Circuit-specific neuromodulation for the treatment of apathy in Alzheimer's Disease

项目摘要/摘要 冷漠是阿尔茨海默氏症中最令人虚弱和最难治疗的神经精神症状之一 疾病(AD)。以前的研究已经强调了前额-纹状体回路参与了神经发病机制。 无动于衷。具体地说，背侧环路，包括背外侧前额叶皮质和背侧纹状体，以及 实例化目标导向规划；腹侧回路，包括腹内侧前额叶皮质和 腹侧纹状体，以及实例化的动机/奖励估值。此外，这两个电路都严重依赖于 多巴胺(DA)的可用性。这项提议将证明这些电路可以被差分调制 采用重复经颅磁刺激(RTMS)对20例冷漠的AD患者进行治疗。第一, 纹状体区域的结构和功能连通性的高级估计将用于推导 个体化皮质rTMS靶点。接下来，患者将在不同的日子里接受三次实验 其中它们在背侧回路靶标、腹侧回路靶标和控制靶标处被刺激。这个 RTMS的影响将通过同步MR-PET扫描进行测量，该扫描将评估 静息状态功能连接(FC)和纹状体11C-拉氯普利BPND(多巴胺的代用品 可用性/发布)。由刺激引起的行为变化将以有效的冷漠和 情绪测量和在计划和奖励的fMRI任务上的激活。我们假设rtms会 仅在受激励的电路中优先调制FC和DA可用性，并且这将伴随 通过执行和激励方面的冷漠方面的具体变化。这项工作将为更大规模的临床试验授粉 它系统地评估了这种干预改善神经退行性患者冷漠的能力。

PROJECT SUMMARY/ABSTRACT Apathy is among the most debilitating and the least treatable neuropsychiatric symptoms in Alzheimer’s Disease (AD). Previous studies have highlighted prefrontal-striatal circuits involved in the neuropathogenesis of apathy. Specifically, a dorsal circuit, encompassing dorsolateral prefrontal cortex and dorsal striatum, and instantiating goal-directed planning; and a ventral circuit, encompassing ventromedial prefrontal cortex and ventral striatum, and instantiating motivation/reward valuation. In addition, both circuits are heavily reliant upon dopamine (DA) availability. This proposal will demonstrate that these circuits can be differentially modulated with repetitive Transcranial Magnetic Stimulation (rTMS) in a group of 20 AD patients with apathy. First, advanced estimates of structural and functional connectivity from striatal regions will be used to derive individualized cortical rTMS targets. Next, patients will undergo three experimental sessions on separate days in which they are stimulated at the dorsal circuit target, the ventral circuit target, and a control target. The impact of rTMS will be measured with simultaneous MR-PET scanning which will assess both changes in resting-state functional connectivity (FC) and striatal 11C-raclopride BPND (a proxy of dopamine availability/release). Behavioral changes resulting from stimulation will be assessed with validated apathy and mood measures and with activation on fMRI tasks of planning and reward. We hypothesize that rTMS will preferentially modulate FC and DA availability only in the circuit stimulated and that this will be accompanied by specific changes in executive and motivational aspects of apathy. This work will pollinate larger clinical trials which systematically assess the ability of this intervention to improve apathy in neurodegenerative patients.