Meta-analysis links auditory hallucinations in schizophrenia to specific brain activity patterns and neurotransmitter systems

This systematic review and meta-analysis examined intrinsic brain activity patterns in schizophrenia patients experiencing auditory verbal hallucinations (AVH). The analysis integrated amplitude of low-frequency fluctuation (ALFF/fALFF) neuroimaging studies with neurochemical mapping and transcriptomic annotation to explore multiscale mechanisms underlying AVH. The study population consisted of schizophrenia patients with AVH, though specific sample sizes and study settings were not reported.

Main findings revealed that AVH consistently associated with increased intrinsic activity in auditory and language networks, reward and motivation circuits, and executive control regions, while showing decreased activity within the sensorimotor network. The meta-analysis highlighted involvement of thalamic-frontal circuitry in distinguishing AVH patients from non-AVH patients. Spatial correlation analyses showed significant coupling between AVH-related functional changes and the normative distribution of cannabinoid (CB1), dopaminergic (D2), noradrenergic (NAT), and metabotropic glutamate (mGluR5) neurotransmitter systems. Gene enrichment analysis of implicated regions indicated transcription characterized by biological pathways related to neurodevelopment, neural circuit formation, and regulation of neural excitability.

No safety or tolerability data were reported as this was a meta-analysis of observational neuroimaging studies. Key limitations include the observational nature of the evidence, heterogeneity in findings within default mode network regions, and absence of reported effect sizes, p-values, or confidence intervals. The authors propose a model suggesting interactions between vulnerabilities and dysregulation drive AVH emergence and persistence, but emphasize these are associations rather than causal relationships.

Practice relevance is restrained to theoretical understanding rather than immediate clinical application. The findings underscore the potential importance of multidimensional biomarkers and may inform future development of precision interventions targeting hallucinations in schizophrenia. However, the evidence does not support specific diagnostic or treatment changes at this time, as it represents neurobiological insights without direct links to clinical outcomes or therapeutic interventions.