Elsevier

NeuroImage

Volume 59, Issue 3, 1 February 2012, Pages 2994-3002
NeuroImage

Caffeine increases the temporal variability of resting-state BOLD connectivity in the motor cortex

https://doi.org/10.1016/j.neuroimage.2011.10.001Get rights and content

Abstract

Correlations between spontaneous fluctuations in the blood oxygenation level dependent (BOLD) signal measured with functional MRI are finding increasing use as measures of functional connectivity in the brain, where differences can potentially predict cognitive performance and diagnose disease. Caffeine, which is a widely consumed neural stimulant and vasoactive agent, has been found to decrease the amplitude and correlation of resting-state BOLD fluctuations, and hence is an important factor to consider in functional connectivity studies. However, because the BOLD signal is sensitive to neural and vascular factors, the physiological mechanisms by which caffeine alters spontaneous BOLD fluctuations remain unclear. Resting-state functional connectivity has traditionally been assessed using stationary measures, such as the correlation coefficient between BOLD signals measured across the length of a scan. However, recent work has shown that the correlation of resting-state networks can vary considerably over time, with periods as short as 10 s. In this study, we used a sliding window correlation analysis to assess temporal variations in resting-state functional connectivity of the motor cortex before and after caffeine ingestion. We found that the temporal variability of BOLD correlation was significantly higher following a caffeine dose, with transient periods of strong correlation alternating with periods of low or negative correlation. This phenomenon was primarily due to increased variability in the phase difference between BOLD time courses in the left and right motor cortices. These results indicate that caffeine may cause underlying spontaneous neural fluctuations to go in and out of coherence more frequently, and emphasizes the need to consider non-stationary measures when studying changes in functional connectivity.

Introduction

Resting-state functional MRI (fMRI) can be used to assess functional connectivity within the brain through the measurement of correlations between spontaneous blood oxygenation level-dependent (BOLD) fluctuations in different regions. Synchronous BOLD fluctuations have been consistently found at rest within functional networks such as the motor cortex, visual cortex, and default mode network (DMN) (Biswal et al., 1995, Lowe et al., 1998, Greicius et al., 2003). A growing number of studies have shown that functional connectivity is altered for cognitive disorders such as multiple sclerosis, epilepsy, Parkinson's, and Alzheimer's disease (Lowe et al., 2002, Greicius et al., 2004, Lui et al., 2008, Kwak et al., 2010), suggesting that resting-state studies can aid in disease diagnosis and improved understanding of disease mechanisms. In addition, inter-subject differences in functional connectivity have been shown to correlate with performance on working memory tasks and intelligence (Hampson et al., 2006, Song et al., 2008).

To date, functional connectivity studies have typically employed stationary metrics obtained with seed-based correlations or independent component analysis computed over an entire resting scan. However, recent work has shown that the correlation strength between different brain regions may vary in time. For example, a study using magnetoencephalography (MEG) found transient formations of widespread correlations in resting-state power fluctuations within the DMN and task positive network (TPN) (de Pasquale et al., 2010). This nonstationary phenomenon was particularly apparent when considering nodes in different hemispheres, which exhibited very low stationary correlation. Another study using fMRI found that the phase angle between spontaneous BOLD fluctuations in the DMN and TPN varied considerably over time, with frequent periods of significant anti-correlation (Chang and Glover, 2010). These studies indicate that coordination of spontaneous neural activity is a dynamic process, and suggest that time varying approaches can provide critical insights into functional connectivity.

Despite the increasing appearance of resting-state functional connectivity studies in the literature, it remains difficult to interpret the physiological mechanisms behind changes in BOLD signal correlations. The BOLD signal provides an indirect measure of neural activity, and is a complex function of changes in cerebral blood flow (CBF), cerebral blood volume, and oxygen metabolism (Buxton et al., 2004). Factors that alter any part of the pathway between neural activity and the BOLD response can change functional connectivity measurements, making it difficult to decipher the origin of this effect. For example, caffeine is a widely used stimulant that has a complex effect on the coupling between neural activity and blood flow (Fredholm et al., 1999, Pelligrino et al., 2010). Through adenosine antagonism, caffeine enhances neural activity by blocking the inhibitory affects of adenosine activation (Dunwiddie and Masino, 2001). In addition, by inhibiting adenosine binding to receptors on smooth muscles cells, caffeine reduces the ability of blood vessels to dilate (Meno et al., 2005, Pelligrino et al., 2010) and causes an overall reduction in baseline cerebral blood flow (Cameron et al., 1990). All of these factors can lead to BOLD signal changes.

Previous work by our group assessing caffeine's effect on resting-state BOLD fluctuations has shown that it reduces both the stationary correlation and amplitude of the fluctuations in the motor cortex (Rack-Gomer et al., 2009). While it is difficult to determine the underlying physiological mechanisms behind this effect, recent studies suggest that it may stem primarily from changes in neural activity coherence. For example, preliminary work by our group with magnetoencephalography (MEG) found similar reductions in the correlation of MEG power fluctuations in the motor cortex, which do not have the same vascular confounds that are present in the BOLD fMRI signal (Tal et al., 2011). In addition, caffeine has been shown to impair motor learning compared to a placebo (Mednick et al., 2008). Since it has been shown that the strength of resting-state functional connectivity is related to memory performance (Hampson et al., 2006), these findings suggest that the caffeine-induced reduction in BOLD correlation may represent underlying neural changes.

In this study, we employed a non-stationary analysis approach to gain further insight into the mechanisms of caffeine's effect on functional connectivity. Specifically, we used a sliding window correlation analysis to assess whether caffeine consistently weakens the correlation over time or if transient periods of strong correlation still exist, albeit less frequently. A persistent and stationary decrease in correlation could be caused by an overall change in the vascular system induced by caffeine. However, it is unlikely that a shift in the state of the vascular system would give rise to an increase in the non-stationarity of the correlations, when viewed on a time scale of tens of seconds. Instead, a caffeine-induced increase in the temporal variability of the correlations would tend to support the existence of greater temporal variability in the coherence of the underlying neural fluctuations.

Section snippets

Experimental protocol

The data used in this study were collected for a previous experiment examining the effects of caffeine on resting-state BOLD connectivity as assessed with stationary correlation measures (Rack-Gomer et al., 2009). Nine healthy volunteers (5 males and 4 females, ages 23 to 41 years) participated in this study after providing informed consent. Participants were instructed to refrain from ingesting caffeine for at least 12 hours prior to being scanned. The estimated daily caffeine usage for each

Results

Stationary measures of functional connectivity (i.e. the correlation computed across all time points) are shown for each subject before and after caffeine ingestion in Fig. 1a, where the solid line represents equality between the two states. Consistent with our previous study (Rack-Gomer et al., 2009), we find that caffeine significantly reduces inter-hemispheric BOLD connectivity in the motor cortex (t(8) = 3.2, p = 0.012). Fig. 1b shows the pre-dose and post-dose functional connectivity measures

Discussion

Caffeine has been previously shown to reduce stationary measures of the correlation between spontaneous BOLD signal fluctuations in the motor cortex (Rack-Gomer et al., 2009). However, because of the complexity of caffeine's interaction with both the neural and vascular systems, it remains unclear how BOLD signal correlation is disrupted. In this study, we examined temporal variations in correlation before and after a 200 mg dose of caffeine to gain more insight into the physiological mechanisms

Acknowledgments

We thank Joanna Perthen and Joy Liau for their assistance with this study. This work was supported in part by a grant from the National Institutes of Health (R01NS051661).

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