The Role of the Cerebellum in Repetitive Behavior Across Species: Childhood Stereotypies and Deer Mice.

Recent studies suggest that the cerebellum may have a significant role in repetitive behaviors. In primary complex motor stereotypies, typically developing children have repetitive movements usually involving rhythmic flapping/waving arm/hand movements. Similarly, the deer mouse animal model exhibits inherited repetitive behaviors, with increased frequencies of spontaneous jumping and rearing. In this study, data from both children with motor stereotypies and deer mice were used to investigate the role of the cerebellum in repetitive behaviors. The 3.0-T MRI volumetric imaging of the cerebellum was obtained in 20 children with primary complex motor stereotypies and 20 healthy controls. In deer mice, cerebellar volume (n = 7/group) and cell counts (n = 9/group) were compared between high- and low-activity animals. Levels of cerebellar neurotransmitters were also determined via HPLC (n = 10/group). In children with stereotypies, (a) there were a statistically significant reduction (compared to controls) in the white matter volume of the posterior cerebellar lobule VI-VII that negatively correlated with motor control and (b) an 8% increase in the anterior vermis gray matter that positively correlated with motor Stereotypy Severity Scores (SSS). In deer mice, (a) there was a significant increase in the volume of the anterior vermal granular cell layer that was associated with higher activity and (b) dentate nucleus cell counts were higher in high activity animals. Similar increases in volume were observed in anterior vermis in children with stereotypies and a deer mouse model of repetitive behaviors. These preliminary findings support the need for further investigation of the cerebellum in repetitive behaviors.

Premorbid functioning as a predictor of outcome in pediatric brain tumor: An initial examination of the normalcy assumption.

BACKGROUND: Research on neurodevelopmental outcome in survivors of pediatric brain tumor (BT) is often based on the assumption of normal development up to the onset of overt symptoms. We sought to verify the "normalcy assumption" and to investigate corollary issues including challenges inherent to the measurement of premorbid neurobehavioral functioning. PROCEDURE: The Brain Radiation Investigative Study Consortium (BRISC) is a prospective longitudinal multisite study of 58 children diagnosed with BT. Premorbid functioning was assessed via retrospective parent report on standardized rating scales and detailed questionnaires. Findings were examined for the sample as a whole and in patients grouped by tumor histology (embryonal and non-embryonal). RESULTS: Mean age at diagnosis was 9.84 years (range, 3-16). The overall sample showed low proportions of pre/postnatal risk factors and delays in development. The proportion of children with clinically significant premorbid attention (18%) problems based on the BASC-2 exceeded expectation of that in healthy children (6.68%). Similar findings were obtained for somatization (18%) and anxiety (14%). Delays in talking were significantly more common in children with embryonal than non-embryonal tumors (P = 0.02). The non-embryonal tumor group had significantly higher overall rates of premorbid psychosocial problems than the embryonal tumor group (P < 0.001). CONCLUSIONS: We describe a rigorous approach to estimating premorbid developmental status in pediatric BT. The findings suggest mixed support for the "normalcy assumption" and highlight the complexity of this concept and need for further investigation. Our results also suggest the need for further study of potential premorbid correlates with tumor histology.

Multivariate genome-wide association study of rapid automatised naming and rapid alternating stimulus in Hispanic American and African-American youth.

