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.

Quantifying excessive mirror overflow in children with attention-deficit/hyperactivity disorder.

OBJECTIVES: Qualitative observations have revealed that children with attention-deficit/hyperactivity disorder (ADHD) show increased overflow movements, a motor sign thought to reflect impaired inhibitory control. The goal of this study was to develop and implement methods for quantifying excessive mirror overflow movements in children with ADHD. METHODS: Fifty right-handed children aged 8.2-13.3 years, 25 with ADHD (12 girls) and 25 typically developing (TD) control children (10 girls), performed a sequential finger-tapping task, completing both left-handed (LHFS) and right-handed finger sequencing (RHFS). Phasic overflow of the index and ring fingers was assessed in 34 children with video recording, and total overflow in 48 children was measured by calculating the total angular displacement of the index and ring fingers with electrogoniometer recordings. RESULTS: Phasic overflow and total overflow across both hands were greater in children with ADHD than in TD children, particularly during LHFS. Separate gender analyses revealed that boys, but not girls, with ADHD showed significantly more total phasic overflow and total overflow than did their gender-matched control children. CONCLUSIONS: The quantitative overflow measures used in this study support past qualitative findings that motor overflow persists to a greater degree in children with ADHD than in age-matched TD peers. The quantitative findings further suggest that persistence of mirror overflow is more prominent during task execution of the nondominant hand and reveal gender-based differences in developmental neural systems critical to motor control. These quantitative measures will assist future physiologic investigation of the brain basis of motor control in ADHD.

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.

Sex differences in cerebral laterality of language and visuospatial processing.

Sex differences on language and visuospatial tasks are of great interest, with differences in hemispheric laterality hypothesized to exist between males and females. Some functional imaging studies examining sex differences have shown that males are more left lateralized on language tasks and females are more right lateralized on visuospatial tasks; however, findings are inconsistent. Here we used functional magnetic resonance imaging to study thirty participants, matched on task performance, during phonological and visuospatial tasks. For each task, region-of-interest analyses were used to test differences in cerebral laterality. Results indicate that lateralization differences exist, with males more left lateralized during the phonological task and showing greater bilateral activity during the visuospatial task, whereas females showed greater bilateral activity during the phonological task and were more right lateralized during the visuospatial task. Our data provide clear evidence for differences in laterality between males and females when processing language versus visuospatial information.

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.

Cortical correlates of neuromotor development in healthy children.

OBJECTIVE: To examine the relationship between acquisition of fine motor skills in childhood and development of the motor cortex. METHODS: We measured finger tapping speed and mirror movements in 43 healthy right-handed subjects (6-26 years of age). While recording surface electromyographic activity from right and left first dorsal interosseus, we delivered focal transcranial magnetic stimulation (TMS) over the hand areas of each motor cortex. We measured motor evoked potential (MEP) threshold, and ipsilateral (iSP) and contralateral (CSP) silent periods. RESULTS: As children got older, finger speeds got faster, MEP threshold decreased, iSP duration increased and latency decreased. Finger tapping speed got faster as motor thresholds and iSP latency decreased, but was unrelated to CSP duration. In all subjects right hemisphere MEP thresholds were higher than those on the left and duration of right hemisphere CSP was longer than that on the left. Children under 10 years of age had higher left hand mirror movement scores, and fewer left hemisphere iSPs which were of longer duration. CONCLUSIONS: Maturation of finger tapping skills is closely related to developmental changes in the motor threshold and iSP latency. Studies are warranted to explore the relationship between these measures and other neuromotor skills in children with motor disorders. SIGNIFICANCE: TMS can provide important insights into certain functional aspects of neurodevelopment in children.

Megalencephaly in NF1: predominantly white matter contribution and mitigation by ADHD.

BACKGROUND: Megalencephaly is a frequent CNS manifestation in neurofibromatosis type 1 (NF1); however, its tissue composition, modification by attention deficit hyperactivity disorder (ADHD), and relationship with unidentified bright objects (UBO) remain controversial. METHODS: Eighteen male patients with NF1, seven of whom had ADHD (NF1+ADHD), were compared with 18 age- and sex-matched controls in terms of MRI-, Talairach-based brain, cerebral, lobar, and sublobar gray and white matter volumes. Twelve subjects with NF1 had UBO in the centrencephalic region, whereas six had no UBO or exclusively infratentorial lesions. RESULTS: Patients with NF1 without ADHD (NF1-pure) had the largest total cerebral, gray, and white matter volumes with larger parietal/somatosensory white matter volumes than controls, particularly if UBO were present in the basal ganglia. All subjects with NF1 (including NF1+ADHD) had larger total and frontal white matter volumes than controls. Smaller frontal/right prefrontal gray matter volumes were found in NF1+ADHD when compared with NF1-pure patients. CONCLUSIONS: The increase in frontal and parietal white matter volumes in male patients with NF1, including the preferential centrencephalic distribution, supports the hypothesis that NF1's white matter pathology encompasses but is not limited to visible UBO. Male patients with NF1+ADHD, as compared with NF1-pure patients, showed frontal reductions that are largely consistent with those found in idiopathic ADHD.

