CAUSAL MECHANISMS OF DISTRIBUTED BRAIN NETWORK FUNCTION DURING EPISODIC MEMORY RETRIEVAL

项目摘要 这一建议源于之前批准的K99奖学金，西北大学作为拟议的R00阶段机构。记忆障碍是许多神经和精神疾病的常见症状，包括阿尔茨海默病和抑郁症，这些疾病给社会带来了沉重的负担。脑刺激是一种潜在的强大的治疗策略，有可能导致情景记忆的改善。然而，它的有效性依赖于精确的刺激靶向，以一种尊重个人大脑功能解剖特点的方式。功能磁共振成像(FMRI)的最新进展使人们能够在个体内精确地定义大脑网络。与记忆障碍特别相关的是，最近在个体中发现了一个分布的网络，其中包括顶后皮质和海马旁皮质--调节记忆的主要刺激目标--的区域，以及分布在额叶、顶叶、颞叶和中线皮质的其他区域。目前还不知道刺激这些额外的分布区域是否会导致记忆改善。如果是这样的话，这可能会为基于刺激的疗法提供更多、可能更容易获得的靶点。在本项目中，将对计划接受颅内监测的癫痫患者进行功能磁共振成像的个体水平网络标测。包括海马旁和顶叶后皮质的分布式网络将在个体患者中被精确地描绘出来，所产生的网络图将被用来选择用于刺激的候选植入电极。通过在情节记忆任务中获得的记录，将在高时间和空间分辨率下表征分布式大脑网络参与情节记忆的特征。录音将允许探索这个网络的电生理特性，以及量化它与邻近网络的分离和相互作用，并将对个别部位进行直接皮质刺激，目的是测试该网络对情节记忆的因果影响。为了实现这个项目，PI将在西北大学范伯格医学院建立一个研究项目，以斯坦福大学在K99培训期间获得的程序、方案和经验为基础，并与神经科学家(Joel Voss博士)合作。和癫痫专家(斯蒂芬·舒勒博士)在西北大学。由此产生的数据将完善目前对涉及情景记忆的神经系统的理解，并重要地为使用个体水平的网络映射来指导颅内脑记录和刺激提供原则证明，这可能对一系列心理健康障碍的刺激疗法具有重要意义。

Project Summary This proposal follows from a previously approved K99 fellowship, with Northwestern University as the proposed R00-phase institution. Memory impairments are common to many neurological and psychiatric disorders, including Alzheimer’s disease and depression, which impose a heavy burden on society. Brain stimulation is a potentially powerful therapeutic strategy with the potential to elicit improvements in episodic memory. However, its efficacy depends on precise targeting of stimulation, in a manner that respects the idiosyncrasies of an individual’s functional brain anatomy. Recent advances in functional magnetic resonance imaging (fMRI) have allowed brain networks to be defined with precision within individuals. Of particular relevance to memory disorders, a distributed network was recently identified within individuals that includes regions of posterior parietal and parahippocampal cortices – prominent stimulation targets for modulation of memory – in combination with other regions distributed throughout frontal, parietal, temporal and midline cortices. It is not known whether stimulation of these additional distributed regions can lead to memory improvements. If so, this could provide additional and potentially more accessible targets for stimulation-based therapies. In this project, individual-level network mapping with fMRI will be performed on epilepsy patients who are scheduled to undergo intracranial monitoring. The distributed network which includes parahippocampal and posterior parietal cortex will be delineated with precision in individual patients and the resulting network maps will be used to select candidate implanted electrodes for stimulation. The involvement of the distributed brain network in episodic memory will be characterized at high temporal and spatial resolution through recordings obtained during an episodic memory task. Recordings will allow the exploration of electrophysiological properties of this network, as well as quantify its separation and interactions with neighboring networks, and direct cortical stimulation will be applied to individual sites with the aim of testing the causal influence of the network on episodic memory. To achieve this project, the PI will establish a research program at the Northwestern University Feinberg School of Medicine, building on procedures, protocols and experience gained at Stanford University during the K99 training, and in collaboration with neuroscientists (Joel Voss, Ph.D.) and epileptologists (Stephan Schuele, Ph. D.) at Northwestern University. The resulting data will refine the current understanding of the neural systems involved in episodic memory, and importantly provide a proof-of-principle for the use of individual-level network mapping to guide intracranial brain recording and stimulation, which could have important implications for stimulation therapies for a range of mental health disorders.