Time of day is associated with paradoxical reductions in global signal fluctuation and functional connectivity

Abstract

The brain exhibits substantial diurnal variation in physiology and function but neuroscience studies rarely report or consider the effects of time of day. Here, we examined variation in resting-state fMRI in around 900 subjects scanned between 8am to 10pm on two different days. Multiple studies across animals and humans have demonstrated that the brain's global signal amplitude (henceforth referred to as "fluctuation") increases with decreased arousal.Thus, in accord with known circadian variation in arousal, we hypothesised that global signal fluctuation would be lowest in the morning, increase in the mid-afternoon and dip in the early evening. Instead, we observed a cumulative decrease (22% between 9am to 9pm) in global signal fluctuation as the day progressed. To put the magnitude of this decrease in context, we note that task-evoked fMRI responses are typically in the order of 1% to 3%. Respiratory variation also decreased with time of day, although control analyses suggested that this did not account for the reduction in GS fluctuation. Finally, time of day was associated with marked decreases in resting state functional connectivity across the whole brain. The magnitude of decrease was significantly stronger than associations between functional connectivity and behaviour (e.g., fluid intelligence). These findings reveal unexpected effects of time of day on the resting human brain, which challenge the prevailing notion that the brain's global signal reflects mostly arousal and physiological artefacts. We conclude by discussing potential mechanisms for the observed diurnal variation in resting brain activity and the importance of accounting for time of day in future studies.

Time-of-day effects in resting-state fMRI: changes in Effective Connectivity and BOLD signal

“…These findings are contradictory to previously reported results that indicate a shift in DMN and MTL FC from morning to evening (Blautzik et al, 2013, Shannon et al, 2013. Interestingly, a recent publication using the same subjects (Human Connectome Project release S1200) reports a cumulative global signal (GS) decrease and whole brain FC decrease throughout the day (Orban et al, 2020), which appear as inconsistent with present findings of constant FC in DMN, SN and CEN. However, the conflicting findings between the current and previously reported results are likely rooted in different methodological approaches used that aimed to separate metabolic factors from connectivity.…”

“…In the present study, the dynamic relationship between functionally connected nodes was assessed using a generative model, namely Dynamic Causal Modelling, which analyses the bidirectional effect each network exhibits with itself and others. By contrast, previous publications reported the functional connectivity, namely the correlational relationship between the nodes of the network, which is based on the temporal correlations of the BOLD signals (Facer-Childs et al, 2019;Orban et al, 2020). One might speculate that those correlative approaches are potentially biased by systematic variations of the underlying BOLD signal, as demonstrated by the present study.…”

“…Interestingly, there were no region-specific effects in the transit times, which indicates that this is a global vascular effect. One might also speculate whether these globally appearing effects in decay and CSD amplitude might also explain the observed time-of-day dependent fluctuations of the global signal as observed by Orban and co-workers, using data from the Human Connectom Project, as well (Orban et al, 2020). It should be noted that the effect sizes are considerably large.…”

“…Recent reports do support the notion that functional connectivity in the DMN is affected by time-of-day and chronotype (Facer-Childs, Campos, Middleton, Skene, & Bagshaw, 2019) and a steady decrease of global signal fluctuation and regional BOLD fluctuations together with whole-brain rs-FC throughout the day (Orban et al, 2020). Orban and colleagues (2020) further present evidence that the association between time-of-day and the reductions in global rs-FC is stronger than the association with fluid intelligence measure.…”

Rest-task modulation of fMRI-derived global signal topography is mediated by transient coactivation patterns

“…However, other studies have shown that the GS is not merely nonneuronal noise, and it contains important information about neuronal activity. For instance, the GS in fMRI exhibits a high correlation to electrophysiological measures on the cortical level [ 4 , 5 ]; its global fluctuation may partly stem from subcortical regions (e.g., basal forebrain) relating to arousal [ 6 , 7 ]; and its variance fluctuates across time of day [ 8 ]. Finally, abnormalities in the level of the GS have been observed in psychiatric disorders like schizophrenia [ 9 ] and bipolar disorder [ 10 ].…”