Unravelling the genetic and molecular basis of low-frequency rTMS induced changes in functional connectivity density in schizophrenia patients with auditory verbal hallucinations.

Auditory verbal hallucinations (AVH) represent a substantial therapeutic challenge in schizophrenia. Low-frequency repetitive transcranial magnetic stimulation (rTMS) has demonstrated potential in reducing AVH, yet the underlying neurobiological mechanisms remain incompletely understood. This study investigated the genetic and molecular processes associated with functional connectivity density (FCD) changes induced by 1 Hz rTMS in schizophrenia patients with AVH. The results revealed that the active stimulation group exhibited significant improvement in positive symptoms and AVH severity compared to the sham control group. Specifically, rTMS increased FCD within the frontoparietal network while decreasing FCD in the language network. Notably, baseline FCD values in these networks were predictive of the extent of symptom amelioration. Gene enrichment analysis indicated that rTMS-induced FCD changes were linked to molecular pathways critical for cellular homeostasis and neuronal function. Among the identified hub genes, GAL emerged as a key regulator of these alternations. Furthermore, neurotransmitter systems were implicated, with alterations in mu-opioid (MU) receptor density mediating the effects of GAL on FCD modifications. These findings highlight a multifaceted interplay among genetic, molecular, and connectivity-based mechanisms underlying the therapeutic efficacy of rTMS in treating AVH.