Temporal Lobe White Matter Alterations in Schizophrenia: A Diffusion Tensor Imaging Tractometry Family Study

Background: Individuals with schizophrenia consistently show abnormalities in white matter (WM) tracts compared to controls. Evidence also suggests that the non-psychotic relatives of individuals with schizophrenia show WM dysfunction. Given the relevance of the temporal lobe to the pathophysiology of schizophrenia, we investigated three key tracts associated with the temporal lobe: (1) the inferior longitudinal fasciculus, which connects the temporal lobe with the occipital lobe; (2) uncinate fasciculus, which connects the temporal lobe with the prefrontal cortex; and (3) fornix, which connects the hippocampus with the hypothalamus. Furthermore, most previous studies investigating WM changes in schizophrenia have used voxel-based analysis, typically of a highly restricted WM skeleton (eg TBSS) or whole-tract mean values from tractography, thereby losing anatomical specificity. The goal of this investigation therefore, was to use sophisticated diffusion tensor imaging (DTI) tractometry analysis to examine along-tract microstructural differences in three major temporal lobe WM tracts in a family study of schizophrenia. Inclusion of both patients and family members allowed a better examination of genetic (familial) liability, as well as disease-related processes. Methods: Twenty-five patients with schizophrenia, 24 non-psychotic healthy relatives, and 27 community controls participated. DTI data were acquired (3T GE) along 60 gradient directions with b-value 1300s/mm2 and corrected for motion and distortion using ExploreDTI. DTI parameters fractional anisotropy (FA) and mean and radial diffusivity (MD, RD) were estimated. A population-based FA-template was constructed, to which all parameter maps were registered. The aforementioned temporal lobe tracts were isolated using targeted tractography. The fornix was further subdivided into left/right anterior columns, body and left/right fimbriae. Parameter values for each subject were calculated at evenly distributed points along the length of the tract masks in template space. ANCOVA was used to investigate the main effect of group membership on mean tract values (between-subject factors: group, gender, covariate: age), whilst the group:position interaction term in a 2-way ANOVA was used to identify group differences at each point along each tract. Results: Both patients with schizophrenia and non-psychotic relatives demonstrated lower mean and radial diffusivity in their fornix compared to controls using age and gender as covariates. Tract profiles illustrated group differences along the entire length of the fornix rather than localized differences. No other significant differences were found between groups. Discussion: We found both schizophrenia patients and their biological relatives had differences in two indices associated with WM microstructure, compared to controls along the length of the fornix; however, in an unexpected direction. Possible reasons for this surprising finding could be a true biological difference, volumetric differences present between groups, or methodological issues associated with DTI analyses in typically sized schizophrenia study populations. Further investigation of the relationship between the DTI parameters, white matter volume and anatomical structures bordering the fornix will be presented to understand these findings. The results of this analysis may allow a better understanding of not only these results, but also other findings of fractional anisotropy changes in schizophreniastatus: accepte