Impact of and research priorities in early onset epilepsy: An investigation of parental concerns.

[Background and aim] Early onset epilepsy is a neurological condition with significant developmental consequences, and presents affected children and families with challenges which pervade many aspects of family life. Whilst the concerns of parents and the impact on quality of life is well documented in qualitative research, little emphasis has been placed on the context of 'early onset', and the implications of these concerns for research priority setting. We aimed to explore parental perspectives regarding concerns and the impact of early onset epilepsy on the child and family, and to identify priorities for future paediatric epilepsy research. [Methods] The Brain development in Early Epilepsy: Parent Priorities (BEE-PP) project employed a mixed methods approach to collect information on parents' experience of having a child diagnosed with early onset epilepsy before 36 months old and aged up to 16 years old. Parents completed an online survey (n = 15) followed by a focus group (n = 5) to explore their main concerns regarding early onset epilepsy, the impact on family life and research priorities. [Results] A thematic analysis of the focus group data generated eight themes related to concerns of parents, the impact on the family and research priorities. The three main concerns identified were the expected trajectory of their child's development, a lack of seizure control following diagnosis and adverse behavioural side effects of medication. Within family life, early onset epilepsy had an impact on sibling autonomy and psychosocial adaptation, poorer parental wellbeing and restricted social and personal activities. The need for clearer information regarding their child's developmental trajectory, and managing the side effects of medication and their interactions with behaviour over time were topics of priority for future epilepsy research. [Interpretation] The impact of early onset epilepsy on the family is pervasive and requires the provision of appropriate healthcare service-led support for families to improve quality of life and children's adjustment to epilepsy. Regular monitoring of the concerns of parents and the impact of the diagnosis would be beneficial for addressing epilepsy-related and psychosocial needs of the wider family throughout their child's development. Implications for future research priority setting with regards to improved clinician-to-parent information sharing and managing the behavioural side effects of medication are discussed.

Early development and epilepsy in tuberous sclerosis complex: A prospective longitudinal study.

AIM: To characterize early changes in developmental ability, language, and adaptive behaviour in infants diagnosed with tuberous sclerosis complex (TSC), and determine whether clinical features of epilepsy influence this pathway. METHOD: Prospective, longitudinal data were collected within the Early Development in Tuberous Sclerosis (EDiTS) Study to track development of infants with TSC (n = 32) and typically developing infants (n = 33) between 3 and 24 months of age. Questionnaire and observational measures were used at up to seven timepoints to assess infants' adaptive behaviour, developmental ability, language, and epilepsy. RESULTS: A significant group by age interaction effect showed that infants with TSC had lower adaptive functioning at 18 to 24 months old (intercept = 88.12, slope estimate = -0.82, p < 0.001) and lower developmental ability scores from 10 months old (intercept = 83.33, slope estimate = -1.44, p < 0.001) compared to typically developing infants. Early epilepsy severity was a significant predictor of these emerging developmental (R2 = 0.35, p = 0.004, 95% confidence interval [CI] -0.08 to -0.01) and adaptive behaviour delays (R2 = 0.34, p = 0.004, 95% CI -0.05 to -0.01]). Lower vocabulary production (intercept = -1.25, slope = -0.12, p < 0.001) and comprehension scores (intercept = 2.39, slope estimate = -0.05, p < 0.001) in infants with TSC at 24 months old were not associated with epilepsy severity. INTERPRETATION: Divergence of developmental ability and adaptive functioning skills occur in infants with TSC from 10 and 18 months, respectively. Associations between early epilepsy severity and impaired development supports the importance of early intervention to reduce seizure severity.

Epilepsy severity mediates association between mutation type and ADHD symptoms in tuberous sclerosis complex.

