The Association Between Anxiety Symptoms and Sleep in School-Aged Children: A Combined Insight From the Children's Sleep Habits Questionnaire and Actigraphy.

The current study assessed the association between anxiety symptoms and sleep in 90 school-aged children, aged 6-12 years (Mage = 108 months, 52.2% male). The Children's Sleep Habits Questionnaire (CSHQ) and 14 nights of actigraphy were used to assess sleep. Anxiety was assessed using the Spence Children's Anxiety Scale (SCAS). A significant association was found between parent-reported anxiety symptoms and current sleep problems (i.e., CSHQ total scores ≥ 41). An examination of SCAS subscales identified a specific association between generalized anxiety disorder (GAD) symptoms and increased parental sleep concerns, including sleep onset delay, sleep duration, and daytime sleepiness. Regarding actigraphy, whilst anxiety was not associated with average sleep variables, a relationship was identified between anxiety and the night-to-night variability of actigraphy-derived sleep schedules.

Visual attention and academic performance in children with developmental disabilities and behavioural attention deficits.

Despite well-documented attention deficits in children with intellectual and developmental disabilities (IDD), distinctions across types of attention problems and their association with academic attainment has not been fully explored. This study examines visual attention capacities and inattentive/hyperactive behaviours in 77 children aged 4 to 11 years with IDD and elevated behavioural attention difficulties. Children with autism spectrum disorder (ASD; n = 23), Down syndrome (DS; n = 22), and non-specific intellectual disability (NSID; n = 32) completed computerized visual search and vigilance paradigms. In addition, parents and teachers completed rating scales of inattention and hyperactivity. Concurrent associations between attention abilities and early literacy and numeracy skills were also examined. Children completed measures of receptive vocabulary, phonological abilities and cardinality skills. As expected, the results indicated that all groups had relatively comparable levels of inattentive/hyperactive behaviours as rated by parents and teachers. However, the extent of visual attention deficits varied as a result of group; namely children with DS had poorer visual search and vigilance abilities than children with ASD and NSID. Further, significant associations between visual attention difficulties and poorer literacy and numeracy skills were observed, regardless of group. Collectively the findings demonstrate that in children with IDD who present with homogenous behavioural attention difficulties, at the cognitive level, subtle profiles of attentional problems can be delineated.

Executive Dysfunction in Female FMR1 Premutation Carriers.

There is now growing evidence of cognitive weakness in female premutation carriers (between 55 and 199 CGG repeats) of the fragile X mental retardation gene, including impairments associated with executive function. While an age-related decline in assessments of executive function has been found for male premutation carriers, few studies have explored whether female carriers show a similar trajectory with age. A total of 20 female premutation carriers and 21 age- and IQ-matched healthy controls completed a battery of tasks assessing executive function tasks, including the behavioural dyscontrol scale (BDS), symbol digit modalities test (SDMT), paced auditory serial addition test (PASAT), Haylings sentence completion test and the digit span task (forward and backward). Performance was compared between premutation carriers and healthy controls, and the association between task performance and age was also ascertained. Compared to controls, female premutation carriers had significant impairment on the BDS, SDMT, PASAT, and Haylings sentence completion task, all of which rely on quick, or timed, responses. Further analyses revealed no significant association between age and task performance for either premutation carriers or controls. This study demonstrates that a cohort of female premutation carriers have deficits on a range of tasks of executive function that require the rapid temporal resolution of responses. We propose that the understanding of the phenotype of premutation carriers will be advanced through use of such measures.

Computerised attention training for children with intellectual and developmental disabilities: a randomised controlled trial.

