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

Anish K Simhal, Kimberly L H Carpenter, Joanne Kurtzberg, Allen Song, Allen Tannenbaum, Lijia Zhang, Guillermo Sapiro, Geraldine Dawson, Anish K Simhal, Kimberly L H Carpenter, Joanne Kurtzberg, Allen Song, Allen Tannenbaum, Lijia Zhang, Guillermo Sapiro, Geraldine Dawson

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.

Conflict of interest statement

Authors KC, GS, and GD reported technology unrelated to the submitted work that has been licensed, have benefited financially from this license, and have a patent. Authors GD, AS, and JK had a patent and have developed technology, data, and/or products that have been licensed to Cryocell, Inc., from which they and Duke University have benefited financially. Author JK was the Director of the Carolinas Cord Blood Bank, Medical Director of Cryocell, Inc., and is a paid consultant for Neurogene. Author GS was affiliated with Apple Inc., the work here reported was initiated before such affiliation and it is independent of it. Allen Song has patents licensed unrelated to the submitted work and receives grants from GE Healthcare unrelated to the submitted work. Author GD was on the Scientific Advisory Boards of Akili Interactive, Inc., Zynerba, Nonverbal Learning Disability Project, and Tris Pharma, is a consultant to Apple, Gerson Lehrman Group, and Guidepoint Global, Inc., and receives book royalties from Guilford Press and Springer Nature. Author GD has stock interests in Neuvana, Inc. Author AT was a consultant for Polaris. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Simhal, Carpenter, Kurtzberg, Song, Tannenbaum, Zhang, Sapiro and Dawson.

Figures

FIGURE 1
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
FIGURE 2
Clinical trial CONSORT diagram from Dawson, Sun (1).
FIGURE 3
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.

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