Neural basis of cognitive reserve: fMRI/TMS studies of memory and aging

描述（申请人提供）：神经退化总是伴随着年龄的增长，但一些老年人仍能保持良好的认知功能。在面对衰老和疾病时维持功能的能力被称为认知储备。认知储备背后的神经基础知识将为认知衰退和痴呆的治疗策略提供信息。这项指导研究科学家发展奖（K01）将为Bruce Luber博士提供必要的培训和技能，使其成为一名具有认知储备神经基础专业知识的独立研究者，应用创新工具，最终可能导致与年龄相关的记忆丧失的新干预措施。认知储备被认为是由两种机制介导的：(1)现有神经网络对衰老影响的弹性（神经储备）；(2)通过招募新网络进行补偿。功能性神经影像学研究已经产生了关于认知储备这些方面的神经基础的假设，但不能检验因果关系。这个K01将使候选人能够使用图像引导的无创脑刺激来测试认知储备这两个方面的神经基础。具体目的是：利用fMRI和比较年轻人和老年人的先进多变量分析来识别与老年人工作记忆相关的神经储备和补偿网络（Aim 1），并利用fMRI引导的经颅磁刺激验证神经储备（Aim 2）和补偿（Aim 3）网络的功能作用。这项工作扩展了候选人的研究，表明fmri引导的针对储备网络的TMS可以改善基线和睡眠剥夺后的工作记忆表现。职业发展计划将提供以下方面的专业知识：1)衰老的认知神经科学，2)经颅磁刺激的临床应用，3)fmri引导的经颅磁刺激作为神经生物学探针的使用，4)临床试验设计和统计分析，以及5)系统神经科学。这种培训和研究经验将使Luber博士实现他的长期目标，将对认知储备机制的先进理解转化为研究和最终更好地治疗老年人认知衰退的新工具。

DESCRIPTION (provided by applicant): Neural degeneration invariably accompanies aging, yet some elders are able to maintain excellent cognitive function. The capacity to sustain function in the face of aging and illness is called cognitive reserve. Knowledge of the neural basis underlying cognitive reserve would inform treatment strategies for cognitive decline and dementia. This Mentored Research Scientist Development Award (K01) will provide Dr. Bruce Luber with the necessary training and skills to become an independent investigator with expertise in the neural basis of cognitive reserve, applying innovative tools that may ultimately lead to novel interventions for age related memory loss. Cognitive reserve is thought to be mediated by two mechanisms: (1) resilience of existing neural networks to the effects of aging (neural reserve), and (2) compensation through enlistment of new networks. Functional neuroimaging studies have generated hypotheses regarding the neural basis of these aspects of cognitive reserve, but cannot test causal relationships. This K01 will equip the candidate to test the neural basis of both aspects of cognitive reserve, using image-guided noninvasive brain stimulation. The specific aims are: to identify neural reserve and compensation networks related to working memory in the elderly using fMRI and advanced multivariate analysis comparing young and older adults (Aim 1), and to validate the functional role of neural reserve (Aim 2) and compensation (Aim 3) networks using fMRI-guided TMS. This work extends the candidate's studies showing that fMRI-guided TMS targeted to a reserve network can improve working memory performance at baseline and following sleep deprivation. The career development plan will provide expertise in: 1) the cognitive neuroscience of aging, 2) the clinical use of TMS, 3) the use of fMRI-guided TMS as a neurobiological probe, 4) clinical trial design and statistical analysis, and 5) systems neuroscience. This training and research experience will position Dr. Luber to achieve his long- term goal to translate an advanced understanding of the mechanisms of cognitive reserve into novel tools to study and ultimately to better treat cognitive decline in the elderly.