Local GABA concentration is related to network-level resting functional connectivity

Charlotte J Stagg, Velicia Bachtiar, Ugwechi Amadi, Christel A Gudberg, Andrei S Ilie, Cassandra Sampaio-Baptista, Jacinta O'Shea, Mark Woolrich, Stephen M Smith, Nicola Filippini, Jamie Near, Heidi Johansen-Berg, Charlotte J Stagg, Velicia Bachtiar, Ugwechi Amadi, Christel A Gudberg, Andrei S Ilie, Cassandra Sampaio-Baptista, Jacinta O'Shea, Mark Woolrich, Stephen M Smith, Nicola Filippini, Jamie Near, Heidi Johansen-Berg

Abstract

Anatomically plausible networks of functionally inter-connected regions have been reliably demonstrated at rest, although the neurochemical basis of these 'resting state networks' is not well understood. In this study, we combined magnetic resonance spectroscopy (MRS) and resting state fMRI and demonstrated an inverse relationship between levels of the inhibitory neurotransmitter GABA within the primary motor cortex (M1) and the strength of functional connectivity across the resting motor network. This relationship was both neurochemically and anatomically specific. We then went on to show that anodal transcranial direct current stimulation (tDCS), an intervention previously shown to decrease GABA levels within M1, increased resting motor network connectivity. We therefore suggest that network-level functional connectivity within the motor system is related to the degree of inhibition in M1, a major node within the motor network, a finding in line with converging evidence from both simulation and empirical studies. DOI: http://dx.doi.org/10.7554/eLife.01465.001.

Keywords: GABA; magnetic resonance spectroscopy; resting state fMRI.

Conflict of interest statement

The authors declare that no competing interests exist.

Figures

Figure 1.. Representative MR spectra.
Figure 1.. Representative MR spectra.
(A) A subject with a high GABA:NAA ratio. (B) A subject with a low GABA:NAA ratio. DOI:http://dx.doi.org/10.7554/eLife.01465.003
Figure 2.
Figure 2.
(A) Group mean motor resting state network. (B) Group mean default mode network. (C–E) Experiment 1: a significant relationship was demonstrated between M1-GABA and functional connectivity within the motor RSN (r = −0.71, p=0.01; C) but not between M1-Glx and motor network functional connectivity (D) nor between M1-GABA and functional connectivity within the DMN (E). DOI:http://dx.doi.org/10.7554/eLife.01465.004
Figure 2—figure supplement 1.. Experiment 2 replicated…
Figure 2—figure supplement 1.. Experiment 2 replicated the findings of experiment 1 in a separate group of 16 young, healthy subjects.
(A) A significant inverse relationship between M1-GABA and functional connectivity within the motor RSN was again demonstrated (r = −0.569, p=0.02). This was both anatomically and neurochemically specific (anatomical specificity: M1-GABA-DMN correlation r = 0.23, p=0.37; M1-GABA-motor vs M1-GABA-DMN: Z = 2.61; p=0.01; neurochemical specificity: M1-Glx-motor RSN correlation: r = −0.406, p=0.11; M1-GABA-motor correlation with Glx covaried out: r = −0.45; p<0.05). (B) As in experiment 1, a significant inverse relationship between the degree of M1-M1 correlation and M1-GABA was found (r = −0.49, p=0.05). DOI:http://dx.doi.org/10.7554/eLife.01465.005
Figure 2—figure supplement 2.
Figure 2—figure supplement 2.
(A) Experiment 3 found that the relationship between M1-GABA and the strength of functional connectivity within the motor RSN was maintained in healthy older adults (r = −0.69, p=0.037). Similarly to experiments 1 and 2 this relationship was both anatomically and neurochemically specific (anatomical specificity: M1-GABA-DMN correlation: r = 0.41, p=0.26; M1-GABA-motor vs M1-GABA-DMN: Z = 2.22; p=0.03; neurochemical specificity: M1-Glx-motor RSN correlation r = 0.13, p=0.73; M1-GABA-motor correlation with Glx covaried out: r = −0.79; p=0.04). (B) A significant relationship between the degree of M1-M1 correlation and M1-GABA was again found (r = −0.62, p=0.035). DOI:http://dx.doi.org/10.7554/eLife.01465.006
Figure 3.. The degree of correlation between…
Figure 3.. The degree of correlation between the left and right primary motor cortices (M1s) was significantly related to M1 GABA levels.
Values shown are raw Pearson’s correlation coefficients for ease of display. As these are not normally distributed all statistical analyses were performed on log-transformed data (see ‘Materials and methods’). (A) Experiment 1 (r = −0.60, p=0.047). (B) Experiment 4: the correlation between left and right M1s was significantly increased after anodal tDCS (t(9) = 1.94, p=0.04). DOI:http://dx.doi.org/10.7554/eLife.01465.007
Figure 3—figure supplement 1.. There was a…
Figure 3—figure supplement 1.. There was a trend towards a relationship between the degree of correlation between the left M1 and the left dorsal premotor cortex (PMd) and M1 GABA levels.
(A) Experiment 1 (r = −0.49, p=0.12). (B) Experiment 2 (r = −0.40, p=0.11). (C) Experiment 3 (r = −0.67, p=0.02). (D) Experiment 4: the correlation between left and right M1s showed a trend towards an increase after anodal tDCS (t(9) = 1.87, p=0.09). DOI:http://dx.doi.org/10.7554/eLife.01465.008
Figure 4.. Anodal tDCS applied to M1,…
Figure 4.. Anodal tDCS applied to M1, which is known to decrease GABA levels, significantly increased functional connectivity within the motor RSN (t(9) = 2.59, p=0.02).
DOI:http://dx.doi.org/10.7554/eLife.01465.009

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