Resting-state functional brain connectivity is related to subsequent procedural learning skills in school-aged children.

This magnetoencephalography (MEG) study investigates how procedural sequence learning performance is related to prior brain resting-state functional connectivity (rsFC), and to what extent sequence learning induces rapid changes in brain rsFC in school-aged children. Procedural learning was assessed in 30 typically developing children (mean age ± SD: 9.99 years ± 1.35) using a serial reaction time task (SRTT). During SRTT, participants touched as quickly and accurately as possible a stimulus sequentially or randomly appearing in one of the quadrants of a touchscreen. Band-limited power envelope correlation (brain rsFC) was applied to MEG data acquired at rest pre- and post-learning. Correlation analyses were performed between brain rsFC and sequence-specific learning or response time indices. Stronger pre-learning interhemispheric rsFC between inferior parietal and primary somatosensory/motor areas correlated with better subsequent sequence learning performance and faster visuomotor response time. Faster response time was associated with post-learning decreased rsFC within the dorsal extra-striate visual stream and increased rsFC between temporo-cerebellar regions. In school-aged children, variations in functional brain architecture at rest within the sensorimotor network account for interindividual differences in sequence learning and visuomotor performance. After learning, rapid adjustments in functional brain architecture are associated with visuomotor performance but not sequence learning skills.

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems.

We report the case of a 7-year-old male of Western European origin presenting with moderate intellectual disability, severe childhood apraxia of speech in the presence of oral and manual dyspraxia, and hypotonia across motor systems including the oral and speech motor systems. Exome sequencing revealed a de novo frameshift protein truncating mutation in the fourth exon of BCL11A, a gene recently demonstrated as being involved in cognition and language development. Making parallels with a previously described patient with a 200 kb 2p15p16.1 deletion encompassing the entire BCL11A gene and displaying a similar phenotype, we characterize in depth how BCL11A is involved in clinical aspects of language development and oral praxis.

Neuropsychological and neurophysiological benefits from white noise in children with and without ADHD.

BACKGROUND: Optimal stimulation theory and moderate brain arousal (MBA) model hypothesize that extra-task stimulation (e.g. white noise) could improve cognitive functions of children with attention-deficit/hyperactivity disorder (ADHD). We investigate benefits of white noise on attention and inhibition in children with and without ADHD (7-12 years old), both at behavioral and at neurophysiological levels. METHODS: Thirty children with and without ADHD performed a visual cued Go/Nogo task in two conditions (white noise or no-noise exposure), in which behavioral and P300 (mean amplitudes) data were analyzed. Spontaneous eye-blink rates were also recorded and participants went through neuropsychological assessment. Two separate analyses were conducted with each child separately assigned into two groups (1) ADHD or typically developing children (TDC), and (2) noise beneficiaries or non-beneficiaries according to the observed performance during the experiment. This latest categorization, based on a new index we called "Noise Benefits Index" (NBI), was proposed to determine a neuropsychological profile positively sensitive to noise. RESULTS: Noise exposure reduced omission rate in children with ADHD, who were no longer different from TDC. Eye-blink rate was higher in children with ADHD but was not modulated by white noise. NBI indicated a significant relationship between ADHD and noise benefit. Strong correlations were observed between noise benefit and neuropsychological weaknesses in vigilance and inhibition. Participants who benefited from noise had an increased Go P300 in the noise condition. CONCLUSION: The improvement of children with ADHD with white noise supports both optimal stimulation theory and MBA model. However, eye-blink rate results question the dopaminergic hypothesis in the latter. The NBI evidenced a profile positively sensitive to noise, related with ADHD, and associated with weaker cognitive control.

Atypical procedural learning skills in children with Developmental Coordination Disorder.

We investigated the procedural learning deficit hypothesis in Developmental Coordination Disorder (DCD) while controlling for global performance such as slower reaction times (RTs) and variability. Procedural (sequence) learning was assessed in 31 children with DCD and 31 age-matched typically developing (TD) children through a serial reaction time task (SRTT). Sequential and random trial conditions were intermixed within five training epochs. Two repeated measures ANOVAs were conducted on a Sequence-Specific Learning Index (SSLI) and a Global Performance Index (GPI, speed/accuracy measure) with Epoch (for SSLI and GPI) and Condition (for GPI) as within-subjects factors, and Group as between-subjects factor. Controlling for RTs differences through normalized RTs, revealed a global reduction of SSLI in children with DCD compared with TD peers suggesting reduced sequence learning skills in DCD. Still, a significant Group x Condition interaction observed on GPI indicated that children from both groups were able to discriminate between sequential and random trials. DCD presented reduced procedural learning skills after controlling for global performance. This finding highlights the importance of considering the general functioning of the child while assessing learning skills in patients.

