Search

BackgroundThe Coronavirus disease 2019 (COVID-19) pandemic has impacted parental and child mental health and wellbeing in the UK. This study aimed to explore the experiences of parents of children with rare neurological and neurodevelopmental conditions with a known or suspected genetic cause (neurogenetic) across the first year of the pandemic in the UK. MethodsSemi-structured interviews were conducted with 11 parents of children with rare neurogenetic conditions. Parents were recruited via opportunity sampling from the CoIN Study, a longitudinal quantitative study exploring the impact of the pandemic on the mental health and wellbeing of families with rare neurogenetic conditions. Interviews were analysed using Interpretative Phenomenological Analysis.ResultsFour main themes were identified: (1) “A varied impact on child wellbeing: from detrimental to ‘no big drama’”; (2) “Parental mental health and wellbeing: impact, changes and coping”; (3) “The world had shut its doors and that was that’: care and social services during the pandemic”; and (4) “Time and luck: abstract concepts central to parents understanding of their pandemic experience”. The majority of parents described experiencing an exacerbation of pre-pandemic challenges due to increased uncertainty and a lack of support, with a minority reporting minimal or positive effects of the pandemic on family wellbeing.ConclusionsThese findings offer a unique insight into the experiences parents of children with rare neurogenetic conditions across the first year of the pandemic in the UK. They highlight that the experiences of parents are not pandemic-specific, and will continue to be highly relevant in a non-pandemic context. Future support should to be tailored to the needs of families identified in this study and implemented across diverse future scenarios to promote coping and positive wellbeing.

Objective To evaluate which early neurocognitive and behavioral precursors are associated with the development of attention-deficit/hyperactivity disorder (ADHD) and whether these are currently targeted in early interventions. Method We conducted 2 systematic reviews and meta-analyses of empirical studies to examine the following: (1) early-life (0−5 years) neurocognitive and behavioral precursors associated with familial likelihood for ADHD, an early ADHD diagnosis/elevated ADHD symptoms, and/or the presence of later-childhood ADHD; and (2) interventions delivered to children aged 0 to 5 years targeting the identified precursors or measuring these as outcomes. Standardized mean differences (Hedges’ g) and pre-post-treatment change scores (SMD) were computed. Results A total of 149 studies (165,095 participants) investigating 8 neurocognitive and behavioral domains met inclusion criteria for part 1. Multi-level random-effects meta-analyses on 136 studies revealed significant associations between ADHD and poorer cognitive (g = −0.46 [95% CIs: −0.59, −0.33]), motor (g = −0.35 [CIs: −0.48, −0.21]) and language (g = −0.43 [CIs: −0.66, −0.19]) development, social (g = 0.23 [CIs: 0.03, 0.43]) and emotional (g = 0.46 [CIs: 0.33, 0.58]) difficulties, early regulatory (g = 0.30 [CIs: 0.18, 0.43]) and sleep (g = 0.29 [CIs: 0.14, 0.44]) problems, sensory atypicalities (g = 0.52 [CIs: 0.16, 0.88]), elevated activity levels (g = 0.54 [CIs: 0.37, 0.72]), and executive function difficulties (g = 0.34 [CIs: 0.05, 0.64] to −0.87 [CIs: −1.35, −0.40]). A total of 32 trials (28 randomized, 4 nonrandomized, 3,848 participants) testing early interventions that targeted the identified precursors met inclusion criteria for part 2. Multi-level random-effects meta-analyses on 22 studies revealed significant intervention-related improvements in ADHD symptoms (SMD = 0.43 [CIs: 0.22, 0.64]) and working memory (SMD = 0.37 [CIs: 0.06, 0.69]). Conclusion Children aged 0 to 5 years with current or later-emerging ADHD are likely to experience difficulties in multiple neurocognitive/behavioral functions. Early interventions show some effectiveness in reducing ADHD symptoms, but their effects on neurocognitive/behavioral difficulties require further study.

Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations on the TSC1/TSC2 genes, which result in alterations in molecular signalling pathways involved in neurogenesis and hamartomas in the brain and other organs. TSC carries a high risk for autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), although the reasons for this are unclear. One proposal is that TSC-related alterations in molecular signalling during neurogenesis lead to atypical development of neural networks, which are involved in the occurrence of ASD and ADHD in TSC. We investigated this proposal in young people with TSC who have been studied longitudinally since their diagnosis in childhood. Electroencephalography (EEG) was used to examine oscillatory connectivity in functional neural networks and local and global network organisation during three tasks (resting-state, attentional and inhibitory control Go/Nogo task, upright and inverted face processing task) in participants with TSC (n = 48) compared to an age- and sex-matched group of typically developing Controls (n = 20). Compared to Controls, the TSC group showed hypoconnected neural networks in the alpha frequency during the resting-state and in the theta and alpha frequencies during the Go/Nogo task (P ≤ .008), as well as reduced local network organisation in the theta and alpha frequencies during the Go/Nogo task (F = 3.95, P = .010). There were no significant group differences in network metrics during the face processing task. Increased connectivity in the hypoconnected alpha-range resting-state network was associated with greater ASD and inattentive ADHD symptoms (rho≥.40, P ≤ .036). Reduced local network organisation in the theta-range during the Go/Nogo task was significantly associated with higher hyperactive/impulsive ADHD symptoms (rho = −.43, P = .041). These findings suggest that TSC is associated with widespread hypoconnectivity in neural networks and support the proposal that altered network function may be involved in the co-occurrence of ASD and ADHD in TSC.

Altered performance monitoring is implicated in obsessive-compulsive disorder (OCD), Gilles de la Tourette syndrome (GTS), attention-deficit/hyperactivity disorder (ADHD) and autism. We conducted a systematic review and meta-analysis of electrophysiological correlates of performance monitoring (error-related negativity, ERN; error positivity, Pe; feedback-related negativity, FRN; feedback-P3) in individuals with OCD, GTS, ADHD or autism compared to control participants, or associations between correlates and symptoms/traits of these conditions. Meta-analyses on 97 studies (5890 participants) showed increased ERN in OCD (Hedge’s g = 0.54[CIs:0.44,0.65]) and GTS (g = 0.99[CIs:0.05,1.93]). OCD also showed increased Pe (g = 0.51[CIs:0.21,0.81]) and FRN (g = 0.50[CIs:0.26,0.73]). ADHD and autism showed reduced ERN (ADHD: g=-0.47[CIs:-0.67,-0.26]; autism: g=-0.61[CIs:-1.10,-0.13]). ADHD also showed reduced Pe (g=-0.50[CIs:-0.69,-0.32]). These findings suggest overlap in electrophysiological markers of performance monitoring alterations in four common neurodevelopmental conditions, with increased amplitudes of the markers in OCD and GTS and decreased amplitudes in ADHD and autism. Implications of these findings in terms of shared and distinct performance monitoring alterations across these neurodevelopmental conditions are discussed. PROSPERO pre-registration code: CRD42019134612.

Dimensional approaches to psychopathology interrogate the core neurocognitive domains interacting at the individual level to shape diagnostic symptoms. Embedding this approach in prospective longitudinal studies could transform our understanding of the mechanisms underlying neurodevelopmental disorders. Such designs require us to move beyond traditional group comparisons and determine which domain-specific atypicalities apply at the level of the individual, and whether they vary across distinct phenotypic subgroups. As a proof of principle, this study examines how the domain of face processing contributes to a clinical diagnosis of Autism Spectrum Disorder (ASD). We used an event-related potentials (ERPs) task in a cohort of 8-month-old infants with (n=148) and without (n=68) an older sibling with ASD, and combined traditional case-control comparisons with machine-learning techniques like supervised classification for prediction of clinical outcome at 36 months and Bayesian hierarchical clustering for stratification into subgroups. Our findings converge to indicate that a broad profile of alterations in the time-course of neural processing of faces is an early predictor of later ASD diagnosis. Furthermore, we identified two brain response-defined subgroups in ASD that showed distinct alterations in different aspects of face processing compared to siblings without ASD diagnosis, suggesting that individual differences between infants contribute to the diffuse pattern of alterations predictive of ASD in the first year of life. This study shows that moving from group-level comparisons to pattern recognition and stratification can help to understand and reduce heterogeneity in clinical cohorts, and improve our understanding of the mechanisms that lead to later neurodevelopmental outcomes.General Scientific SummaryThis study suggests that neural processing of faces is diffusely atypical in Autism Spectrum Disorder, and that it represents a strong candidate predictor of outcome at an individual level in the first year of life.

