Charlotte Tye

Attention and inhibition in children with ASD, ADHD and co-morbid ASD + ADHD: an event-related potential study

BACKGROUND Substantial overlap has been reported between attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Deficits in executive function (EF) are characteristic of both disorders but these impairments have not been compared directly across pure and co-morbid cases using event-related potentials (ERPs). METHOD Behavioural parameters and ERPs were recorded during a flankered cued-continuous performance test (CPT-OX) administered to 8-13-year-old boys with ASD (n = 19), ADHD (n = 18), co-morbid ASD + ADHD (n = 29) and typically developing controls (TD; n = 26). Preparatory processing (contingent negative variation, CNV) and attentional orienting (Cue-P3) at cues, response execution at targets (Go-P3), inhibitory processing at non-targets (NoGo-P3) and conflict monitoring between target and non-target trials (Go-N2 v. NoGo-N2) were examined. RESULTS Categorical diagnoses and quantitative trait measures indicated that participants with ADHD (ADHD/ASD + ADHD) made more omission errors and exhibited increased reaction-time (RT) variability and reduced amplitude of the Cue-P3 and NoGo-P3 compared to TD/ASD participants. Participants with ASD (ASD/ ASD + ADHD) demonstrated reduced N2 enhancement from Go to NoGo trials compared to TD/ADHD participants. Participants with ASD-only displayed enhanced CNV amplitude compared to ASD + ADHD and TD participants. CONCLUSIONS Children with ADHD show deficits in attentional orienting and inhibitory control whereas children with ASD show abnormalities in conflict monitoring and response preparation. Children with co-morbid ASD + ADHD present as an additive co-occurrence with deficits of both disorders, although non-additive effects are suggested for response preparation. Measuring ERPs that index attention and inhibition is useful in disentangling cognitive markers of ASD and ADHD and elucidating the basis of co-occurring ASD + ADHD to guide clinical assessment.

Omega-3 polyunsaturated fatty acid supplementation and cognition: A systematic review and meta-analysis

Background: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are promoted as cognitive enhancers with consumption recommended in the general population and those with neurocognitive deficits such as attention deficit hyperactivity disorder (ADHD). However, evidence from randomised placebo-controlled trials is inconclusive. Aims: This study aimed to conduct a systematic review and meta-analysis examining the effect of n-3 PUFA supplementation on cognition in healthy populations and those with ADHD and related disorders (RDs). Methods: Databases were searched for randomised controlled trials (RCTs) in adults and school-aged children (who were healthy and typically developing (TD) or had ADHD or a related-neurodevelopmental disorder (ADHD+RD) which assessed the effects of n-3 PUFA on cognition. Results: In the 24 included studies n-3 PUFA supplementation, in the whole sample and the TD and ADHD+RD subgroup, did not show improvements in any of the cognitive performance measures. In those with low n-3 PUFA status, supplementation improved short-term memory. Conclusions: There is marginal evidence that n-3 PUFA supplementation effects cognition in those who are n-3 PUFA deficient. However, there is no evidence of an effect in the general population or those with neurodevelopmental disorders. This has important implications given the widespread advertisement and consumption of n-3 PUFA; claims of cognitive benefit should be narrowed.

Electrophysiological markers of genetic risk for attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder with complex genetic aetiology. The identification of candidate intermediate phenotypes may facilitate the detection of susceptibility genes and neurobiological mechanisms underlying the disorder. Electroencephalography (EEG) is an ideal neuroscientific approach, providing a direct measurement of neural activity that demonstrates reliability, developmental stability and high heritability. This systematic review evaluates the utility of a subset of electrophysiological measures as potential intermediate phenotypes for ADHD: quantitative EEG indices of arousal and intraindividual variability, and functional investigations of attention, inhibition and performance monitoring using the event-related potential (ERP) technique. Each measure demonstrates consistent and meaningful associations with ADHD, a degree of genetic overlap with ADHD and potential links to specific genetic variants. Investigations of the genetic and environmental contributions to EEG/ERP and shared genetic overlap with ADHD might enhance molecular genetic studies and provide novel insights into aetiology. Such research will aid in the precise characterisation of the clinical deficits seen in ADHD and guide the development of novel intervention and prevention strategies for those at risk.