How the Spreading and Intensity of Interictal Epileptic Activity Are Associated with Visuo-Spatial Skills in Children with Self-Limited Focal Epilepsy with Centro-Temporal Spikes.

This paper investigates brain-behaviour associations between interictal epileptic discharges and cognitive performance in a population of children with self-limited focal epilepsy with centro-temporal spikes (SeLECTS). Sixteen patients with SeLECTS underwent an extensive neuropsychological assessment, including verbal short-term and episodic memory, non-verbal short-term memory, attentional abilities and executive function. Two quantitative EEG indices were analysed, i.e., the Spike Wave Index (SWI) and the Spike Wave Frequency (SWF), and one qualitative EEG index, i.e., the EEG score, was used to evaluate the spreading of focal SW to other parts of the brain. We investigated associations between EEG indices and neuropsychological performance with non-parametric Spearman correlation analyses, including correction for multiple comparisons. The results showed a significant negative correlation between (i) the awake EEG score and the Block Tapping Test, a visuo-spatial short-term memory task, and (ii) the sleep SWI and the Tower of London, a visuo-spatial planning task (pcorr < 0.05). These findings suggest that, in addition to the usual quantitative EEG indices, the EEG analysis should include the qualitative EEG score evaluating the spreading of focal SW to other parts of the brain and that neuropsychological assessment should include visuo-spatial skills.

Cognitive, perceptual, and motor profiles of school-aged children with developmental coordination disorder.

Developmental coordination disorder (DCD) is a heterogeneous condition. Besides motor impairments, children with DCD often exhibit poor visual perceptual skills and executive functions. This study aimed to characterize the motor, perceptual, and cognitive profiles of children with DCD at the group level and in terms of subtypes. A total of 50 children with DCD and 31 typically developing (TD) peers (7-11 years old) underwent a comprehensive neuropsychological (15 tests) and motor (three subscales of the Movement Assessment Battery for Children-2) assessment. The percentage of children with DCD showing impairments in each measurement was first described. Hierarchical agglomerative and K-means iterative partitioning clustering analyses were then performed to distinguish the subtypes present among the complete sample of children (DCD and TD) in a data-driven way. Moderate to large percentages of children with DCD showed impaired executive functions (92%) and praxis (meaningless gestures and postures, 68%), as well as attentional (52%), visual perceptual (46%), and visuomotor (36%) skills. Clustering analyses identified five subtypes, four of them mainly consisting of children with DCD and one of TD children. These subtypes were characterized by: (i) generalized impairments (8 children with DCD), (ii) impaired manual dexterity, poor balance (static/dynamic), planning, and alertness (15 DCD and 1 TD child), (iii) impaired manual dexterity, cognitive inhibition, and poor visual perception (11 children with DCD), (iv) impaired manual dexterity and cognitive inhibition (15 DCD and 5 TD children), and (v) no impairment (25 TD and 1 child with DCD). Besides subtle differences, the motor and praxis measures did not enable to discriminate between the four subtypes of children with DCD. The subtypes were, however, characterized by distinct perceptual or cognitive impairments. These results highlight the importance of assessing exhaustively the perceptual and cognitive skills of children with DCD.

Atypical resting-state functional brain connectivity in children with developmental coordination disorder.

Children with developmental coordination disorder (DCD) present lower abilities to acquire and execute coordinated motor skills. DCD is frequently associated with visual perceptual (with or without motor component) impairments. This magnetoencephalography (MEG) study compares the brain resting-state functional connectivity (rsFC) and spectral power of children with and without DCD. 29 children with DCD and 28 typically developing (TD) peers underwent 2 × 5 min of resting-state MEG. Band-limited power envelope correlation and spectral power were compared between groups using a functional connectome of 59 nodes from eight resting-state networks. Correlation coefficients were calculated between fine and gross motor activity, visual perceptual and visuomotor abilities measures on the one hand, and brain rsFC and spectral power on the other hand. Nonparametric statistics were used. Significantly higher rsFC between nodes of the visual, attentional, frontoparietal, default-mode and cerebellar networks was observed in the alpha (maximum statistics, p = .0012) and the low beta (p = .0002) bands in children with DCD compared to TD peers. Lower visuomotor performance (copying figures) was associated with stronger interhemispheric rsFC within sensorimotor areas and power in the cerebellum (right lobule VIII). Children with DCD showed increased rsFC mainly in the dorsal extrastriate visual brain system and the cerebellum. However, this increase was not associated with their coordinated motor/visual perceptual abilities. This enhanced functional brain connectivity could thus reflect a characteristic brain trait of children with DCD compared to their TD peers. Moreover, an interhemispheric compensatory process might be at play to perform visuomotor task within the normative range.

