Synchronization of neuronal activity, often associated with network oscillations, is thought to provide a means for integrating anatomically distributed processing in the brain. Neuronal processing, however, involves simultaneous oscillations in various frequency bands. The mechanisms involved in the integration of such spectrally distributed processing have remained enigmatic. We demonstrate, using magnetoencephalography, that robust cross-frequency phase synchrony is present in the human cortex among oscillations with frequencies from 3 to 80 Hz. Continuous mental arithmetic tasks demanding the retention and summation of items in the working memory enhanced the cross-frequency phase synchrony among α (∼10 Hz), β (∼20 Hz), and γ (∼30-40 Hz) oscillations. These tasks also enhanced the “classical” within-frequency synchrony in these frequency bands, but the spatial patterns of α, β, and γ synchronies were distinct and, furthermore, separate from the patterns of cross-frequency phase synchrony. Interestingly, an increase in task load resulted in an enhancement of phase synchrony that was most prominent between γ- and α-band oscillations. These data indicate that cross-frequency phase synchrony is a salient characteristic of ongoing activity in the human cortex and that it is modulated by cognitive task demands. The enhancement of cross-frequency phase synchrony among functionally and spatially distinct networks during mental arithmetic tasks posits it as a candidate mechanism for the integration of spectrally distributed processing.

Changes in chloride (Cl⁻) homeostasis may be involved in the generation of some epileptic activities. In this study, we asked whether Cl⁻homeostasis, and thus GABAergic signaling, is altered in tissue from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Slices prepared from this human tissue generated a spontaneous interictal-like activity that was initiated in the subiculum. Records from a minority of subicular pyramidal cells revealed depolarizing GABA_Areceptor-mediated postsynaptic events, indicating a perturbed Cl⁻homeostasis. We assessed possible contributions of changes in expression of the potassium–chloride cotransporter KCC2. Doublein situhybridization showed that mRNA for KCC2 was absent from ∼30% of CaMKIIα (calcium/calmodulin-dependent protein kinase IIα)-positive subicular pyramidal cells. Combining intracellular recordings with biocytin-filled electrodes and KCC2 immunochemistry, we observed that all cells that were hyperpolarized during interictal events were immunopositive for KCC2, whereas the majority of depolarized cells were immunonegative. Bumetanide, at doses that selectively block the chloride-importing potassium–sodium–chloride cotransporter NKCC1, produced a hyperpolarizing shift in GABA_Areversal potentials and suppressed interictal activity. Changes in Cl⁻transporter expression thus contribute to human epileptiform activity, and molecules acting on these transporters may be useful antiepileptic drugs.