Sex differences in connectivity of the subgenual anterior cingulate cortex

We previously reported that women exhibit greater heat pain adaptation to a prolonged painful stimulus and greater habituation to repeated painful stimuli than men. The neural mechanism underlying this sex difference is unknown. However, Bingel et al. (2007) have shown that pain habituation after 8 days of daily pain testing is associated with an increase in pain-evoked activity of the subgenual anterior cingulate cortex (sgACC), suggesting that pain habituation may be mediated via connectivity between the sgACC and the descending pain antinociceptive system. Therefore, we investigated whether women have stronger functional connectivity (FC) and greater structural connectivity (SC) compared to men between the sgACC and the descending antinociceptive system. Our analyses revealed that (1) women exhibited greater FC between the sgACC and the periaqueductal gray (PAG), raphe nucleus, medial thalamus, and anterior midcingulate cortex (aMCC) than men; (2) men had stronger sgACC FC with the anterior insula and temporoparietal junction than women; (3) women and men exhibited comparable SC of the sgACC with the PAG, thalamus, aMCC, anterior insula, and amygdala; and (4) men have stronger sgACC SC with the hypothalamus than women. These data indicate that brain circuitry in women may provide for greater engagement of the descending modulation system mediating pain habituation. In contrast, in men, the salience network may be more engaged, which could support greater sustained attention to pain, thereby preventing pain habituation. Furthermore, the hypothalamus findings suggest a more powerful stress and endorphin-based system at play in men than women.