This study explored whether high autistic traits, high attention deficit hyperactivity disorder (ADHD) traits and their interaction were associated with quality of life (QoL) in a sample of 556 of young-adult twins (Mean age 22 years 5 months, 52% Female). Four participant groups were created: high autistic traits, high ADHD traits, high autistic/ADHD traits, and low ADHD/autistic traits. High autistic traits were associated with lower QoL across domains (physical, psychological, social, and environmental). High ADHD traits associated with lower physical, psychological, and environmental QoL. The interaction of autistic and ADHD traits was not significant in any domain. While mental health difficulties were associated with lower QoL, after accounting for mental health, most relationships between autistic traits, ADHD traits and QoL remained.

Background: The impact of the COVID-19 pandemic on the wellbeing of parents and children in the general population has been well-documented. This study investigated wellbeing in parents of and children with rare neurogenetic conditions, who may have been at greater risk of negative impact on mental health and behavioural challenges during the first UK lockdown. Method: An online survey data was completed by parents of children with a rare neurogenetic condition between May and July 2020 (CoIN sample; N=123) and compared to responses from parents of children in the wider population (Co-SPACE sample; N=2121). Measures of wellbeing included the 21-item Depression, Anxiety and Stress Scale for parents and the Strength and Difficulties Questionnaire for child behaviour. Results: Parent anxiety was significantly higher in CoIN (MedianAnx = 4) than Co-SPACE (MedianAnx = 2). Parent-rated internalising, externalising and impact of child behavioural difficulties were also significantly higher in CoIN (MedianInt = 9.5; MedianExt = 11, MedianImp = 8) than Co-SPACE (MedianInt = 6; MedianExt = 7, MedianImp = 1). Only group differences in child behaviour and impact remained significant when matching for demographic factors and were also larger than previously reported pre-pandemic differences. Discussion: Families of children with rare neurogenetic conditions reported poorer wellbeing during the first lockdown compared to the wider population, affecting both parents and children. This likely reflects pre-existing complex needs, which should be prioritised during future national crises. Investigation of changes in wellbeing in this population over the course of the pandemic is warranted.

To examine the association between perinatal adversities and neurodevelopmental outcome in tuberous sclerosis complex (TSC).The Tuberous Sclerosis 2000 study is a prospective, longitudinal UK study of TSC. In phase 1, mutation type, TSC family history, tuber characteristics, presence of cardiac rhabdomyomas, seizure characteristics, and intellectual ability were assessed in 125 children affected with TSC (64 females, 61 males; median age 39mo, range 4-254). In phase 2, 88 participants (49 females, 39 males; median age 148mo, range 93-323) were assessed for neurodevelopmental outcomes including intellectual ability, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Perinatal histories of 88 participants with TSC and 80 unaffected siblings were collected retrospectively using the Obstetric Enquiry Schedule and coded with a modified Gillberg Optimality Scale to measure levels of perinatal adversity. Data were analysed using Mann-Whitney U tests, Spearman's rank correlation, and linear regression with robust standard errors.Children with familial TSC experienced significantly greater perinatal adversity than unaffected siblings. Perinatal adversity was higher in children with TSC-affected mothers than those with unaffected mothers. There was no significant association between perinatal adversities and neurodevelopmental outcomes after controlling for confounders.Maternal TSC is a significant marker of elevated perinatal risk in addition to risks incurred by fetal genotype. Pregnancies complicated by maternal or fetal TSC require higher vigilance, and mechanisms underlying increased perinatal adversity require further research.Higher perinatal adversity is associated with familial tuberous sclerosis complex (TSC). Maternal TSC was associated with higher frequencies of several perinatal risk markers. Paternal TSC was not associated with higher levels of perinatal adversity. Perinatal adversity levels in TSC1 and TSC2 subgroups did not differ significantly. Perinatal adversities were not associated with neurodevelopmental outcomes.

