Neurite Orientation Dispersion and Density Imaging (NODDI) and Duration of Untreated Psychosis in Antipsychotic Medication-Naïve First Episode Psychosis Patients.

Background: Diffusion tensor imaging suggests that white matter alterations are already evident in first episode psychosis patients (FEP) and may become more prominent as the duration of untreated psychosis (DUP) increases. But because the tensor model lacks specificity, it remains unclear how to interpret findings on a biological level. Here, we used a biophysical diffusion model, Neurite Orientation Dispersion and Density Imaging (NODDI), to map microarchitecture in FEP, and to investigate associations between DUP and microarchitectural integrity. Methods: We scanned 78 antipsychotic medication-naïve FEP and 64 healthy controls using a multi-shell diffusion weighted sequence and used the NODDI toolbox to compute neurite density (ND), orientation dispersion index (ODI) and extracellular free water (FW) maps. AFNI's 3dttest++ was used to compare diffusion maps between groups and to perform regression analyses with DUP. Results: We found that ND was decreased in commissural and association fibers but increased in projection fibers in FEP. ODI was largely increased regardless of fiber type, and FW showed a mix of increase in decrease across fiber tracts. We also demonstrated associations between DUP and microarchitecture for all NODDI indices. Conclusions: We demonstrated that complex microarchitecture abnormalities are already evident in antipsychotic-naïve FEP. ND alterations are differentially expressed depending on fiber type, while decreased fiber complexity appears to be a uniform marker of white matter deficit in the illness. Importantly, we identified an empirical link between longer DUP and greater white matter pathology across NODDI indices, underscoring the critical importance of early intervention in this devastating illness.

A longitudinal neurite and free water imaging study in patients with a schizophrenia spectrum disorder.

Diffusion tensor imaging (DTI) studies show widespread white matter abnormalities in schizophrenia, but it is difficult to directly relate these parameters to biological processes. Neurite orientation dispersion and density imaging (NODDI) is geared toward biophysical characterization of white matter microstructure, but only few studies have leveraged this technique to study white matter alterations. We recruited 42 schizophrenia patients (30 antipsychotic-naïve and 12 currently untreated) and 42 matched controls in this prospective study. We assessed the orientation dispersion index (ODI) and extracellular free water (FW) using single-shell DTI data before and after a 6-week trial of risperidone. Longitudinal data were available for 27 patients. Voxelwise analyses showed significantly increased ODI in the posterior limb of the internal capsule in unmedicated patients (242 voxels; x = -24; y = 6; z = 6; p < 0.01; α < 0.04), but no alterations in FW. Whole brain measures did not reveal alterations in ODI but a 6.3% trend-level increase in FW in unmedicated SZ (t = -1.873; p = 0.07). Baseline ODI was negatively correlated with subsequent response to antipsychotic treatment (r = -0.38; p = 0.049). Here, we demonstrated altered fiber complexity in medication-naïve and unmedicated patients with a schizophrenia spectrum illness. Lesser whole brain fiber uniformity was predictive of poor response to treatment, suggesting this measure may be a clinically relevant biomarker. Interestingly, we found no significant changes in NODDI indices after short-term treatment with risperidone. Our data show that biophysical diffusion models have promise for the in vivo evaluation of brain microstructure in this devastating neuropsychiatric syndrome.