Beth Patricia Johnson

The molecular genetic architecture of attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common childhood behavioral condition which affects 2–10% of school age children worldwide. Although the underlying molecular mechanism for the disorder is poorly understood, familial, twin and adoption studies suggest a strong genetic component. Here we provide a state-of-the-art review of the molecular genetics of ADHD incorporating evidence from candidate gene and linkage designs, as well as genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs) and rare copy number variations (CNVs). Bioinformatic methods such as functional enrichment analysis and protein–protein network analysis are used to highlight biological processes of likely relevance to the aetiology of ADHD. Candidate gene associations of minor effect size have been replicated across a number of genes including SLC6A3, DRD5, DRD4, SLC6A4, LPHN3, SNAP-25, HTR1B, NOS1 and GIT1. Although case-control SNP-GWAS have had limited success in identifying common genetic variants for ADHD that surpass critical significance thresholds, quantitative trait designs suggest promising associations with Cadherin13 and glucose–fructose oxidoreductase domain 1 genes. Further, CNVs mapped to glutamate receptor genes (GRM1, GRM5, GRM7 and GRM8) have been implicated in the aetiology of the disorder and overlap with bioinformatic predictions based on ADHD GWAS SNP data regarding enriched pathways. Although increases in sample size across multi-center cohorts will likely yield important new results, we advocate that this must occur in parallel with a shift away from categorical case-control approaches that view ADHD as a unitary construct, towards dimensional approaches that incorporate endophenotypes and statistical classification methods.

A closer look at visually guided saccades in autism and Asperger’s disorder

Motor impairments have been found to be a significant clinical feature associated with autism and Asperger’s disorder (AD) in addition to core symptoms of communication and social cognition deficits. Motor deficits in high-functioning autism (HFA) and AD may differentiate these disorders, particularly with respect to the role of the cerebellum in motor functioning. Current neuroimaging and behavioral evidence suggests greater disruption of the cerebellum in HFA than AD. Investigations of ocular motor functioning have previously been used in clinical populations to assess the integrity of the cerebellar networks, through examination of saccade accuracy and the integrity of saccade dynamics. Previous investigations of visually guided saccades in HFA and AD have only assessed basic saccade metrics, such as latency, amplitude, and gain, as well as peak velocity. We used a simple visually guided saccade paradigm to further characterize the profile of visually guided saccade metrics and dynamics in HFA and AD. It was found that children with HFA, but not AD, were more inaccurate across both small (5°) and large (10°) target amplitudes, and final eye position was hypometric at 10°. These findings suggest greater functional disturbance of the cerebellum in HFA than AD, and suggest fundamental difficulties with visual error monitoring in HFA.

SACCADE ADAPTATION IN AUTISM AND ASPERGER'S DISORDER

Autism and Aspergers disorder (AD) are neurodevelopmental disorders primarily characterized by deficits in social interaction and communication, however motor coordination deficits are increasingly recognized as a prevalent feature of these conditions. Although it has been proposed that children with autism and AD may have difficulty utilizing visual feedback during motor learning tasks, this has not been directly examined. Significantly, changes within the cerebellum, which is implicated in motor learning, are known to be more pronounced in autism compared to AD. We used the classic double-step saccade adaptation paradigm, known to depend on cerebellar integrity, to investigate differences in motor learning and the use of visual feedback in children aged 9-14 years with high-functioning autism (HFA; IQ>80; n=10) and AD (n=13). Performance was compared to age and IQ matched typically developing children (n=12). Both HFA and AD groups successfully adapted the gain of their saccades in response to perceived visual error, however the time course for adaptation was prolonged in the HFA group. While a shift in saccade dynamics typically occurs during adaptation, we revealed aberrant changes in both HFA and AD groups. This study contributes to a growing body of evidence centrally implicating the cerebellum in ocular motor dysfunction in autism. Specifically, these findings collectively imply functional impairment of the cerebellar network and its inflow and outflow tracts that underpin saccade adaptation, with greater disturbance in HFA compared to AD.

Handwriting in children with ADHD.

Objective: Children with ADHD–combined type (ADHD-CT) display fine and gross motor problems, often expressed as handwriting difficulties. This study aimed to kinematically characterize the handwriting of children with ADHD using a cursive letter l’s task. Method: In all, 28 boys (7-12 years), 14 ADHD-CT and 14 typically developing (TD), without developmental coordination disorder (DCD) or comorbid autism, wrote a series of four cursive letter l’s using a graphics tablet and stylus. Results: Children with ADHD-CT had more inconsistent writing size than did TD controls. In addition, ADHD-CT symptom severity, specifically inattention, predicted poorer handwriting outcomes. Conclusion: In a sample of children with ADHD-CT who do not have DCD or autism, subtle handwriting differences were evident. It was concluded that handwriting might be impaired in children with ADHD in a manner dependent on symptom severity. This may reflect reports of underlying motor impairment in ADHD.