BACKGROUND: Children with intellectual and developmental disabilities (IDD) experience heightened attention difficulties which have been linked to poorer cognitive, academic and social outcomes. Although, increasing research has focused on the potential of computerised cognitive training in reducing attention problems, limited studies have assessed whether this intervention could be utilised for those with IDD. This study aimed to assess the efficacy of a computerised attention training programme in children with IDD. METHODS: In a double-blind randomised controlled trial, children (n = 76; IQ < 75) aged 4-11 years were assigned to an adaptive attention training condition or a nonadaptive control condition. Both conditions were completed at home over a 5-week period and consisted of 25 sessions, each of 20-min duration. Outcome measures (baseline, posttraining and 3-month follow-up) assessed core attention skills (selective attention, sustained attention and attentional control) and inattentive/hyperactive behaviour. RESULTS: Children in the attention training condition showed greater improvement in selective attention performance compared to children in the control condition (SMD = 0.24, 95% CI 0.02, 0.45). These improvements were maintained 3 months after training had ceased (SMD = 0.26, 95% CI 0.04, 0.48). The attention training programme was not effective in promoting improvements in sustained attention, attentional control or inattentive/hyperactive behaviours. CONCLUSIONS: The findings suggest that attention training may enhance some aspects of attention (selective attention) in children with IDD, but the small to medium effect sizes indicate that further refinement of the training programme is needed to promote larger, more global improvements.

Maternal predictors of anxiety risk in young males with fragile X.

Children with fragile X syndrome (FXS) demonstrate high rates of anxiety disorders, with 65-83% meeting diagnostic criteria. The severity of anxiety symptoms in FXS has been shown to be partially predicted by elevated negative affect across early childhood [Tonnsen et al. (2013a); J Abnorm Child Psychol 41:267-280]. This association suggests that biologically driven vulnerability emerges early in development, as is reported in non-clinical populations. However, anxiety emergence is likely moderated by multifaceted genetic, biological and environmental risk and protective factors. Mothers with the FMR1 premutation have been shown to exhibit elevated parenting stress and internalizing symptoms, which have each been associated with child behavior problems [Bailey et al. (2008a); Am J Med Genet Part A 146A:2060-2069 and Bailey et al. (2008b) Am J Med Genet Part A 146A:720-729]. Despite these findings, it is unclear whether maternal factors directly relate to anxiety vulnerability in high-risk children with FXS, a question essential to informing targeted, family-sensitive treatment. The present study examines how maternal protective and risk factors relate to child inhibition reflected in (1) child anxiety symptoms, (2) child trajectories of negative affect, and (3) the association between child anxiety and negative affect. Primary predictors include maternal parenting stress, indicators of mental health risk (anxiety and depressive symptoms), and maternal optimism. We also examine genetic correlates in mothers (CGG repeats, activation ratio, mRNA). Our findings suggest that behavioral inhibition in young children with FXS is associated with higher parenting stress and lower optimism, and higher parenting stress is associated with lower maternal X-activation ratio. These findings underscore the need for family-sensitive treatment strategies for anxiety disorders in children with FXS.

Impaired response inhibition is associated with self-reported symptoms of depression, anxiety, and ADHD in female FMR1 premutation carriers.

Fragile X Mental Retardation 1 (FMR1) premutation carriers (PM-carriers) have a defective trinucleotide expansion on the FMR1 gene that is associated with continuum of neuropsychological and mental disorders. Currently, little is known about the distinct subcomponents of executive function potentially impaired in female PM-carriers, and there have been no investigations into associations between executive function and incidences of mental disorders. A total of 35 female PM-carriers confirmed by Asuragen triple primed PCR DNA testing and 35 age- and intelligence-matched controls completed tests of executive function (i.e., response inhibition and working memory) and self-reported on social anxiety, depression, and ADHD predominantly inattentive (ADHD-PI) symptoms. Compared to controls, PM-carriers were significantly elevated on self-reported social anxiety and ADHD-PI symptoms. Irrespective of mental symptoms, female PM-carries performed significantly worse than controls on a response inhibition test, and further investigations revealed significant correlations between executive function performance and self-reported symptoms of anxiety, depression and ADHD-PI. Critically, among PM-carriers with good executive function performance, no women exceeded threshold markers for probable caseness of mental disorder. However, rates of probable caseness were elevated in those with average performance (response inhibition: social anxiety: 41.7%; depression: 20%; ADHD: 44.4%; working memory: social anxiety: 27.3%; depression: 9.1%; ADHD: 18.2%) and highly elevated for those with poor executive function performance (response inhibition: social anxiety: 58.3%; depression: 80%; ADHD: 55.6%; working memory: social anxiety: 100%; depression: 50%; ADHD: 83.3%). These data suggest that subtle executive dysfunction may be a useful neuropsychological indicator for a range of mental disorders previously reported in female PM-carriers.

