Associations among maternal lifetime trauma, psychological symptoms in pregnancy, and infant stress reactivity and regulation.

Maternal trauma has intergenerational implications, including worse birth outcomes, altered brain morphology, and poorer mental health. Research investigating intergenerational effects of maternal trauma on infant stress reactivity and regulation is limited. Maternal mental health during pregnancy may be a contributor: psychopathology is a sequela of trauma exposure and predictor of altered self-regulatory capacity in offspring of affected mothers. We assessed associations among maternal lifetime trauma and infant stress responsivity, mediated by psychological symptoms in pregnancy. Mothers reported lifetime trauma history and anxiety, depressive, and posttraumatic stress symptoms during pregnancy. At infant age 6 months, stress reactivity and regulation were assessed via maternal behavior ratings (Infant Behavior Questionnaire-Revised, IBQ-R) and behavioral (negative mood) and physiological (respiratory sinus arrhythmia, RSA) markers during a laboratory stressor (Still-Face Paradigm). Maternal trauma was directly associated with lower infant physiological regulation and indirectly associated with lower levels of both infant behavioral and physiological regulation via higher maternal anxiety during pregnancy. Maternal trauma was also indirectly associated with higher infant reactivity via higher maternal anxiety during pregnancy. Post hoc analyses indicated differential contributions of maternal prenatal versus postnatal anxiety to infant outcomes. Findings highlight potential contributory mechanisms toward maladaptive child stress response, which has been associated with poor behavioral, cognitive, and academic outcomes.

Performance on the ROCF at 8 Years Predicts Academic Achievement at 16 Years in Individuals with Dextro-Transposition of the Great Arteries.

OBJECTIVE: This study examined longitudinal associations between performance on the Rey-Osterrieth Complex Figure-Developmental Scoring System (ROCF-DSS) at 8 years of age and academic outcomes at 16 years of age in 133 children with dextro-transposition of the great arteries (d-TGA). METHOD: The ROCF-DSS was administered at the age of 8 and the Wechsler Individual Achievement Test, First and Second Edition (WIAT/WIAT-II) at the ages of 8 and 16, respectively. ROCF-DSS protocols were classified by Organization (Organized/Disorganized) and Style (Part-oriented/Holistic). Two-way univariate (ROCF-DSS Organization × Style) ANCOVAs were computed with 16-year academic outcomes as the dependent variables and socioeconomic status (SES) as the covariate. RESULTS: The Organization × Style interaction was not statistically significant. However, ROCF-DSS Organization at 8 years was significantly associated with Reading, Math, Associative, and Assembled academic skills at 16 years, with better organization predicting better academic performance. CONCLUSIONS: Performance on the ROCF-DSS, a complex visual-spatial problem-solving task, in children with d-TGA can forecast academic performance in both reading and mathematics nearly a decade later. These findings may have implications for identifying risk in children with other medical and neurodevelopmental disorders affecting brain development.

Parental history of moderate to severe infantile malnutrition is associated with cognitive deficits in their adult offspring.

OBJECTIVES: We compared the IQ and academic achievement of the young adult offspring of parents malnourished in infancy and those of a healthy control group in order to test the hypothesis that the offspring of previously malnourished individuals would show IQ and academic deficits that could be related to reduced parental socioeconomic status. METHODS: We conducted a group comparison study based on a community sample in Barbados (Barbados Nutrition Study). Participants were adult children ≥16 years of age whose parents had been malnourished during the first year of life (n = 64; Mean age 19.3 years; 42% male) or whose parents were healthy community controls (n = 50; Mean age 19.7 years; 48% male). The primary outcome was estimated IQ (Wechsler Abbreviated Scale of Intelligence); a secondary outcome was academic achievement (Wide Range Achievement Test - Third Edition). Data were analyzed using PROC MIXED with and without adjusting for parental socioeconomic status (Hollingshead Index of Social Position). RESULTS: IQ was reduced in the offspring of previously malnourished parents relative to the offspring of controls (9.8 point deficit; P < 0.01), but this difference was not explained by parental socioeconomic status or parental IQ. The magnitude of the group difference was smaller for basic academic skills and did not meet criteria for statistical significance. DISCUSSION: The deleterious impact of infant malnutrition on cognitive function may be transmitted to the next generation; however, this intergenerational effect does not appear to be explained by the reduced socioeconomic status or IQ of the parent generation.

