Funding information:
This study was supported by grants-in-aid for scientific research from the Natural Science Foundation of Shanghai [grant number 21ZR1411300] and Shenkang Clinical
Study Foundation of Shanghai [grant number SHDC2020CR4061] to Dr. Han; the National Natural Science Foundation of China [grant number 82171264], Shanghai Municipal Health and Family Planning Commission Research Project [grant number 2019SY015], Science and Technology Commission of Shanghai Municipality [grant number 21511102000], and Medical Engineering Fund of Fudan University [grant number yg2021-008] to Dr. Li. The sponsors have no involvements in study design, data collection and interpretation, writing of the manuscript, and the decision to submit the manuscript for publication.
ABSTRACT :
Purpose: Chronic corneal pain is the most common symptom of dry eye disease, while the central sensitization mechanisms underlying remain unclear.
Methods: Excision of extra orbital lacrimal glands was used to establish dry eye model. Corneal hypersensitivity and anxiety behavior were tested after surgery. The amplitude of low-frequency fluctuation was used for determining brain functional activity. C-Fos, Brain-derived neurotrophic factor, and cytokine levels in corresponding brain regions were tested.
Results: Compared to the Sham group, the amplitude of low-frequency fluctuation signals in the supplemental somatosensory area, secondary auditory cortex, agranular insular cortex, temporal association areas, and ectorhinal cortex brain areas were enhanced in dry eye group. Amplitude of low-frequency fluctuation signal in the insular cortex was related to corneal hypersensitivity (p < 0.01). C-Fos (P < 0.001), brain-derived neurotrophic factor (P < 0.01), TNF-α, IL-6 and IL-1β (P < 0.05) increased, while IL-10 levels (P < 0.05) decreased in the insular cortex in the dry eye group. Surgery-induced corneal hypersensitivity and upregulation of inflammatory cytokines, but not anxiety, could be blocked by insular cortex injection of Tyrosine Kinase receptor B agonist cyclotraxin-B (P< 0.01).
Conclusions : This research presents the map of functional brain by amplitude of low-frequency fluctuation associated with chronic corneal pain. Brain-derived neurotrophic factor-Tyrosine Kinase receptor B signaling-related neuroinflammation in the insular cortex might contribute to dry eye-related chronic corneal pain. This measure could potentially help clinicians improve therapeutic approach to pain control and development of diagnostic approach.
Keywords : Dry eye disease, chronic corneal pain, central sensitization, insular cortex, amplitude of low-frequency fluctuation