Human Gamma Oscillations during Slow Wave Sleep preferred phases for all cases presenting statistically significant phase-sycnhronization across all slow waves and associated with IN-phase (top histogram) and ANTI-phase (bottom histogram) patterns. Phases of the corresponding SW are given for reference (blue line on top) (n = 8 subjects). doi:10.1371/journal.pone.0033477.g007 contrast, ANTI-phase patterns tended to appear during the negative phase of the scalp slow wave. They were more expressed in temporal regions and had only a few dominant peaks in the high gamma range (around 70 and 95 Hz). 3) The spatial coherence of gamma events occurring at different intracranial contacts during slow waves was only local and fell off quickly with distance. A first novel finding of our study was that spontaneous gamma oscillations from 30 to 120 Hz, recorded at the macroscopic EEG level, were strongly expressed during deep sleep in the human cortex. This may be surprising because faster rhythmic EEG activity were generally reported in relation to waking functions such as sensory perception, attention or memory [18–20]. Furthermore, several previous EEG studies have reported that gamma activity is highest during wakefulness and REM, and lowest during SWS, in both humans [21,22] and animals [23]. As mentioned before [11], this discordance could be explained by the fact that, in those previous studies, fast oscillatory activities were estimated through an average over several minutes of recording which is not an appropriate methodology for the detection of transient events lasting only few hundred milliseconds and separated by long periods of silence. Our results are nevertheless in agreement with LFPs observations in sleeping or anesthetized animals reporting activations in the beta/low gamma and high gamma ranges during the depolarization phase of the slow wave [3–7,24]. Furthermore, our observations are consistent with a recent microelectrode study reporting that distinct narrow band oscillations in the low (40–80 Hz) and high (80–120 Hz) gamma ranges were locally expressed in the LFPs of the human cortex during SWS [11]. In accordance, we confirmed with clinical macroelectrodes in the human cortex that different discrete spectral peaks can be consistently identified in the low and high gamma range. On the basis of these observations, we can postulate that our recorded gamma oscillations reflect the same local, highly synchronous field activities as those recorded with microelectrodes. The possibility to record these oscillations with intracranial macroelectrodes of large surface area greater than 1 mm2 suggests that an activity of ,100 mm3 of brain tissue should be involved here [25]. As previously shown [26,27], minimal eye movements (so-called microsaccades) can induce gamma activities in scalp EEG but also in intracranial recordings. We think however that the gamma activities reported in our analyses are unlikely the product of such a kind of artifacts but instead the result of a physiological cortical activity. Arguments in favor of this are: (1) we analyzed only periods during NREM, and in particular during slow wave sleep stages where the eye movements (rolling eye balls) are minimum compared to wake or REM sleep stages; (2) while, when they appeared, gamma-activities were clearly visible on intracranial contacts, they were absent at the scalp level; (3) gamma activities reported here were found to be modulated by the slow oscillations, known to generate no phasic motor events. A second novel observation of the present study was the existence of two gamma patterns in the human cortex defined by their relations with the phases of the cortical slow oscillations. In most of the cases, gamma oscillations were correlated with positive peaks of scalp slow waves, confirming previous animal data suggesting that gamma oscillations occur during the active component of the slow wave (‘UP’ state). This observation of enhanced gamma activities during surface-positive components of slow oscillations is also consistent with the grouping of spindle and beta activities reported for human scalp EEG [13,14]. This depolarization phase is associated with increased cortical firing, which drives the generation of spindle, beta and gamma oscillations in thalamo-cortical feedback loops [3]. In addition, we also reported ANTI-phase gamma events, having distinctive frequency/spatial properties and appearing preferentially during surface-negative components of slow waves corresponding to cortical cellular hyperpolarization. These ANTI-phase patterns had onset times highly concentrated around the negative peak of the scalp slow waves, in contrast to the phases of their maximal amplitude times, more scattered over a wider interval. This further suggests that ANTI-phase gamma events were initiated at the beginning of the DOWN state, known to be precisely synchro- nized [28]. Interestingly, cellular activities and gamma oscillations were already reported in the rat hippocampus to emerge during the neocortical-paleocortical DOWN states [5]. One explanation for our reported ANTI-phase patterns, particularly expressed over the temporal cortex, is that hippocampal projections to the cortex drive fast rhythmic post-synaptic EPSPs during the hyperpolariz- ing (surface negative) phase of the slow wave, associated with cortical firing silence. The global lack of correlation between higher density of gamma oscillations and epileptogenic tissue provides some reassurance, albeit indirect, that gamma activity was not mainly caused by epilepsy. Nevertheless, it cannot be fully excluded that ANTI-phase patterns were not generated by aberrant synchronization remote from chronic epileptic circuits. Additional research is here needed to precise the neuronal origins of this new type of pattern. Thanks to the relatively large sample size as well as to a broad spatial sampling, we were able to evaluate in our study the intracranial coherence of gamma oscillations over a comprehen- sive extent of the human cerebral cortex. According to our observations, gamma oscillations were frequently phase-locked over short-distances, but this synchronization decreased rapidly in space. This local spatial coherence between close-by electrodes could be explained by the large surface area of the used macroelectrode that may record partly overlapping source distributions. In the same way, it has been reported in felines that the coherence at approximately zero phase lag between activities in high-frequency ranges was only observed for cortical sites located within few millimeters of distance (,5 mm) [3]. Our findings are also consistent with other studies in humans that were not able to demonstrate gamma band coherence at large distance (greater than 14 mm) between intracranial EEG sites [29]. This short-range spatial confinement of coherent fast rhythms is consistent with previous observations during wakefulness reporting that fast oscillations are synchronized locally in both space and time, as shown by the very restricted cortical areas and time windows in which coherent fast oscillations appear [30]. What could be the function of these gamma patterns? As proposed before, the network dynamics during active states of deep sleep have been proposed to be equivalent to those observed during the waking state [31,32]. In agreement with this proposal, our observations of gamma during SWS are very similar to gamma responses induced by a variety of waking tasks reflecting an increased alertness and also recorded with intracranial EEG [19,33,34]. Furthermore, activation patterns during SWS are also known to be close to the waking default mode network (DMN) [35,36]. Following this similarity, it has been proposed that gamma oscillations during SWS may reflect recalled events PLoS ONE | www.plosone.org 10 April 2012 | Volume 7 | Issue 4 | e33477