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1.  The Learning Disabilities Network (LeaDNet): Using Neurofibromatosis Type 1 (NF1) as a Paradigm for Translational Research 
Learning disabilities and other cognitive disorders represent one of the most important unmet medical needs and a significant source of lifelong disability. To accelerate progress in this area, an international consortium of researchers and clinicians, the Learning Disabilities Network (LeaDNet), was established in 2006. Initially, LeaDNet focused on neurofibromatosis type 1 (NF1), a common single gene disorder with a frequency of 1:3,000. Although NF1 is best recognized as an inherited tumor predisposition syndrome, learning, cognitive, and neurobehavioral deficits account for significant morbidity in this condition and can have a profound impact on the quality of life of affected individuals. Recently, there have been groundbreaking advances in our understanding of the molecular, cellular, and neural systems underpinnings of NF1-associated learning deficits in animal models, which precipitated clinical trials using a molecularly targeted treatment for these deficits. However, much remains to be learned about the spectrum of cognitive, neurological, and psychiatric phenotypes associated with the NF1 clinical syndrome. In addition, there is a pressing need to accelerate the identification of specific clinical targets and treatments for thesephenotypes. The successeswith NF1 have allowed LeaDNet investigators to broaden their initial focus to other genetic disorders characterized by learning disabilities and cognitive deficits including other RASopathies (caused by changes in the Ras signaling pathway). The ultimate mission of LeaDNet is to leverage an international translational consortium of clinicians and neuroscientists to integrate bench-to-bedside knowledge across a broad range of cognitive genetic disorders, with the goal of accelerating the development of rational and biologically based treatments.
PMCID: PMC4074877  PMID: 22821737
neurofibromatosis type 1; learning disabilities; RAS/MAPK pathway; neurodevelopmental disorders; Learning Disabilities Network
2.  Summary of evidence-based guideline update: Evaluation and management of concussion in sports 
Neurology  2013;80(24):2250-2257.
To update the 1997 American Academy of Neurology (AAN) practice parameter regarding sports concussion, focusing on 4 questions: 1) What factors increase/decrease concussion risk? 2) What diagnostic tools identify those with concussion and those at increased risk for severe/prolonged early impairments, neurologic catastrophe, or chronic neurobehavioral impairment? 3) What clinical factors identify those at increased risk for severe/prolonged early postconcussion impairments, neurologic catastrophe, recurrent concussions, or chronic neurobehavioral impairment? 4) What interventions enhance recovery, reduce recurrent concussion risk, or diminish long-term sequelae? The complete guideline on which this summary is based is available as an online data supplement to this article.
We systematically reviewed the literature from 1955 to June 2012 for pertinent evidence. We assessed evidence for quality and synthesized into conclusions using a modified Grading of Recommendations Assessment, Development and Evaluation process. We used a modified Delphi process to develop recommendations.
Specific risk factors can increase or decrease concussion risk. Diagnostic tools to help identify individuals with concussion include graded symptom checklists, the Standardized Assessment of Concussion, neuropsychological assessments, and the Balance Error Scoring System. Ongoing clinical symptoms, concussion history, and younger age identify those at risk for postconcussion impairments. Risk factors for recurrent concussion include history of multiple concussions, particularly within 10 days after initial concussion. Risk factors for chronic neurobehavioral impairment include concussion exposure and APOE ε4 genotype. Data are insufficient to show that any intervention enhances recovery or diminishes long-term sequelae postconcussion. Practice recommendations are presented for preparticipation counseling, management of suspected concussion, and management of diagnosed concussion.
PMCID: PMC3721093  PMID: 23508730
3.  Computerized Assessment of Cognitive Late Effects among Adolescent Brain Tumor Survivors 
Journal of neuro-oncology  2013;113(2):333-340.
Advantages of computerized assessment of neuropsychological functions include improved standardization and increased reliability of response time variables. ImPACT (Immediate Post-Concussion Assessment and Cognitive Testing) is a computerized battery developed for monitoring recovery following mild brain injuries that assesses attention, memory and processing speed. Despite evidence that core areas of deficit among cancer survivors are those assessed by ImPACT, it has not previously been used with this population.
Twenty four childhood brain tumor (BT) survivors treated with conformal radiation therapy (mean age= 15.7±1.6; mean age at irradiation= 9.8±2.5), twenty solid tumor (ST) survivors treated without CNS-directed therapy (mean age= 16.2±1.8) and twenty healthy siblings (mean age= 15.1± 1.6 years) were administered an age modified version of ImPACT. Additional computerized measures of working memory and recognition memory were administered.