Motor Abnormalities in Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Are Associated With Regional Grey Matter Volumes.

Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are associated with motor impairments, with some children holding a comorbid diagnosis of Developmental Coordination Disorder (DCD). However, DCD is underdiagnosed in these populations and the volume abnormalities that contribute to explaining these motor impairments are poorly understood. In this study, motor abilities as measured by the Developmental Coordination Disorder Questionnaire (DCDQ) were compared between children with ADHD, children with ASD and typically developing (TD) children, aged 8-12 years old. Additionally, the association between the DCDQ scores (general coordination, fine motor/handwriting, control during movement, total) and regional volume abnormalities were explored in 6 regions of interest (pre-central gyrus, post-central gyrus, inferior parietal cortex, superior frontal gyrus, middle frontal gyrus, medial frontal gyrus), within each group and across all participants. Children with ASD and children with ADHD showed impaired motor abilities in all the DCDQ-derived scores compared to TD children. Additionally, most children with ASD or ADHD had an indication or suspicion of DCD. Within the ASD group, coordination abilities were associated with the volume of the right medial frontal gyrus, and within the ADHD group, the total DCDQ score was associated with the volume of the right superior frontal gyrus. This study underlines the importance of routinely checking motor abilities in populations with ASD or ADHD in clinical practise and contributes to the understanding of structural abnormalities subtending motor impairments in these disorders.

Relationship Between White Matter Abnormalities and Neuropsychological Measures in Children With ADHD.

Objective: Using Diffusion Tensor Imaging (DTI), to investigate microstructural white matter differences between ADHD and typically developing children (TDC), and their association with inhibition and working memory performance usually impaired in ADHD. Method: Fractional anisotropy (FA) and mean diffusivity (MD) were estimated in 36 noncomorbid children with a Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) diagnosis of combined type ADHD and 20 TDC. Correlations between FA/MD and Stop Signal Task and N-Back performance parameters were computed. Results: Working memory performance was significantly associated with MD in the superior longitudinal fasciculus (SLF) and the cingulum in the ADHD group. No between-group differences in FA/MD reached significance, after controlling for between-group head motion differences. Conclusion: The association between white matter integrity in the cingulum and the SLF and working memory performance confirms previous studies. Our results also show that when critical conditions are controlled (age, comorbidity, head motion), no ADHD-related structural abnormality (FA/MD) are observed, in line with prior suggestions.

Disorder-specific brain volumetric abnormalities in Attention-Deficit/Hyperactivity Disorder relative to Autism Spectrum Disorder.

The overlap/distinctiveness between Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) has been increasingly investigated in recent years, particularly since the DSM-5 allows the dual diagnosis of ASD and ADHD, but the underlying brain mechanisms remain unclear. Although both disorders are associated with brain volumetric abnormalities, it is necessary to unfold the shared and specific volume abnormalities that could contribute to explain the similarities and differences in the clinical and neurocognitive profiles between ADHD and ASD. In this voxel-based morphometry (VBM) study, regional grey matter volumes (GMV) were compared between 22 children with ADHD, 18 children with ASD and 17 typically developing (TD) children aged 8 to 12 years old, controlling for age and total intracranial volume. When compared to TD children or children with ASD, children with ADHD had a larger left precuneus, and a smaller right thalamus, suggesting that these brain abnormalities are specific to ADHD relative to ASD. Overall, this study contributes to the delineation of disorder-specific structural abnormalities in ADHD and ASD.

ADHD and ASD: distinct brain patterns of inhibition-related activation?

