Investigating scale-free (i.e., fractal) functional connectivity in the brain has recently attracted increasing attention. Although numerous methods have been developed to assess the fractal nature of functional coupling, these typically ignore that neurophysiological signals are assemblies of broadband, arrhythmic activities as well as oscillatory activities at characteristic frequencies such as the alpha waves. While contribution of such rhythmic components may bias estimates of fractal

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... tivity, they are also likely to represent neural activity and coupling emerging from distinct mechanisms. Irregular-resampling auto-spectral analysis (IRASA) was recently introduced as a tool to separate fractal and oscillatory components in the power spectrum of neurophysiological signals by statistically summarizing the power spectra obtained when resampling the original signal by several non-integer factors. Here we introduce multiple-resampling cross-spectral analysis (MRCSA) as an extension of IRASA from the univariate to the bivariate case, namely, to separate the fractal component of the cross-spectrum between two simultaneously recorded neural signals by applying the same principle. MRCSA does not only provide a theoretically unbiased estimate of the fractal cross-spectrum (and thus its spectral exponent) but also allows for computing the proportion of scale-free coupling between brain regions. As a demonstration, we apply MRCSA to human electroencephalographic recordings obtained in a word generation paradigm. We show that the cross-spectral exponent as well as the proportion of fractal coupling increases almost uniformly over the cortex during the rest-task transition, likely reflecting neural desynchronization. Our results indicate that MRCSA can be a valuable tool for scale-free connectivity studies in characterizing various cognitive states, while it also can be generalized to other applications outside the field of neuroscience.