Hippocampus shape deformation: a potential diagnostic biomarker for chronic back pain in women

Sex differences in the quality and prevalence of chronic pain are manifold, with females generally presenting higher incidence and severity. Uncovering chronic pain-related sex differences informs neural mechanisms and may lead to novel treatment routes. In a multi-center morphological study (total n=374), we investigated whether the shape of subcortical regions would reflect sex differences in back pain. Given the hormone-dependent functions of the hippocampus, and its role in the transition to chronic pain, this region constituted our primary candidate. We found that the anterior part of the left hippocampus (alHP) presented outer deformation in females with chronic back pain (CBP), identified in CBP in the USA (n=77 females vs. n=78 males) and validated in a Chinese dataset (n=29 females vs. n=58 males with CBP, in contrast to n=53 female and n=43 male healthy controls). Next, we examined this region in subacute back pain (SBP) who persisted with back pain a year later (SBPp; n=18 females vs. n=18 males), and in a subgroup with persistent back pain for 3-years. Weeks after onset of back pain there was no deformation within alHP, but at 1-year and 3-years females exhibited a trend for outer deformation. The alHP partly overlapped with the subiculum and entorhinal cortex, whose functional connectivity, in healthy subjects, was associated with emotional and episodic memory related terms (Neurosynth, reverse inference). These findings suggest that in females alHP undergoes anatomical changes with pain persistence, highlighting sexually-dimorphic involvement of emotional and episodic memory-related circuitry with chronic pain.