Attention across modalities as a longitudinal predictor of early outcomes: The case of fragile X syndrome

Attention, Brain and Cognitive Development Group, Department of Experimental Psychology, University of Oxford, Oxford, UK.
Journal of Child Psychology and Psychiatry (Impact Factor: 6.46). 12/2011; 53(6):641-50. DOI: 10.1111/j.1469-7610.2011.02515.x
Source: PubMed

ABSTRACT   Fragile X syndrome (FXS) is an early diagnosed monogenic disorder, associated with a striking pattern of cognitive/attentional difficulties and a high risk of poor behavioural outcomes. FXS therefore represents an ideal model disorder to study prospectively the impact of early attention deficits on behaviour.
  Thirty-seven boys with FXS aged 4-10 years and 74 typically developing (TD) boys took part. Study 1 was designed to assess visual and auditory attention at two time-points, 1 year apart. Study 2 investigated attention to multimodal information. Both tested attention markers as longitudinal predictors of risk for poor behaviour in FXS.
  Children with FXS attended less well than mental-age matched TD boys and experienced greater difficulties with auditory compared to visual stimuli. In addition, unlike TD children, they did not benefit from multimodal information. Attention markers were significant predictors of later behavioural difficulties in boys with FXS.
  Findings demonstrate, for the first time, greater difficulties with auditory attention and atypical processing of multimodal information, in addition to pervasive global attentional difficulties in boys with FXS. Attention predicted outcomes longitudinally, underscoring the need to dissect what drives differing developmental trajectories for individual children within a seemingly homogeneous group.

