White matter correlates of clinical function in schizophrenia using diffusion tensor imaging.

Dear Editors: There is by now a robust body of evidence from the diffusion tensor imaging (DTI) literature that structural differences likely exist in patients with schizophrenias and may be linked to some of the clinical manifestations of this illness1. DTI is a magnetic resonance imaging technique that measures localized water diffusivity reflecting the geometric properties and directionality of both axonal membrane and myelin in large white matter tracts of the brain. The most often found DTI abnormalities in the brain of patients with schizophrenia include lower prefrontal and temporal lobe FA, as well as lower FA in the anterior cingulum, arcuate and uncinate fasciculi. Far fewer studies have attempted to correlate FA changes with clinical measures2–4. We report on a tract-based spatial statistics (TBSS)5 analysis of white matter fractional anisotropy (FA) differences between unmedicated patients with schizophrenia and controls. As a secondary and exploratory analysis, we also report on WM correlates of clinical measures (PANSS, SANS and Calgary depression scale) in the schizophrenia subgroup. We enrolled thirteen unmedicated subjects (mean age 37.4 years) and sixteen controls (mean age 41.1 years, no DSM-IV axis I diagnosis). Subjects and controls did not differ significantly in any demographic variables except employment status. Subjects with schizophrenia had not used medications for at least two weeks prior to scanning. Subjects’ mean PANS score was 91+/− 17, mean SANS 47 +/− 16 and Calgary Depression Scale mean 3.6 +/− 3.4. Each participant had MRI scanning performed using a 3T clinical MRI scanner with a SENSE coil (Intera, Philips Medical Systems; Bothell, WA). DTI acquisition consisted of a single-shot spin echo, echo planar imaging acquisition with a parallel imaging factor of 2 and a partial Fourier factor of 80% with TR = 5 seconds, TE = 100 ms, slice thickness = 3 mm, gap = 0.3 mm, field of view (FOV) = 256mm, number of slices = 30, matrix = 112×112 (interpolated to 256×256). For each slice, one image was acquired with no additional diffusion weighting and six diffusion weighted images with b=1000 s/mm2 using the scheme described elsewhere6. The diffusion-weighted acquisitions were repeated three times and averaged on the scanner to improve the signal to noise ratio. DTI data was processed using FSL (http://www.fmrib.ox.ac.uk/fsl/). The resulting FA maps were processed with the standard TBSS algorithm described in detail elsewhere5. Tract localization using this skeleton was achieved using a DTI based white matter atlas7. We investigated group differences in FA between patients with schizophrenia and controls employing a voxel-wise non-parametric Brunner Munzel test, using the NPM software package (version released on October 12, 2008; http://www.sph.sc.edu/comd/rorden/npm/). Voxel-wise FA differences were corrected for multiple comparisons through false discovery rate8 threshold of 1% for our primary outcome measure (FA group difference) and 5% for our secondary outcomes (FA correlation with clinical measures). Table 1 reports the results of the voxel-wise group comparison and correlations. Although this study suffers from several limitations (modest sample size, post-hoc analysis, lack of medication history) our results replicate previously published findings about FA differences in schizophrenia. In general, we found decreased diffusivity in WM tracks of the prefrontal cortex, the SLF as well as extensive and diffuse cerebellar WM, especially in the vicinity of the SCP. These results are consistent with several other studies and appear to be in part suggestive of Andreasen’s proposed cortico-cerebellar-thalamic-cortical (CCTCC) circuit for schizophrenia9. This study suggests that gross anatomical abnormalities play a role either in the pathogenesis or development of the illness. We did not, however, replicate other documented findings: most significantly the often-reported finding of decreased FA in the temporal lobe and the corpus callosum10. Finally, we report an area of significantly increased FA in the subject population corresponding to occipital projections of the corpus callosum. This is, to the best of our knowledge, a previously unreported finding. Table 1 DTI group difference and regression analysis results. We also found that total PANSS score was robustly correlated bilaterally with FA in an anterior portion of the occipital lobe bordering on the parietal lobe. Neither SANS nor PANSS positive symptoms scores were found to be significantly correlated to FA.