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Alterations in large-scale brain intrinsic functional connectivity (FC), i.e., coherence between fluctuations of ongoing activity, have been implicated in major depressive disorder (MDD). Yet, little is known about the frequency-dependent alterations of FC in MDD. We calculated frequency specific degree centrality (DC) – a measure of overall FC of a brain region – within 10 distinct frequency sub-bands accessible from the full range of resting-state fMRI BOLD fluctuations (i.e., 0.01–0.25 Hz) in 24 healthy controls and 24 MDD patients. In healthy controls, results reveal a frequency-specific spatial distribution of highly connected brain regions – i.e., hubs – which play a fundamental role in information integration in the brain. MDD patients exhibited significant deviations from the healthy DC patterns, with decreased overall connectedness of widespread regions, in a frequency-specific manner. Decreased DC in MDD patients was observed predominantly in the occipital cortex at low frequencies (0.01–0.1 Hz), in the middle cingulate cortex, sensorimotor cortex, lateral parietal cortex, and the precuneus at middle frequencies (0.1–0.175 Hz), and in the anterior cingulate cortex at high frequencies (0.175–0.25 Hz). Additionally, decreased DC of distinct parts of the insula was observed across low, middle, and high frequency bands. Frequency-specific alterations in the DC of the temporal, insular, and lateral parietal cortices correlated with symptom severity. Importantly, our results indicate that frequency-resolved analysis within the full range of frequencies accessible from the BOLD signal – also including higher frequencies (>0.1 Hz) – reveals unique information about brain organization and its changes, which can otherwise be overlooked.

Frequency-Dependent Spatial Distribution of Functional Hubs in the Human Brain and Alterations in Major Depressive Disorder