Down But Not Out: The K-complex, a defining characteristic of slow wave sleep, is the largest spontaneously occurring component of the healthy human electroencephalogram (EEG) but little is known about its physiological characteristics in the human cortex. Cash et al. (p. 1084 ) investigated the intracortical origin of K-complexes in humans undergoing surgery for epileptic seizures. In simultaneous subdural EEG and intracortical multisite microelectrode recordings, K complexes represented cortical downstates reflecting a decrease in neural firing. These down-states are a fundamental mode of cortical operation that have been well studied in animals and may contribute to sleep preservation and memory consolidation.

Ripples are high-frequency oscillation bursts in the mammalian hippocampus mainly present during Non-REM sleep. In rodents they occur in association with sharp waves and are grouped by the cortical slow oscillation such that, in parallel with sleep spindles, ripple activity is suppressed during the hyperpolarized down-state and enhanced during the depolarized up-state. The temporal coupling between slow oscillations, spindles and ripples has been suggested to serve a hippocampo-neocortical dialogue underlying memory consolidation during sleep. Here, we examined whether a similar coupling exists between these oscillatory phenomena in humans. In sleep recordings from seven epileptic patients, scalp-recorded slow oscillations and spindles as well as parahippocampal ripples recorded from foramen ovale electrodes were identified by automatic algorithms. Additionally, ripple and spindle root mean square activity was determined for relevant frequency bands. Ripple density was higher during Non-REM than REM sleep (P < 0.001). Ripple activity distinctly decreased time-locked to slow oscillation negative half-waves in the three patients without temporal structural alterations (P < 0.001), whereas in the four patients with severe mesiotemporal structural alterations this coupling was obscure. Generally, in the patients ripple activity was increased before spindle peaks and distinctly decreased after the peak (P < 0.001). Ripples were consistently associated with interictal spikes suggesting that spike–ripple complexes represent an epileptic transformation of sharp wave–ripple complexes in the epileptic hippocampus. Our findings are consistent with the notion of a hippocampo-to-neocortical information transfer during sleep that is linked to coordinate ripple and spindle activity, and that in the intact temporal lobe is synchronized to cortical slow oscillations.

Brain electrical activity is largely composed of oscillations at characteristic frequencies. These rhythms are hierarchically organized and are thought to perform important pathological and physiological functions. The slow wave is a fundamental cortical rhythm that emerges in deep non-rapid eye movement sleep. In animals, the slow wave modulates delta, theta, spindle, alpha, beta, gamma and ripple oscillations, thus orchestrating brain electrical rhythms in sleep. While slow wave activity can enhance epileptic manifestations, it is also thought to underlie essential restorative processes and facilitate the consolidation of declarative memories. Animal studies show that slow wave activity is composed of rhythmically recurring phases of widespread, increased cortical cellular and synaptic activity, referred to as active- or up-state, followed by cellular and synaptic inactivation, referred to as silent- or down-state. However, its neural mechanisms in humans are poorly understood, since the traditional intracellular techniques used in animals are inappropriate for investigating the cellular and synaptic/transmembrane events in humans. To elucidate the intracortical neuronal mechanisms of slow wave activity in humans, novel, laminar multichannel microelectrodes were chronically implanted into the cortex of patients with drug-resistant focal epilepsy undergoing cortical mapping for seizure focus localization. Intracortical laminar local field potential gradient, multiple-unit and single-unit activities were recorded during slow wave sleep, related to simultaneous electrocorticography, and analysed with current source density and spectral methods. We found that slow wave activity in humans reflects a rhythmic oscillation between widespread cortical activation and silence. Cortical activation was demonstrated as increased wideband (0.3–200 Hz) spectral power including virtually all bands of cortical oscillations, increased multiple- and single-unit activity and powerful inward transmembrane currents, mainly localized to the supragranular layers. Neuronal firing in the up-state was sparse and the average discharge rate of single cells was less than expected from animal studies. Action potentials at up-state onset were synchronized within ±10 ms across all cortical layers, suggesting that any layer could initiate firing at up-state onset. These findings provide strong direct experimental evidence that slow wave activity in humans is characterized by hyperpolarizing currents associated with suppressed cell firing, alternating with high levels of oscillatory synaptic/transmembrane activity associated with increased cell firing. Our results emphasize the major involvement of supragranular layers in the genesis of slow wave activity.

Sleep‐associated memory consolidation is thought to rely on coordinated information transfer between the hippocampus and neocortex brought about during slow wave sleep (SWS) by distinct local field potential oscillations. Specifically, findings in animals have led to the concept that ripples originating from hippocampus combine with spindles to provide a fine‐tuned temporal frame for a persistent transfer of memory‐related information to the neocortex. The present study focused on characterizing the temporal relationship between parahippocampal ripple activity (80–140 Hz) and spindles recorded from frontal, parietal and parahippocampal cortices in 12 epilepsy patients implanted with parahippocampal foramen ovale electrodes. Overall, parietal and parahippocampal spindles showed closer relationships to parahippocampal ripple activity than frontal spindles, with the latter following parietal and parahippocampal spindles at a variable delay of up to 0.5 s. On a timescale of seconds, ripple activity showed a continuous increase before the peak of parietal and parahippocampal spindles, and decreased thereafter. At a fine timescale of milliseconds, parahippocampal ripple activity was tightly phase‐locked to the troughs of these spindles. The demonstration of spindle phase‐locked ripple activity in humans is consistent with the idea of a temporally fine‐tuned hippocampus‐to‐neocortex transfer of information taking place during SWS.

Endocannabinoid signaling is a key regulator of synaptic neurotransmission throughout the brain. Compelling evidence shows that its perturbation leads to development of epileptic seizures, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. To elucidate whether long-term reorganization of endocannabinoid signaling occurs in epileptic patients, we performed comparative expression profiling along with quantitative electron microscopic analysis in control (postmortem samples from subjects with no signs of neurological disorders) and epileptic (surgically removed from patients with intractable temporal lobe epilepsy) hippocampal tissue. Quantitative PCR measurements revealed that CB₁cannabinoid receptor mRNA was downregulated to one-third of its control value in epileptic hippocampus. Likewise, the cannabinoid receptor-interacting protein-1a mRNA was decreased, whereas 1b isoform levels were unaltered. Expression of diacylglycerol lipase-α, an enzyme responsible for 2-arachidonoylglycerol synthesis, was also reduced by ∼60%, whereas its related β isoform levels were unchanged. Expression level ofN-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D and fatty acid amide hydrolase, metabolic enzymes of anandamide, and 2-arachidonoylglycerol's degrading enzyme monoacylglycerol lipase did not change. The density of CB₁immunolabeling was also decreased in epileptic hippocampus, predominantly in the dentate gyrus, where quantitative electron microscopic analysis did not reveal changes in the ratio of CB₁-positive GABAergic boutons, but uncovered robust reduction in the fraction of CB₁-positive glutamatergic axon terminals. These findings show that a neuroprotective machinery involving endocannabinoids is impaired in epileptic human hippocampus and imply that downregulation of CB₁receptors and related molecular components of the endocannabinoid system may facilitate the deleterious effects of increased network excitability.