Addressing fusiform gyrus dysfunction in schizophrenia, theory of mind, and implications for antipsychotics' response and resistance: A systematic review and critical appraisal

Background: The Fusiform Gyrus (FG), a brain region relevant for the interaction between cognitive processes and emotional behavior, especially emotion recognition and interpretation of social cues, has been linked to the pathophysiology of schizophrenia conceptualized as a disorder of aberrant synaptic function and brain connectivity as well as characterized by disruptions in thought processes, perceptions, emotional responsiveness, and Theory of Mind (ToM). Disrupted FG connectivity has been reported in schizophrenia; however, no systematic review has addressed this issue in a comprehensive and critical manner. Methods: We conducted a systematic review of PubMed, Embase, and Scopus from database inception to February 2026 following PRISMA guidelines. We included peer-reviewed neuroimaging studies using functional magnetic resonance imaging to assess functional connectivity or task-related activation of the FG in patients with schizophrenia compared with healthy controls. Results: We identified 2765 articles from different sources. After duplicate removal, 959 articles were screened at the title-abstract level, 269 articles were reviewed for full-texts, and 86 eligible articles were included. Across fMRI studies, the FG emerged as a central node of dysconnectivity. Drug-naïve patients showed heterogeneous FG alterations, with increased local activity and network centrality reported in some studies and reduced interhemispheric and functional connectivity in others, alongside reduced FG activation on visual, affective, and sensory tasks reported more broadly across schizophrenia samples. First-episode psychosis patients were characterized by FG hypoconnectivity associated with negative symptoms and socio-cognitive impairment. Treatment-responsive patients demonstrated partial normalization or modulation of fusiform connectivity and network centrality following antipsychotic treatment. In contrast, treatment-resistant schizophrenia patients showed persistent hypoactivation and reduced connectivity, correlating with cognitive deficits and negative symptoms. Conclusions: The FG appears to function as a dynamic, state-sensitive hub underlying perceptual, emotional, and cognitive disturbances in schizophrenia, in line with impaired ToM.