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

失忆是人类最具毁灭性的痛苦之一。睡眠对学习和记忆很重要，因为它可以促进记忆的巩固——在清醒时形成的新记忆转化为稳定的记忆，并与先前存在的长期记忆相结合。对事实和事件的记忆（陈述性记忆）尤其如此，这取决于人类海马体内和周围的大脑区域。有证据表明，陈述性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大脑额叶皮质区域之间的相互作用介导的。在这个项目中，研究人员旨在研究睡眠对癫痫患者植入深度电极进行临床监测的学习和记忆的影响。这种设置为直接记录人类大脑内部，包括单个神经元的水平，提供了难得的机会。该项目还提供了一个独特的机会来刺激睡眠期间的大脑，这对于建立睡眠和巩固之间的因果关系是必要的。这项研究将推进关于特定睡眠过程如何帮助记忆巩固的科学知识，并通过在这一综合领域培养学生和开发新方法来造福社会。研究结果可能对患有影响记忆的神经系统疾病的人有所启示。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。拟议的研究研究睡眠在记忆巩固中的因果作用，并基于一个机会，直接记录和刺激从人类大脑到单个神经元水平的神经元活动。在征得知情同意后，加州大学洛杉矶分校的癫痫患者将在睡眠期间植入颅内深度电极，参与学习/记忆范式，并结合录音和颅内电刺激。研究人员打算让参与者在睡觉前完成一项学习任务，在睡眠中记录和控制大脑活动，并在睡眠后评估随后的记忆，从而超越最先进的技术。首先，他们将验证睡眠对记忆巩固的行为益处。这项研究将在加州大学洛杉矶分校进行，对象是癫痫患者（PI: Itzhak Fried），同时与以色列尤瓦尔·尼尔博士的实验室（健康志愿者）合作。该研究将开发并验证可靠且敏感的范式，以了解睡眠，特别是短时间小睡对具有可变记忆表现的个体的陈述性记忆的有益影响。这项研究的重点是一项涉及物体-位置关联的学习任务，以及物体和人物图像之间的配对关联。其次，研究小组将确定与不睡觉的情况相比，哪些睡眠活动与学习和记忆的改善最相关。最后，研究小组将通过颅内刺激评估因果机制，以确定内源性慢振荡刺激是否促进记忆巩固。一个关键的预测是，与不受干扰的睡眠相比，与这种实时闭环刺激相结合的睡眠将在更大程度上有益于记忆表现。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.