The alteration of the brainstem functional connectivity in the first episode and drug-native generalized anxiety disorder and its transcriptional patterns.

BACKGROUND: Although the brainstem abnormality has been reported in anxiety disorders, there is a scarcity of research targeting the brainstem's functional aberration in generalized anxiety disorder (GAD). The underlying transcriptional basis of brainstem dysfunction in GAD was also poorly elucidated.

METHODOLOGY: This study recruited 100 first-episode drug-naive GAD patients and 85 healthy controls (HCs) to investigate brainstem functional connectivity (FC) alteration in GAD. Fifty-three patients completed four weeks of paroxetine monotherapy. Machine learning methods were employed to evaluate the discriminative and prognostic assessment ability of the brainstem. Using transcriptomics analysis, gene expression patterns related to brainstem FC changes were investigated.

RESULT: Compared with HCs, GAD patients exhibited reduced brainstem FC with the visual processing cortex, sensorimotor cortex, prefrontal cortex, and cerebellar lobules IV-VI/ crus I. After treatment, a normalized trend was found in decreased left brainstem-right middle occipital gyrus FC. The classification and prediction model trained using brainstem FC as features performed well to identify GAD patients from HCs and evaluate treatment response at the individual level. Results of imaging transcriptomics analysis were enriched in oxidative stress response, nuclear regulation, and epigenetic pathways.

CONCLUSION: This study highlighted the key role of brainstem dysfunction and the disrupted brainstem FC may link to the impaired visual-associated cognition, anxiety generation, and somatic symptoms in GAD. The machine learning method and imaging-transcriptional analysis investigated the FC as a characteristic neuroimaging alteration in GAD and its underlying neurobiological mechanism.