Bridgette L. Tonnsen

Heart Activity and Autistic Behavior in Infants and Toddlers with Fragile X Syndrome.

The present study contrasted physiological arousal in infants and toddlers with fragile X syndrome to typically developing control participants and examined physiological predictors early in development to autism severity later in development in fragile X syndrome. Thirty-one males with fragile X syndrome (ages 8-40 months) and 25 age-matched control participants were included. The group with fragile X syndrome showed shorter interbeat intervals (IBIs), lower vagal tone (VT), and less modulation of IBI. Data suggested a nonlinear effect with IBI and autistic behavior; however, a linear effect with VT and autistic behavior emerged. These findings suggest that atypical physiological arousal emerges within the first year and predicts severity of autistic behavior in fragile X syndrome. These relationships are complex and dynamic, likely reflecting endogenous factors assumed to reflect atypical brain function secondary to reduced fragile X mental retardation protein. This research has important implications for the early identification and treatment of autistic behaviors in young children with fragile X syndrome.

Trajectory and Predictors of Depression and Anxiety Disorders in Mothers With the FMR1 Premutation.

BACKGROUND Although the FMR1 premutation is associated with elevated prevalence of psychiatric disorders, the longitudinal course of symptoms has not been established. The present study followed a sample of women with the FMR1 premutation to characterize the incidence, stability, and predictors of mood and anxiety disorders across a 3-year period. METHODS Participants included 83 women with the FMR1 premutation (mean age = 38.35) who completed the Structured Clinical Interview for DSM-IV Axis I Disorders at two time points, 3 years apart. Additional information was obtained regarding demographic, child, and biomedical (e.g., medication, menopause, CGG repeats) factors. RESULTS We found increased prevalence of major depressive disorder (MDD) and anxiety disorders over time, with adverse outcomes predicted by complex interactions among biological, behavioral, and environmental risk factors. Lifetime MDD increased from 46% to 54% and lifetime anxiety disorders increased from 28% to 35%. Midrange CGG repeats, elevated child problem behaviors, and divorced marital status conveyed elevated risk for psychiatric diagnoses. Primary ovarian insufficiency was highly prevalent (41%) but did not account for elevated rates of psychiatric diagnoses. Medication use was highly reported (41%), particularly in women with MDD or anxiety, with selective serotonin reuptake inhibitors reported as the most commonly used medication across diagnostic groups. CONCLUSIONS The elevated prevalence of depression and anxiety in women with the FMR1 premutation is a clear and pressing concern given the frequent occurrence of the FMR1 premutation in the general community and the adverse outcomes-at both individual and systems levels-associated with psychiatric disorders in this population.

Developmental trajectories of attentional control in preschool males with fragile X syndrome

Attention problems are among the most impairing features associated with fragile X syndrome (FXS). However, few studies have examined behavioral development of inhibitory control in very young children with FXS. We examined attentional control in 3-6 year boys with FXS using both an experimental inhibitory control paradigm and parent-report of attention problems. Study 1 examined attentional control in FXS compared to comparison groups matched on chronological and mental age. To determine the stability of impairments over time in FXS, Study 2 examined patterns of developmental change in an expanded longitudinal sample. Across studies, males with FXS demonstrated persistent impairments in inhibitory control and parent-reported attention problems. Inhibitory control was related to, but not solely driven by, lower mental age. Although parent-rated attention problems remained stable across ages, inhibitory control improved with time. Children with more severe attention problems often displayed initially poorer inhibitory control. However, these trajectories also improved more rapidly with age. Our findings indicate that despite persistent deficits in attentional control in young children with FXS, multi-method assessment can be used to capture developmental growth that should be further supported through early, targeted intervention.

Biobehavioral Indicators of Social Fear in Young Children With Fragile X Syndrome

Anxiety is among the most impairing conditions associated with Fragile X syndrome (FXS) and is putatively linked to atypical physiological arousal. However, few studies have examined this association in young children with FXS. The authors examined whether patterns of arousal and behavior during an experimental stranger approach paradigm differ between a cross-sectional sample of 21 young children with FXS and 19 controls (12-58 months old). Groups did not differ in mean levels of behavioral fear. Unlike the control group, however, the FXS group demonstrated increased facial fear at older ages, as well as age-dependent changes in associations between heart activity and distress vocalizations. These findings may inform theoretical models of anxiety etiology in FXS and early detection efforts.

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.

Temperament factor structure in fragile X syndrome: the children's behavior questionnaire.