Lexical retrieval pre- and posttemporal lobe epilepsy surgery in a pediatric sample.

PURPOSE: This study aimed to evaluate lexical retrieval, presurgery and postsurgery, among children and adolescents who had undergone temporal lobe resection for intractable epilepsy and to compare outcomes in patients whose surgery involved the left temporal lobe or the right temporal lobe. MATERIALS AND METHODS: A retrospective chart review identified 36 patients from a major pediatric epilepsy treatment center who had undergone temporal lobe resection (21 underwent left temporal lobe resection; 15 underwent right temporal lobe resection) for intractable epilepsy and who had completed neuropsychological testing that included a measure of confrontation naming (Boston Naming Test, BNT) and verbal fluency (Delis-Kaplan Executive Function System (D-KEFS) Fluency) prior to and after surgery. Linear mixed effects regression models were used to evaluate presurgery and postsurgery changes and to compare the left temporal lobe resection group with the right temporal lobe resection group. PRINCIPAL RESULTS: Confrontation naming performance declined after left, but not right, temporal lobe resection (p<0.05). This effect was not documented for verbal fluency. MAJOR CONCLUSIONS: Left temporal lobe resection for intractable epilepsy is associated with a decline in lexical retrieval. The risk of decline in specific language functions following surgery involving the left temporal lobe should be incorporated in the counseling of patients and families in decision-making with regard to surgery.

Cognitive ability changes and dynamics of cortical thickness development in healthy children and adolescents.

Intelligence quotient (IQ) scores tend to remain stable across the lifespan. Nevertheless, in some healthy individuals, significant decreases or increases in IQ have been observed over time. It is unclear whether such changes reflect true functional change or merely measurement error. Here, we applied surface-based corticometry to investigate vertex-wise cortical surface area and thickness correlates of changes in Full Scale IQ (FSIQ), Performance IQ (PIQ) and Verbal IQ (VIQ) in a representative sample of children and adolescents (n=188, mean age=11.59years) assessed two years apart as part of the NIH Study of Normal Brain Development. No significant associations between changes in IQ measures and changes in cortical surface area were observed, whereas changes in FSIQ, PIQ, and VIQ were related to rates of cortical thinning, mainly in left frontal areas. Participants who showed reliable gains in FSIQ showed no significant changes in cortical thickness on average, whereas those who exhibited no significant FSIQ change showed moderate declines in cortical thickness. Importantly, individuals who showed large decreases in FSIQ displayed the steepest and most significant reductions in cortical thickness. Results support the view that there can be meaningful cognitive ability changes that impact IQ within relatively short developmental periods and show that such changes are associated with the dynamics of cortical thickness development.

Impaired IQ and academic skills in adults who experienced moderate to severe infantile malnutrition: a 40-year study.

OBJECTIVES: To evaluate IQ and academic skills in adults who experienced an episode of moderate-to-severe infantile malnutrition and a healthy control group, all followed since childhood in the Barbados Nutrition Study. METHODS: IQ and academic skills were assessed in 77 previously malnourished adults (mean age = 38.4 years; 53% male) and 59 controls (mean age = 38.1 years; 54% male). Group comparisons were carried out by multiple regression and logistic regression, adjusted for childhood socioeconomic factors. RESULTS: The previously malnourished group showed substantial deficits on all outcomes relative to healthy controls (P < 0.0001). IQ scores in the intellectual disability range (< 70) were nine times more prevalent in the previously malnourished group (odds ratio = 9.18; 95% confidence interval = 3.50-24.13). Group differences in IQ of approximately one standard deviation were stable from adolescence through mid-life. DISCUSSION: Moderate-to-severe malnutrition during infancy is associated with a significantly elevated incidence of impaired IQ in adulthood, even when physical growth is completely rehabilitated. An episode of malnutrition during the first year of life carries risk for significant lifelong functional morbidity.

Malnutrition in the first year of life and personality at age 40.

