Figure 3. Task-dependent correlations of GABA change with BOLD change.

(a) GLM covariance analysis of GABA change with BOLD change within a masked region defined by the MRS voxel probability map (i.e. gray matter voxels within each participant’s MRS voxels with minimum 50% probability, as outlined in black). We used fMRI data (i.e. first two vs. last two fMRI runs) that were collected closer to the time when GABA was collected (before vs. after training). Activations are shown in radiological co-ordinates. GABA change correlated negatively with BOLD change for the Signal-in-Noise task (green to blue color bar), while positively for the Feature-differences task (orange to yellow color bar). The color bars indicate Pearson’s r. (b) Correlation of change in GABA and BOLD extracted from an independently defined region of interest; that is BOLD was extracted from the voxel clusters in posterior occipito-temporal cortex that resulted from the covariance analysis of fMRI with behavioral improvement (Figure 1c). This analysis showed opposite and significantly different correlations (SN: r = −0.58 CI=[−0.82,–0.22], FD: r = 0.70 CI=[0.37, 0.90], Fisher’s z = 4.19, p<0.0001) and corroborated the results shown in Figure 3a. Including data from participants that were trained for an additional eighth run showed similar results, as the analyses including seven training runs from all participants (Figure 3—figure supplement 1). In particular, a) the whole brain covariance analysis of BOLD change with GABA change showed similar activation maps (Figure 3—figure supplement 1a), b) the correlations between GABA change and BOLD change (extracted from the voxels activated in the independent covariance analysis with behavioral improvement, Figure 1—figure supplement 4b) remained significantly different between tasks (Fisher’s z = 3.26, p=0.001, Figure 3—figure supplement 1b). Finally, moderation analysis showed a significant interaction between GABA change, task and BOLD change (Figure 3—figure supplement 2).

Figure 3—figure supplement 1. Correlations of GABA change and BOLD change for Signal-in-Noise vs Feature differences task including eighth training run.

Including data from participants that were trained for an additional eighth run resulted in similar results as data from seven runs across all participants: (a) the whole brain covariance analysis of BOLD change with GABA change showed similar activation maps with the analysis using seven training runs (Figure 3a), (b) the correlations between GABA change and BOLD change (extracted from the voxels activated in the independent covariance analysis with behavioral improvement, Figure 1—figure supplement 4b) remained significantly different between tasks (Fisher’s z = 3.26, p=0.001).

Figure 3—figure supplement 2. Task-dependent GABAergic plasticity moderates the relationship of functional brain plasticity and behavioral improvement.

We conducted moderation analyses to test whether task-dependent training moderates (a) the influence of GABA change on behavioral improvement and (b) the relationship between GABA and BOLD change. Model (a) was significant (F(3,27)=3.06, p=0.04), with a significant interaction between Task and GABA (F(1,27)=8.56, p=0.01; R-square change = 0.24), indicating that task-dependent training moderates the influence of GABA change on behavioral improvement. Model (b) was significant when the outcome variable was either GABA (F(3,29)= 6.28, p=0.002; Task x BOLD interaction: F(1,29)=16.27, p=0.0004; R-square change = 0.34) or BOLD (F(3,29)=8.55, p=0.0003; Task x GABA interaction: F(1,29)=24.58, p=0.00003; R-square change = 0.45), indicating that task-dependent plasticity moderates the relationship between change in GABA and BOLD. Finally, to test whether GABA, as moderated by task-dependent training, moderates the influence of BOLD on behavioral improvement, we tested a moderated moderation model (c). This analysis allowed us to test whether the influence that an independent variable (i.e. BOLD) has on the outcome (i.e. behavior) is moderated by one or more moderator variables (i.e. GABA, task). We found that this model was significant (F(7,28)= 3.77, p=0.01) and the interaction between Task, GABA and BOLD was significant (F(1,28)= 7.17, p=0.01; R-square change = 0.13). This result suggests that task-dependent GABAergic inhibition moderates the influence of functional brain plasticity on behavioral improvement. We further tested a model with Task and BOLD as moderators of the influence of GABA on behavior. This model was significant (F(5,30)= 3.26, p=0.02); however the interactions between GABA, Task and BOLD were not significant; that is, i) GABA x Task: F(1,30)=0.04, p=0.85; ii) GABA x BOLD: F(1,30)=0.02, p=0.89, suggesting that BOLD does not significantly moderate the relationship between GABA change and behavioral improvement.