Taking advanced diffusion imaging to the clinic for pediatric patients with ADHD

We propose to develop clinically feasible methods for the acquisition and analysis of advanced diffusion magnetic resonance imaging (dMRI) of pediatric patients and apply it to study micro and macro level pathology in attention-deficit hyperactivity-disorder (ADHD). Advanced dMRI techniques can provide details about the layout of white matter pathways in the brain, that are not possible using the current clinical standard of diffusion tensor imaging (DTI). However, these advanced protocols require long scan times and any motion during this time results in artifacts and loss of signal.

As a result, dMRI acquisition of children becomes a challenging task, particularly if they are hyperactive (as in ADHD). In this grant application, we propose several novel algorithms for fast acquisition and reconstruction of advanced dMRI protocols. In particular, we will use our multi-slice acquisition protocol (as opposed to the standard single-slice acquisition) along with a scheme to recover dMRI signals from very few measurements. This will dramatically reduce scan time and make it possible to obtain advanced dMRI scans of pediatric patients (in a clinic). We will validate our methods on several test subjects and then apply them to the study of children and adolescents with ADHD. In particular, we will analyze global connectivity properties of the anatomical neural networks in ADHD along with local diffusion based microstructural properties that may be affected due to pathology. Thus, the improvements suggested in this proposal will bring advanced dMRI protocols to the clinic and allow us to quantify micro and macro level abnormalities in patients with any type of psychiatric or neurological disorder.

Hong Y, O'Donnell LJ, Savadjiev P, Zhang F, Wassermann D, Pasternak O, Johnson H, Paulsen J, Vonsattel J-P, Makris N, et al. Genetic Load Determines Atrophy in Hand Cortico-striatal Pathways in Presymptomatic Huntington's Disease. Hum Brain Mapp. 2018.Abstract
Huntington's disease (HD) is an inherited neurodegenerative disorder that causes progressive breakdown of striatal neurons. Standard white matter integrity measures like fractional anisotropy and mean diffusivity derived from diffusion tensor imaging were analyzed in prodromal-HD subjects; however, they studied either a whole brain or specific subcortical white matter structures with connections to cortical motor areas. In this work, we propose a novel analysis of a longitudinal cohort of 243 prodromal-HD individuals and 88 healthy controls who underwent two or more diffusion MRI scans as part of the PREDICT-HD study. We separately trace specific white matter fiber tracts connecting the striatum (caudate and putamen) with four cortical regions corresponding to the hand, face, trunk, and leg motor areas. A multi-tensor tractography algorithm with an isotropic volume fraction compartment allows estimating diffusion of fast-moving extra-cellular water in regions containing crossing fibers and provides quantification of a microstructural property related to tissue atrophy. The tissue atrophy rate is separately analyzed in eight cortico-striatal pathways as a function of CAG-repeats (genetic load) by statistically regressing out age effect from our cohort. The results demonstrate a statistically significant increase in isotropic volume fraction (atrophy) bilaterally in hand fiber connections to the putamen with increasing CAG-repeats, which connects the genetic abnormality (CAG-repeats) to an imaging-based microstructural marker of tissue integrity in specific white matter pathways in HD. Isotropic volume fraction measures in eight cortico-striatal pathways are also correlated significantly with total motor scores and diagnostic confidence levels, providing evidence of their relevance to HD clinical presentation.