BACKGROUND: Rapid automatised naming (RAN) and rapid alternating stimulus (RAS) are reliable predictors of reading disability. The underlying biology of reading disability is poorly understood. However, the high correlation among RAN, RAS and reading could be attributable to shared genetic factors that contribute to common biological mechanisms. OBJECTIVE: To identify shared genetic factors that contribute to RAN and RAS performance using a multivariate approach. METHODS: We conducted a multivariate genome-wide association analysis of RAN Objects, RAN Letters and RAS Letters/Numbers in a sample of 1331 Hispanic American and African-American youth. Follow-up neuroimaging genetic analysis of cortical regions associated with reading ability in an independent sample and epigenetic examination of extant data predicting tissue-specific functionality in the brain were also conducted. RESULTS: Genome-wide significant effects were observed at rs1555839 (p=4.03×10-8) and replicated in an independent sample of 318 children of European ancestry. Epigenetic analysis and chromatin state models of the implicated 70 kb region of 10q23.31 support active transcription of the gene RNLS in the brain, which encodes a catecholamine metabolising protein. Chromatin contact maps of adult hippocampal tissue indicate a potential enhancer-promoter interaction regulating RNLS expression. Neuroimaging genetic analysis in an independent, multiethnic sample (n=690) showed that rs1555839 is associated with structural variation in the right inferior parietal lobule. CONCLUSION: This study provides support for a novel trait locus at chromosome 10q23.31 and proposes a potential gene-brain-behaviour relationship for targeted future functional analysis to understand underlying biological mechanisms for reading disability.

Causal Attribution Profiles as a Function of Reading Skills, Hyperactivity, and Inattention.

The causes that individuals attribute to reading outcomes shape future behaviors, including engagement or persistence with learning tasks. Although previous reading motivation research has examined differences between typical and struggling readers, there may be unique dynamics related to varying levels of reading and attention skills. Using latent profile analysis, we found 4 groups informed by internal attributions to ability and effort. Reading skills, inattention, and hyperactivity/impulsivity were investigated as functional correlates of attribution profiles. Participants were 1,312 youth (8-15 years of age) of predominantly African American and Hispanic racial/ethnic heritage. More adaptive attribution profiles had greater reading performance and lower inattention. The reverse was found for the least adaptive profile with associations to greater reading and attention difficulties. Distinct attribution profiles also existed across similar-achieving groups. Understanding reading-related attributions may inform instructional efforts in reading. Promoting adaptive attributions may foster engagement with texts despite learning difficulties and, in turn, support reading achievement.

Predicting changes in adaptive functioning and behavioral adjustment following treatment for a pediatric brain tumor: A report from the Brain Radiation Investigative Study Consortium.

BACKGROUND: Children are at risk for behavioral and adaptive difficulties following pediatric brain tumor. This study explored whether familial/demographic, developmental, diagnostic, or treatment-related variables best predict posttreatment behavioral and adaptive functioning. METHODS: Participants included 40 children (mean age = 12.76 years, SD = 4.01) posttreatment (mean time since diagnosis = 1.99 years, SD = 0.21) for pediatric brain tumor. Parents rated children's behavioral adjustment and adaptive functioning and provided demographic and developmental histories. Diagnostic and treatment-related information was abstracted from medical records. RESULTS: Ratings of adaptive and behavioral functioning approximately 2 years postdiagnosis were within the average range, although the percentage of children exceeding clinical cutoffs for impairment in adaptive skills exceeded expectation, particularly practical skills. Premorbid behavior problems and tumor size predicted posttreatment adaptive functioning. After accounting for adaptive functioning near diagnosis, premorbid behavior problems predicted declines in adaptive functioning 2 years postdiagnosis. After accounting for adjustment near diagnosis, no variables predicted declines in behavioral adjustment. CONCLUSIONS: Children may be vulnerable to reduced adaptive functioning following pediatric brain tumor treatment, especially in practical skills. Assessing prediagnosis functioning and diagnostic and treatment-related variables may improve our ability to predict those at greatest risk, although those factors may be less helpful in identifying children likely to develop behavioral difficulties. Screening of these factors in tertiary care and long-term follow-up settings may improve identification of those at greatest need for support services.