Background: Tuberous Sclerosis Complex (TSC) is a single gene disorder carrying high risk of autism spectrum disorder (ASD). Various neurological complications increase the risk of ASD but the way risk factors operate together is unclear. We aimed to explore risk pathways to ASD by modelling the interplay between genetic mutation (TSC1/TSC2), cortical tuber count, seizure type and severity. Methods: The Tuberous Sclerosis 2000 Study is a UK longitudinal study of the natural history of TSC. We recruited newly diagnosed children (N=125) and collected data on mutation, cortical tuber count (cranial MRI/CT), seizure history, and IQ. ASD and IQ assessments were carried out at 10-year follow up (N=86, M age=13.1 years). Structural equation modelling (SEM) was used to explore pathways that mediate between mutation and ASD symptoms. Results: Risk of ASD was high: 39.5% met research criteria for ASD and a further 41.9% showed autistic traits. SEM resulted in two indirect pathways, with cortical tuber count and occurrence/severity of epileptic spasms in infancy mediating between mutation and ASD (mutation-tubers-spasms-ASD, B=2.08, 95%CI 0.15–8.02; mutation-spasms-ASD, B=2.98, 95%CI 0.04–8.89). Concurrent seizures (B=3.08, 95%CI 0.42–6.18) and IQ (B=-117.10, 95%CI -183.57–-59.16) were also associated with ASD symptoms. Conclusions: There was significantly elevated risk of ASD and subclinical autistic traits. Tuber count and severity of spasms predicted ASD severity, suggesting that prevention/control of seizures in infancy may decrease severity of ASD symptoms. ASD was occasionally reported in the absence of overt seizures in infancy, so their causal role requires further investigation.

This cohort study investigates whether N290 latency to faces vs nonfaces is associated with autism polygenic scores and cross-disorder polygenic scores in infants with and without a family history of autism.

Early difficulties in engaging attentive brain states in social settings could affect learning and have cascading effects on social development. We investigated this possibility using multichannel electroencephalography during a face/non-face paradigm in 8-month-old infants with (FH, n = 91) and without (noFH, n = 40) a family history of autism spectrum disorder (ASD). An event-related potential component reflecting attention engagement, the Nc, was compared between FH infants who received a diagnosis of ASD at 3 years of age (FH-ASD; n = 19), FH infants who did not (FH-noASD; n = 72) and noFH infants (who also did not, hereafter noFH-noASD; n = 40). ‘Prototypical’ microstates during social attention were extracted from the noFH-noASD group and examined in relation to later categorical and dimensional outcome. Machine-learning was used to identify the microstate features that best predicted ASD and social adaptive skills at three years. Results suggested that whilst measures of brain state timing were related to categorical ASD outcome, brain state strength was related to dimensional measures of social functioning. Specifically, the FH-ASD group showed shorter Nc latency relative to other groups, and duration of the attentive microstate responses to faces was informative for categorical outcome prediction. Reduced Nc amplitude difference between faces with direct gaze and a non-social control stimulus and strength of the attentive microstate to faces contributed to the prediction of dimensional variation in social skills. Taken together, this provides consistent evidence that atypical attention engagement precedes the emergence of difficulties in socialization and indicates that using the spatio-temporal characteristics of whole-brain activation to define brain states in infancy provides an important new approach to understanding of the neurodevelopmental mechanisms that lead to ASD.

