UUnniivveerrssiittyy ooff SSoouutthh CCaarroolliinnaa SScchhoollaarr CCoommmmoonnss Faculty Publications Psychology, Department of 11-2013 PPhhyyssiioollooggiiccaall aarroouussaall iinn aauuttiissmm aanndd ffrraaggiillee XX ssyynnddrroommee:: GGrroouupp ccoommppaarriissoonnss aanndd lliinnkkss wwiitthh pprraaggmmaattiicc llaanngguuaaggee Jessica Klusek University of South Carolina - Columbia, [email protected] G E. Martin M Losh Follow this and additional works at: https://scholarcommons.sc.edu/psyc_facpub Part of the Medicine and Health Sciences Commons, and the Psychology Commons PPuubblliiccaattiioonn IInnffoo Preprint version American Journal on Intellectual and Developmental Disabilities, Volume 118, 2013, pages 475-495. © American Journal on Intellectual and Developmental Disabilities, 2013, American Association on Intellectual and Developmental Disabilities Klusek, J., Martin, G. E., Losh, M. (2013). Physiological arousal in autism and fragile X syndrome: Group comparisons and links with pragmatic language. American Journal on Intellectual and Developmental Disabilities, 118, 475-495. http://dx.doi.org/10.1352/1944.7558-118.6.475 This Article is brought to you by the Psychology, Department of at Scholar Commons. It has been accepted for inclusion in Faculty Publications by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. 1 DOI:10.1352/1944.7558-118.6.000 Printed: Yes LRF: Arousal in Autism and Fragile X Physiological Arousal in Autism and Fragile X Syndrome: Group Comparisons and Links With Pragmatic Language Jessica Klusek, Gary E. Martin, and Molly Losh Abstract This study tested the hypothesis that pragmatic (i.e., social) language impairment is linked to arousal dysregulation in autism spectrum disorder (ASD) and fragile X syndrome (FXS). Forty boys with ASD, 39 with FXS, and 27 with typical development (TD), aged 4–15 years, participated. Boys with FXS were hyperaroused compared to boys with TD but did not differ from boys with ASD. Dampened vagal tone predicted pragmatic impairment in ASD, and associations emerged between cardiac activity and receptive/expressive vocabulary across groups. Findings support autonomic dysfunction as a mechanism underlying pragmatic impairment in ASD and suggest that biophysiological profiles are shared in ASD and FXS, which has implications for understanding the role of fragile X mental retardation-1 (FMR1, the FXS gene) in the pathophysiology of ASD. Key Words: autism; ASD; fragile X syndrome; arousal; vagal tone; heart rate; pragmatic language; social communication; endophenotype 2 Fragile X syndrome (FXS) is a monogenic disorder associated with significantly increased risk for autism spectrum disorder (ASD; Cohen, Pichard, & Tordjman, 2005). Pragmatic language impairment is seen in both ASD and FXS (Landa, 2000; Losh, Martin, Klusek, Hogan-Brown, & Sideris, 2012; Sudhalter & Belser, 2001), yet it is unknown whether such impairments arise from similar underlying impairments. Physiological dysregulation (e.g., elevated heart rate and differences in the functioning of the parasympathetic “rest and restore” system) has been documented in FXS and idiopathic ASD and, in FXS, has been hypothesized to be a causal factor in pragmatic language impairments (e.g., Belser & Sudhalter, 1995). The present study investigated the role of physiological dysregulation in pragmatic language deficits in ASD and FXS, examining physiological arousal in relation to clinically based and standardized assessments of pragmatic language across groups. Further understanding of arousal, a biophysiological marker for stress, as a mechanism linked with pragmatic language impairments of ASD and FXS may have implications for the development of targeted interventions and lend insight into shared biological pathways in ASD and FXS that can be traced back to the gene that causes FXS, fragile X mental retardation-1 (FMR1). Genetic Basis of ASD and FXS ASD is characterized by atypical social and communicative development along with repetitive and restricted behavioral patterns (American Psychiatric Association, 2013). Affecting approximately 1 in 88 individuals, ASD is seen at high levels, and there is an urgent need to understand the etiological basis of the disorder (CDC, 2012). Evidence supports a strong genetic component in the etiology of ASD although the exact genetic underpinnings still remain undefined (Devlin & Scherer, 2012). The genetic basis of ASD is thought to be heterogeneous and complex with many different gene-gene and gene-environment interactions leading to the 3 common phenotypic endpoint of ASD (Abrahams & Geschwind, 