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Differential Effects of a Behavioral Treatment Probe on Social Gaze Behavior in Fragile X Syndrome and Non-Syndromic Autism Spectrum Disorder

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Title: Differential Effects of a Behavioral Treatment Probe on Social Gaze Behavior in Fragile X Syndrome and Non-Syndromic Autism Spectrum Disorder
Language: English
Authors: Scott S. Hall (ORCID 0000-0003-4797-1819), Tobias C. Britton
Source: Journal of Autism and Developmental Disorders. 2024 54(7):2719-2732.
Availability: Springer. Available from: Springer Nature. One New York Plaza, Suite 4600, New York, NY 10004. Tel: 800-777-4643; Tel: 212-460-1500; Fax: 212-460-1700; e-mail: customerservice@springernature.com; Web site: https://link.springer.com/
Peer Reviewed: Y
Page Count: 14
Publication Date: 2024
Sponsoring Agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (DHHS/NIH)
Contract Number: R01HD081336
Document Type: Journal Articles
Reports - Research
Descriptors: Social Development, Interpersonal Competence, Behavior Change, Nonverbal Communication, Physiology, Symptoms (Individual Disorders), Task Analysis, Intellectual Disability, Outcomes of Treatment, Autism Spectrum Disorders, Males, Children, Matched Groups, Therapy, Interpersonal Relationship, Relaxation Training, Measurement, Comparative Analysis, Early Intervention
DOI: 10.1007/s10803-023-05919-6
ISSN: 0162-3257
1573-3432
Abstract: The purpose of this study was to examine potential differences in social learning between individuals with fragile X syndrome (FXS), the leading known inherited cause of intellectual disability, and individuals with non-syndromic autism spectrum disorder (ASD). Thirty school-aged males with FXS and 26 age and symptom-matched males with non-syndromic ASD, were administered a behavioral treatment probe designed to improve levels of social gaze during interactions with others. The treatment probe was administered by a trained behavior therapist over two days in our laboratory and included reinforcement of social gaze in two alternating training conditions -- looking while listening and looking while speaking. Prior to each session, children in each group were taught progressive muscle relaxation and breathing techniques to counteract potential increased hyperarousal. Measures included the rate of learning in each group during treatment, in addition to levels of social gaze and heart rate obtained during administration of a standardized social conversation task administered prior to and following the treatment probe. Results showed that learning rates obtained during administration of the treatment probe were significantly less steep and less variable for males with FXS compared to males with non-syndromic ASD. Significant improvements in social gaze were also observed for males with FXS during the social conversation task. There was no effect of the treatment probe on heart rate in either group. These data reveal important differences in social learning between the two groups and have implications for early interventions in the two conditions.
Abstractor: As Provided
Entry Date: 2024
Accession Number: EJ1432992
Database: ERIC
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  Value: <anid>AN0178677505;aut01jul.24;2024Jul31.05:05;v2.2.500</anid> <title id="AN0178677505-1">Differential Effects of a Behavioral Treatment Probe on Social Gaze Behavior in Fragile X Syndrome and Non-Syndromic Autism Spectrum Disorder </title> <p>The purpose of this study was to examine potential differences in social learning between individuals with fragile X syndrome (FXS), the leading known inherited cause of intellectual disability, and individuals with non-syndromic autism spectrum disorder (ASD). Thirty school-aged males with FXS and 26 age and symptom-matched males with non-syndromic ASD, were administered a behavioral treatment probe designed to improve levels of social gaze during interactions with others. The treatment probe was administered by a trained behavior therapist over two days in our laboratory and included reinforcement of social gaze in two alternating training conditions - looking while listening and looking while speaking. Prior to each session, children in each group were taught progressive muscle relaxation and breathing techniques to counteract potential increased hyperarousal. Measures included the rate of learning in each group during treatment, in addition to levels of social gaze and heart rate obtained during administration of a standardized social conversation task administered prior to and following the treatment probe. Results showed that learning rates obtained during administration of the treatment probe were significantly less steep and less variable for males with FXS compared to males with non-syndromic ASD. Significant improvements in social gaze were also observed for males with FXS during the social conversation task. There was no effect of the treatment probe on heart rate in either group. These data reveal important differences in social learning between the two groups and have implications for early interventions in the two conditions.</p> <p>Keywords: Fragile X syndrome; Gaze avoidance; Behavioral treatment; Eye tracking; Non-syndromic ASD</p> <p>Copyright comment Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</p> <p>Maintaining appropriate levels of social gaze while listening and speaking to others is a prerequisite skill for the development and maintenance of broader social-communication skills in typically developing individuals (Degutyte & Astell, [<reflink idref="bib11" id="ref1">11</reflink>]) as well as for individuals with autism spectrum disorder (ASD) (Moriuchi et al., [<reflink idref="bib39" id="ref2">39</reflink>]). During a typical social interaction, an individual receives a multitude of cues, non-verbal gestures and facial expressions that aid the exchange of information between the interacting partners (Rogers et al., [<reflink idref="bib45" id="ref3">45</reflink>]). Extensive work has determined that engaging in appropriate social gaze is critical for language development, emotion recognition, social engagement, and general learning through joint attention (Brooks & Meltzoff, [<reflink idref="bib2" id="ref4">2</reflink>]; Csibra & Gergely, [<reflink idref="bib10" id="ref5">10</reflink>]; Emery, [<reflink idref="bib14" id="ref6">14</reflink>]; Farroni et al., [<reflink idref="bib15" id="ref7">15</reflink>]; Itier & Batty, [<reflink idref="bib31" id="ref8">31</reflink>]; Morales et al., [<reflink idref="bib38" id="ref9">38</reflink>]; Senju & Johnson, [<reflink idref="bib47" id="ref10">47</reflink>]). Indeed, individuals with ASD who actively seek to avoid or minimize social interaction by looking or turning away from the faces of others are likely to miss a significant number of social learning opportunities, resulting in impaired social-communication skills and overall delayed developmental trajectories (Doherty-Sneddon et al., [<reflink idref="bib13" id="ref11">13</reflink>]; Riby et al., [<reflink idref="bib42" id="ref12">42</reflink>]).</p> <p>A striking example of this phenomenon is the social gaze avoidance exhibited by individuals with fragile X syndrome (FXS), the most common known inherited cause of intellectual disability (Hagerman, [<reflink idref="bib19" id="ref13">19</reflink>]). First described by Martin and Bell (Martin & Bell, [<reflink idref="bib34" id="ref14">34</reflink>]), the syndrome occurs due to mutations of the fragile X messenger ribonucleoprotein 1 (<emph>FMR1</emph>) gene (Herring et al., [<reflink idref="bib27" id="ref15">27</reflink>]) at locus 27.3 on the long arm of the X chromosome, affecting approximately 1 in 3,000–4,000 males and 1 in 6,000–8,000 females in the general population (Crawford et al., [<reflink idref="bib9" id="ref16">9</reflink>]; Hunter et al., [<reflink idref="bib29" id="ref17">29</reflink>]; Verkerk et al., [<reflink idref="bib54" id="ref18">54</reflink>]). Mutations to the gene results in reduced or absent fragile X messenger ribonucleoprotein (FMRP), a key protein involved in synaptic plasticity and dendritic maturation in the brain (Greenough et al., [<reflink idref="bib18" id="ref19">18</reflink>]; Soden & Chen, [<reflink idref="bib48" id="ref20">48</reflink>]) producing a cascade of developmental and cognitive deficits including mild to moderate impairment in intellectual and adaptive functioning and autistic-like behaviors including impairments in reciprocal social interaction, receptive and expressive communication skills and presence of repetitive behaviors (Reiss & Dant, [<reflink idref="bib41" id="ref21">41</reflink>]).