The association between attention-deficit/hyperactivity disorder (ADHD) and tuberous sclerosis complex (TSC) is widely reported, with support for the role of epilepsy, yet the mechanisms underlying the association across development are unclear. The Tuberous Sclerosis 2000 Study is a prospective longitudinal study of TSC. In Phase 1 of the study, baseline measures of epilepsy, cortical tuber load, and mutation were obtained with 125 children ages 0-16 years. In Phase 2, at an average of 8 years later, ADHD symptoms were measured for 81 of the participants. Structural equation modeling revealed an indirect pathway from genetic mutation, to cortical tuber load, to epileptic spasm severity in infancy, to ADHD symptoms in middle childhood and adolescence, in addition to a pathway linking current seizure severity to ADHD symptoms. Findings were retained when intelligence quotient (IQ) was entered as a correlated factor. The findings support a cascading developmental pathway to ADHD symptoms mediated by early-onset and severe epilepsy in the first 2 years of life. This warrants detailed investigation of seizure characteristics and cognitive and behavioral sequelae associated with ADHD from early in life, to further the understanding of the association between ADHD and early-onset epilepsy across syndromic and non-syndromic populations.

Alpha oscillatory activity during attentional control in children with Autism Spectrum Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD), and ASD+ADHD.

BACKGROUND: Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) share impairments in top-down and bottom-up modulation of attention. However, it is not yet well understood if co-occurrence of ASD and ADHD reflects a distinct or additive profile of attention deficits. We aimed to characterise alpha oscillatory activity (stimulus-locked alpha desynchronisation and prestimulus alpha) as an index of integration of top-down and bottom-up attentional processes in ASD and ADHD. METHODS: Children with ASD, ADHD, comorbid ASD+ADHD, and typically-developing children completed a fixed-choice reaction-time task ('Fast task') while neurophysiological activity was recorded. Outcome measures were derived from source-decomposed neurophysiological data. Main measures of interest were prestimulus alpha power and alpha desynchronisation (difference between poststimulus and prestimulus alpha). Poststimulus activity linked to attention allocation (P1, P3), attentional control (N2), and cognitive control (theta synchronisation, 100-600 ms) was also examined. ANOVA was used to test differences across diagnostics groups on these measures. Spearman's correlations were used to investigate the relationship between attentional control processes (alpha oscillations), central executive functions (theta synchronisation), early visual processing (P1), and behavioural performance. RESULTS: Children with ADHD (ADHD and ASD+ADHD) showed attenuated alpha desynchronisation, indicating poor integration of top-down and bottom-up attentional processes. Children with ADHD showed reduced N2 and P3 amplitudes, while children with ASD (ASD and ASD+ADHD) showed greater N2 amplitude, indicating atypical attentional control and attention allocation across ASD and ADHD. In the ASD group, prestimulus alpha and theta synchronisation were negatively correlated, and alpha desynchronisation and theta synchronisation were positively correlated, suggesting an atypical association between attentional control processes and executive functions. CONCLUSIONS: ASD and ADHD are associated with disorder-specific impairments, while children with ASD+ADHD overall presented an additive profile with attentional deficits of both disorders. Importantly, these findings may inform the improvement of transdiagnostic procedures and optimisation of personalised intervention approaches.

Perinatal adversities in tuberous sclerosis complex: Determinants and neurodevelopmental outcomes.

AIM: To examine the association between perinatal adversities and neurodevelopmental outcome in tuberous sclerosis complex (TSC). METHOD: 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. RESULTS: 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. INTERPRETATION: 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. WHAT THIS PAPER ADDS: 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.

Uncovering neurodevelopmental paths to autism spectrum disorder through an integrated analysis of developmental measures and neural sensitivity to faces.

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.

Long-term cognitive outcomes in tuberous sclerosis complex.

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.

Immune signatures and disorder-specific patterns in a cross-disorder gene expression analysis.

BACKGROUND: Recent studies point to overlap between neuropsychiatric disorders in symptomatology and genetic aetiology. AIMS: To systematically investigate genomics overlap between childhood and adult attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and major depressive disorder (MDD). METHOD: Analysis 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). RESULTS: Weighted 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. CONCLUSIONS: Our 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.

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.

