Functional neuroimaging of working memory in survivors of childhood brain tumors and healthy children: Associations with coping and psychosocial outcomes

Purpose: Pediatric brain tumors are the second most common cancer diagnosis in individuals under age 20 and research has documented significant neurocognitive, psychosocial, and emotional late effects. Associations among these deficits have not been adequately considered and the role of survivors’ coping with stress in relation to deficits is unknown. Further, research has yet to examine neurobiological processes related to neurocognitive, psychosocial, and emotional difficulties in survivors through the use of functional neuroimaging. Method: Questionnaire measures and functional neuroimaging were used to examine the neurocognitive, psychosocial, and emotional functioning and coping responses of survivors of pediatric brain tumors (N = 17; age 8–16) and healthy children (N = 15). Results: Survivors experienced elevated levels of psychosocial and behavioral/emotional difficulties relative to healthy controls and normative data. Increases in brain activation in prefrontal and other anterior regions in response to a working memory task were associated with better psychosocial functioning, use of engagement coping strategies, and less use of disengagement coping strategies. Regression analyses suggest coping accounts for a significant portion of the association between brain activation and behavioral/emotional functioning. Conclusions: This study extends late-effects research by examining neurobiological processes associated with psychosocial and emotional difficulties. These findings contribute to our understanding of difficulties in survivors and provide a foundation for research exploring these associations and mediators of deficits in future longitudinal studies.     

Executive functioning and health-related quality of life in pediatric sickle cell disease

Research consistently indicates that children with sickle cell disease (SCD) face multiple risk factors for neurocognitive impairment. Despite this, no empirical research to date has examined the impact of neurocognitive functioning on quality of life for this pediatric group. Thus, the current study aims to examine the relationship between executive functioning and quality of life in a sample of children with SCD and further explore psychosocial and family/caregiver resources as moderators of this relationship. A total of 45 children with SCD aged 8 to 16 years and their caregivers completed measures of quality of life, behavioral ratings of executive functioning, and psychosocial functioning. Hierarchical linear regression models were utilized to determine the impact of executive functioning on quality of life and further test the interaction effects of proposed moderating variables. Controlling for age, pain, and socioeconomic status (SES), executive functioning was found to significantly predict child- and parent-reported quality of life among youth with SCD. Psychosocial resources of the primary caregiver or family was not found to moderate the relationship between executive functioning and quality of life. These results provide the first empirical evidence that lower executive skills negatively predict quality of life for children with SCD, supporting clinical and research efforts which aim to establish efficacious interventions that target cognitive decrements within this pediatric population.     

Neurocognitive outcomes in children with chronic kidney disease: Current findings and contemporary endeavors

Given the rise in chronic kidney disease (CKD) in both children and adults, CKD has recently been targeted as a public health priority. Childhood onset kidney disease is generally a noncurable and progressive condition that leads to kidney failure by early adulthood. Fortunately, improved identification of kidney problems allows for early intervention, which is thought to slow progression toward end-stage renal disease. In addition, medical interventions for pediatric end-stage renal disease have also improved, allowing children to take advantage of lifesaving renal replacement treatments such as dialysis and kidney transplantation. In spite of improvements in identification and treatment, CKD causes both direct and indirect insults to a variety of organ systems. This paper reviews recently published studies pertaining to the neurocognitive and psychosocial impact of CKD on children of various ages and at various stages of kidney failure. Specific attention is focused on summarizing peer reviewed research that describes associations between kidney functioning and cognitive functioning, language acquisition, visual spatial abilities, memory, and executive functioning. In addition, peer reviewed research describing psychosocial outcomes associated with CKD related to academic achievement, social-behavioral functioning, and quality of life are summarized. The authors also identified disease-specific factors that likely mediate neurocognitive outcomes (e.g., anemia, hypertension, cardiovascular) and endorse the importance of continued interdisciplinary research collaborations that will provide a better understanding of the mechanisms responsible for improved neurocognitive functioning after transplantation. The authors conclude this review by describing a multicenter, prospective, longitudinal, National Institutes of Health funded study that is currently examining the developmental outcomes of children with mild to moderate CKD. The authors speculate that the Chronic Kidney Disease in Children Prospective Cohort Study (CKiD) findings will provide additional evidence-based guidance for clinicians and researchers working with children and adolescents with deteriorating kidney function to improve medical and developmental outcomes.     