2008). Single-gene disorders, such as FXS, are implicated in about 10% of cases of ASD (Betancur, 2011). The study of ASD within the context of associated genetic conditions provides a better-understood genetic paradigm for studying ASD, which may provide a starting point for pinning down pathophysiological mechanisms (Abrahams & Geschwind, 2008; Hagerman, Hoem, & Hagerman, 2010). While the etiological basis of ASD is complex and heterogeneous, FXS can be traced back to a single genetic cause: a trinucleotide expansion on the FMR1 gene (Pieretti et al., 1991). This expansion silences the gene and halts the production of fragile X mental retardation protein (FMRP), which is highly expressed in the brain and is thought to play a role in synaptic development (Hagerman & Hagerman, 2002). Deficiency in FMRP appears to underlie the neurobehavioral profile of FXS, which includes intellectual disability, language impairment, social difficulties, anxiety, and hyperactivity (Baumgardner, Reiss, Freund, & Abrams, 1995; Hagerman, 2002; Reiss & Dant, 2003). Strikingly, 50%–75% of individuals with FXS meet criteria for ASD, and those who do not reach diagnostic thresholds nevertheless show symptoms consistent with ASD, such as reduced eye gaze and repetitive behaviors (Hagerman et al., 1986; Hall, Lightbody, & Reiss, 2008; Harris et al., 2008). This significantly elevated risk for ASD suggests that the FMR1 mutation may play a role in the development of autistic symptoms, potentially through interactions with other genes that are involved in ASD (Hagerman, Au, & Hagerman, 2011). For example, FMRP assists in the translation of several proteins that are dysregulated in idiopathic ASD (e.g., neuroexin, CYFIP, PTEN), and the absence of FMRP in FXS has a detrimental effect on the normal expression of other genes (see Hagerman et al., 2010). In fact, a large number of 4 autism susceptibility genes are known interactors with FMR1 (Darnell & Klann, 2013; Darnell et al., 2011; Iossifov et al., 2012). The FMR1 mutation may therefore disrupt the normal function of a number of autism susceptibility genes, lowering the threshold of interacting genetic effects needed to produce ASD. In this way, FXS provides a simplified genetic model that may be useful in identifying genetic or molecular pathways implicated in ASD. Pragmatic Language in ASD and FXS Evidence suggests that individuals with idiopathic and FXS-associated ASD show similar symptom profiles on omnibus measures of autism symptomatology (Dissanayake, Bui, Bulhak- Paterson, Huggins, & Loesch, 2009; Rogers, Wehner, & Hagerman, 2001). Specific features of the language profiles associated with ASD, such as pragmatic language impairment, also appear to be shared in idiopathic ASD and ASD within the context of FXS (Losh, Martin, et al., 2012). Pragmatic language is defined as the use of language in social contexts to communicate meaning (Bates, 1976; McTear & Conti-Ramsden, 1992; Prutting, 1982). Pragmatic language difficulties are a universally observed feature of ASD (Landa, 2000; Tager-Flusberg, Paul, & Lord, 2005). For example, turn-taking, topic maintenance, and communicative repair skills are deficient in ASD (Adams, Green, Gilchrist, & Cox, 2002; Capps, Kehres, & Sigman, 1998; Geller, 1998; Paul et al., 1987; Tager-Flusberg & Anderson, 1991; Volden, 2004). Atypical pragmatic features such as echolalia, perseveration, and bizarre word choice are seen at increased rates in ASD (Ghaziuddin & Leonore, 1996; Ross, 2002; Schuler & Prizant, 1985), and narrative (storytelling) skills are impaired as well (Capps, Losh, & Thurber, 2000; Diehl, Bennetto, & Young, 2006; Losh & Capps, 2003; Loveland, McEvoy, & Tunali, 1990; Tager-Flusberg, 1995). Differences in pragmatic language use are thought to be a genetically meaningful feature of ASD, given that subclinical pragmatic differences present at increased rates among unaffected relatives of 5 individuals with ASD (Landa et al., 1992; Losh, Childress, Lam, & Piven, 2008) and show patterns suggestive of intrafamilial transmission (Klusek, Losh, & Martin, 2012). Pragmatic language deficits are also seen in FXS. For example, conversation in FXS is characterized by impaired topic maintenance (Roberts et al., 2007; Sudhalter & Belser, 2001; Sudhalter, Cohen, Silverman, & Wolf-Schein, 1990; Wolf-Schein et al., 1987), poor ability to repair communicative breakdowns (Abbeduto et al., 2008), and stereotyped and perseverative language (Belser & Sudhalter, 2001; Martin et al., 2012; McDuffie et al., 2010; Roberts et al., 2007; Sudhalter et al., 1990; Wolf-Schein et al., 1987). Importantly, children with