Elsevier

NeuroImage

Volume 59, Issue 2, 16 January 2012, Pages 1631-1638
NeuroImage

To wake or not to wake? The two-sided nature of the human K-complex

https://doi.org/10.1016/j.neuroimage.2011.09.013Get rights and content

Abstract

Sleep fosters performance but likewise renders creatures insensitive to environmental threat. The brain balances between sleep promotion and protection during light sleep. One associated electrophysiological hallmark is the K-complex (KC), the sleep promoting versus arousal inducing role of which is under debate. We examined 37 subjects using EEG-combined fMRI and found KC-associated positive BOLD signal changes in subcortical (brainstem, thalamus), sensory and motor, midline and regions which form part of the default mode network, and negative changes in the anterior insula. Connectivity analysis revealed the primary auditory cortex as the first region to be influenced during the KC and that midline regions activated successively from front to back in association with the sleep protecting part of the KC. Our findings support thalamic involvement in KC mediation and an association of KCs with subcortical arousal mechanisms: activations in sensory areas suggest the existence of low level information processing during KC limited by anterior insula disengagement suggesting a two-sided nature of the KC: it embodies an arousal with subsequent sleep-guarding counteraction that might on the one hand serve periodical monitoring of the environment with basic information processing and on the other hand protect the continuity of sleep and thus its restoring effect.

Highlights

► Human in vivo findings support animal studies: thalamic involvement in KC mediation. ► KC reflects subcortical arousal and low level information processing. ► Arousal process is limited by disengagement of saliency network (anterior insula). ► Sleep preserving counteraction is promoted by cerebral midline structures.

Introduction

Sleep describes a period of reduced consciousness. The ability of the organism to react to stimuli is preserved making sleep a reversible physiological state in contrast to states of pathologically reduced responsiveness such as coma or the vegetative state (Cirelli and Tononi, 2008). Sleep is subdivided into stages with different arousal thresholds (drowsiness, light sleep, deep sleep) and categorized based on features of the electroencephalogram (EEG) changing from high-frequency, low-voltage oscillations during wakefulness over higher voltage, slower waves representing light non-rapid eye movement (NREM) sleep to high-voltage, slow wave activity during deep sleep (Saper et al., 2010).

The K-complex (KC) is one major graphoelement of the adult non-REM sleep EEG. It characterizes sleep stage 2, an intermediate epoch between drowsiness and deep sleep. Loomis and colleagues first described that this “K wave or complex appears […] either spontaneously or as the result of stimulation” (Loomis et al., 1938). Neurophysiologically, the KC indeed represents a multimodal fronto-central evoked response with a longer refractory period and different late components (N350, N550 and P900) than primary sensory evoked potentials (Colrain, 2005, Colrain et al., 2000, Gora et al., 1999, Halasz, 2005).

Functionally, it is under debate whether the KC plays a sleep protective role (Bastien et al., 2000, Cash et al., 2009, Colrain, 2005, Nicholas et al., 2002, Wauquier et al., 1995) promoting deeper sleep, or whether it is correlated with a cortical arousal (Ehrhart et al., 1981, Halasz, 1993). Accordingly, the KC has been ascribed a janus-faced role (Bastien et al., 2000, Halasz, 2004, Halasz, 2005, Terzano and Parrino, 2000, Terzano et al., 2005). Sleep stage transitions are thought to happen relatively rapidly when the system passes a critical state (Beenhakker and Huguenard, 2009), and it is conceivable that the KC marks instances when the system approaches but eventually does not cross the critical line.

