**2. Neurobiology of sleep**

#### **2.1 Sleep architecture and physiology**

The heterogeneous nature of sleep can be seen in human and in most animal polysomnographic (PSG) records, which traditionally use electrophysiological techniques including electroencephalography (EEG), electromyography (EMG) and electrooculography (EOG) to characterize sleep at system levels. In humans, overnight sleep is characterized by a cyclic occurrence of non-REM sleep and REM sleep. Non-REM sleep includes lighter sleep stages 1 and 2 and stages 3 and 4 of the deeper slow wave sleep (SWS) (Rechtschaffen & Kales, 1968). Whereas SWS dominates the first half of the night, REM sleep and stage 2 of non-REM sleep dominate the second half. This ultradian dynamics reflects the circadian regulation of sleep that is distinguishable from its homeostatic regulation seen after sleep deprivation or prolonged wakefulness (Borbély 1982; Borbély & Ackermann, 1999). Normally, sleep onset begins with a brief period of stage 1 of non-REM sleep, which is subsequently followed by sleep deepening marked by appearance of stage 2 of non-REM sleep and a further progressive transition to stages 3 and 4 of SWS. The latter is followed by a relatively short transient of stage 2 of non-REM sleep, after which a period of REM sleep appears. This progression of sleep stages, and in particular, the non-REM sleep - REM sleep alternation forms one sleep cycle with approximately 90 min duration. About 5 or more such sleep cycles are usually observed in the normal human overnight sleep (Broughton, 1987; Rechschaffen & Kales, 1968; Sinton & McCarley, 2000).

#### **2.2 Electrophysiological signatures of sleep stages**

156 Neuroimaging – Cognitive and Clinical Neuroscience

role for sleep in human cognitive abilities (Mander et al., 2008; Schabus et al., 2006; 2008; Yoo et al., 2007b), heuristic creativity and insightfulness (Cai et al., 2009; Stickgold et al., 1999; 2001; Wagner et al., 2004; Yordanova et al., 2008; 2009; 2010), constructive thinking and decision making (Durrant et al., 2011; Venkatraman et al., 2011), and emotional regulation (Walker, 2009; Walker & van der Helm, 2009). The latter engages consolidation of emotional memory (Nishida et al., 2009; Wagner et al., 2001; 2006; Walker, 2009) and emotional processing (Gujar et al., 2011a; 2011b; Yoo et al., 2007a). Collectively, these various associations suggest that sleep provides unique conditions for off-line memory consolidation, reconsolidation and information reprocessing to take place. However, it is still not precisely known whether these mechanisms are distinctly different from the restoring and energetic functions of sleep, whether the two types of functions are coupled,

Many electroencephalographic (EEG) and neuroimaging studies including functional magnetic resonance imaging (fMRI) have found that the structural and functional organization of the neural substrate undergoes changes during sleep in relation to human cognition. The entity of neural mechanisms underpinning cognitive and psychological functions of the brain is generally recognized as brain plasticity, i.e., as the capability of the neural substrate to reorganize over time as a result of previous experiences. In this chapter, studies demonstrating that sleep affects cognition by neural plasticity mechanisms in humans will be updated and overviewed to provide a converging framework for better understanding the role of sleep for memory, cognitive abilities and psychological functioning. Since mechanisms of brain plasticity are closely related to sleep physiology, architecture and neurobiological regulation, the reader will be first introduced to

The heterogeneous nature of sleep can be seen in human and in most animal polysomnographic (PSG) records, which traditionally use electrophysiological techniques including electroencephalography (EEG), electromyography (EMG) and electrooculography (EOG) to characterize sleep at system levels. In humans, overnight sleep is characterized by a cyclic occurrence of non-REM sleep and REM sleep. Non-REM sleep includes lighter sleep stages 1 and 2 and stages 3 and 4 of the deeper slow wave sleep (SWS) (Rechtschaffen & Kales, 1968). Whereas SWS dominates the first half of the night, REM sleep and stage 2 of non-REM sleep dominate the second half. This ultradian dynamics reflects the circadian regulation of sleep that is distinguishable from its homeostatic regulation seen after sleep deprivation or prolonged wakefulness (Borbély 1982; Borbély & Ackermann, 1999). Normally, sleep onset begins with a brief period of stage 1 of non-REM sleep, which is subsequently followed by sleep deepening marked by appearance of stage 2 of non-REM sleep and a further progressive transition to stages 3 and 4 of SWS. The latter is followed by a relatively short transient of stage 2 of non-REM sleep, after which a period of REM sleep appears. This progression of sleep stages, and in particular, the non-REM sleep - REM sleep alternation forms one sleep cycle with approximately 90 min duration. About 5 or more such sleep cycles are usually observed in the normal human overnight sleep (Broughton,

or whether the latter simply facilitate the cognitive functions of sleep.

neurobiology of sleep.

