Effects of a computerized working memory training program on working memory, attention, and academics in adolescents with severe LD and comorbid ADHD: a randomized controlled trial.

BACKGROUND: Youths with coexisting learning disabilities (LD) and attention deficit hyperactivity disorder (ADHD) are at risk for poor academic and social outcomes. The underlying cognitive deficits, such as poor working memory (WM), are not well targeted by current treatments for either LD or ADHD. Emerging evidence suggests that WM might be improved by intensive and adaptive computerized training, but it remains unclear whether this intervention would be effective for adolescents with severe LD and comorbid ADHD. METHODS: A total of sixty 12- to 17-year olds with LD/ADHD (52 male, 8 female, IQ > 80) were randomized to one of two computerized intervention programs: working memory training (Cogmed RM) or math training (Academy of Math) and evaluated before and 3 weeks after completion. The criterion measures of WM included auditory-verbal and visual-spatial tasks. Near and far transfer measures included indices of cognitive and behavioral attention and academic achievement. RESULTS: Adolescents in the WM training group showed greater improvements in a subset of WM criterion measures compared with those in the math-training group, but no training effects were observed on the near or far measures. Those who showed the most improvement on the WM training tasks at school were rated as less inattentive/hyperactive at home by parents. CONCLUSIONS: Results suggest that WM training may enhance some aspects of WM in youths with LD/ADHD, but further development of the training program is required to promote transfer effects to other domains of function.

Sex differences in sensorimotor mu rhythms during selective attentional processing.

We used magnetoencephalography to investigate the effect of directed attention on sensorimotor mu (8-12 Hz) response (mu reactivity) to non-painful electrical stimulation of the median nerve in healthy adults. Mu desynchronization in the 10-12 Hz bandwidth is typically observed during higher-order cognitive functions including selective attentional processing of sensorimotor information (Pfurtscheller, Neuper, & Krauz, 2000). We found attention-related sex differences in mu reactivity, with females showing (i) prolonged mu desynchrony when attending to somatosensory stimuli, (ii) attentional modulation of the mu response based on whether attention was directed towards or away from somatosensory stimuli, which was absent in males, and (iii) a trend for greater neuronal excitability of the primary somatosensory region suggesting greater physiological responsiveness to sensory stimulation overall. Our findings suggest sex differences in attentional control strategies when processing somatosensory stimuli, whose salience may be greater for females. These sex differences in attention to somatosensory stimuli may help elucidate the well-documented sex biases in pain processing wherein females typically report greater sensitivity to experimental and clinical pain.

Cortical dynamics of selective attention to somatosensory events.

Recent studies have shown evidence of somatosensory deficits in individuals with attentional difficulties yet relatively little is known about the role of attention in the processing of somatosensory input. Neuromagnetic imaging studies have shown that rhythmic oscillations within the human somatosensory cortex are strongly modulated by somatosensory stimulation and may reflect the normal processing of such stimuli. However, few studies have examined how attention influences these cortical oscillations. We examined attentional effects on human somatosensory oscillations during median nerve stimulation by conducting time-frequency analyses of neuromagnetic recordings in healthy adults. We found that selective attention modulated somatosensory oscillations in the alpha, beta, and gamma bands that were both phase-locked and non-phase-locked to the stimulus. In the primary somatosensory cortex (SI), directing the subject's attention toward the somatosensory stimulus resulted in increased gamma band power (30-55 Hz) that was phase-locked to stimulus onset. Directed attention also produced an initial suppression (desynchrony) followed by enhancement (synchrony) of beta band power (13-25 Hz) that was not phase-locked to the stimulus. In the secondary somatosensory cortex (SII), directing attention towards the stimulus increased phase-locked alpha (7-9 Hz) power approximately 30 ms after onset of phase-locked gamma in SI, followed by a non-phase-locked increase in alpha power. We suggest that earlier phase-locked oscillatory power may reflect the relay of input from SI to SII, whereas later non-phase-locked rhythms reflect stimulus-induced oscillations that are modulated by selective attention and may thus reflect enhanced processing of the stimulus underlying the perception of somatosensory events.

