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

项目总结/摘要 冷漠是阿尔茨海默氏症中最令人衰弱和最难治疗的神经精神症状之一 疾病（AD）。以前的研究强调了前额叶-纹状体回路参与神经发病机制 冷漠。具体来说，背侧回路，包括背外侧前额叶皮层和背侧纹状体， 实例化目标导向计划;和腹侧回路，包括腹内侧前额叶皮层， 腹侧纹状体，和实例化动机/奖励评价。此外，这两个电路都严重依赖于 多巴胺（DA）的可用性。这个建议将证明，这些电路可以差分调制 重复经颅磁刺激（rTMS）在一组20名AD患者的冷漠。第一、 纹状体区域的结构和功能连接的先进估计将用于推导 个体化皮层rTMS靶点。接下来，患者将在不同的日子接受三次实验性治疗 其中在背侧回路目标、腹侧回路目标和控制目标处刺激它们。的 rTMS的影响将通过同步MR-PET扫描来测量，该扫描将评估 静息态功能连接（FC）和纹状体11 C-raclopride BPND（多巴胺的替代物 可用性/释放）。刺激引起的行为变化将通过经验证的冷漠进行评估， 情绪措施和激活的fMRI任务的计划和奖励。我们假设rTMS将 优先调节FC和DA的可用性只在电路刺激，这将伴随着 冷漠的执行力和动机方面的具体变化。这项工作将为更大规模的临床试验提供帮助 该研究系统地评估了这种干预改善神经退行性疾病患者冷漠的能力。

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.