Performance-based and parent ratings of attention in children treated for a brain tumor: The significance of radiation therapy and tumor location on outcome

Children are at increased risk for cognitive difficulties following the diagnosis and treatment of a brain tumor. Radiation therapy (RT) and tumor location are commonly-cited predictors of neurocognitive functioning. Disruptions to foundational neurocognitive processes such as attention, working memory, and processing speed underlie declines on measures of general intellectual functioning. While several studies have examined visual sustained attention in pediatric brain tumor patients, auditory sustained attention has yet to be examined. This study employs a longitudinal design to examine performance-based and parent ratings of attention in children undergoing surgical resection of a brain tumor (n = 29) and treated with (n = 11) or without (n = 18) RT at 6.79 months post-surgery (baseline) and then again at 30.56 months post-surgery (follow-up). The measures include an auditory continuous performance test (CPT) and parent ratings of attention and hyperactivity on a behavior rating scale. Ultimately, children treated with and without RT performed similarly on performance-based and parent ratings of attention. However, the performance on the auditory CPT differed according to tumor location, with children with infratentorial tumors committing more inattention and inhibitory control errors compared to children with supratentorial tumors. Parent ratings did not differ according to tumor location, and parent ratings and auditory sustained attention performance are not significantly correlated. The findings are interpreted in the context of neurocognitive and brain development.     

Evidence for the Syndrome of Nonverbal Learning Disabilities in Children with Brain Tumors

This study examined the predicted utility of the Nonverbal Learning Disabilities syndrome (NLD) (Rourke, 1995) for characterizing neurocognitive and psychosocial outcomes in 123 children with brain tumors. Children with brain tumors were found to be at high risk of having a specific academic deficit, particularly in arithmetic. Children with arithmetic deficit evidenced a higher rate of impairment on nonverbal tasks than on verbal tasks, whereas children with reading deficit evidenced a higher rate of impairment on verbal tasks than on nonverbal tasks. However, significant differences between children with arithmetic and reading deficits were not found for all of the component features of the NLD syndrome, and arithmetic deficit was not related to treatment with irradiation.     

Cognitive training programs for childhood cancer patients and survivors: A critical review and future directions

A robust literature has developed documenting neurocognitive late effects in survivors of leukemia and central nervous system (CNS) tumors, the most frequent cancer diagnoses of childhood. Patterns of late effects include deficits in attention and concentration, working memory, processing speed, and executive function, as well as other domains. As childhood cancer survivors are living longer, ameliorating deficits both in broad and specific neurocognitive domains has been increasingly recognized as an endeavor of paramount importance. Interventions to improve cognitive functioning were first applied to the field of pediatric oncology in the 1990s, based on strategies used effectively with adults who had sustained a traumatic brain injury (TBI). Compilation and modification of these techniques has led to the development of structured cognitive training programs, with the effectiveness and feasibility of such interventions currently an active area of research. Consequently, the purpose of this critical review is to: (1) review cognitive training programs intended to remediate or prevent neurocognitive deficits in pediatric cancer patients and survivors, (2) critically analyze training program strengths and weaknesses to inform practice, and (3) provide recommendations for future directions of clinical care and research.     

Neurodevelopment and chronic illness: Mechanisms of disease and treatment

Successful treatment of many childhood diseases once considered terminal has resulted in the emergence of long-term effects of the disease or consequences of treatment that were previously unrecognized. Many of these long-term effects involve the central nervous system (CNS) and are developmental in the way that they emerge over time. Because we are now able to observe the natural history of childhood diseases such as sickle cell anemia or HIV, or the consequences of treatment of disease such as leukemia, brain tumors, or kidney disease, we are also able to study a number of biological mechanisms that result in long-term neurocognitive impairment. While some of the neurodevelopmental outcomes can be directly linked to structural damage of the CNS, other systems (e.g., hematologic, immunologic, pulmonary) appear to play crucial indirect roles in the development of the CNS and neurocognitive abilities because of the way that they affect the course of brain development and activity of the brain across time. Important interactions between acute disease factors, biological mechanisms, age at the time of disease or treatment effect, and disruptions in patterns of development after successful treatment or management all provide support for a neurodevelopmental model of childhood chronic illness. Testing this model may make it possible to more accurately predict the timing and degree of severity of long-term neurodevelopmental consequences, provide guidance for improved treatment and prevention, and offer better understanding of neurodevelopmental disruptions that occur in other non-chronic illness related disabilities.     

