Trajectories of Heart Activity Across Infancy to Early Childhood Differentially Predict Autism and Anxiety Symptoms in Fragile X Syndrome

Fragile X syndrome (FXS) is a monogenic disorder characterized by high rates of autism spectrum disorder (ASD) and anxiety. A longstanding hyperarousal hypothesis in FXS has argued that ANS dysfunction underpins many symptoms of FXS. However, the developmental onset and trajectory of ANS dysfunction, as well as the consequences of ANS dysfunction on later psychiatric symptoms, remain poorly understood in FXS. Insight into the emergence, trajectory, and consequences of ANS dysfunction across early development in FXS has critical implications for prevention, intervention, and optimal outcomes in both typical and atypical development. This longitudinal study investigated whether and when males with FXS evidence atypical ANS function from infancy through early childhood, and how trajectories of ANS function across infancy and early childhood predict ASD and anxiety symptom severity later in development. Participants included 73 males with FXS and 79 age-matched typically developing (TD) males. Baseline heart activity was recorded at multiple assessments between 3 and 83 months of age, resulting in 372 observations. General arousal and parasympathetic activity were indexed via interbeat interval (IBI) and respiratory sinus arrhythmia (RSA), respectively. ASD and anxiety symptoms were assessed at 36 months of age or later in a subgroup of participants (FXS = 28; TD = 25). Males with FXS exhibited atypical patterns of developmental change in ANS function across infancy and early childhood. As a result, ANS dysfunction became progressively more discrepant across time, with the FXS group exhibiting significantly shorter IBI and lower RSA by 29 and 24 months of age, respectively. Shorter IBI at 24 months and a flatter IBI slope across development predicted elevated anxiety symptoms, but not ASD symptoms, later in childhood in both FXS and TD males. Reduced RSA at 24 months predicted elevated ASD symptoms, but not anxiety symptoms, in both groups. Developmental change in RSA across early development did not predict later anxiety or ASD symptoms. This is the first longitudinal study to examine the hyperarousal hypothesis in infants and young children with FXS. Findings suggest that hyperarousal (i.e., shorter IBI, lower RSA) is evident in males with FXS by 24-29 months of age. Interestingly, unique aspects of early ANS function differentially relate to later ASD and anxiety symptoms. General arousal, indexed by shorter IBI that becomes progressively more discrepant from TD controls, predicts later anxiety symptoms. In contrast, parasympathetic-related factors, indexed by lower levels of RSA, predict ASD symptoms. These findings support the hyperarousal hypothesis in FXS, in that ANS dysfunction evident early in development predicts later-emerging symptoms of ASD and anxiety. This study also have important implications for the development of targeted treatments and interventions that could potentially mitigate the long-term effects of hyperarousal in FXS

Cluttering in the Speech of Young Men With Fragile X Syndrome

Purpose: Cluttering is a fluency disorder that has been noted clinically in individuals with fragile X syndrome (FXS). Yet, cluttering has not been systematically characterized in this population, hindering identification and intervention efforts. This study examined the rates of cluttering in male young adults with FXS using expert clinical opinion, the alignment between expert clinical opinion and objectively quantified features of cluttering from language transcripts, and the association between cluttering and aspects of the FXS phenotype. Method: Thirty-six men with FXS (aged 18-26 years; M = 22, SD = 2.35) contributed language samples and completed measures of nonverbal cognition, autism symptoms, anxiety, and symptoms of attention-deficit/hyperactivity disorder (ADHD). The presence of cluttering was determined by the consensus of two clinical experts in fluency disorders based on characteristics exhibited in the language sample. Cluttering features (speech rate, disfluencies, etc.) were also objectively quantified from the language transcripts. Results: Clinical experts determined that 50% of participants met the criteria for a cluttering diagnosis. Phrase repetitions were the most salient feature that distinguished individuals who cluttered. Although the presence of cluttering was not associated with autism symptoms or mean length of utterance, cluttering was more likely to occur when nonverbal cognitive ability was higher, ADHD symptoms were elevated, and anxiety symptoms were low. Conclusions: Half of the male young adults with FXS exhibited cluttering, which supports FXS as a genetic diagnosis that is highly enriched for risk of cluttering. Cluttering was associated with increased ADHD symptoms and cognitive ability and reduced anxiety symptoms. This study contributes a new description of the clinical presentation of cluttering in men with FXS and may lead to improved understanding of the potential underlying mechanisms of cluttering and eventual refinements to treatment and diagnosis

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk. Current long-term therapies to prevent arterial occlusion in diabetes are focussed on anti-platelet agents, a strategy that fails to address the contribution of coagulation proteins to the enhanced thrombotic milieu. Moreover, antiplatelet treatment is associated with bleeding complications, particularly with newer agents and more aggressive combination therapies, questioning the safety of this approach. Therefore, to safely control thrombosis risk in diabetes, an alternative approach is required with the fibrin network representing a credible therapeutic target. In the current review, we address diabetes-specific mechanistic pathways responsible for hypofibrinolysis including the role of clot structure, defects in the fibrinolytic system and increased incorporation of anti-fibrinolytic proteins into the clot. Future anti-thrombotic therapeutic options are discussed with special emphasis on the potential advantages of modulating incorporation of the anti-fibrinolytic proteins into fibrin networks. This latter approach carries theoretical advantages, including specificity for diabetes, ability to target a particular protein with a possible favourable risk of bleeding. The development of alternative treatment strategies to better control residual thrombosis risk in diabetes will help to reduce vascular events, which remain the main cause of mortality in this condition

A Comparison of Respiratory Sinus Arrhythmia in Children with Autism or Typical Development Across Communicative and Cognitive Contexts

University of Minnesota Ph.D. dissertation. July 2020. Major: Speech-Language-Hearing Sciences. Advisor: Lizbeth Finestack. 1 computer file (PDF); vii, 95 pages.The diagnosis autism spectrum disorder (ASD), and the assessment of its severity is impeded by the subjective nature of most diagnostic tools. Objective measurements are needed to assist diagnosis and treatment monitoring for ASD. This study investigates physiological responses of children with ASD compared to children who are developing typically, while completing tasks varying in social cognitive demands. The primary measure of interest is respiratory sinus arrhythmia (RSA), a measure of parasympathetic nervous system response to the heart. Parasympathetic influence on the heart promotes a calmer state in a given environment. When parasympathetic activity increases, heart rate decreases and variability between heartbeats increases. RSA is a measure of variability in heart activity within parameters of the heart’s natural oscillatory patterns due to breathing. An increase in RSA is beneficial in some contexts that require social interaction, such as a child playing with their caregiver. A decrease in RSA is beneficial in contexts that require an increase in attentional and cognitive resources, such as an executive functioning task. In individuals with ASD, RSA has been found to differ across social and cognitive contexts. RSA in both contexts has also been found to predict performance on measures of social adaptability, language ability, and ASD symptom severity. This study compared RSA in 12 children with ASD and 8 children with typical development between the ages of 5 and 8 years across five communicative and cognitive contexts. We also investigated relationships between RSA values in each context to performance on standardized measures of cognitive, language, and social functioning. Children with ASD had significantly lower RSA in a speaking context, narrative language sample context, and executive functioning context than children with TD. For children with ASD, significant correlations were found between measures of RSA during the narrative and executive functioning contexts and expressive, receptive, and pragmatic language ability; ASD symptom severity; and parent reported measures of behavior and executive functioning abilities. The current study supports the view that RSA is a promising measure for use in assessment of ASD, and possibly a valuable tool for speech-language therapists working with this population. More research is warranted in a larger sample of children with ASD