Transcriptomic and Neurotransmitter Insights Into Gray Matter Volume Changes From 1 Hz rTMS in Treating Schizophrenia With Auditory Verbal Hallucinations

Abstract

Background: Auditory verbal hallucinations (AVH) are prominent positive symptoms of schizophrenia that frequently prove resistant to conventional antipsychotic treatments. Low-frequency repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising intervention for AVH; however, the underlying neurobiological mechanisms mediating its efficacy remain incompletely understood. Methods: In this study, schizophrenia patients with AVH were randomly assigned to either an active stimulation group or a sham control group. The active stimulation group received 1 Hz rTMS targeting the left temporoparietal junction (TPJ), while the sham group underwent an identical procedure without actual stimulation. Structural MRI scans were conducted before and after treatment to evaluate changes in gray matter volume (GMV). Further analyses examined associations between GMV changes and both gene expression profiles and neurotransmitter receptor densities. Results: Active rTMS stimulation resulted in a significant reduction in AVH symptoms and was associated with increased GMV in specific cortical regions related to sensory and cognitive processing. These structural changes correlated with gene sets enriched in neuroplasticity-related pathways, such as cell morphogenesis, chromatin remodeling, and vesicle cytoskeletal trafficking. Notable changes were also observed in neurotransmitter receptor densities, particularly for serotonin (5HT1a), dopamine (D1), and glutamate (mGluR5) receptors. Multiple linear regression analysis identified specific hub gene expressions, such as ANK1, and patterns of neurotransmitter density, especially mGluR5, as significant predictors of GMV changes following rTMS stimulation. Conclusion: Low-frequency rTMS induced GMV changes, coupled with alterations in gene expression and neurotransmitter receptor densities, contribute to symptom alleviation in schizophrenia patients with AVH. These findings support rTMS as a promising intervention for targeting the neurobiological substrates underlying AVH in schizophrenia.