Heather M. Conklin

Adolescents' Performance on the Iowa Gambling Task: Implications for the Development of Decision Making and Ventromedial Prefrontal Cortex.

Healthy adolescents (79 girls, 66 boys), ages 9-17, completed the Iowa Gambling Task (IGT; A. Bechara, A. R. Damasio, H. Damasio, & S. W. Anderson, 1994) as well as working memory (digit span) and behavioral inhibition (go/no-go) tasks. Cross-sectional age-related changes were seen on all 3 tasks. Gender differences were seen in IGT deck preference and attentional variables (i.e., go/no-go hit rate and forward digit span). After age, gender, and general intellectual abilities were controlled for, IGT performance was not predicted by working memory or behavioral inhibition scores. Findings suggest that the ventromedial prefrontal cortex or its connections are functionally maturing during adolescence in a manner that can be distinguished from maturation of other prefrontal regions. Development of these functions may continue into young adulthood.

Late Effects of Conformal Radiation Therapy for Pediatric Patients With Low-Grade Glioma: Prospective Evaluation of Cognitive, Endocrine, and Hearing Deficits

PURPOSE We conducted a prospective trial to evaluate late effects in pediatric patients with low-grade glioma (LGG) treated with conformal radiation therapy (CRT). PATIENTS AND METHODS Between August 1997 and August 2006, 78 pediatric patients with LGG (mean age, 9.7 years; standard deviation, +/-4.4 years) received 54 Gy of CRT with a 10-mm clinical target volume margin. Tumor locations were diencephalon (n = 58), cerebral hemisphere (n = 3), and cerebellum (n = 17). Baseline and serial evaluations were performed to identify deficits in cognition, endocrine function, and hearing. Deficits were correlated with clinical factors and radiation dose within specific normal tissue volumes. RESULTS Cognitive effects of CRT through 5 years after CRT correlated with patient age, neurofibromatosis type 1 status, tumor location and volume, extent of resection, and radiation dose. The effect of age exceeded that of radiation dose; patients younger than 5 years experienced the greatest decline in cognition. Before CRT, growth hormone (GH) secretion abnormality was diagnosed in 24% of tested patients, and 12% had precocious puberty. The 10-year cumulative incidence of GH replacement was 48.9%; of thyroid hormone replacement, 64.0%; of glucocorticoid replacement, 19.2%; and of gonadotropin-releasing hormone analog therapy, 34.2%. The mean +/- standard errors of the cumulative incidence of hearing loss at 10 years did not exceed 5.7% +/- 3.3% at any frequency. CONCLUSION To our knowledge, this is the largest series of prospectively followed children with LGG to undergo irradiation. Adverse effects are limited and predictable for most patients; however, this study provides additional evidence that CRT should be delayed for young patients and identifies the potential benefits of reducing radiation dose to normal brain.

Working Memory Performance in Typically Developing Children and Adolescents: Behavioral Evidence of Protracted Frontal Lobe Development

Post-mortem histological and in vivo neuroimaging findings both reveal frontal lobe development that extends beyond the adolescent years. Few studies have examined whether this protracted neurodevelopment coincides with improvements in adolescent performance on putative frontal lobe tasks. An instrumental function supported by the frontal lobes is working memory, the ability to maintain and manipulate information “online.” This study investigated the performance of typically developing children and adolescents on a battery of working memory tasks. Findings revealed an improvement in performance on most working memory tasks across the adolescent years. In contrast, no improvement was observed on tasks largely supported by more posterior neural substrates. Current findings indicate a similar unfolding of the executive aspects of verbal working memory as previously demonstrated with spatial working memory. Factor analysis revealed a grouping of working memory tasks based largely on task demands, irrespective of working memory domain, adding support for process-specific models of prefrontal organization. Important implications for typical and atypical frontal lobe development are discussed.