Disproportionate increases of white matter in right frontal lobe in Tourette syndrome.

OBJECTIVE: Based on previous findings implicating abnormalities of cortico-striatal-thalamo-cortical circuitry in Tourette syndrome (TS), the authors performed a volumetric analysis of frontal and nonfrontal tissue (gray + white matter) in boys with TS, with and without attention deficit hyperactivity disorder (ADHD). METHODS: Frontal and nonfrontal gray and white matter compartment volumes, obtained by a MRI protocol, were analyzed with a 2 x 2 factorial multivariate analysis of variance approach for associations with a TS or ADHD factor in 11 boys with TS only, 14 with TS + ADHD, 12 with ADHD only, and 26 healthy boys. RESULTS: In subjects with TS, the right frontal lobe showed a larger proportion of white matter. In addition, results were consistent with previous reports of reduced frontal lobe volumes associated with ADHD. Our analyses suggested these reductions to be mainly the consequence of smaller gray matter volumes, particularly on the left. CONCLUSIONS: These findings, suggesting the volumetric composition of frontal lobe tissue to be different in TS, support the hypothesis proposing frontostriatal pathway involvement in the pathophysiology of the disorder. Differences in composition of right frontal lobe attributable to white matter do not definitively implicate the hypothesized fiber pathways; however, considered in the context of the unilateral directionality of frontal-striatal circuitry, these results suggest the white matter connections as one explanation for basal ganglia anomalies (loss of normal left > right asymmetry) in TS.

Oculomotor abnormalities in attention deficit hyperactivity disorder: a preliminary study.

BACKGROUND: Prevailing hypotheses suggest that attention deficit hyperactivity disorder (ADHD) is secondary to dysfunction of motor intentional systems mediated by prefrontal circuitry. Oculomotor paradigms provide a mechanism for examining and localizing dysfunction at the interface between movement and cognition. OBJECTIVE: Three different saccade tasks (reflexive or prosaccades, antisaccades, and memory-guided saccades) were used to examine functions necessary for the planning and the execution of eye movements, including motor response preparation, response inhibition, and working memory. METHODS: The study included 19 children with ADHD, divided into two groups: a group of 8 children on methylphenidate at the time of testing and a group of 11 children not taking any psychoactive medication. Results from the two groups were compared with those from 25 age- and gender-matched normal control children. RESULTS: Both groups of children with ADHD made significantly more directional errors than did controls on the antisaccade task and significantly more anticipatory errors than did controls on the memory-guided saccade task, findings that are consistent with deficits in response inhibition. There were no significant differences in prosaccade latency, although unmedicated children with ADHD showed significantly greater variability in latency on the prosaccade task than did controls. On the memory-guided saccade task there were no significant differences in saccade accuracy; however, unmedicated children with ADHD showed longer saccade latency than did either controls or medicated children with ADHD. CONCLUSIONS: Oculomotor findings suggest that deficits in prefrontal functions, in particular response inhibition, contribute to behavioral abnormalities observed in ADHD. Findings also suggest that the administration of methylphenidate is associated with improvements in the consistency of motor response. Although there were no observed improvements in response inhibition with methylphenidate, conclusions await a design in which subjects complete testing both on and off medication.

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.

Depth of lesion model in children and adolescents with moderate to severe traumatic brain injury: use of SPGR MRI to predict severity and outcome.

