Beyond bendy joints: number of variant connective tissue features predicts neurodivergent characteristics in hypermobile individuals with anxiety

Beyond bendy joints: number of variant connective tissue features predicts neurodivergent characteristics in hypermobile individuals with anxiety | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Beyond bendy joints: number of variant connective tissue features predicts neurodivergent characteristics in hypermobile individuals with anxiety Jenny Csecs, Lisa Quadt, Georgia Savage, Geoff Davies, Parashar Ramanuj, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5563877/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract The goal of this study was to determine whether the number of connective tissue features in hypermobility is associated with level of neurodivergent characteristics and establish whether autonomic reactivity is a mechanistic factor in the relationship between variant connective tissue and neurodivergent characteristics. 99 adult participants were assessed for joint hypermobility syndrome/hypermobile Ehlers-Danlos-Syndrome and filled out screening questionnaires for autism and ADHD. 99% of participants met criteria for generalized joint hypermobility, and 57% for hypermobile Ehlers-Danlos-Syndrome. 47% of participants scored above screening threshold for autism and 20% for ADHD. All measures were significantly correlated. Level of autonomic reactivity (as measured by the Body Perception Questionnaire) mediated the relationship between number of connective tissue features and neurodivergence, even after controlling for anxiety level. This shows that autonomic reactivity has a potential mechanistic role in the established link between variant connective tissue and neurodivergence, opening novel pathways for research and clinical care. Biological sciences/Neuroscience/Diseases of the nervous system/Anxiety Biological sciences/Neuroscience/Diseases of the nervous system/Autism spectrum disorders Biological sciences/Neuroscience/Diseases of the nervous system/Chronic pain Health sciences/Medical research/Translational research Autism ADHD autonomic nervous system joint hypermobility Ehlers Danlos Syndrome Figures Figure 1 Introduction Neurodivergence (e.g., autism, attention deficit hyperactivity disorder (ADHD)) frequently co-occurs with poor mental and physical health, with potentially devastating consequences for the wellbeing and quality of life of neurodivergent individuals of all ages (Ayres, Parr et al. 2018 , Asherson 2020 ). Neurodivergent individuals have a decreased life expectancy of up to 30 years (Hirvikoski, Mittendorfer-Rutz et al. 2016 ), and experience substantial barriers to effective healthcare (Doherty, Neilson et al. 2022 ). Insight into factors that contribute to the poor health status of neurodivergent people is therefore much needed. One potential factor is the overrepresentation of hereditary connective tissue disorders in this population (Doğan, Taner and Evcik 2011 , Cederlöf, Larsson et al. 2016 , Casanova, Baeza-Velasco et al. 2020 ). Variant connective tissue, often expressed as joint hypermobility, may be present in approximately 20% of the general population (Mulvey, Macfarlane et al. 2013 ), and in up to 51% of the neurodivergent population (Csecs, Iodice et al. 2022 ). When joint hypermobility is experienced in combination with medical symptoms a diagnosis of hypermobility spectrum disorder (HSD) (previously known as joint hypermobility syndrome (JHS)) or Ehlers-Danlos Syndrome (EDS) (of which hypermobile EDS (hEDS) is by far the most common) may be present (Malfait, Francomano et al. 2017 ) A population-based matched cohort study (nationwide registry) in Sweden (n = 1771), showed that individuals with EDS are 7.4 times more likely to be autistic than a comparison group, and 5.6 times more likely to have an ADHD diagnosis than those without EDS (Cederlöf, Larsson et al. 2016 ). Moreover, autistic children have a greater frequency of presence of generalised joint hypermobility compared to a matched group of non-autistic children (Shetreat-Klein, Shinnar and Rapin 2014 ) and the frequency of presence of generalised joint hypermobility in children with ADHD (n = 86) is 74% compared to 13% of a comparison group (Shiari, Saeidifard and Zahed 2013 ). Variant connective tissue often underlies poor physical and mental health, including chronic pain and fatigue (Voermans and Knoop 2011 , Mulvey, Macfarlane et al. 2013 , Hakim, De Wandele et al. 2017 ), gastrointestinal difficulties (Fikree, Chelimsky et al. 2017 ), gynaecological and obstetric problems (Hugon-Rodin, Lebègue et al. 2016 , Pezaro, Pearce and Reinhold 2018 ) and psychological health difficulties, particularly anxiety (Cederlöf, Larsson et al. 2016 , Bulbena, Baeza-Velasco et al. 2017 , Sharp, Critchley and Eccles 2021 ). Variant connective tissue also affects the function of the autonomic nervous system, and has been shown to link neurodivergence and dysautonomia mechanistically (Csecs, Iodice et al. 2022 ). Neural interactions that support autonomic regulation include homeostatic reflexes and allostatic control, which are both tightly coupled to viscerosensory feedback signals from internal bodily organs; i.e., interoception (Quadt, Critchley and Nagai 2022 ). A hallmark of neurodivergence is a difference in sensory processing, and this includes interoceptive differences (Proff, Williams et al. 2021 ). Joint hypermobility is also associated with differences in sensory processing, which include paraesthesia, hyperaesthesia, hyperacusis and hyperosmia (Hamonet, Gompel et al. 2014 , Colombi, Dordoni et al. 2015 , Baeza-Velasco, Grahame