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脑节律背后的神经元活动对于许多形式的记忆巩固至关重要。丘脑皮层睡眠纺锤波，即，在12 Hz左右持续0.5 - 3 s的渐增和渐减振荡呈现中枢内源性节律。特别是，睡眠纺锤波和皮质慢振荡（SO，~ 1 Hz）和更快（~ 150 Hz）的海马波纹之间的精细时间耦合被认为反映了神经再激活和记忆巩固。然而，纺锤波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波和涟漪持续时间对记忆处理的重要性。此外，纺锤波持续时间随着年龄的增长和多种神经精神疾病而减少。然而，纺锤波持续时间对记忆巩固的因果作用的直接证据缺失。应用非侵入性脑刺激方法，如电刺激或听觉刺激，可以促进睡眠节律并改善记忆，为研究睡眠节律对记忆巩固的因果作用提供了工具。此外，其他人和我们都认为人类的特质特征，特别是认知能力指标和基线睡眠参数，是个体对脑刺激敏感性的相关标志。这种个体间的差异可以很好地解释在一些研究中刺激功效的变异性和刺激的记忆益处的再现性差。在这个项目中，我们的目标首先是直接针对持续的睡眠纺锤波的持续时间，以探索的因果关系的作用，长时间的纺锤波区域间的时间相互作用和记忆性能的实验和计算。我们提出了一种新的闭环调幅听觉刺激设计，振幅振荡在受试者的个人主轴频率。作为实验的补充，我们将进一步开发我们的海马丘脑-皮质神经块模型，该模型可以自发地产生SO、纺锤波和波纹。我们将通过计算探索刺激参数对睡眠节律的影响，特别是纺锤持续时间以及纺锤波耦合，这不能通过非侵入性方法在健康人中进行实验研究。为了在个体受试者水平上获得关于刺激功效的可靠信息，我们的第二个目标是表征认知能力、非学习基线EEG和刺激功效对记忆巩固和EEG测量之间的相互作用。在计算模型中，在刺激时，由相关模型参数控制的SO和主轴特性的影响是用于调查的示例性参数。我们的长期目标是根据我们的实验和计算建模结果开发个性化的刺激方法，用于未来的应用，例如，用于精准医疗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.