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.

The effect of methylphenidate on very low frequency electroencephalography oscillations in adult ADHD.

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 (.02-0.2Hz) 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=9.4months). 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.

European Autism GEnomics Registry (EAGER): protocol for a multicentre cohort study and registry.

INTRODUCTION: Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants' genetic profiles. METHODS AND ANALYSIS: EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will be given a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent to the study to access pre-existing clinical data. Participants will be added to the EAGER registry and data will be shared externally through established AIMS-2-TRIALS mechanisms. ETHICS AND DISSEMINATION: To date, EAGER has received full ethical approval for 11 out of the 13 sites in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023), Spain (HCB/2023/0038, PIC-164-22), Sweden (Dnr 2023-06737-01), Ireland (230907) and Italy (CET_62/2023, CEL-IRCCS OASI/24-01-2024/EM01, EM 2024-13/1032 EAGER). Findings will be disseminated via scientific publications and conferences but also beyond to participants and the wider community (eg, the AIMS-2-TRIALS website, stakeholder meetings, newsletters).

Neural connectivity abnormalities in autism: insights from the Tuberous Sclerosis model.

Autism Spectrum Disorder (ASD) is a behavioral syndrome caused by complex genetic and non-genetic risk factors. It has been proposed that these risk factors lead to alterations in the development and 'wiring' of brain circuits and hence, the emergence of ASD. Although several lines of research lend support to this theory, etiological and clinical heterogeneity, methodological issues and inconsistent findings have led to significant doubts. One of the best established, albeit rare, causes of ASD is the genetic condition Tuberous Sclerosis Complex (TSC), where 40% of individuals develop ASD. A recent study by Peters and Taquet et al. analyzed electroencephalography (EEG) data using graph theory to model neural 'connectivity' in individuals with TSC with and without ASD and cases with 'idiopathic' ASD. TSC cases exhibited global under-connectivity and abnormal network topology, whereas individuals with TSC + ASD demonstrated similar connectivity patterns to those seen in individuals with idiopathic ASD: decreased long- over short-range connectivity. The similarity in connectivity abnormalities in TSC + ASD and ASD suggest a common final pathway and provide further support for 'mis-wired' neural circuitry in ASD. The origins of the connectivity changes, and their role in mediating between the neural and the cognitive/behavioral manifestations, will require further study.Please see related research article here http://www.biomedcentral.com/1741-7015/11/54.

Face processing in young adults with autism and ADHD: An event related potentials study.

Background: Atypicalities in perception and interpretation of faces and emotional facial expressions have been reported in both autism and attention-deficit/hyperactivity disorder (ADHD) during childhood and adulthood. Investigation of face processing during young adulthood (18 to 25 years), a transition period to full-fledged adulthood, could provide important information on the adult outcomes of autism and ADHD. Methods: In this study, we investigated event-related potentials (ERPs) related to visual face processing in autism, ADHD, and co-occurring autism and ADHD in a large sample of young adults (N = 566). The groups were based on the Diagnostic Interview for ADHD in Adults 2.0 (DIVA-2) and the Autism Diagnostic Observation Schedule-2 (ADOS-2). We analyzed ERPs from two passive viewing tasks previously used in childhood investigations: (1) upright and inverted faces with direct or averted gaze; (2) faces expressing different emotions. Results: Across both tasks, we consistently found lower amplitude and longer latency of N170 in participants with autism compared to those without. Longer P1 latencies and smaller P3 amplitudes in response to emotional expressions and longer P3 latencies for upright faces were also characteristic to the autistic group. Those with ADHD had longer N170 latencies, specific to the face-gaze task. Individuals with both autism and ADHD showed additional alterations in gaze modulation and a lack of the face inversion effect indexed by a delayed N170. Conclusion: Alterations in N170 for autistic young adults is largely consistent with studies on autistic adults, and some studies in autistic children. These findings suggest that there are identifiable and measurable socio-functional atypicalities in young adults with autism.

