ALTERED FUNCTIONAL CONNECTIVITY OF FUSIFORM GYRUS AND DISORGANIZATION DOMAIN AS CORE CORRELATES OF TREATMENT- RESISTANT SCHIZOPHRENIA: A RESTING-STATE FMRI STUDY
Authors: Ciccarelli *Mariateresa , Iasevoli Felice , Barone Annarita , Vellucci Licia , De Simone Giuseppe , Tranfa Mario , Cocozza Sirio , Pontillo Giuseppe , Brunetti Arturo , de Bartolomeis Andrea 
Published: February 2025

Abstract

Background
The neurobiology underlying treatment-resistant schizophrenia (TRS) has not been fully elucidated1. This project provides a preliminary dissection of the neurobiological underpinnings of cognitive dysfunction in schizophrenia (SCZ), such as the disorganization factor, as a core clinical and pathophysiological correlate of TRS2. In this context, TRS shows putative unique neuroimaging correlates compared to treatment-responsive schizophrenia (non-TRS)3, probably related to specific functional disconnection patterns, with an emergent involvement of the Fusiform Gyrus (FG).

Aims & Objectives
This study aims to reveal the potential links between the aberrant functional connectivity of the FG and the disruption of cognitive performance rated through the proxy domain of disorganization in TRS. The objective of this study is to identify a functional biomarker that may predict the response to antipsychotics in schizophrenia.

Methods
We enrolled 49 patients with SCZ (34 M, 15 F, age 37.5 ±9.7 years), along with 55 healthy controls (HC) (30 M, 25 F, age 42.4 ±15.7 years) matched in age and sex. Patients were classified as TRS (N= 22) or non-TRS (N= 27), paired with demographic and clinical variables. The clinical features were evaluated using PANSS and the 5-factor model. T-test for PANSS scores was performed using SPSS software (p&lt; 0.01). All subjects underwent a 3T resting-state functional magnetic resonance imaging (rs-fMRI) brain scan, and the data were processed using the CONN toolbox with a seed-to-voxel connectivity analysis approach, testing a functional connectivity (FC) map of the fusiform gyrus between the groups (HC vs. SZ and TRS vs. non-TRS). The statistical significance level was set at (p&lt; 0.05 FWER corrected).

Results
TRS patients showed significantly higher scores compared with non-TRS in the PANSS 5-factor model Positive (p= 0.007), Negative (p= 0.006), and Disorganization factors (p= 0.001). Considering the FG, a cluster of increased FC in TRS compared with non-TRS patients emerged in the right putamen (p=0.005).

Discussion & Conclusion
TRS is associated with a cluster of increased rs-FC in FG seed within the right putamen and a more severe disorganization feature compared to non-TRS, suggesting an aberrant connectivity preferentially affected in TRS. Further studies may contribute to identifying functional biomarkers of altered connectivity in schizophrenia to predict the pharmacological response to antipsychotics.

References
1. Iasevoli F, Avagliano C, D'Ambrosio L, Barone A, Ciccarelli M, De Simone G, Mazza B, Vellucci L, de Bartolomeis A. Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal. Biomedicines. 2023 Mar 14;11(3):895. doi: 10.3390/biomedicines11030895. PMID: 36979877; PMCID: PMC10046109.
2. Barone A, De Prisco M, Altavilla B, Avagliano C, Balletta R, Buonaguro EF, Ciccarelli M, D'Ambrosio L, Giordano S, Latte G, Matrone M, Milandri F, Francesco DN, Vellucci L, de Bartolomeis A. Disorganization domain as a putative predictor of Treatment Resistant Schizophrenia (TRS) diagnosis: A machine learning approach. J Psychiatr Res. 2022 Nov;155:572-578. doi: 10.1016/j.jpsychires.2022.09.044. Epub 2022 Sep 29. PMID: 36206601.
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