The interplay between executive control and motor functioning in Williams syndrome.

Previous studies suggest that individuals with Williams syndrome (WS), a rare genetically based neurodevelopmental disorder, show specific weaknesses in visual attention and response inhibition within the visuospatial domain. Here we examine the extent to which impairments in attentional control extend to the visuomotor domain using a well-validated measure of choice stepping reaction time (CSRT) in individuals with WS. We examined the interaction between executive control and visually guided stepping using a verbal fluency dual-task or Go/NoGo paradigm during CSRT performance. Relationships between dual-task and inhibitory stepping and behavioural inattention and hyperactivity were also examined. Our results showed clear dual-task costs in stepping response times when performing a concurrent cognitive task in the WS group when compared to spatial and verbal ability matched typically developing controls. Although no group differences in stepping accuracy were observed between the WS and typically developing control groups, the WS group showed progressive slowing and more variable response times across the duration of the Go/NoGo task. These results suggest dysfunction in circuits involved in top-down attentional control processes in WS. These findings provide novel evidence that core executive control deficits in WS extend to the visuomotor domain, and impact on ADHD-related inattentive symptoms.

Selective spatial processing deficits in an at-risk subgroup of the fragile X premutation.

Until a decade ago, it was assumed that males with the fragile X premutation were unaffected by any cognitive phenotype. Here we examined the extent to which CGG repeat toxicity extends to visuospatial functioning in male fragile X premutation carriers who are asymptomatic for a late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). Thirty-three premutation males aged 20-68 years [divided into two groups: 16 low-repeat carriers (CGG ≥ 55 ≤ 100) and 17 high-repeat carriers (CGG>100)] with a family history of fragile X syndrome and 62 non-affected adult males with normal FMR1 alleles were recruited. Subjects underwent neuropsychological tests of visuospatial and visual working memory functioning and visuoperceptual processing. On measures of visuospatial processing, the high-repeat carriers performed significantly worse than the normal allele group when age and IQ were covaried out. With increasing age and only in carriers of a larger (>100 repeats) premutation allele was there a greater decrement in visuospatial working memory functioning. Performance on spatial and perceptual judgement tasks failed to show similar specificity in males within the upper premutation range. We conclude that identification of selective visuospatial impairments in carriers of a larger premutation allele indicates greater CGG repeat toxicity in specific neural regions. Longitudinal follow-up studies will be needed to determine whether subtle decline in visuospatial functioning is associated with the later onset of motor symptoms of FXTAS.

Association of the DAT1 genotype with inattentive behavior is mediated by reading ability in a general population sample.

Attention deficit hyperactivity disorder (ADHD) and reading disability (RD) frequently co-occur in the child population and therefore raise the possibility of shared genetic etiology. We used a quantitative trait loci (QTL) approach to assess the involvement of the dopamine transporter (DAT1) gene polymorphism in mediating reading disability and poor attention in a general population sample of primary school children aged 6-11 years in the UK. The potential confounding effects of IQ and chronological age were also investigated. We found an independent association between the homozygous DAT1 10/10 repeat genotype and RD that was not accounted for by the level of ADHD symptoms. This finding suggests that the DAT1 gene polymorphism may influence a common neural mechanism underlying both reading acquisition and ADHD symptoms.

Gamified Attention Training in the Primary School Classroom: A Cluster-Randomized Controlled Trial.

Objective: This randomized controlled trial evaluated the efficacy of attention training delivered in class on cognitive attention processes, inattention, hyperactivity, working memory, and numeracy in primary school children. Method: Eight classes (n = 98 children; 5-9 years) were cluster randomized to gamified attention training, a placebo program, or a no-contact control condition. Assessments were conducted at baseline, immediately after the 5-week intervention (posttraining), and 6 months later (follow-up). Results: Posttraining, attention training was associated with reduced inattention and hyperactivity within the classroom compared with controls, and reduced hyperactivity at home compared with the no-contact control. At follow-up, reduced hyperactivity within the classroom compared with the no-contact control persisted. No effects of training on cognitive attention processes, working memory, and numeracy were observed posttraining. Conclusion: Classroom-based attention training has select benefits in reducing inattention and hyperactivity, but may not promote gains in cognitive or academic skills in primary school children.

