Permeability-diffusivity modeling vs. fractional anisotropy on white matter integrity assessment and application in schizophrenia

Introduction: Diffusion tensor imaging (DTI) assumes a single pool of anisotropically diffusing water to calculate fractional anisotropy (FA) and is commonly used to ascertain white matter (WM) deficits in schizophrenia. At higher b-values, diffusion-signal decay becomes bi-exponential, suggesting the presence of two, unrestricted and restricted, water pools. Theoretical work suggests that semi-permeable cellular membrane rather than the presence of two physical compartments is the cause. The permeability-diffusivity (PD) parameters measured from bi-exponential modeling may offer advantages, over traditional DTI-FA, in identifying WM deficits in schizophrenia.

Methods: Imaging was performed in N = 26/26 patients/controls (age = 20-61 years, average age = 40.5 ± 12.6). Imaging consisted of fifteen b-shells: b = 250-3800 s/mm(2) with 30 directions/shell, covering seven slices of mid-sagittal corpus callosum (CC) at 1.7 × 1.7 × 4.6 mm. 64-direction DTI was also collected. Permeability-diffusivity-index (PDI), the ratio of restricted to unrestricted apparent diffusion coefficients, and the fraction of unrestricted compartment (Mu) were calculated for CC and cingulate gray matter (GM). FA values for CC were calculated using tract-based-spatial-statistics.

Results: Patients had significantly reduced PDI in CC (p ≅ 10(- 4)) and cingulate GM (p = 0.002), while differences in CC FA were modest (p ≅ .03). There was no group-related difference in Mu. Additional theoretical-modeling analysis suggested that reduced PDI in patients may be caused by reduced cross-membrane water molecule exchanges.

Conclusion: PDI measurements for cerebral WM and GM yielded more robust patient-control differences than DTI-FA. Theoretical work offers an explanation that patient-control PDI differences should implicate abnormal active membrane permeability. This would implicate abnormal activities in ion-channels that use water as substrate for ion exchange, in cerebral tissues of schizophrenia patients.