Emotional dysfunction and childhood behavioral disturbance

该项目确立了关于行为障碍基础的一系列核心神经生物学发现，特别是具有冷酷无情特征(减少内疚和同理心)的行为障碍； (I)Cd+CU与对他人恐惧的加工受损有关，这种损害与杏仁核对这些表达的反应减少有关。这种损害是针对恐惧表情的，而不是愤怒表情的。这些数据使我们能够理解这种疾病患者同理心缺陷的基础。 (Ii)Cd+Cu与决策受损有关，这种损害与腹内侧额叶皮质强化信息(行为导致奖惩的可能性有多大)的表征中断有关。这些数据使我们能够了解这种疾病患者决策障碍的基础。 (3)有注意缺陷多动障碍(ADHD)但无CD的患者在杏仁核对恐惧表情的反应或腹内侧额前皮质强化信息的信号传递方面都没有困难。这一点很重要，因为CD和ADHD通常发生在同一个年轻人身上。大约65%患有CD+CU的年轻人也符合ADHD的标准。然而，通过证明患有ADHD但没有CD的年轻人在恐惧表达或强化加工方面没有问题，我们可以确定这些困难与CD+CU有关，而不是与ADHD共病有关。 在最近完成或目前正在进行的研究中，我们扩展了我们先前的工作，表明： (1)Cd+CU的共情缺陷延伸到对他人疼痛的反应。这些缺陷也与杏仁核对另一个人疼痛的反应减少有关。 (Ii)决策障碍不仅与前额叶腹内侧皮质强化信息表征的缺陷有关，而且与前额叶腹内侧皮质和尾状回预测错误信号的表征缺陷有关。当个体意外地受到奖励或惩罚时，大脑中就会出现预测错误的信号。这一信号很重要，因为它促使人们快速了解引发这种强化的行为与强化本身之间的联系。糟糕的预测错误信号意味着更糟糕的情绪学习，从而更糟糕的决策。 (Iii)与莱本鲁夫特博士合作，我们已经表明，尽管患有CD+CU的青少年和儿童双相情感障碍在行为上表现出一些相似的决策障碍，但这些障碍的神经基础明显不同。Cd+CU与腹内侧额叶皮质和尾状核在强化信息和预测错误信号的表征方面的功能障碍有关。儿童双相情感障碍并非如此。相反，儿童双相情感障碍与组织侧额叶和顶叶皮质对注意力控制重要的区域的困难有关。患有Cd+CU的青少年在这些能力方面没有表现出损害。 重要的是，我们的经验性工作将患有CD+CU的青年与患有ADHD和双相情感障碍的青年区分开来，这使我们能够进一步明确针对这种疾病的Cd+CU青年的神经生物学描述。此外，这项工作使我们能够确定CD+CU中哪些神经区域被破坏，从而为可能使CD+CU青年受益的干预措施提供线索。关键的是，这项工作使我们能够确定可用于评估这一人群的治疗效果的客观生物标记。目前，我的团队正在制定方案，利用该方案中确定的功能磁共振生物标记物任务，调查CD+CU青年患者的两种治疗干预措施，以评估治疗效果。

This project has established a series of core neuro-biological findings regarding the basis of Conduct Disorder (CD), particularly CD with Callous-Unemotional traits (reduced guilt and empathy); CD+CU: (i) CD+CU is associated with impaired processing of the fear of others and this impairment is associated with a reduced response by the amygdala to these expressions. This impairment is specific to fearful expressions and not seen to angry expressions. These data allow us to understand the basis of the empathy deficit in patients with this disorder. (ii) CD+CU is associated with impaired decision making and this impairment is associated with disruption in the representation of reinforcement information (how likely the action is to result in reward/ punishment) within ventromedial prefrontal cortex. These data allow us to understand the basis of the decision making impairment in patients with this disorder. (iii) Patients with Attention Deficit Hyperactivity Disorder (ADHD) but without CD show no difficulties in either their amygdala response to fearful expressions or the signaling of reinforcement information within ventromedial prefrontal cortex. This is important because CD and ADHD are often seen in the same youth. About 65% of our youth with CD+CU also meet criteria for ADHD. However, by showing that youth with ADHD, but without CD, show no problems in fearful expression or reinforcement processing, we can be sure that these difficulties are linked to CD+CU rather than the comorbid ADHD. In studies either recently completed or currently on-going, we have extended our earlier work by showing that: (i) The empathy deficits in CD+CU extend to the response to another individuals pain. These deficits are also related to reduced amygdala responses to another individuals pain. (ii) The decision making impairments are not only associated with deficiencies in the representation of reinforcement information within ventromedial prefrontal cortex but also with deficiencies within ventromedial frontal cortex and the caudate with respect to prediction error signaling. Prediction error signaling occurs in the brain when the individual unexpectedly receives reward or punishment. This signaling is important as it prompts rapid learning of the association between actions that elicited this reinforcement and the reinforcement itself. Poor prediction error signaling means poorer emotional learning and consequently poorer decision making. (iii) In collaboration with Dr. Leibenluft, we have shown that while youth with CD+CU and childhood bipolar disorder behaviorally show some similarities in their decision making impairment, the neural basis of these impairments are markedly different. CD+CU is associated with difficulties in ventromedial prefrontal cortex and caudate functioning with respect to the representation of reinforcement information and prediction error signaling. Childhood bipolar disorder is not. Instead, childhood bipolar disorder is associated with difficulties in organizing regions of lateral frontal and parietal cortex important for attentional control. Youth with CD+CU show no impairment in these capacities. Importantly, our empirical work distinguishing youth with CD+CU from youth with ADHD and youth with bipolar disorder allows us to further specify a neurobiological account of youth with CD+CU that is specific to this disorder. Moreover, this work allows us to determine which neural regions are disrupted in CD+CU and thus provides clues with respect to interventions that might benefit youth with CD+CU. Critically, this work has allowed us to identify objective bio-markers that can be used to assess treatment efficacy in this population. Currently, my group is developing protocols investigating two treatment interventions in youth with CD+CU using the fMRI biomarker tasks identified within this protocol to assess treatment efficacy.