Univariate ANOVAs revealed group differences (p< .05) on measures of recognition memory, spatial working memory, processing speed and reaction time, with BT survivors performing significantly worse than ST survivors and siblings. Pearson correlation coefficients revealed significant associations between ImPACT memory tasks and computerized forced choice recognition tasks (rs= .30-.33, p< .05). Multiple surgical resections, hydrocephalus and CSF shunt placement most consistently predicted worse ImPACT performance using linear mixed models (p< .05).
The ImPACT test battery demonstrated sensitivity to cognitive late effects experienced by some BT survivors with clinical predictors of performance consistent with the pediatric oncology literature. Correlations with measures of similar constructs provide evidence for convergent validity. Findings offer initial support for the utility of ImPACT for monitoring of cognitive late effects.
PMCID: PMC3679205  PMID: 23525951
pediatric; cancer; ImPACT
4.  Response Time Variability is Related to Parent Ratings of Inattention, Hyperactivity and Executive Function 
Journal of attention disorders  2010;15(7):10.1177/1087054709356379.
Individuals with Attention-Deficit/Hyperactivity Disorder (ADHD) are often characterized as inconsistent across many contexts. ADHD is also associated with deficits in executive function. We examined the relationships between response time variability on five brief computer tasks to parents’ ratings of ADHD-related features and executive function in a group of children with a broad range of ADHD symptoms from none to full diagnosis.
We tested 98 children (mean age 9.9±1.4 yrs; 66 boys) from community clinics on short Tasks of Executive Control (TEC) and the Eriksen Flanker Task, while a parent completed the Conners Parent Rating Scale and Behavior Rating Inventory of Executive Function.
Variability for two of the TEC tasks explained significant proportions of the variance of all five ADHD-related Conners subscales and several executive function subscales. By contrast, variability on the flanker task or mean response times for any task were not associated with any rating scale.
The significant dimensional relationships observed between variability measures and parent ratings support the utility of response time variability as an objective measure in ADHD and aspects of executive functioning that is superior to response time means or accuracy measures.
PMCID: PMC3863378  PMID: 20686098
Attention-Deficit/Hyperactivity Disorder; Intra-subject Variability; Rating Scales; Executive Function
5.  Low frequency oscillations of response time explain parent ratings of inattention and hyperactivity/impulsivity 
European child & adolescent psychiatry  2012;21(2):10.1007/s00787-011-0237-6.
Greater intra-subject variability (ISV) in response time is a heritable endophenotype of Attention-Deficit/Hyperactivity Disorder (ADHD). Spontaneous low frequency oscillations (LFO; 0.01–0.1 Hz) observed in brain functional magnetic resonance signals might account for such behavioral variability. Recently, we demonstrated that ISV in response time (RT) explained ratings of ADHD symptoms. Building on this finding, here we hypothesized that LFO in RT time-series would explain these ratings, both independently and in addition to RT coefficient of variation (CV). To measure RT-LFO, we applied Morlet wavelet transform to the previously collected RT data. Our community sample consisted of 98 children (including 66 boys, mean age 9.9±1.4 years), who completed four computer Tasks of Executive Control. Conners’ Parent Rating Scale ratings were obtained. RT-LFO of three tasks significantly explained ratings of inattention, hyperactivity and three global Conners subscales. Additionally, RT-LFO during two tasks that included an inhibitory component increased the proportions of variance explained in subscales of both inattention and hyperactivity/impulsivity, beyond the effects of RT-CV. Three specific low frequency bands (Slow 5: 0.01-0.027 Hz; Slow 4: 0.027-0.073 Hz; Slow 3: 0.073-0.20 Hz) were strongly related to the ADHD scales. We conclude that RT-LFO predict dimensional ratings of ADHD symptoms both independently and in addition to RTCV. Results suggest that frequency analyses are a suitable methodology to link behavioral responses to putative underlying physiological processes.
PMCID: PMC3821733  PMID: 22287035
Attention-Deficit/Hyperactivity Disorder; Intra-subject Variability; Frequency Analyses; Rating Scales
6.  Assessment of Executive Function in Preschool-Aged Children 
Assessment of the overarching self-regulatory mechanisms, or executive functions, in any age group is challenging, in part due to the complexity of this domain, in part due to their dynamic essence, and in part due to the inextricable links between these central processes and the associated domain-specific processes, such as language, motor function, and attention, over which they preside. While much progress has been made in clinical assessment approaches for measuring executive functions in adults and to some extent in adolescents and school-aged children, the toolkit for the preschool evaluator remains sparse. The past decade, however, has seen a substantial increase in attention to executive functions in very young children from a developmental neuropsychological perspective. With this has come a necessity for better, more specific, and more internally valid performance measures, many of which are now described in the experimental literature. Few such tasks, however, have adequately demonstrated psychometric properties for clinical application. We present two performance tasks designed to tap selective aspects of executive function in preschoolers that are emerging from the experimental laboratory and hold promise of appropriate reliability and validity for the clinical laboratory. Performance tests alone, however, are insufficient to develop a comprehensive picture of a child’s executive functioning. Thus, we present a rating scale of preschoolers’ executive function in the everyday context, and advocate a model of executive function assessment that incorporates both controlled performance tasks that target specific aspects of executive function and parent/teacher ratings that target more global aspects of self- regulation in the everyday context.