Anomalous Brain Development Is Evident in Preschoolers With Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a common neurological disorder with symptom onset early in childhood. Growing evidence suggests anomalous brain development across multiple brain regions is evident in school-aged children; however, few studies have examined whether such differences are notable in the preschool years when symptom onset typically occurs. METHODS: High resolution anatomical (MPRAGE) images and cognitive and behavioral measures were analyzed in a total of 90 medication-naïve preschoolers, ages 4-5 years (52 with ADHD, 38 controls; 64.4% boys). RESULTS: Results revealed reductions in bilateral frontal, parietal, and temporal lobe gray matter volumes in children with ADHD relative to typically developing children, with largest effect sizes noted for right frontal and left temporal lobe volumes. Examining frontal lobe sub-regions, the largest between group effect sizes were evident for left orbitofrontal cortex, left primary motor cortex (M1), and left supplementary motor complex (SMC). ADHD-related reductions in specific sub-regions (left prefrontal, left premotor, left frontal eye field, left M1, and right SMC) were significantly correlated with symptom severity, such that higher ratings of hyperactive/impulsive symptoms were associated with reduced cortical volumes. CONCLUSIONS: These findings represent the first comprehensive examination of cortical volume in preschool children with ADHD, providing evidence that anomalous brain structure in ADHD is evident very early in development. Furthermore, findings set the stage for developing our understanding of the way in which developmental trajectories of anomalous brain development are associated with the unfolding of symptoms in childhood ADHD. (JINS, 2018, 24, 531-539).

Dose-volume metrics and their relation to memory performance in pediatric brain tumor patients: A preliminary study.

BACKGROUND: Advances in radiation treatment (RT), specifically volumetric planning with detailed dose and volumetric data for specific brain structures, have provided new opportunities to study neurobehavioral outcomes of RT in children treated for brain tumor. The present study examined the relationship between biophysical and physical dose metrics and neurocognitive ability, namely learning and memory, 2 years post-RT in pediatric brain tumor patients. PROCEDURE: The sample consisted of 26 pediatric patients with brain tumor, 14 of whom completed neuropsychological evaluations on average 24 months post-RT. Prescribed dose and dose-volume metrics for specific brain regions were calculated including physical metrics (i.e., mean dose and maximum dose) and biophysical metrics (i.e., integral biological effective dose and generalized equivalent uniform dose). We examined the associations between dose-volume metrics (whole brain, right and left hippocampus), and performance on measures of learning and memory (Children's Memory Scale). RESULTS: Biophysical dose metrics were highly correlated with the physical metric of mean dose but not with prescribed dose. Biophysical metrics and mean dose, but not prescribed dose, correlated with measures of learning and memory. CONCLUSIONS: These preliminary findings call into question the value of prescribed dose for characterizing treatment intensity; they also suggest that biophysical dose has only a limited advantage compared to physical dose when calculated for specific regions of the brain. We discuss the implications of the findings for evaluating and understanding the relation between RT and neurocognitive functioning.

Reading-Related Causal Attributions for Success and Failure: Dynamic Links With Reading Skill.

The present study investigated the relation among reading skills and attributions, naming speed, and phonological awareness across a wide range of reading skill. Participants were 1,105 school-age children and youths from two understudied populations: African Americans and Hispanic Americans. Individual assessments of children ranging in age from 8 to 15 years were conducted for reading outcomes, cognitive and linguistic predictors of reading, and attributions for success and failure in reading situations. Quantile regressions were formulated to estimate these relations across the full skill span of each outcome. Reading-related attributions predicted contextual word recognition, sight word and decoding fluency, and comprehension skills. Attributions to ability in success situations were positively related to each outcome across the full span. On three reading outcomes, this relation strengthened at higher skill levels. Attributions to effort in success situations were consistently and negatively related to all reading outcomes. The results provide evidence that the strength of the relation between reading and attributions varies according to reading skill levels, with the strongest evidence for ability-based attributions in situations of reading success.

Achievement attributions are associated with specific rather than general learning delays.

The causal attributions that children make for success and failure have been associated with later reading motivation and ability perceptions, which have the potential to impact future task engagement. Few studies have investigated whether such attributions are domain specific, that is linked with the specific skill in question, or a general motivational set. Even fewer studies have examined these relationships among diverse racial and ethnic subgroups. The present study examined differences in success and failure attributions among children with and without reading delay (RD) and general language impairments (LI), in a predominately Hispanic and African American sample. Participants were 1311 children, 8 to 15 years old. Significant differences in ability attributions were observed between participants with and without RD and LI, with no additive effect for cases with co-occurring reading and language impairments. When reading and vocabulary were evaluated continuously, significant and substantial positive relationships were observed between skill and ability attributions in situations of success, and negative associations observed in situations of failure. Weaker relationships were observed for vocabulary, though vocabulary did function as a moderator in the relationship between reading skill and ability attributions, with stronger associations at higher vocabulary levels. Overall, the findings suggest that ability attributions for reading success and failure are linked with reading skill and/or deficits, and not with general language impairments.

