A comparative study of modified suanzaoren decoction versus estazolam in chronic insomnia disorder: Clinical outcomes and thalamocortical network changes.

Chronic insomnia disorder (CID) is associated with widespread abnormalities in thalamic functional connectivity (FC). For CID patients with the yin-deficiency and fire-excess syndrome, Modified Suanzaoren Decoction (MSZRD) and estazolam are common treatments, but their longitudinal associations with thalamic networks remain unclear. This study was a non-randomized, patient-preference controlled trial. Eighty-two CID patients with yin-deficiency and fire-excess syndrome received a 6-week treatment with either MSZRD or estazolam based on preference. Additionally, 54 healthy controls (HCs) were recruited for baseline comparison. Clinical scales, polysomnography, and resting-state fMRI data were collected pre- and post-treatment. Using the Human Brainnetome Atlas, the thalamus was parcellated into eight subregions. We examined baseline group differences and longitudinal FC changes, and identified genes associated with the baseline FC alterations for enrichment analysis. At baseline, CID patients showed significantly increased FC in pathways involving the medial pre-frontal thalamus, posterior parietal thalamus, lateral pre-frontal thalamus, and caudal temporal thalamus with multiple cortical regions. After treatment, the MSZRD group showed greater improvement than the estazolam group on subjective and objective measures. While FC decreased in the MSZRD group between the left occipital thalamus and right middle frontal gyrus, and between the right occipital thalamus and right angular gyrus, it increased in the estazolam group for these connections. Enrichment analysis of genes associated with baseline FC alterations identified pathways related to synaptic organization, cytoskeletal stability, and metabolism. These findings provide preliminary evidence that CID is associated with enhanced thalamocortical connectivity consistent with the thalamus-centric hyperarousal model, and that MSZRD and estazolam show different clinical and neural correlates. However, due to the non-randomized design and baseline FC differences, these findings are hypothesis-generating and require validation in future randomized mechanistic studies.