Intrinsic brain activity and multiscale mechanisms of auditory verbal hallucinations in schizophrenia: A systematic review and meta-analysis.

Auditory verbal hallucinations (AVH) represent one of the most debilitating symptoms in schizophrenia. The amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF), derived from resting-state fMRI, serve as robust metrics for intrinsic brain activity; however, the network-level architecture and biological substrates underlying AVH-related ALFF/fALFF alternations have not yet been systematically elucidated. In this study, we conducted a comprehensive systematic review and meta-analysis of ALFF/fALFF studies in schizophrenia patients with AVH, integrating neurochemical mapping and transcriptomic annotation to provide a multilevel mechanistic perspective. Across studies, AVH were consistently associated with increased intrinsic activity in auditory and language networks, reward and motivation circuits, and executive control regions, along with decreased activity within sensorimotor network, whereas alternations within default mode network regions were more heterogeneous. Meta-analysis further highlighted the involvement of thalamic-frontal circuitry in distinguishing AVH patients from non-AVH patients. Spatial correlation analysis demonstrated significant coupling between AVH-related functional changes and the normaltive distribution of key neurotransmitter systems, including the cannabinoid (CB1), dopaminergic (D2), noradrenergic (NAT), and metabotropic glutamate (mGluR5) . Gene enrichment analysis additionally revealed that implicated regions were transcriptionally characterized by biological pathways related to neurodevelopment, neural circuit formation, and regulation of neural excitability. By integrating these convergent results, we propose a systems-level model in which early genetic and neurodevelopmental vulnerabilities interacts with ongoing neurotransmitter dysregulation and large-scale network dysfunction, ultimately driving the emergence and persistence of AVH in schizophrenia. These findings underscore the importance of multidimensional biomarkers and may inform the development of precision interventions targeting hallucinations in schizophrenia.