and Bravo 2017 ). Interoception therefore offers a window into the link between autonomic dysregulation, neurodivergence and variant connective tissue, where autonomic reactivity may be conceptualized as heightened sensitivity to interoceptive signals. While associations are apparent in the aforementioned research and case studies (Sinibaldi, Ursini and Castori 2015 ), the relationship between joint hypermobility, autonomic and interoceptive dysfunction, and neurodivergence requires further investigation and understanding (Bulbena, Baeza-Velasco et al. 2017 ). In the current study, we used screening data from a sample of potential participants for a clinical trial of an interoceptive therapy for people with joint hypermobility and anxiety (Davies, Csecs et al. 2021 ). None of the participants had formal diagnoses of neurodivergent conditions. We aimed, first; to estimate the frequency of autism and ADHD by establishing in this cohort who scored above threshold for screening criteria for these neurodivergent conditions and, second; to test whether autonomic reactivity was a potential mechanistic factor in the relationship between variant connective tissue and neurodivergence. Methods Study design and participants This study used screening data gathered during the assessment phase of the Altering Dynamics of Autonomic Processing Therapy (ADAPT) trial (ISRCTN17018615), which was a randomised controlled trial comparing two non-drug therapies for anxiety in joint hypermobility (Davies, Csecs et al. 2021 ). We assessed 99 adults (age ≥ 18 years) interested in taking part in the ADAPT trial. Initial inclusion criteria were a score of ≥ 2 points on a five-part joint hypermobility questionnaire (Hakim and Grahame 2003 ) at screening, or having a hypermobility related diagnosis: Joint Hypermobility Syndrome (JHS), Hypermobility Spectrum Disorder (HSD), Ehlers-Danlos Syndrome (EDS), and having anxiety (scored ≥ 16 on the Beck Anxiety Inventory at screening). Exclusion criteria for the ADAPT trial included major psychiatric disorders (except co-occurring depression, as it is commonly seen in anxiety) and previously confirmed diagnosis of a neurodevelopmental condition (e.g., autism or ADHD). For this sub-study, we used data from the full screening interview. All inclusion and exclusion criteria for the ADAPT trial are available in the published protocol (Davies, Csecs et al. 2021 ). Procedure Participants were initially screened for eligibility via phone by a research assistant. If they met initial criteria, they were referred to a research clinical psychologist to obtain informed consent and conduct the full screening interview, alongside the research assistant. Due to COVID-19 restrictions, this assessment was conducted by completing questionnaires online via Qualtrics and meeting researchers over video-conferencing software. See published protocol (Davies, Csecs et al. 2021 ) for complete list of assessment measures. Outcomes Variant connective tissue Variant connective tissue was assessed using the 5-part questionnaire (5PQ) for joint hypermobility, (Hakim and Grahame 2003 ) (scores of ≥ 2), the Brighton Criteria for JHS, and the 2017 hEDS criteria (Castori, Tinkle et al. 2017 ) – see Supplementary Table 1 for full diagnostic criteria. The hEDS diagnostic checklist has 3 criteria which need to be met: Criterion 1 – Generalised Joint Hypermobility (i.e. Beighton score ≥ 5 in pubertal men and women to age 50 or ≥ 4 if over age 50), Criterion 2 – two or more features (A, B or C) must be present (i.e. ≥ 5/12 of feature A, e.g. ‘unusually soft or velvety skin’; feature B: positive family history of hEDS; ≥ 1 of feature C: 3 items e.g. ‘chronic, widespread pain for ≥ 3 months) and Criterion 3 – all 3 prerequisites must be met (e.g. ‘absence of unusual skin fragility, which should prompt consideration of other types of EDS’). It was not possible to determine the last item of Criterion 2A (aortic root dilatation with Z-score > + 2) as participants did not undergo echocardiography as part of the study protocol (Eccles, Thompson et al. 2021 ). The hypermobility assessments were administered as clinical examinations by a trained clinician/researcher. hEDS Criterion 2A items were used to quantify the number of connective tissue features (Eccles, Thompson et al. 2021 ). Autism The Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R, (Ritvo, Ritvo et al. 2011 ), (endorsed by NICE Clinical guideline [CG142] (NICE 2021 )) was used in combination with a clinical interview, as part of a screening process for autism; this involved assessing autistic characteristics across 4 domains: Social Relatedness, Circumscribed Interests, Language and Sensory Motor. It consists of 80 self-report statements (e.g. ‘I often use words and phrases from movies and television in conversations’), with four options to choose from per statement (i.e. ‘true now and when I was young’, ‘true now only’, ‘true only when I was younger than 16’ and ‘never true’). Scores range from 0-240 and the threshold of likely autism is ≥ 65 (sensitivity = 97%, specificity = 100%) (Ritvo, Ritvo et al. 2011 ). The study’s patient and public involvement group considered the RAADS-R to be a more acceptable screening tool for a sample that was likely to include mostly people who identified as female. Scores from the RAADS-R were subsequently used in conjunction with the clinical interview with Clinical Psychologists as part of the trial eligibility assessment; autistic characteristics which warranted further investigation (i.e. total RAADS-R score ≥ 65) (Nyrenius, Eberhard et al. 2022 , Shaw, Doherty et al. 2022 ) were explored and, if appropriate, participants