Executive Functioning in Children and Adolescents with Major Depressive Disorder

The present investigation examined neurocognitive functioning, focusing on executive functioning (EF), in 39 children and adolescents with Major Depressive Disorder (MDD) and 24 healthy control subjects all ages 8 to 17 years. The Wechsler Intelligence Scale for Children-Third Edition along with several measures of executive functioning including the Wisconsin Card Sorting Task, Trail Making Test, Controlled Oral Word Association Test, and the Stroop Color Word Test were administered. The neurocognitive profiles for the group of depressed children and adolescents were grossly intact as most scores on intellectual and EF measures fell within the average range and did not differ from the comparison group. Mental processing speed was decreased in the MDD versus normal control group and 27% of the depressed group performed below average on the Trail Making Test. This investigation provided a good base from which to compare future literature on EF in outpatients with early-onset MDD.     

Psychosocial Functioning in Children and Adolescents with Extreme Obesity

The aim of this study was to investigate the psychosocial differences among obese pediatric patients, particularly those who are "extremely obese" as compared to "obese." Information was collected for 249 subjects at a multidisciplinary treatment clinic for obese youth. A battery of measures was administered and demographic data and height/weight was obtained. The results showed positive correlations between degree of obesity, psychosocial functioning, and quality of life. Specifically, the "extremely obese" were significantly more depressed, more socially anxious, and had poorer quality of life than the "obese" group. Girls and Caucasians were more socially anxious than boys and African Americans, respectively. There is mounting evidence that children and adolescents who are extremely obese are most at risk for psychiatric and medical disorders. Thus, targeting this group for assessment and/or designing treatment options specific for "extremely obese" youth is critical for the successful management of this population.     

Neurocognitive functioning of preschool children with uncomplicated epilepsy

Only few studies are available on the cognitive functioning of preschool children with uncomplicated epilepsy. The aim of this study was to describe the neurocognitive functioning of 3–6-year-old children with uncomplicated epilepsy. A subgroup of children with uncomplicated epilepsy from a population based cohort of preschool children with active epilepsy (N = 64) participated in the study. The neurocognitive functioning of these children (N = 13) was compared to that of matched healthy controls (N = 13). The Wechsler's Primary and Preschool Scale of Intelligence - Revised and the Developmental Neuropsychological Assessment were administered. The intellectual functioning of the children with uncomplicated epilepsy was within normal range, but differed significantly from that of healthy controls, which was contrary to expectations. Statistically significant differences emerged between the study and the control group in Verbal IQ and Full Scale IQ, but no differences were found in Performance IQ. The children with uncomplicated epilepsy also had minor neurocognitive difficulties in verbal short-term memory (p <.01) compared to healthy children. The result suggests that uncomplicated epilepsy in preschool children may interfere with language and verbal short-term memory functions. Further studies with detailed neuropsychological assessments and follow-up time are needed to gain more insight into the developmental course of children with uncomplicated epilepsy. Also, because of the developmental risks reported in this study, psychological screening and detailed neuropsychological assessment are recommended in clinical practice.     

Parent Report of Attention Problems Predicts Later Adaptive Functioning in Children with Brain Tumors

Children with brain tumors are at risk for psychological and behavioral difficulties. This study examined the ability of parent report of attention problems, withdrawal, anxiety, and depression, as well as IQ, to predict later adaptive functioning in 42 children treated for brain tumors. Age at diagnosis, SES, gender, and scores on the Neurological Predictor Scale (NPS) also were examined as predictors. Parent report of attention problems, SES, and NPS were significant predictors of later adaptive functioning across domains. This finding highlights the ability of parent report of attention problems to predict later adaptive functioning in children treated for brain tumors.     

Is knowledge of family history related to psychosocial functioning? Comparison of adolescents living in institutional care and adolescents living with their biological families

We tested adolescents growing up in institutional care and adolescents living with their birth families using the ‘Do you know?’ scale and other measures of psychosocial functioning. We found that children living in group homes knew significantly less of their family history, exhibited more behavioural problems and had a more external locus of control. Moreover, the correlations between self-esteem and knowledge of family history were significantly different between the groups. This may suggest that the contribution of the knowledge of family history to self-esteem is different depending on the quality of family history. We also found a significant correlation between locus of control and behavioural problems for the children in institutional care, but not children living with their birth families, which may indicate that their behavioural problems may partially stem from the sense of lack of control over their lives.     