OBJECTIVES: The utility of a depth of lesion classification using an SPGR MRI sequence in children with moderate to severe traumatic brain injury (TBI) was examined. Clinical and depth of lesion classification measures of TBI severity were used to predict neurological and functional outcome after TBI. METHODS: One hundred and six children, aged 4 to 19, with moderate to severe TBI admitted to a rehabilitation unit had an SPGR MRI sequence obtained 3 months afterTBI. Acquired images were analyzed for location, number, and size of lesions. The Glasgow coma scale (GCS) was the clinical indicator of severity. The deepest lesion present was used for depth of lesion classification. Speed of injury was inferred from the type of injury. The disability rating scale at the time of discharge from the rehabilitation unit (DRS1) and at 1 year follow up (DRS2) were functional outcome measures. RESULTS: The depth of lesion classification was significantly correlated with GCS severity, number of lesions, and both functional measures, DRS1 and DRS2. This result was more robust for time 1, probably due to the greater number of psychosocial factors impacting on functioning at time 2. Lesion volume was not correlated with the depth of lesion model. In multivariate models, depth of lesion was most predictive of DRS1, whereas GCS was most predictive of DRS2. CONCLUSIONS: A depth of lesion classification of TBI severity may have clinical utility in predicting functional outcome in children and adolescents with moderate to severe TBI.

Oculomotor abnormalities in boys with tourette syndrome with and without ADHD.

OBJECTIVE: To assess saccadic eye movements in boys with Tourette syndrome (TS) with and without attention-deficit hyperactivity disorder (ADHD), comparing performance with that of an age-matched group of male controls. METHOD: Three different saccade tasks (prosaccades, antisaccades, and memory-guided saccades) were used to examine functions necessary for the planning and execution of eye movements, including motor response preparation, response inhibition, and working memory. The study included 14 boys with TS without ADHD (TS-only), 11 boys with TS and ADHD (TS+ADHD), and 10 male controls. RESULTS: Latency of prosaccades was prolonged in boys with TS (both with and without ADHD) compared with controls. Variability in prosaccade latency was greater in the groups of boys with TS+ADHD compared with both the TS-only and control groups. Response inhibition errors on both the antisaccade task (directional errors) and memory-guided saccade task (anticipatory errors) were increased in boys with TS+ADHD compared with those with TS-only. There were no significant differences among the three groups in accuracy of memory-guided saccades. CONCLUSIONS: Oculomotor findings suggest that TS is associated with delay in initiation of motor response as evidenced by excessive latency on prosaccades. Signs of impaired response inhibition and variability in motor response appear to be associated with the presence of ADHD.

Evidence for a deficit in procedural learning in children and adolescents with autism: implications for cerebellar contribution.

To examine the hypothesis that abnormalities in those cognitive functions for which cerebellar components have been implicated contribute to the pathophysiology of autism, tests of judgment of explicit time intervals and procedural learning were administered to 11 participants with autism and 17 age-and-IQ-matched controls. Results indicated that the group with autism demonstrated significant impairments in procedural learning compared with the group of controls. No significant difference in judgment of explicit time intervals was found. The data suggest that deficits in procedural learning may contribute to the cognitive and behavioral phenotype of autism; these deficits may be secondary to abnormalities in cerebellar-frontal circuitry.

How children with neurofibromatosis type 1 differ from "typical" learning disabled clinic attenders: nonverbal learning disabilities revisited.

To further investigate cognitive deficits in children with Neurofibromatosis Type 1 (NF-1), children with NF-1 were compared to typical learning disabled clinic attenders (LD-clinic), all of whom had reading disabilities, as well as to a group with no disabilities (NoDx). Results indicated that both the NF-1 group and LD-clinic group had reading and reading-related deficits when compared to the NoDx group; however, the NF-1 group was more globally language impaired than the LD-clinic group. In addition, the NF-1 group scored significantly lower than the LD-clinic group, but not the NoDx group, on the visuospatial measures, thus confirming that children with NF-1 have visuospatial deficits not typical of a general LD-clinic population. The NF-1 group was not impaired in comparison to the NoDx group on certain language and visuospatial tasks that were previously found to be deficits in sibling pairwise matched designs; thus, the importance of considering genetic and familial context when studying the impact of genetic disorders on cognition was demonstrated.

Judgment of duration in individuals with ataxia-telangiectasia.

Several clinical investigations with adults suggest that the cerebellum may be critical for judgment of explicit time intervals; however, little work has been done in populations with lesions of the cerebellum acquired during development. We evaluated 17 individuals with ataxia-telangiectasia (AT), an autosomal recessive disorder with on-set in early childhood characterized by diffuse, almost selective, degeneration of the cerebellar cortex, and 21 normal controls, matched for age. Because patients with AT have motor impairment, verbal IQ (VIQ) was used to estimate intelligence; VIQ was significantly lower in the group with AT (p < .0001). Participants were tested using a test of judgment of duration that has been found to be impaired in adults with cerebellar lesions and a contrasting auditory control task (not impaired in adults with cerebellar lesions) involving judgment of pitch. After statistically controlling for VIQ, the 2 groups did not differ significantly on judgment of pitch, but those with AT performed significantly worse than controls on judgment of duration (p = .01). Children and adolescents with AT show deficits in judgment of duration but not of pitch, suggesting that the cerebellum may be critical for judgment of explicit time intervals at all ages.

