Cyclic extranasal neurostimulation for dry eye disease: a 4-week stimulation and 6-week intermission regimen based on neural adaptation dynamics.

Although the between-group differences in mean change scores did not reach statistical significance (OSDI: P = 0.215, Cohen’s d = 0.36, Fig. 4 c ; SPEED: P = 0.462, Cohen’s d = 0.22, Fig. 4 f, the 4-week group consistently showed a greater magnitude of improvement in both subjective symptom scores compared to the 2-week group (Fig. 4 b, d).

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Conversely, the 4-week group exhibited a strong trend toward neural adaptation at treatment completion (Visit 2, Day 28), where the mean increase in tear secretion was markedly attenuated and no longer reached conventional statistical significance (7.58 ± 4.98 mm/5 min pre-stimulation vs. 8.76 ± 4.92 mm/5 min post-stimulation, Δ = 1.18 ± 4.17 mm/5 min, 95% CI: − 0.01 to 2.37 mm/5 min, P = 0.051, Cohen's d = 0.28 ; Fig. 2 c).

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