Higher Tablet Use Is Associated With Better Sustained Attention Performance but Poorer Sleep Quality in School-Aged Children.

There are growing concerns that increased screen device usage may have a detrimental impact on classroom behaviour and attentional focus. The consequences of screen use on child cognitive functioning have been relatively under-studied, and results remain largely inconsistent. Screen usage may displace the time usually spent asleep. The aim of this study was to examine associations between screen use, behavioural inattention and sustained attention control, and the potential modifying role of sleep. The relations between screen use, behavioural inattention, sustained attention and sleep were investigated in 162 6- to 8-year-old children, using parent-reported daily screen use, the SWAN ADHD behaviour rating scale, The sustained attention to response task and the children's sleep habits questionnaire. Tablet use was associated with better sustained attention performance but was not associated with classroom behavioural inattention. Shorter sleep duration was associated with poorer behavioural inattention and sustained attention. Sleep quality and duration did not act as mediators between screen usage and behavioural inattention nor sustained attention control. These findings suggest that careful management of the amount of time spent on electronic screen devices could have a beneficial cognitive impact on young children. The results also highlight the critical role of sleep in enhancing both behavioural attention and sustained attention, which are essential for supporting cognitive development and learning.

Mapping self-reports of working memory deficits to executive dysfunction in Fragile X Mental Retardation 1 (FMR1) gene premutation carriers asymptomatic for FXTAS.

Fragile X Syndrome is a neurodevelopmental disorder that is caused by the silencing of a single gene on the X chromosome, the Fragile X Mental Retardation 1 (FMR1) gene. In recent years, the premutation ("carrier") status has received considerable attention and there is now an emerging consensus that despite intellectual functioning being within the average range premutation males present with subtle executive function impairments that include poor inhibitory control, working memory deficits, and poor planning skills. The ranges of these skills, although not nearly as severe as seen in the full mutation, nonetheless serve to differentiate males with the premutation from males in the unaffected population. In the present study we extend these findings to suggest that behavioral markers, specifically self-report on the Brown Attention-Deficit Disorder Rating Scales, may serve as a clinically useful indicator or "signature" of the Fragile X Premutation status. We discuss the possibility that this measure provides a means to identify those at greatest risk for developing the newly identified neurodegenerative disorder that affects some premutation males - Fragile X Tremor/Ataxia Syndrome (FXTAS).

A child-focused version of the Attention Network Task designed to investigate interactions between the attention networks, including the endogenous orienting network.

A new variation of the Attention Network Task (ANT) was designed to measure the functioning of and interactions between the alerting, exogenous and endogenous visual spatial orienting, and executive control systems in young school children. Previous research has produced mixed results regarding typical functioning of the attention networks in six-year-olds; no ANT has measured the functioning of the endogenous network. This Staged ANT tested the Alerting, Exogenous, and Endogenous orienting networks in separate conditions. Two hundred and forty-seven children (average age 6 years, 103 girls) completed the task. There was no clear benefit of the alerting cue until the spatial orienting cues were introduced into the task, suggesting task complexity was needed before alerting benefits were observed. The validity effect of the exogenous cue was very strong: in contrast, the validity effect of the endogenous cue was very weak. The flanker effect was very strong. A benefit of the alerting cue was shown during both the exogenous and endogenous conditions, while a cost of the alerting cue was shown during the invalid exogenous trials. Neither the alerting nor validity effects interacted with the flanker effect. These results suggest that the alerting cue primes the exogenous and endogenous systems for the upcoming cues. Once the complexity of the task increases with the addition of the flankers, the alerting effect attenuates. The alerting and the two orienting networks interact together but the executive attention network acts independently, in children aged 6 years.

Lifespan changes in working memory in fragile X premutation males.

