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

ObjectiveConduct 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. DesignALFF 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 Spearmans rho. Analyses were conducted at both whole-brain and network levels, with sensitivity analyses to evaluate the impact of frequency brands. SettingFour 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. ParticipantsIncluded 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 MeasuresTo identify group differences and symptom associations in mood and psychosis-spectrum disorders using ALFF and lfSE. ResultsALFF in psychosis-spectrum was significantly lower than mood disorders and controls (qs<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 (qs<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 RelevanceWidespread, 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. Key PointsO_ST_ABSQuestionC_ST_ABSHow do the amplitude and complexity of low-frequency oscillations in fMRI signals associate with psychosis-spectrum and mood disorders? FindingsFindings suggest that the amplitude and complexity of low-frequency oscillation are associated with mood and psychosis-spectrum disorders in a wide-spread and global manner. Complexity, which is well-studied in EEG but not fMRI-- emerged as a promising measure for further research. Our results also support a frequency-based behavioral encoding system operating in the BOLD signal. MeaningOur findings indicate that mood and psychosis-spectrum disorders differ from healthy controls in a mechanistically distinct way, as well as from one another across the whole brain. They also suggest that differences in low-frequency oscillations may represent shared and distinct markers of mental health and may help in developing treatment strategies that target these disruptions.