Temporal Structure in Resting-State fMRI under Marginal and Cross-Spectral Surrogate Controls

Abstract

Resting-state functional MRI is commonly analyzed using correlations between regional signals and their frequency spectra, which characterize average connectivity and spectral properties but may miss other aspects of temporal organization. Measures of temporal complexity offer complementary information about the recurrence of signal patterns, how fluctuations vary across timescales, and signal roughness. These properties may reveal disease-related alterations in brain activity, offering opportunities for biomarker discovery and insights into mechanisms of neurological and psychiatric disorders. Here we examined sample entropy (SampEn), multifractal de-trended fluctuation analysis (MFDFA), and Higuchi curve shapes in 732 scans from 270 ADNI participants, including cognitively normal individuals, people with mild cognitive impairment, and people with dementia. Using the seven Yeo resting-state networks (Yeo-7), we compared recordings with randomized signals preserving either each networks amplitude distribution and approximate spectrum (IAAFT), or the complete cross-spectrum across networks. If these properties fully explained temporal complexity, real recordings should resemble their randomized references. We therefore counted how often each real recording was the strongest outlier among itself and 20 references. This occurred in 21.7%, 12.7%, and 44.2% of 5,124 network-visits for SampEn, MFDFA, and Higuchi, versus 5.5%, 5.1%, and 6.3% in surrogate-only controls. Cross-spectrum-preserving references yielded 39.8%, 17.5%, and 49.8%. Simulations showed that changes in sampling or signal processing, including abrupt changes in signal amplitude, can produce similar differences without changing the underlying dynamics. The measures showed repeatability across visits but did not improve retrospective prediction of changes in Clinical Dementia Rating Sum of Boxes (CDR-SB) scores. These findings identify temporal features not reproduced by the tested spectral controls and provide a basis for evaluating their potential as disease biomarkers.