Introduction
Dry eye disease (DED) affects 5%-55% of people worldwide1. Chronic corneal pain is the most common symptom of DED, including burning, aching, dryness, and itching2. Although chronic corneal pain often falls outside the scope of DED therapy, reduces work productivity, impacts the quality of life and even psychological statement3, the underlying mechanism of chronic corneal pain related to DED remains unclear.
Interestingly, the corneal pain symptom severity does not correlate well with ocular surface findings, suggesting the pain symptoms might amplify during transferring to the higher nervous system. Recently, several studies have revealed central sensitization and neuroinflammation may contribute to the development of chronic corneal pain of DED4. The abnormal sensory message transmitted to the central nervous system (CNS) may affect the excitability of sensory neurons in associated brain regions and induce chronic pain symptoms. However, the representative brain areas of chronic corneal pain and cellular and molecular mechanisms have not been well screened and clarified. Rs-fMRI based on the blood oxygenation level-dependent (BOLD) signal could approve a novel approach to detect spontaneous neuronal activity in different brain regions. The amplitude of low-frequency fluctuation (ALFF) is an index of low-frequency oscillations representing the BOLD signal fluctuations in the gray matter. It features an optimal balance between test-retest reliability and replicability of all rs-fMRI indicators5,6. C-Fos has been reported as a marker of neuronal activity in specific areas of brain in pain models7. Thus, using ALFF and c-Fos to evaluate the differences in neuronal activity of brain between chronic corneal pain model and the sham may provide novel information about central sensitization mechanisms related to chronic corneal pain.
In the present study, we established a model of DED by excising extra orbital glands and confirmed the changes in mechanical and chemical pain thresholds. Meanwhile, rs-fMRI was performed to investigate the alternation of brain functional activity related to chronic corneal pain. Next, c-Fos was tested in higher ALFF value brain regions. Finally, brain derived neurotrophic factor (BDNF) and the secretion of proinflammatory molecules in higher ALFF value brain regions were also explored to determine their contribution to the central sensitization mechanism. Our results provide a novel insight into the contribution of CNS to chronic corneal pain.