Widespread alterations of diffusion tensor imaging metrics in patients with schizophrenia without current auditory hallucinations

Background Studies have linked auditory hallucinations (AH) in schizophrenia-spectrum disorders (SCZ) to altered cerebral white matter microstructure within the language and auditory processing circuitry (LAPC). However, the neuroanatomical distribution and specificity to the LAPC remains unclear. Here, we investigated the relationship between AH and DTI among patients with SCZ using diffusion tensor imaging (DTI). Methods We included patients with SCZ with (AH+; n=59) and without (AH-; n=81) current AH, and 140 age-and-sex-matched controls. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were extracted from 39 fibre tracts. We used principal component analysis (PCA) to identify general factors of variation across fibre tracts and DTI metrics. Regression models adjusted for sex, age, and age2 were used to compare tract-wise DTI metrics and PCA factors between AH+, AH-, and healthy controls and to assess associations with clinical characteristics. Results Widespread differences relative to controls were observed for MD and RD in patients without current AH. Only limited differences in two fibre tracts were observed between AH+ and controls. Unimodal PCA factors based on MD, RD, and AD, as well as multimodal PCA factors, differed significantly relative to controls for AH-, but not AH+. We did not find any significant associations between PCA factors and clinical characteristics. Conclusions Contrary to previous studies, DTI metrics differed mainly in patients without current AH compared to controls, indicating a widespread neuroanatomical distribution. Our results challenge the notion that altered DTI metrics in the LAPC is a specific feature underlying AH. ### Competing Interest Statement OAA has received a speaker's honorarium from Lundbeck and Sunovion and is a consultant for HealthLytix. IA has received a speaker's honorarium from Lundbeck. The other authors report no conflicts of interest. ### Funding Statement The work was supported by The Research Council of Norway (grant numbers 223273, 274359), the K. G. Jebsen Foundation (grant number SKGJ-MED-008), South-Eastern Norway Regional Health Authority (grant numbers 2017-097, 2019-104, 2020-020), the Swedish Research Council (K2012-61X-15078-09-3, K2015-62X-15077-12-3, 2017-00949), the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, the Knut and Alice Wallenberg Foundation, and the HUBIN project. ### 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 studies were carried out in accordance with the Helsinki Declaration and all participants provided written informed consent. The TOP project was approved by the Regional Committee for Medical Research Ethics and the Norwegian Data Inspectorate. The HUBIN project was approved by the Swedish Ethical Review Authority at Karolinska Institutet. Data handling complied with Norwegian Data Protection Authority and GDPR regulations. 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 Given a formal data sharing agreement and approval from the local ethics committees, access to the data presented in this study can be provided upon reasonable request to the authors.