Sex Effects on Mirror Overflow during Finger Tapping in Children with ADHD.

OBJECTIVES: The presence of excessive mirror overflow in children with Attention Deficit/Hyperactivity Disorder (ADHD) is discussed in numerous published reports. These reports, however, include a limited age range in their samples. The objective of this study is to examine the effects of diagnosis and sex on mirror overflow and standard deviation (SD) of tap time in children with and without ADHD across a larger age range (5-12 years) of children. METHODS: One-hundred and forty-eight children with ADHD and 112 age- and sex-matched typically developing (TD) children completed a finger sequencing task. Mirror overflow, SD of tap time, and mean tap time were measured using finger twitch transducers. RESULTS: Results reveal a significant diagnostic effect on mirror overflow such that boys and girls with ADHD demonstrate increased overflow compared to same-sex TD children. Boys with ADHD demonstrated more variable tap times compared to TD boys; no diagnostic effect was observed in the girls. CONCLUSIONS: Boys with ADHD exhibit anomalous motor variability; girls with ADHD show similar levels of variability as TD girls. Boys and girls with ADHD exhibit similar levels of excessive mirror overflow. This lack of sex differences on mirror overflow is distinct from reports finding sex effects on overflow and could result from an examination of a broader age range than is included in prior reports. Adolescent data would provide a greater understanding of the trajectory of anomalous mirror overflow across development. Examination of functional and structural connectivity would expand the current understanding of the neurobiological foundation of motor overflow.

Pre-appointment online assessment of patient complexity: Towards a personalized model of neuropsychological assessment.

Recent events such as the global pandemic of COVID-19 have challenged neuropsychologists to scale up their capacity to conduct portions of their assessment remotely. While more complex patients will likely continue to require on-site, office-based interaction and assessment, the current emergency-based expansion of online and telehealth evaluation practices may ultimately lay the groundwork for more routine, online assessment of patients with less complex presentations in the future. To this end, the current study evaluated a pre-appointment, online methodology for differentiating referred pediatric patients based upon the scope and severity of their caregiver-reported adaptive, academic, attentional, behavioral, and emotional impairment. Prior to on-site assessment, parents/caregivers of 2197 children (Mean age = 10.0y, range = 4-19y, 62% male) completed an online developmental history form screening for symptoms of adaptive, attentional, learning, affective, and behavioral impairment; 71% of those children eventually underwent assessment. Using latent class analysis, the data supported a reproducible 4-class model consisting of groups of children at increased risk for: 1) severe multi-domain dysfunction; the "High Complexity" group, 30%, 2) behavioral-affective (but not academic) dysregulation; the "Behavioral Focus" group, 13%, 3) academic (but not behavioral-affective) problems; the "Academic and Inattention" group, 37%, and 4) patients with minimal clinical complexity; the "Low Complexity" group, 20%. Comparison of pre-visit classification with day-of-assessment standardized test scores supported the validity of patient subtypes. Moving forward, pre-appointment clarification of patient complexity may support efficient patient triage with regard to assessment modality (e.g., on-site or online) and length of appointment (e.g., comprehensive or targeted).

Investigation of the Clinical Utility of the BRIEF2 in Youth With and Without Intellectual Disability.

OBJECTIVE: Executive function (EF) difficulties are commonly found in youth with intellectual disability (ID). Given mixed results from studies using performance-based EF measures, the EF profile has not been well characterized for this population. No published work has examined the clinical utility of the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF2) in distinguishing EF in ID. We hypothesized that the BRIEF2 would show greater elevations in youth with ID compared to the Average IQ comparison group. METHODS: Participants included a large sample of 504 youth (157 in ID group; aged 8-18 years) referred for (neuro)psychological evaluation (2015-2019) and identified as meeting criteria for either ID or Average IQ comparison group. RESULTS: Significant elevations were found across BRIEF2 indices and scales. Only mild elevations were noted in selective cognitive regulation scales within the Average IQ group. Groups differed significantly across all EF dimensions, with greater differences observed in behavioral regulation (Self-Monitoring, Inhibition), Shift, and Working Memory. An elevated but less variable pattern of index scores was noted in ID, while the overall pattern of scaled scores appeared similar between groups. CONCLUSIONS: The less variable and consistently elevated profile may suggest fewer EF dimensions in individuals with ID than the model proposed in the test manual. Similar profiles between groups may reflect differences in severity, rather than differences in constructs measured by the EF factors, per se. Additional examination is needed to confirm potential structural differences in EF for youth with ID as measured by BRIEF2, with a clinical implication for greater efficiency of EF assessment in this population.