PMCID: PMC3648805  PMID: 16161093
Executive function; preschool; developmental neuropsychology
7.  Recommendations for the Use of Common Outcome Measures in Pediatric Traumatic Brain Injury Research 
Journal of Neurotrauma  2012;29(4):678-705.
This article addresses the need for age-relevant outcome measures for traumatic brain injury (TBI) research and summarizes the recommendations by the inter-agency Pediatric TBI Outcomes Workgroup. The Pediatric Workgroup's recommendations address primary clinical research objectives including characterizing course of recovery from TBI, prediction of later outcome, measurement of treatment effects, and comparison of outcomes across studies. Consistent with other Common Data Elements (CDE) Workgroups, the Pediatric TBI Outcomes Workgroup adopted the standard three-tier system in its selection of measures. In the first tier, core measures included valid, robust, and widely applicable outcome measures with proven utility in pediatric TBI from each identified domain including academics, adaptive and daily living skills, family and environment, global outcome, health-related quality of life, infant and toddler measures, language and communication, neuropsychological impairment, physical functioning, psychiatric and psychological functioning, recovery of consciousness, social role participation and social competence, social cognition, and TBI-related symptoms. In the second tier, supplemental measures were recommended for consideration in TBI research focusing on specific topics or populations. In the third tier, emerging measures included important instruments currently under development, in the process of validation, or nearing the point of published findings that have significant potential to be superior to measures in the core and supplemental lists and may eventually replace them as evidence for their utility emerges.
PMCID: PMC3289848  PMID: 21644810
children; infants; outcome assessment; TBI
8.  School and the Concussed Youth – Recommendations for Concussion Education and Management 
School learning and performance is arguably the critical centerpiece of child and adolescent development, and there can be significant temporary upset in cognitive processing after a mild traumatic brain injury, also called a concussion. This injury results in a cascade of neurochemical abnormalities, and in the wake of this dysfunction, both physical activity and cognitive activity become sources of additional neurometabolic demand on the brain and may cause symptoms to re-emerge or worsen. This paper provides a foundation for post-injury management of cognitive activity, particularly in the school setting, including design and implementation of school-wide concussion education and management programs. Definitions of cognitive over-exertion and cognitive rest are provided, with guidelines for managing cognitive load in individuals based on their symptom profile and neurocognitive performance. On a broader scale, guidance for the development of comprehensive concussion education and management programs in schools is provided. Proactive management could facilitate recovery by ensuring less cognitive exertion and stress during the recovery period.
PMCID: PMC3208828  PMID: 22050944
concussion; mild traumatic brain injury; student-athlete; student; school; accommodations; management
9.  Neurocognitive Functioning in Adult Survivors of Childhood Non-Central Nervous System Cancers 
We sought to measure self-reported neurocognitive functioning among survivors of non-central nervous system (CNS) childhood cancers, overall and compared with a sibling cohort, and to identify factors associated with worse functioning.
In a retrospective cohort study, 5937 adult survivors of non-CNS cancers and 382 siblings completed a validated neuropsychological instrument with subscales in task efficiency, emotional regulation, organization, and memory. Scores were converted to T scores; scores in the worst 10% of siblings’ scores (ie, T score ≥63) were defined as impaired. Non-CNS cancer survivors and siblings were compared with multivariable linear regression and log-binomial regression. Among survivors, log-binomial models assessed the association of patient and treatment factors with neurocognitive dysfunction. All statistical tests were two-sided.
Non-CNS cancer survivors had similar or slightly worse (<0.5 standard deviation) mean test scores for all four subscales than siblings. However, frequencies of impaired survivors were approximately 50% higher than siblings in task efficiency (13.0% of survivors vs 7.3% of siblings), memory (12.5% vs 7.6%), and emotional regulation (21.2% vs 14.4%). Impaired task efficiency was most often identified in patients with acute lymphoblastic leukemia who received cranial radiation therapy (18.1% with impairment), myeloid leukemia who received cranial radiation therapy (21.2%), and non-Hodgkin lymphoma (13.9%). In adjusted analysis, diagnosis age of younger than 6 years, female sex, cranial radiation therapy, and hearing impairment were associated with impairment.
A statistically and clinically significantly higher percentage of self-reported neurocognitive impairment was found among survivors of non-CNS cancers than among siblings.
PMCID: PMC2886093  PMID: 20458059
10.  Neurocognitive Status in Long-Term Survivors of Childhood CNS Malignancies: A Report from the Childhood Cancer Survivor Study 
Neuropsychology  2009;23(6):705-717.
