Decreased cortical gyrification and surface area in the left medial parietal cortex in patients with treatment-resistant and ultratreatment-resistant schizophrenia

Aim: Validating the vulnerabilities and pathologies underlying treatment-resistant schizophrenia (TRS) is an important challenge in optimizing treatment. Gyrification and surface area (SA), reflecting neurodevelopmental features, have been linked to genetic vulnerability to schizophrenia. The aim of this study was to identify gyrification and SA abnormalities specific to TRS. Methods: We analyzed 3T magnetic resonance imaging findings of 24 healthy controls (HCs), 20 responders to first-line antipsychotics (FL-Resp), and 41 patients with TRS, including 19 clozapine responders (CLZ-Resp) and 22 FL- and clozapine-resistant patients (patients with ultratreatment-resistant schizophrenia [URS]). The local gyrification index (LGI) and associated SA were analyzed across groups. Diagnostic accuracy was verified by receiver operating characteristic curve analysis. Results: Both CLZ-Resp and URS had lower LGI values than HCs (P = 0.041, Hedges g [g(H)] = 0.75; P = 0.013, g(H) = 0.96) and FL-Resp (P = 0.007, g(H) = 1.00; P = 0.002, g(H) = 1.31) in the left medial parietal cortex (Lt-MPC). In addition, both CLZ-Resp and URS had lower SA in the Lt-MPC than FL-Resp (P < 0.001, g(H) = 1.22; P < 0.001, g(H) = 1.75). LGI and SA were positively correlated in non-TRS (FL-Resp) (rho = 0.64, P = 0.008) and TRS (CLZ-Resp + URS) (rho = 0.60, P < 0.001). The areas under the receiver operating characteristic curve for non-TRS versus TRS with LGI and SA in the Lt-MPC were 0.79 and 0.85, respectively. SA in the Lt-MPC was inversely correlated with negative symptoms (rho = -0.40, P = 0.018) and clozapine plasma levels (rho = -0.35, P = 0.042) in TRS. Conclusion: LGI and SA in the Lt-MPC, a functional hub in the default-mode network, were abnormally reduced in TRS compared with non-TRS. Thus, altered LGI and SA in the Lt-MPC might be structural features associated with genetic vulnerability to TRS.