Contains fulltext : 231789.pdf (Publisher’s version ) (Closed access) BACKGROUND: Autism spectrum disorder (ASD) is highly heterogeneous in its etiology and manifestation. The neurobiological processes underlying ASD development are reflected in multiple features, from behaviour and cognition to brain functioning. An integrated analysis of these features may optimize the identification of these processes. METHODS: We examined cognitive and adaptive functioning and ASD symptoms between 8 and 36 months in 161 infants at familial high risk for ASD and 71 low-risk controls; we also examined neural sensitivity to eye gaze at 8 months in a subsample of 140 high-risk and 61 low-risk infants. We used linked independent component analysis to extract patterns of variation across domains and development, and we selected the patterns significantly associated with clinical classification at 36 months. RESULTS: An early process at 8 months, indicating high levels of functioning and low levels of symptoms linked to higher attention to gaze shifts, was reduced in infants who developed ASD. A longitudinal process of increasing functioning and low levels of symptoms was reduced in infants who developed ASD, and another process suggesting a stagnation in cognitive functioning at 24 months was increased in infants who developed ASD. LIMITATIONS: Although the results showed a clear significant trend relating to clinical classification, we found substantial overlap between groups. CONCLUSION: We uncovered underlying processes that acted together early in development and were associated with clinical outcomes. Our results highlighted the complexity of emerging ASD, which goes beyond the borders of clinical categories. Future work should integrate genetic data to investigate the specific genetic risks linked to these processes.

Actigraphy, an objective measure of motor activity, reliably indexes increased movement levels in attention-deficit/hyperactivity disorder (ADHD) and may be useful for diagnosis and treatment-monitoring. However, actigraphy has not been examined in complex neurodevelopmental conditions. This study used actigraphy to objectively measure movement levels in individuals with a complex neurodevelopmental genetic disorder, tuberous sclerosis (TSC). Thirty participants with TSC (11–21 years, 20 females, IQ = 35–108) underwent brief (approximately 1 h) daytime actigraph assessment during two settings: movie viewing and cognitive testing. Multiple linear regressions were used to test associations between movement measurements and parent-rated ADHD symptoms. Correlations were used to examine associations between actigraph measures and parent-rated ADHD symptoms and other characteristics of TSC (symptoms of autism spectrum disorder (ASD), intellectual ability (IQ), epilepsy severity, cortical tuber count). Higher movement levels during movies were associated with higher parent-rated ADHD symptoms. Higher ADHD symptoms and actigraph-measured movement levels during movies were positively associated with ASD symptoms and negatively associated with IQ. Inter-individual variability of movement during movies was not associated with parent-rated hyperactivity or IQ but was negatively associated with ASD symptoms. There were no associations with tuber count or epilepsy. Our findings suggest that actigraph-measured movement provides a useful correlate of ADHD in TSC.

Impaired face processing is proposed to play a key role in the early development of autism spectrum disorder (ASD) and to be an endophenotypic trait which indexes genetic risk for the disorder. However, no published work has examined the development of face processing abilities from infancy into the school-age years and how they relate to ASD symptoms in individuals with or at high-risk for ASD. In this novel study we investigated neural and behavioural measures of face processing at age 7 months and again in mid-childhood (age 7 years) as well as social-communication and sensory symptoms in siblings at high (n = 42) and low (n = 35) familial risk for ASD. In mid-childhood, high-risk siblings showed atypical P1 and N170 event-related potential correlates of face processing and, for high-risk boys only, poorer face and object recognition ability compared to low-risk siblings. These neural and behavioural atypicalities were associated with each other and with higher social-communication and sensory symptoms in mid-childhood. Additionally, more atypical neural correlates of object (but not face) processing in infancy were associated with less right-lateralised (more atypical) N170 amplitudes and greater social-communication problems in mid-childhood. The implications for models of face processing in ASD are discussed.