Among survivors of childhood cancer, those with Central Nervous System (CNS) malignancies have been found to be at greatest risk for neuropsychological dysfunction in the first few years following diagnosis and treatment. This study follows survivors to adulthood to assess the long term impact of childhood CNS malignancy and its treatment on neurocognitive functioning.
Participants & Methods
As part of the Childhood Cancer Survivor Study (CCSS), 802 survivors of childhood CNS malignancy, 5937 survivors of non-CNS malignancy and 382 siblings without cancer completed a 25 item Neurocognitive Questionnaire (CCSS-NCQ) at least 16 years post cancer diagnosis assessing task efficiency, emotional regulation, organizational skills and memory. Neurocognitive functioning in survivors of CNS malignancy was compared to that of non-CNS malignancy survivors and a sibling cohort. Within the group of CNS malignancy survivors, multiple linear regression was used to assess the contribution of demographic, illness and treatment variables to reported neurocognitive functioning and the relationship of reported neurocognitive functioning to educational, employment and income status.
Survivors of CNS malignancy reported significantly greater neurocognitive impairment on all factors assessed by the CCSS-NCQ than non-CNS cancer survivors or siblings (p<.01), with mean T scores of CNS malignancy survivors substantially more impaired that those of the sibling cohort (p<.001), with a large effect size for Task Efficiency (1.16) and a medium effect size for Memory (.68). Within the CNS malignancy group, medical complications, including hearing deficits, paralysis and cerebrovascular incidents resulted in a greater likelihood of reported deficits on all of the CCSS-NCQ factors, with generally small effect sizes (.22-.50). Total brain irradiation predicted greater impairment on Task Efficiency and Memory (Effect sizes: .65 and .63, respectively), as did partial brain irradiation, with smaller effect sizes (.49 and .43, respectively). Ventriculoperitoneal (VP) shunt placement was associated with small deficits on the same scales (Effect sizes: Task Efficiency .26, Memory .32). Female gender predicted a greater likelihood of impaired scores on 2 scales, with small effect sizes (Task Efficiency .38, Emotional Regulation .45), while diagnosis before age 2 years resulted in less likelihood of reported impairment on the Memory factor with a moderate effect size (.64). CNS malignancy survivors with more impaired CCSS-NCQ scores demonstrated significantly lower educational attainment (p<.01), less household income (p<.001) and less full time employment (p<.001).
Survivors of childhood CNS malignancy are at significant risk for impairment in neurocognitive functioning in adulthood, particularly if they have received cranial radiation, had a VP shunt placed, suffered a cerebrovascular incident or are left with hearing or motor impairments. Reported neurocognitive impairment adversely affected important adult outcomes, including education, employment, income and marital status.
PMCID: PMC2796110  PMID: 19899829
Neurocognitive functioning; brain tumors; CNS malignancies; Childhood Cancer Survivor Study
11.  Reliability and Validity of the Childhood Cancer Survivor Study Neurocognitive Questionnaire 
Cancer  2008;113(8):2188-2197.
Up to 40% of childhood cancer survivors may experience neurocognitive impairment in one or more specific domains. As such, regular monitoring has been recommended for patients exposed to cranial irradiation and/or antimetabolite chemotherapy. This study reports the results of a questionnaire developed to identify those survivors who may be experiencing neurocognitive problems.
Participants for this study were 7,121 members of the Childhood Cancer Survivor Study cohort (6,739 survivors and 382 siblings). These participants completed a new neurocognitive questionnaire designed to assess functions commonly affected by cancer therapy, as well as a standard measure of emotional functioning. A measure of cognitive and emotional functioning was also completed on a subset of the patients roughly seven years prior to the current questionnaire. Responses to the questionnaires among subgroups of survivors were then analyzed to examine the reliability and validity of the new neurocognitive questionnaire.
Four reliable factors were identified that assessed task efficiency, emotional regulation, organization, and memory skills. These neurocognitive factors accurately discriminated between survivors who were at “high risk” for neurocognitive dysfunction, due to neurologic abnormalities or a history of intensive focal cranial irradiation, from healthy “low risk” survivors and siblings.
The questionnaire demonstrated excellent reliability, as well as construct and discriminative validity. It appears to be a practical and efficient tool for monitoring neurocognitive outcomes in adult survivors of pediatric cancer.
Condensed Abstract
Regular monitoring of neurocognitive functioning is recommended for pediatric cancer survivors exposed to cranial irradiation and/or antimetabolite chemotherapy. The Childhood Cancer Survivor Study - Neurocognitive Questionnaire appears to be a practical and efficient tool for such monitoring.
PMCID: PMC2574840  PMID: 18792068
Childhood Cancer Survivor Study; neurocognitive; questionnaire; late effects

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