Changes in the geometry and robustness of diffusion tensor imaging networks: Secondary analysis from a randomized controlled trial of young autistic children receiving an umbilical cord blood infusion

Abstract

Diffusion tensor imaging (DTI) has been used as an outcome measure in clinical trials for several psychiatric disorders but has rarely been explored in autism clinical trials. This is despite a large body of research suggesting altered white matter structure in autistic individuals. The current study is a secondary analysis of changes in white matter connectivity from a double-blind placebo-control trial of a single intravenous cord blood infusion in 2-7-year-old autistic children (1). Both clinical assessments and DTI were collected at baseline and 6 months after infusion. This study used two measures of white matter connectivity: change in node-to-node connectivity as measured through DTI streamlines and a novel measure of feedback network connectivity, Ollivier-Ricci curvature (ORC). ORC is a network measure which considers both local and global connectivity to assess the robustness of any given pathway. Using both the streamline and ORC analyses, we found reorganization of white matter pathways in predominantly frontal and temporal brain networks in autistic children who received umbilical cord blood treatment versus those who received a placebo. By looking at changes in network robustness, this study examined not only the direct, physical changes in connectivity, but changes with respect to the whole brain network. Together, these results suggest the use of DTI and ORC should be further explored as a potential biomarker in future autism clinical trials. These results, however, should not be interpreted as evidence for the efficacy of cord blood for improving clinical outcomes in autism. This paper presents a secondary analysis using data from a clinical trial that was prospectively registered with ClinicalTrials.gov(NCT02847182).

Keywords: biomarkers; clinical trial; diffusion tensor imaging; stem cells; white matter.

FIGURE 1

Illustration of ORC on exemplar networks. (A) Example of positive ORC. Multiple pathways between two brain regions implies that information between those regions may withstand small perturbations. (B) Example of negative ORC. A single pathway between two brain regions implies that information shared between “ROI A” and “ROI B” can be altered easily. Only a single connection would need to be perturbed.

FIGURE 2

Clinical trial CONSORT diagram from Dawson, Sun (1).

FIGURE 3

(A) Edges found during the streamline analysis. N1: Left Inferior Frontal Gyrus (IFG)—pars opercularis. N2: Left rostral middle frontal gyrus. N3. Left caudal middle frontal gyrus. N4. Right IFG—pars triangularis. N5. Rostral middle frontal gyrus. (B) Edges found during the Ollivier-Ricci curvature (ORC) analysis. N1: Left cuneus cortex. N2: Left fusiform gyrus. N3: Right caudal anterior cingulate cortex. N4: Left IFG—pars triangularis.