Neurophysiological responses to faces and gaze direction differentiate children with ASD, ADHD and ASD + ADHD

Children with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) demonstrate face processing abnormalities that may underlie social impairment. Despite substantial overlap between ASD and ADHD, ERP markers of face and gaze processing have not been directly compared across pure and comorbid cases. Children with ASD (n=19), ADHD (n=18), comorbid ASD+ADHD (n=29) and typically developing (TD) controls (n=26) were presented with upright/inverted faces with direct/averted gaze, with concurrent recording of the P1 and N170 components. While the N170 was predominant in the right hemisphere in TD and ADHD, children with ASD (ASD/ASD+ADHD) showed a bilateral distribution. In addition, children with ASD demonstrated altered response to gaze direction on P1 latency and no sensitivity to gaze direction on midline-N170 amplitude compared to TD and ADHD. In contrast, children with ADHD (ADHD/ASD+ADHD) exhibited a reduced face inversion effect on P1 latency compared to TD and ASD. These findings suggest children with ASD have specific abnormalities in gaze processing and altered neural specialisation, whereas children with ADHD show abnormalities at early visual attention stages. Children with ASD+ADHD are an additive co-occurrence with deficits of both disorders. Elucidating the neural basis of the overlap between ASD and ADHD is likely to inform aetiological investigation and clinical assessment.

Altered neurophysiological responses to emotional faces discriminate children with ASD, ADHD and ASD + ADHD

There are high rates of overlap between autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Emotional impairment in the two disorders, however, has not been directly compared using event-related potentials (ERPs) that are able to measure distinct temporal stages in emotional processing. The N170 and N400 ERP components were measured during presentation of emotional face stimuli to boys with ASD (n=19), ADHD (n=18), comorbid ASD+ADHD (n=29) and typically developing controls (n=26). Subjects with ASD (ASD/ASD+ADHD) displayed reduced N170 amplitude across all stimuli, particularly for fearful versus neutral facial expressions. Conversely, subjects with ADHD (ADHD/ASD+ADHD) demonstrated reduced modulation of N400 amplitude by fearful expressions in parietal scalp regions and happy facial expressions in central scalp regions. These findings indicate a dissociation between disorders on the basis of distinct stages of emotion processing; while children with ASD show alterations at the structural encoding stage, children with ADHD display abnormality at the contextual processing stage. The comorbid ASD+ADHD group presents as an additive condition with the unique deficits of both disorders. This supports the use of objective neural measurement of emotional processing to delineate pathophysiological mechanisms in complex overlapping disorders.

The effect of omega-3 polyunsaturated fatty acid supplementation on emotional dysregulation, oppositional behaviour and conduct problems in ADHD: A systematic review and meta-analysis

BACKGROUND A number of randomised controlled trials report a beneficial effect of omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation on emotional lability (EL) and related domains (e.g. oppositional behaviour, conduct problems). Given that n-3 PUFA supplementation shows a significant effect on reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) and that EL and related behaviours commonly co-occurs with ADHD, it is important that there is a more conclusive picture as to the effect of n-3 PUFA on these co-occurring clinical domains. METHODS Databases (Ovid Medline, Embase, Psychinfo) were searched for trials assessing the effects of n-3 PUFA on EL, oppositional behaviour, aggression and conduct problems. We included trials in children who had ADHD or a related neurodevelopmental disorder. RESULTS Of the 1775 identified studies, 10 were included in the meta-analysis. In the primary analyses n-3 PUFA supplementation did not show improvements in measures of EL, oppositional behaviour, conduct problems or aggression. However subgroup analyses of higher quality studies and those meeting strict inclusion criteria found a significant reduction in EL and oppositional behaviour. LIMITATIONS A number of treatment effects may have failed to reach statistical significance due to small sample sizes and within and between study heterogeneity in terms of design and study participants. CONCLUSIONS These results exclude the possibility of moderate to large effects. They provide suggestive evidence of small effects of n-3 PUFA on reducing EL and oppositional behaviour in subgroups of children with ADHD.

Intellectual abilities in tuberous sclerosis complex: risk factors and correlates from the Tuberous Sclerosis 2000 Study.

BACKGROUND Tuberous sclerosis complex (TSC) is associated with intellectual disability, but the risk pathways are poorly understood. METHOD The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of the natural history of TSC. One hundred and twenty-five UK children age 0-16 years with TSC and born between January 2001 and December 2006 were studied. Intelligence was assessed using standardized measures at ≥2 years of age. The age of onset of epilepsy, the type of seizure disorder, the frequency and duration of seizures, as well as the response to treatment was assessed at interview and by review of medical records. The severity of epilepsy in the early years was estimated using the E-Chess score. Genetic studies identified the mutations and the number of cortical tubers was determined from brain scans. RESULTS TSC2 mutations were associated with significantly higher cortical tuber count than TSC1 mutations. The extent of brain involvement, as indexed by cortical tuber count, was associated with an earlier age of onset and severity of epilepsy. In turn, the severity of epilepsy was strongly associated with the degree of intellectual impairment. Structural equation modelling supported a causal pathway from genetic abnormality to cortical tuber count to epilepsy severity to intellectual outcome. Infantile spasms and status epilepticus were important contributors to seizure severity. CONCLUSIONS The findings support the proposition that severe, early onset epilepsy may impair intellectual development in TSC and highlight the potential importance of early, prompt and effective treatment or prevention of epilepsy in tuberous sclerosis.