</p> <p>Early reports of aberrant social behavior in FXS described the "fragile X handshake" in which individuals typically avert their gaze and turn their body away when extending a hand to greet a new individual (Wolff et al., [<reflink idref="bib56" id="ref22">56</reflink>]). Since then, it has been shown that individuals with FXS, particularly males, exhibit high levels of social gaze avoidance and other social escape behaviors during interactions with others, particularly with unfamiliar people (Cohen et al., [<reflink idref="bib3" id="ref23">3</reflink>], [<reflink idref="bib5" id="ref24">5</reflink>]; Hall et al., [<reflink idref="bib20" id="ref25">20</reflink>]). In a naturalistic eye-tracking study for example, Hall and colleagues ([<reflink idref="bib21" id="ref26">21</reflink>]) reported that males with FXS spent significantly less time looking at the eyes of an experimenter and exhibited shorter inter-bout episodes of social gaze when compared to age- and symptom-matched controls (Hall et al., [<reflink idref="bib21" id="ref27">21</reflink>]). Males with FXS have been shown to exhibit significantly increased levels of physiological arousal, as evidenced by higher heart-rate levels, lower vagal tone and lower heart-rate variability compared to typically developing controls (Hall, Lightbody, Hall et al. [<reflink idref="bib23" id="ref28">23</reflink>], [<reflink idref="bib25" id="ref29">25</reflink>]). Males with FXS have also been reported to exhibit high levels of social gaze avoidance even with family members compared to controls diagnosed with non-syndromic ASD (i.e., ASD without a known genetic cause) but have similar levels of adaptive behavior and autistic symptomatology (Wilkinson et al., [<reflink idref="bib55" id="ref30">55</reflink>]). Several authors have suggested that individuals with FXS demonstrate a so-called "warm up" effect in which social gaze may improve during extended social interactions (Hall, Lightbody, Hall et al. [<reflink idref="bib23" id="ref31">23</reflink>], [<reflink idref="bib25" id="ref32">25</reflink>]; Roberts et al. [<reflink idref="bib44" id="ref33">44</reflink>]). Although the developmental trajectory of social gaze avoidance in FXS is unknown, recent research also suggests that social gaze avoidance in FXS appears to emerge during infancy and increases in severity during childhood before reaching relative stability during adolescence and young adulthood (Roberts et al., [<reflink idref="bib43" id="ref34">43</reflink>]).</p> <p>Several authors have suggested that the mechanisms underlying social gaze avoidance may differ between individuals with FXS and individuals with non-syndromic ASD (Wilkinson et al., [<reflink idref="bib55" id="ref35">55</reflink>]). For example, studies of social gaze avoidance in individuals with FXS indicate that this behavior results from high levels of anxiety or hyperarousal that ultimately manifests as a form of gaze aversion (Cohen et al., [<reflink idref="bib3" id="ref36">3</reflink>], [<reflink idref="bib4" id="ref37">4</reflink>], [<reflink idref="bib5" id="ref38">5</reflink>]; Cornish et al., [<reflink idref="bib8" id="ref39">8</reflink>], [<reflink idref="bib7" id="ref40">7</reflink>]; Hall et al., [<reflink idref="bib22" id="ref41">22</reflink>]). Conversely, social gaze avoidance exhibited by some individuals with non-syndromic ASD may be related to deficits in attentional or associative mechanisms, manifesting as a form of gaze indifference (Moriuchi et al., [<reflink idref="bib39" id="ref42">39</reflink>]; Senju & Johnson, [<reflink idref="bib47" id="ref43">47</reflink>]). Studies have also indicated that gaze avoidance may be related to hyperarousal in some individuals with non-syndromic ASD (Stuart et al., [<reflink idref="bib50" id="ref44">50</reflink>]). These different mechanisms have different implications for interventions. For instance, interventions designed to minimize potential anxiety or hyperarousal combined with systematic exposure to social gaze may be beneficial for individuals who experience social gaze aversion whereas interventions designed to increase the motivation for social gaze may be beneficial for individuals who experience gaze indifference (Moriuchi et al., [<reflink idref="bib39" id="ref45">39</reflink>]).</p> <p>To examine the efficacy of behavioral treatments for social gaze aversion, Gannon and colleagues ([<reflink idref="bib17" id="ref46">17</reflink>]) administered a brief behavioral skills training intervention designed to promote social gaze in 20 males with FXS ages 8 to 18 years. During sessions, the participant was taught to employ progressive muscle relaxation and breathing techniques to decrease the potential for hyperarousal and received reinforcement for increased looking while listening and looking while speaking. Sessions were administered by a trained behavior therapist over 2 days. These authors reported that improvements in social gaze behavior occurred over the two days of training without participants experiencing increased levels of physiological arousal (Gannon et al., [<reflink idref="bib17" id="ref47">17</reflink>]). However, the specificity of the intervention is unknown.</p> <p>In the present study, we examined potential differences in social learning between individuals with FXS and individuals with non-syndromic ASD by administering the behavioral treatment probe devised by Gannon et al. ([<reflink idref="bib17" id="ref48">17</reflink>]) to matched cohorts of participants with FXS and participants with non-syndromic ASD and comparing the learning rates obtained during administration of the treatment probe. We had three hypotheses. First, we hypothesized that at baseline, participants with FXS would exhibit significantly lower levels of social gaze and significantly higher levels of physiological arousal compared to participants with non-syndromic ASD. Second, we hypothesized that during the intervention, learning rates would be significantly less steep and less variable for participants with FXS compared to participants with non-syndromic ASD. Finally, we hypothesized that at post-test, participants with FXS would exhibit significantly increased levels of social gaze and significantly decreased levels of physiological arousal compared to participants with non-syndromic ASD.</p> <hd id="AN0178677505-2">Methods</hd> <p></p> <hd id="AN0178677505-3">Participants</hd> <p>Participants were recruited via advertisements posted on the National Fragile X Foundation website, relevant Facebook groups and community behavioral health providers for individuals with FXS and other developmental disabilities inviting parents to complete an online screening survey about their child. The introduction to the screener stated that the study was designed to evaluate a social skills intervention for males with FXS and other developmental disabilities ages 7 to 18 years and that parents would need to complete the screener to determine if their son was eligible for the study. The first part of the screener contained questions pertaining to the participant's sex, age, and diagnosis. The second part of the screener contained questions from the Eye Contact Avoidance Scale (ECAS) (Hall & Venema, [<reflink idref="bib26" id="ref49">26</reflink>]).</p> <p>Participants were eligible for inclusion in the study if they were male, aged between 7 and 18 years old, and had obtained a total score of 30 points or more on the ECAS, indicating high levels of social gaze avoidance. For participants with FXS, evidence of aberrant methylation on the <emph>FMR1</emph> gene (> 200 CGG repeats) was confirmed by genetic report. Participants in the non-syndromic ASD were eligible if they did not have a known genetic cause of ASD. Participants in each group were excluded if they had other neurological or sensory impairments (e.g., head trauma and blindness), if they had any other known medical, psychiatric, or behavioral conditions that would preclude participation in the study and if they engaged in frequent or severe problem behaviors (e.g., self-injury, aggression, property destruction and/or elopement).</p> <p>Sixty-five participants (33 with FXS, 32 with non-syndromic ASD) met the inclusion criteria and travelled with their primary caregiver for the in-laboratory assessment and treatment probe evaluation. The Vineland Adaptive Behavior Scales, Second Edition (Sparrow et al., [<reflink idref="bib49" id="ref50">49</reflink>]) was administered to measure levels of adaptive behavior and the Social Responsiveness Scale, 2nd Edition (Constantino, [<reflink idref="bib6" id="ref51">6</reflink>]) was administered to measure levels of social impairment. All participants were then administered the Autism Diagnostic Observation Schedule, 2nd Edition (ADOS-2) (Lord et al., [<reflink idref="bib33" id="ref52">33</reflink>]) using either Module 1 (single words), Module 2 (phrase speech) or Module 3 (verbally fluent). Three males in the FXS group were unable to remain seated in a chair for the duration of the tasks and 6 males in the non-syndromic ASD group received scores in the no autism range on the ADOS-2. Fifty-six participants (30 FXS, 26 non-syndromic ASD) ages 7 to 18 years were therefore included in the present study. The demographic characteristics of the participants are shown in Table 1 [Table 1]. The groups were well matched in terms of age, adaptive behavior and degree of autistic symptomatology. Twenty-two (73.3%) males with FXS were classified in the autism range, 5 (16.6%) were classified in the autism spectrum range and 3 (10.0%) were classified in the "no autism" range on the ADOS-2 whereas 20 (77.0%) males with non-syndromic ASD were classified in the autism range, and 6 (23.0%) were classified in the autism spectrum range. Eight males with FXS had a mosaic genotype (four males with size mosaicism and four males with methylation mosaicism). The remaining 22 males with FXS had a fully methylated full mutation. Males with FXS received significantly lower scores on the Social Communication subscale of the SRS-2 compared to males with non-syndromic ASD (t(<reflink idref="bib54" id="ref53">54</reflink>) = -2.47, p =.017, d = − 0.62 [95% CI = -1.16, − 0.09]). Males with FXS were also more likely to be taking psychotropic medications compared to males with non-syndromic ASD (X<sups>2</sups>(<reflink idref="bib1" id="ref54">1</reflink>) = 5.61, p =.018).