Molecularly confirmed Kabuki (Niikawa-Kuroki) syndrome patients demonstrate a specific cognitive profile with extensive visuospatial abnormalities.

BACKGROUND: Kabuki (Niikawa-Kuroki) syndrome (KS) is caused by disease-causing variants in either of two components (KMT2D and KDM6A) of the histone methylation machinery. Nearly all individuals with KS have cognitive difficulties, and most have intellectual disability. Recent studies on a mouse model of KS suggest disruption of normal adult neurogenesis in the granule cell layer of the dentate gyrus of the hippocampus. These mutant mice also demonstrate hippocampal memory defects compared with littermates, but this phenotype is rescued postnatally with agents that target the epigenetic machinery. If these findings are relevant to humans with KS, we would expect significant and disproportionate disruption of visuospatial functioning in these individuals. METHODS: To test this hypothesis, we have compiled a battery to robustly explore visuospatial function. We prospectively recruited 22 patients with molecularly confirmed KS and 22 IQ-matched patients with intellectual disability. RESULTS: We observed significant deficiencies in visual motor, visual perception and visual motor memory in the KS group compared with the IQ-matched group on several measures. In contrast, language function appeared to be marginally better in the KS group compared with the IQ-matched group in a sentence comprehension task. CONCLUSIONS: Together, our data suggest specific disruption of visuospatial function, likely linked to the dentate gyrus, in individuals with KS and provide the groundwork for a novel and specific outcome measure for a clinical trial in a KS population.

GABA and Glutamate in Children with Primary Complex Motor Stereotypies: An 1H-MRS Study at 7T.

BACKGROUND AND PURPOSE: Complex motor stereotypies are rhythmic, repetitive, fixed, purposeful but purposeless movements that stop with distraction. They can occur in otherwise normal healthy children (primary stereotypies) as well in those with autism spectrum disorders (secondary stereotypies). The underlying neurobiologic basis for these movements is unknown but is thought to involve cortical-striatal-thalamo-cortical pathways. To further clarify potential neurochemical alterations, gamma-aminobutyric acid (GABA), glutamate, glutamine, N-acetylaspartate, and choline levels were measured in 4 frontostriatal regions by using (1)H MRS at 7T. MATERIALS AND METHODS: A total of 18 children with primary complex motor stereotypies and 24 typically developing controls, ages 5-10 years, completed MR spectroscopy at 7T. Single voxel STEAM acquisitions from the anterior cingulate cortex, premotor cortex, dorsolateral prefrontal cortex, and striatum were obtained, and metabolites were quantified with respect to Cr by using LCModel. RESULTS: The 7T scan was well tolerated by all the participants. Compared with the controls, children with complex motor stereotypies had lower levels of GABA in the anterior cingulate cortex (GABA/Cr, P = .049; GABA/Glu, P = .051) and striatum (GABA/Cr, P = .028; GABA/Glu, P = .0037) but not the dorsolateral prefrontal cortex or the premotor cortex. Glutamate, glutamine, NAA, and Cho levels did not differ between groups in any of the aforementioned regions. Within the complex motor stereotypies group, reduced GABA to Cr in the anterior cingulate cortex was significantly associated with greater severity of motor stereotypies (r = -0.59, P = .021). CONCLUSIONS: These results indicate possible GABAergic dysfunction within corticostriatal pathways in children with primary complex motor stereotypies.

