Chronic ocular pain is associated with smaller selective hippocampal subfield in highly symptomatic patients

Chronic ocular pain (COP) defines any type of pain in the eye persisting for more than 3 months and is often accompanied by symptoms that extend beyond the ocular system, including central nervous system (CNS) alterations reflected in mood disturbances and cognitive changes. Emerging evidence suggests the hippocampus plays a role in pain modulation, but its involvement in COP has not yet been investigated. We aimed to identify structural changes in the hippocampus associated with COP to identify potential links between persistent pain and CNS effects. Structural T1-weighted MRI scans were obtained from highly symptomatic COP patients (n=23, 15 M, mean age 55.0 ± 10.3 years) and controls with no pain (n=14, 12 M, mean age 56.1 ± 8.0 years). Hippocampal subfields were segmented using hippocampal subfield segmentation module in FreeSurfer (v. 7.4.1). Statistical analyses included independent samples t-tests or Mann-Whitney U-tests with false discovery rate (FDR) correction, multivariable general linear models adjusting for migraine, analgesic use, and depressive symptoms. The right subiculum showed a statistically significant smaller volume in COP compared with controls (FDR-adjusted p = 0.01), with a similar trend in the left subiculum (FDR-adjusted p = 0.07). The hippocampal fissure also showed smaller volumes in the COP group, although these did not remain significant after correction. In multivariable models, COP remained selectively associated with lower right subiculum volume and showed a trend level interaction with migraine status. These findings suggest subfield specific hippocampal involvement in CNS alterations associated with chronic ocular pain. PERSPECTIVE: This article presents specific hippocampal structural differences in chronic ocular pain (COP), with a robust association between COP and smaller right subiculum volume after multivariable adjustment. The results support hippocampal involvement in chronic pain, supporting a neurobiological substrate for COP related central symptoms and providing a candidate imaging biomarker for further studies.