idiopathic ASD and FXS with comorbid ASD perform comparably on standardized pragmatic language assessments, and pragmatic language abilities are associated with FMR1-related genetic variation in FXS (Losh, Martin, et al., 2012). Furthermore, recent research suggests that pragmatic language profiles overlap in the broad autism phenotype and the FMR1 premutation. Female carriers of the FMR1 premutation and mothers of individuals with ASD exhibit conversational pragmatic language difficulties that are elevated in comparison to controls and which are not only similar in severity but also show qualitative overlap as evidenced by similar performance on pragmatic subdomains (see Losh, Klusek, et al., 2012). Together, these studies suggest that FMR1 may be involved in pragmatic language impairments associated with ASD. Although significant overlap in pragmatic language deficits in ASD and FXS has been documented (along with overlapping pragmatic language profiles in unaffected genetic carriers in FXS and ASD, i.e., parents), it is unclear whether the pragmatic impairments in these groups stem from common underlying factors; only a handful of studies have directly compared neurobiological characteristics in these disorders, and very few have related those features to pragmatic language. While arousal dysregulation has also been proposed as a mechanism 6 underlying social deficits in idiopathic ASD (e.g., Dawson & Lewy, 1989), most theories of ASD have focused on neurocognitive models to account for pragmatic language impairment, such as impaired social cognition or central coherence (Martin & McDonald, 2003). On the other hand, several studies have proposed arousal dysregulation as a cause of pragmatic language difficulties in FXS (Belser & Sudhalter, 1995; Cohen, 1995). In this model, arousal dysmodulation causes an individual to remain “on edge” during social situations, over time leading to social withdrawal and limiting opportunities to learn skills through interaction with others (Rubin & Burgess, 1991). Given that physiological regulatory deficits have also been documented in ASD (Bal et al., 2010; Ming, Julu, Brimacombe, Connor, & Daniels, 2005), this study explored physiological dysregulation as a predictor of pragmatic language deficits in both disorders. Physiological Arousal in ASD and FXS The present study focused on cardiac indices of physiological arousal: heart rate (a measure of general arousal) and respiratory sinus arrhythmia (RSA), an index of parasympathetic control of the heart via the vagal nerve (Porges, 2007). These indices of physiological functioning are thought to mark one’s capacity for engagement with the social environment (Porges & Furman, 2011). Heart rate. Increased general arousal, indexed by elevated heart rate, is a hallmark feature of FXS (Heilman, Harden, Zageris, Berry-Kravitz, & Porges, 2011; Roberts, Boccia, Bailey, Hatton, & Skinner, 2001; Roberts, Tonnsen, Robinson, & Shinkareva, 2012). It is unclear whether heart rate is also elevated in ASD as there is great inconsistency across prior reports, possibly due to differences in sample characteristics and the heterogeneity that is characteristic of ASD. Increased heart rate has been detected in ASD in comparison to typical and 7 developmentally delayed comparison groups (Bal et al., 2010; Goodwin et al., 2006; Mathewson et al., 2011; Woodard et al., 2012) although a number of other reports have found heart rate in ASD to be similar to that of controls (Althaus, Mulder, Mulder, Aarnoudse, & Minderaa, 1999; Corona, Dissanayake, Arbelle, Wellington, & Sigman, 1998; Sigman, Dissanayake, Corona, & Espinosa, 2003). Hyperarousal is hypothesized to underlie communication deficits (e.g., Belser & Sudhalter, 1995; Belser & Sudhalter, 2001)although few studies have directly examined this hypothesis in ASD or FXS. One study of children with ASD found that elevated heart rate was associated with reduced use of communicative gestures (Patriquin, Scarpa, Friedman, & Porges, 2011). Another preliminary report examining two males with FXS found that perseverative and tangential language was associated with increased arousal as indexed by skin conductance responses (Belser & Sudhalter, 1995). Vagal tone. The vagal nerve works as part of the parasympathetic “rest and restore” system, counteracting sympathetic “fight or flight” excitation to promote a physiological state that facilitates social engagement (see Porges & Furman, 2011). Numerous studies of typical development link high vagal tone with enhanced social skills (e.g., Blair & Peters, 2003; Calkins & Keane, 2004; Kok & Fredrickson, 2010). Reduced vagal tone is well documented in FXS (Hall, Lightbody, Huffman, Lazzeroni, & Reiss, 2009; Heilman et al., 2011; Roberts et al., 2001; Roberts et al., 2012). Some investigations of ASD have also detected dampened vagal tone (Bal et al., 2010; Mathewson et al., 2011; Ming et al., 2005; Porges et al., 2013; Van Hecke et al., 2009) although reports are inconsistent (Althaus et al., 1999; Levine et al., 2012; Toichi & Kamio, 2003). Diminished vagal tone has been shown to relate to poorer receptive vocabulary and social skills in children with ASD (Patriquin et al., 2011; Van Hecke et al., 2009) and with more severe autistic traits in toddlers with FXS (Roberts et al., 2012). 