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