Comparison of neuropsychological functioning in pediatric posterior fossa tumor survivors: Medulloblastoma, low-grade astrocytoma, and healthy controls.

BACKGROUND: Neuropsychological comparison of medulloblastoma (MB) and cerebellar low-grade astrocytoma (LGA) survivors to controls can clarify treatment-related neurocognitive late effects. While both brain tumor groups undergo surgery to the posterior fossa, children with MB additionally receive craniospinal irradiation with boost and chemotherapy. This study provides an updated comparison of neuropsychological functioning in these two groups and examines effects of demographic risk factors upon outcomes. PROCEDURE: Forty-two children (16 MB, nine LGA, and 17 controls) completed measures of intellectual functioning, verbal learning/memory, visual-motor integration, and fine-motor functioning. The effects of age at diagnosis, time since diagnosis, gender, fatigue, and social status on neuropsychological functioning were examined. RESULTS: MB survivors demonstrated the worst neurocognitive late effects, but they were less severe and extensive than in prior studies. LGA survivors' mean scores were below normative expectations in working memory, processing speed, and fine-motor functioning. In this overall sample, processing speed difficulties were independent of fine-motor functioning and fatigue. Higher parental education was associated with better intellectual functioning, working memory, delayed recall, and visual-motor integration. Neuropsychological function was not associated with gender, age at diagnosis, or time since diagnosis. CONCLUSION: The results support that contemporary treatment approaches with craniospinal irradiation plus boost and chemotherapy confer the greatest risk for late effects, while surgical resection is associated with subtle but important neurocognitive difficulties. Ultimately, this study furthers our understanding of factors impacting neuropsychological function in pediatric MB and LGA survivors and contributes to empirical support for close monitoring and targeted interventions into survivorship.

Unique white matter microstructural patterns in ADHD presentations-a diffusion tensor imaging study.

Attention-deficit/hyperactivity disorder predominantly inattentive (ADHD-PI) and combined (ADHD-C) presentations are likely distinct disorders that differ neuroanatomically, neurochemically, and neuropsychologically. However, to date, little is known about specific white matter (WM) regions differentiating ADHD presentations. This study examined differences in WM microstructure using diffusion tensor imaging (DTI) data from 20 ADHD-PI, 18 ADHD-C, and 27 typically developed children. Voxel-wise analysis of DTI measurements in major fiber bundles was carried out using tract-based spatial statistics (TBSS). Clusters showing diffusivity abnormalities were used as regions of interest for regression analysis between fractional anisotropy (FA) and neuropsychological outcomes. Compared to neurotypicals, ADHD-PI children showed higher FA in the anterior thalamic radiations (ATR), bilateral inferior longitudinal fasciculus (ILF), and in the left corticospinal tract (CST). In contrast, the ADHD-C group exhibited higher FA in the bilateral cingulum bundle (CB). In the ADHD-PI group, differences in FA in the left ILF and ATR were accompanied by axial diffusivity (AD) abnormalities. In addition, the ADHD-PI group exhibited atypical mean diffusivity in the forceps minor (FMi) and left ATR and AD differences in right CB compared to healthy subjects. Direct comparison between ADHD presentations demonstrated radial diffusivity differences in FMi. WM clusters with FA irregularities in ADHD were associated with neurobehavioral performance across groups. In conclusion, differences in WM microstructure in ADHD presentations strengthen the theory that ADHD-PI and ADHD-C are two distinct disorders. Regions with WM irregularity seen in both ADHD presentations might serve as predictors of executive and behavioral functioning across groups. Hum Brain Mapp 37:3323-3336, 2016. © 2016 Wiley Periodicals, Inc.

Executive and social functioning in pediatric posterior fossa tumor survivors and healthy controls.

Background: Executive and social functioning difficulty is well established in pediatric brain tumor survivors. Few studies have compared posterior fossa (PF) tumor survivors in comparison to their peers. The relationship between attention, processing speed, working memory, fatigue, and executive and social functioning was investigated to better understand the factors that impact executive and social functioning in PF tumor populations. Methods: Sixteen medulloblastomas, 9 low-grade astrocytomas (LGAs), and 17 healthy controls recruited from 4 sites completed measures of working memory and processing speed, and self-reported fatigue. One parent completed questionnaires on executive and social functioning. Results: There were no significant differences among all 3 groups on parent-reported executive and social functioning; of note, parents of LGA survivors expressed greater concerns regarding behavioral and cognitive regulation than did parents of medulloblastoma survivors and healthy controls. Parent-reported attention was related to parent-reported emotion, behavior, and cognitive regulation. Worse self-reported fatigue was associated with greater emotional dysregulation for the 2 PF tumor groups. Conclusions: Parents of PF tumor survivors described their children as performing similarly to their peers in most facets of executive and social functioning. While LGA survivors are traditionally thought to have more favorable outcomes, our finding of parent-reported executive functioning concerns to be worse for this group highlights the importance of long-term follow-up for all PF tumor survivors. Additionally, significant effects of attention on aspects of executive functioning in PF tumor survivors may inform current clinical practice and the future development of more effective interventions.