Association of ADHD and the Protogenin gene in the chromosome 15q21.3 reading disabilities linkage region.

Twin studies indicate genetic overlap between symptoms of attention deficit hyperactivity disorder (ADHD) and reading disabilities (RD), and linkage studies identify several chromosomal regions possibly containing common susceptibility genes, including the 15q region. Based on a translocation finding and association to two specific alleles, the candidate gene, DYX1C1, has been proposed as the susceptibility gene for RD in 15q. Previously, we tested markers in DYX1C1 for association with ADHD. Although we identified association for haplotypes across the gene, we were unable to replicate the association to the specific alleles reported. Thus, the risk alleles for ADHD are yet to be identified. The susceptibility alleles may be in a remote regulatory element, or DYX1C1 may not be the risk gene. To continue study of 15q, we tested a coding region change in DYX1C1, followed by markers across the gene Protogenin (PRTG) in 253 ADHD nuclear families. PRTG was chosen based on its location and because it is closely related to DCC and Neogenin, two genes known to guide migratory cells and axons during development. The markers in DYX1C1 were not associated to ADHD when analyzed individually; however, six markers in PRTG showed significant association with ADHD as a categorical trait (P = 0.025-0.005). Haplotypes in both genes showed evidence for association. We identified association with ADHD symptoms measured as quantitative traits in PRTG, but no evidence for association with two key components of reading, word identification and decoding was observed. These findings, while preliminary, identify association of ADHD to a gene that potentially plays a role in cell migration and axon growth.

Association study of the nicotinic acetylcholine receptor alpha4 subunit gene, CHRNA4, in attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric condition with a strong genetic component. Evidence from pharmacological, clinical and animal studies has suggested that the nicotinic system could be involved in the disorder. Previous studies have implicated the nicotinic acetylcholine receptor alpha4 subunit gene, CHRNA4, in ADHD. Particularly, a polymorphism in the exon 2-intron 2 junction of CHRNA4 has been associated with severe inattention defined by latent class analysis. In the current study, we used the transmission disequilibrium test (TDT) to investigate four polymorphisms encompassing this region of CHRNA4 for association with ADHD in a sample of 264 nuclear families from Toronto. No significant evidence of biased transmission was observed for any of the marker alleles for ADHD defined as a categorical trait (all subtypes included), although one haplotype showed marginal evidence of under-transmission. No association was found with the ADHD predominantly inattentive subtype or with symptom dimension scores of inattention. On the contrary, nominally significant evidence of association of individual markers was obtained for the ADHD combined subtype and with teacher-rated hyperactivity-impulsivity scores, with the same haplotype being under-transmitted. Based on our results and others, CHRNA4 may be involved in ADHD; however, its role in ADHD symptomatology remains to be clarified.

Interference control in attention-deficit/hyperactivity disorder: differential Stroop effects for colour-naming versus counting.

Deficits in interference control are ascribed to patients suffering from ADHD by a number of cognitive theories. However, previous research using the Stroop Colour Word Interference Task has demonstrated mixed results that may be explained by methodological issues (e.g., possible impact of colour perception abilities on interference liability, different approaches to calculate interference scores, conflation of speed and accuracy factors). Hence, this study included two computerized versions of the Stroop (Colour-Stroop, Counting Stroop) which allowed to calculate separate measures of speed and accuracy, provided a more rigorous approach to calculate interference, and permitted to investigate the effects of stimulus properties on interference. Participants were 14 children with a DSM-IV diagnosis of ADHD combined type and 15 matched controls. Children completed a traditional Stroop as well as both a computerized Colour- and Counting-Stroop. Results indicated that the ADHD group showed higher interference scores than controls in the Colour-Stroop, but not in the Counting-Stroop. Thus, interference control may be not generally impaired in ADHD, and examinations with the Colour Stroop should be interpreted with care.

Color perception deficits in co-existing attention-deficit/hyperactivity disorder and chronic tic disorders.

