Putative Neuroimmune Mechanisms and Candidate Biomarkers of rTMS Efficacy in Improving Negative Symptoms of Schizophrenia: Evidence Boundaries and Translational Pathways.
Negative symptoms in schizophrenia often persist for prolonged periods, severely impairing patients' social functioning, while the therapeutic benefits of existing pharmacological treatments remain limited. Recent meta-analyses suggest that high-frequency stimulation of the left dorsolateral prefrontal cortex (L-DLPFC) provides short-term adjunctive benefits for negative symptoms, with effects ranging from small to moderate. However, treatment response is influenced by the stimulation parameters, target localization, and patient characteristics; thus, overall therapeutic efficacy remains heterogeneous. In patients with schizophrenia, peripheral immune-inflammatory abnormalities may occur, and some inflammatory markers are associated with disease stage, cognitive function, and negative symptom severity. Repetitive transcranial magnetic stimulation (rTMS) can modulate the prefrontal cortex and related brain networks, but its effects on immune-inflammatory processes, neuroendocrine-autonomic function, and neuroplasticity remain to be further elucidated. This review summarizes the immune-inflammatory mechanisms underlying negative symptoms, the clinical efficacy of rTMS, and the biological link between them, and discusses the potential of inflammatory markers for patient stratification and treatment-response prediction. In the future, standardized symptom assessment, stimulation parameters, and target localization are warranted, alongside repeated biological sample collection, prespecified stratified analyses, and external validation. Until inflammatory markers have been sufficiently validated with respect to predictive performance, reproducibility, and clinical net benefit, they should not be used alone to determine rTMS treatment eligibility, select stimulation parameters, or guide stratification decisions.