Choline Levels in the Pregenual Anterior Cingulate Cortex Associated with Unpleasant Pain Experience and Anxiety.

Abstract

In vivo proton magnetic resonance spectroscopy is a non-invasive technique used to measure biochemical molecules such as choline, glutamate, glutamine, and γ-Aminobutyric acid (GABA), many of which are relevant to anxiety and pain. However, the relationship between these neurotransmitters/metabolites and their implications for anxiety and subjective experience of pain is not yet fully understood. The objective of this cross-sectional study was to investigate the association between anxiety and pain ratings with levels of total choline, glutamate and GABA in brain regions known to be involved in anxiety and emotional experience of pain, specifically pregenual anterior cingulate cortex (pgACC) and dorsal anterior cingulate cortex (dACC). The levels of the neurotransmitters/metabolites were measured using GABA-edited Mescher-Garwood PRESS for GABA measurements, with the OFF-sequence measurements for total choline (tCho) and Glx (combined glutamate + glutamine). The total choline (tCho) signal in our analysis included glycerophosphocholine (GPC) and phosphocholine (PC), consistent with standard practices in MRS studies. This approach ensures a robust estimation of tCho concentrations across participants. The study collected data from 38 participants (17 males and 21 females). The analysis revealed a significant correlation between anxiety ratings before a standardized pain provocation and the rated pain unpleasantness during the pain provocation. tCho correlated negatively with these parameters in pgACC. A linear regression analysis indicated that tCho levels in pgACC has a significant negative association with anxiety and perceived pain when controlling for age, depressive symptoms, and alcohol and tobacco intake. We also found that sex significantly moderates the relationship between pgACC choline levels and pain unpleasantness. The study suggests that levels of choline, an essential precursor of acetylcholine, are associated with anxiety and perceived pain. These levels may influence how Glx and GABA contribute to affective pain experiences by modulating the balance between excitatory and inhibitory signals. However, future research is needed to identify the mechanisms involved. Furthermore, the study indicates that sex is a significant factor in this relationship, with lower choline levels being associated with higher pain ratings in females but not in males. This highlights the significance of addressing sex as a biological factor in pain research to better understand the different responses to treatments and to facilitate the development more effective interventions in the future.