Brain Network Connectivity and Executive Function in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia

Abstract

Chemotherapeutic agents used to treat acute lymphoblastic leukemia (ALL), the most common cancer affecting young children, have been associated with long-term cognitive impairments that reduce quality of life. Executive dysfunction is one of the most consistently observed deficits and can have substantial and pervasive effects on academic success, occupational achievement, psychosocial function, and psychiatric status. We examined the neural mechanisms of executive dysfunction by measuring structural and functional connectomes in 161 long-term survivors of pediatric ALL, age 8-21 years, who were treated on a single contemporary chemotherapy-only protocol for standard/high- or low-risk disease. Lower global efficiency, a measure of information exchange and network integration, of both structural and functional connectomes was found in survivors with executive dysfunction compared with those without dysfunction (p < 0.046). Patients with standard/high- versus low-risk disease and those who received greater number of intrathecal treatments containing methotrexate had the lowest network efficiencies. Patients with executive dysfunction also showed hyperconnectivity in sensorimotor, visual, and auditory-processing regions (p = 0.037) and poor separation between sensorimotor, executive/attention, salience, and default mode networks (p < 0.0001). Connectome disruption was consistent with a pattern of delayed neurodevelopment that may be associated with reduced resilience, adaptability, and flexibility of the brain network. These findings highlight the need for interventions that will prevent or manage cognitive impairment in survivors of pediatric acute lymphoblastic leukemia.

Keywords: DTI; chemotherapy; connectome; executive function; leukemia; resting state fMRI.

FIG. 1.

Functional Regional Connectivity. Patients with executive dysfunction demonstrated hyperconnectivity among several regions compared with patients without executive dysfunction (p = 0.037, corrected). Regions are shown as spheres and their connections as lines, which are weighted by the test statistic for that connection (i.e., thicker line = greater hyperconnectivity). LAMG, left amygdala; LHIP, left hippocampus; LPAL, left palladium; LPOST, left postcentral gyrus; LSTG, left superior temporal gyrus; LPUT, left putamen; RPAL, right palladium; RPOST, right postcentral gyrus; RSPAR, right superior parietal; RSTG, right superior temporal gyrus.

FIG. 2.

Functional Network Modules. Patients with executive dysfunction demonstrated lower modularity (p < 0.001) compared with patients without executive dysfunction, indicating lower separation among networks, consistent with hyperconnectivity. Nonimpaired patients (top) showed distinct salience, sensorimotor, default mode, and executive/attention networks, while the impaired group (bottom) demonstrated overlap between sensorimotor and attention/executive, default mode and attention/executive, and salience and sensorimotor networks. Regions are shown as spheres colored by module membership.

FIG. 3.

Structural Network Efficiency by Age at Diagnosis Groups. Dividing the sample by age at diagnosis into quantiles or K-means clusters suggested that children approximately age 5 or younger at diagnosis demonstrated the greatest vulnerability to disruption of brain network efficiency; p values are FDR corrected. FDR, false discovery rate.