Baseline GABA concentration and fMRI response
Research highlight
►GABA concentration inversely correlates with fMRI response in visual cortex ►GABA concentration inversely correlates with baseline CBV in visual cortex ►GABA concentration inversely correlates with CBV reactivity in visual cortex ►GABA concentration positively correlates with CBFw-ASL contrast in visual cortex.
Introduction
Coordination between glutamatergic excitatory neurons and γ-aminobutyric acid (GABA)-ergic inhibitory interneurons is fundamental to the regulation of neuronal firing rates in cerebral cortex (Buzsaki et al., 2007, Fergus & Lee, 1997). Such coordination is believed to have direct relevance to functional magnetic resonance imaging (fMRI) contrast (Buzsaki et al., 2007, Logothetis et al., 2001), and imbalances in excitatory and inhibitory processes are believed to be implicated in several neuropathological conditions such as stroke (Blicher et al., 2009, Cetas et al., 2009, Hutchinson et al., 2002), schizophrenia (Uhlhaas and Singer, 2010), autoimmune inflammation (Bhat et al., 2010), Parkinson's disease (Hershey et al., 2003) and epilepsy (Bernard et al., 2000, Meldrum, 1991). Both GABA changes and fMRI changes are seen in motor learning and decision speed in healthy subjects (Floyer-Lea & Matthews, 2005, Floyer-Lea et al., 2006, Sumner et al., 2010) and may be of interest in rehabilitation after stroke (Stagg et al., 2009, Swayne et al., 2008) and therefore investigations that focus on the relationship between GABA and fMRI reactivities may be useful for understanding post-stroke plasticity mechanisms.
While much is known regarding the molecular behavior of excitatory and inhibitory processes (Buzsaki et al., 2007, Lujan et al., 2005), comparatively little is known regarding the role of such processes on fMRI contrast. Recently, it was demonstrated that synaptic inhibition, as measured by baseline GABA concentration and magnetic resonance spectroscopy (MRS), is inversely correlated with the blood oxygenation level-dependent (BOLD) fMRI signal change in human visual cortex (Muthukumaraswamy et al., 2009) and rat somatosensory cortex (Chen et al., 2005), and directly correlated with negative BOLD responses in anterior cingulate cortex (Northoff et al., 2007). These observations demonstrate that cortical inhibition is related to the fMRI response and that inter-subject variability in BOLD responses can be at least partially attributed to variations in cortical inhibition. The observation is additionally intriguing as it demonstrates an MR-measurable link between neurotransmitter level and hemodynamic response.
Multi-modality imaging, incorporating fMRI and MRS, is promising as an approach for understanding brain function, as it allows for measurement of both neurotransmitters and hemodynamic reactivity to be assessed without contrast agents or neuroactive compounds. However, the most commonly used fMRI contrast mechanism, which exploits BOLD contrast (Ogawa et al., 1990), is complexly dependent on cerebral blood flow (CBF), cerebral blood volume (CBV), and the cerebral metabolic rate of oxygen consumption (CMRO2) and it is unclear how the relationship between GABA and the ensemble BOLD fMRI response is influenced by these components. Therefore, understanding the relationship between BOLD fMRI's constituent parameters and inhibition would be useful.
Arterial spin labelling (ASL) has emerged as a non-invasive MRI approach for measuring both baseline CBF and CBF response to stimulus (Golay & Petersen, 2006, Williams et al., 1992, Wong et al., 1998), and, more recently, vascular-space-occupancy (VASO) has emerged as a method for measuring baseline arterial CBV (aCBV) (Donahue et al., 2010) and total CBV response to stimulus (Lu et al., 2003). In this study, we investigate the relationship between baseline GABA and hemodynamic reactivity in human visual cortex by performing GABA spectroscopy, BOLD fMRI, CBF-weighted (CBFw) ASL fMRI and CBV-weighted (CBVw) vascular-space-occupancy (VASO) fMRI. In addition, baseline CBF and aCBV is compared with baseline GABA levels.
It is unclear precisely what role GABA may play on the hemodynamic constituents of the BOLD signal. One hypothesis is that neuronal firing rates and in turn energy utilization will be lower in regions of high GABA. Alternatively, a positive correlation could be possible since inhibitory firing could result in increased energy consumption, or, higher baseline inhibition could result in a higher level of hemodynamic and metabolic response necessary to overcome the baseline inhibition.
Based on recent findings (Muthukumaraswamy et al., 2009), as well as the known comparatively small fraction (15–20%) of total oxidative metabolism accounted for by inhibitory interneurons relative to excitatory neurons (Buzsaki et al., 2007, Patel et al., 2005), we hypothesize (i) an inverse relationship between BOLD, CBFw-ASL and CBVw-VASO reactivities with baseline GABA and (ii) that baseline ASL-CBF and iVASO-aCBV will inversely correlate with baseline GABA. Results will elucidate any possible relationship between hemodynamic MR contrasts and baseline GABA with a relationship providing a platform for non-invasively investigating how specific hemodynamic parameters are influenced by GABAergic tone.
Section snippets
Materials and methods
All volunteers (n = 12; age = 30 ± 4 yrs; 6 male/6 female) provided informed, written consent and were scanned at 3.0 T (Siemens Tim Trio, Erlangen, Germany). An MRS protocol was implemented for GABA quantification and a separate MRI protocol was implemented for assessing MR hemodynamic metrics.
Results
Fig. 1 shows experimental MEGA-PRESS spectra (n = 12) and GABA peaks (GABA+, gray shading) for all volunteers. The approximate location of the spectroscopy voxel is shown below. There is a noticeable peak at the frequency offset of 3.0 ppm, which is attributable to GABA+.
The estimated GABA+/Cr concentrations and uncertainties for each of the subjects are shown in Table 1. Also included in Table 1 are the uncertainties in the GABA fit quantities as a percentage of the fit intensity, the total
Discussion
These results reveal that baseline GABA inversely correlates with BOLD reactivity, VASO-measured CBVw reactivity and iVASO-measured baseline aCBV in the visual cortex, thereby providing evidence that baseline inhibitory neurotransmitter levels are related to variability in hemodynamic fMRI measures. Unexpectedly, the ASL-measured CBF exhibits a positive trend with GABA, for both baseline CBF signal and CBF signal change in response to stimulus. The TTP in the ASL signal shows a positive
Conclusions
BOLD and CBVw-VASO reactivities are inversely correlated with baseline GABA in human visual cortex, whereas CBFw-ASL measures show a more complex trend which may be explained by blood velocity discrepancies or elevated hemodynamic requirement to overcome increased resting inhibition. A link between neurochemical and MR-measured hemodynamic responses is demonstrated, suggesting that future fMRI experiments that probe the mechanistic relationships between cortical activity and GABAergic
Acknowledgments
We are grateful to Steven Knight for the experimental assistance and Richard Edden for the helpful conversations. This work was funded by The Dunhill Medical Trust and via a grant awarded by the National Institute of Health Research (NIHR) Oxford Biomedical Research Centre.
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Equal contribution.
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Permanent Address: FM Kirby Research Center, The Kennedy Krieger Institute, Baltimore, MD 21205, USA.