A prospective study of cerebral, frontal lobe, and temporal lobe volumes and neuropsychological performance in children with primary brain tumors treated with cranial radiation.

BACKGROUND: Cranial radiation therapy (RT) is an important component in the treatment of pediatric brain tumors. However, it can result in long-term effects on the developing brain. This prospective study assessed the effects of cranial RT on cerebral, frontal lobe, and temporal lobe volumes and their correlation with higher cognitive functioning. METHODS: Ten pediatric patients with primary brain tumors treated with cranial RT and 14 age- and sex-matched healthy children serving as controls were evaluated. Quantitative magnetic resonance imaging and neuropsychological assessments (language, memory, auditory and visual processing, and vocabulary) were performed at the baseline and 6, 15, and 27 months after RT. The effects of age, the time since RT, and the cerebral RT dose on brain volumes and neuropsychological performance were analyzed with linear mixed effects model analyses. RESULTS: Cerebral volume increased significantly with age in both groups (P = .01); this increase in volume was more pronounced in younger children. Vocabulary performance was found to be significantly associated with a greater cerebral volume (P = .05) and a lower RT dose (P = .003). No relation was observed between the RT dose and the cerebral volume. There was no difference in the corresponding neuropsychological tests between the 2 groups. CONCLUSIONS: This prospective study found significant relations among the RT dose, cerebral volumes, and rate of vocabulary development among children receiving RT. The results of this study provide further support for clinical trials aimed at reducing cranial RT doses in the pediatric population. Cancer 2017;161-168. © 2016 American Cancer Society.

Attention-Deficit/Hyperactivity Disorder: A Historical Neuropsychological Perspective.

The behavior patterns of hyperactivity, impulsivity and inattention that would ultimately become recognized as Attention-Deficit Hyperactivity Disorder (ADHD) have been described for centuries. Nevertheless, in the past 35 years, advances in diagnostic methods, identification of biomarkers, and treatments have advanced at an exponential rate. ADHD is now recognized as the most common behavioral disorder of childhood, with risks extending well into adulthood for both males and females, leading to its identification as a significant public health issue. This historical neuropsychological review of ADHD emphasizes scientific highlights in the past 35 years related to ADHD, including the evolution of the diagnosis (from Hyperkinetic Reaction of Childhood to ADHD), influential theories (executive functions, cognitive-energetic, delay aversion), landmark treatment studies (Multimodal Treatment of ADHD [MTA] and Preschool ADHD Treatment Study [PATS]), and advances in brain mapping techniques (anatomic, functional, and resting state magnetic resonance imaging, diffusion tensor imaging). The review concludes by highlighting the challenges of studying and treating a heterogeneous neurodevelopmental disorder like ADHD, with emphasis on associated disorders and conditions (learning disabilities, sluggish cognitive tempo), special populations (girls, preschoolers, adults), and recommendations for scientific inquiry in the next 35 years. Neuropsychologists are well positioned to address the clinical and research challenges of the next generation of studies, especially involving advances in understanding the sexual dimor.phism, full developmental course, and dynamic risks associated with ADHD. (JINS, 2017, 23, 916-929).

Efficacy of parent-delivered behavioral therapy for primary complex motor stereotypies.

