Noninvasive Cortical Stimulation to Improve Memory in Mild Cognitive Impairment

翻译后摘要：轻度认知障碍（MCI）进行了高风险的进展，由于阿尔茨海默氏症的痴呆症 疾病（AD）。然而，目前还没有有效的治疗方法。对于患有MCI的老年人， 他们面临的问题和不确定性对他们的日常运作、能力和信心产生了负面影响， 参与具有挑战性的认知活动，从而提高他们的生活质量。很大一部分成年人 MCI要么服用胆碱酯酶抑制剂，要么尝试过，但这些批准的治疗方法疗效较低 副作用似乎超过了治疗效果 本研究的目的是测试MCI的非药物治疗的疗效， 无创脑刺激（NIBS）。早期对AD痴呆患者的研究发现， 经颅磁刺激（rTMS，NIBS的一种形式）改善了整体认知功能和活动， 日常生活考虑到在AD中，神经元损失和突触功能障碍沿着脑网络进展，这些 AD痴呆患者的早期脑刺激研究表明， 脑刺激的效果在已发表的极少数MCI的rTMS研究中， 看起来相当大然而，目前尚不清楚背外侧前额叶皮层（DLPFC）， 在大多数先前MCI/AD rTMS试验中使用的刺激部位是实现最大 有效的作用，包括对情景记忆的作用。重要的是，当其他研究者使用rTMS 刺激健康年轻人的侧顶叶皮质（LPC）部位，rTMS对记忆的显著影响 几周后就可以测量了。此外，大脑区域的功能连接选择性地增加， 包括后扣带皮层（PCC），在遗忘型MCI中受影响的大脑网络的“枢纽”。 因为刺激DLPFC和LPC可能各自具有不同的效果，我们设计了这个初步试验， 有两个积极的rTMS治疗组：DLPFC和LPC。第三组，假手术对照组，也将被包括在内 来完成一个对照随机双盲试验对于三组中的每一组，刺激将是 根据AD研究中获得的效果，双侧。主要假设是主动rTMS（对 刺激部位）在改善记忆方面将优于假手术对照组上级。职能变化的计量 将计算连通性，以检查是否有证据表明rTMS改变了 PCC与大脑的其他区域。除了观察rTMS对功能连接的影响外， 认知有关的皮质部位刺激，遗传标记将被收集，以解决 反应的异质性。为了跟踪rTMS对记忆力影响的持久性，将跟踪参与者 比之前的任何研究都要长（干预后长达6个月）。如果这项研究发现rTMS可以改善记忆 在患有MCI的老年人中，这种非药物治疗的进一步临床开发最终可以 改善数百万患有MCI的老年人的生活，他们患痴呆症的风险增加。

Abstract: Mild Cognitive Impairment (MCI) carries a high risk of progression to dementia due to Alzheimer's disease (AD). Yet, there are currently no effective treatments. For older adults with MCI, the cognitive problems and uncertainty they face negatively impacts their everyday functioning, capacity and confidence to engage in challenging cognitive activities, and thus their quality of life. A substantial proportion of adults with MCI either take cholinesterase inhibitors or have tried them, but the low efficacy of these approved treatments for AD appears outweighed by their side effects. The goal of this study is to test the efficacy of a non-pharmacological treatment for MCI that involves noninvasive brain stimulation (NIBS). Early studies in AD dementia patients have found that repetitive transcranial magnetic stimulation (rTMS, a form of NIBS) improved global cognitive function and activities of daily living. Given that in AD, neuronal loss and synaptic dysfunction progress along brain networks, these early studies of brain stimulation in AD dementia suggest there is sufficient neuroplasticity for efficacious effects of brain stimulation. Of the very few rTMS studies in MCI that have been published, the effect size appears to be moderately large. However, it is not clear whether the dorsolateral prefrontal cortex (DLPFC), the stimulation site used in most of the prior MCI/AD rTMS trials, is the optimal site for achieving the most efficacious effects including effects on episodic memory. Importantly, when other investigators used rTMS to stimulate a lateral parietal cortical (LPC) site in healthy young adults, significant effects of rTMS on memory were measurable weeks later. Moreover, functional connectivity of brain regions was selectively increased, including the posterior cingulate cortex (PCC), a “hub” of brain networks that is affected in amnestic MCI. Because stimulation of the DLPFC and the LPC may each have distinct effects, we designed this pilot trial to have two active rTMS treatment groups: DLPFC and LPC. A third group, a sham-control, will also be included to achieve a controlled, randomized, double-blind trial. For each of the three groups, stimulation will be bilateral, based on effects achieved in the AD studies. The primary hypothesis is that active rTMS (to either site of stimulation) will be superior to sham-control in improving memory. Measures of change in functional connectivity will be computed to examine whether there is evidence that rTMS changes connectivity of the PCC with other regions of the brain. In addition to looking at effects of rTMS on functional connectivity and cognition in relation to the cortical site stimulated, genetic markers will be collected toward addressing heterogeneity of response. To track the durability of rTMS effects on memory, participants will be followed longer than in any prior study (up to 6 months after the intervention). If this study finds rTMS improves memory in older adults with MCI, further clinical development of this non-pharmacological treatment could ultimately improve the lives of millions of older adults who have MCI and are at an increased risk of developing dementia.