Assessment of attention in preschoolers.

In the past two decades, there has been an increased interest in the assessment and treatment of preschool children presenting with concerns about attention problems. This article reviews the research and clinical literature involving assessment of attention and related skills in the preschool years. While inattention among preschoolers is common, symptoms alone do not necessarily indicate a disorder, and most often represent a normal variation in typical preschool child development. Thus, accurate identification of "disordered" attention in preschoolers can be challenging, and development of appropriate, norm-referenced tests of attention for preschoolers is also difficult. The current review suggests that comprehensive assessment of attention and related functions in the preschool child should include thorough review of the child's history, planned observations, and formal psychometric testing. The three primary methods of psychometric assessment that have been used to characterize attentional functioning in preschool children include performance-based tests, structured caregiver interviews, and rating scales (parent, teacher, and clinician). Among performance-based methods for measurement of attention in the preschool years, tests have been developed to assess sustained attention, selective (focused) attention, span of attention (encoding/manipulation), and (top-down) controlled attention--including freedom from distractibility and set shifting. Many of these tests remain experimental in nature, and review of published methods yields relatively few commercially available, nationally normed tests of attention for preschoolers, and an overall dearth of reliability and validity studies on the available measures.

A preliminary neuroimaging study of preschool children with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder that, by current definition, has onset prior to age 7 years. MRI studies have provided some insight into brain differences associated with ADHD, but thus far have almost exclusively focused on children ages 7 years and older. To better understand the neurobiological development of ADHD, cortical and subcortical brain development should be systematically examined in younger children presenting with symptoms of the disorder. High-resolution anatomical (MPRAGE) images, acquired on a 3.0T scanner, were analyzed in a total of 26 preschoolers, ages 4-5 years (13 with ADHD, 13 controls, matched on age and sex). The ADHD sample was diagnosed using DSM-IV criteria, and screened for language disorders. Cortical regions were delineated and measured using automated methods in Freesurfer; basal ganglia structures were manually delineated. Children with ADHD showed significantly reduced caudate volumes bilaterally; in contrast there were no significant group differences in cortical volume or thickness in this age range. After controlling for age and total cerebral volume, left caudate volume was a significant predictor of hyperactive/impulsive, but not inattentive symptom severity. Anomalous basal ganglia, particularly caudate, development appears to play an important role among children presenting with early onset symptoms of ADHD.

Low cerebellar vermis volumes and impaired neuropsychologic performance in children treated for brain tumors and leukemia.

BACKGROUND AND PURPOSE: Injury of the cerebellar vermis may occur in children with brain malignancies. Because the vermis is involved in motor and cognitive functioning, the goal of this prospective longitudinal study was to evaluate treatment-related changes in vermal volumes and neuropsychologic performance in children receiving brain radiation of the cerebellum. MATERIALS AND METHODS: Ten patients (mean age, 11.6 years) and 10 healthy children (mean age, 12.1 years) were examined. Lobar vermal volumes and performance on neuropsychologic tests evaluating motor, visual, verbal, attention, memory, and executive functions were assessed at baseline and at 6-month follow-up visits. RESULTS: At baseline, lower mean vermal volumes and impaired performance on visual-spatial and fine-motor tasks were detected in patients. At 6-month follow-up, further decrease in vermal volumes was detected only in patients with medulloblastoma, who received the largest radiation doses to the entire vermis. The volume decrease was not associated with reduction in neuropsychologic performance compared with baseline. At 6-month follow-up, data from all subjects revealed an association between smaller vermal volumes and slower fine-motor speed and lower visual-spatial skills. CONCLUSIONS: Reduced brain-tissue volumes following radiation have been reported previously in pediatric patients. In this study, lower vermal volumes were detected even earlier, before radiation treatment was initiated or completed. Six months postradiation, vermal volume decreases detected in patients with medulloblastoma were not accompanied by declines in already poor neuropsychologic performance. In addition to radiation, the presence of brain malignancies and preradiation treatment may be important factors affecting cerebellar vermis tissue.

