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.