Attention-deficit/hyperactivity (ADHD) and autism spectrum (ASD) disorders often co-occur. In both cases, response inhibition deficits and inhibition-related atypical brain activation have been reported, although less consistently in ASD. Research exploring the overlap/distinctiveness between ADHD and ASD has significantly increased in recent years, but direct comparison of the inhibition-related neuronal correlates between these disorders are scarce in the literature. This study aimed at disentangling the shared and specific inhibitory brain dysfunctions in ASD and ADHD. Using functional magnetic resonance imaging (fMRI), brain activity was compared between children with ADHD, ASD and typically developing (TD) children aged 8-12 years during an inhibition stop-signal task, using stringent inclusion criteria. At the behavioural level, only children with ADHD exhibited inhibition deficits when compared with the TD group. Distinct patterns of brain activity were observed during successful inhibition. In children with ADHD, motor inhibition was associated with right inferior parietal activation, whereas right frontal regions were activated in children with ASD. Between-group comparisons disclosed higher middle frontal activation in the ASD group compared with the ADHD and the TD groups. Our results evidence different patterns of activation during inhibition in these two disorders, recruiting different regions of the fronto-parietal network associated to inhibition. Besides brain activity differences, behavioural inhibition deficits found only in children with ADHD further suggest that reactive inhibition is one of the core deficits in ADHD, but not in ASD. Our findings provide further evidence contributing to disentangle the shared and specific inhibitory dysfunctions in ASD and ADHD.

Dopamine transporter genotype modulates brain activity during a working memory task in children with ADHD.

Dopamine active transporter gene (DAT1) is a candidate gene associated with attention-deficit/hyperactivity disorder (ADHD). The DAT1 variable number tandem repeat (VNTR)-3' polymorphism is functional and 9R carriers have been shown to produce more DAT than 10R homozygotes. We used functional magnetic resonance imaging (fMRI) to investigate the effects of this polymorphism on the neural substrates of working memory (WM) in a small but selected population of children with ADHD, naïve of any psychotropic treatment and without comorbidity. MRI and genotype data were obtained for 36 children (mean age: 10,36 +/- 1,49 years) with combined-type ADHD (9R n = 15) and 25 typically developing children (TDC) (mean age: 9,55 +/- 1,25 years) (9R n = 12). WM performance was similar between conditions. We found a cross-over interaction effect between gene (9R vs. 10R) and diagnosis (TDC vs. ADHD) in the orbito-frontal gyrus, cerebellum and inferior temporal lobe. In these areas, WM-related activity was higher for 9R carriers in ADHD subjects and lower in TDC. In ADHD children only, 10R homozygotes exhibited higher WM-related activity than 9R carriers in a network encompassing the parietal and the temporal lobes, the ventral visual cortex, the orbito-frontal gyrus and the head of the caudate nucleus. There was no significant results in TDC group. Our preliminary findings suggest that DAT1 VNTR polymorphism can modulate WM-related brain activity ADHD children.

Hyperactivity in motor response inhibition networks in unmedicated children with attention deficit-hyperactivity disorder.

OBJECTIVES: Hypo/reduced activity in motor response inhibition (RI) cerebral networks was recently proposed as a promising specific neurobiological marker of attention deficit-hyperactivity disorder (ADHD). Before adopting such a pattern as a key diagnosis tool, we aim to replicate in an independent study the mechanisms underlying reduced RI-related activity in ADHD, after controlling for potentially confounding effects. METHODS: In this fMRI study, we investigated the neural networks mediating successful and failed motor RI in children with ADHD and typically developing children (TDC) using the stop-signal task (SST) paradigm. RESULTS: In contrast to hypofrontality predictions, children with ADHD exhibit increased neural activity during successful response inhibition in an RI-related brain network encompassing the indirect and/or hyperdirect pathways between the basal ganglia and cortex. Voxel-based morphometry analyses have further evidenced reduced grey matter volume in the left caudate in children with ADHD, which paralleled higher functional responses. Finally, connectivity analyses disclosed tighter coupling between a set of cortical regions and the right caudate as well as the right IFG, networks involved in successful RI. CONCLUSIONS: Hypo/reduced activity in RI cerebral networks in children with ADHD cannot at this time be considered as a systematic biomarker for ADHD.

EEG Dynamics of a Go/Nogo Task in Children with ADHD.

