Elsevier

NeuroImage

Volume 124, Part A, 1 January 2016, Pages 24-31
NeuroImage

Differences in the resting-state fMRI global signal amplitude between the eyes open and eyes closed states are related to changes in EEG vigilance

https://doi.org/10.1016/j.neuroimage.2015.08.053Get rights and content

Highlights

  • Abbreviations: global signal amplitude (GSamp); eyes open (EO); eyes closed (EC)

  • Changes (EO–EC) in GSamp are inversely correlated with changes in EEG vigilance.

  • EO–EC relation between GSamp and vigilance is comparable to caffeine-related relation.

Abstract

In resting-state functional connectivity magnetic resonance imaging (fcMRI) studies, measures of functional connectivity are often calculated after the removal of a global mean signal component. While the application of the global signal regression approach has been shown to reduce the influence of physiological artifacts and enhance the detection of functional networks, there is considerable controversy regarding its use as the method can lead to significant bias in the resultant connectivity measures. In addition, evidence from recent studies suggests that the global signal is linked to neural activity and may carry clinically relevant information. For instance, in a prior study we found that the amplitude of the global signal was negatively correlated with EEG measures of vigilance across subjects and experimental runs. Furthermore, caffeine-related decreases in global signal amplitude were associated with increases in EEG vigilance. In this study, we extend the prior work by examining measures of global signal amplitude and EEG vigilance under eyes-closed (EC) and eyes-open (EO) resting-state conditions. We show that changes (EO minus EC) in the global signal amplitude are negatively correlated with the associated changes in EEG vigilance. The slope of this EO–EC relation is comparable with the slope of the previously reported relation between caffeine-related changes in the global signal amplitude and EEG vigilance. Our findings provide further support for a basic relationship between global signal amplitude and EEG vigilance.

Introduction

In recent years, resting-state functional magnetic resonance imaging (fMRI) has been increasingly used as a tool to study functional brain connectivity in both health and disease (Fox and Raichle, 2007). The functional connectivity measures used in resting-state fMRI reflect the temporal synchrony of blood oxygenation level dependent (BOLD) signals across brain regions (Biswal et al., 1995, Fox et al., 2005, Fransson, 2005, Raichle et al., 2001). These connectivity measures are often dominated by the presence of a global signal component that appears to varying extents across the brain. To deal with this effect, many studies have adopted a pre-processing approach referred to as global signal regression (GSR), in which the global signal component is regressed out of the measured BOLD signals prior to the computation of connectivity measures. This approach has been shown to increase the spatial specificity of the correlation maps and to better reveal the anti-correlation between resting-state networks (e.g., the default mode network and the task positive network) (Birn, 2012, Fox et al., 2005, Greicius et al., 2003). However, there is some concern about the use of GSR, as it has been shown to introduce systematic biases into correlation-based measures of functional connectivity (Fox et al., 2009, Hahamy et al., 2014, Murphy et al., 2009, Saad et al., 2012). At present, there is not a universally agreed upon standard regarding the use of GSR, with some studies employing GSR, other studies using alternate noise reduction methods, and yet another set of studies that perform analyses with and without the use of GSR (Yeo et al., 2015).

In conjunction with the ongoing discussion regarding the use of GSR, there has also been interest in developing a better understanding of the global signal. In a study of resting monkeys, Scholvinck et al. (2010) reported that the local field potential power measured at a single cortical site exhibited widespread correlation with BOLD fMRI signals, providing evidence of a neural basis for the global signal. A recent study in sleep-deprived monkeys has demonstrated that specific neurophysiological events observed during sleep are associated with large scale fluctuations in cerebral blood volume and may therefore represent a significant contribution to the global signal (Liu et al., 2015a, Liu et al., 2015b). Using simultaneous EEG-fMRI measures in human subjects, we have shown that the amplitude of the global signal was inversely correlated with electroencephalographic (EEG) measures of vigilance across subjects and experimental runs (Wong et al., 2013), with higher vigilance states characterized by lower global signal amplitudes (defined as the standard deviation of the global signal). In addition, we found that increases in EEG vigilance measures associated with the ingestion of caffeine were significantly correlated with decreases in the global signal amplitude. There is also some evidence that the global signal may carry diagnostic information. For example Yang et al. (2014) recently reported that the variance of the global signal was significantly higher in patients with schizophrenia as compared to normal controls. However, the authors of that study acknowledged that the potential confound of vigilance differences between groups would need to be carefully considered in follow-up work.

In this study, we extend our prior work to determine whether the previously described relation between the global signal and vigilance would also be observed when contrasting measures obtained in the eyes-open versus eyes-closed states. Prior studies have shown that resting-state fMRI activity is significantly different between the eyes-closed and eyes-open conditions (Bianciardi et al., 2009, Jao et al., 2013, McAvoy et al., 2008, Patriat et al., 2013, Xu et al., 2014, Yan et al., 2009, Yang et al., 2007, Yuan et al., 2014, Zou et al., 2009). In general, these studies have found that the amplitude of the resting-state BOLD signal is decreased in the eyes-open condition as compared to the eyes-closed condition. For example, Jao et al. (2013) found that the average variance of the BOLD signal (i.e., signal variances computed on a per-voxel basis and then averaged across the brain) was significantly lower in the eyes-open condition. Furthermore, in our earlier studies, we reported that global signal effects were generally lower in the eyes-open condition as compared to the eyes-closed condition (Wong et al., 2012, Wong et al., 2013). Taking into account the prior findings, we hypothesized that decreases in global signal amplitude associated with opening of the eyes would be correlated with increases in EEG vigilance measures. We also examined whether the relationship between changes in the global signal amplitude and vigilance observed with the opening of the eyes would be similar to the relationship previously observed with the administration of caffeine (Wong et al., 2013).

Section snippets

Experimental protocol

Twelve healthy volunteers were initially enrolled in this study after providing informed consent. Two subjects were not able to complete the entire study, resulting in a final sample size of 10 subjects (4 males and 6 females, aged 24 to 33 years with an average age of 25.6 years). As prior work has shown that differences in dietary caffeine consumption may cause variability in the BOLD response (Laurienti et al., 2002), we recruited caffeine-naive subjects who consumed less than 50 mg caffeine

Results

In Fig. 1a, we show the relation between the changes (EO–EC) in the global signal amplitudes and the respective changes in EEG vigilance across all epochs that included primarily awake states (84% of all EC epochs) with some epochs of stage N1 and N2 (14.4% and 1.6% of all EC epochs, respectively). Note that all EO epochs were assessed to be in the Wake stage. There was a significant negative correlation (r =  0.84; p = 0.005) between the changes in global signal amplitude and EEG vigilance. This

Discussion

We have shown that changes in the global signal amplitude (EO–EC) are negatively correlated with the associated changes in EEG vigilance measures. The slope of the relationship obtained with EO–EC changes was comparable to the slope of the previously reported relationship between caffeine-related changes in the global signal amplitude and EEG vigilance (as measured in the EC condition). These findings were robust with respect to variations in the analysis procedure. In particular, as a recent

Acknowledgments

This work was supported in part by NIH Grants R01NS051661, R21MH096495 and R21MH102578, and ONR MURI Award No. N00014-10-1-0072.

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