</p> <p>Table 1 Demographic and clinical characteristics of participants in each group</p> <p> <ephtml> <table frame="hsides" rules="groups"><thead><tr><th align="left" /><th align="left"><p>FXS</p><p>(<italic>n</italic> = 30)</p></th><th align="left"><p>Non-syndromic ASD</p><p>(<italic>n</italic> = 26)</p></th><th align="left"><p>t/X2</p></th><th align="left"><p>p</p></th><th align="left"><p>Cohen's d</p><p>[95% CI]</p></th></tr></thead><tbody><tr><td align="left"><p>Age in years (<italic>M</italic>, <italic>SD</italic>)</p></td><td align="left"><p>13.05 (2.77)</p></td><td char="." align="char"><p>12.83 (3.83)</p></td><td align="left"><p>0.27</p></td><td align="left"><p>NS</p></td><td char="?" align="char"><p>0.07 [−0.46, 0.59]</p></td></tr><tr><td align="left"><p>Adaptive Behavior<sup>a</sup> (<italic>M</italic>, <italic>SD</italic>)</p></td><td align="left" /><td align="left" /><td align="left" /><td align="left" /><td align="left" /></tr><tr><td align="left"><p>Communication skills</p></td><td align="left"><p>68.0 (10.4)</p></td><td char="." align="char"><p>71.8 (11.0)</p></td><td align="left"><p>−1.33</p></td><td align="left"><p>NS</p></td><td char="?" align="char"><p>−0.35 [−0.88, 0.17]</p></td></tr><tr><td align="left"><p>Daily Living skills</p></td><td align="left"><p>74.8 (15.0)</p></td><td char="." align="char"><p>73.2 (12.4)</p></td><td align="left"><p>0.42</p></td><td align="left"><p>NS</p></td><td char="?" align="char"><p>0.11 [−0.41, 0.64]</p></td></tr><tr><td align="left"><p>Socialization skills</p></td><td align="left"><p>71.4 (12.9)</p></td><td char="." align="char"><p>66.8 (8.8)</p></td><td align="left"><p>1.49</p></td><td align="left"><p>NS</p></td><td char="?" align="char"><p>0.41 [−0.12, 0.94]</p></td></tr><tr><td align="left"><p>Adaptive Behavior Composite</p></td><td align="left"><p>69.8 (11.7)</p></td><td char="." align="char"><p>69.0 (9.1)</p></td><td align="left"><p>0.27</p></td><td align="left"><p>NS</p></td><td char="?" align="char"><p>0.07 [−0.45, 0.60]</p></td></tr><tr><td align="left"><p>Language skills (<italic>N</italic>,%)</p></td><td align="left" /><td align="left" /><td align="left" /><td align="left" /><td align="left" /></tr><tr><td align="left"><p>Single words<sup>b</sup></p></td><td align="left"><p>1 (3.2%)</p></td><td char="." align="char"><p>1 (4.0%)</p></td><td align="left"><p>5.05</p></td><td align="left"><p>NS</p></td><td align="left" /></tr><tr><td align="left"><p>Phrase speech<sup>c</sup></p></td><td align="left"><p>12 (38.7%)</p></td><td char="." align="char"><p>3 (12.0%)</p></td><td align="left" /><td align="left" /><td align="left" /></tr><tr><td align="left"><p>Verbally fluent<sup>d</sup></p></td><td align="left"><p>18 (58.1%)</p></td><td char="." align="char"><p>21 (84.0%)</p></td><td align="left" /><td align="left" /><td align="left" /></tr><tr><td align="left"><p>ASD severity (<italic>M</italic>, <italic>SD</italic>) <sup>e</sup></p></td><td align="left"><p>6.71 (2.27)</p></td><td char="." align="char"><p>7.58 (1.44)</p></td><td align="left"><p>−1.64</p></td><td align="left"><p>NS</p></td><td char="?" align="char"><p>−0.44 [−0.98, 0.08]</p></td></tr><tr><td align="left"><p>Social impairment <sup>f</sup></p></td><td align="left" /><td align="left" /><td align="left" /><td align="left" /><td align="left" /></tr><tr><td align="left"><p>Social Awareness</p></td><td align="left"><p>65.64 (10.48)</p></td><td char="." align="char"><p>69.76 (9.84)</p></td><td align="left"><p>−1.59</p></td><td align="left"><p>NS</p></td><td char="?" align="char"><p>−0.40 [−0.93, 0.13]</p></td></tr><tr><td align="left"><p>Social Cognition</p></td><td align="left"><p>74.48 (12.01)</p></td><td char="." align="char"><p>75.72 (13.69)</p></td><td align="left"><p>−0.38</p></td><td align="left"><p>NS</p></td><td char="?" align="char"><p>−0.09 [−0.62, 0.43]</p></td></tr><tr><td align="left"><p>Social Communication</p></td><td align="left"><p>72.97 (11.21)</p></td><td char="." align="char"><p>79.66 (9.99)</p></td><td align="left"><p>−2.47</p></td><td align="left"><p>0.017</p></td><td char="?" align="char"><p>−0.62 [−1.16,−0.09]</p></td></tr><tr><td align="left"><p>Social Motivation</p></td><td align="left"><p>71.18 (14.35)</p></td><td char="." align="char"><p>74.72 (12.12)</p></td><td align="left"><p>−1.04</p></td><td align="left"><p>NS</p></td><td char="?" align="char"><p>−0.26 [−0.79, 0.26]</p></td></tr><tr><td align="left"><p>Repetitive behavior</p></td><td align="left"><p>79.48 (15.52)</p></td><td char="." align="char"><p>81.03 (13.94)</p></td><td align="left"><p>−0.41</p></td><td align="left"><p>NS</p></td><td char="?" align="char"><p>−0.10 [−0.63, 0.42]</p></td></tr><tr><td align="left"><p>Total score</p></td><td align="left"><p>75.70 (10.73)</p></td><td char="." align="char"><p>79.55 (9.59)</p></td><td align="left"><p>−1.48</p></td><td align="left"><p>NS</p></td><td char="?" align="char"><p>−0.37 [−0.91, 0.15]</p></td></tr><tr><td align="left"><p>Race</p></td><td align="left" /><td align="left" /><td align="left" /><td align="left" /><td align="left" /></tr><tr><td align="left"><p>Asian</p></td><td align="left"><p>1 (3.3%)</p></td><td char="." align="char"><p>4 (15.4%)</p></td><td align="left"><p>5.04</p></td><td align="left"><p>NS</p></td><td align="left" /></tr><tr><td align="left"><p>Native Hawaiian</p></td><td align="left"><p>1 (3.3%)</p></td><td char="." align="char"><p>1 (3.8%)</p></td><td align="left" /><td align="left" /><td align="left" /></tr><tr><td align="left"><p>Black</p></td><td align="left"><p>5 (16.7%)</p></td><td char="." align="char"><p>3 (11.5%)</p></td><td align="left" /><td align="left" /><td align="left" /></tr><tr><td align="left"><p>White</p></td><td align="left"><p>20 (66.7%)</p></td><td char="." align="char"><p>12 (46.2%)</p></td><td align="left" /><td align="left" /><td align="left" /></tr><tr><td align="left"><p>More than one race</p></td><td align="left"><p>3 (10%)</p></td><td char="." align="char"><p>6 (23.1%)</p></td><td align="left" /><td align="left" /><td align="left" /></tr><tr><td align="left"><p>Psychotropic medication use (%)</p></td><td align="left"><p>21 (70.0%)</p></td><td char="." align="char"><p>10 (38.5%)</p></td><td align="left"><p>5.61</p></td><td align="left"><p>0.018</p></td><td align="left" /></tr><tr><td align="left"><p>Stimulants</p></td><td align="left"><p>14 (46.7%)</p></td><td char="." align="char"><p>9 (34.6%)</p></td><td align="left"><p>0.278</p></td><td align="left"><p>NS</p></td><td align="left" /></tr><tr><td align="left"><p>Antidepressants</p></td><td align="left"><p>9 (30.0%)</p></td><td char="." align="char"><p>7 (26.9%)</p></td><td align="left" /><td align="left" /><td align="left" /></tr><tr><td align="left"><p>Antipsychotics</p></td><td align="left"><p>3 (10.0%)</p></td><td char="." align="char"><p>3 (11.5%)</p></td><td align="left" /><td align="left" /><td align="left" /></tr><tr><td align="left"><p>Antihypertensives</p></td><td align="left"><p>9 (30.0%)</p></td><td char="." align="char"><p>6 (23.1%)</p></td><td align="left" /><td align="left" /><td align="left" /></tr></tbody></table> </ephtml> </p> <p> <sups>a</sups>Vineland Adaptive Behavior Scales, 2nd Edition (VABS-II; Sparrow et al. [<reflink idref="bib49" id="ref55">49</reflink>]) <sups>b</sups>Module 1 of Autism Diagnostic Observation Schedule, 2nd Edition (ADOS-2; Lord et al., [<reflink idref="bib33" id="ref56">33</reflink>]) <sups>c</sups>Module 2 of ADOS-2 <sups>d</sups>Module 3 of ADOS-2 <sups>e</sups>Comparison severity score (CSS) of ADOS-2 <sups>f</sups>Social Responsiveness Scale, 2nd Edition (SRS-2; Constantino, [<reflink idref="bib6" id="ref57">6</reflink>])</p> <hd id="AN0178677505-4">Procedure</hd> <p>Each participant was evaluated over four successive days in our laboratory. On Day 1 (baseline), a social conversation task was conducted with a female examiner to measure levels of social gaze behavior at baseline (Hall et al., [<reflink idref="bib21" id="ref58">21</reflink>]). On Days 2 and 3, participants received sessions of the treatment probe conducted by a trained female therapist (see below). On Day 4 (post-treatment) the social conversation task was administered with a different female examiner.</p> <hd id="AN0178677505-5">Social Conversation Task (Baseline and Post-treatment)</hd> <p>A female examiner sat directly opposite the participant and engaged the participant in a conversation for 5 min while participant social gaze was recorded on a Tobii X120 eye-tracker (Tobii Pro Inc.). The eye-tracker was positioned on the table between the experimenter and the participant to record levels of social gaze (Hall et al., [<reflink idref="bib21" id="ref59">21</reflink>]). The examiner began the interaction by saying "Ok, we are going to have a conversation and I need you to look me in the eyes as much as possible while we are talking". The examiner then proceeded to engage the participant in a simple conversation, asking about familiar topics such as the participant's family, friends, and hobbies. The examiner kept her head as still as possible while looking directly at the participant, but in all other aspects acted as naturally as possible. If the participant did not make eye contact for 30 s, the examiner reminded the participant to make eye contact and to continue looking at her.</p> <p> <emph>Heart rate.</emph> To measure levels of physiological arousal, we used a Polar A360 fitness tracker heart rate monitor to record participant heart rate in beats per minute (bpm). The Polar A360 fitness tracker has a built-in heart rate sensor that measures heart rate from the wrist. The participant wore the bracelet snugly on top of their wrist, just behind the wrist bone throughout the conversation. Heart rate was recorded during the 5-minute conversation conducted at baseline and at post-treatment by pressing the appropriate icon on the touch screen of the wristwatch to begin recording and pressing the icon again to stop the recording at the end of the conversation. Data were then downloaded to Microsoft Excel and the average heart rate over each 5-minute period was then calculated. We also plotted the heart rate data in 20-second intervals to examine any variability in heart rate levels during presentation of the task.