪些PVS/NV 心理过程预测抑郁青年的自杀行为。

PROJECT SUMMARY/ABSTRACT Suicide is a major public health concern in adolescents and the second leading cause of death in this age group, highlighting the need to investigate suicide in adolescents. The two most prominent risk factors for completed suicide in youth are a past suicide attempt and a diagnosis of a depressive episode, each independently representing a 10- to 30-fold increased risk for completed suicide. However, while over 80% of suicidal youth present with depressive symptoms at the time of the attempt, only 30% of depressed youth will ever attempt suicide. These data suggest that depressed adolescents with prior suicide attempts represent a distinct neurobiological subgroup. However, at present, we have no biomarkers to identify those depressed youth who will engage in suicidal behavior. This proposal addresses this concern. Our proposed model is: (1) anhedonia is associated with heightened suicidal risk in depressed youth; (2) both positive valence (PVS) deficits (reward expectancy, attainment, positive prediction error) and negative valence (NVS) hyperactivity (negative prediction error, pain avoidance) contribute to anhedonia and underlie suicidal behavior in depressed youth; (3) the habenula (Hb), a small limbic hub, plays a key role in PVS/NVS processes by inhibiting reward signaling in response to pain and loss; and (4) recent advances in high-resolution MRI address prior technical constraints in studying small structures such as the Hb. These advances now allow us to study the neuronal circuitry underlying PVS and NVS in a neuroanatomically rigorous framework. In support, we documented that of adolescent depression’s core symptoms, only anhedonia, not irritability, was associated with suicidality among depressed youth. Similarly, we found that both anhedonia and entrapment were independently associated with suicidality in acutely suicidal hospitalized individuals. We also developed the reward flanker (RFT) and reward prediction error (RPET) fMRI tasks and identified brain function during reward anticipation, attainment, and positive and negative prediction errors. Notably, both RPET and a thermal pain task elicited measurable Hb activation. Additionally, utilizing an optimized segmentation and seeding approach, we mapped Hb intrinsic functional connectivity in adults and in adolescents with psychiatric symptoms. Building upon our work, we propose a tightly integrative study to test the overall hypothesis that both PVS deficiency and NVS hyperactivity underlie suicidal behavior in depressed youth. We will study 30 suicidal and 30 non-suicidal depressed adolescents, ages 12-17, group matched for age, sex, and handedness. All will have comprehensive clinical evaluations (diagnoses, behavioral measures, computerized reward task). Neuroimaging studies will include structural MRI, resting-state and task fMRI (RFT, RPET, thermal pain). Machine learning algorithms will be used to examine which PVS/NVS processes predict suicidal behavior in depressed youth.