Fragile X syndrome is the world's most common hereditary cause of developmental delay in males and is now well characterized at the biological, brain and cognitive levels. The disorder is caused by the silencing of a single gene on the X chromosome, the FMR1 gene. The premutation (carrier) status, however, is less well documented but has an emerging literature that highlights a more subtle profile of executive cognitive deficiencies that mirror those reported in fully affected males. Rarely, however, has the issue of age-related declines in cognitive performance in premutation males been addressed. In the present study, we focus specifically on the cognitive domain of working memory and its subcomponents (verbal, spatial and central executive memory) and explore performance across a broad sample of premutation males aged 18-69 years matched on age and IQ to unaffected comparison males. We further tease apart the premutation status into those males with symptoms of the newly identified neurodegenerative disorder, the fragile X-associated tremor/ataxia syndrome (FXTAS) and those males currently symptom-free. Our findings indicate a specific vulnerability in premutation males on tasks that require simultaneous manipulation and storage of new information, so-called executive control of memory. Furthermore, this vulnerability appears to exist regardless of the presence of FXTAS symptoms. Males with FXTAS symptoms demonstrated a more general impairment encompassing phonological working memory in addition to central executive working memory. Among asymptomatic premutation males, we observed the novel finding of a relationship between increased CGG repeat size and impairment to central executive working memory.

Reduced caudate volume and cognitive slowing in men at risk of fragile X-associated tremor ataxia syndrome.

Fragile X-associated tremor ataxia syndrome is an inherited neurodegenerative disorder caused by premutation expansions (55-200 CGG repeats) of the FMR1 gene. There is accumulating evidence to suggest that early cognitive and brain imaging signs may be observed in some premutation carriers without motor signs of FXTAS, but few studies have examined the relationships between subcortical brain volumes and cognitive performance in this group. This study examined the relationships between caudate volume and select cognitive measures (executive function and information processing speed) in men at risk of developing FXTAS and controls with normal FMR1 alleles (<45 CGG repeats). The results showed that men with premutation alleles performed worse on measures of executive function and information processing speed, and had significantly reduced caudate volume, compared to controls. Smaller caudate volume in the premutation group was associated with slower processing speed. These findings provide preliminary evidence that early reductions in caudate volume may be associated with cognitive slowing in men with the premutation who do not present with cardinal motor signs of FXTAS. If confirmed in future studies with larger PM cohorts, these findings will have important implications for the identification of sensitive measures with potential utility for tracking cognitive decline.

Development of static and dynamic perception for luminance-defined and texture-defined information.

The development of static and dynamic perception for stimuli requiring different levels of neural analysis was assessed by measuring orientation-identification and direction-identification thresholds for both lower-level [or first-order (FO)] and higher-level [or second-order (SO)] stimuli as a function of age. Results demonstrate that both lower-level and higher-level perception continue to develop during school-age years in both dynamic and static domains. When compared with adult levels, dynamic performance for 5-6-year-olds is significantly decreased for SO, but not for the FO perception; however, type of stimulus (FO vs. SO) did not affect the development of static perception. We therefore suggest that levels of stimulus complexity should be considered an important variable when assessing and making inferences regarding the typical and atypical development of static and dynamic perception.

Age-dependent cognitive changes in carriers of the fragile X syndrome.

Fragile X syndrome is a neurodevelopmental disorder that is caused by the silencing of a single gene on the X chromosome, the fragile X mental retardation 1 (FMR1) gene. Affected individuals display a unique neurocognitive phenotype that includes significant impairment in inhibitory control, selective attention, working memory, and visual-spatial cognition. In contrast, little is known about the trajectory and specificity of any cognitive impairment associated with the fragile X premutation (i.e., "carrier status") or its relationship with the recently identified neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). In the present study, we evaluated a broad sample of 40 premutation males (PM) aged 18-69 years matched on age and IQ to 67 unaffected comparison males (NC). Performance was compared across a range of cognitive domains known to be impaired in fragile X syndrome (i.e., "full mutation"). Tremor was also assessed using a self-report neurological questionnaire. PM displayed statistically significant deficits in their ability to inhibit prepotent responses, differentiating them from NC from age 30 onwards. With increasing age, the two groups follow different trajectories, with PM developing progressively more severe problems in inhibitory control. This deficit also has a strong co-occurrence in males displaying FXTAS-related symptomatology (p<.001). Selective attention was also impaired in PM but did not show any disproportionate aging effect. No other cognitive deficits were observed. We conclude that an inhibitory deficit and its impact across the lifespan are specifically associated with the fragile X premutation status, and may be a precursor for development of a more severe form of cognitive impairment or dementia, which has been reported in patients with the diagnosis of FXTAS.

