NSF/SBE-BSF: The role of sleep in memory consolidation: intracranial human electrophysiology and electrical stimulation

记忆力丧失是人类疾病中最具破坏性的痛苦之一。睡眠对学习和记忆很重要，因为它改善了记忆巩固--将清醒时形成的新记忆转化为稳定的记忆，并整合到预先存在的长期记忆中。对于事实和事件的记忆(陈述性记忆)尤其如此，它依赖于人类海马体及其周围的大脑区域。有证据表明，陈述性的海马体依赖记忆在被称为慢波睡眠的睡眠阶段得到巩固，在这个阶段，大的慢波主导着大脑活动。这种巩固被认为是由海马体和额叶皮质脑区之间的相互作用所调节的。在这个项目中，研究人员的目标是研究睡眠对植入深度电极的癫痫患者学习和记忆的影响，以用于临床监测。这种设置为直接从人脑内部进行记录提供了难得的机会，包括在单个神经元的水平上。该项目还提供了一个在睡眠期间刺激大脑的独特机会，这是建立睡眠和巩固之间的因果关系所必需的。这项研究将促进关于特定睡眠过程如何帮助巩固记忆的科学知识，并通过培训学生在这一综合领域的学生，并开发新的方法来造福社会。这一结果可能会对患有影响记忆的神经障碍的个人产生影响。结果将通过参加会议和讲习班以及媒体渠道和互联网广泛传播。这项拟议的研究研究了睡眠在巩固记忆中所起的因果作用，其基础是一个记录和刺激神经元活动的机会，直接从人脑到单个神经元的水平。经知情同意后，加州大学洛杉矶分校植入颅内深部电极的癫痫患者将参与学习/记忆范例，结合睡眠中的记录和颅内电刺激。研究人员打算让参与者在睡觉前执行一项学习任务，记录和操纵睡眠期间的大脑活动，并评估睡眠后的后续记忆，从而超越最先进的水平。首先，他们将验证睡眠对巩固记忆的行为益处。这项研究将在加州大学洛杉矶分校对癫痫患者(PI：Itzhak Fry)进行，并与Yuval Nir博士在以色列的实验室(与健康志愿者)合作进行。这项研究将开发和验证可靠和敏感的范式，以了解睡眠的有益影响，特别是小睡片刻对记忆能力不同的个体的陈述性记忆的影响。这项研究关注的是一项学习任务，该任务涉及物体-位置关联以及物体和人物图像之间的配对关联。其次，研究小组将确定哪些睡眠活动与学习和记忆改善的相关性最好，而不是没有睡眠的情况。最后，该团队将通过颅内刺激来评估因果机制，以确定锁定于内源性慢振荡的刺激是否促进记忆巩固。一个关键的预测是，与这种实时闭环刺激相结合的睡眠将在更大程度上改善记忆性能，而不是不受干扰的睡眠。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Memory loss is one of the most devastating afflictions of the human condition. Sleep is important for learning and memory because it improves memory consolidation - the transformation of new memories that are formed during wakefulness into stable memories that are integrated into pre-existing long-term memories. This is particularly true for memory for facts and events (declarative memory), which depends on brain regions in and around the human hippocampus. There is evidence that declarative hippocampus-dependent memories are consolidated during a sleep-stage called slow-wave-sleep, where large slow waves dominate brain activity. This consolidation is thought to be mediated by interactions between the hippocampus and brain areas in the frontal cortex. In this project, the researchers aim to study the effects of sleep on learning and memory in epilepsy patients implanted with depth electrodes for clinical monitoring. This setting provides a rare opportunity for direct recordings from inside the human brain, including at the level of individual neurons. The project also affords a unique opportunity to stimulate the brain during sleep, which is necessary for establishing a causal relationship between sleep and consolidation. This research will advance scientific knowledge on how specific sleep processes aid memory consolidation, and benefit society by training students in this integrative field, and developing new methods. The results may have implications for individuals suffering from neurological disorders affecting memory. Results will be disseminated broadly through participation in conferences and workshops, as well as media channels and the internet. The proposed research studies the causal role that sleep plays in memory consolidation, and is based on a an opportunity to record and stimulate neuronal activity directly from the human brain down to the level of single neurons. Upon informed consent, epilepsy patients at UCLA implanted with intracranial depth electrodes will participate in learning/memory paradigms combined with recordings and intracranial electrical stimulation during sleep. The researchers intend to advance beyond the state-of-the-art by having participants perform a learning task before sleep, record and manipulate brain activity during sleep, and evaluate subsequent memory after sleep. First, they will validate the behavioral benefits of sleep on memory consolidation. This study will be performed at UCLA with epilepsy patients (PI: Itzhak Fried), and in parallel in collaboration with Dr. Yuval Nir's lab in Israel (with healthy volunteers). The study will develop and validate paradigms that are reliable and sensitive to the beneficial effects of sleep, and short naps in particular, on declarative memory among individuals with variable memory performance. The study focuses on a learning task involving object-position associations, as well as paired associations between object and person images. Second, the research team will determine which sleep activities correlate best with learning and memory improvements as compared to no-sleep conditions. Finally, the team will evaluate causal mechanisms through intracranial stimulation to determine whether stimulation locked to endogenous slow oscillations promotes memory consolidation. A key prediction is that sleep in conjunction with such real-time closed-loop stimulation will benefit memory performance to a greater extent than undisturbed sleep.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.