Early patterns of temperament lay the foundation for a variety of developmental constructs such as self-regulation, psychopathology, and resilience. Children with fragile X syndrome (FXS) display unique patterns of temperament compared to age-matched clinical and non-clinical samples, and early patterns of temperament have been associated with later anxiety in this population. Despite these unique patterns in FXS and recent reports of atypical factor structure of temperament questionnaires in Williams Syndrome (Leyfer, John, Woodruff-Borden, & Mervis, 2012), no studies have examined the latent factor structure of temperament scales in FXS to ensure measurement validity in this sample. The present study used confirmatory factor analysis to examine the factor structure of a well-validated parent-reported temperament questionnaire, the Childrens Behavior Questionnaire (Rothbart, Ahadi, Hershey, & Fisher, 2001), in a sample of 90 males with FXS ages 3-9 years. Our data produced a similar, but not identical, three-factor model that retained the original CBQ factors of negative affectivity, effortful control, and extraversion/surgency. In particular, our FXS sample demonstrated stronger factor loadings for fear and shyness than previously reported loadings in non-clinical samples, consistent with reports of poor social approach and elevated anxiety in this population. Although the original factor structure of the Childrens Behavior Questionnaire is largely retained in children with FXS, differences in factor loading magnitudes may reflect phenotypic characteristics of the syndrome. These findings may inform future developmental and translational research efforts.

Middle School Students' Attitudes Toward a Peer With Autism Spectrum Disorder: Effects of Social Acceptance and Physical Inclusion

Students with autism spectrum disorder (ASD) often experience peer conflict and social challenges, which likely relate to compounded characteristics of both the child with ASD and his or her peers. However, few studies have experimentally investigated these associations to inform prevention and intervention efforts. The present study used social networking blogs to examine how middle school students’ attitudes toward a fictional peer with ASD, Charlie, vary according to whether Charlie was (a) physically included with typically developing peers and (b) socially accepted. Participants expressed less favorable attitudes when Charlie was socially excluded by his peers, regardless of whether his peers had disabilities. More favorable attitudes were associated with participant popularity, previous exposure to ASD, younger age, and being female. Charlie’s ASD status was associated with more negative anticipated peer attitudes. These results indicate that facilitating positive, public social experiences of students with ASD may promote positive attitudes and social acceptance by peers.

Prevalence of Autism Spectrum Disorders among Children with Intellectual Disability.

Autism spectrum disorders (ASD) often co-occur with intellectual disability (ID) and are associated with poorer psychosocial and family-related outcomes than ID alone. The present study examined the prevalence, stability, and characteristics of ASD estimates in 2,208 children with ASD and ID identified through the South Carolina Autism and Developmental Disabilities Network. The prevalence of ASD in ID was 18.04%, relative to ASD rates of 0.60%-1.11% reported in the general South Carolina population. Compared to children with ASD alone, those with comorbid ID exhibited increased symptom severity and distinct DSM-IV-TR profiles. Further work is needed to determine whether current screening, diagnostic, and treatment practices adequately address the unique needs of children and families affected by comorbid ASD and ID diagnoses.

Neural correlates of face processing in etiologically-distinct 12-month-old infants at high-risk of autism spectrum disorder

Neural correlates of face processing were examined in 12-month-olds at high-risk for autism spectrum disorder (ASD), including 21 siblings of children with ASD (ASIBs) and 15 infants with fragile X syndrome (FXS), as well as 21 low-risk (LR) controls. Event-related potentials were recorded to familiar and novel face and toy stimuli. All infants demonstrated greater N290 amplitude to faces than toys. At the Nc component, LR infants showed greater amplitude to novel stimuli than to their mother’s face and own toy, whereas infants with FXS showed the opposite pattern of responses and ASIBs did not differentiate based on familiarity. These results reflect developing face specialization across high- and low-risk infants and reveal neural patterns that distinguish between groups at high-risk for ASD.

Curvilinear Association Between Language Disfluency and FMR1 CGG Repeat Size Across the Normal, Intermediate, and Premutation Range

Historically, investigations of FMR1 have focused almost exclusively on the clinical effects of CGG expansion within the categories of the premutation (55–200 CGG repeats) and fragile X syndrome (>200 CGG repeats). However, emerging evidence suggests that CGG-dependent phenotypes may occur across allele sizes traditionally considered within the “normal” range. This study adopted an individual-differences approach to determine the association between language production ability and CGG repeat length across the full range of normal, intermediate, and premutation alleles. Participants included 61 adult women with CGG repeats within the premutation (n = 37), intermediate (i.e., 41–54 repeats; n = 2), or normal (i.e., 6–40 repeats; n = 22) ranges. All participants were the biological mothers of a child with a developmental disorder, to control for the potential effects of parenting stress. Language samples were collected and the frequency of language disfluencies (i.e., interruptions in the flow of speech) served as an index of language production skills. Verbal inhibition skills, measured with the Hayling Sentence Completion Test, were also measured and examined as a correlate of language disfluency, consistent with theoretical work linking language disfluency with inhibitory deficits (i.e., the Inhibition Deficit Hypothesis). Blood samples were collected to determine FMR1 CGG repeat size. A general linear model tested CGG repeat size of the larger allele (allele-2) as the primary predictor of language disfluency, covarying for education level, IQ, age, and CGG repeats on the other allele. A robust curvilinear association between CGG length and language disfluency was detected, where low-normal (∼ <25 repeats) and mid-premutation alleles (∼90–110 repeats) were linked with higher rates of disfluency. Disfluency was not associated with inhibition deficits, which challenges prior theoretical work and suggests that a primary language deficit could account for elevated language disfluency in FMR1-associated conditions. Findings suggest CGG-dependent variation in language production ability, which was evident across individuals with and without CGG expansions on FMR1.