</p> <hd id="AN0178677505-6">Treatment Probe (Days 2 and 3)</hd> <p>The treatment probe was conducted on Day 2 and 3 to provide two days of successive treatment. To ensure consistency across days, all treatment procedures were administered in the same way across the two days. All training sessions were conducted in a room that contained a table or desk, chairs, and high-to-moderately preferred tangible items and activities as identified using the multiple stimulus without replacement (MSWO) protocol described by DeLeon and Iwata (DeLeon & Iwata, [<reflink idref="bib12" id="ref60">12</reflink>]). All experimenters and observers who participated in the study had previous experience in the use of behavioral interventions for children with developmental disabilities.</p> <p>Sessions began by introducing a variety of deep breathing and progressive muscle relaxation techniques designed to decrease potential levels of physiological arousal previously employed in FXS by Gannon and colleagues (Gannon et al., [<reflink idref="bib17" id="ref61">17</reflink>]). Participants were shown laminated cards containing icons for a <emph>pufferfish</emph>, <emph>snowman</emph>, <emph>turtle</emph>, <emph>cat</emph>, <emph>batman</emph>, and <emph>lemon</emph>, and were asked to choose three of the exercises they would like to complete. The therapist then modeled the exercises, prompted the participant to engage in the exercises, and provided verbal feedback when the participant completed each exercise. These exercises generally took 5 min to complete and were conducted prior to each block of discrete trials. Once the participant had completed the relaxation exercises, the participant was required to sit in a chair directly facing the therapist and to engage with the examiner in a series of discrete trials. Participants were not encouraged to use relaxation at any other time.</p> <p>Discrete trial instruction consisted of blocks of <emph>looking while listening</emph> trials alternated with blocks of <emph>looking while speaking</emph> trials. To initiate blocks of looking while listening trials, the therapist stated, "I'm going to talk to you about something and I want you to look at my eyes while I talk to you". Topics included the therapist telling a story (e.g., "Let me tell you about the time I went to...Let me tell you about the movie I saw this weekend..."), or providing information, such as discussing the steps to make a peanut butter and jelly sandwich. To initiate blocks of looking while speaking trials, the therapist stated, "I want to learn more about you, I want you to tell me about the things you enjoy doing. Please look at my eyes while you talk to me." The therapist asked the participant questions about things they liked, activities they enjoyed doing, school (teacher, favorite subjects, friends, sports, etc.), their favorite foods, their family, where they live, etc. Depending on the participant's verbal abilities, the therapist asked open-ended questions to encourage more conversation. While almost all participants could speak in full sentences at least some of the time (see Table 1), the therapist accommodated the needs of those who rarely spoke in full sentences by asking simple questions that required either one word or yes/no responses.</p> <p>On each trial, an observer (who was also present in the room) recorded the duration of social gaze using a computer program that operated a percentile reinforcement schedule (Hall, Maynes, et al., [<reflink idref="bib25" id="ref62">25</reflink>]). <emph>Social gaze</emph> was defined as the participant orienting his head toward the therapist so that his eyes looked directly at the therapist's face. The observer pressed the onset button on the program when the participant began to look at the therapist and pressed the offset button on the program when the participant stopped looking at the therapist. The percentile schedule program then automatically determined whether that response was a criterion response. Note that the program requires two parameters to be pre-specified: the probability of reinforcing a criterion response (<emph>w</emph>), and the number of prior observations (<emph>m</emph>) to be included in the calculation (Galbicka, [<reflink idref="bib16" id="ref63">16</reflink>]). In the current study, the values for <emph>w</emph> and <emph>m</emph> were set at 0.5 and 10 respectively so that the value of the current response would be considered a criterion response only if it exceeded 5 of the previous 10 response values (i.e., the median response value).</p> <p>On each trial, if the duration of social gaze met the criterion for reinforcement, the therapist delivered verbal praise (e.g., "Good job!"), and awarded a token on a token board (a magnetic erase board). If the participant did not engage in social gaze, or duration of social gaze did not meet criteria for reinforcement, increased verbal and gestural prompting was used to promote social gaze on the next trial. Verbal prompting included reminders such as, "Remember to keep looking at me while I talk" before a new verbal prompt was delivered. For gestural prompts, the therapist pointed both fingers in the direction of the participant's eyes and moved both fingers to point at his/her eyes. For verbal prompts, the therapist provided a verbal reminder for the participant to engage in appropriate social gaze. For physical prompts, the therapist placed an open hand on either side of the participant's face without touching to orient their face toward the therapist. As the participant earned tokens, he was reminded of his chosen reinforcer periodically and of how many more tokens would be needed to reach the goal of 10 tokens. Once the participant had received 10 tokens, he was allowed to play with his preferred item for 5 min, the board was then erased, and the count restarted. If the participant ended a session before earning all 10 tokens, the tokens would carry over to the next session.</p> <p>All participants received standard training of at least 200 trials of the treatment probe i.e., two blocks of 50 looking while listening trials and two blocks of 50 looking while speaking trials delivered in an alternating treatments ABAB design. To examine the effect of extended training, 15 males with FXS and 15 males with non-syndromic ASD received an additional 200 training trials i.e., two additional blocks of 50 looking while listening trials and two additional blocks of 50 looking while speaking trials delivered in an alternating treatments ABAB design. Participants were randomly assigned to receive either standard training (200 trials) or extended training (400 trials).</p> <p>Inter-observer agreement on the duration of social gaze was checked for 12.5% of the trials for each participant. On inter-observer agreement trials, the therapist simultaneously recorded the duration of the participant's social gaze using a stopwatch and noted the duration on a datasheet. Agreement between the observer and the therapist was computed using the intra-class correlation (ICC) coefficient computed across trials for each participant. The mean ICC across participants was 0.98 (range = 0.95 to 1.00) indicating that the agreement between observers was excellent.</p> <p> <emph>Data Analysis</emph>. All eye-tracking data were analyzed using Tobii Studio 3. For each participant, social gaze was quantified for all fixations that fell within a 52 cm x 28 cm box encompassing the therapist's face. A fixation was defined using the I-VT Fixation Filter in Tobii Studio with the filter interpolating over 100ms gaps to account for temporary loss of data (e.g., blinking and reflections) and discarding all fixations shorter than 60ms (Hessl et al., [<reflink idref="bib28" id="ref64">28</reflink>]). The dependent variables for the social conversation task were the percentage dwell time recorded on the eye-tracker and heart rate in beats per minute (bpm) recorded on the wristwatch over the 5-minute session. All heart rate files were checked for missed and/or double beats and the data were visually inspected by plotting the data across time.