BACKGROUND: Early childhood malnutrition is associated with cognitive and behavioral impairment during childhood and adolescence, but studies in adulthood are limited. METHODS: Using the NEO-PI-R personality inventory, we compared personality profiles at 37-43 years of age (M 40.3 years, SD 1.9) of Barbadian adults who had experienced moderate-to-severe protein-energy malnutrition (PEM) in the first year of life (n = 77) with healthy controls, who were former classmates of the index cases and were matched for age, gender, and handedness in childhood (n = 57). The previously malnourished participants had been rehabilitated, with good health and nutrition documented up to 12 years of age, and study participants were followed longitudinally from childhood to 40 years. Group comparisons were adjusted for childhood and adolescent standard of living, with and without correcting for IQ. RESULTS: At the broad domain or factor level, previously malnourished participants had higher scores on Neuroticism and lower scores on Extraversion, Openness, Agreeableness, and Conscientiousness than did the healthy controls. At the subdomain or facet level, previously malnourished participants reported more anxiety, vulnerability, shyness and lowered sociability, less intellectual curiosity, greater suspiciousness of others, a more egocentric than altruistic orientation, and a lowered sense of efficacy or competence. CONCLUSIONS: Malnutrition limited to the first year of life with good health and nutrition documented up to 12 years of age is associated with a significant overrepresentation of adult personality trait scores outside of the average range. This outcome has important implications for a variety of important life and mental health outcomes.

Acute cognitive and behavioral effects of systemic corticosteroids in children treated for inflammatory bowel disease.

Systemic corticosteroids are a mainstay of treatment for many pediatric medical conditions. Although their impact on the central nervous system has been well-studied in animal models and adults, less is known about such effects in pediatric populations. The current study investigated acute effects of corticosteroids on memory, executive functions, emotion, and behavior in children and adolescents with inflammatory bowel disease (IBD). Patients 8-17 years with IBD (Crohn's disease, CD; ulcerative colitis, UC) on high-dose prednisone (n = 33) and IBD patients in remission off steroids (n = 33) completed standardized neuropsychological tests and behavior rating scales. In the IBD sample as a whole, few steroid effects were found for laboratory cognitive measures, but steroid-treated patients were rated as exhibiting more problems with emotional, and to a lesser extent with cognitive function in daily life. Steroid effects, assessed by laboratory measures and questionnaires, were more prevalent in CD than UC patients; UC patients on steroids sometimes performed better than controls. Sleep disruption also predicted some outcomes, diminishing somewhat the magnitude of the steroid effects. Corticosteroid therapy can have acute effects on cognition, emotion, and behavior in chronically ill children; the clinical and long-term significance of these effects require further investigation.

Functional and structural differences in the hippocampus associated with memory deficits in adult survivors of acute lymphoblastic leukemia.

BACKGROUND: Radiation and chemotherapy targeted to the central nervous system (CNS) can cause cognitive impairment, including impaired memory. These memory impairments may be referable to damage to hippocampal structures resulting from CNS treatment. PROCEDURE: In the present study, we explored episodic memory and its neuroimaging correlates in 10 adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy and both systemic and intrathecal chemotherapy and 10 controls matched for age and sex, using a subsequent memory paradigm after episodic encoding of visual scenes. RESULTS: We report behavioral, structural, and functional changes in the brains of the adult survivors. They demonstrated poorer recognition memory, hippocampal atrophy, and altered blood oxygenation level-dependent (BOLD) signal in the hippocampus. Whole brain statistical map analysis revealed increased BOLD signal/activation in several brain regions during unsuccessful encoding in ALL survivors, potentially reflecting ineffective neural recruitment. Individual differences in memory performance in ALL participants were related to magnitude of BOLD response in regions associated with successful encoding. CONCLUSIONS: Taken together, these findings describe long term neuroimaging correlates of cognitive dysfunction after childhood exposure to CNS-targeted cancer therapies, suggesting enduring damage to episodic memory systems.

Neuropsychological outcomes of a randomized trial of prednisone versus dexamethasone in acute lymphoblastic leukemia: findings from Dana-Farber Cancer Institute All Consortium Protocol 00-01.

