Neurodevelopmental consequences of pediatric cancer and its treatment: applying an early adversity framework to understanding cognitive, behavioral, and emotional outcomes

Abstract

Today, children are surviving pediatric cancer at unprecedented rates, making it one of modern medicine's true success stories. However, we are increasingly becoming aware of several deleterious effects of cancer and the subsequent "cure" that extend beyond physical sequelae. Indeed, survivors of childhood cancer commonly report cognitive, emotional, and psychological difficulties, including attentional difficulties, anxiety, and posttraumatic stress symptoms (PTSS). Cognitive late- and long-term effects have been largely attributed to neurotoxic effects of cancer treatments (e.g., chemotherapy, cranial irradiation, surgery) on brain development. The role of childhood adversity in pediatric cancer - namely, the presence of a life-threatening disease and endurance of invasive medical procedures - has been largely ignored in the existing neuroscientific literature, despite compelling research by our group and others showing that exposure to more commonly studied adverse childhood experiences (i.e., domestic and community violence, physical, sexual, and emotional abuse) strongly imprints on neural development. While these adverse childhood experiences are different in many ways from the experience of childhood cancer (e.g., context, nature, source), they do share a common element of exposure to threat (i.e., threat to life or physical integrity). Therefore, we argue that the double hit of early threat and cancer treatments likely alters neural development, and ultimately, cognitive, behavioral, and emotional outcomes. In this paper, we (1) review the existing neuroimaging research on child, adolescent, and adult survivors of childhood cancer, (2) summarize gaps in our current understanding, (3) propose a novel neurobiological framework that characterizes childhood cancer as a type of childhood adversity, particularly a form of early threat, focusing on development of the hippocampus and the salience and emotion network (SEN), and (4) outline future directions for research.

Emotion‐related brain organization and behavioral responses to socioemotional stimuli in pediatric cancer survivors with posttraumatic stress symptoms

“…However, as we emphasize in our recent review of neuroimaging studies of pediatric cancer 16 , there may be shared aspects of cancer (e.g., threat to life, treatments) that may affect brain organization. Indeed, several published studies report similar neural alterations in patients/survivors with different cancer types, and that PTSS and other emotion-related outcomes are reported across a range of diagnoses 16 . In addition, although we examined behavior during an emotion processing task, amygdala centrality was assessed during a resting-state condition.…”

“…37,51 Thus, although there are many potential received. However, as we emphasize in our recent review of neuroimaging studies of pediatric cancer, 16 there may be shared aspects of cancer (e.g., threat to life and treatments) that may affect brain organization. Indeed, several published studies report similar neural alterations in patients/survivors with different cancer types, and that PTSS and other emotion-related outcomes are reported across a range of diagnoses.…”

“…Indeed, several published studies report similar neural alterations in patients/survivors with different cancer types, and that PTSS and other emotion-related outcomes are reported across a range of diagnoses. 16 In addition, although we examined behavior during an emotion-processing task, amygdala centrality was assessed during a resting-state condition. Thus, it is unclear if neural patterns would be consistent (or exacerbated) during emotion-related processing.…”

“…9,10,15 Variability in emotional reactions likely map on to underlying neural and behavioral mechanisms that may help to understand pathophysiological mechanisms, identify children at risk for emotion-related problems and/or long-term impairment, and inform the development of more targeted neurobiologically informed interventions. However, most neural and behavioral research on pediatric cancer has focused on cognitive consequences (e.g., attention; see review by Marusak et al 16 ). One behavioral pattern potentially linked to the development of emotion-related problems is faster reaction time to negative stimuli, which may reflect an attentional bias toward negative information processing.…”

“…This hypothesis derives from the idea that children's stressful experiences with cancer and its treatment can shape their underlying neurodevelopment and how they process threatening or ambiguous cues in the environment. 16 Previous studies have shown that exposure to other stressors during development (e.g., violence and abuse) can impact amygdala-based emotion networks in the brain and lead to altered behavioral responses to emotional stimuli. 35,36 Therefore, we also tested for group differences in measures of amygdala centrality (i.e., degree and betweenness centrality), and associations between amygdala centrality and PTSS and behavioral response patterns.…”