This study aimed to develop a time–frequencymethod for measuring directional interactions over time and frequency from scalp-recorded electroencephalographic (EEG) signals in a way that is less affected by volume conduction and amplitude scaling. We modified the time-varying generalized partial directed coherence (tv-gPDC) method, by orthogonalization of the strictly causal multivariate autoregressive model coefficients, to minimize the effect of mutual sources. The novel measure, generalized orthogonalized PDC (gOPDC), was tested first using two simulated models with feature dimensions relevant to EEG activities.We then used the method for assessing event-related directional information flow fromflash-evoked responses in neonatal EEG. For testing statistical significance of the findings, we followed a thresholding procedure driven by baseline periods in the same EEG activity. The results suggest that the gOPDC method 1) is able to remove common components akin to volume conduction effect in the scalp EEG, 2) handles the potential challenge with different amplitude scaling within multichannel signals, and 3) can detect directed information flow within a subsecond time scale in nonstationary multichannel EEG datasets. This method holds promise for estimating directed interactions between scalp EEG channels that are commonly affected by the confounding impact of mutual cortical sources.