</p> <p>The primary dependent variable recorded during discrete trial training was the cumulative duration of social gaze emitted in blocks of 10 training trials in each training condition. We then computed the slope of the learning curves to index the rate of learning in each condition. Given the significantly greater variability in the data obtained by males with non-syndromic ASD, we applied a logarithmic transformation on the data to equalize the variances across the two groups. To examine the effect of the training across trials and condition type, we conducted a 2 (group) x 2 (condition) x 2 (time) repeated measures Analysis of Variance (ANOVA) on the transformed data. Note that the time variable has two levels because each condition was conducted twice within an ABAB design. We used partial eta squared as a measure of effect size. To examine potential predictors of social gaze during the training, we computed Pearson correlations between demographic variables and the slopes observed in each condition. To examine potential changes in social gaze and heart rate measured during the social conversation task, we used modified Brinley plots (Blampied, [<reflink idref="bib1" id="ref65">1</reflink>]). This graphical technique is useful for examining the effect of an intervention by depicting the data for each case as a coordinate pair across the two time points (e.g., baseline on the X axis and post-treatment on the Y axis) (McLay et al., [<reflink idref="bib36" id="ref66">36</reflink>]). For measures where increases in scores reflect improvement (e.g., social gaze), data points that lie above the 45° diagonal line (i.e., X = Y) are indicative of a therapeutic effect. For measures where decreases in scores reflect improvement (i.e., heart rate), data points that lie below the 45° diagonal line (i.e., X = Y) are indicative of a therapeutic effect. The number of cases (N), Cohen's <emph>dav</emph> Effect Size with a 95% confidence interval, and the Common Language Effect Size (CLES) were also calculated and shown on each graph. The CLES represents the probability (expressed as a percentage) that a score sampled at random from the post-treatment scores will be better than a score sampled at random from the pre-treatment score (Lakens, [<reflink idref="bib32" id="ref67">32</reflink>]; McGraw & Wong, [<reflink idref="bib35" id="ref68">35</reflink>]). The CLES and Cohen's <emph>dav</emph> were calculated using the software available from Lakens ([<reflink idref="bib32" id="ref69">32</reflink>]). Finally, to determine whether taking the average heart rate over 5 min may have masked subtle and transient variations in physiological arousal, we also plotted the heart rate data in 20-second intervals throughout the task and compared the data at the beginning and end of the task.</p> <hd id="AN0178677505-7">Results</hd> <p></p> <hd id="AN0178677505-8">Baseline Social Gaze</hd> <p>Mean percentage dwell time to the face recorded at baseline during the social conversation task was significantly lower in males with FXS (<emph>M</emph> = 9.5%, <emph>SD</emph> = 8.1%) compared to males with non-syndromic ASD (<emph>M</emph> = 22.6%, <emph>SD</emph> = 23.1%), (<emph>t</emph>(32.8) = -2.85, p =.007, d = − 0.77 [95% CI: -1.32, − 0.23]). There were no associations between levels of social gaze recorded at baseline and age or adaptive behavior on the VABS-II adaptive behavior composite score in either group. For males with FXS, levels of social gaze were significant negatively associated with the severity of autistic symptoms on the ADOS-2 (r(<reflink idref="bib30" id="ref70">30</reflink>) = − 0.44, p =.011) indicating that males with FXS who had higher levels of autistic symptoms exhibited lower levels of social gaze at baseline.</p> <hd id="AN0178677505-9">Baseline Heart Rate</hd> <p>The mean heart rate levels recorded at baseline during the social conversation task was 97.46 bpm (<emph>SD</emph> = 12.32) for males with FXS and 92.54 bpm (<emph>SD</emph> = 12.05 bpm) for males with non-syndromic ASD, a non-significant difference between the groups. In males with FXS, there was a significant negative association between heart-rate levels and age (r(<reflink idref="bib24" id="ref71">24</reflink>) = − 0.524, p =.009), indicating that younger males with FXS had higher heart-rates. There were no associations between heart-rate levels recorded at baseline and adaptive behavior, psychotropic medication use, or autistic symptom severity in either group. There was also no association between heart-rate levels and social gaze recorded on the eye-tracker in either group at baseline.</p> <hd id="AN0178677505-10">Treatment Probe</hd> <p>Figure 1 shows the learning curves obtained in each condition during administration of the treatment probe for each group. [Figure 1]. The data in the left panel shows the learning curves plotted for all 56 participants (30 FXS, 26 non-syndromic ASD) across the first 200 trials. A 2 (group) x 2 (condition) x 2 (time) repeated measures ANOVA conducted on the slopes revealed a significant main effect of group indicating that learning slopes were significantly less steep for males with FXS (<emph>M</emph> = 120.8 s) compared to males with non-syndromic ASD (<emph>M</emph> = 254.1 s) (F(<reflink idref="bib1" id="ref72">1</reflink>,<reflink idref="bib56" id="ref73">56</reflink>) = 16.42, p <.001, partial eta<sups>2</sups> = 0.227). There was also a significant main effect of time indicating that learning slopes were significantly steeper as the training progressed (F(<reflink idref="bib1" id="ref74">1</reflink>,<reflink idref="bib56" id="ref75">56</reflink>) = 4.82, p <.05, partial eta<sups>2</sups> = 0.079). There was no main effect of condition or interaction effects.</p> <p>Graph: Fig. 1 Learning curves obtained during each condition for each group across trials. Error bars are standard errors</p> <p>The data in the right panel show the learning curves plotted for the 30 participants (15 FXS, 15 controls) who received extended training. These data showed a similar pattern.</p> <p>A 2 (group) x 2 (condition) x 2 (time) repeated measures ANOVA revealed a significant main effect of group (F(<reflink idref="bib1" id="ref76">1</reflink>,<reflink idref="bib26" id="ref77">26</reflink>) = 9.43, p <.001, partial eta<sups>2</sups> = 0.266) indicating that the learning slopes were significantly less steep for males with FXS (<emph>M</emph> = 145.4 s) compared to matched controls with non-syndromic ASD (<emph>M</emph> = 243.6 s) during the extended training sessions. There was also a significant main effect of time indicating that learning slopes were significantly steeper as the training progressed (F(<reflink idref="bib1" id="ref78">1</reflink>,<reflink idref="bib26" id="ref79">26</reflink>) = 16.25, p = < 0.001, partial eta<sups>2</sups> = 0.385). Again, there was no main effect of condition or interaction effects.</p> <p>To examine the variability in the data in more detail, we determined the number of males with non-syndromic ASD who obtained learning slopes that were greater than 1 SD above the mean of males with FXS. During the first Listening condition, 13 of 26 males with non-syndromic ASD obtained learning slopes that were more than 1 SD above the mean of the FXS group, compared to 2 of 30 males with FXS, a significant difference in distribution between the two groups X<sups>2</sups>(<reflink idref="bib1" id="ref80">1</reflink>) = 13.34, p <.001). Similarly, during the first Speaking condition, 11 of 26 males with non-syndromic ASD had learning slopes that were more than 1 SD above the mean of the FXS group, compared to 4 of 30 males with FXS, a significant difference in distribution between the two groups X<sups>2</sups>(<reflink idref="bib1" id="ref81">1</reflink>) = 5.96, p =.015).</p> <hd id="AN0178677505-11">Predictors of Performance During the Treatment Probe</hd> <p>We computed correlations between demographic variables (age, adaptive behavior, autistic symptomatology) and the learning slopes in the looking while listening and looking while speaking conditions. In males with non-syndromic ASD, there were significant negative correlations between scores obtained on the Social Awareness subscale of the SRS-2 and the slopes obtained in the looking while listening condition (r(<reflink idref="bib26" id="ref82">26</reflink>) = − 0.500, p <.01) and the slopes obtained in the looking while speaking condition (r(<reflink idref="bib26" id="ref83">26</reflink>) = − 0.484, p <.05). There was also a significant negative correlation between scores obtained on the Social Cognition subscale of the SRS-2 and the slopes obtained in the looking while listening condition in this group (r(<reflink idref="bib26" id="ref84">26</reflink>) = − 0.388, p <.05). These data indicated that participants with non-syndromic ASD who had greater impairments in social awareness and social cognition exhibited less steep learning slopes. There were no associations between the demographic variables and the slopes in the FXS group.</p> <hd id="AN0178677505-12">Effects of the Treatment Probe on Social Gaze and Heart Rate</hd> <p>Figure 2 shows modified Brinley plots depicting the social gaze data recorded on the eye-tracker for cases in each group as a coordinate pair across the two time points (i.e., baseline on the X axis and post-treatment on the Y axis). Each data point represents the average dwell time for a participant over the 5-minute interaction. Data points that lie <uline>above</uline> the 45° diagonal line (i.e., X = Y) indicate a therapeutic effect. Also shown are the number of cases (N), Cohen's <emph>dav</emph> Effect Size, and the Common Language Effect Size (CLES) [Fig. 2].</p> <p>Graph: Fig. 2 Modified Brinley plots showing individual change in levels of social gaze recorded on the eye-tracker at baseline and at post-treatment for each group</p> <p>Following training, the mean percentage dwell time to the face recorded on the eye-tracker was 14.6% (<emph>SD</emph> = 12.6%) for males with FXS and 27.1% (<emph>SD</emph> = 22.9%) for males with non-syndromic ASD. As shown in the plots, the standardized mean difference effect size (<emph>dav</emph>) from baseline to post-treatment was 0.49 [95% CI: 0.05, 0.91] for males with FXS and 0.20 [95% CI: − 0.10, 0.49] for males with non-syndromic ASD. These data indicated that improvements in social gaze following the treatment probe were fairly large for males with FXS and that improvements in social gaze were more modest for males with non-syndromic ASD. The Common Language Effect Size (CLES) was 66% for males with FXS and 60% for males with non-syndromic ASD. Note that the outlier in the FXS group was due to one of the participants with FXS having a partially methylated full mutation. For this individual, social gaze increased from 14 to 60%, consistent with better functional outcomes for this genotype (Meng et al., [<reflink idref="bib37" id="ref85">37</reflink>]; Tassone et al., [<reflink idref="bib51" id="ref86">51</reflink>]). Note that the results were similar when this participant was removed from the analysis.