Reproducible Effects of Sex and Acquisition Order on Multiple Global Signal Metrics: Implications for Functional Connectivity Studies of Phenotypic Individual Differences Using fMRI

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PURPOSE: The identification of relationships between individual differences in functional connectivity (FC) and behavior has been the focus of considerable investigation. Although emerging evidence has identified relationships between FC and cognitive performance, relationships between FC and measures of affect, including depressed mood, anhedonia, and anxiety, and decision-making style, including impulsivity and sensation seeking, appear to be more inconsistent across the literature. This may be due to low power, methodological differences across studies, including the use of global signal correction (GSR), or uncontrolled characteristics of the population. METHODS: Here, we evaluated measures of FC, regional variance, and global signal (GS) across six functional MRI (fMRI) sequences of different tasks and resting states and their relationship with individual differences in self-reported measures of symptoms of depression, anxiety, impulsivity, reward sensitivity, and sensation seeking, as well as demographic variables and acquisition order, within groups of distressed and healthy young adults (18-25 years old). FINDINGS: Adopting a training/testing sample structure to the analysis, we found no evidence of reproducible brain/behavior relationships despite identifying regions and connections that reflect reliable between-scan individual differences. However, summary measures of the GS were reproducibly associated with sex: The most consistent finding was an increase in low frequency variance of the blood-oxygenation-level-dependent (BOLD) signal from all gray matter regions in males relative to females. Post hoc analysis of GS topography yielded sex differences in a number of regions, including cerebellum and putamen. In addition, effects of paradigm acquisition order were observed on GS measures, including an increase in BOLD signal variance across time. In an exploratory analysis, a specific relationship between sex and relative high-frequency within-scanner motion was observed. CONCLUSIONS: Together, the findings suggest that FC relationships with affective measures may be inconsistent or modest, but that global phenomena related to state and individual differences can be robust and must be evaluated, particularly in studies of psychiatric disorders such as mood disorders or ADHD, which show sex differences.

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