TMS in Primary Progressive Aphasia: Modulation of Brain Networks and Language

摘要 这项拟议的研究考察了无创重复经颅磁疗的潜在益处。 刺激(RTMS)对原发性进行性失语(PPA)患者行为和语言神经回路的影响 通常是阿尔茨海默病及相关疾病(ADRD)的失语症变种。中国的长期目标是 研究计划是部署rTMS干预措施治疗PPA。这项建议建立在初步的基础上 有证据表明，背外侧前额叶皮质rTMS可改善PPA患者的语言能力。 第一个目标是复制和扩展rTMS对PPA中语言的影响。第二个目标是评估 这些影响存在于不同的PPA亚型中，并决定了哪些亚型或哪些亚型更有可能受益 从rTMS到背外侧前额叶皮质。针对这些目标的培训将发展候选人在以下方面的专长 使用rTMS和神经心理学工具对PPA患者进行临床研究。短期目标包括 获得语言评估和纵向分析方法方面的专业知识，这将促进候选人的 评估rTMS在PPA中诱导持久效应的有效性的长期目标。第三个目标是检查 通过测定rTMS对大鼠脑内神经细胞功能连接的影响来探讨rTMS的作用机制 大脑的语言网络。针对这一目标的培训将使应聘者的专业知识超越脑部成像 网络来调节它们，使其在PPA中获得临床益处。为实现这一目标而进行的培训将进一步发展 应聘者在形态计量分析方面的专长，以量化和控制灰质和白质的影响 购买力平价损失。所有目标将通过在拟议项目中收集的新数据来实现。有关培训，请访问 马萨诸塞州总医院和哈佛医学院社区允许访问资源和 为候选人的培训和职业生涯的目标提供许多必要技术方面的导师和顾问 目标。前额叶背外侧皮质的rTMS将分一次和连续进行 10次会议。语言和其他认知能力将通过神经心理评估进行衡量。 语言网络的功能连通性将使用静息状态的功能磁学来测量 磁共振成像(RsfMRI)。脑体积和白质完整性将通过结构性测量 磁共振成像(MRI)和弥散张量成像(DTI)。使用纵向数据，瞬变 并将评估TMS随着时间的推移对行为和语言网络的持久影响。两国之间的关系 将研究rTMS引起的语言变化与大脑功能连接的变化。如果rsfMRI 它被证明是神经变化的可靠指标，它可能被证明是预测TMS治疗的生物标志物 响应性。目标的完成将增强我们对行为和 RTMS的神经调节机制，并告知未来优化PPA治疗的试验，符合 NIDCD关于开发新的干预战略以改善PPA结果的战略计划。

SUMMARY The proposed research examines the potential benefits of non-invasive repetitive transcranial magnetic stimulation (rTMS) to behavior and language neurocircuit in patients with Primary Progressive Aphasia (PPA), usually an aphasic variant of Alzheimer's disease and related disorders (ADRD). A long-term goal of the research program is to deploy rTMS interventions for treatment of PPA. The proposal builds upon preliminary evidence showing that rTMS to dorsolateral prefrontal cortex improves language abilities in patients with PPA. The first aim is to replicate and extend the effects of rTMS on language in PPA. The second aim is to assess these effects in different subtypes of PPA and determine which subtype or subtypes are more likely to benefit from rTMS to dorsolateral prefrontal cortex. Training for these aims will develop the candidate's expertise in using rTMS and neuropsychological tools for clinical research in patients with PPA. Short-term goals include obtaining expertise in language assessments and longitudinal analytic methods that will further the candidate's long-term goal of assessing the efficacy of rTMS to induce durable effects in PPA. The third aim is to examine the neural mechanism of action of rTMS by measuring the effects of rTMS on functional connectivity of the brain's language network. Training for this aim will extend the candidate's expertise beyond imaging brain networks into modulating them for clinical benefits in PPA. Training for this aim will additionally develop the candidate's expertise in morphometric analyses to quantify and control for the effect of gray and white matter loss in PPA. All aims will be obtained by new data collected in the proposed project. Training available at Massachusetts General Hospital and Harvard Medical School community allows access to resources and mentors and advisors in the many techniques necessary to the aims of the candidate's training and career goals. rTMS over the dorsolateral prefrontal cortex will be administered in a single session and in consecutive 10 sessions. Language and other cognitive abilities will be measured with neuropsychological assessments. The language network functional connectivity will be measured using resting-state functional magnetic resonance imaging (rsfMRI). The brain volume and white matter integrity will be measured with structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Using longitudinal data, the transient and durable effects of TMS on behavior and language network over time will be assessed. The relationship of rTMS-induced changes in language with changes in brain functional connectivity will be examined. If rsfMRI proves to be a reliable measure of neural change, it may prove to be a biomarker for predicting TMS treatment responsiveness. Completion of the aims will enhance our understanding of the behavioral and neuromodulatory mechanisms of rTMS and inform future trials that optimize treatments for PPA, in line with the NIDCD strategic plans on developing novel intervention strategies to improve outcomes in PPA.