Gender differences in brain activation on a mental rotation task.

Few neuroimaging studies have explored gender differences on mental rotation tasks. Most studies have utilized samples with both genders, samples mainly consisting of men, or samples with six or fewer females. Graduate students in science fields or liberal arts programs (20 males, 20 females) completed a mental rotation task during functional magnetic resonance imaging (fMRI). When a pair of cube figures was shown, the participant made a keypad response based on whether the pair is the same/similar or different. Regardless of gender, the bilateral middle frontal gyrus, bilateral intraparietal sulcus (IPS), and the left precuneus were activated when a subject tried to solve the mental rotation task. Increased activation in the right inferior frontal gyrus/middle frontal gyrus, the left precuneus/posterior cingulate cortex/cuneus region, and the left middle occipital gyrus was found for men as compared to women. Better accuracy and shorter response times were correlated with an increased activation in the bilateral intraparietal sulcus. No significant brain activity differences related to mental rotation were found between academic majors. These findings suggest that networks involved in visual attention appear to be more strongly activated in the mental rotation tasks in men as compared to women. It also suggests that men use a more automatic process when analyzing complex visual reasoning tasks while women use a more top-down process.

Updates on attention-deficit/hyperactivity disorder and learning disorders.

The relationship of attention-deficit/hyperactivity disorder (ADHD) to learning disorders was reviewed and included reading disability, mathematics learning disability, and nonverbal learning disability. Genetic, neuroimaging, and neuropsychological functioning were examined for each disorder, along with a discussion of any existing literature when ADHD co-occurred with the disorder. All the disorders were found to frequently co-occur with ADHD. A review of the underlying neuroanatomic and neurofunctional data found specific structures that frequently co-occur in these disorders with others that are specific to the individual diagnosis. Aberrations in structure and/or function were found for the caudate, corpus callosum, and cerebellum, making these structures sensitive for the disorder but not specific. Suggestions for future research, particularly in relation to intervention, are provided.

Diagnostic Classification of ADHD Versus Control: Support Vector Machine Classification Using Brief Neuropsychological Assessment.

Objective: Common methods for clinical diagnosis include clinical interview, behavioral questionnaires, and neuropsychological assessment. These methods rely on clinical interpretation and have variable reliability, sensitivity, and specificity. The goal of this study was to evaluate the utility of machine learning in the prediction and classification of children with ADHD-Combined presentation (ADHD-C) using brief neuropsychological measures (d2 Test of Attention, Children with ADHD-C and typically developing control children completed semi-structured clinical interviews and measures of attention/concentration and parents completed symptom severity questionnaires. Method: We used a forward feature selection method to identify the most informative neuropsychological features for support vector machine (SVM) classification and a decision tree model to derive a rule-based model. Results: The SVM model yielded excellent classification accuracy (100%) of individual children with and without ADHD (1.0). Decision tree algorithms identified individuals with and without ADHD-C with 100% sensitivity and specificity. Conclusion:This study observed highly accurate statistical diagnostic classification, at the individual level, in a sample of children with ADHD-C. The findings suggest data-driven behavioral algorithms based on brief neuropsychological data may present an efficient and accurate diagnostic tool for clinicians.

Differential trajectories of neurocognitive functioning in females versus males following treatment for pediatric brain tumors.

BACKGROUND: Female and male trajectories of cerebellar and lobar brain structures are sexually dimorphic, making sex a potential candidate moderator of neurocognitive late effects from radiation treatment. We sought to evaluate longitudinal neurocognitive functioning in male versus female children treated for posterior fossa brain tumors. METHODS: Fifty-one female and 63 male survivors of posterior fossa tumors completed neuropsychological testing at 2 timepoints. We included patients treated with surgical resection, chemotherapy, and radiation therapy. Multilevel mixed modeling was used to predict IQ score as a function of patient sex following treatment (~2 or ~4 years post treatment). Effect sizes were used as a measure of clinical significance. RESULTS: Multilevel models resulted in a significant sex by time interaction (F = 6.69, P = 0.011). Females' cognitive scores were considerably higher compared with males at 4 years posttreatment. Females demonstrated an average improvement of 7.61 standard score IQ points compared with a decline of 2.97 points for males at 4 years follow-up. Effect sizes for female IQ compared with male IQ at 4 years posttreatment were between 0.8 and 0.9. CONCLUSION: Trajectories of neurocognitive functioning following posterior fossa tumor treatment differed between female and male children. Sexual dimorphism in radiation late effects may alter treatment decisions in children. Research into sex-specific neuroprotective mechanisms underlying neurocognitive development following pediatric brain tumor treatments is warranted.

