Altered hemispheric lateralization of cortico-basal ganglia-thalamic network associated with gene expression and neurotransmitter profiles as potential biomarkers for panic disorder

Functional brain lateralization, a key feature of the human brain that shows alterations in various mental disorders, remains poorly understood in panic disorder (PD), and its investigation may provide valuable insights into the neurobiological underpinnings of psychiatric conditions. This study investigates hemispheric lateralization in drug-naive patients with PD before and after treatment, explores its associations with gene expression and neurotransmitter profiles, and examines its utility for diagnosis and treatment outcome prediction. Fifty-eight patients and 85 healthy controls (HCs) were enrolled. Clinical assessments and resting-state functional magnetic resonance imaging scans were conducted before and after a 4-week paroxetine monotherapy. Intra-hemispheric functional connectivity strength (FCS), inter-hemispheric FCS, and parameter of asymmetry (PAS) were calculated. Imaging-transcriptomic and imaging-neurotransmitter correlation analyses were conducted. PAS was used in machine learning models for classification and treatment outcome prediction. Compared with HCs, patients exhibited enhanced intra-hemispheric FCS and decreased PAS in the caudate nucleus/pallidum and thalamus, with associated genes, dopamine and serotonin receptor densities, and vesicular acetylcholine transporter densities linking these lateralization alterations to neural signaling and synaptic function. FCS and PAS results were consistent across different correlation thresholds (0.15, 0.2, and 0.25). No significant changes in FCS or PAS were observed following treatment. PAS demonstrated excellent performance in classification (accuracy = 75.52 %) and treatment outcomes prediction (r = 0.763). Hemispheric lateralization in the cortico-basal ganglia-thalamic network was significantly altered in patients with PD, with these changes linked to disruptions in genes and neurotransmitter profiles which are associated with neural signal transduction and synaptic function. PAS shows promise as a biomarker for PD diagnosis and treatment outcome prediction.