BACKGROUND: Studies investigating event-related potential (ERP) evoked in a Cue-Go/NoGo paradigm have shown lower frontal N1, N2 and central P3 in children with attention-deficit/hyperactivity disorder (ADHD) compared to typically developing children (TDC). However, the electroencephalographic (EEG) dynamics underlying these ERPs remain largely unexplored in ADHD. METHODS: We investigate the event-related spectral perturbation and inter-trial coherence linked to the ERP triggered by visual Cue-Go/NoGo stimuli, in 14 children (7 ADHD and 7 TDC) aged 8 to 12 years. RESULTS: Compared to TDC, the EEG dynamics of children with ADHD showed a lower theta-alpha ITC concomitant to lower occipito-parietal P1-N2 and frontal N1-P2 potentials in response to Cue, Go and Nogo stimuli; an upper alpha power preceding lower central Go-P3; a lower theta-alpha power and ITC were coupled to a lower frontal Nogo-N3; a lower low-gamma power overall scalp at 300 ms after Go and Nogo stimuli. CONCLUSION: These findings suggest impaired ability in children with ADHD to conserve the brain oscillations phase associated with stimulus processing. This physiological trait might serve as a target for therapeutic intervention or be used as monitoring of their effects.

Grey matter volume differences associated with gender in children with attention-deficit/hyperactivity disorder: A voxel-based morphometry study.

Female participants have been underrepresented in previous structural magnetic resonance imaging reports on attention-deficit/hyperactivity disorder (ADHD). In this study, we used optimized voxel-based morphometry to examine grey matter volumes in a sample of 33 never-medicated children with combined-type ADHD and 27 typically developing (TD) children. We found a gender-by-diagnosis interaction effect in the ventral anterior cingulate cortex (ACC), whereby boys with ADHD exhibited reduced volumes compared with TD boys, while girls with ADHD showed increased volumes when compared with TD girls. Considering the key role played by the ventral ACC in emotional regulation, we discuss the potential contribution of these alterations to gender-specific symptoms' profiles in ADHD.

Grey matter volumes in treatment naïve vs. chronically treated children with attention deficit/hyperactivity disorder: a combined approach.

Psychostimulants are the first-line treatment in attention deficit/hyperactivity disorder (ADHD), but their effects on brain development remain poorly understood. In particular, previous structural magnetic resonance imaging (sMRI) studies only investigated treatment effects on grey matter (GM) volumes in selected regions of interest (ROIs). In this study, voxel-based morphometry (VBM) was used to assess medication-related GM volume differences across the entire brain. Automated tracing measurements of selected ROIs were also obtained. Three groups (77 participants aged 7-to-13 year old) underwent MRI scans and were compared: never-medicated children with ADHD (n=33), medicated (methylphenidate) children with ADHD (n=20) and typically developing children (TD; n=24). Optimised VBM was used to investigate regional GM volumes, controlling for age and gender. Automated tracing procedures were also used to assess the average volume of the caudate nucleus, the amygdala and the nucleus accumbens. When compared to both medicated children with ADHD and TD children, never-medicated children with ADHD exhibited decreased GM volume in the insula and in the middle temporal gyrus. When compared to TD children, medicated children with ADHD had decreased GM volume in the middle frontal gyrus and in the precentral gyrus. Finally, ROI analyses revealed a significant association between duration of treatment and GM volume of the left nucleus accumbens in medicated children with ADHD. In conclusion, this study documents potential methylphenidate-related GM volume normalization and deviation in previously unexplored brain structures, and reports a positive association between treatment history and GM volume in the nucleus accumbens, a key region for reward-processing.

Structural correlates of COMT Val158Met polymorphism in childhood ADHD: a voxel-based morphometry study.

OBJECTIVES: The Val158-allele of the catechol-O-methyltransferase (COMT) Val158Met (rs4680) functional polymorphism has been identified as a risk factor for antisocial behaviour in attention-deficit/hyperactivity disorder (ADHD). Here, we used voxel-based morphometry to investigate the effects of Val158Met polymorphism on grey matter (GM) volumes in a sample of 7-13-year-old children. METHODS: MRI and genotype data were obtained for 38 children with combined-type ADHD and 24 typically developing (TD) children. Four regions of interest were identified: striatum, cerebellum, temporal lobe and inferior frontal gyrus (IFG). RESULTS: When compared to TD children, those with ADHD had a significant decrease of GM volume in the IFG. Volume in this region was negatively correlated with ratings of hyperactivity/impulsivity symptoms. Furthermore, the smaller GM volume in the IFG was attributed to the presence of the Met158-allele, as only children with ADHD carrying a Met158-allele exhibited such decrease in the IFG. Children with ADHD homozygotes for the Val158-allele presented increased GM volume in the caudate nucleus when compared with TD children. CONCLUSIONS: This study provides the first evidence of a modulation of ADHD-related GM volume alterations by Val158Met in two key regions, possibly mediating the relationship between Val158Met polymorphism and antisocial behaviour in children with ADHD.