Orbitofrontal cortex hypergyrification in hallucinating schizophrenia patients: surface ratio as a promising brain biomarker

Background There has been increasing interest in the study of brain gyrification in schizophrenia since it may provide additional useful information on the cytoarchitecture and connectivity of the brain. Various methods have been developed to estimate brain gyrification that, so far, have yielded mixed and inconclusive results in schizophrenia studies. To the best of our knowledge, an alternative method to compute brain gyrification, known as surface ratio (SR), has not yet been applied to a schizophrenia sample. Our aim in this study was to assess whether SR could provide new insights on the brain structure of schizophrenia patients and the severity of symptoms. We also computed a more established brain gyrification measure, namely absolute mean curvature (AMC), for comparison. Method We processed and analyzed a total of 63 magnetic resonance images, 25 from schizophrenia patients with treatment-resistant auditory verbal hallucinations (SCH-H), 18 from schizophrenia patients without hallucinations (SCH-NH), and 20 from healthy controls (HC). We estimated brain gyrification with SR and AMC employing CAT software. Results The SR measure mainly revealed that SCH-H patients had a more folded orbitofrontal cortex than SCH-NH patients and HC. Gyrification in this region was also negatively associated with positive symptoms, specifically with the delusions and conceptual disorganization items, only in the SCH-H group. Conversely, SCH-NH and HC showed more SR than SCH-H in other frontal areas. As for the AMC measure, we identified two areas where HC showed more gyrification than SCH-H patients, but no relationships arose with symptoms. Discussion We hypothesize that the hypergyrification of the orbitofrontal cortex displayed by SCH-H patients, as captured by the SR measure, suggests aberrant and/or excessive wiring in these patients, which in turn could give rise to auditory verbal hallucinations. Alternatively, we comment on potential compensatory mechanisms that may better explain the negative association between orbitofrontal gyrification and positive symptomatology. Importantly, the estimation of brain gyrification with the SR measure seems to capture the most relevant differences and associations, making it a promising biomarker in schizophrenia research. ### Competing Interest Statement Dr. Roldán has served as advisor or speaker for the companies Otsuka, Rovi and Angelini (unrelated to the present work). ### Funding Statement CN is supported by a Sara Borrell contract (CD20/00142) from the Instituto de Salud Carlos III, co-funded by the European Social Fund (ESF). MJP receives funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) and from the Generalitat de Catalunya through recognition of consolidate group or research (SGR17/001343). This project was supported by La Marató de TV3 (grant number 091230), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain (grant number FIS 08/0475), Ona Corporation (AMA DABLAM Research Project, IIBSP-AMA-2016-99), and partly funded by CERCA (Centres de Recerca de Catalunya) Programme/Generalitat de Catalunya. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Hospital de la Santa Creu i Sant Pau ethics committee and complied with the provisions of the World Medical Association Declaration of Helsinki. All the participants and/or their legal representatives provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.