Preliminary findings suggest that color perception, particularly of blue-yellow stimuli, is impaired in attention-deficit/hyperactivity disorder (ADHD) as well as in chronic tic disorders (CTD). However, these findings have been not replicated and it is unclear what these deficits mean for the comorbidity of ADHD + CTD. Four groups (ADHD, CTD, ADHD + CTD, controls) of children with similar age, IQ and gender distribution were investigated with the Farnsworth-Munsell 100 Hue Test (FMT) and the Stroop-Color-Word Task using a factorial design. Color perception deficits, as indexed by the FMT, were found for both main factors (ADHD and CTD), but there were no interaction effects. A preponderance of deficits on the blue-yellow compared to the red-green axis was detected for ADHD. In the Stroop task only the 'pure' ADHD group showed impairments in interference control and other parameters of Stroop performance. No significant correlations between any FMT parameter and color naming in the Stroop task were found. Basic color perception deficits in both ADHD and CTD could be found. Beyond that, it could be shown that these deficits are additive in the case of comorbidity (ADHD + CTD). Performance deficits on the Stroop task were present only in the 'pure' ADHD group. Hence, the latter may be compensated in the comorbid group by good prefrontal capabilities of CTD. The influence of color perception deficits on Stroop task performance might be negligible.

Association of the dopamine receptor D1 gene, DRD1, with inattention symptoms in families selected for reading problems.

Twin studies have provided evidence for shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) and specific reading disabilities (RD), with this overlap being highest for the inattentive symptom dimension of ADHD. Previously, we found evidence for association of the dopamine receptor D1 gene (DRD1) with ADHD, and with the inattentive symptom dimension in particular. This, combined with evidence for working memory (WM) deficits in individuals with RD or ADHD, and the importance of D1 receptors in attentional processes and WM function, suggests that DRD1 may be a common genetic influence underlying both disorders. Here, in a study of 232 families ascertained through probands with reading problems, we tested for association of the DRD1 gene with RD, as a categorical trait, and with quantitative measures of key reading component skills, WM ability, and inattentive symptoms. Although no associations were found with RD, or with reading component skills or verbal WM, we found evidence for association with inattentive behaviour. Specifically, DRD1 Haplotype 3, the haplotype previously found to be associated with inattentive symptoms in ADHD, is also associated with parent- and teacher-reported symptoms of inattention in this sample selected for reading problems (P=0.023 and 0.004, respectively). Together, the replicated finding of Haplotype 3 association with inattentive symptoms in two independent study samples strongly supports a role for DRD1 in attentional ability. Furthermore, the association of DRD1 with inattention, but not with RD, or the other reading and reading-related phenotypes analysed, suggests that DRD1 contributes uniquely to inattention, without overlap for reading ability.

Association of the glutamate receptor subunit gene GRIN2B with attention-deficit/hyperactivity disorder.

The glutamatergic signaling pathway represents an ideal candidate susceptibility system for attention-deficit/hyperactivity disorder (ADHD). Disruption of specific N-methyl-D-aspartate-type glutamate receptor subunit genes (GRIN1, 2A-D) in mice leads to significant alterations in cognitive and/or locomotor behavior including impairments in latent learning, spatial memory tasks and hyperactivity. Here, we tested for association of GRIN2B variants with ADHD, by genotyping nine single nucleotide polymorphisms (SNPs) in 205 nuclear families identified through probands with ADHD. Transmission of alleles from heterozygous parents to affected offspring was examined using the transmission/disequilibrium test. Quantitative trait analyses for the ADHD symptom dimensions [inattentive (IA) and hyperactive/impulsive (HI)] and cognitive measures of verbal working memory and verbal short-term memory were performed using the fbat program. Three SNPs showed significantly biased transmission (P < 0.05), with the strongest evidence of association found for rs2,284,411 (chi(2)= 7.903, 1 degree of freedom, P= 0.005). Quantitative trait analyses showed associations of these markers with both the IA and the HI symptom dimensions of ADHD but not with the cognitive measures of verbal short-term memory or verbal working memory. Our data suggest an association between variations in the GRIN2B subunit gene and ADHD as measured categorically or as a quantitatively distributed trait.