AIM: Primary complex motor stereotypies (CMS) are persistent, patterned, repetitive, rhythmic movements in young people with typical development. This study evaluated the efficacy of an instructional DVD as a home-based, parent-administered, behavioral therapy for primary CMS. METHOD: Eighty-one children with primary CMS were enrolled. Primary outcome measures included the Stereotypy Severity Scale (SSS) - Motor and Impairment scores, and Stereotypy Linear Analog Scale (SLAS). Mean CMS onset was 13.4 months (SD 13.1). Eligibility required observed CMS. Psychiatric disorders were not exclusionary and a stable medication regimen was required. Intellectual disability, neurological disorder, autism spectrum disorder, and tics were exclusionary. Initial assessments were completed via REDCap before receipt of the DVD. Fifty-four of the 81 children (34 male, 20 female; mean age 8y 2mo, SD 1.42, range 7-14y) completed assessments at 1, 2, or 3 months after receiving the DVD. RESULTS: Reductions (baseline to last assessment) in SSS Motor, SSS Impairment, and SLAS scores (all p<0.001) represented change ratios of -15%, -24%, and a -20% respectively. Greatest relative treatment benefit was observed by younger children (ages 7-8y), and by 1 month after receipt of DVD, while a parent global assessment scale showed progressive improvement throughout the study. INTERPRETATION: An instructional DVD for parent-delivered behavioral therapy was a safe, effective intervention for primary CMS.

Correction to: A prospective study of corpus callosum regional volumes and neurocognitive outcomes following cranial radiation for pediatric brain tumors.

AbstractThe published version of this article unfortunately contained an error. Author "E. Mark Mahone" has been published incorrectly by capturing "Mark Mahone" as family name when it should only be "Mahone". Given in this article is the corrected name.

Long-term effects of radiation therapy on white matter of the corpus callosum: a diffusion tensor imaging study in children.

BACKGROUND: Despite improving survival rates, children are at risk for long-term cognitive and behavioral difficulties following the diagnosis and treatment of a brain tumor. Surgery, chemotherapy and radiation therapy have all been shown to impact the developing brain, especially the white matter. OBJECTIVE: The purpose of this study was to determine the long-term effects of radiation therapy on white matter integrity, as measured by diffusion tensor imaging, in pediatric brain tumor patients 2 years after the end of radiation treatment, while controlling for surgical interventions. MATERIALS AND METHODS: We evaluated diffusion tensor imaging performed at two time points: a baseline 3 to 12 months after surgery and a follow-up approximately 2 years later in pediatric brain tumor patients. A region of interest analysis was performed within three regions of the corpus callosum. Diffusion tensor metrics were determined for participants (n=22) who underwent surgical tumor resection and radiation therapy and demographically matched with participants (n=22) who received surgical tumor resection only. RESULTS: Analysis revealed that 2 years after treatment, the radiation treated group exhibited significantly lower fractional anisotropy and significantly higher radial diffusivity within the body of the corpus callosum compared to the group that did not receive radiation. CONCLUSION: The findings indicate that pediatric brain tumor patients treated with radiation therapy may be at greater risk of experiencing long-term damage to the body of the corpus callosum than those treated with surgery alone.

Predictors of adaptive functioning and psychosocial adjustment in children with pediatric brain tumor: a report from the Brain Radiation Investigative Study Consortium.

BACKGROUND: Children are at risk for psychosocial and adaptive morbidities following diagnosis of and treatment for a pediatric brain tumor. This study examined whether familial/demographic, developmental, diagnostic, or treatment-related variables best predict the acute psychosocial adjustment and adaptive functioning of children soon after an initial diagnosis. PROCEDURE: Participants included 56 children (mean age = 10.72, SD = 4.02) newly diagnosed with a pediatric brain tumor. Parents completed background/demographic forms and completed ratings of children's behavioral and emotional symptoms, and adaptive behavior. Diagnostic and treatment-related information was abstracted from medical records. RESULTS: Parent ratings of behavioral symptoms and adaptive functioning were within normative expectation, although rates of clinical impairment in adaptive functioning exceeded expected rates. A combination of familial/demographic and diagnostic variables were associated with acute functioning. In multiple regressions, tumor size best predicted adaptive functioning after initial diagnosis, whereas tumor location best predicted variance in behavioral symptoms. CONCLUSIONS: Children may be more vulnerable to acute impairment in adaptive functioning following diagnosis of a pediatric brain tumor, but rates of behavioral symptoms were within expectation. Familial, sociodemographic, and diagnostic variables may help to identify those most at risk of impairment. Screening of these factors within tertiary care settings will be useful to identify those most in need of psychosocial care during the initial phases of treatment.