Help-seeking and helping behavior in children as a function of psychosocial competence

Research on prosocial behavior has supported the belief that psychosocial competence characteristics enhance helping behavior. Tyler and others have hypothesized that helpseeking is also a constructive competence-related behavior. The present investigation was designed to assess whether the correlates of psychosocial competence differences found in more effective psychosocial functioning among primary school children in the U.S. would characterize children in India and be reflected in their help-seeking and helping behaviors. Twenty-eight pairs of 8 to 10-year-old children participated in this 3 × 2 factorial design study. High and low competence subjects were selected using scores on the Psychosocial Competence Incomplete Stories Test (PCIST) adapted for Indian children. Results show that constructiveness of helpseeking and helping were a function of psychosocial competence. This was also a three-way interaction effect of sex and psychosocial competence level of the helpseeker and of the helper on the level of constructiveness of help-seeking behavior. Tyler and colleagues had previously demonstrated that children from the U.S. who are more psychosocially competent (more self-efficacious, interpersonally trusting, and actively planful) function more effectively in their lives. The current results extend those findings by demonstrating that help-seeking and helping behavior are also a function of these psychosocial competence characteristics. They also indicate sex differences in the relationship of psychosocial competence to interpersonal interactions among these children in India. Psychosocial competence and developmental and cultural implications are noted.     

Timed performance weaknesses on computerized tasks in pediatric brain tumor survivors: A comparison with sibling controls

With more children surviving a brain tumor, insight into the late effects of the disease and treatment is of high importance. This study focused on profiling the neurocognitive functions that might be affected after treatment for a pediatric brain tumor, using a broad battery of computerized tests. Predictors that may influence neurocognitive functioning were also investigated. A total of 82 pediatric brain tumor survivors (PBTSs) aged 8–18 years (M = 13.85, SD = 3.15, 49% males) with parent-reported neurocognitive complaints were compared to a control group of 43 siblings (age M = 14.27, SD = 2.44, 40% males) using linear mixed models. Neurocognitive performance was assessed using measures of attention, processing speed, memory, executive functioning, visuomotor integration (VMI), and intelligence. Tumor type, treatment, tumor location, hydrocephalus, gender, age at diagnosis, and time since diagnosis were entered into regression analyzes as predictors for neurocognitive functioning. The PBTSs showed slower processing speeds and lower intelligence (range effect sizes .71–.82, p < .001), as well as deficits in executive attention, short-term memory, executive functioning, and VMI (range effect sizes .40–.57, p < .05). Older age at assessment was associated with better neurocognitive functioning (B = .450, p < .001) and younger age at diagnosis was associated with lower intelligence (B = .328, p < .05). Medical risk factors, e.g., hydrocephalus, did not show an association with neurocognitive functioning. Late effects in PBTSs include a broad range of neurocognitive deficits. The results suggest that even PBTSs that were traditionally viewed as low risk for neurocognitive problems (e.g., surgery only, no hydrocephalus) may suffer from decreased neurocognitive functioning.     

Cumulative risk disparities in children's neurocognitive functioning: a developmental cascade model

The current longitudinal study examined the role of cumulative social risk on children's theory of mind (ToM) and executive functioning (EF) across early development. Further, we also tested a cascade model of development in which children's social cognition at 18 months was hypothesized to predict ToM and EF at age 4.5 through intermediary language skills at age 3. We then examined whether this developmental mechanism varied as a function of social risk status. Participants were 501 children recruited when they were newborns, at which point eight psychosocial risk factors were assessed and combined into a metric of cumulative social disadvantage. Families were followed up at 18 months, at which point four social‐cognitive skills were assessed using developmentally sensitive tasks: joint attention, empathy, cooperation, and self‐recognition. Language was measured at age 3 using a standardized measure of receptive vocabulary. At age 3 and 4.5, EF and ToM were measured using previously validated tasks. Results showed that there were notable cumulative risk disparities in overall neurocognitive skill development, and these effects became more differentiated over time. Support was also found for a developmental mechanism wherein the effect of social cognition at 18 months on ToM and EF in the preschool period operated specifically through children's receptive language ability at age 3. This pathway functioned similarly for children with both low‐ and high‐risk backgrounds. These results extend previous findings by documenting the role of cumulative social disadvantage on children's neurocognition and the pathways that link key neurocognitive abilities across early development.     