**2. Neurobiology of sleep** 

**2.1 Sleep architecture and physiology** 

1987; Rechschaffen & Kales, 1968; Sinton & McCarley, 2000).

The distinct sleep stages of either human overnight sleep or human daily naps can be determined by their specific "macroscopic" electrophysiological signatures, which are described by Rechschaffen & Kales (1968) and are commonly used for human sleep stages scoring. Unlike the desynchronized mode of EEG activity during wakefulness, the electrophysiological signatures of different sleep stages are more complex, which reflects a more heterogeneous nature of sleep than that of wake (Hobson & Pace-Schott, 2002). Basically, wakefulness is divided into active wake, characterized by desynchronized lowvoltage fast EEG activity including beta (~ 15-30 Hz) and gamma (> 30 Hz) rhythms as well as by theta (~ 5 Hz) EEG activity with frontal-midline location, and quiet wake, characterized by posterior alpha (~ 10 Hz) and central sigma (~ 12-14 Hz) EEG rhythms that replace the desynchronized EEG mode of the active wake (Niedermeyer, 1993). The electrophysiological signatures of both active and quiet are show in Figure 1.

Sleep initiation is described as a replacement of waking EEG by theta or slower rhythms paralleled by an appearance of very slow circular eye movements, and both electrophysiological features form stage 1 of non-REM sleep (Broughton, 1987; Sinton & McCarley, 2000). Stage 2 of non-REM sleep is defined by presence of the classical EEG sleep spindles oscillating at ~ 12-15 Hz with central-parietal location, slower sleep spindles oscillating at ~ 9-13 Hz with frontal location and sporadic biphasic slow waves known as Kcomplexes (Anderer et al., 2001; De Gennaro & Ferrara, 2003). Sleep spindles are present also in the deeper SWS stages, but in less pronounced and discrete forms, among which spindle activity in the frequency range of ~ 8-12 Hz with frontal location is recognized to dominate SWS (Cantero et al., 2002; Salih et al., 2009). K-complexes are regarded as precursors of EEG components of the SWS (Amzica & Steriade, 1997; De Gennaro & Ferrara, 2003). These "macroscopic" human electrophysiological signatures of distinct sleep-wake stages are shown in Figure 1.

SWS is hallmarked by synchronous high-voltage (> 75 µV) EEG delta (~ 1-4 Hz) waves and slow (< 1 Hz) oscillations (SO) (Achrermann & Borbely, 1997; Crunelli & Hughes, 2010; Steriade et al., 1993), both recognized as slow wave activity (SWA) (Fig. 1). SO are also shown to occur in stage 2 of non-REM sleep (Crunelli & Hughes, 2010; Nir et al., 2011), and the SO during both stage 2 of non-REM sleep and SWS are shown to group and synchronize sleep spindles and delta waves (Mölle et al., 2002; Mölle et al., 2004; Steriade, 2001). Whereas sleep spindles originate form interactions between thalamo-cortical circuits involving γaminobutyric (GABA)-ergic thalamic neurons and glutamate-ergic cortical neurons (De Gennaro & Ferrara, 2003; Steriade, 2006), SO are shown to have a neocortical origin (Achrermann & Borbely, 1997; Nir et al., 2011; Steriade et al., 1993), although they are also proposed to emerge form the thalamus (Crunelli & Hughes, 2010). Another important EEG signature of SWS seen not only in animals but also in human intracranial EEG recordings, is reflected by hippocampal sharp-wave/ripple (SWR) bursts. Hippocampal sharp waves generated in the hippocampal CA3 region are fast depolarizing events, on which highfrequency oscillations (~ 80-200 Hz) originating from an interaction between inhibitory interneurons and pyramidal cells in CA1 (so-called ripples) are superimposed (Buzsáki, 2006; Csicsvari et al., 1999). Notably, SO have been shown to group also SWR in rodents (Battaglia et al., 2004; Sirota et al., 2003), and a temporal phase-coupling between SO, sleep spindles and SWR has been demonstrated in human depth EEG records during SWS (Clemens et al., 2007; 2011; Nir et al., 2011). The complex relationship between these sleep signatures is regarded as reflecting brain plasticity mechanisms at a system level, which is

The Memory, Cognitive and Psychological Functions of Sleep:

sleep (Gottesmann, 1999; Pace-Schott & Hobson, 2002).

**2.4 Neuroimaging of sleep and wake** 

**2.3 Mechanisms of sleep regulation** 

Update from Electroencephalographic and Neuroimaging Studies 159

REM in rats and felines (Callaway et al., 1987; Stickgold et al, 2001), as well as in humans (Lim et al, 2007; Miyauchi et al., 2009), and are suggested to reflect both dream mental states of REM sleep and cognitive processing during this sleep stage (Stickgold et al., 2001). REM sleep signatures are shown to reflect mechanisms of brain plasticity at synaptic and genetic levels (Ribeiro et al., 1999; 2002), which may promote not only REM sleep specific processes, but also a further transformation of consolidated memories (Walker & Stickgold, 2010).