Regional Volumetric Differences Based on Structural MRI in Children With Two Subtypes of ADHD and Controls.

OBJECTIVE: The purpose of this study was to compare groups of children with two subtypes of ADHD and controls on selected regions using volumetric magnetic resonance imaging (MRI) measures. Children with ADHD were expected to have smaller volumes of the anterior cingulate cortex (ACC) and caudate. Parent behavioral rating measures of hyperactivity were predicted to relate to the volume of the caudate and attention with the ACC. METHOD: There were a total of 74 children in the final sample (27 controls, 25 ADHD:Combined type [ADHD:C], 22 ADHD:Inattentive type [ADHD:I]). RESULTS: Findings indicated that the ADHD:C group had bilaterally smaller volumes of the caudate and ACC compared with the other two groups. In addition, parent ratings of attention and hyperactivity significantly predicted the right volume of the ACC, whereas hyperactivity ratings predicted the volume of the right caudate. Analysis of the ADHD groups without the control confirmed these findings. CONCLUSION: These findings indicate that different structures are related to the ADHD subtypes and suggest that they may be different phenotypes.

Social functioning using direct and indirect measures with children with High Functioning Autism, nonverbal learning disability, and typically developing children.

Social perception is an important underlying foundation for emotional development and overall adaptation. The majority of studies with children with High Functioning Autism (HFA) or nonverbal learning disabilities (NLD) evaluating social functioning have used measures of parent and/or teacher ratings. The present study utilized parent and teacher ratings of behavior as well as executive functioning in addition to direct measures of social perception. Three groups participated in this study (control [n = 38] HFA [n = 36], NLD [n = 31]). Results indicated that the HFA group experienced the most difficulty understanding emotional cues on the direct measure while both the HFA and NLD groups experienced difficulty with nonverbal cues. Significant difficulties were reported on the parent rating scale for sadness and social withdrawal for both clinical groups. Executive functioning was found to be particularly problematic for the clinical groups. The direct social perception measure was highly correlated with the measures of executive functioning and reflects the contribution that executive functions have on social functioning. These findings suggest that the clinical presentation on behavior rating scales may be very similar for children with HFA and NLD. Moreover, it appears that measures of executive functioning are sensitive to the clinical difficulties these groups experience. The findings also suggest there is a commonality in these disorders that warrants further investigation.

An integrated feature ranking and selection framework for ADHD characterization.

Today, diagnosis of attention deficit hyperactivity disorder (ADHD) still primarily relies on a series of subjective evaluations that highly rely on a doctor's experiences and intuitions from diagnostic interviews and observed behavior measures. An accurate and objective diagnosis of ADHD is still a challenge and leaves much to be desired. Many children and adults are inappropriately labeled with ADHD conditions, whereas many are left undiagnosed and untreated. Recent advances in neuroimaging studies have enabled us to search for both structural (e.g., cortical thickness, brain volume) and functional (functional connectivity) abnormalities that can potentially be used as new biomarkers of ADHD. However, structural and functional characteristics of neuroimaging data, especially magnetic resonance imaging (MRI), usually generate a large number of features. With a limited sample size, traditional machine learning techniques can be problematic to discover the true characteristic features of ADHD due to the significant issues of overfitting, computational burden, and interpretability of the model. There is an urgent need of efficient approaches to identify meaningful discriminative variables from a higher dimensional feature space when sample size is small compared with the number of features. To tackle this problem, this paper proposes a novel integrated feature ranking and selection framework that utilizes normalized brain cortical thickness features extracted from MRI data to discriminate ADHD subjects against healthy controls. The proposed framework combines information theoretic criteria and the least absolute shrinkage and selection operator (Lasso) method into a two-step feature selection process which is capable of selecting a sparse model while preserving the most informative features. The experimental results showed that the proposed framework generated the highest/comparable ADHD prediction accuracy compared with the state-of-the-art feature selection approaches with minimum number of features in the final model. The selected regions of interest in our model were consistent with recent brain-behavior studies of ADHD development, and thus confirmed the validity of the selected features by the proposed approach.