8 In addition to examining vagal activity at rest, the measurement of vagal tone specifically during social-communicative interactions can shed light on physiological adaption to social demands. In typical development (TD), children who show the greatest increases in vagal tone in response to social contexts have better receptive and expressive language abilities, and children who exhibit vagal withdrawal are more likely to present with anxiety, depression, and internalizing problems (Heilman et al., 2008; Suess & Bornstein, 2000). Few studies have investigated physiological profiles of ASD and FXS during social-communicative contexts in order to determine how these profiles might relate to atypical pragmatic language features. In one study of children with FXS, Hall et al. (2009) found that vagal tone during conversation with an examiner did not relate to the extent of gaze avoidance exhibited by the children although the authors did not measure other pragmatic features. In another study of young children with ASD, vagal tone during a social listening task (child-directed speech) prospectively predicted later parent-reported social-communication abilities, and baseline vagal tone was predictive of later skills (Watson, Baranek, Roberts, David, & Perryman, 2010). In sum, little is known about the role of the physiological system in pragmatic language deficits in ASD and FXS, and no studies, to our knowledge, have directly compared cardiac indicators of physiological profiles in ASD and FXS, limiting our understanding of biophysiological pathways that may be shared in ASD and FXS and could be linked to similar behavioral endpoints (such as pragmatic language). Study Rationale and Hypotheses This study addressed the hypothesis that physiological dysregulation in ASD and FXS is linked with pragmatic language impairment. The study addressed two primary questions: 1. Do cardiac indicators of physiological activity differ in boys with ASD, FXS, and TD during resting and conversational contexts? Prior to examining associations between arousal and 9 pragmatic language in each group, it was important to establish profiles of physiological activity and determine any differences and similarities across groups. To do so, we examined group differences in heart rate and vagal tone measured at rest and during unstructured conversation with an examiner. 2. Do cardiac indicators of physiological activity predict pragmatic language impairment in ASD, FXS, and TD? We examined within-group associations between physiological activity (at rest and during conversation) and pragmatic language ability, measured in separate contexts. We also examined associations with behavioral symptoms of anxiety, which could importantly relate to both cardiac activity and pragmatic language impairment. Method Participants Participants included 40 school-aged boys with idiopathic ASD, 39 boys with full-mutation FXS, and 28 boys with TD, aged 4–15 years. Participants were drawn from a larger pool of children participating in ongoing longitudinal studies of speech/language in FXS and ASD, which have been described previously (see Losh et al, 2012; Zajac, Harris, Roberts, & Martun, 2009). Given the longitudinal design of the larger studies, in some instances an individual participant had available data from several different time points. In these cases, the time point was selected that best facilitated group-level matching on chronological age given that age has a known impact on cardiac activity (Alkon et al., 2003; Bar-Haim, Marshall, & Fox, 2000). All participants spoke English as their primary language and were regularly using sentences of three or more words. Only boys participated in the study because girls with FXS are generally less severely affected and show more heterogeneous profiles (Hagerman, 2004). Recruitment was focused in the Eastern and Midwestern regions of the United States through local advertisement and through