A mega-analysis of low frequency resting-state measures in mood and psychosis-spectrum disorders

Objective: Conduct a mega-analysis of two complementary measures of resting-state functional magnetic resonance imaging (rsfMRI) dynamics-amplitude of low-frequency fluctuation (ALFF) and low-frequency spectral entropy (lfSE)-in mood and psychosis-spectrum disorders to evaluate group differences and clinical symptom associations. Design: ALFF and lfSE were calculated at the node-level by filtering data from 0.01 Hz to 0.08 Hz, regressing demographic variables, and harmonizing sites. Group differences were assessed using the Wilcoxon signed test. Symptom associations were evaluated with Spearman's rho. Analyses were conducted at both whole-brain and network levels, with sensitivity analyses to evaluate the impact of frequency brands. Setting: Four independent open-source case-control datasets with resting-state functional magnetic resonance imaging were used: the Center for Biomedical Research Excellence, the Human Connectome Project for Early Psychosis, the Strategic Research Program for Brain Sciences, and the UCLA Consortium for Neuropsychiatric Phenomics. Participants: Included participants had a mood disorder (bipolar, dysthymia, or major depressive disorder, n=228, aged 38.31 ± 12.56 years), a psychosis-spectrum disorder (early psychosis, schizophrenia spectrum disorder, or mood disorder with psychotic symptoms, n=318, aged 29.8 ± 13.21 years), or a healthy control (n=535, aged 39.89 ± 15.3 years). Main outcomes and Measures: To identify group differences and symptom associations in mood and psychosis-spectrum disorders using ALFF and lfSE. Results: ALFF in psychosis-spectrum was significantly lower than mood disorders and controls (q's<0.001) at the whole-brain and network levels. lfSE in controls was significantly lower than both psychosis-spectrum and mood disorders at the whole-brain and network levels (q's<0.001). Whole-brain ALFF is positively associated with mood symptoms (rho=0.27, p<0.05). Whole-brain lfSE is negatively associated with positive (rho=-0.13, p<0.05) and mood (rho=-0.38, p<0.01) symptoms. A greater sensitivity of group differences and symptom associations to frequency ranges was observed in mood disorders. ALFF is sensitive to medication. Conclusions and Relevance: Widespread, global differences in ALFF and lfSE underly psychosis-spectrum and mood disorders. lfSE may be applicable for wider use in fMRI. Differences in spectral measures of brain dynamics may represent shared and distinct markers of mental health.