Comparison among children with children with autism spectrum disorder, nonverbal learning disorder and typically developing children on measures of executive functioning.

It has been suggested that children with nonverbal learning disabilities (NLD) or Asperger's Syndrome (AS) may show difficulties with executive functioning. There were 3 groups in this study who completed a neuropsychological battery of visual-spatial, executive functioning, and reasoning tasks; AS (n = 37), NLD (n = 31), and controls (n = 40). Results indicated that children in both clinical groups scored within average limits on measures of spatial reasoning and verbal ability. Fluid reasoning was also found to be within average ranges for all groups. The AS group experienced significant problems with cognitive flexibility compared to the other two groups. In contrast the NLD group showed fewer difficulties with cognitive flexibility but more problems with visual sequencing. These findings suggest that performance on executive function measures for children with AS or NLD is remarkably similar with subtle differences present.

Volumetric MRI differences in treatment naïve and chronically treated adolescents with ADHD-combined type.

OBJECTIVE: The purpose of this study was to determine whether there are differences in the volume of specific brain regions using magnetic resonance imaging (MRI) between children and adolescents with ADHD and controls and whether such differences are related to the participants' history of stimulant treatment. METHOD: A total of 16 healthy controls, 16 children, and adolescents with ADHD-combined (ADHD-C) type with a history of stimulant treatment, and 13 children and adolescents with ADHD-C type treatment naïve participated. RESULTS: Total frontal, prefrontal, and caudate volumes were larger for children and adolescents with ADHD compared with controls with no differences based on medication history with larger right gray and white matter prefrontal volumes in the ADHD groups. A medication difference was found with the right anterior cingulate cortex smaller in children and adolescents without a treatment history. CONCLUSION: These findings suggest that aberrant prefrontal and caudate volumes in ADHD-C may compromise functioning of the frontostriatal circuitry.

Anterior cingulate cortex and symptom severity in attention-deficit/hyperactivity disorder.

The cause of attention-deficit/hyperactivity disorder (ADHD) has been linked to abnormalities in prefrontal-striatal-cerebellar networks, but the brain-behavioral correlates are relatively equivocal. Children with ADHD and healthy controls underwent MRI and neuropsychological testing. Brain cortical thickness was analyzed for the bilateral rostral and caudal anterior cingulate cortex (ACC). Inhibitory control was assessed with the Stroop Inhibition test, and ADHD symptom severity was assessed with parent and teacher behavioral questionnaires. Brain-behavior relationships were calculated between cortical thickness and behavioral measures with regression models. Children with ADHD had significant cortical thinning in the right rostral ACC but nonsignificant thinning in right caudal, left caudal, or left rostral ACC compared with healthy control children after statistical correction for multiple comparisons. Further, right rostral ACC thickness predicted a significant amount of the variance in parent- and teacher-reported symptoms of ADHD. Exploratory analysis showed that cortical thickness was not related to psychostimulant medication history. Symptoms of ADHD may be related to reductions in cortical thickness in the right anterior attention network, a region implicated in behavioral error detection, impulsivity, and inhibitory control.

A critical review of the literature on NLD as a developmental disorder.

The extant research on nonverbal learning disability (NLD) was analyzed in this review. Studies were defined for use in the review as those that appeared in a peer-reviewed journal and included participants characterized as having NLD. Each study also needed to provide a statistical analysis of dependent variables. An a priori system was used to evaluate the quality of the research. Of the 88 publications found, 32 met criteria for inclusion in the review, with 6 meeting full criteria as strong studies. The diagnostic criteria used and the research findings are briefly discussed, as are proposed guidelines for future research.

Magnetic resonance imaging volumetric findings in children with Asperger syndrome, nonverbal learning disability, or healthy controls.

BACKGROUND: The purpose of the present study was to evaluate selected regions of interest in children and adolescents with nonverbal learning disabilities (NVLD), Asperger syndrome (AS), and age-matched healthy controls using magnetic resonance imaging (MRI). It was hypothesized that children with AS would show larger volumes of the amygdala and hippocampal regions than the other groups. It was also hypothesized that both clinical groups would show differences in the caudate and anterior cingulate cortex (ACC). METHOD: There were a total of 89 children in the final sample (31 controls, 29 NVLD, 29 AS). Each child completed a MRI scan as well as basic cognitive screening measures. High-resolution T1-weighted MR volumetric images were acquired. The volume of gray matter, white matter, cerebrospinal fluid (CSF), amygdala, hippocampus, and anterior cingulate cortex (ACC) was obtained. RESULTS: The hypothesis that the AS group would show larger hippocampal and amygdala volumes than the other groups was confirmed. For the AS and NVLD groups, the ACC was found to be significantly smaller than that of the control group. CONCLUSIONS: These results suggest that the ACC and amygdala/hippocampal regions are deficient in children with AS, likely contributing to difficulty with modulating of emotional reactivity.

