Investigating the functional role of long-duration sleep spindles in memory consolidation via non-invasive brain stimulation

睡眠期间自发产生的大脑节律下的神经元活动对许多形式的记忆巩固至关重要。丘脑皮质睡眠纺锤波，即在12赫兹左右的振荡，持续时间为0.5~3小时，呈中枢性内源性节律。特别是睡眠纺锤体与皮层慢振荡(~1 Hz)和快得多(~150 Hz)的海马波之间的细微时间耦合被认为反映了神经的重新激活和记忆的巩固。然而，纺锤体在这种多区域交流中的作用仍然知之甚少。一些研究已经揭示了纺锤形和波纹持续时间对记忆处理的重要性。此外，纺锤体的持续时间随着年龄的增长而减少，在多种神经精神障碍中也是如此。然而，关于纺锤体持续时间在记忆巩固中的因果作用的直接证据尚不清楚。非侵入性脑刺激方法的应用，如电刺激或听觉刺激，可以促进睡眠节律，改善记忆，为研究睡眠节律对记忆巩固的因果作用提供了工具。此外，其他人和我们建议，人类的特征样特征，特别是认知能力指标和基线睡眠参数，可以作为个人对大脑刺激易感性的相关标志。在一些研究中，这种个体间的差异可以很好地解释刺激效果的差异和刺激记忆益处的较差重复性。在这个项目中，我们首先从实验和计算两个方面直接针对持续睡眠纺锤波的持续时间，以探索长持续时间纺锤波对区域间时间交互作用和记忆表现的因果作用。我们提出了一种新颖的闭环调幅听觉刺激设计，其幅度在受试者个人的主轴频率上振荡。作为实验的补充，我们将进一步开发我们的海马丘脑-皮质神经团模型，该模型可以自发地产生SOS、纺锤体和波纹。我们将通过计算探索刺激参数对睡眠节律的影响，特别是纺锤波持续时间以及纺锤波耦合，这是健康人体无法用非侵入性方法进行实验研究的。为了在个体被试水平上获得关于刺激效能的可靠信息，我们的第二个目标是表征认知能力、非学习基线脑电和刺激效能在记忆巩固和脑电测量上的交互作用。在计算模型中，SO的影响和由相关模型参数控制的纺锤体性质在刺激时是用于研究的示例性参数。我们的长期目标是基于我们的实验和计算模型结果开发个性化的刺激方法，用于未来的应用，例如，在精密医学和治疗记忆问题的患者。

Neuronal activity underlying spontaneously generated brain rhythms during sleep are crucial for many forms of memory consolidation. Thalamocortical sleep spindles, i.e., waxing and waning oscillations at around 12 Hz lasting from 0.5 to 3 s present a central endogenous rhythm. In particular, the fine temporal coupling between sleep spindles and both the cortical slow oscillation (SO, ~ 1 Hz) and much faster (~ 150 Hz) hippocampal ripples is suggested to reflect neural reactivation and memory consolidation. However, the contribution of spindles in this multi-regional communication remains poorly understood. Several studies have revealed the importance of spindle and ripple durations for memory processing. Furthermore, spindle duration decreases with age and in multiple neuropsychiatric disorders. Direct evidence for a causal role of spindle duration on memory consolidation is missing, however. The application of non-invasive brain stimulation methods such as electric or auditory stimulation can boost sleep rhythms and improve memory providing a tool to investigate the causal role of sleep rhythms for memory consolidation. Moreover, others and we have suggested trait-like features in humans, especially cognitive ability metrics and baseline sleep parameters, to be relevant markers for the susceptibility of an individual to brain stimulation. Such inter-individual variances may well explain variabilities in stimulation efficacy and poor reproducibility of memory benefits of stimulation in some studies. In this project, we firstly aim to directly target the duration of ongoing sleep spindles to explore the causal role of long-duration spindles on inter-regional temporal interactions and memory performance both experimentally and computationally. We propose a novel Closed-Loop Amplitude-Modulated auditory Stimulation design with amplitudes oscillating at subjects’ individual spindle frequency. Complimentary to experiments we will further develop our hippocampal thalamo-cortical neural mass model that can spontaneously generate SOs, spindles and ripples. We will computationally explore effects of stimulation parameters on sleep rhythms especially the spindle duration as well as spindle-ripple coupling, which can not be investigated by non-invasive methods in healthy humans experimentally. To obtain reliable information on stimulation efficacy at the individual subject level, we secondly aim to characterize interactions between cognitive ability, non-learning baseline EEG and stimulation efficacy on memory consolidation and EEG measures. In the computational model, the impact of SO and spindle properties controlled by relevant model parameters, at the time of stimulation, are exemplary parameters for investigation. Our long-term goal is to develop individualized stimulation methods based on our experimental and computational modelling results for future applications, e.g., in precision medicine and for treatments of patients with memory problems.