Fibre density and fibre-bundle cross-section of the corticospinal tract are distinctly linked to psychosis-specific symptoms in antipsychotic-naïve patients with first-episode schizophrenia

Abstract

Multiple lines of research support the dysconnectivity hypothesis of schizophrenia. However, findings on white matter (WM) alterations in patients with schizophrenia are widespread and non-specific. Confounding factors from magnetic resonance image (MRI) processing, clinical diversity, antipsychotic exposure, and substance use may underlie some of the variability. By application of refined methodology and careful sampling, we rectified common confounders investigating WM and symptom correlates in a sample of strictly antipsychotic-naïve first-episode patients with schizophrenia. Eighty-six patients and 112 matched controls underwent diffusion MRI. Using fixel-based analysis (FBA), we extracted fibre-specific measures such as fibre density and fibre-bundle cross-section. Group differences on fixel-wise measures were examined with multivariate general linear modelling. Psychopathology was assessed with the Positive and Negative Syndrome Scale. We separately tested multivariate correlations between fixel-wise measures and predefined psychosis-specific versus anxio-depressive symptoms. Results were corrected for multiple comparisons. Patients displayed reduced fibre density in the body of corpus callosum and in the middle cerebellar peduncle. Fibre density and fibre-bundle cross-section of the corticospinal tract were positively correlated with suspiciousness/persecution, and negatively correlated with delusions. Fibre-bundle cross-section of isthmus of corpus callosum and hallucinatory behaviour were negatively correlated. Fibre density and fibre-bundle cross-section of genu and splenium of corpus callosum were negative correlated with anxio-depressive symptoms. FBA revealed fibre-specific properties of WM abnormalities in patients and differentiated associations between WM and psychosis-specific versus anxio-depressive symptoms. Our findings encourage an itemised approach to investigate the relationship between WM microstructure and clinical symptoms in patients with schizophrenia.

Keywords: First-episode antipsychotic-naïve schizophrenia; Fixel-based analysis; Psychopathology; Substance use; White matter.

Fig. 1

Fixel-based analyses. Figure 1 illustrates the top row a Diffusion tensor imaging (DTI) provides general information about the diffusion signal within a voxel (blue box). The measures derived are averaged to one single principal direction of axonal fibres (demonstrated by the elongated oval), which is affected by crossing fibre populations. b Using spherical deconvolution, the fixel-based analyses (FBA) enable identification of the individual fibre populations with different orientations (purple and green axons) within the voxel. Quantifiable measures are extracted for each individual fibre population. c The bottom row illustrates the fixel-based measures of fibre density (FD), fibre-bundle cross-section (FC), and the combined measure of fibre density and fibre-bundle cross-section (FDC). Reduced FD reflects a decrease in the microscopical intra-cellular volume of axons within a voxel. Reduced FC indicates a macroscopic decrease of the cross-sectional size of a particular fibre bundle

Fig. 2

Group difference on fibre density. Figure 2 illustrates the location of the main group difference on FD comparing patients with schizophrenia with healthy controls. Group comparisons were performed using Multivariate General Linear Model (GLM). Family-wise error (FWE) with a threshold of p < 0.05 was applied to correct for multiple comparisons. Top row 1A is the significant group difference in the body of corpus callosum in an axial and coronal plane, comparing the full sample of patients with schizophrenia with healthy controls. The cluster is coloured yellow–red according to effect size of the group difference, enhanced in image 1B. Bottom row 2A is the significant group difference in middle cerebellar peduncle in an axial and coronal plane, comparing the subsample of patients and controls with no recreational substance use. Significant fixels are coloured red, while non-significant fixels are black, enabling the identification of crossing fibres, enhanced in image 2B

Fig. 3

Correlations between fixel-wise measures and psychosis-specific symptoms. Top image illustrates the localization of the significant correlations between fixel-wise measures and the PANSS items P1 and P6 in corticospinal tract (CST) in the substance-free sample. Blue colours indicate negative correlations, red/yellow colours indicate positive correlations. Colour is graded according to beta estimate as proxy to effect size. Images are displayed in radiological directions. Bottom row: scatterplots illustrate the associations between FDC of the significant fixels of CST and the items scores of P1 and P6, respectively. a anterior, FDC fibre density and cross-section, i inferior, l left, p posterior, r right, s superior