Investigating neuroanatomical underpinnings of apathy in ADRD through neuroimaging and electrical manipulation

由于治疗选择有限，阿尔茨海默病(AD)患者经常出现麻木症状， 相关痴呆(ADRD)和帕金森病(PD)，显著影响患者的生活质量和 照顾者。尽管对额叶皮质和大脑皮质的基本作用有充分的了解 皮层下结构在冷漠综合征和目标导向行为(GDB)方面，挥之不去的差距仍然存在 从神经退化到冷漠发展的因果联系。因此，对知识的零散理解 冷漠的认知和神经解剖学基础，阻碍了神经生物学靶向的发展 治疗痴呆症患者的神经精神衰弱问题。虽然我们的长期目标是发展 作为对ADRD和PD冷漠的有效治疗，本应用程序的总体目标是(I)测试 局灶性神经变性导致ADRD和PD患者冷漠的影响可以用不同的 奖励和努力敏感度-认知过程是GDB不可或缺的，以及(Ii)在PD参与者中提到的RECESS 深部脑刺激手术(DBS)，众所周知，后来发展成高冷漠的比率，直接测试 刺激丘脑底核(STN)和连接的额叶-皮质下回路，将导致 GDB中的即时更改。中心假设是，无论初级神经病理或位置如何 沿着神经回路，既有萎缩，观察到结构和功能的连通性变化，也有电 沿着前额-基底节网络的刺激，直接改变GDB，表现为冷漠。二 提出了独立的目标：目标1.结合所有三个研究群体(PD n=100，FTD n=50，和 ADn=100)，评估奖励和努力敏感度的独立效应，作为两者之间的机械联系 基底节-额叶网络的神经变性和特定维度的冷漠的发展，通过 确定(A)冷漠的三个维度中的每一个的神经解剖学基础 维度冷漠量表(DAS)，它提供了三个冷漠维度的子分，以及(B)奖励和 苹果收集任务(AGT)的努力敏感度，以及(C)评估奖励和努力敏感度作为解释 神经成像指标和冷漠维度的中介者。AGT是一台30分钟的计算机 以努力为基础的决策范式，其中报酬与努力相权衡。与RDoC一致 框架中，AGT允许通过将GDB的组件与不同的 神经解剖学基础。在目标2中，对于PD-DBS参与者，确定电刺激是否 STN直接改变奖励和努力信息处理，从而改变GDB。证明因果关系 DBS对帕金森病患者动机行为变化的影响，而多巴胺能药物，我们将 在三个时间点评估他们在AGT上的表现：(I)基线和术后6个月(Ii)DBS- 关闭和(Iii)DBS-ON。总体而言，这项研究将为新的干预措施(即病毒)确定切实的治疗目标 载体、聚焦超声)，从而使临床医生能够处理痴呆症相关情况下的冷漠。

With limited treatment options, apathetic symptoms often experienced by patients with Alzheimer's disease (AD), related dementias (ADRD) and Parkinson's Disease (PD), significantly impact the quality of life of patients and caregivers. Despite a well-grounded understanding of the essential roles played by frontal cortical and subcortical structures on the apathy syndrome and on goal-directed behavior (GDB), lingering gaps remain on the causal links from neurodegeneration to the development of apathy. Thus, the fragmented understanding of the cognitive and neuroanatomical basis of apathy, stands on the way of developing neuro-biologically targeted treatments for this debilitating neuropsychiatric issue across dementias. While our long-term goal is to develop an effective treatment for apathy in ADRD and PD, the overall objectives of this application are to (i) test whether the effects of focal neurodegeneration leading to apathy in ADRD and PD can be explained by differences in reward and effort sensitivity - cognitive processes integral to GDB, and (ii) in PD participants referred to receive deep-brain stimulation surgery (DBS), who are known to later develop high rates of apathy, directly test whether stimulation of the subthalamic nucleus (STN) and connected frontal-subcortical circuits, would result in immediate changes in GDB. The central hypothesis is that, regardless of the primary neuropathology or location along the neural circuit, both atrophy, observed as structural and functional connectivity changes, and electrical stimulation along the prefrontal-basal ganglia network, directly alter GDB and manifest as apathy. Two independent aims are proposed: Aim 1. With all three study populations combined (PD n=100, FTD n=50, and AD n=100), evaluate the independent effects of reward and effort sensitivity as a mechanistic link between neurodegeneration of basal ganglia-to-frontal network and the development of specific dimensions of apathy, by identifying the neuroanatomical underpinnings for (A) each of the three dimensions of apathy as measured by Dimensional Apathy Scale (DAS), which provides subscores for three apathy dimensions, and (B) reward and effort sensitivity from the Apple Gather task (AGt), and (C) evaluating reward and effort sensitivity as explanatory mediators for neuroimaging metrics and apathy dimensions. The AGt is a 30-minute computer administered effort-based decision-making paradigm in which rewards are weighed against effort. Consistent with the RDoC framework, the AGt allows a mechanistic approach to apathy by dissociating components of GDB with distinct neuroanatomical substrates. In Aim 2, for PD-DBS participants, determine whether electrical manipulation of the STN directly alters reward and effort information processing and consequently GDB. To demonstrate a causal effect of DBS on changes in motivated behavior in PD participants, while `on' dopaminergic medications, we will assess their performance on AGt at three time points: (i) baseline, and 6-months postoperatively with (ii) DBS- OFF and (iii) DBS-ON. Overall, this study will identify tangible therapeutic targets for novel interventions (i.e viral vectors, focused ultrasound), and thus, enable clinicians to manage apathy in dementia-related conditions.