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Objectives: Motor coordination problems are frequent in children with attention deficit/hyperactivity disorder (ADHD). We performed a genome-wide association study to identify genes contributing to motor coordination problems, hypothesizing that the presence of such problems in children with ADHD may identify a sample of reduced genetic heterogeneity., Methods: Children with ADHD from the International Multicentre ADHD Genetic (IMAGE) study were evaluated with the Parental Account of Children's Symptoms. Genetic association testing was performed in PLINK on 890 probands with genome-wide genotyping data. Bioinformatics enrichment-analysis was performed on highly ranked findings. Further characterization of the findings was conducted in 313 Dutch IMAGE children using the Developmental Coordination Disorder Questionnaire (DCD-Q)., Results: Although none of the findings reached genome-wide significance, bioinformatics analysis of the top-ranked findings revealed enrichment of genes for motor neuropathy and amyotrophic lateral sclerosis. Genes involved in neurite outgrowth and muscle function were also enriched. Among the highest ranked genes were MAP2K5, involved in restless legs syndrome, and CHD6, causing motor coordination problems in mice. Further characterization of these findings using DCD-Q subscales found nominal association for 15 SNPs., Conclusions: Our findings provide clues about the aetiology of motor coordination problems, but replication studies in independent samples are necessary.

Impulsivity in terms of aggression, suicide or poor cognitive control has been associated with low synaptic availability of serotonin (5-HT) in adults and children. However, characteristics of the 5-HT transporter have not been studied in children with attention-deficit/hyperactivity disorder (ADHD: combined type), where impulsivity is a core symptom. Here, we explored in 20 children with ADHD the relationship of the density (Bmax) and affinity (Kd) of the platelet 5-HT transporter measured with [3H]paroxetine to both clinical ratings of impulsivity (Conners' Parent Questionnaire), and an experimental measure of impulsivity (the ability to withhold a prepotent response in the "stop-signal" paradigm). Decreases of affinity (increased Kd) correlated with a low probability of response inhibition, but not with the clinical ratings of impulsivity. However, ratings of distractibility and impulsivity correlated with the experimental measure of response-inhibition. In contrast, increased transporter affinity (low Kd) correlated modestly with higher ratings of aggressive and externalising behaviour. Bmax was not associated with any behavioural score. We conclude that the synaptic availability of 5-HT is under the control of the 5-HT transporter binding site affinity and that low affinity may be related to cognitive impulsivity (distractibility). Increased affinity of the transporter may also be related to conduct disturbance.

Prepulse inhibition (PPI) is a measure of the influence of a stimulus (S1) on the response elicited by a second stimulus (S2) occurring shortly afterwards. Most S1/S2 measures of gating have used behavioural startle and the P50 event-related potential (ERP) amplitudes to detect PPI in a simple paired stimulus paradigm. We report on two behavioural (reaction time, RT, and the electromyographically recorded response of the musculus orbicularis oculi, EMG) and 5 ERP measures of PPI where S2 was the target in an auditory two-tone discrimination. Subjects were 21 healthy controls (CON), 11 obsessive-compulsive (OCD) and 9 schizophrenic patients (SCH). The prepulse 100 ms before S2 induced more omission errors and longer RTs compared to 500ms S1-S2 interval in all subjects. PPI was also evident in EMG, P50, N1, P3 but not P2 or N2 amplitudes of CON subjects. SCH patients showed attenuation of PPI on the same measures. OCD patients were characterized only by their slow RT and a marginal attenuation of PPI of the EMG response. A correlational analysis implied separate relationships of ERP indices of PPI to the cognitive and psychomotor consequences of the prepulse on behavioural and discrimination responses. However, SCH patients showed a general rather than a specific impairment of these indices.

Five components were studied in 4 subtraction waveforms derived from ERPs obtained in passive and active conditions of a 3-tone oddball task (common = 70%, C, 0.8 KHz; deviant = 15%, D, 2 KHz; 1.4 KHz = 15%, t, also used as a target (T)). These waveforms reflect different stimulus-mismatch processes and thus their topography could be revealing of different brain regions mediating them. The following mismatches were studied: stimulus-mismatch (deviant--common, D/C, rarity and pitch confounded), pitch-mismatch (T--deviant, T/D, rarity not target features controlled), attention-mismatch (T-t), T/t, controlled for pitch and rarity to show the influence of target features). These are compared with Goodin's procedure [G-wv, (T--common (active))--(t--common (passive))]. There were main site effects in normalized data in all cases (not P2 and N2 latency). There were separate frontal and posterior contributions to P1, with the former emphasized where target comparisons were involved. Frontal N1 peaks, largest in D/C, spread posterior and to the right where target matching was involved. P2 posterior maxima were also less localized where target features were involved in the comparison. N2 topography was similar between waveforms but spread slightly more to each side in the T/t comparison. Onset was earlier in the D/C comparison. Parietal P3 peaks in waves based on target-ERPs showed a left temporal shift (vs D/C), though in T/D P3 was in fact maximal on the right. Thus an attentional effect is evident as early as 60 ms. Target features modify the anteroposterior distribution of positivity and negativity for the early components and in the lateralization of P3-like positivity. A comparison of waveforms by latency of potential shift (running t-test) vs peak identification (MANOVA) is illustrated and discussed. D/C and T/t (rather than T/D or G-wv) waveforms are recommended for distinguishing comparator mechanisms for stimulus- and task-relevant features.

Normalized event-related potential (ERP) data were analysed for topographical differences of ERP amplitude or latency in two conditions of a 3-tone oddball paradigm. The aim was to compare perception-related features relating to tone-type (passive non-task condition) with focussed attention-related features (active discrimination of target from non-target) in 5 ERP components from 23 young healthy subjects. The tones used were a common standard (70%, 0.8 KHz), a deviant standard (15%, 2 KHz) and a 1.4 KHz tone (15%, t) also used as the target (T). A site x tone interaction was obtained for P1 amplitude (augmenting with pitch anterior to posterior). The opposite tendency was seen for P2 to the right of midline maxima. No interaction was obtained for N1 amplitude. Condition became relevant for the N2-P3 complex. Frontal N2 amplitude increased after rare tones in the active condition. Posterior P3 peak size distinguished between tone (more widespread response to the common tone) and condition (more right-sided in the passive condition). The common tone elicited more widespread shift to the right than the rare tones. Latency was affected by condition from the P2 onwards and confirmed many of the amplitude interactions. This report extends and qualifies well-known main effects of tone and condition through main site effects to lateral sites. It supports claims of multiple sources of ERP components, except for N1 and P2. The contributions of these sources are influenced by tone-features (from P1) and the presence or absence of focussed attention (from the N2-P3 complex).