ELEVATED INTRINSIC CORTICAL CURVATURE IN TREATMENT-RESISTANT SCHIZOPHRENIA: STRUCTURAL DEFORMATION OF FUNCTIONAL ACTIVITY AREAS
Authors: Torres-Carmona *Edgardo , Ueno Fumihiko , Iwata Yusuke , Nakajima Shinichiro , Song Jianmeng , Mar Wanna , Abdolizadeh Ali , Agarwal Sri Mahavir , De Luca Vincenzo , Remington Gary , Gerretsen Philip , Graff-Guerrero Ariel 
Published: February 2025

Abstract

Background
Growing research shows abnormal brain structure and connectivity in patients with treatment-resistant schizophrenia (TRS) compared to first-line-responders (TxR) and healthy-controls (HC). While differences are documented as early as first-episode-psychosis (FEP), standard measures of structure and connectivity including thickness, volume, functional connectivity, and diffusion, show susceptibility to antipsychotic treatment and interpatient heterogeneity that limit their clinical and research use for TRS. In this regard, Intrinsic-Cortical-Curvature (ICC), a highly sensitive neurodevelopmental measure of both structure and connectivity, associated with the position and spread of functional activity areas, may provide a novel approach for the assessment and differentiation of TRS. Indeed, preliminary studies have not only linked elevations of ICC with TRS-like traits in FEP, including worsening cognition at follow-ups and reduced response to treatment, but methodology comparison studies have also proven ICC to be especially sensitive to schizophrenia differences compared to more common extrinsic gyrification measures. Despite this evidence, due to the previous complexity and computational demands required for ICC quantification, ICC research in schizophrenia and TRS remains scarce.

Aim
Our goal was to investigate whether differences in ICC between TRS, TxR and HC exist, their association to symptomology, and susceptibility to antipsychotic treatment, as a possible marker for treatment-resistance.

Methods
ICC was assessed from brain imaging data acquired using 3T high resolution magnetic resonance imaging (MRI). Regions of interest associated with TRS literature were processed, including the bilateral anterior-cingulate-cortices (ACC), dorsolateral-prefrontal- cortices (DLPFC), temporal-cortices, and parietal-cortices of TxR=38, TRS (clozapine-resistant ClzR- =30, clozapine-responders ClzR+=37), and HC=52. Positive, negative, and cognitive symptom severity was assessed (PANSS, MMSE, EXIT), along with chlorpromazine-equivalence (APT) and nicotine-use (NIC) to assess possible interactions.

Results
ICC elevations were observed in temporal-cortices of ClzR- and ClzR+ compared to HC (p=0.001), and DLPFC of ClzR- compared to TxR and HC (p&lt;0.001). ICC elevations correlated with reduced cognition (p&lt;0.007) and negative symptomology (p=0.036) in ClzR-. LH- temporal and parietal-cortices correlated with reduced cognition in ClzR+ (p=0.018) and TxR (p=0.008), respectively. No ICC/APT/NIC interactions were found (p&gt;0.092).

Conclusion
Results show elevations of ICC in patients with TRS, particularly in regions associated with glutamatergic dysregulation. Elevations of ICC were also associated with reduced cognition, primarily in ClzR-. Considering ICC was not associated with APT or NIC, future research may prove ICC a resilient marker associated with TRS abnormalities.