</p> <p>Figure 3 shows modified Brinley plots depicting heart-rate levels recorded in each group as a coordinate pair across the two time points (i.e., baseline on the X axis and post-treatment on the Y axis). Again, each data point represents the average heart rate for a participant over the 5-minute interaction. Data points that lie <uline>below</uline> the 45° diagonal line (i.e., X = Y) indicate a therapeutic effect (i.e., reduced physiological arousal) [Fig. 3]. Following the treatment probe, the mean heart rate was 96.6 bpm (<emph>SD</emph> = 14.6) in males with FXS and 95.8 bpm (<emph>SD</emph> = 13.4) in males with non-syndromic ASD. As shown by the data in Fig. 3, there was no effect of the treatment probe on heart rates in either group.</p> <p>Graph: Fig. 3 Modified Brinley plots showing individual change in heart rate recorded at baseline and at post-treatment for each group</p> <p>Figure 4 shows the heartrate data plotted in 20 s intervals during the social conversation task at baseline and at post-treatment [Fig. 4]. At baseline, the mean heart rate at the beginning of the conversation was 96.1 bpm (<emph>SD</emph> = 15.4) for males with FXS and 91.1 bpm (<emph>SD</emph> = 15.1) for males with non-syndromic ASD and this increased only slightly to 99.3 bpm (<emph>SD</emph> = 13.05) and 94.0 bpm (<emph>SD</emph> = 14.6) respectively at the end of the conversation. Similarly, at post-treatment, the mean heart rate at the beginning of the conversation was 95.8 bpm (<emph>SD</emph> = 13.5) for males with FXS and 90.4 bpm (<emph>SD</emph> = 15.6) for males with non-syndromic ASD and increased only slightly to 97.8 bpm (<emph>SD</emph> = 14.9) and 93.3 bpm (<emph>SD</emph> = 15.4) respectively at the end of the conversation. These data show that physiological arousal was relatively stable throughout the interaction both at baseline and at post-treatment for both groups.</p> <p>Graph: Fig. 4 Mean heart rate levels recorded during the social conversation task at baseline and at post-treatment for each group. Error bars are standard errors</p> <hd id="AN0178677505-13">Discussion</hd> <p>An increasing body of literature suggests potential differences in the mechanisms underlying social gaze avoidance commonly exhibited by males with FXS and males with non-syndromic ASD. To test these differences, we administered a targeted behavioral treatment probe to both groups and compared the outcomes. The treatment probe, which targeted symptoms of social gaze aversion, involved implementing methods to decrease potential physiological arousal combined with reinforcement for looking while listening and looking while speaking to an unfamiliar therapist. We found that learning slopes were significantly attenuated in males with FXS compared to males with non-syndromic ASD. Indeed, levels of social gaze exhibited by males with FXS were approximately half the levels of social gaze observed in males with non-syndromic ASD at baseline. Following the treatment probe, levels of social gaze increased in males with FXS without concomitant increases in physiological arousal. This finding is important because many professionals have suggested that "forcing" eye contact may be contraindicated in FXS given that males with FXS commonly exhibit increased levels of anxiety and other escape behaviors when required to interact with others (Fragile X Clinical & Research Consortium, [<reflink idref="bib40" id="ref87">40</reflink>]). The data from the current study indicate that social gaze aversion can, in fact, be amenable to change without resulting in increased levels of physiological arousal. This could be beneficial for many individuals with FXS as well as individuals with non-syndromic ASD because maintaining appropriate levels of social gaze with others has been shown to increase social opportunities as well as learning new skills such as emotion recognition and joint attention skills.</p> <p>A striking finding was the significantly higher variability in learning rates obtained by males with non-syndromic ASD. It seems likely that the increased variability in the non-syndromic ASD group could be attributed to the potential differences in underlying mechanisms in this group. For example, individuals in the non-syndromic ASD group who had shallower learning slopes (i.e., were more similar to those with FXS), may have found social gaze to be more aversive. Indeed, during the first looking while listening condition, we found that half of males with non-syndromic ASD had learning slopes that were within 1 SD of the mean of the FXS group. However, we did not find any association between social gaze levels and heart rate during the social conversation task in either group. It is therefore unclear whether the shallower learning slopes obtained in this subgroup was related to gaze aversion per se.</p> <p>To examine the effect of treatment dosage on levels of social gaze, approximately half of participants received an additional 200 trials across the two days in addition to the standard 200 training trials that all participants received. Interestingly, there was no effect of dose on the data suggesting that delivering more trials does not necessarily result in greater improvements in social gaze. Indeed, the absence of a group x time interaction effect indicated that the difference between the groups stayed about the same over time. One explanation for this finding concerns the possibility that delivering training trials at such a high rate in such a short amount of time could result in increased fatigue. Indeed, we noted a slight fatigue effect toward the end of the sessions in the individual learning curves for some participants. Future studies will need to determine the optimal dose of the treatment to be delivered.</p> <p>We recruited males who exhibited high levels of social gaze avoidance in each group with the assumption that participants with this phenotype would also exhibit high levels of concomitant anxiety. During our social conversation task, mean heart rate levels were approximately 97 bpm in males with FXS and 93 bpm in males with non-syndromic ASD, suggesting that heart rate levels were somewhat elevated. We note, however, that inclusion of a true baseline (at rest) would provide more context as to whether the social conversation task caused a hyperaroused state for this sample. Following the treatment probe, heart-rate levels remained at the same level in both groups. There are several possible explanations for this finding. First, it is possible that the relaxation sessions delivered by the therapist were of insufficient duration or were not comprehensive enough to be beneficial to the participants. Although we attempted to monitor heart rate levels during treatment sessions to determine whether the relaxation sessions resulted in decreased physiological arousal, many of the participants could not tolerate wearing the wrist monitor for extended periods of time. We were also concerned that requiring the participant to continue wearing the monitor would disrupt the treatment sessions. We therefore could not reliably obtain heart rate data during implementation of the looking while listening and looking while speaking conditions. Second, the duration of the treatment probe was extremely short (i.e., 2 days) and it is possible that this time frame was too short to expect significant change. Implementing the treatment across additional days or weeks could result in greater changes in levels of physiological arousal. It is also possible that taking the average heart rate over the 5-minute conversation task may have masked subtle and transient variations in physiological arousal over time. However, when we plotted the heart rate data at a finer temporal resolution, heart rates appeared to be relatively stable over time. Lastly, the therapy was delivered in an unfamiliar setting and the therapist who implemented the training was not familiar to the participant. It is possible therefore that the therapy could have been more successful if delivered in the participant's home by someone who was more familiar with the participant (e.g., a parent or family friend).</p> <p>Strengths of study include the use of a percentile reinforcement schedule to automate the shaping process during the training and to minimize potential satiation effects. All participants thus received the same amount of reinforcement, regardless of whether they exhibited high or low levels of social gaze. We also employed a novel eye-tracking paradigm that required the participant to maintain eye contact with a live person (Hall et al., [<reflink idref="bib21" id="ref88">21</reflink>]). Previous studies have employed eye-tracking paradigms where photographs of faces are presented to participants on a computer screen (Hessl et al., [<reflink idref="bib28" id="ref89">28</reflink>]). We believe these paradigms lack ecological validity and could compromise the ability to detect potential treatment effects. We also alternated blocks of looking while listening trials with blocks of looking while speaking trials during the training in order to systematically train each type of skill. This design allowed us to examine whether social gaze was more or less likely to occur on each type of trial. Given the increased social demands or "cognitive load" involved in looking while speaking (Turkstra, [<reflink idref="bib53" id="ref90">53</reflink>]), we expected that males with FXS would be less likely to exhibit social gaze on looking while speaking trials compared to looking while listening trials. Interestingly, we found no difference between the learning slopes obtained on looking while listening trials versus looking while speaking trials in either group of participants. Studies in typically developing individuals have shown that individuals tend to look less while speaking. A limitation of the data is that we were unable to parse the data collected on the eye tracker into times when the participant was looking while listening versus times when the participant was looking while speaking.