Survival and long-term health and cognitive outcomes after low-grade glioma

Long-term morbidity for children with low-grade glioma (LGG) requires exposure-specific characterization. Overall survival (OS) and progression-free survival (PFS) were estimated for 361 children diagnosed with LGG between 1985 and 2007 at a single institution. Five-year survivors (n = 240) received risk-based clinical assessment. Cumulative incidence of late effects 15 years from diagnosis were estimated. Risk factors for adverse health were identified using Fine and Grays approach to Coxs proportional hazards model, accounting for death as a competing risk. OS at 15 years was 86% (95% confidence interval [CI] 82%-90%), and PFS was 55% (95% CI 51%-58%). Among the 240 5-year survivors, the 5-, 10-, and 15-year cumulative incidence of adverse outcomes included blindness: 10%, 13%, and 18%, respectively; hearing loss: 8%, 14%, and 22%; obesity/overweight: 18%, 35%, and 53%; hyperinsulinism: 1%, 5%, and 24%; growth hormone deficiency: 13%, 27%, and 29%;thyroid hormone deficiency: 16%, 28%, and 33%; and adrenocorticotropic hormone (ACTH) deficiency: 12%, 22%, and 26%. Multivariable models demonstrated radiation therapy to be a significant independent predictor of hearing loss, growth hormone deficiency, abnormal thyroid function, and ACTH deficiency. Diencephalic location was a statistically significant independent risk factor for blindness, growth hormone deficiency, abnormal thyroid function, and ACTH deficiency. Among the 182 5-year survivors assessed for intellectual function, 34% had an intelligence quotient (IQ) below average (<85), associated with younger age at diagnosis, epilepsy, and shunt placement. Survivors of childhood LGG experience substantial long-term adverse effects that continue to increase well beyond the 5-year survival time point.

Predicting Change in Academic Abilities After Conformal Radiation Therapy for Localized Ependymoma

PURPOSE Conformal radiation therapy (CRT) aims to limit the highest radiation dose to the tissue volume at risk while sparing surrounding normal tissues. This study investigated whether treatment of childhood ependymoma with CRT would preserve cognitive function. Academic competence was chosen as the primary outcome measure given it is a measure of applied cognitive abilities in a childs natural setting. PATIENTS AND METHODS Eighty-seven pediatric patients diagnosed with ependymoma received CRT in which doses ranging from 54.0 to 59.4 Gy were prescribed to the postoperative tumor bed with a 10-mm clinical target volume margin. Cognitive testing was conducted at the start of CRT, 6 months, and annually after the start of CRT. The median length of follow-up was 59.6 months. Academic testing included subtests from the Wechsler Individual Achievement Test (WIAT) and the Achenbach Child Behavior Checklist. RESULTS Linear mixed models with random coefficients revealed a modest but significant decline in reading scores during follow-up (WIAT slope estimate -0.064 +/- 0.028 points/month; P = .026). Math and spelling performance remained stable. Supratentorial tumor location and multiple surgeries were predictive of worse reading performance at CRT baseline. Male sex, longer symptomatic interval, pre-CRT chemotherapy, pre-existing endocrine deficiencies, hydrocephalus, and younger age at CRT (< 5 years) were predictive of a significant decline in reading scores over time. CONCLUSION CRT may result in better long-term cognitive outcomes when compared to conventional radiation therapy approaches. Reading appears more vulnerable than other academic skills and may decline over time despite stable intellectual functioning.

Working memory performance following paediatric traumatic brain injury

Primary objective: The present study investigated working memory ability in children who sustained moderate-to-severe traumatic brain injuries in relation to pre-injury, injury-related and developmental factors. It was hypothesized that there would be a correlation between performance- and rater-based working memory measures; factors predictive of working memory impairment would include earlier age at injury, more severe injury, longer time since injury and poorer overall cognitive functioning; and working memory performance would be significantly impaired when compared to normative populations. Methods and procedures: Working memory was assessed in 62 children using a traditional performance measure (digit span backward) and parent report (Behaviour Rating Inventory of Executive Function (BRIEF)). Main outcomes and results: Contrary to prediction, there was no statistical association between performance- and rater-based measures of working memory. Regression analyses revealed injury severity, time-since-injury, overall cognitive ability and attention span were predictive of working memory performance. As a group, working memory was impaired relative to normative samples on both measures. Conclusions: Performance- and rater-based working memory measures, while not significantly correlated, are both sensitive to acquired cognitive dysfunction following paediatric traumatic brain injury. Demographic and clinical factors may be used to predict cognitive outcomes, educate caregivers and design clinical interventions.

Attention and Working Memory Abilities in Children Treated for Acute Lymphoblastic Leukemia

To extend investigation beyond global cognitive measures prevalent in the literature, this study examined attention and working memory (WM) abilities of survivors of childhood acute lymphoblastic leukemia (ALL), the separate contributions of attention and WM to intelligence quotient (IQ), and their association with neuroimaging changes.