For the understanding of the KC, we will distinguish a subcortical from a cortical arousal level. i) At a level confined to the brainstem, arousal can consist of only a change of autonomic functions. As a consequence of especially mesencephalic brain stem activity the thalamic relay neuron membrane potential can be influenced and thalamic signal transmission thereby reinstalled (Evans, 2003). ii) Additionally, an unspecific broad cerebral excitation can be brought about by pontomesencephalic nuclei via the intrathalamic and midline thalamic nuclei. Cortically, primary and maybe secondary sensory areas might resume information processing which the KC has been related to (Bastuji and Garcia-Larrea, 1999, Cash et al., 2009, Halasz, 2005, Niiyama et al., 1995). The resumption of information processing in primary sensory areas should also include a change in thalamic activity from the oscillatory burst mode to the relay mode allowing for accurate signal transmission (Evans, 2003). iii) At a higher level of processing external or self-awareness might be reinstalled. In this context, apart from the brainstem, thalamus and sensory areas, the lateral frontal–parietal regions subserving external awareness as well as the default mode network (DMN), related to self-awareness, are of particular interest (Vanhaudenhuyse et al., 2011, Boly et al., 2008, Larson-Prior et al., 2009, Raichle et al., 2001).

The thalamus is centrally involved in arousal mechanisms and sensory signal transduction, and hence a thalamic association with the KC can be expected. Furthermore, electrophysiological data support the assumption that the thalamus plays a crucial role in the mediation of graphoelements (sleep spindles, delta waves) following the KC (Amzica and Steriade, 2002, Nicholas et al., 2006, Steriade and Amzica, 1998).

We used electroencephalography (EEG)-correlated functional magnetic resonance imaging (fMRI) to elucidate the function of the KC by relating it to brain areas exhibiting associated activity changes and examining the effective connectivity between these regions. Specifically, we hypothesized that the KC reflects a subcortical arousal with a limited cortical arousal in the form of low level cortical information processing. Therefore, we expected to find KC-associated positive blood oxygen level-dependent (BOLD) signal changes in the brainstem, the thalamus and primary sensory areas, especially the primary auditory cortex, and an associated connectivity precluding higher level processing.

Section snippets

Subjects

37 (age range 20–31, mean age 24 years) of 149 healthy, non-sleep-deprived subjects who participated in the study (written informed consent, approval by the local ethics committee) were analyzed. A sub-selection of subjects was necessary to ensure valid fMRI designs at the single subject level as well as a balanced design at the second level (group analysis). Subjects were included if they met a priori selection criteria which provided a sufficient number of data points (EPI volumes and KCs) for

EEG

A total of 37 subjects were included in the analysis, the number of N2 segments, stages and K-complexes included into further analysis alongside two example hypnograms are displayed in Fig. 1.

fMRI group analysis

The second level random effects group analysis revealed KC-correlated BOLD cerebral gray matter signal changes in bilateral primary and associative auditory as well as visual cortices, para- and postcentral (Area 4 d and 6) gyrus including the supplementary motor area, the fusiform gyrus, the precentral,

Discussion

In 37 healthy adults studied with EEG/fMRI during stage 2 sleep we found KC-associated positive BOLD signal changes in subcortical (brainstem, thalamus), cerebellar, sensory and motor (auditory, and visual, sensorimotor cortices), midline (anterior and midcingulate gyrus, precuneus) and regions which form part of the default mode network (prefrontal cortex, inferior parietal lobule, precuneus). Negative BOLD signal changes were detected in the anterior insula bilaterally. The effective

Conclusion

Our human in vivo multi-modal data corroborate previous animal studies demonstrating a thalamic involvement in the mediation of the KC and provide evidence for a two-sided nature of the evoked KC: (1) association with a subcortical arousal with low level information processing limited by disengagement of saliency network regions; and (2) a sleep preserving counteraction promoted by cerebral midline structures. The KC may hence reconcile two vital though seemingly contradictory processes:

Acknowledgments

This work was funded by the Bundesministerium für Bildung und Forschung (grant 01 EV 0703) and LOEWE Neuronale Koordination Forschungsschwerpunkt Frankfurt (NeFF). We thank Sandra Anti, Ralf Deichmann and Steffen Volz for extensive MRI support, Christian Kell for his important input regarding the saliency network, David E. Linden for a very helpful discussion on the P300, our reviewers for their intellectual input, Torben E. Lund for providing a matlab implementation of the RETROICOR method,

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