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.

Sex Differences in the Association between Household Income and Children’s Executive Function

“…Executive function is a set of mental skills that include working memory, flexible thinking, and self-control [38,39]. While memory and flexible thinking reflect other dimensions of executive function, response time, correct go responses to "go signals", and correct stops to stop signs all reflect a domain of executive function that is associated with motor control, inhibiting, impulsivity, and response time [40][41][42][43][44]. Executive "brake failure" following executive control of response inhibition as well as the fast response to the go signals all reflect aspects of executive function [45,46].…”

Neurodevelopmental Consequences of Pediatric Cancer and Its Treatment: The Role of Sleep

“…A recent study evaluated patients aged between 8 and 21 years treated with a single chemotherapy protocol with methotrexate and demonstrated a brain connectome dysfunction; the results were consistent with a delay in neurodevelopment (especially in younger children), which could be associated with reduced recovery capacity, adaptability and flexibility of the brain network [34].…”

“…In addition, the excessive daytime sleepiness caused by this disease can negatively impact on the child's learning, behavior and school performance [75] and cause an alteration of the cerebral gray matter in the areas involved in learning and emotional functions [77]. Thus it is important to treat this pathology, often also found in children with oncological pathologies [12,78], in whom neurocognitive problems can arise both as a consequence of cancer or of its treatment, as previously described [17,18,31,32,34,35]. As mentioned above, both OSA and cancer can cause structural changes in the brain, especially in the earliest stages of the child's development [3,10,[29][30][31][32]77].…”

“…-Damage of the hippocampus and other areas involved in memory emotion circuits (amygdala, thalamus, striatum, substantia nigra/ventral tegmental area) [10,[29][30][31][32] -Dendrite and axonal growth damage [10] • damage of prefrontal functions [29,31,32,35,36] • brain connectivity disruption [34] • leukoencephalopathy [13,36] -Increase in tau protein (axonal damage and neurodegeneration), increase in GFAP (associated with attention deficit) [36] • neuroinflammation (increase in C-reactive protein, IL, and tumor necrosis factorα) [9,26,31,32] • hypothalamic-pituitary-adrenal axis alteration [37] The relationship and interactions between pediatric cancer, chemotherapy, sleep and CNS development/damage and cognitive function are complex and schematically represented in Figure 1. The above results highlight the need for interventions that prevent or manage cognitive impairment in pediatric ALL; in recent years, the results of cognitive behavioral therapy (CBT) and physical activity in pediatric patients with ALL or solid CNS tumors have been examined, with improvement of brain function and an increase in white matter and hippocampal volume [38][39][40].…”

“…Furthermore, the maturation of slow waves in childhood seems to be a new marker for monitoring brain connections, giving to sleep the role of a major player in brain maturation processes [60]. Myelination processes that occur from childhood to adolescence, leading to the maturation of nerve fibers and allowing neurodevelopmental mechanisms, take place especially during sleep, which, therefore, plays a key role in brain maturation and learning; in the course of pediatric cancer, a widespread involvement is observed not only of the gray matter, but also of the white matter [3,10,30,36], with the consequent disruption of brain connectivity, impaired learning processes and reduced cognitive performance [34,35]. Good sleep quality, with an adequate representation of slow-wave sleep, is therefore important for brain connectivity and neurodevelopment.…”