ABSTRACT Chronic ocular surface pain (COSP) affects approximately 5-15% of the US population at some time in their lives at an estimated cost of over $55 billion annually. People with COSP experience painful eye burning, irritation, and aching, leading to functional impairment and decreased quality of life. Conventional treatments directed at the ocular surface – the perceived pain source – are inadequate for pain relief in over 50% of patients. We hypothesize that some individuals with COSP also suffer symptoms driven by central nervous system (CNS) dysfunction, similar to chronic overlapping pain conditions, rather than solely pathological problems in the eye. These chronic overlapping pain conditions (e.g., fibromyalgia or interstitial cystitis/bladder pain syndrome) show clear nociplastic mechanisms, where the pain results from amplified and/or dysregulated CNS signaling and sensory processing. Our premise is supported by nociplastic pain features observed in COSP. These include: (a) pain with minimal ocular surface signs (sign/symptom discordance), (b) multisite pain and CNS-mediated somatic symptoms (fatigue), (d) augmented CNS pain processing on evoked sensory testing and neuroimaging, and (e) persistent pain after topical anesthetic. To date, no comprehensive study has investigated the clinical, neurobiological, and treatment response features of nociplastic pain in a cohort of COSP sufferers. We will rigorously define the role of nociplastic pain in COSP with a large, representative cohort of patients (N=200) using established clinical phenotypic, neurobiological, and treatment response features. We propose that as sign/symptom discordance increases so will features indicative of nociplastic pain. In Aim 1, we will clinically phenotype COSP participants using validated patient-reported outcome measures and ocular exams. In Aim 2, we will compare the neurobiological features of nociplastic pain across the discordance spectrum among a subset of Aim 1 participants. For this intensive examination subset, we will use multimodal evoked sensory testing and structural/functional brain MRI to assess regions important for pain perception and modulation. Similarly, we hypothesize that patients with high pain discordance will exhibit amplified multisensory perception and increased pro-nociceptive functional connectivity. In Aim 3, we will examine and validate predictors of COSP pain responses before and after application of a topical anesthetic to the ocular surface. The use of topical anesthetic should block peripherally induced discomfort to allow for clarification of pain origination. We hypothesize that patients with heightened nociplastic pain features will have reduced anesthetic response. Findings from the study have the potential to fundamentally change the way ocular pain syndromes are conceptualized, diagnosed, and treated. The work is likely to identify new integrative CNS-directed pain treatments for patients with COSP and will provide f...