Cognitive and Neural Mechanisms of Antisocial Behavior in Frontotemporal Dementia

摘要：反社会行为在额颞叶痴呆（FTD）患者中很常见。这些行为 导致严重的发病率，在极端情况下可能导致犯罪。然而，尽管它是世界上 具有挑战性和问题性的症状，以管理临床，机制导致反社会行为， FTD未知，治疗仍然有限。目前提案的目标是确定 导致FTD中反社会行为的认知和神经机制。了解这些 机制将通过改善临床评价以监测FTD患者的发作， 和反社会行为的进展，有助于开发新的药理学和神经调节 治疗策略，并告知犯罪的FTD患者的法律的和伦理治疗。目标1 I 将研究神经机制和假设，即FTD患者的反社会行为将有 我在患有反社会行为的患者中发现了一个预先定义的大脑区域网络萎缩， 局灶性脑损伤我将使用我最近开发的一种新的神经成像方法来验证这一假设， 使用人类连接体和单个受试者萎缩图的经验证的所谓萎缩网络图 将神经症状定位到大脑网络而不是孤立的区域。在目标2中，我将研究 认知机制和具有反社会行为的FTD患者存在特定损害的假设 在道德决策中。我的长期目标是使用多模式神经成像和决策任务， 更好地了解导致痴呆症中反社会行为和其他行为问题的机制 患者为了实现这一目标，提出了一个培训计划，以学习更多的研究技能，在功能 神经影像学方法（培训目标1）和社会决策的神经心理学（培训目标2）。 在领导力，生物统计学和赠款写作方面的额外培训将为我实现独立做好准备 （培训目标3）。一个由专家组成的指导小组已经成立，以帮助我实现这些培训目标， 由丹尼尔克拉森博士（主要导师），行为神经学家谁研究奖励为基础的 神经退行性疾病患者的决策和功能性神经影像学;大卫扎尔德博士（合作， 他是一位神经心理学家和认知神经科学家，使用功能性神经成像来研究 以及班尼特兰德曼博士（共同导师），一位神经成像师， 开发了计算方法来研究衰老过程中的神经影像学变化。该团队还将包括博士。 Hakmook Kang（合作者），具有神经影像学专业知识的生物统计学家，Catherine Chang博士， 具有功能连接专业知识的神经成像师，以及凯瑟琳兰金博士（外部顾问）， 神经心理学家，擅长对FTD的社会和情绪处理进行心理测量评估。

ABSTRACT: Antisocial behavior is common in patients with frontotemporal dementia (FTD). These behaviors result in significant morbidity and can lead to crimes in extreme cases. Yet despite being one of the most challenging and problematic symptoms to manage clinically, the mechanisms leading to antisocial behavior in FTD are unknown, and treatments remain limited. The goal of the current proposal is to determine the cognitive and neural mechanisms leading to antisocial behavior in FTD. Understanding these mechanisms will have a major impact on FTD patients by improving clinical evaluations to monitor the onset and progression of antisocial behaviors, helping to develop novel pharmacologic and neuromodulatory treatment strategies, and informing legal and ethical treatment of FTD patients who commit crimes. In Aim 1 I will examine the neural mechanisms and the hypothesis that FTD patients with antisocial behavior will have atrophy in a pre-defined network of brain regions I identified in patients with antisocial behaviors caused by focal brain lesions. I will test this hypothesis using a new neuroimaging method I recently developed and validated called atrophy network mapping that uses the human connectome and single-subject atrophy maps to localize neurological symptoms to brain networks rather than an isolated region. In Aim 2 I will examine the cognitive mechanisms and the hypothesis that FTD patients with antisocial behavior have specific impairments in moral decision-making. My long-term goal is to use multimodal neuroimaging and decision-making tasks to better understand the mechanisms leading to antisocial behavior and other behavioral problems in dementia patients. To achieve this goal, a training plan is proposed to learn additional research skills in functional neuroimaging methods (Training goal 1) and the neuropsychology of social decision-making (Training Goal 2). Additional training in leadership, biostatistics, and grant-writing will prepare me to achieve independence (Training goal 3). A mentorship team of experts has been assembled to help me achieve these training goals, consisting of Dr. Daniel Claassen (primary mentor), a behavioral neurologists who studies reward-based decision-making and functional neuroimaging in patients with neurodegenerative disorders; Dr. David Zald (co- primary mentor), a neuropsychologist and cognitive neuroscientist who uses functional neuroimaging to study decision-making in aging and antisocial behavior; and Dr. Bennett Landman (co-mentor), a neuroimager who develops computational methods to study neuroimaging changes in aging. The team will also include Dr. Hakmook Kang (collaborator), a biostatistician with expertise in neuroimaging, Dr. Catherine Chang, a neuroimager with expertise in functional connectivity, and Dr. Katherine Rankin (external consultant), a neuropsychologist with expertise in psychometric assessments of social and emotional processing in FTD.