Association of the calcyon gene (DRD1IP) with attention deficit/hyperactivity disorder.

Attention deficit/hyperactivity disorder (ADHD) is a childhood-onset disorder characterized by marked inattention, hyperactivity and impulsivity. The dopaminergic system has been hypothesized to be involved in the development of ADHD. Positive associations have been found for the dopamine receptors D1 and D5 genes, suggesting that other genes involved in D1/D5 signalling may also contribute to ADHD. In this study, we tested the calcyon gene (DRD1IP), which encodes a brain-specific D1-interacting protein involved in D1/D5 receptors calcium signalling, for association with ADHD. The inheritance of nine polymorphisms in the calcyon gene was examined in a sample of 215 nuclear families, with 260 affected children, using the transmission/disequilibrium test. The most common haplotype, designated C1, demonstrated significant evidence for excess transmission. Quantitative trait analyses of this haplotype showed significant relationships with both the inattentive (parent's rating, P=0.006; teacher's rating, P=0.003) and hyperactive/impulsive (parent's rating, P=0.004) dimensions of the disorder. Two of the nine marker alleles included in haplotype C1, rs4838721A located approximately 10 kb 5' of the gene and rs2275723C located 10 bp upstream of the exon 5 acceptor splice site, also showed significant evidence for association when analysed individually. As these two variants are not predicted to alter calcyon function, we screened the gene exons by sequencing. No variation in the coding region was identified, suggesting that a causal variant allele resides elsewhere in a regulatory sequence of the gene. These findings support the proposed involvement of the calcyon gene in ADHD and implicate haplotype C1 as containing a risk allele.

Tapping and anticipation performance in attention deficit hyperactivity disorder.

The objective of this study was to examine the precise timing of a motor response in a sample of adolescents with ADHD and comparison participants. 46 participants with ADHD (M age=15.6, SD=1.4; 40 boys) and 44 control participants (M age=15.3, SD=1.4; 40 boys) were recruited through a metropolitan hospital. Participants were administered a tapping task and an anticipation task. Adolescents with ADHD displayed significantly more intra-individual variability on the visual 1000-msec. frequency interval of the tapping task and displayed lower accuracy on the cued and uncued trials of the anticipation task than comparison participants. Intra-individual variability on the tapping task was correlated with intra-individual variability on the anticipation task within both the ADHD and control groups. These findings suggest that adolescents with ADHD have impairments in both the cognitive representation and motor production of the precise timing of a motor response.

The SNAP25 gene as a susceptibility gene contributing to attention-deficit hyperactivity disorder.

The synaptosomal-associated protein of 25 kDa gene (SNAP25) has been suggested as a genetic susceptibility factor in attention-deficit hyperactivity disorder (ADHD) based on the mouse strain coloboma. This strain is hemizygous for the SNAP25 gene and displays hyperactivity that responds to dextroamphetamine, but not to methylphenidate. Previously, we reported association of SNAP25 and ADHD using two polymorphisms. To further investigate this gene, we screened the exons for DNA variation and genotyped ten additional polymorphisms in an expanded sample of families from Toronto and a second sample of families collected in Irvine, CA. Significant results were observed in the Toronto sample for four markers, although not in the Irvine sample. The paper discusses the possible influence of the selection criteria on these differential results. The Irvine sample selected subjects that met the DSM-IV combined subtype diagnosis, whereas the Toronto sample included all subtypes. Analysis of the DSM-IV subtypes in the Toronto sample indicated that the differential results were not attributable to ADHD subtype. Differences in ethnicity, differential medication response, and other clinical characteristics of the samples cannot be ruled out at this time. Quantitative analysis of the dimensions of hyperactivity/impulsivity and inattention in the Toronto sample found that both behavioral traits were associated with SNAP25. Our findings continue to support SNAP25 in the susceptibility to ADHD.

Support for EKN1 as the susceptibility locus for dyslexia on 15q21.