Shared Genetic Influences on ADHD Symptoms and Very Low-Frequency EEG Activity: A Twin Study.

BACKGROUND   Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex aetiology. The identification of candidate intermediate phenotypes that are both heritable and genetically linked to ADHD may facilitate the detection of susceptibility genes and elucidate aetiological pathways. Very low-frequency (VLF; <0.5 Hz) electroencephalographic (EEG) activity represents a promising indicator of risk for ADHD, but it currently remains unclear as to whether it is heritable or genetically linked to the disorder. METHODS   Direct-current (DC)-EEG was recorded during a cognitive activation condition in 30 monozygotic and dizygotic adolescent twin pairs concordant or discordant for high ADHD symptom scores, and 37 monozygotic and dizygotic matched-control twin pairs with low ADHD symptom scores. Structural equation modelling was used to quantify the genetic and environmental contributions to the phenotypic covariance between ADHD and VLF activity. RESULTS   Attention deficit hyperactivity disorder was significantly associated with reduced VLF power during cognitive activation, which suggests reduced synchronization of widespread neuronal activity. Very low-frequency power demonstrated modest heritability (0.31), and the genetic correlation (-0.80) indicated a substantial degree of overlap in genetic influences on ADHD and VLF activity. CONCLUSIONS   Altered VLF activity is a potential candidate intermediate phenotype of ADHD, which warrants further investigation of underlying neurobiological and genetic mechanisms.

Genetic overlap between ADHD symptoms and EEG theta power.

Biological markers that are grounded in neuroscience may facilitate understanding of the pathophysiology of complex psychiatric disorders. One of the most consistent and robust neural abnormalities in attention deficit hyperactivity disorder (ADHD) is increased EEG power in the theta band at rest (4-8Hz). The present study used a twin design to estimate the extent of genetic overlap between increased theta power and risk for ADHD in order to validate theta power as a marker of genetic risk for ADHD. At rest, EEG was measured in 30 monozygotic and dizygotic adolescent twin pairs concordant or discordant for high ADHD symptom scores and 37 monozygotic and dizygotic control twin pairs with low ADHD symptom scores. Structural equation modelling was used to estimate the heritability of theta power and partition the genetic and environmental contributions to the overlap between ADHD and theta power. A significant phenotypic correlation between ADHD symptoms and elevated theta power was found. Theta power demonstrated moderate to high heritability estimates (0.77) and moderate genetic correlations with ADHD (0.35) suggesting shared genetic influences. Increased theta power is a candidate biological marker of genetic risk for ADHD, which warrants further investigation of the neurobiological mechanisms that underlie the genetic relationship.

Response time variability under slow and fast-incentive conditions in children with ASD, ADHD and ASD+ADHD

Background Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) show significant behavioural and genetic overlap. Both ADHD and ASD are characterised by poor performance on a range of cognitive tasks. In particular, increased response time variability (RTV) is a promising indicator of risk for both ADHD and ASD. However, it is not clear whether different indices of RTV and changes to RTV according to task conditions are able to discriminate between the two disorders. Methods Children with ASD (n = 19), ADHD (n = 18), ASD + ADHD (n = 29) and typically developing controls (TDC; n = 26) performed a four‐choice RT task with slow‐baseline and fast‐incentive conditions. Performance was characterised by mean RT (MRT), standard deviation of RT (SD‐RT), coefficient of variation (CV) and ex‐Gaussian distribution measures of Mu, Sigma and Tau. Results In the slow‐baseline condition, categorical diagnoses and trait measures converged to indicate that children with ADHD‐only and ASD + ADHD demonstrated increased MRT, SD‐RT, CV and Tau compared to TDC and ASD‐only. Importantly, greater improvement in MRT, SD‐RT and Tau was demonstrated in ADHD and ASD + ADHD from slow‐baseline to fast‐incentive conditions compared to TDC and ASD‐only. Conclusions Slower and more variable RTs are markers of ADHD compared to ASD and typically developing controls during slow and less rewarding conditions. Energetic factors and rewards improve task performance to a greater extent in children with ADHD compared to children with ASD. These findings suggest that RTV can be distinguished in ASD, ADHD and ASD + ADHD based on the indices of variability used and the conditions in which they are elicited. Further work identifying neural processes underlying increased RTV is warranted, in order to elucidate disorder‐specific and disorder‐convergent aetiological pathways.