Hypothalamic functional connectivity, depressive symptoms, and post-treatment SOREMPs in narcolepsy type 1: links to...

Narcolepsy type 1 (NT1) is characterized by sleep-onset rapid eye movement periods (SOREMPs), reflecting dysregulated rapid eye movement (REM) sleep control. Treatment response variability in SOREMP persistence remains poorly understood, particularly regarding hypothalamic functional connectivity (FC) and depressive symptoms. This study investigated clinical, polysomnographic, and neuroimaging differences between NT1 patients with low (0-1) versus high (≥2) post-treatment SOREMPs, and explored whether hypothalamic FC mediates the relationship between depressive symptoms and SOREMPs outcomes. One hundred ten NT1 patients were categorized into low (n = 62) and high (n = 48) post-treatment SOREMPs groups. Demographic, clinical variables (symptoms and questionnaires), and polysomnography (PSG)/multiple sleep latency test (MSLT) parameters were compared. Resting-state fMRI assessed hypothalamic FC with whole-brain regions. LASSO regression modeled associations between FC, sleep latency, and clinical variables, while mediation analysis tested hypothalamic pathways as mediators of depression-SOREMP relationships. High post-treatment SOREMPs patients exhibited shorter pre/post-treatment REM sleep latency, lower post-treatment wakefulness index, and higher depressive symptom prevalence compared to low SOREMPs patients. Hypothalamic FC differed significantly between groups: low SOREMPs patients showed enhanced connectivity in right medial hypothalamus-right thalamus/left precuneus, left medial hypothalamus-left inferior parietal lobule (IPL), and right lateral hypothalamus-left IPL pathways, but reduced connectivity in left lateral hypothalamus-right insula/left anterior cingulate cortex pathways (p < 0.05, GRF-corrected). LASSO regression identified left medial hypothalamus-left IPL FC as a significant predictor of post-treatment MSLT mean sleep latency (β = 0.272, p = 0.001), alongside age (β = -0.256, p = 0.002) and pre-treatment sleep latency (β = 0.392, p < 0.001). Mediation analysis revealed complete mediation by two hypothalamic pathways: depressive symptoms predicted reduced right lateral hypothalamus-left IPL FC (indirect effect: 0.15-1.05), associated with fewer SOREMPs, and increased left lateral hypothalamus-right insula FC (indirect effect: 0.08-1.14), associated with more SOREMPs. Hypothalamic-parietal/insular FC abnormalities link depressive symptoms to post-treatment SOREMP variability in NT1, with specific pathways mediating opposing effects on REM sleep regulation. These findings highlight hypothalamic connectivity as a critical neural substrate for treatment response, integrating sleep-wake and emotional processing networks. Targeting these pathways may improve personalized management for NT1 patients with comorbid depression and treatment-resistant SOREMPs.