Atypical Resting State Functional Connectivity and Deficits in Cognition in Pediatric Brain Tumor Patients Treated with Proton Beam Radiation

Abstract

Survivors of pediatric brain tumors experience significant cognitive deficits from their diagnosis and treatment. Currently, robust predictors of cognitive outcome are limited. The current study aims to assess cognitive function and resting state functional connectivity MRI (rsfcMRI) in pediatric brain tumor patients that have received proton beam radiation therapy (PBRT). Patients ages 4-18 years old with diagnosis of a brain tumor treated with PBRT underwent rsfcMRI scanning during regularly scheduled clinical imaging along with cognitive assessment utilizing the NIH Toolbox Cognition Battery. Scores for the NIH Toolbox were adjusted for highest level of education of both participant and mother, age, sex, and race/ethnicity. A total of 18 patients were eligible for analysis with a median age at time of PBRT of 10.7 years (range 7.2 - 17.9 years). Radiation volume was whole brain for 5 patients (28%) and conformal for 13 patients (72%). Follow-up rsfcMRI acquisition and cognitive testing occurred at median time of 12 months post-radiation (range 1 - 58 months). Functional connectivity within the dorsal attention network (DAN) was significantly decreased with 67% of study subjects having connectivity strength greater than 2 SD below the mean of age- and sex-matched controls (p<0.0001). Significant impairments were also observed in connectivity strength of the somatomotor ventral (p<0.0001), default mode (p<0.0001), parietal memory (p<0.0001) and salience networks (p<0.001) when compared to controls. Functional connectivity between the DAN and default mode, and parietal memory networks was significantly different compared to matched controls (p<0.001). Neurocognitive testing of study subjects demonstrated significant impairments in total composite, fluid composite and attention/inhibition scores with more than 40% of study subjects scoring greater than 1 SD below the mean of normalized controls for each of these tests (p<0.01). Mean attention/inhibition (p<0.001) and total composite scores (p<0.001) for study subjects were significantly decreased when compared to normalized scores. Irradiated pediatric patients with brain tumors demonstrated significant deficits in attention and total composite performance. Furthermore, rsfcMRI revealed significant differences in functional connectivity in multiple networks in our study population when compared to healthy controls. Further research is needed to assess the potential use of rsfcMRI as a predictive marker of cognitive outcome in pediatric brain tumor patients.