Understanding macrographia in children with autism spectrum disorders

It has been consistently reported that children with autism spectrum disorders (ASD) show considerable handwriting difficulties, specifically relating to accurate and consistent letter formation, and maintaining appropriate letter size. The aim of this study was to investigate the underlying factors that contribute to these difficulties, specifically relating to motor control. We examined the integrity of fundamental handwriting movements and contributions of neuromotor noise in 26 children with ASD aged 8-13 years (IQ>75), and 17 typically developing controls. Children wrote a series of four cursive letter ls using a graphics tablet and stylus. Children with ASD had significantly larger stroke height and width, more variable movement trajectory, and higher movement velocities. The absolute level of neuromotor noise in the velocity profiles, as measured by power spectral density analysis, was significantly higher in children with ASD; relatively higher neuromotor noise was found in bands >3 Hz. Our findings suggest that significant instability of fundamental handwriting movements, in combination with atypical biomechanical strategies, contribute to larger and less consistent handwriting in children with ASD.

Ischaemic stroke: the ocular motor system as a sensitive marker for motor and cognitive recovery

Objective To evaluate the sensitivity of measuring cognitive processing in the ocular motor system as a marker for recovery of deficit in post stroke patients. Methods 15 patients (mean age 60.6 years, mean National Institutes of Health Stroke Scale (NIHSS) score 2.25) and 10 age matched control subjects (mean age 63.3 years) participated in the study. We included mildly affected acute stroke patients without a visual field defect or gaze palsy. Patients were examined at onset and at 1 month and 3 months post stroke by testing ocular motor function, NIHSS, modified Rankin Scale (mRS) and standard cognitive function assessments. Results Significant differences were found in measures of ocular motor function between groups at stroke onset as well as between the first test and follow-up in patients. At 3 months, function had not returned to normal baseline. Ocular motor function was more sensitive in identifying cognitive dysfunction and improvement compared with NIHSS or mRS. Conclusions Standard neurological assessments of stroke patients are weighted significantly towards motor and sensory function, underestimating cognitive deficits. Ocular motor assessment demonstrates cognitive effects of even mild stroke and may provide improved quantifiable measurements of cognitive recovery post stroke. We demonstrated abnormality in patients just after onset, extending beyond 3 months, when there was apparent full recovery of motor and sensory function, implying more widespread disruption of cognitive mechanisms, consistent with the subjective complaints received from patients. This may provide insight into cognitive rehabilitation strategies leading to improved functional outcomes.

An association between a dopamine transporter gene (SLC6A3) haplotype and ADHD symptom measures in nonclinical adults

Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self‐reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3′UTR and intron 8 of DAT1, the 10‐repeat and 6‐repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7‐repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS‐G and CAARS‐H (DSM‐IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS‐G was also found for the 7‐repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and individual differences in ADHD symptoms in adults.

Ocular motor disturbances in autism spectrum disorders: systematic review and comprehensive meta-analysis

There has been considerable focus placed on how individuals with autism spectrum disorder (ASD) visually perceive and attend to social information, such as facial expressions or social gaze. The role of eye movements is inextricable from visual perception, however this aspect is often overlooked. We performed a series of meta-analyses based on data from 28 studies of eye movements in ASD to determine whether there is evidence for ocular motor dysfunction in ASD. Tasks assessed included visually-guided saccade tasks, gap/overlap, anti-saccade, pursuit tasks and ocular fixation. These analyses revealed evidence for ocular motor dysfunction in ASD, specifically relating to saccade dysmetria, difficulty inhibiting saccades and impaired tracking of moving targets. However there was no evidence for deficits relating to initiating eye movements, or engaging and disengaging from simple visual targets. Characterizing ocular motor abnormalities in ASD may provide insight into the functional integrity of brain networks in ASD across development, and assist our understanding of visual and social attention in ASD.

Left anterior cingulate activity predicts intra-individual reaction time variability in healthy adults.

Within-subject, or intra-individual, variability in reaction time (RT) is increasingly recognised as an important indicator of the efficiency of attentional control, yet there have been few investigations of the neural correlates of trial-to-trial RT variability in healthy adults. We sought to determine the neural correlates of intra-individual RT variability during a go/no-go response inhibition task in 27 healthy, male participants. We found that reduced trial-to-trial RT variability (i.e. greater response stability) was significantly associated with greater activation in the left pregenual anterior cingulate. These results support the role of the left anterior cingulate in the dynamic control of attention and efficient response selection. Greater understanding of intra-individual RT variability and top-down attentional control in healthy adults may help to inform disorders that impact executive/attentional control, such as attention deficit hyperactivity disorder and schizophrenia.

Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study

Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.