Experiences of parents of children with rare neurogenetic conditions during the COVID-19 pandemic: an interpretative phenomenological analysis.

BACKGROUND: The 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. METHODS: Semi-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. RESULTS: Four 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' perspectives of how they coped during the pandemic". 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 positive effects of the pandemic on family wellbeing. CONCLUSIONS: These 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 were 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 and implemented across diverse future scenarios to promote coping and positive wellbeing.

Is quality of life related to high autistic traits, high ADHD traits and their Interaction? Evidence from a Young-Adult Community-Based twin sample.

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.

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.

Quality of life, functional impairment and continuous performance task event-related potentials (ERPs) in young adults with ADHD and autism: A twin study.

Background: Young adulthood is a key developmental period for understanding outcomes of childhood onset attention-deficit/hyperactivity disorder (ADHD) and autism. Measurement of functional impairment and quality of life (QoL) can provide important information on the real-life challenges associated with these conditions. Event-related potential (ERP) measures from the continuous performance task (CPT) have long been identified as altered in ADHD and autism but the role of these functions in the aetiological pathway to the disorders and associated impact on quality of life in young adulthood is unknown. Method: We investigated the relationships between ADHD and autism, functional impairment, quality of life, and ERP measures from the cued CPT (CPT-OX) in a young adult twin sample (566 participants aged 22.43 ± 0.96 years old). Results: We observed significant phenotypic correlations between ADHD/autism and lower quality of life with specific genetic overlap between ADHD and physical health, psychological, and environmental aspects. We found significant phenotypic and genetic correlations between ADHD and functional impairment in all domains, as well as between autism and impairment in social functioning and lower impairment in risk-taking. Both ADHD and autism were associated with attenuated amplitude of inhibitory and proactive control ERPs, with large genetic contributions to the overlap. We also found significant phenotypic correlations between these ERP measures and Weiss Functional Impairment Rating Scale (WFIRS) and QoL. Conclusion: This is the first study to investigate the phenotypic and genetic relationships between ADHD and autism, functional impairment, quality of life and ERP measures in young adulthood. Our findings could represent a step towards identifying ERP measures that are related to behaviour in the absence of overt symptoms.

Oscillatory neural network alterations in young people with tuberous sclerosis complex and associations with co-occurring symptoms of autism spectrum disorder and attention-deficit/hyperactivity disorder.

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.

White matter disruptions related to inattention and autism spectrum symptoms in tuberous sclerosis complex.

Tuberous sclerosis complex is a rare genetic multisystem condition that is associated with a high prevalence of neurodevelopmental disorders such as autism and attention-deficit/hyperactivity disorder. The underlying neural mechanisms of the emergence of these symptom domains in tuberous sclerosis complex remain unclear. Here, we use fixel-based analysis of diffusion-weighted imaging, which allows for the differentiation between multiple fibre populations within a voxel, to compare white matter properties in 16 participants with tuberous sclerosis complex (aged 11-19) and 12 age and sex matched control participants. We further tested associations between white matter alterations and autism and inattention symptoms as well as cognitive ability in participants with tuberous sclerosis complex. Compared to controls, participants with tuberous sclerosis complex showed reduced fibre density cross-section (FDC) in the dorsal branch of right superior longitudinal fasciculus and bilateral inferior longitudinal fasciculus, reduced fibre density (FD) in bilateral tapetum, and reduced fibre cross-section (FC) in the ventral branch of right superior longitudinal fasciculus. In participants with tuberous sclerosis complex, the extent of FDC reductions in right superior longitudinal fasciculus was significantly associated with autism traits (social communication difficulties and restricted, repetitive behaviours), whereas FDC reductions in right inferior longitudinal fasciculus were associated with inattention. The observed white matter alterations were unrelated to cognitive ability. Our findings shed light on the fibre-specific biophysical properties of white matter alterations in tuberous sclerosis complex and suggest that these regional changes are selectively associated with the severity of neurodevelopmental symptoms.