AbstractSeizure prediction is the grand challenge of epileptology. However, effort was devoted to prediction of focal seizures, while generalized seizures were regarded as stochastic events. Long-lasting local field potential (LFP) recordings containing several hundred generalized spike and wave discharges (SWDs), acquired at eight locations in the cortico-thalamic system of absence epileptic rats, were iteratively analyzed in all possible combinations of either two or three recording sites, by a wavelet-based algorithm, calculating the product of the wavelet-energy signaling increases in synchronicity. Sensitivity and false alarm rate of prediction were compared between various combinations, and wavelet spectra of true and false positive predictions were fed to a random forest machine learning algorithm to further differentiate between them. Wavelet analysis of intracortical and cortico-thalamic LFP traces showed a significantly smaller number of false alarms compared with intrathalamic combinations, while predictions based on recordings in Layers IV, V, and VI of the somatosensory-cortex significantly outreached all other combinations in terms of prediction sensitivity. In 24-h out-of-sample recordings of nine Genetic Absence Epilepsy Rats from Strasbourg (GAERS), containing diurnal fluctuations of SWD occurrence, classification of true and false positives by the trained random forest further reduced the false alarm rate by 71%, although at some trade-off between false alarms and sensitivity of prediction, as reflected in relatively low F1 score values. Results provide support for the cortical-focus theory of absence epilepsy and allow the conclusion that SWDs are predictable to some degree. The latter paves the way for the development of closed-loop SWD prediction-prevention systems. Suggestions for a possible translation to human data are outlined.