Mapping symptom-general and symptom-specific targets for transcranial magnetic stimulation in schizophrenia: an electric-field modeling meta-analysis

Negative, positive, and cognitive symptoms of schizophrenia relate to disruptions in partially distinct brain circuits. Although promising, transcranial magnetic stimulation (TMS) strategies across and within symptom domains remain to be established due to TMS protocol heterogeneity. For this, we combined standard meta-analysis with electric field (E-field) modeling to identify stimulation sites where E-field strength was associated most significantly with clinical improvement. Standard meta-analysis of randomized, sham-controlled studies in 4283 patients demonstrated the benefit of TMS across symptom domains, regardless of target or protocol. TMS significantly improved negative and cognitive symptoms with high-frequency stimulation applied to the left prefrontal cortex, whereas positive symptoms improved with low-frequency TMS applied to the left temporoparietal cortex. In-depth examination of these results with E-field modeling identified stimulation of the left dorsomedial prefrontal cortex (L-DMPFC), left orbitofrontal cortex (L-OFC), and left cerebellar crus II and right lobule IX to be significantly associated with improvement across all symptom domains. Greater overlap of studies' stimulation targets with L-DMPFC and L-OFC related to improved outcomes. For negative symptoms, E-field distribution in L-DMPFC and L-OFC related most significantly to clinical improvement. Greater proximity to L-DMPFC stimulation site indicated better outcomes, with trend-level significance for L-OFC. In the cognitive domain, E-field distribution in the left dorsolateral prefrontal cortex was related to clinical improvement. Finally, the strongest E-field association with clinical improvement was found in the right cerebellar lobules VIIIA, VIIIB, and IX for positive symptoms. These results support symptom-general and symptom-specific TMS approaches for distinct therapeutic goals towards personalized neuromodulation in schizophrenia.