Proton MR spectroscopy correlates of frontal lobe function in healthy children.

BACKGROUND AND PURPOSE: Neuroimaging methods have been used to improve our understanding of the topographic organization of the brain. In our study, proton (1)H-MR spectroscopic imaging was used to evaluate frontal lobe function. The goal was to determine the relationship between neuropsychological measures of frontal lobe function and levels of a surrogate neuronal marker, N-acetylaspartate (NAA), in typically developing healthy children and adolescents. MATERIALS AND METHODS: Fifty-one healthy children (25 girls; 6.2-18.3 years of age; mean age, 12.3 +/- 3.6 years) were examined. All children completed a neuropsychological assessment including measures of attention, executive function, memory, language, and visual and motor skills. (1)H-MR spectroscopic imaging was performed by using a multisection spin-echo sequence at 1.5T. General linear model analysis of covariance was used to examine the relationship between the neuropsychological test scores and NAA/creatine (Cr) ratios, controlling for age and sex. RESULTS: A positive relationship between frontal lobe white matter NAA/Cr ratio and performance on 2 neuropsychological tests associated with frontal lobe function was detected. The Purdue Pegboard right-hand scores were higher with increasing NAA/Cr in the left frontal white matter (P = .047), and Stanford-Binet-IV "Bead Memory" scores improved with increasing NAA/Cr ratio in the right frontal white matter (P = .032). CONCLUSIONS: An association between frontal white matter NAA/Cr ratios and 1) measures of manual speed and dexterity, and 2) visual working memory was detected. Our data may provide a quantitative basis for assessment of frontal lobe impairments in disease states.

Age-related changes in motor subtle signs among girls and boys with ADHD.

OBJECTIVE: To examine differences in age-related improvement in motor speed and neurologic subtle signs (overflow and dysrhythmia) among boys and girls with and without attention-deficit hyperactivity disorder (ADHD). METHOD: Diagnosis of ADHD was determined by structured parent interview and administration of ADHD-specific and broad behavior rating scales. Motor function was assessed using the revised Physical and Neurological Assessment of Subtle Signs. Three primary outcome variables were obtained: 1) total time, 2) total overflow, and 3) total dysrhythmia. Effects of age, group, and sex were assessed. RESULTS: Both control and ADHD groups showed improvement on timed tasks with age; however, controls were consistently faster across the age span. Controls and girls with ADHD showed steady age-related reduction of overflow and dysrhythmia, whereas boys with ADHD had little improvement in these signs through age 14 years. CONCLUSION: Results indicated that girls with attention-deficit hyperactivity disorder (ADHD) performed similarly to age-matched controls on a quantified motor examination. These results parallel patterns of findings from neuroimaging studies, in which neurologic anomalies in areas related to motor control are present in boys with ADHD, but more equivocal in girls with ADHD. Sex-related differences observed in children with ADHD likely extend beyond symptom presentation to development of motor control, and are likely related to earlier brain maturation in girls.

Dyspraxia in autism: association with motor, social, and communicative deficits.