Adults with ADHD describe self-medicating with cannabis, with some reporting a preference for cannabis over ADHD medications. A small number of psychiatrists in the US prescribe cannabis medication for ADHD, despite there being no evidence from randomised controlled studies. The EMA-C trial (Experimental Medicine in ADHD-Cannabinoids) was a pilot randomised placebo-controlled experimental study of a cannabinoid medication, Sativex Oromucosal Spray, in 30 adults with ADHD. The primary outcome was cognitive performance and activity level using the QbTest. Secondary outcomes included ADHD and emotional lability (EL) symptoms. From 17.07.14 to 18.06.15, 30 participants were randomly assigned to the active (n=15) or placebo (n=15) group. For the primary outcome, no significant difference was found in the ITT analysis although the overall pattern of scores was such that the active group usually had scores that were better than the placebo group (Est=-0.17, 95%CI-0.40 to 0.07, p=0.16, n=15/11 active/placebo). For secondary outcomes Sativex was associated with a nominally significant improvement in hyperactivity/impulsivity (p=0.03) and a cognitive measure of inhibition (p=0.05), and a trend towards improvement for inattention (p=0.10) and EL (p=0.11). Per-protocol effects were higher. Results did not meet significance following adjustment for multiple testing. One serious (muscular seizures/spasms) and three mild adverse events occurred in the active group and one serious (cardiovascular problems) adverse event in the placebo group. Adults with ADHD may represent a subgroup of individuals who experience a reduction of symptoms and no cognitive impairments following cannabinoid use. While not definitive, this study provides preliminary evidence supporting the self-medication theory of cannabis use in ADHD and the need for further studies of the endocannabinoid system in ADHD.

Aim: To investigate the interdependence between risk factors associated with long-term intellectual development in individuals with tuberous sclerosis complex (TSC). Method: The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of individuals with TSC. In phase 1 of the study, baseline measures of intellectual ability, epilepsy, cortical tuber load, and mutation were obtained for 125 children (63 females, 62 males; median age=39mo). In phase 2, at an average of 8 years later, intellectual abilities were estimated for 88 participants with TSC and 35 unaffected siblings. Structural equation modelling was used to determine the risk pathways from genetic mutation through to IQ at phase 2. Results: Intellectual disability was present in 57% of individuals with TSC. Individuals without intellectual disability had significantly lower mean IQ compared to unaffected siblings, supporting specific genetic factors associated with intellectual impairment. Individuals with TSC who had a slower gain in IQ from infancy to middle childhood were younger at seizure onset and had increased infant seizure severity. Structural equation modelling indicated indirect pathways from genetic mutation, to tuber count, to seizure severity in infancy, through to IQ in middle childhood and adolescence. Interpretation: Early-onset and severe epilepsy in the first 2 years of life are associated with increased risk of long-term intellectual disability in individuals with TSC, emphasizing the importance of early and effective treatment or prevention of epilepsy. What this paper adds: Intellectual disability was present in 57% of individuals with tuberous sclerosis complex (TSC). Those with TSC without intellectual disability had significantly lower mean IQ compared to unaffected siblings. Earlier onset and greater severity of seizures in the first 2 years were observed in individuals with a slower gain in intellectual ability. Risk pathways through seizures in the first 2 years predict long-term cognitive outcomes in individuals with TSC.