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    • "PNAS 2011), but not yet related to within-syndrome variability in the human patient population. In a large scale prospective longitudinal study, a cognitive marker of attentional variation for boys with FXS, their visual attention abilities at ages four to 10 years, predicted individual differences in ADHD symptoms when followed up 1 year later, even after controlling for individual differences in IQ (Scerif et al., 2012). This study indicated that prospective cognitive markers of ADHD risk can be identified early in FXS, and need to be tested in future in other disorders at high ADHD risk. "
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    ABSTRACT: Background Through the increased availability and sophistication of genetic testing, it is now possible to identify causal diagnoses in a growing proportion of children with neurodevelopmental disorders. In addition to developmental delay and intellectual disability, many genetic disorders are associated with high risks of psychopathology, which curtail the wellbeing of affected individuals and their families. Beyond the identification of significant clinical needs, understanding the diverse pathways from rare genetic mutations to cognitive dysfunction and emotional–behavioural disturbance has theoretical and practical utility.Methods We overview (based on a strategic search of the literature) the state-of-the-art on causal mechanisms leading to one of the most common childhood behavioural diagnoses – attention deficit hyperactivity disorder (ADHD) – in the context of specific genetic disorders. We focus on new insights emerging from the mapping of causal pathways from identified genetic differences to neuronal biology, brain abnormalities, cognitive processing differences and ultimately behavioural symptoms of ADHD.FindingsFirst, ADHD research in the context of rare genotypes highlights the complexity of multilevel mechanisms contributing to psychopathology risk. Second, comparisons between genetic disorders associated with similar psychopathology risks can elucidate convergent or distinct mechanisms at each level of analysis, which may inform therapeutic interventions and prognosis. Third, genetic disorders provide an unparalleled opportunity to observe dynamic developmental interactions between neurocognitive risk and behavioural symptoms. Fourth, variation in expression of psychopathology risk within each genetic disorder points to putative moderating and protective factors within the genome and the environment.ConclusionA common imperative emerging within psychopathology research is the need to investigate mechanistically how developmental trajectories converge or diverge between and within genotype-defined groups. Crucially, as genetic predispositions modify interaction dynamics from the outset, longitudinal research is required to understand the multi-level developmental processes that mediate symptom evolution.
    Journal of Child Psychology and Psychiatry 12/2014; 56(3). DOI:10.1111/jcpp.12374 · 6.46 Impact Factor
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    • "Without an accurate memory trace to compare against deviant tones, individuals with FXS may be less able to identify unexpected stimuli (Naatanen et al., 2007). Interestingly, in studies where participants were asked to respond to, rather than to passively attend deviant stimuli, FXS patients provided more false positives and were slower to respond, suggesting confusion as to the veracity of a stimulus (Scerif et al., 2012; Van der Molen et al., 2012a). "
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    ABSTRACT: Fragile X syndrome (FXS) is an inherited form of intellectual disability and autism. Among other symptoms, FXS patients demonstrate abnormalities in sensory processing and communication. Clinical, behavioral, and electrophysiological studies consistently show auditory hypersensitivity in humans with FXS. Consistent with observations in humans, the Fmr1 KO mouse model of FXS also shows evidence of altered auditory processing and communication deficiencies. A well-known and commonly used phenotype in pre-clinical studies of FXS is audiogenic seizures. In addition, increased acoustic startle response is seen in the Fmr1 KO mice. In vivo electrophysiological recordings indicate hyper-excitable responses, broader frequency tuning, and abnormal spectrotemporal processing in primary auditory cortex of Fmr1 KO mice. Thus, auditory hyper-excitability is a robust, reliable, and translatable biomarker in Fmr1 KO mice. Abnormal auditory evoked responses have been used as outcome measures to test therapeutics in FXS patients. Given that similarly abnormal responses are present in Fmr1 KO mice suggests that cellular mechanisms can be addressed. Sensory cortical deficits are relatively more tractable from a mechanistic perspective than more complex social behaviors that are typically studied in autism and FXS. The focus of this review is to bring together clinical, functional, and structural studies in humans with electrophysiological and behavioral studies in mice to make the case that auditory hypersensitivity provides a unique opportunity to integrate molecular, cellular, circuit level studies with behavioral outcomes in the search for therapeutics for FXS and other autism spectrum disorders.
    Frontiers in Cellular Neuroscience 02/2014; 8:19. DOI:10.3389/fncel.2014.00019 · 4.29 Impact Factor
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    • "Hyperactivity is often described as the most intense and pervasive symptom of ADHD, especially in young children with FXS, and difficulty with attention regulation and impulse control are also frequently reported [Tranfaglia, 2011]. Attention problems have been hypothesized to be a predictor of challenging behavioral outcomes; early difficulties in visual attention have been shown to be related to later hyperactive behaviors in children with FXS [Scerif et al., 2012]. Furthermore, a global dysregulation of autonomic nervous system functioning, noted in individuals with FXS [Hall et al., 2009], may drive not only difficulties with attention regulation, hyperactivity, and impulsivity , but also may contribute to the sensory sensitivity and tactile defensiveness often described [Tranfaglia, 2011]. "
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    ABSTRACT: Behavior problems are a common challenge for individuals with fragile X syndrome (FXS) and constitute the primary clinical outcome domain in trials testing new FXS medications. However, little is known about the relationship between caregiver-reported behavior problems and co-occurring conditions such as anxiety and attention problems. In this study, 350 caregivers, each with at least one son or daughter with full-mutation FXS, rated one of their children with FXS using the Aberrant Behavior Checklist-Community Version (ABC-C); the Anxiety subscale of the Anxiety, Depression, and Mood Scale; and the Attention/Hyperactivity Items from the Symptom Inventories. In addition to examining family consequences of these behaviors, this study also sought to replicate psychometric findings for the ABC-C in FXS, to provide greater confidence for its use in clinical trials with this population. Psychometric properties and baseline ratings of problem behavior were consistent with other recent studies, further establishing the profile of problem behavior in FXS. Cross-sectional analyses suggest that selected dimensions of problem behavior, anxiety, and hyperactivity are age related; thus, age should serve as an important control in any studies of problem behavior in FXS. Measures of anxiety, attention, and hyperactivity were highly associated with behavior problems, suggesting that these factors at least coincide with problem behavior. However, these problems generally did not add substantially to variance in caregiver burden predicted by elevated behavior problems. The results provide further evidence of the incidence of problem behaviors and co-occurring conditions in FXS and the impact of these behaviors on the family. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2014; 164(1):141-55. DOI:10.1002/ajmg.a.36232 · 2.16 Impact Factor
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