Impact of the Fragile X mental retardation 1 (FMR1) gene premutation on neuropsychiatric functioning in adult males without fragile X-associated Tremor/Ataxia syndrome: a controlled study.

Fragile X Syndrome is the most common heritable form of mental retardation caused by silencing of the FMR1 gene, which arises from intergenerational trinucleotide repeat expansion leading to full mutation. An intermediary carrier condition, known as the premutation, is characterized by expansion up to 200 repeats without concomitant gene silencing. This prevalent allelic variant was initially thought to be free of phenotypic effects. However, recent reports have identified a degenerative disease, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) in older men as well as premature ovarian failure in women. Previously reports are inconsistent regarding the neuropsychiatric phenotype associated with premutation due to small sample sizes, ascertainment bias, lack of adequate control groups, administration of measures with poor psychometric properties, and the confounding effects of FXTAS. We addressed these problems by conducting a controlled study of male carriers (n = 40) of the premutation without manifest symptoms of FXTAS, comparing their responses on specific, reliable, and valid measures of neuropsychiatric functioning to those of individuals with shared family environment (n = 22) and non-carrier comparison males (n = 43). Multivariate analyses revealed that the premutation confers significant risk for working memory difficulties, an associated feature of Attention-Deficit Disorder. Furthermore, both the family controls and men with premutation exhibited higher rates of Alcohol Abuse as compared to non-carrier control men. These findings highlight the importance of recognizing the distinct phenotypic outcomes that characterize the Fragile X premutation and the subtle risk factors that can act as precursors to more significant psychiatric impairment.

ß-glucuronidase use as a single internal control gene may confound analysis in FMR1 mRNA toxicity studies.

Relationships between Fragile X Mental Retardation 1 (FMR1) mRNA levels in blood and intragenic FMR1 CGG triplet expansions support the pathogenic role of RNA gain of function toxicity in premutation (PM: 55-199 CGGs) related disorders. Real-time PCR (RT-PCR) studies reporting these findings normalised FMR1 mRNA level to a single internal control gene called ß-glucuronidase (GUS). This study evaluated FMR1 mRNA-CGG correlations in 33 PM and 33 age- and IQ-matched control females using three normalisation strategies in peripheral blood mononuclear cells (PBMCs): (i) GUS as a single internal control; (ii) the mean of GUS, Eukaryotic Translation Initiation Factor 4A2 (EIF4A2) and succinate dehydrogenase complex flavoprotein subunit A (SDHA); and (iii) the mean of EIF4A2 and SDHA (with no contribution from GUS). GUS mRNA levels normalised to the mean of EIF4A2 and SDHA mRNA levels and EIF4A2/SDHA ratio were also evaluated. FMR1mRNA level normalised to the mean of EIF4A2 and SDHA mRNA levels, with no contribution from GUS, showed the most significant correlation with CGG size and the greatest difference between PM and control groups (p = 10-11). Only 15% of FMR1 mRNA PM results exceeded the maximum control value when normalised to GUS, compared with over 42% when normalised to the mean of EIF4A2 and SDHA mRNA levels. Neither GUS mRNA level normalised to the mean RNA levels of EIF4A2 and SDHA, nor to the EIF4A2/SDHA ratio were correlated with CGG size. However, greater variability in GUS mRNA levels were observed for both PM and control females across the full range of CGG repeat as compared to the EIF4A2/SDHA ratio. In conclusion, normalisation with multiple control genes, excluding GUS, can improve assessment of the biological significance of FMR1 mRNA-CGG size relationships.