State-dependent reactivity of anterior cingulate cortex neurochemistry and downstream autonomic arousal in intrusive thinking

Unwanted intrusive thoughts play a key role in the onset, maintenance, and relapse of stress-related psychopathological conditions and are usually accompanied by a physiological fight-or-flight response. However, the mechanisms underlying the persistence of this maladaptive process remain unclear. This study employed a multimodal approach, integrating proton magnetic resonance spectroscopy, resting-state functional connectivity, and heart rate monitoring, to investigate gamma-aminobutyric acid (GABA) and glutamate-mediated neurometabolism during intrusive thinking, alongside central and peripheral autonomic nervous system activity. In individuals meeting diagnostic criteria for Generalized Anxiety Disorder (n = 29), an experimental induction of intrusive thoughts was associated with an increase in anterior cingulate cortex (ACC) GABA+ (macromolecular-contaminated), which correlated with suppressed autonomic reactivity. This relationship was mediated by the dispositional tendency to engage in intrusive thinking and was accompanied by reduced resting-state activation of the central autonomic network. Conversely, age- and sex-matched healthy controls (n = 29) exhibited a reduction in ACC GABA + and increased autonomic reactivity during intrusive thinking. While limited by a cross-sectional design, these findings suggest that pathological intrusive thinking may be maintained through neurometabolic negative reinforcement mechanisms involving both the central and autonomic nervous systems. If corroborated, current results may inform the development of targeted treatments aimed at disrupting such reinforcement processes.