We investigated key event-related brain potential markers (ERPs) derived from a flanked continuous performance task (CPT) and whether these would show phenotypic associations with ADHD (attention-deficit/hyperactivity disorder) in a population-based sample. We further explored whether there was preliminary evidence that such ERPs could also index genetic risk for ADHD (depending on finding phenotypic associations). Sixty-seven male-only twin pairs (N = 134; aged 12-15) from a subsample of the Twins’ Early Development Study, concordant and discordant for ADHD symptoms, performed the flanked CPT (or CPT-OX) while electroencephalography (EEG) was recorded. ERPs were obtained for cue (P3, CNV or contingency negative variation), go (P3, N2) and nogo trials (P3, N2). We found no phenotypic associations between CPT-derived ERPs and ADHD – the sizes of the estimated phenotypic correlations were nonsignificant and very small (r’s = -.11 to .04). Twin-model fitting analyses using structural equation modelling provided preliminary evidence that some of the ERPs were heritable (with the most robust effect for go-P3 latency), but there was limited evidence of any genetic associations between ERPs and ADHD, although with the caveat that our sample was small and hence had limited power. Overall, unlike in previous research, there was no evidence of phenotypic (nor preliminary evidence for genetic) associations between ADHD and CPT-derived ERPs in this study. Hence, it may be currently premature for genetic analyses of ADHD to be guided by CPT-derived ERP parameters (unlike alternative cognitive-neurophysiological approaches which may be more promising). Further research with better-powered, population-based, genetically-informative and cross-disorder samples are required, which could be facilitated by emerging mobile EEG technologies.

Purpose – Tuberous sclerosis complex (TSC) is a genetic disorder with a high prevalence of autism spectrum disorder (ASD), yet no single genetic, neurological or neurophysiological risk marker is necessary or sufficient to increase risk for ASD. This paper aims to discuss the utility of adopting a developmental perspective. Design/methodology/approach – The increasing number of TSC infants presenting with abnormalities prenatally provides a unique opportunity to study risk pathways to ASD from birth. Here, the authors review findings to date that support the investigation of infants with TSC to further our understanding of typical and atypical development. Findings – Evidence has accumulated from studies of infants at familial risk for ASD (“baby siblings”) to suggest that early markers of ASD are present in the first year of life. The early waves of prospective studies of infants with TSC indicate dynamic changes in developmental trajectories to ASD and are likely to provide insight into cascading effects of brain “insult” early in development. Emerging evidence of phenotypic and biological homology between syndromic and idiopathic cases of ASD supports the notion of a convergence of risk factors on a final common pathway in ASD. Originality/value – The delineation of brain-based biomarkers of risk, prediction and treatment response in TSC will be critical in aiding the development of targeted intervention and prevention strategies for those infants at high risk of poorer developmental outcomes.

Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are common and impairing neurodevelopmental disorders that frequently co-occur. The neurobiological mechanisms involved in ASD and ADHD are not fully understood. However, alterations in large-scale neural networks have been proposed as core deficits in both ASD and ADHD and may help to disentangle the neurobiological basis of these disorders and their co-occurrence. In this study, we examined similarities and differences in large-scale oscillatory neural networks between boys aged 8-13 years with ASD (n = 19), ADHD (n = 18), ASD + ADHD (n = 29) and typical development (Controls, n = 26). Oscillatory neural networks were computed using graph-theoretical methods from electroencephalographic (EEG) data collected during an eyes-open resting-state and attentional control and social cognition tasks in which we previously reported disorder-specific atypicalities in oscillatory power and event-related potentials (ERPs). We found that children with ASD showed significant hypoconnectivity in large-scale networks during all three task conditions compared to children without ASD. In contrast, children with ADHD showed significant hyperconnectivity in large-scale networks during the attentional control and social cognition tasks, but not during the resting-state, compared to children without ADHD. Children with co-occurring ASD + ADHD did not differ from children with ASD when paired with this group and vice versa when paired with the ADHD group, indicating that these children showed both ASD-like hypoconnectivity and ADHD-like hyperconnectivity. Our findings suggest that ASD and ADHD are associated with distinct alterations in large-scale oscillatory networks, and these atypicalities present together in children with both disorders. These alterations appear to be task-independent in ASD but task-related in ADHD, and may underlie other neurocognitive atypicalities in these disorders. [Abstract copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.]

