Anterior insular cortex glutamate-glutamine (Glx) levels predict general psychopathology via heightened error sensitivity.

INTRODUCTION

The anterior insular cortex (AIC) integrates interoceptive, cognitive-emotional, and error-monitoring signals, and is consistently hyperactive in anxiety and depression. Converging evidence links elevated glutamate + glutamine (Glx) in fronto-insular regions to stress reactivity; however, it is unknown whether AIC Glx relates to a transdiagnostic general psychopathology factor (G-score) or to the tendency to overweight prediction errors during learning. We therefore combined functional MRS (fMRS) with reinforcement-learning modeling to test whether (i) baseline AIC Glx predicts the G-score derived from bifactor analysis of PHQ-9, GAD-7, and STAI-X1, and (ii) task-evoked Glx changes track individual differences in error sensitivity during gain- and loss-based learning.

METHODS

Fifty-six healthy adults (22 ± 2 yr, 16 women) completed the questionnaires and performed a two-armed bandit task (40 loss then 40 gain trials) while single-voxel semi-LASER spectra were acquired from AIC and medial prefrontal cortex (mPFC) at rest and during each block. Six Rescorla-Wagner variants were fitted to the choices; the best model (based on the lowest LOOIC) included error sensitivity, decision temperature, and value decay. Glx (CRLB < 20%) was quantified using LCModel and analyzed with repeated-measures ANOVA and Bonferroni-corrected correlations; mediation was assessed using Baron-Kenny steps (α = 0.05).

RESULTS

Baseline AIC Glx correlated with the G-score ( = 0.39, = 0.004) and with error sensitivity for gains and losses (≈0.41-0.44, ≤ 0.005); mPFC Glx showed no such relations. AIC Glx fell during gain learning (-2.21%, = 0.034) and remained low post-task, whereas mPFC Glx was unchanged. Error sensitivity fully mediated the AIC-Glx/G-score link; associations were specific to Glx, not other metabolites.

DISCUSSION

Higher excitatory tone in the AIC appears to enlarge prediction-error weighting, which in turn amplifies a shared anxiety-depression dimension. Dynamic Glx reductions during reward learning suggest acute metabolic demand superimposed on a trait-like baseline that biaes cognition. Targeting insular glutamatergic function-pharmacologically or via neuromodulation-may therefore mitigate maladaptive error processing that underlies internalizing psychopathology.