A systematic review and narrative synthesis of functional neuroimaging studies for chronic ocular surface pain

Chronic ocular surface pain (COSP) is a debilitating condition of the eye driven by nociceptive, nociplastic, and neuropathic mechanisms. While individual studies using functional neuroimaging techniques to investigate ocular pain exist, the full extent, methodologies, and cumulative findings of this body of literature have not been systematically synthesized. Using a systematic review approach, we identified 5 articles evaluating the use of functional neuroimaging in COSP patients from an initial pool of 643 unique studies. All studies used functional magnetic resonance imaging exclusively as their functional neuroimaging modality, and 4 included photophobia as a manifestation of COSP. Across the studies, there were a total of 107 adult patients enrolled, of whom 83 were cases (37.3% female) with active COSP/photophobia and 24 were controls (29.2% female). The results of the studies demonstrate that light robustly recruits trigeminocortical nociceptive networks (spinal trigeminal/brainstem, S1, insula, anterior midcingulate), with partial attenuation after interventions such as topical anesthesia, botulinum toxin, or FL-41 lenses. Mechanistically, photophobia may reflect convergence of melanopsin/intrinsically photosensitive retinal ganglion cells signaling with trigeminothalamic pathways, motivating brain-based biomarkers alongside surface metrics. The consistency in study design, imaging hardware, and analytical pipelines across the 5 primary articles facilitates direct comparison but also highlights current limitations in the broader generalizability and diversity of the field. Notably, the paucity of neurophysiological studies limits our mechanistic understanding of COSP in terms of neural oscillations that can be potential targets of neuromodulatory interventions.