Association between binge eating and attention-deficit/hyperactivity disorder in two pediatric community mental health clinics.

OBJECTIVE: Attention-Deficit/ Hyperactivity Disorder (ADHD) has been linked with obesity; however its relationship with binge eating (BE) is less clear. We aimed to explore the associations among ADHD, weight, and BE in pediatric mental health clinics. METHOD: We retrospectively reviewed consecutive intakes in two pediatric mental health clinics (N = 252). BE was assessed using the C-BEDS scale. Associations between ADHD, BE, and BMI-z score were assessed via regression. RESULTS: Mean age was 10.8 (3.7 SD) years. Twelve percent (n = 31) had BE. The association between ADHD and BE was statistically significant (OR 16.1, p < .001), and persisted after adjusting for comorbid diagnoses, medications, demographic variables, and clinic. There was a statistically significant association between ADHD and BMI z-scores (ß = 0.54, p < .001). After adjusting for BE, the relationship between ADHD and BMI z-scores was attenuated (ß = 0.35, p = .025), and the coefficient for BE was decreased (ß = 0.75, p = .001). Although stimulant use was associated with a three-fold increase in odds of BE (OR 3.16, p = .006), stimulants were not associated with greater BMI-z scores (ß = 0.18, p = .32). DISCUSSION: There was a significant association between ADHD and BE in two pediatric mental health clinics. Although these data are cross-sectional, and cannot be used to make causal inferences, these findings are compatible with the hypothesis that BE partially mediates the association between ADHD and BMI z-scores. In mental health clinics, children with ADHD may present as overweight or obese. Further, children with ADHD may exhibit BE. Future prospective studies should elucidate the complex relationships among ADHD, weight, stimulants, and BE.

Pediatric loss of control eating syndrome: Association with attention-deficit/hyperactivity disorder and impulsivity.

OBJECTIVE: Despite data linking Attention-deficit/Hyperactivity Disorder (ADHD) and adult binge eating, there are limited data in children with loss of control (LOC) eating. We examined inhibitory control in children with LOC eating syndrome (LOC-ES) and its association with ADHD. METHOD: 79 children (8-14 years) over the fifth weight percentile were recruited, irrespective of LOC eating or ADHD status. The Eating Disorder Examination for Children and the Standard Pediatric Eating Episode Interview assessed LOC-ES. ADHD diagnosis was determined by the Schedule for Affective Disorders and Schizophrenia for children and Conners-3 (Parent Report) DSM-IV Scales of Inattention and/or Hyperactivity (T score > 65). The Go/No-Go (GNG) Task and the Behavior Regulation Inventory of Executive Function (BRIEF) assessed impulse control. RESULTS: Odds of LOC-ES were increased 12 times for children with ADHD (adjusted odds ratio [aOR] = 12.68, 95% confidence interval [CI] = 3.11, 51.64, p < 0.001), after adjusting for BMI z scores and relevant covariates. Children had 1.17 times higher odds of reporting LOC-ES with every 5% increase in GNG Commission Rate (aOR = 1.17, CI = 1.01, 1.36, p < 0.05) and 1.25 times higher odds of reporting LOC-ES with every 5 unit T-score increase in BRIEF Inhibit Scale (aOR = 1.25, CI = 1.04, 1.50, p < 0.05). DISCUSSION: Children with ADHD had significantly greater odds of LOC-ES compared to children without ADHD. Children with LOC-ES had significantly greater impulse control deficits on performance-based neuropsychological assessments and on parent reports than children without LOC-ES. These findings suggest a need to investigate possible shared mechanisms such as impulse control deficits, among children with LOC-ES and ADHD.

Neuropsychological function in children with primary complex motor stereotypies.

