Changes of cortical and corticospinal excitability, as a function of sleep deprivation have been studied, using EEG power maps and several TMS measures in 33 normal subjects before and after a 40-h sleep deprivation (SD). The effects of SID were independently assessed by subjective and EEG measures of sleepiness, the latter being represented in terms of cortical maps for different frequency bands. Short intracortical facilitation (SICF) and inhibition (SICI) were measured by the paired-pulse TMS technique with different inter-stimulus intervals. Besides standardized motor threshold (MT), lower threshold (LT) and upper threshold (UT) were also determined. Subjective sleepiness severely increased as a consequence of SD, paralleled by a drastic decrease of alertness. EEG topography showed large increases in delta and theta activity, mainly evident at fronto-central areas. Standard MTs, as well as LTs and UTs, all increased as a consequence of SD. SICF also showed a significant increase as compared to pre-deprivation values, but only in females. The increase of theta activity was strongly associated in the left frontal and prefrontal cortex to a smaller decrease of corticospinal excitability, expressed by MTs, and a larger increase of intracortical facilitation, expressed by SICF. TMS and EEG measures converge in indicating that SD has severe effects on both cortical and corticospinal excitability, as shown respectively by the increases of slow-frequency EEG power and MTs. The SICF enhancement in females and the results of the combined topographical analysis of EEG and TMS changes are coherent with the hypothesis that cortical TMS-evoked responses are higher as a consequence of a longer wakefulness. However, the lack of an increase in cortical excitability after prolonged wakefulness in males suggests some caution in the generalization of these effects, that deserve further investigation. (C) 2007 Elsevier Inc. All rights reserved.