Glutamate levels in the cingulate cortex are associated with objective markers of pain sensitivity by way of pre-stimulus alpha band oscillations.

Pain varies substantially from one individual to the next. Understanding the role of brain function in variations to pain, both in health and disease, represents an important steppingstone towards individualized pain management. This study aimed to investigate the association between glutamate levels and pain sensitivity, and whether this is mediated by alpha band oscillations. Fifty-one healthy individuals were recruited for this study. Laser evoked potentials (LEPs) and pain ratings were recorded in response to 20 stimuli applied at 4 different intensities (2.75, 3, 3.25, 3.5 J) to the right volar forearm. Brain alpha band oscillations (7-13 Hz) were extracted from the pre-stimulus timeframe (-1000 ms to -100 ms). Single-voxel magnetic resonance spectroscopy data were collected to estimate regional differences in glutamate levels across the anterior (ACC) and posterior cingulate cortex (PCC) using a 3 T scanner. Cluster analysis of LEPs revealed two clusters (high vs. low N2P2 amplitudes). Glutamate levels were reduced in the PCC versus ACC in the 'low LEP' (t = 3.6, p < 0.001), but not 'high LEP' cluster (t = 1.08, p = 0.285). Causal mediation analysis revealed that the effect of ACC:PCC glutamate ratio on LEP peak-to-peak amplitudes was mediated via pre-stimulus alpha band oscillations (βindirect = -25.6(-63.9, -2.4), p = 0.034]. This study indicates that glutamate levels across the cingulate cortexshape subsequent brain responses to noxious input, and that this is mediated by pre-stimulus alpha band oscillations. Both brain metabolites and oscillations thus likely play a vital role in individual variabilities in experimental pain.