BACKGROUND: Dexamethasone is more efficacious than prednisone in the treatment of acute lymphoblastic leukemia (ALL), but has also been associated with greater toxicity. We compared neuropsychological outcomes for patients treated on DFCI ALL Consortium Protocol 00-01, which included a randomized comparison of the two steroid preparations during post-induction therapy in children and adolescents with ALL. PROCEDURE: Between 2000 and 2005, 408 children with standard-risk or high-risk ALL treated on Dana-Farber Cancer Institute Consortium Protocol 00-01 were randomly assigned to prednisone or dexamethasone administered as 5-day pulses every 3 weeks for 2 years, beginning at week 7 of treatment. Blinded neuropsychological testing was completed for 170 randomized patients (prednisone, N = 76; dexamethasone, N = 94), all of whom were in continuous complete remission after completion of therapy. RESULTS: Outcomes were comparable for most variables, although patients on the dexamethasone arm performed more poorly on a measure of fluid reasoning (P = 0.02). They also tended to be more likely to be enrolled in special education (dexamethasone, 33% vs. prednisone, 20%, P = 0.09). CONCLUSIONS: Dexamethasone has well documented benefit in treatment of ALL. Although formal testing provided little indication of increased risk for neurotoxicity relative to prednisone, the somewhat greater utilization of special education services by patients treated with dexamethasone merits further investigation.

Infant malnutrition is associated with persisting attention deficits in middle adulthood.

Infantile malnutrition is known to be associated with cognitive and behavioral impairment during childhood and adolescence. Data pertaining to longer-term effects on behavioral outcomes in adulthood are limited. In this study, we report associations between infantile malnutrition and attention problems in adults at midlife. Attention problems were assessed by the Conners Adult ADHD Rating Scales (CAARS) and the Conners Continuous Performance Test (CPT) in 145 Barbadian adults (aged 37-43 y) who had been followed longitudinally since childhood. Previously malnourished participants (n = 80) had experienced moderate to severe protein-energy malnutrition in the first year of life and were successfully rehabilitated thereafter. They were compared with healthy adults (n = 65) who were former classmates of the index cases and who had been matched for age, sex, and handedness in childhood. Multiple regression analyses showed persisting effects of childhood malnutrition on both the CAARS and the CPT, independent of effects of household standard of living assessed in childhood. The malnutrition effect on the CAARS ratings was independent of IQ, whereas this effect was attenuated for the CPT after adjustment for IQ. Teacher-reported attention problems in childhood predicted attention problems in adulthood, indicating continuity over the life span. Infantile malnutrition may have long-term effects on attentional processes nearly 40 y after the episode, even with excellent long-term nutritional rehabilitation and independent of socioeconomic conditions in childhood and adolescence. This finding has major public health implications for populations exposed to early childhood malnutrition.

Four-year longitudinal performance of a population-based sample of healthy children on a neuropsychological battery: the NIH MRI study of normal brain development.

The National Institutes of Health (NIH) Magnetic Resonance Imaging (MRI) Study of Normal Brain Development is a landmark study in which structural and metabolic brain development and behavior are followed longitudinally from birth to young adulthood in a population-based sample of healthy children. Cross-sectional findings from the neuropsychological test battery have been previously described (Waber et al., 2007). The present report details 4-year longitudinal neuropsychological outcomes for those children who were aged 6 to 18 years at baseline (N = 383), of whom 219 (57.2%) completed all 3 visits. Primary observations were (1) individual children displayed considerable variation in scores across visits on the same measures; (2) income-related differences were more prominent in the longitudinal than in the cross-sectional data; (3) no association between cognitive and behavioral measures and body mass index; and (4) several measures showed practice effects, despite the 2-year interval between visits. These data offer an unparalleled opportunity to observe normative performance and change over time on a set of standard and commonly used neuropsychological measures in a population-based sample of healthy children. They thus provide important background for the use and interpretation of these instruments in both research settings and clinical practice.

Neuropsychological outcomes of standard risk and high risk patients treated for acute lymphoblastic leukemia on Dana-Farber ALL consortium protocol 95-01 at 5 years post-diagnosis.