Neuroanatomical and neuropsychological correlates of the cerebellum in children with attention-deficit/hyperactivity disorder--combined type.

OBJECTIVE: Studies of healthy individuals and those with cerebellar damage have implicated the cerebellum in a variety of cognitive and behavioral processes. Decreased cerebellar volume has been found in children with attention-deficit/hyperactivity disorder (ADHD) and differentially related to behavioral outcomes. The present study investigated whether smaller cerebellar vermis volume was present in children with ADHD-combined type (ADHD-C) compared with controls and whether volume related to parent- and teacher-reported levels of ADHD symptomatology. METHOD: T1-weighted magnetic resonance images and parent- and teacher-reported ADHD symptoms were acquired for 32 children diagnosed with ADHD-C and 15 typically developing controls. Participants were right-handed, had no comorbid diagnoses of learning disabilities, conduct disorder, or affective/mood disorder, and were 9 to 15 years of age. RESULTS: Participants with ADHD-C showed significantly smaller volume in the posterior inferior vermis compared with controls. No statistically significant differences were observed for cerebral volume, anterior vermis volume, posterior superior volume, or total cerebellar volume. Regression analyses indicated that a significant amount of the variance in parent-reported Behavior Assessment System for Children, Second Edition, Hyperactivity and Attention and Conners Restless/Impulsive ratings was explained by volume of the posterior inferior vermis. CONCLUSIONS: Consistent with previous studies, children with ADHD had smaller volume in the posterior inferior vermis. New findings emerged with smaller volume of the posterior inferior vermis predicting a significant amount of the variance in parent-reported hyperactivity, attention, and restlessness/impulsivity. Thus, symptoms of hyperactivity and inattention in ADHD may be partly explained by smaller volume of the cerebellar vermis and its connections within the cerebrum.

Response inhibition and academic abilities in typically developing children with attention-deficit-hyperactivity disorder-combined subtype.

Research in Attention-Deficit/Hyperactivity Disorder (ADHD) generally utilizes clinical samples or children with comorbid psychiatric diagnoses. Findings indicated that children with ADHD experience academic underachievement and poor performance on measures of response inhibition (RI). Less is known, about the neuropsychological profile of typically developing children with ADHD. The aim of the current study was twofold: (1) determine if academic skills and RI were impaired in typically developing children with ADHD-combined subtype (ADHD-C) and (2) determine to what extent RI may predict academic abilities. Children with ADHD-C did not differ on any academic domain from controls. Children with ADHD-C performed more poorly than controls on RI measures. Regression analyses suggest that Written Expression ability was significantly influenced by RI. No other academic domain was related to RI. Results suggest that children with ADHD-C may experience impairments in RI despite adequate academic functioning. Impaired RI is not solely responsible for difficulties found in academic skills in ADHD-C.

A magnetic resonance imaging study of the cerebellar vermis in chronically treated and treatment-naïve children with attention-deficit/hyperactivity disorder combined type.

BACKGROUND: Because of its dense connections to the prefrontal cortex and basal ganglia, the cerebellum is thought to play an important role in cognition. Numerous magnetic resonance imaging (MRI) studies have found abnormalities in the cerebellum in children with attention-deficit/hyperactivity disorder (ADHD). While some studies in animal and human models suggest that certain brain structures are affected by chronic stimulant medication, it is unclear whether the cerebellum is also affected. The purpose of the current study was to determine if cerebellar morphology was different in treatment-naïve versus chronically treated children with ADHD. METHODS: There were 32 boys and 15 girls total (N = 47) that comprised three groups: ADHD-combined type (ADHD-C) children with no history of stimulant medication treatment (n = 14), ADHD-C children chronically treated with stimulant medication (n = 18), and typically developing control children (n = 15). RESULTS: Treatment-naïve children with ADHD had significantly smaller area in the posterior inferior vermis (lobules VIII-X) than both chronically treated children with ADHD (p = .004) and typically developing control children (p = .001). No differences were observed between chronically treated children with ADHD and control children. CONCLUSIONS: The results from this study suggest that chronic stimulant treatment may normalize the development of important areas of the cerebellar vermis in children with ADHD.