White Matter Microstructure Alterations and Their Link to Symptomatology in Early Psychosis and Schizophrenia

Background and Hypothesis Studies on schizophrenia feature diffusion magnetic resonance imaging (dMRI) to investigate white matter (WM) anomalies. The heterogeneity in the possible interpretations of these metrics highlights the importance of increasing their specificity. Here, we characterize WM pathology in early psychosis (EP) and schizophrenia (SZ) with increased specificity using advanced dMRI metrics: Diffusion Kurtosis Imaging and White Matter Track Integrity – Watson (WMTI-W) biophysical model. This enables us to better characterize WM abnormalities and relate them to the patient’s symptomatology. Study Design dMRI-derived microstructure features were extracted from all of WM and from individual tracts in 275 individuals. 93 patients with EP and 47 with SZ were compared respectively to 135 age-range matched healthy controls (HC). The relationships between the dMRI metrics in WM and various clinical scales were investigated in each patient group. Study Results WM diffusivities were higher, while kurtosis was lower in EP and SZ vs HC. Differences were more pronounced in EP than SZ. WMTI-W model parameters suggest alterations to the extra-axonal compartment in EP and SZ, consistent with abnormal myelin integrity and WM deterioration. Patient groups showed clustered but non-significant correlations between dMRI metrics and psychotic symptoms. Depressive dimensions were significantly associated with decreased diffusivities in WM, while manic scales correlated with increased diffusivities and reduced kurtosis. Conclusions dMRI patterns in EP and SZ highly suggest WM deterioration in comparison to HC. DMRI changes better align with affective dimensions, while the relationship with psychotic symptoms may be confounded by competing pathological effects on the microstructure and disease heterogeneity. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Swiss National Science Foundation (PCEFP2-194260, to I.J.), the National Center of Competence in Research (NCCR) SYNAPSY - The Synaptic Bases of Mental Diseases from the Swiss National Science Foundation (n 51NF40 - 185897 to KQD & PC) and the Foundation Alamaya. Dr Alameda is supported by Carigest fellowship and by Frutiger Adrian et Simone fellowship. The authors have nothing to disclose and there are no conflicts of interest. Dr Dwir is supported by Frutiger Adrian et Simone fellowship. ### 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 conducted in accordance with the Declaration of Helsinki and approved by the local Ethics Committee of the Canton of Vaud (Switzerland) under authorization numbers CER-VD 382/11 and 2018-01731. 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 Data is not available for public use.