Dyslexia has been linked to a number of chromosomal regions including 15q. Recently a gene, EKN1, with unknown function in the linked region, was identified via a translocation breakpoint. This gene was further supported as a susceptibility locus by association studies in a Finnish sample. We investigated the possibility of this locus as a susceptibility gene contributing to dyslexia, analyzed as a categorical trait, and analyzed key reading phenotypes as quantitative traits using six polymorphisms including the two previously reported to be associated with dyslexia. In our sample of 148 families identified through a proband with reading difficulties, we found significant evidence for an association to dyslexia analyzed as a categorical trait and found evidence of association to the reading and related processes of phonological awareness, word identification, decoding, rapid automatized naming, language ability, and verbal short-term memory. However, association was observed with different alleles and haplotypes than those reported to be associated in a Finnish sample. These findings provide support for EKN1 as a risk locus for dyslexia and as contributing to reading component processes and reading-related abilities. Based on these findings, further studies of this gene in independent samples are now required to determine the relationship of this gene to dyslexia.

Glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene as a positional candidate for attention-deficit/hyperactivity disorder in the 16p13 region.

The glutamate system may be involved in the development of attention-deficit/hyperactivity disorder (ADHD) based on animal models and the role of N-methyl-D-aspartate receptors (NMDAR) in cognition and motor processes. A follow-up study of the first genome scan for ADHD identified significant evidence for linkage to the 16p13 region. The glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A) gene that encodes the 2A subunit of the NMDA receptor, resides in this region and a recent study has reported an association between this gene and ADHD. We tested for linkage between the alleles and haplotypes of four polymorphisms at the GRIN2A locus and ADHD in our sample of 183 nuclear families with 229 affected children. In contrast to previous findings, we did not identify any evidence for a relationship of these markers and ADHD. Owing to the role of GRIN2A in aspects of cognition, we investigated the relationship of this gene to the cognitive phenotypes of inhibitory control, verbal short-term memory and verbal working memory. There was no significant evidence of linkage between GRIN2A and these phenotypes. While the results were not significant in our sample, the previous association finding suggests that further study of this gene is warranted.

Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests the dopamine receptor D1 gene, DRD1, to be a good candidate for involvement. Here, we tested for linkage of DRD1 to ADHD by examining the inheritance of four biallelic DRD1 polymorphisms [D1P.5 (-1251HaeIII), D1P.6 (-800HaeIII), D1.1 (-48DdeI) and D1.7 (+1403Bsp1286I)] in a sample of 156 ADHD families. Owing to linkage disequilibrium between alleles at the four markers, only three haplotypes are common in our sample. Using the transmission/disequilibrium test (TDT), we observed a strong bias for transmission of Haplotype 3 (1.1.1.2) from heterozygous parents to their affected children (P=0.008). Furthermore, using quantitative trait TDT analyses, we found significant and positive relationships between Haplotype 3 transmission and the inattentive symptoms, but not the hyperactive/impulsive symptoms, of ADHD. These findings support the proposed involvement of DRD1 in ADHD, and implicate Haplotype 3, in particular, as containing a potential risk factor for the inattentive symptom dimension of the disorder. Since none of the four marker alleles comprising Haplotype 3 is predicted to alter DRD1 function, we hypothesize that a functional DRD1 variant, conferring susceptibility to ADHD, is on this haplotype. To search for such a variant we screened the DRD1 coding region, by sequencing, focusing on the children who showed preferential transmission of Haplotype 3. DNA from 41 children was analysed, and no sequence variations were identified, indicating that the putative DRD1 risk variant for ADHD resides outside of the coding region of the gene.

Time perception deficits in attention-deficit/ hyperactivity disorder and comorbid reading difficulties in child and adolescent samples.

