Promoting adaptive neuroplasticity in mild cognitive impairment

描述（由申请人提供）： 美国人口老龄化威胁着我们的医疗基础设施，特别是因为阿尔茨海默病（AD）的发病率预计在未来几十年将增加两倍。这一问题在退伍军人管理局医疗保健系统中更为严重，超过40%的退伍军人年龄在65岁或以上，而普通人群中这一比例为13%。记忆缺陷是AD的特征，并导致功能障碍、生活质量降低、照顾者倦怠增加，并最终导致机构化。轻度认知障碍（MCI）的诊断确定了那些有记忆缺陷但在日常生活中保持相对独立的人。由于这些患者转化为AD的风险大大增加，MCI提供了一个窗口，在此窗口内干预可以最大限度地提高记忆功能并延长独立性。这项拟议中的研究特别关注记忆策略训练和非侵入性脑刺激的突破性结合。 记忆策略是帮助患者克服记忆缺陷的认知“工具”。我们的初步数据表明，记忆策略对提高记忆力是有效的，但（1）并非所有患者都能从训练中受益，（2）患者难以将其概括为新信息。在这些早期的研究中，我们已经使用功能性磁共振成像（fMRI）来识别策略使用的神经相关性，这表明左腹外侧前额叶皮层是这样一个神经系统。 重要区域。经颅直流电刺激（tDCS）是一种非侵入性脑刺激形式，用于增强神经可塑性并提高行为训练技术（例如，中风后运动康复）。因此，该研究的中心前提是tDCS可以增强腹外侧前额叶皮层的功能，从而诱导适应性神经可塑性变化，并增加MCI患者记忆策略训练的疗效。 在这项随机、双盲研究中，受试者将完成5个连续治疗阶段，在这些治疗阶段中，他们将在目标大脑区域接受活性或假tDCS，并结合记忆策略训练。患者将接受基于实验室和现实世界的记忆测试，以检查策略概括以及训练前后的fMRI扫描。将在3个月随访时检查记忆测试和fMRI改善的持续性。功能磁共振成像的使用将提供有关作用机制的关键信息，特别是目标脑区（vlPFC）是否确实介导了行为改善。 预计相对于假手术组，活性tDCS组将表现出基于生态学的记忆测量的持续改善以及腹外侧前额叶皮质内的激活增加。我们还将研究增加的大脑激活和对目标大脑区域介导的其他认知过程的一般影响之间的关系。这项首创的研究有可能将更多的“基础”科学发现转化为针对我们老龄化人口的神经解剖学和功能上有意义的治疗方法。

DESCRIPTION (provided by applicant): The aging US population threatens to overwhelm our healthcare infrastructure, especially since the rate of Alzheimer's disease (AD) alone is expected to triple in the coming decades. This problem is compounded in the VA Healthcare System, where over 40 percent of veterans are age 65 or older compared to 13 percent within the general population. Memory deficits are characteristic of AD and cause functional impairment, reduced quality of life, increased caregiver burnout, and eventual institutionalization. The diagnosis of mild cognitive impairment (MCI) identifies those with memory deficits but who remain relatively independent in everyday life. Because these patients are at substantially increased risk of converting to AD, MCI provides a window within which interventions could maximize memory functioning and prolong independence. The proposed study focuses specifically on a groundbreaking combination of mnemonic strategy training and non- invasive brain stimulation. Mnemonic strategies are cognitive "tools" that help patients work around memory deficits. Our preliminary data suggest that mnemonic strategies are effective for improving memory but that (1) not all patients benefit from training and (2) patients have difficulty generalizing them to new information. We have used functional magnetic resonance imaging (fMRI) in these earlier studies to identify the neural correlates of strategy use, which suggest that the left ventrolateral prefrontal cortex is one such vital region. Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation that is used to enhance neuroplasticity and improve the efficacy of behavioral training techniques (e.g., motor rehabilitation after stroke). Thus, the central premise of the proposed study is that tDCS can enhance functioning in the ventrolateral prefrontal cortex, thereby inducing adaptive neuroplastic change and increasing the efficacy of mnemonic strategy training in patients with MCI. In this randomized, double-blind study, participants will complete 5 consecutive treatment sessions in which they receive either active or sham tDCS over the targeted brain region in combination with mnemonic strategy training. Patients will undergo both laboratory-based and real-world memory testing to examine strategy generalization as well as fMRI scanning before and after training. Persistence of memory test and fMRI improvements will be examined at a 3-month follow-up. The use of fMRI will provide critical information about the mechanisms of action, especially whether the targeted brain region (vlPFC) does, in fact, mediate behavioral improvement. It is expected that, relative to the sham group, the active tDCS group will demonstrate persistent improvement in ecologically-based measures of memory as well as increased activation within the ventrolateral prefrontal cortex. We will also examine the relationship between increased brain activation and generalized effects on other cognitive processes mediated by the targeted brain region. This first-of-its-kind study has the potential to meaningfully translate more "basic" science findings into neuroanatomically targeted and functionally meaningful treatments for our aging population.