Mak-McCully Rachel A, Deiss Stephen R, Rosen Burke Q, Jung Ki-Young, Sejnowski Terrence J, Bastuji Hélène, Rey Marc, Cash Sydney S, Bazhenov Maxim, Halgren Eric
Department of Neurosciences, University of California, San Diego, San Diego, California, United States of America.
Computer Science and Engineering Department, University of California, San Diego, San Diego, California, United States of America.
PLoS Comput Biol. 2014 Sep 25;10(9):e1003855. doi: 10.1371/journal.pcbi.1003855. eCollection 2014 Sep.
Sleep spindles and K-complexes (KCs) define stage 2 NREM sleep (N2) in humans. We recently showed that KCs are isolated downstates characterized by widespread cortical silence. We demonstrate here that KCs can be quasi-synchronous across scalp EEG and across much of the cortex using electrocorticography (ECOG) and localized transcortical recordings (bipolar SEEG). We examine the mechanism of synchronous KC production by creating the first conductance based thalamocortical network model of N2 sleep to generate both spontaneous spindles and KCs. Spontaneous KCs are only observed when the model includes diffuse projections from restricted prefrontal areas to the thalamic reticular nucleus (RE), consistent with recent anatomical findings in rhesus monkeys. Modeled KCs begin with a spontaneous focal depolarization of the prefrontal neurons, followed by depolarization of the RE. Surprisingly, the RE depolarization leads to decreased firing due to disrupted spindling, which in turn is due to depolarization-induced inactivation of the low-threshold Ca2+ current (IT). Further, although the RE inhibits thalamocortical (TC) neurons, decreased RE firing causes decreased TC cell firing, again because of disrupted spindling. The resulting abrupt removal of excitatory input to cortical pyramidal neurons then leads to the downstate. Empirically, KCs may also be evoked by sensory stimuli while maintaining sleep. We reproduce this phenomenon in the model by depolarization of either the RE or the widely-projecting prefrontal neurons. Again, disruption of thalamic spindling plays a key role. Higher levels of RE stimulation also cause downstates, but by directly inhibiting the TC neurons. SEEG recordings from the thalamus and cortex in a single patient demonstrated the model prediction that thalamic spindling significantly decreases before KC onset. In conclusion, we show empirically that KCs can be widespread quasi-synchronous cortical downstates, and demonstrate with the first model of stage 2 NREM sleep a possible mechanism whereby this widespread synchrony may arise.
睡眠纺锤波和K复合波（KCs）定义了人类非快速眼动睡眠（NREM）的2期（N2）。我们最近发现，K复合波是由广泛的皮层沉默所表征的孤立下行状态。我们在此证明，使用皮层脑电图（ECOG）和局部经皮层记录（双极立体脑电图，bipolar SEEG），K复合波在头皮脑电图以及大部分皮层中可以是准同步的。我们通过创建首个基于电导的N2睡眠丘脑皮层网络模型来生成自发纺锤波和K复合波，从而研究同步K复合波产生的机制。只有当模型包括从受限的前额叶区域到丘脑网状核（RE）的弥散投射时，才会观察到自发K复合波，这与恒河猴最近的解剖学发现一致。模拟的K复合波始于前额叶神经元的自发局灶性去极化，随后是丘脑网状核的去极化。令人惊讶的是，丘脑网状核的去极化由于纺锤波活动受到破坏而导致放电减少，而这又是由于去极化诱导的低阈值Ca2+电流（IT）失活所致。此外，尽管丘脑网状核抑制丘脑皮层（TC）神经元，但丘脑网状核放电减少会导致TC细胞放电减少，同样是因为纺锤波活动受到破坏。由此导致的对皮层锥体神经元兴奋性输入的突然去除进而导致下行状态。根据经验，K复合波也可能在维持睡眠时由感觉刺激诱发。我们通过使丘脑网状核或广泛投射的前额叶神经元去极化，在模型中重现了这一现象。同样，丘脑纺锤波活动的破坏起到了关键作用。更高水平的丘脑网状核刺激也会导致下行状态，但这是通过直接抑制TC神经元实现的。对一名患者的丘脑和皮层进行的立体脑电图记录证明了模型的预测，即丘脑纺锤波活动在K复合波开始前会显著减少。总之，我们通过实验表明K复合波可以是广泛的准同步皮层下行状态，并利用首个NREM睡眠2期模型证明了这种广泛同步可能出现的一种机制。