Altered power of resting-state neurophysiological activity has been associated with autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), which commonly co-occur. We compared resting-state neurophysiological power in children with ASD, ADHD, co-occurring ASD + ADHD, and typically developing controls. Children with ASD (ASD/ASD + ADHD) showed reduced theta and alpha power compared to children without ASD (controls/ADHD). Children with ADHD (ADHD/ASD + ADHD) displayed decreased delta power compared to children without ADHD (ASD/controls). Children with ASD + ADHD largely presented as an additive co-occurrence with deficits of both disorders, although reduced theta compared to ADHD-only and reduced delta compared to controls suggested some unique markers. Identifying specific neurophysiological profiles in ASD and ADHD may assist in characterising more homogeneous subgroups to inform treatment approaches and aetiological investigations.

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) often co-occur. Children with ASD and ADHD demonstrate deficits in adaptive functioning, yet pure and comorbid groups have not been directly compared. Vineland Adaptive Behaviour Scales (VABS-II) data were examined in boys with ASD (n = 17), ADHD (n = 31) and ASD + ADHD (n = 38). Results demonstrated lower socialisation and composite scores and greater discrepancy between cognitive and adaptive abilities in the ASD + ADHD group compared to the ADHD-only group. Significant associations were shown between reduced adaptive functioning and autism symptoms, but not ADHD symptoms. Children with ASD + ADHD present with exacerbated impairments in adaptive functioning relative to children with ADHD, associated with ASD symptoms. Disentangling variation in adaptive skills may aid the assessment of complex cases.

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.

BackgroundSubstantial 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).MethodBehavioural 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.ResultsCategorical 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.ConclusionsChildren 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.

BackgroundRecent studies point to overlap between neuropsychiatric disorders in symptomatology and genetic aetiology.AimsTo systematically investigate genomics overlap between childhood and adult attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and major depressive disorder (MDD).MethodAnalysis of whole-genome blood gene expression and genetic risk scores of 318 individuals. Participants included individuals affected with adult ADHD (n = 93), childhood ADHD (n = 17), MDD (n = 63), ASD (n = 51), childhood dual diagnosis of ADHD–ASD (n = 16) and healthy controls (n = 78).ResultsWeighted gene co-expression analysis results reveal disorder-specific signatures for childhood ADHD and MDD, and also highlight two immune-related gene co-expression modules correlating inversely with MDD and adult ADHD disease status. We find no significant relationship between polygenic risk scores and gene expression signatures.ConclusionsOur results reveal disorder overlap and specificity at the genetic and gene expression level. They suggest new pathways contributing to distinct pathophysiology in psychiatric disorders and shed light on potential shared genomic risk factors.

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

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.

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.

BackgroundTuberous sclerosis complex (TSC) is associated with intellectual disability, but the risk pathways are poorly understood.MethodThe 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.ResultsTSC2 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.ConclusionsThe 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.

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.

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 (4–8 Hz). 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.

Altered very low-frequency electroencephalographic (VLF-EEG) activity is an endophenotype of ADHD in children and adolescents. We investigated VLF-EEG case-control differences in adult samples and the effects of methylphenidate (MPH). A longitudinal case-control study was conducted examining the effects of MPH on VLF-EEG (.02–0.2 Hz) during a cued continuous performance task. 41 untreated adults with ADHD and 47 controls were assessed, and 21 cases followed up after MPH treatment, with a similar follow-up for 38 controls (mean follow-up = 9.4 months). Cases had enhanced frontal and parietal VLF-EEG and increased omission errors. In the whole sample, increased parietal VLF-EEG correlated with increased omission errors. After controlling for subthreshold comorbid symptoms, VLF-EEG case-control differences and treatment effects remained. Post-treatment, a time by group interaction emerged; VLF-EEG and omission errors reduced to the same level as controls, with decreased inattentive symptoms in cases. Reduced VLF-EEG following MPH treatment provides preliminary evidence that changes in VLF-EEG may relate to MPH treatment effects on ADHD symptoms; and that VLF-EEG may be an intermediate phenotype of ADHD. Further studies of the treatment effect of MPH in larger controlled studies are required to formally evaluate any causal link between MPH, VLF-EEG and ADHD symptoms.