The regulation of sleep is active in its own rights, and is closely related to sleep's physiology and functions (Hobson, 2005; Pace-Schott & Hobson, 2002). The respective neurobiological mechanisms are represented by complex reciprocal interactions between different neuronal populations and their chemical modulators and transmitters in distinct functional states across sleep-wake cycle leading to distinct functional states (Gottesmann, 1999; Hobson et al., 1975; Hobson & Peace-Schott, 2002; Peace-Schott & Hobson, 2002). Two major brain regions are mostly considered in sleep regulation, especially when functions of sleep are concerned (Pace-Schott & Hobson, 2002). The first engages neuronal populations located in the diencephalon, in particular, the hypothalamus, mostly involved in the circadian regulation of sleep. The second brain region engages brainstem or meso-pontine and basal forebrain nuclei spread in the reticular ascending system (RAS) and projecting noradrenaline (NA), serotonin (5-Hydroxytryptamine, 5-HT) and acetylcholine (Ach) neuromodulatory signals to upper brain structures including the basal ganglia and amygdala, thalamus, hippocampus, and cortex. These mechanisms are essential for the ultradian alternating expression of non-REM sleep-REM sleep periods (Gottesmann, 1999; Hobson et al., 1975; Pace-Schott & Hobson, 2002). Briefly, during wake, brainstem/mesopontine NA, 5-HT, Ach, and hypothalamic histamine (HIS) neurons projecting to upper brain structures and cortex, are all active, thus sustaining functional brain states optimal to the environmental requirements (Gottesmann, 1999; Hobson & Pace-Schott, 2002; Pace-Schott & Hobson, 2002). As sleep deepens from stages 1 and 2 to SWS, all these neuromodulators progressively decrease their activities, with their lowest levels observed during SWS. This leads to strongly diminished or lacking RAS neuromodulation of upper brain structures and cortex, which in turn, is responsible for the appearance of non-REM sleep EEG signals represented by sleep spindles, K-complexes and SWA, all originating from thalamo-cortical and cortico-cortical interplay (McCormick & Bal, 1997; Pace-Schott & Hobson, 2002; Steriade & Timofeev, 2003). In REM sleep, all NA, 5-HT and HIS neurons cease their firing. In contrast, Ach excessive over-activity emerges projecting to the cortex and all sub-cortical structures, which produces the electrophysiological signatures of REM

Several neuroimaging studies using either fMRI or positron-emission tomography (PET) have investigated the pattern of brain activation across wake, non-REM and REM sleep. These studies have demonstrated that anterior cingulate cortex, right and left amygdaloid complexes, pons, parahippocampal cortex, and extrastriate visual cortex are more active during REM sleep compared with wake and non-REM sleep, whereas the activation of other brain areas including right and left dorsolateral prefrontal cortices, right and left parietal cortices and precuneus, posterior cingulate cortex, and primary visual cortex, is suppressed in REM sleep compared with wake. All these brain regions have been shown to be the most

important for the memory consolidation and reconsolidation during SWS (Diekelmann & Born, 2010).

Fig. 1. Electrophysiological signatures of distinct sleep-wake stages: EEG recorded from Fz, Cz and Pz, vertical (v) and horizontal (h) eye movements, and electromyogram (m). Calibration marks are set-up at 100 µV, time (horizontal) marks are 1 s.

Unlike non-REM sleep electrophysiology, REM sleep EEG signatures (Fig. 1) include lowvoltage desynchronized wake-like EEG activity comprising theta and fast (beta and gamma) rhythms accompanied by a swift occurrence of rapid eye movements (REM) upon lack of muscle tone (Aserinsky & Kleitman, 1953; Cantero et al., 2003; Clemens et al., 2009). Hippocampal theta rhythm is a prominent REM sleep EEG signature in rodents (Gottesmann, 1999; Kirov & Moyanova, 2002) and felines (Hobson & Pace Schott, 2002), while in human hippocampus and neocortex it is less coherent (Cantero et al., 2003). Further, REM sleep is hallmarked by ponto-geniculo-occipital (PGO) waves. PGO waves are driven by intense bursts of synchronized activity that propagate from the pontine brainstem mainly to the lateral geniculate nucleus and visual cortex (Callaway et al., 1987; Hobson & Pace-Schott, 2002; Pace-Schott & Hobson, 2002). They occur in temporal association with REM in rats and felines (Callaway et al., 1987; Stickgold et al, 2001), as well as in humans (Lim et al, 2007; Miyauchi et al., 2009), and are suggested to reflect both dream mental states of REM sleep and cognitive processing during this sleep stage (Stickgold et al., 2001). REM sleep signatures are shown to reflect mechanisms of brain plasticity at synaptic and genetic levels (Ribeiro et al., 1999; 2002), which may promote not only REM sleep specific processes, but also a further transformation of consolidated memories (Walker & Stickgold, 2010).