BACKGROUND: Our objective was to investigate time perception in Attention-Deficit/Hyperactivity Disorder (ADHD) with and without comorbid reading difficulties (RD) in child and adolescent participants. METHOD: In study 1, 50 children with ADHD (31 ADHD, 19 ADHD+RD) and age-matched healthy controls (n = 50) completed three psychophysical tasks: duration discrimination (target duration of 400 ms versus a foil duration), frequency discrimination (a control condition to evaluate general perceptual ability), and a duration estimation task using the method of reproduction for intervals of 400 ms, 2000 ms, and 6000 ms. Study 2 used the same tasks with an adolescent sample (35 ADHD, 24 ADHD+RD, 39 controls). RESULTS: In both studies, children and adolescents with ADHD and ADHD+RD displayed some impairments in duration discrimination and the precision with which they reproduced the intervals on the estimation task, particularly the shorter 400 ms interval. The most severe impairments tended to occur in the comorbid ADHD+RD group. No impairments were found on the frequency discrimination task. ADHD participants also displayed significant intra-individual variability in their performance on the estimation task. Finally, short-term and working memory, estimated full-scale IQ, and teacher report of hyperactivity/impulsivity were found to differentially predict performance on the time perception measures in the adolescent clinical sample. CONCLUSIONS: Deficits in duration discrimination, duration estimation, and intra-individual performance variability may have cascaded effects on the temporal organisation of behaviour in children and adolescents with ADHD and ADHD+RD.

The attributions of children with Attention-Deficit/ Hyperactivity Disorder for their problem behaviors.

This study investigated the attributions children with ADHD make about their most problematic symptoms. Children were interviewed to determine the degree to which they felt their behavior was controllable, stable, global, and stigmatizing; and about the locus of the cause of their behavior. Participants were 16 children with ADHD (10 boys, 6 girls), and 16 children without ADHD (9 boys, 7 girls), ages 7 to 13. The present study demonstrated that children with ADHD viewed their most problematic behaviors as less within their control and more global across situations than children without ADHD. Children with ADHD were more likely than children without ADHD to view their most problematic behavior as always having been present, but were no more likely to view their most problematic behavior as persisting into the future. No significant group differences emerged on the locus of causality dimension. With regards to stigmatization, girls without ADHD reported that their behaviors can bother their teachers, parents, and peers, whereas girls and boys with ADHD did not perceive their behavior as bothersome.

The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder.

Recent research has suggested that serotonin, in addition to dopamine, may be involved in the development of attention deficit hyperactivity disorder (ADHD). Serotonin regulates dopaminergic neurotransmission in some areas of the brain via several 5-HT receptors including 5-HT1B. Animal studies have suggested the involvement of the 5-HT1B receptors in locomotor behaviour. For these reasons, we hypothesized that the 5-HT1B receptor gene may be a good candidate for genetic studies of ADHD. We tested for linkage disequilibrium between the 5-HT1B G861C polymorphism and ADHD in 115 families using the transmission disequilibrium test (TDT). We found evidence for a trend towards excess transmission of the 861G allele (chi(2) = 2.91, P = 0.09) that when further analysed for parental allele transmissions exhibited significantly greater paternal transmission of the G allele (chi(2) = 4.80, P = 0.03) to the affected child. Although preliminary, results from this study provide additional evidence that serotonin genes may be important risk factors for the development of ADHD.

Validity of the Brown ADD scales: an investigation in a predominantly inattentive ADHD adolescent sample with and without reading disabilities.

The Brown ADD Scale for Adolescents is widely used in clinical settings, yet, no published studies have investigated divergent and concurrent validity and specificity and sensitivity to inattentive ADHD symptomatology. Ninety-eight participants (13 to 16 years) were classified as ADHD/I and/or reading disabled (RD) using Kiddie Schedule for Affective Disorder and Schizophrenia (K-SADS), Conners' Rating Scales (CRS-R), and Ontario Child Health Study Scales (OCHSS), WRAT3, and WRMT-R. The results were: 29 ADHD/I; 12 RD, 16 ADHD/I with RD; and, 41 controls. The RD group was included to evaluate specificity. The Brown was administered but not used in classification. The ADHD groups scored higher on the Brown subscales compared with the other two groups. The recommended cutoffs resulted in high rates of false negatives but few false positives; this suggests good specificity but poor sensitivity. There were moderate correlations among the Brown, CRS-R, and OCHSS. The Brown can be useful in screening out ADHD; however, its low sensitivity precludes its usefulness in diagnosing ADHD.