Language-based cognitive functioning in parents of offspring with ADHD comorbid for Tourette syndrome or learning disabilities.

The parents of children diagnosed with attention deficit hyperactivity disorder (ADHD) were examined for characteristics symptomatic of 2 comorbidities (Co) within their offspring with ADHD: Tourette syndrome (TS) and language-based learning disabilities (LD). A 2 x 2 multivariate analysis of variance design was used; the parents were divided according to whether the offspring with ADHD had TS (Co-TS) or not (No Co-TS) and whether offspring had LD (Co-LD) or not (No Co-LD). Parents (86 mothers and 70 fathers) were administered the short form of the Wechsler Adult Intelligence Scale--Revised (WAIS-R; Wechsler, 1981), subtests of the Woodcock-Johnson Cognitive and Achievement Batteries (Woodcock & Johnson, 1989), and word fluency (semantic and letter; Benton & Hamsher, 1989; Wiig & Semel, 1987). The fathers of offspring with Co-TS were more likely to be diagnosed with LD and had lower WAIS-R Vocabulary, Arithmetic, and Picture Arrangement scores. In addition, when the WAIS-R full scale IQ was used as a covariate, these fathers had lower Woodcock-Johnson Oral Vocabulary, Spelling, and Reading scores (as measured by Letter-Word Identification). The mothers of children with Co-TS had lower WAIS-R Vocabulary scores. Parents of the children with No Co-TS showed a higher proportion of error patterns on the word fluency tasks involving repetitions and rule breaks. The findings show that it was the parents of the children with Co-TS, not the parents of the children with Co-LD, who showed language-based learning problems. In separate discriminant analyses for the fathers and mothers, when the aforementioned significant parental measures were used as predictors, 81% of offspring with Co-TS were correctly classified as having a diagnosis of TS, solely on the basis of characteristics in their parents.

Subcortical volumes in girls with tourette syndrome: support for a gender effect.

OBJECTIVE: To test whether girls with Tourette syndrome (TS) show subcortical morphology that differentiates them from control subjects. METHODS: MRI-based subcortical assessment was completed on 19 girls with TS age 7 to 15 years, 11 with TS only, and 8 with TS plus attention deficit hyperactivity disorder (TS + ADHD), and on 21 age- and sex-matched controls. The structures measured were the caudate, putamen, globus pallidus, and lateral ventricle volumes. Whole-brain-corrected volumes and asymmetry indices were compared using two- and three-group designs (i.e., TS versus control; TS-only versus TS + ADHD versus control). RESULTS: Two-group comparisons demonstrated no robust significant differences between girls with TS and gender-matched controls. Three-group comparisons demonstrated that TS-only subjects had significantly small lateral ventricles compared with TS + ADHD and control subjects. Because the two-group comparisons of the current study differed from previous reports of putamen asymmetry index as a marker for TS, retrospective comparisons with data from boys were performed. These additional comparisons showed that girls with TS had putamen asymmetry indices similar to those of boys with TS; however, control girls also showed those same patterns. CONCLUSIONS: Basal ganglia volume and asymmetry differences do not distinguish the girls with TS from matched controls. Gender differences confound the association between putamen asymmetry and TS. Although the numbers are small and the clinical significance is unclear, this study further indicates that girls with TS-only have smaller lateral ventricular volumes than control subjects and those with TS + ADHD.

Relationship of cognitive functioning, whole brain volumes, and T2-weighted hyperintensities in neurofibromatosis-1.

Using quantitative magnetic resonance imaging morphometry, we report that the whole brain volumes of patients with neurofibromatosis-1 are significantly larger than normal, confirm the prevalence of macrocephaly as about 50%, and report that macrocephaly in patients with neurofibromatosis-1 does not appear to be related to the familial or sporadic origin of the neurofibromatosis-1 or to the presence or absence of T2-weighted hyperintensities. No strong relationship emerged between the extent of neurofibromatosis-1-associated impairment of cognitive functions and degree of macrocephaly; however, the macrocephalic neurofibromatosis-1 group did have a significant verbal impairment relative to the nonmacrocephalic neurofibromatosis-1 group in vocabulary (P < .009).