Human cortical activity has been intensively examined at frequencies ranging from 0.5 Hz to several hundred Hz. Recent studies have, however, reported also infraslow fluctuations in neuronal population activity, magnitude of electroencephalographic oscillations, discrete sleep events, as well as in the occurrence of interictal events. Here we use direct current electroencephalography to demonstrate large-scale infraslow oscillations in the human cortex at frequencies ranging from 0.02 to 0.2 Hz. These oscillations, which are not detectable in conventional electroencephalography because of its limited recording bandwidth (typical lower limit 0.5 Hz), were observed in widespread cortical regions. Notably, the infraslow oscillations were strongly synchronized with faster activities, as well as with the interictal epileptic events and K complexes. Our findings suggest that the infraslow oscillations represent a slow, cyclic modulation of cortical gross excitability, providing also a putative mechanism for the as yet enigmatic aggravation of epileptic activity during sleep.epilepsy ͉ slow cortical oscillations ͉ phase synchrony ͉ direct current electroencephalography ͉ full-band electroencephalography A large body of literature has characterized functional and clinical correlates of cortical oscillatory activity seen in the human electroencephalography (EEG) at frequencies ranging from 0.5 Hz to several hundred Hz (1). In addition to these relatively fast EEG oscillations, some studies have demonstrated infraslow fluctuations in, for instance, neuronal population activity (2-5), EEG power (5-9), discrete sleep events (arousals, spindles, K complexes) (9-12), as well as in the occurrence of epileptic events (4, 11, 13). These observations have raised the possibility that the human cortex may generate infraslow oscillations (ISOs) underlying such fluctuations. ISOs are not detectable in conventional EEG because of its limited recording bandwidth (typical lower limit, 0.5 Hz; ref. 1).In the present study, we used direct current (DC)-coupled EEG scalp recordings (14-16) to demonstrate that ISOs are, in fact, a salient, large-scale feature of the human EEG. They were tightly associated with a cyclic modulation of fast EEG activity as well as discrete EEG events such as K complexes and interictal activity. In analogy with recent studies demonstrating that slow delta oscillations (0.5-1 Hz) may modulate brain excitability (17, 18), our data points to a role of ISOs in the control of gross cortical excitability. Our findings also provide a window on the modulation of interictal epileptiform events (IIEs) and on sleep-epilepsy interactions in the human brain. MethodsSubjects and EEG Recording. We studied 16 subjects (four females; average age, 34.3 years; range, 16-51 years) during overnight (n ϭ 9) or daytime (n ϭ 7) sleep. This study was approved by the Human Subjects Committee of the University of Washington. Twelve subjects were recorded using a custom-made 16-channel DC-coupled EEG amplifier and Ag͞AgCl electrodes (refs....

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During non-rapid eye movement (NREM) sleep (stage N3), when consciousness fades, cortico-cortical interactions are impaired while neurons are still active and reactive. Why is this? We compared cortico-cortical evoked-potentials recorded during wakefulness and NREM by means of time-frequency analysis and phase-locking measures in 8 epileptic patients undergoing intra-cerebral stimulations/recordings for clinical evaluation. We observed that, while during wakefulness electrical stimulation triggers a chain of deterministic phase-locked activations in its cortical targets, during NREM the same input induces a slow wave associated with an OFF-period (suppression of power>20Hz), possibly reflecting a neuronal down-state. Crucially, after the OFF-period, cortical activity resumes to wakefulness-like levels, but the deterministic effects of the initial input are lost, as indicated by a sharp drop of phase-locked activity. These findings suggest that the intrinsic tendency of cortical neurons to fall into a down-state after a transient activation (i.e. bistability) prevents the emergence of stable patterns of causal interactions among cortical areas during NREM. Besides sleep, the same basic neurophysiological dynamics may play a role in pathological conditions in which thalamo-cortical information integration and consciousness are impaired in spite of preserved neuronal activity.

Spontaneous transients of correlated activity are a characteristic feature of immature brain structures, where they are thought to be crucial for the establishment of precise neuronal connectivity. Studies on experimental animals have shown that this kind of early activity in cortical structures is composed of long-lasting, intermittent network events, which undergo a developmental decline that is closely paralleled by the maturation of GABAergic inhibition. In order to examine whether similar events occur in the immature human cortex, we performed direct current-coupled electroencephalography (EEG) recordings from sleeping preterm babies. We show now that much of the preterm EEG activity is confined to spontaneous, slow activity transients. These transients are characterized by a large voltage deflection that nests prominent oscillatory activity in several frequency bands covering the whole frequency spectrum of the preterm EEG (<0.1-30 Hz). The slow voltage deflections had an amplitude of up to 800 microV. Most of these 'giant' events originated in the temporo-occipital areas, with a maximum rate of about 8/min, and their occurrence as well as amplitude showed a decline by the time of normal birth. In age-matched fetal brain tissue, this decrease in the spontaneous activity transients was associated with a developmental up-regulation of the neuronal chloride extruder K+-Cl- cotransporter 2, a crucial molecule for the generation of inhibitory GABAergic Cl- currents. Our work indicates that slow endogenous activity transients in the immature human neocortex are mostly confined to the prenatal stage and appear to be terminated in parallel with the maturation of functional GABAergic inhibition.

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