AIM: Complex motor stereotypies (CMS) are patterned, repetitive, rhythmic, and involuntary movements that persist over time. They are divided into two subgroups dependent on the presence of other developmental problems: 'primary' (development is otherwise typical) or 'secondary' (associated with autism, intellectual disability, or sensory deficits). There are no currently published studies that examine neuropsychological function in children with primary CMS. This case-control study examines whether children with primary CMS manifest neurobehavioral deficits. METHOD: Fifty-seven children with primary CMS (32 males, 25 females; mean age 6y 8mo, SD 2y 4mo, range 4-12y) with negative screens for autism and 57 comparison participants (32 males, 25 females; mean age 6y 6mo, SD 2y 1mo) completed neuropsychological assessments of IQ, reading ability, attention, language, and motor and executive functions. Parents completed ratings of their child's repetitive movement severity. RESULTS: The CMS group performed significantly less well than comparison participants on motor skills and IQ tests (both p<0.01), although IQ was consistently in the average range. One-third of the CMS group showed signs of developmental motor coordination difficulties. Parent report of stereotypy severity was significantly associated with parent report of inattention and executive dysfunction. INTERPRETATION: Children with primary CMS were found to have largely intact neuropsychological profiles. Stereotypy severity appears to be associated with executive dysfunction. Although motor difficulties were observed in children with CMS, these were not correlated with parent report of symptom severity.

Diffusion tensor imaging of deep gray matter in children treated for brain malignancies.

PURPOSE: Previous DTI studies reported microstructural changes in white matter of patients receiving treatment for brain malignancies. The primary aim of this prospective pilot longitudinal study was to examine if DTI can detect microstructural changes in deep gray matter (as evaluated by the apparent diffusion coefficient, ADC) between pediatric patients treated with cranial radiation therapy and typically developing healthy children. The relationship between ADC and neurobehavioral performance was also examined. METHODS: ADC was measured at 1.5 T in the caudate, putamen, globus pallidus, thalamus, and hippocampus in nine patients (mean age 11.8 years) and nine age-matched healthy controls. The study was designed with four visits: baseline, 6-month, 15-month, and 27-month follow-ups. RESULTS: Patients had 24 % higher overall mean ADC in the hippocampus compared with controls (p = 0.003). Post hoc analyses revealed significantly elevated ADC at baseline (p = 0.003) and at the 27-month follow-up (p = 0.006). Nevertheless, patients performed normally on a verbal memory test considered to be a hippocampus-related function. Relative to controls, patients' performance on the tests of the visual-spatial working memory decreased over time (group by visit, p = 0.036). Both patients and controls showed a decline in motor speed with increasing ADC in the globus pallidus and putamen. CONCLUSIONS: Childhood brain malignancies and their treatment may affect gray matter microstructure as measured by water diffusion. Significant findings in the hippocampus but not other regions suggest that differences in tissue sensitivity to disease- and treatment-related injury among gray matter regions may exist. ADC in basal ganglia may be associated with motor performance.

Impact of placebo assignment in clinical trials of tic disorders.

BACKGROUND: Understanding the impact of placebo treatment is pivotal to the correct interpretation of clinical trials. The aim of present study was to examine the placebo effect in tic disorders. METHODS: Raw data were obtained for 6 placebo-controlled parallel and cross-over trials that involved medical interventions for tic disorders. Tic severity was measured using the Yale Global Tic Severity Scale. Placebo effect was defined as an improvement of at least 30% over baseline scores in the total tic score and was considered clinically relevant when at least 10% of patients in the placebo-arm met that benchmark. RESULTS: In total, 91 placebo-treated patients (80% males; mean age, 16.5 years; standard deviation, 10.5 years) were included. Although there was a trend toward improvement in the total tic scores after placebo administration (P=0.057), the magnitude of the placebo effect was small (Cohen's d=0.16) but relevant (19% of the sample). Females were more likely than males to have a placebo effect. CONCLUSIONS: The magnitude of the placebo effect in tic disorders appeared to be small. Further longitudinal studies using objective assessments for tic disorders are warranted to confirm the current results. © 2013 Movement Disorder Society.