</p> <p>Although we recruited a well-matched group of participants with non-syndromic ASD who had similar symptoms to males with FXS, we excluded participants who displayed frequent levels of challenging behaviors (i.e., aggression, self-injury, property destruction, or elopement) in both groups. We did this to ensure that these behaviors would not interfere with the implementation of the treatment probe. However, we recognize that the samples included in the present study may not be representative of males with FXS and males with non-syndromic ASD in general. It is therefore unclear whether individuals who commonly exhibit behavioral challenges would be able to benefit from the treatment. Another potential limitation concerns the fact that the therapists and examiners included in this study were female. Although we did this to control for potential sex effects, it is possible that the outcome of the training could have been different had we included a male therapist or examiner. Future studies will need to examine whether social gaze patterns in FXS are affected by the sex of the interacting social partner. Finally, we included specific modifications to the intervention to account for participants with different levels of verbal ability. Although no relationship was found between adaptive behavior levels and the learning slopes in either group, it should be noted that a greater proportion of participants in the non-syndromic ASD group appeared to be verbally fluent according to the ADOS-2 module administered. This could have accounted for some of the variance in learning slopes in the non-syndromic ASD group. Language ability should therefore be controlled in future studies.</p> <p>The present study needs to be set in the context of other behavioral treatment studies designed to promote social gaze in individuals with FXS and non-syndromic ASD. In a recent review of the literature, Hustyi and colleagues reported that a variety of intervention strategies had been employed by researchers over the past 45 years to promote social gaze in these individuals, including discrete trial instruction, prompting, modeling and imitation (Hustyi et al., [<reflink idref="bib30" id="ref91">30</reflink>]). However, limited data were available concerning the generalization, maintenance and social validity of these interventions and the authors found that only 12 studies had been conducted in naturalistic settings such as the participant's home, school or community setting. Over the past few decades, there has been a shift away from clinic-based interventions in which interventions are administered directly by trained clinicians, and toward interventions that can be administered in partnership with parents, teachers and other key stakeholders in naturalistic settings (Schuck et al., [<reflink idref="bib46" id="ref92">46</reflink>]). For example, there is emerging evidence to suggest that patterns of social communication can be improved by having a more accepting social partner and that behavioral interventions are more likely to be successful if family members are involved in the construction of these interventions (Schuck et al., [<reflink idref="bib46" id="ref93">46</reflink>]). The next step will therefore be to evaluate the treatment probe in more naturalistic settings, where family members and the participants themselves can be involved in the decision-making process, ensuring that the procedures are appropriate and acceptable to participants and their families. In the review by Hustyi and colleagues, only 17 of the 41 studies reviewed included information about whether the procedures were appropriate or acceptable to participants and their families. Future studies should therefore involve key stakeholders (e.g., caregivers, providers and payers) in the autistic/FXS communities to determine their thoughts about this intervention and whether it is something they want and need.</p> <p>An important consideration for designing interventions targeted to social gaze also concerns obtaining the perspective of autistic individuals themselves. In a qualitative study of messages and videos posted on the Internet by adolescents and adults with self-declared diagnoses of ASD, Trevisan and colleagues reported that many individuals described adverse reactions (e.g., physiological arousal, fear/anxiety and threat responses) or sensory overload (e.g., audiovisual integration difficulties) when making eye contact with others, suggesting that these individuals predominantly experienced an aversion to social gaze (Trevisan et al., [<reflink idref="bib52" id="ref94">52</reflink>]). At the same time, many individuals recognized the importance of social gaze in facilitating social interactions with others in general and as a result employed a variety of strategies to improve their social gaze (e.g., exposure and practice) or compensated for difficulties with social gaze. Although these first-hand accounts are subject to significant selection bias, these data suggest that many autistic individuals themselves are open to improving their social gaze behavior and commonly engage in strategies to overcome these difficulties.</p> <p>This is the first study to compare the effects of a targeted behavioral treatment probe on levels of social gaze in males with FXS and males with non-syndromic ASD. Interestingly, two studies have examined whether pharmacological agents targeted to the downstream effects of reduced FMRP can promote levels of social gaze in individuals with FXS. In the first study, Hall and colleagues (Hall et al., [<reflink idref="bib24" id="ref95">24</reflink>]) examined whether administration of the neuropeptide oxytocin could result in improvements in levels of social gaze in a small group of eight males with FXS, ages 13 to 28 years. Each participant received either 24 IU intranasal oxytocin, 48 IU intranasal oxytocin or placebo administered on separate days spaced one week apart. These authors found that social gaze increased during administration of the 24 IU oxytocin compared to placebo. In the second study, Hessl and colleagues (Hessl et al., [<reflink idref="bib28" id="ref96">28</reflink>]) examined the effect of mavoglurant, a negative allostatic modulator of mGlur5 activity, on social gaze behavior in 57 adolescent and adult participants with FXS. Participants were randomized to receive either 25 mg, 50 mg, or 100 mg mavoglurant or placebo over 12 weeks. These authors reported that social gaze behavior during a passive viewing eye-tracking task increased in participants who had received 25 mg mavoglurant compared to those who had received placebo. However, the effects of these pharmacological agents on levels of social gaze was limited in these studies. It seems likely that any pharmacological agent would need to be tested in the context of a behavioral learning platform such as the one presented here. The present study will therefore inform future combination studies in which syndrome-specific pharmacological agents are tested in tandem with targeted behavioral interventions. We also hope that the study will pave the way toward the design of future "syndrome-specific" behavioral interventions and broader efforts to ameliorate social anxiety in young children with FXS.</p> <hd id="AN0178677505-14">Author Contribution</hd> <p>Both authors contributed to the study conception and design, material preparation, data collection and analysis. SSH drafted the manuscript and TCB edited the manuscript for critical content. Both authors read and approved the final manuscript.</p> <hd id="AN0178677505-15">Funding</hd> <p>This research was supported by NIH grant number R01HD081336 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (PI: S.S. Hall) at the National Institutes of Health.</p> <hd id="AN0178677505-16">Declarations</hd> <p></p> <hd id="AN0178677505-17">Conflict of Interest</hd> <p>The authors declare no potential conflict of interest with respect to the research, authorship and/or publication of this article.</p> <hd id="AN0178677505-18">Publisher's Note</hd> <p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p> <ref id="AN0178677505-19"> <title> References </title> <blist> <bibl id="bib1" idref="ref54" type="bt">1</bibl> <bibtext> Blampied NM. Analyzing therapeutic change using modified Brinley plots: history, construction, and interpretation. 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PreciseRelevancyScore: 0
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Differential Effects of a Behavioral Treatment Probe on Social Gaze Behavior in Fragile X Syndrome and Non-Syndromic Autism Spectrum Disorder
– Name: Language
  Label: Language
  Group: Lang
  Data: English
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Scott+S%2E+Hall%22">Scott S. Hall</searchLink> (ORCID <externalLink term="http://orcid.org/0000-0003-4797-1819">0000-0003-4797-1819</externalLink>)<br /><searchLink fieldCode="AR" term="%22Tobias+C%2E+Britton%22">Tobias C. Britton</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="SO" term="%22Journal+of+Autism+and+Developmental+Disorders%22"><i>Journal of Autism and Developmental Disorders</i></searchLink>. 2024 54(7):2719-2732.