BACKGROUND: Children treated for acute lymphoblastic leukemia (ALL) as High Risk (HR) patients may be more vulnerable to neurocognitive late effects because of the greater intensity of their therapy. We compared neuropsychological outcomes in children treated for Standard Risk (SR) or HR ALL on Dana-Farber Cancer Institute (DFCI) Consortium ALL Protocol 95-01. We also evaluated their performance relative to normative expectations. PROCEDURE: Between 1996 and 2000, 498 children with newly diagnosed ALL were treated on Protocol 95-01, 298 of whom were eligible for neuropsychological follow-up. A feature of this protocol was modification of risk group criteria to treat more children as SR rather than HR patients, intended to minimize toxicities. Testing was completed at a median of 5.3 years post-diagnosis for 211 patients (70.8%; ages 6-25 years; 45.5% male; 40% HR), all of whom were in continuous complete remission. RESULTS: Test scores for both groups were generally at or above normative expectation, with the exception of verbal working memory, processing complex visual information, and parent ratings of metacognitive skills. After adjusting for covariates, the SR group performed better on measures of IQ and academic achievement, working memory and visual learning. Effect sizes, however, were only in the small to moderate range. CONCLUSIONS: HR patients exhibited neuropsychological deficits relative to SR patients, though the differences were modest in degree. Modification of the risk group criteria to treat more children on the SR protocol therefore likely afforded some benefit in terms of neurocognitive late effects.

Infant malnutrition predicts conduct problems in adolescents.

OBJECTIVES: The purpose of this study was to compare the prevalence of conduct problems in a well-documented sample of Barbadian adolescents malnourished as infants and a demographic comparison group and to determine the extent to which cognitive impairment and environmental factors account for this association. METHODS: Behavioral symptoms were assessed using a 76-item self-report scale in 56 Barbadian youth (11-17 years of age) with histories of protein-energy malnutrition (PEM) limited to the first year of life and 60 healthy classmates. Group comparisons were carried out by longitudinal and cross-sectional multiple regression analyses at 3 time points in childhood and adolescence. RESULTS: Self-reported conduct problems were more prevalent among previously malnourished youth (P < 0.01). Childhood IQ and home environmental circumstances partially mediated the association with malnutrition. Teacher-reported classroom behaviors at earlier ages were significantly correlated with youth conduct problems, confirming the continuity of conduct problems through childhood and adolescence. DISCUSSION: Self-reported conduct problems are elevated in children and adolescents with histories of early childhood malnutrition. Later vulnerability to increased conduct problems appears to be mediated by the more proximal neurobehavioral effects of the malnutrition on cognitive function and by adverse conditions in the early home environment.

Functional abdominal pain symptom severity: Associations between cognition and emotion in a pediatric sample.

Functional abdominal pain (FAP) is a common physical complaint in children and adolescents. Prior research has documented associations between FAP symptoms and mood, especially internalizing behaviors. Limited research is available examining the association between symptom burden and cognitive function in this pediatric population. This study explored associations between FAP symptoms, internalizing behaviors, and cognitive and school function in children and adolescents. Twenty-seven participants (mean age = 12.6 years, range 8.8-16.5; 33% male) diagnosed with FAP completed assessments of cognitive, emotional, and behavioral function, as well as FAP symptom severity. Mean performances on cognitive tests were within age-expected ranges. Within this context, however, higher overall burden of FAP symptoms was associated with slower processing speed, more self-reported metacognitive problems and internalizing behaviors, and more school absences. Cognitive function was systematically associated with internalizing behaviors but not physical symptoms. Overall, findings revealed that FAP may be associated with cognitive inefficiencies in addition to internalizing problems. Cognitive symptoms may be linked to internalizing behaviors associated with FAP.

Special Education Services and School-Related Quality of Life in Children With Learning Disorders and Their Families: A One-Year Follow-Up Study.

Learning disorders can have adverse impacts on children and families extending beyond the academic skills deficits. The goal of the present study was to assess the impact of the school's response, following an independent evaluation, for child and family school-related quality of life (QOL). We hypothesized that a positive school response would be associated with improved QOL. Parents completed the LDQOL/15, a brief measure of school-related QOL, at the time that their child received an independent evaluation and again a year later (N = 155). At follow-up, parents reported the tenor of the school's response to the evaluation and whether special education services had changed. QOL problems were very high in this referred population, with 66% of respondents rating a level of problems in the clinical range at baseline. Predicted interactions between time of assessment (baseline/follow-up) and the school's response to the evaluation were confirmed for all outcome variables; a positive school response was associated with improved QOL. Nevertheless, the overall prevalence of school-related QOL problems remained high a year after the evaluation. These findings indicate that special education interventions can mitigate learning disabilities' impacts, but even with these services, many children with learning disorders and their families continue to be significantly affected.