Psychosocial functioning of borderline patients and axis II comparison subjects followed prospectively for six years

The purpose of this study was to determine the course of the psychosocial functioning of patients with borderline personality disorder (BPD) over 6 years of prospective follow-up. The psychosocial functioning of 290 patients meeting both DIB-R and DSM-III-R criteria for BPD and 72 patients meeting DSM-III-R criteria for another Axis II disorder (and neither criteria set for BPD) was assessed at baseline using a semistructured interview of demonstrated reliability. Over 94% of surviving patients were reinterviewed about their psychosocial functioning blind to all previously collected information at three distinct follow-up waves: 2-, 4-, and 6-year follow-up. The psychosocial functioning of borderline patients improved substantially over time, with the percentage meeting criteria for good overall psychosocial functioning increasing from 26% at baseline to 56% during the third wave of follow-up. Despite this improvement, borderline patients functioned significantly more poorly than Axis II comparison subjects, particularly in the area of vocational achievement. However, a more detailed examination revealed that borderline patients who had experienced a symptomatic remission during the course of the study functioned significantly better both socially and vocationally than never-remitted borderline patients. More specifically, they were significantly more likely to have a good relationship with a spouse/partner and at least one parent, good work/school performance, a sustained work/school history, a GAF score of 61 or higher (43% vs. 0% 6 years after their index admission), and to have good overall psychosocial functioning (66% vs. 27% at 6 year follow-up). Taken together, the results of this study suggest that psychosocial improvement is both common among borderline patients and strongly related to their symptomatic status.     

Moderating Effects of Neurocognitive Abilities on the Relationship between Temperament and Global Functioning

Clear links between temperament, psychopathology, and neuropsychological functioning exist; however the interrelations among temperament and neuropsychology, and their impact on functioning in typically developing children is not as well understood. This study examined the degree to which neuropsychological functioning, as measured by the NEPSY, moderates the impact of temperament on global functioning, as measured by the Children's Global Assessment Scale (CGAS), in 74 typically developing preschoolers. Temperament was assessed via parent ratings on the Children's Behavior Questionnaire (CBQ) and teacher ratings on the Temperament Assessment Battery for Children – Revised (TABC-R). Moderation analyses revealed significant interactions between verbal-executive skills and both child emotionality and lack of task persistence in predicting global functioning. The interaction patterns were mostly consistent across measures and indicated that when lower neurocognitive scores were coupled with higher levels of expressed negative emotions and more difficulties in task persistence, global functioning was at its lowest. In contrast better neurocognitive functioning mitigated the impact of high expressed emotions on global functioning. These findings support past literature and indicate that emotional and cognitive functioning interact to effect young children's global functioning.     

Neuropsychological functioning and social functioning of survivors of pediatric brain tumors: evidence of nonverbal learning disability.

The purpose of the study was to examine if survivors of pediatric brain tumors exhibit a pattern of performance consistent with nonverbal learning disability (NVLD) and to explore the relationship between neuropsychological and social functioning in these children. A comprehensive neuropsychological battery and objective measures of psychosocial function designed to assess NVLD were administered to 15 survivors of brain tumors, ages 8-12 years. Despite the small sample size, a trend for better verbal skills compared to nonverbal skills was found using composite scores. Parents reported significant social deficits and a tendency for greater internalizing behavior problems as expected in NVLD. Additionally, there was a trend for a positive association between nonverbal scores and social function. Further research is needed to determine if the NVLD pattern observed is attributable to white matter damage of the right hemisphere. Routine neuropsychological and psychosocial assessment and intervention are indicated.     

Parent-reported executive functioning in young children treated for cancer

It is well known that children treated for cancer are at risk for cognitive and functional impairments. Such research is largely based on studies of late effects in school-aged or older children. However, far less is known about executive function weaknesses in preschool-aged children treated for cancer. Thus, the aim of this study was to examine executive functioning in a clinically referred sample of young oncology patients, and its association with broader domains of functioning. Data from 61 young children with cancer, who were referred for clinical cognitive evaluations, were abstracted and included in this study. Patients were 5.00 years of age (SD = 0.72) at assessment, 54.1% male, and two-thirds (63.9%) had been treated for brain tumors. Most executive functions were significantly discrepant from the mean, with 47.5% of preschoolers having parent-reported working memory concerns within the clinically significant range. There were no differences in executive functioning based on diagnosis or treatment status. Parent-reported executive functioning was strongly correlated with global intelligence and adaptive functioning, with some indices also associated with nonverbal problem solving and pre-academic skills. Ultimately, results indicate the presence of emerging weaknesses in executive functioning in young children with cancer, and add to a growing body of literature highlighting the potential cognitive and behavioral risks associated with a cancer diagnosis in early childhood.