Genetic Mediators of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia

PURPOSE Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for neurocognitive problems, with significant interindividual variability in outcome. This study examined genetic polymorphisms associated with variability in neurocognitive outcome. PATIENTS AND METHODS Neurocognitive outcomes were evaluated at the end of therapy in 243 survivors treated on an institutional protocol featuring risk-adapted chemotherapy without prophylactic cranial irradiation. Polymorphisms in genes related to pharmacokinetics or pharmacodynamics of antileukemic agents, drug metabolism, oxidative stress, and attention problems in noncancer populations were examined as predictors of outcome, using multiple general linear models and controlling for age at diagnosis, sex, race, and treatment intensity. RESULTS Compared with national norms, the cohort demonstrated significantly higher rates of problems on direct assessment of sustained attention (P = .01) and on parent ratings of attention problems (P = .02). Children with the A2756G polymorphism in methionine synthase (MS) were more likely to demonstrate deficits in attentiveness (P = .03) and response speed (P = .02), whereas those with various polymorphisms in glutathione S-transferase demonstrated increased performance variability (P = .01) and reduced attentiveness (P = .003). Polymorphisms in monoamine oxidase (T1460CA) were associated with increased attention variability (P = .03). Parent-reported attention problems were more common in children with the Cys112Arg polymorphism in apoliopoprotein E4 (P = .01). CONCLUSION These results are consistent with our previous report of association between attention problems and MS in an independent cohort of long-term survivors of childhood ALL treated with chemotherapy only. The results also raise the possibility of an impact from genetic predispositions related to oxidative stress and CNS integrity.

Recognition memory for faces in schizophrenia patients and their first-degree relatives.

It has consistently been shown that schizophrenia patients are impaired in recognition memory for faces. However, studies have not examined the specificity of this deficit relative to other cognitive functions nor the relationship between this deficit and particular schizophrenia symptoms. In addition, no studies have examined recognition memory for faces in unaffected biological relatives of schizophrenia patients who likely share some of the genetic diathesis for this disorder without presenting the potential confounds of mentally ill study samples. The Faces subtests from the Wechsler Memory Scale-Third Edition were used to evaluate recognition memory for faces in 39 schizophrenia patients, 33 of their first-degree relatives and 56 normal controls. Both schizophrenia patients and their relatives were impaired, relative to control participants, in recognition memory for faces after partialing out group differences in spatial attention or verbal memory. Further, recognition memory for faces was associated with positive symptoms in the schizophrenia group and schizotypal personality traits in the relative group. These findings may have important implications for reducing etiological heterogeneity among schizophrenia populations, identifying disorder susceptibility among their relatives and furthering understanding of disorder etiology.

Learning and Memory Following Conformal Radiation Therapy for Pediatric Craniopharyngioma and Low-Grade Glioma

PURPOSE The primary objective of this study was to examine whether children with low-grade glioma (LGG) or craniopharyngioma had impaired learning and memory after conformal radiation therapy (CRT). A secondary objective was to determine whether children who received chemotherapy before CRT, a treatment often used to delay radiation therapy in younger children with LGG, received any protective benefit with respect to learning. METHODS AND MATERIALS Learning and memory in 57 children with LGG and 44 children with craniopharyngioma were assessed with the California Verbal Learning Test-Childrens Version and the Visual-Auditory Learning tests. Learning measures were administered before CRT, 6 months later, and then yearly for a total of 5 years. RESULTS No decline in learning scores after CRT was observed when patients were grouped by diagnosis. For children with LGG, chemotherapy before CRT did not provide a protective effect on learning. Multiple regression analyses, which accounted for age and tumor volume and location, found that children treated with chemotherapy before CRT were at greater risk of decline on learning measures than those treated with CRT alone. Variables predictive of learning and memory decline included hydrocephalus, shunt insertion, younger age at time of treatment, female gender, and pre-CRT chemotherapy. CONCLUSIONS This study did not reveal any impairment or decline in learning after CRT in overall aggregate learning scores. However, several important variables were found to have a significant effect on neurocognitive outcome. Specifically, chemotherapy before CRT was predictive of worse outcome on verbal learning in LGG patients. In addition, hydrocephalus and shunt insertion in craniopharyngioma were found to be predictive of worse neurocognitive outcome, suggesting a more aggressive natural history for those patients.