– Name: Avail
  Label: Availability
  Group: Avail
  Data: Springer. Available from: Springer Nature. One New York Plaza, Suite 4600, New York, NY 10004. Tel: 800-777-4643; Tel: 212-460-1500; Fax: 212-460-1700; e-mail: customerservice@springernature.com; Web site: https://link.springer.com/
– Name: PeerReviewed
  Label: Peer Reviewed
  Group: SrcInfo
  Data: Y
– Name: Pages
  Label: Page Count
  Group: Src
  Data: 14
– Name: DatePubCY
  Label: Publication Date
  Group: Date
  Data: 2024
– Name: SourceSuprt
  Label: Sponsoring Agency
  Group: SrcSuprt
  Data: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (DHHS/NIH)
– Name: NumberContract
  Label: Contract Number
  Group: NumCntrct
  Data: R01HD081336
– Name: TypeDocument
  Label: Document Type
  Group: TypDoc
  Data: Journal Articles<br />Reports - Research
– Name: Subject
  Label: Descriptors
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Social+Development%22">Social Development</searchLink><br /><searchLink fieldCode="DE" term="%22Interpersonal+Competence%22">Interpersonal Competence</searchLink><br /><searchLink fieldCode="DE" term="%22Behavior+Change%22">Behavior Change</searchLink><br /><searchLink fieldCode="DE" term="%22Nonverbal+Communication%22">Nonverbal Communication</searchLink><br /><searchLink fieldCode="DE" term="%22Physiology%22">Physiology</searchLink><br /><searchLink fieldCode="DE" term="%22Symptoms+%28Individual+Disorders%29%22">Symptoms (Individual Disorders)</searchLink><br /><searchLink fieldCode="DE" term="%22Task+Analysis%22">Task Analysis</searchLink><br /><searchLink fieldCode="DE" term="%22Intellectual+Disability%22">Intellectual Disability</searchLink><br /><searchLink fieldCode="DE" term="%22Outcomes+of+Treatment%22">Outcomes of Treatment</searchLink><br /><searchLink fieldCode="DE" term="%22Autism+Spectrum+Disorders%22">Autism Spectrum Disorders</searchLink><br /><searchLink fieldCode="DE" term="%22Males%22">Males</searchLink><br /><searchLink fieldCode="DE" term="%22Children%22">Children</searchLink><br /><searchLink fieldCode="DE" term="%22Matched+Groups%22">Matched Groups</searchLink><br /><searchLink fieldCode="DE" term="%22Therapy%22">Therapy</searchLink><br /><searchLink fieldCode="DE" term="%22Interpersonal+Relationship%22">Interpersonal Relationship</searchLink><br /><searchLink fieldCode="DE" term="%22Relaxation+Training%22">Relaxation Training</searchLink><br /><searchLink fieldCode="DE" term="%22Measurement%22">Measurement</searchLink><br /><searchLink fieldCode="DE" term="%22Comparative+Analysis%22">Comparative Analysis</searchLink><br /><searchLink fieldCode="DE" term="%22Early+Intervention%22">Early Intervention</searchLink>
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1007/s10803-023-05919-6
– Name: ISSN
  Label: ISSN
  Group: ISSN
  Data: 0162-3257<br />1573-3432
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: The purpose of this study was to examine potential differences in social learning between individuals with fragile X syndrome (FXS), the leading known inherited cause of intellectual disability, and individuals with non-syndromic autism spectrum disorder (ASD). Thirty school-aged males with FXS and 26 age and symptom-matched males with non-syndromic ASD, were administered a behavioral treatment probe designed to improve levels of social gaze during interactions with others. The treatment probe was administered by a trained behavior therapist over two days in our laboratory and included reinforcement of social gaze in two alternating training conditions -- looking while listening and looking while speaking. Prior to each session, children in each group were taught progressive muscle relaxation and breathing techniques to counteract potential increased hyperarousal. Measures included the rate of learning in each group during treatment, in addition to levels of social gaze and heart rate obtained during administration of a standardized social conversation task administered prior to and following the treatment probe. Results showed that learning rates obtained during administration of the treatment probe were significantly less steep and less variable for males with FXS compared to males with non-syndromic ASD. Significant improvements in social gaze were also observed for males with FXS during the social conversation task. There was no effect of the treatment probe on heart rate in either group. These data reveal important differences in social learning between the two groups and have implications for early interventions in the two conditions.
– Name: AbstractInfo
  Label: Abstractor
  Group: Ab
  Data: As Provided
– Name: DateEntry
  Label: Entry Date
  Group: Date
  Data: 2024
– Name: AN
  Label: Accession Number
  Group: ID
  Data: EJ1432992
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=eric&AN=EJ1432992
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1007/s10803-023-05919-6
    Languages:
      – Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 14
        StartPage: 2719
    Subjects:
      – SubjectFull: Social Development
        Type: general
      – SubjectFull: Interpersonal Competence
        Type: general
      – SubjectFull: Behavior Change
        Type: general
      – SubjectFull: Nonverbal Communication
        Type: general
      – SubjectFull: Physiology
        Type: general
      – SubjectFull: Symptoms (Individual Disorders)
        Type: general
      – SubjectFull: Task Analysis
        Type: general
      – SubjectFull: Intellectual Disability
        Type: general
      – SubjectFull: Outcomes of Treatment
        Type: general
      – SubjectFull: Autism Spectrum Disorders
        Type: general
      – SubjectFull: Males
        Type: general
      – SubjectFull: Children
        Type: general
      – SubjectFull: Matched Groups
        Type: general
      – SubjectFull: Therapy
        Type: general
      – SubjectFull: Interpersonal Relationship
        Type: general
      – SubjectFull: Relaxation Training
        Type: general
      – SubjectFull: Measurement
        Type: general
      – SubjectFull: Comparative Analysis
        Type: general
      – SubjectFull: Early Intervention
        Type: general
    Titles:
      – TitleFull: Differential Effects of a Behavioral Treatment Probe on Social Gaze Behavior in Fragile X Syndrome and Non-Syndromic Autism Spectrum Disorder
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Scott S. Hall
      – PersonEntity:
          Name:
            NameFull: Tobias C. Britton
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 01
              M: 07
              Type: published
              Y: 2024
          Identifiers:
            – Type: issn-print
              Value: 0162-3257
            – Type: issn-electronic
              Value: 1573-3432
          Numbering:
            – Type: volume
              Value: 54
            – Type: issue
              Value: 7
          Titles:
            – TitleFull: Journal of Autism and Developmental Disorders
              Type: main
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