Impaired performance of skilled gestures, referred to as dyspraxia, is consistently reported in children with autism; however, its neurological basis is not well understood. Basic motor skill deficits are also observed in children with autism and it is unclear whether dyspraxia observed in children with autism can be accounted for by problems with motor skills. Forty-seven high-functioning children with an autism spectrum disorder (ASD), autism, or Asperger syndrome (43 males, four females; mean age 10y 7m [SD 1y 10m], mean Full-scale IQ (FSIQ) 99.4 [SD 15.9]), and 47 typically developing (TD) controls (41 males, six females; mean age 10y 6m [SD 1y 5m], mean FSIQ 113.8 [SD 12.3], age range 8-4y) completed: (1) the Physical and Neurological Assessment of Subtle Signs, an examination of basic motor skills standardized for children, and (2) a praxis examination that included gestures to command, to imitation, and with tool-use. Hierarchical regression was used to examine the association between basic motor skill performance (i.e. times to complete repetitive limb movements) and praxis performance (total praxis errors). After controlling for age and IQ, basic motor skill was a significant predictor of performance on praxis examination. Nevertheless, the ASD group continued to show significantly poorer praxis than controls after accounting for basic motor skill. Furthermore, praxis performance was a strong predictor of the defining features of autism, measured using the Autism Diagnostic Observation Schedule, and this correlation remained significant after accounting for basic motor skill. Results indicate that dyspraxia in autism cannot be entirely accounted for by impairments in basic motor skills, suggesting the presence of additional contributory factors. Furthermore, praxis in children with autism is strongly correlated with the social, communicative, and behavioral impairments that define the disorder, suggesting that dyspraxia may be a core feature of autism or a marker of the neurological abnormalities underlying the disorder.

Subtle executive impairment in children with autism and children with ADHD.

BACKGROUND: The executive functions of inhibition, planning, flexible shifting of actions, and working memory are commonly reported to be impaired in neurodevelopmental disorders. METHOD: We compared these abilities in children (8-12 years) with high functioning autism (HFA, n = 17), attention deficit-hyperactivity disorder (ADHD, n = 21) and healthy controls (n = 32). Response inhibition was assessed using the Stroop Color and Word Test (Golden, 1978). Problem solving, set-shifting, and nonverbal memory were assessed using three tasks, respectively, from the CANTAB (Cambridge Cognition, 1996): the Stockings of Cambridge task; the Intra-Dimensional/Extra-Dimensional set-shifting task; and the Spatial Working Memory task (SWM) with tokens hidden behind 3, 4, 6, and 8 boxes. RESULTS: There were no group differences on the response inhibition, planning, or set-shifting tasks. On the SWM task, children with HFA made significantly more between-search errors compared with controls on both the most difficult problems (8-box) and on the mid-difficulty problems (6-box); however, children with ADHD made significantly more errors compared to controls on the most difficult (8-box) problems only. CONCLUSION: Our findings suggest that spatial working memory is impaired in both ADHD and HFA, and more severely in the latter. More detailed investigation is needed to examine the mechanisms that differentially impair spatial working memory, but on this set of tasks there appears to be sparing of other executive functions in these neuropsychiatric developmental disorders.

Executive function in fluency and recall measures among children with Tourette syndrome or ADHD.

This study assessed two relevant aspects of executive dysfunction in children with either Tourette syndrome (TS) or ADHD. Process variables derived from existing neuropsychological measures were used to clarify the executive function construct. Clustering of responses on measures of verbal fluency, figural fluency, and verbal learning was examined to assess strategic response organization. Rule breaks, intrusions, and repetition errors were recorded to assess inhibition errors. No significant differences were found among the three groups (TS, ADHD, and controls) on tasks of response organization (clustering). In our sample, both the ADHD and the TS groups were largely free from executive function impairment, and their performance on the fluency and list learning tasks was in the average range. There was a significant group difference on one of the disinhibition variables, with both TS and ADHD groups showing significantly more intrusions on verbal list learning trials than controls. When more traditional total score variables were analyzed among the three groups, there were no significant differences; however, analysis of effect size revealed medium-to-large effect sizes for Letter Word Fluency total score differences (ADHD vs. controls), and for Semantic Word Fluency total score differences (ADHD vs. TS), with the ADHD group having weaker performance in both comparisons. Results provide some support for the use and analysis of process variables-particularly those related to inhibition and intrusion errors, in addition to the total score variables when assessing executive function deficits in children with ADHD and TS. While group differences may be found, children with uncomplicated TS should not routinely be considered to have significant executive function impairments, and when deficits are found, they may be attributable to other comorbid disorders.