Effects of Maternal and Child Lifetime Traumatic Stress Exposures, Infant Temperament, and Caregiving Quality on Preschoolers' Executive Functioning.

We examined effects of maternal and child lifetime traumatic stress exposures, infant temperament, and caregiving quality on parent ratings of preschoolers' executive functioning (EF). Maternal lifetime trauma was associated with preschoolers' EF problems; this association was mediated by greater child trauma exposure. Infant temperament was associated with EF abilities, particularly among females. Among males, infant extraversion/surgency mediated the association of maternal lifetime trauma with poorer child EF. Caregiving quality was negatively associated with maternal and child trauma exposures but did not predict child EF. Findings have implications for interventions to identify children at risk for poor EF and optimize outcomes.

Cortical thickness correlates of specific cognitive performance accounted for by the general factor of intelligence in healthy children aged 6 to 18.

Prevailing psychometric theories of intelligence posit that individual differences in cognitive performance are attributable to three main sources of variance: the general factor of intelligence (g), cognitive ability domains, and specific test requirements and idiosyncrasies. Cortical thickness has been previously associated with g. In the present study, we systematically analyzed associations between cortical thickness and cognitive performance with and without adjusting for the effects of g in a representative sample of children and adolescents (N=207, Mean age=11.8; SD=3.5; Range=6 to 18.3 years). Seven cognitive tests were included in a measurement model that identified three first-order factors (representing cognitive ability domains) and one second-order factor representing g. Residuals of the cognitive ability domain scores were computed to represent g-independent variance for the three domains and seven tests. Cognitive domain and individual test scores as well as residualized scores were regressed against cortical thickness, adjusting for age, gender and a proxy measure of brain volume. g and cognitive domain scores were positively correlated with cortical thickness in very similar areas across the brain. Adjusting for the effects of g eliminated associations of domain and test scores with cortical thickness. Within a psychometric framework, cortical thickness correlates of cognitive performance on complex tasks are well captured by g in this demographically representative sample.

Neurobehavioral side effects of corticosteroids during active treatment for acute lymphoblastic leukemia in children are age-dependent: report from Dana-Farber Cancer Institute ALL Consortium Protocol 00-01.

BACKGROUND: Although corticosteroids remain a mainstay of treatment for acute lymphoblastic leukemia (ALL), they can cause troublesome neurobehavioral changes during active treatment, especially in young children. We evaluated acute neurobehavioral side effects of corticosteroid therapy in preschool versus school-age children by obtaining structured reports weekly for 1 month. PROCEDURE: Parents of 62 children (2-17 years) treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 00-01 participated during the continuation phase of treatment. Patients received cyclical twice-daily 5-day courses of prednisone (PRED; 40 mg/m(2) /day) or dexamethasone (DEX; 6 mg/m(2) /day). Parents completed behavior rating scales about their child weekly during one steroid cycle [baseline (Day 0), active steroid (Day 7), post-steroid (Days 14 and 21)]. RESULTS: Behavioral side effects increased significantly (P < 0.001) during the steroid week for preschool children (<6 years) on measures of emotional control, mood, behavior regulation, and executive functions, returning to baseline during the two "off-steroid" weeks. In contrast, school-age children (≥ 6 years) did not demonstrate an increase in side effects during the steroid week. Steroid type (PRED vs. DEX) was not a significant predictor of neurobehavioral side effects. CONCLUSIONS: Preschool children are at greater risk for neurobehavioral side effects during active steroid treatment for ALL than school-age children and adolescents. DEX was not associated with more neurobehavioral side effects than PRED. Counseling of families about side-effects should be adapted according to age. The observed effects, moreover, were transient, reducing concerns about longer-term neurobehavioral toxicities.