were recommended to be referred for full autism assessments. ADHD The Wender Utah Rating Scale (WURS, designed for adults to rate their own childhood behaviour; (Ward, Wender and Reimherr 1993 ) was used to assess ADHD characteristics. This was combined with a clinical interview with a Clinical Psychologist, as part of our screening process for ADHD. The WURS has 61 self-report items which are rated in relation to presence and severity during childhood (e.g. ‘acting without thinking, impulsive’ is rated on a 5-point Likert scale from ‘0 = not at all or very slightly’ to ‘4 = very much’), 25 of the items are totalled to produce an overall score. Scoring 46/100 or more is suggestive of ADHD (sensitivity = 86%, specificity = 99%, (Ward, Wender and Reimherr 1993 )), and further explored in the clinical interview. Where appropriate, participants were recommended to be referred for full ADHD assessments. Autonomic reactivity The Body Perception Questionnaire (BPQ (Porges 1993 )) subscale ‘Autonomic Nervous System Reactivity’ was used as a self-report measure for autonomic reactivity. The scale contains 27 items of sensations related to autonomic nervous system reactivity, e.g., “My heart often beats irregularly”, that are rated in terms of frequency on a five-point scale ranging from ‘never’ to ‘always’. Scores range between 27 and 108. Statistical Analyses Participants were assessed as to whether they met criteria for generalised joint hypermobility, JHS, and hEDS (including number of connective tissue features in Criterion 2A (Castori, Tinkle et al. 2017 )). Total scores from the RAADS-R (including from the 4 domains and as an overall score) and from the relevant 25 items on the WURS were evaluated against the clinical cut-offs. The ‘Autonomic Reactivity’ subscale was also totalled as part of the BPQ. We ran separate bivariate correlation analyses of differential relationships between number of connective tissue features (hEDS Criterion 2A), RAADS total and RAADS sensory motor scores, WURS total scores, and autonomic reactivity. Missing data were handled by excluding cases pairwise To examine potential causal associations between neurodivergence, connective tissue features, and autonomic reactivity, we performed separate mediation analyses using PROCESS macro v3.5 for SPSS by Hayes ( 2017 ). The 95% bootstrapped confidence interval for the indirect effect was based on 5,000 samples and considered significant if the bootstrapped confidence intervals do not cross zero. We ran two separate mediation analyses with RAADS sensory motor scores and WURS scores as outcome variables. In both models, the predictor variable was number of connective tissue features, and the mediator variable was autonomic reactivity scores. In an additional analysis anxiety level was used as a co-variate. Missing data All participants self-reported they had hypermobility and data were available for the RAADS (n = 96, 97%), WURS (n = 98, 99%) and BPQ (n = 98, 99%) as part of screening before the full clinical assessment. The majority of the sample completed full hypermobility assessments as part of the clinical assessment; a small number of participants did not complete the full hypermobility assessments due to being ineligible at screening before further assessment (i.e., Beck Anxiety Inventory score < 16, n = 6). Given the low numbers of missing data, we used listwise exclusion. Patient and Public Involvement This specific sub-study of the ADAPT trial was motivated by our ongoing Patient and Public Involvement (PPI) work. We regularly correspond with patients and members of the public who express the wish for more research on the intersection of connective tissue disorders/joint hypermobility and neurodivergence. For the ADAPT trial, a Lived Experience Advisory Panel (LEAP) was formed via Sussex Partnership NHS Trust to engage patients and public in the design of the study, design of materials for ethical approval, and strategies for recruitment and dissemination (Davies, Csecs et al. 2021 ). Meetings were held regularly with the LEAP group and informed the choice of assessment questionnaires used in this sub-study. LEAP members and other PPI contacts will support the dissemination of findings among interested members of the public in an accessible manner. The authorship team includes individuals with lived experience of hypermobility and neurodivergence. Results Participants Ninety-nine participants were assessed as part of the ADAPT trial. Most participants identified as female (n = 90, 91%), six identified as male (6%), one participant identified as non-binary, one participant identified as gender fluid, and one participant identified as transgender male. The mean age of participants was 38.6 years (SD = 12). At screening, participants who disclosed a formal diagnosis of autism or ADHD were excluded, as per the original trial protocol which was focussed on anxiety alone. Outcome measures – screening thresholds for hypermobility, autism and ADHD Table 1 summarizes outcome scores and number and percentage of participants scoring above threshold for JHS, hEDS, autism, and ADHD. Almost half of participants scored above the clinical cut-off for likely autism (n = 45, Table 1 ). Following further assessment as part of the clinical interview, Clinical Psychologists recommended that 34 participants were referred for full autism assessments (34% of total sample). One-fifth of participants scored above the clinical cut-off for likely ADHD (n = 20). Following further assessment as part of the clinical interview, Clinical Psychologists recommended that 14 participants were referred for full ADHD assessments (14% of total sample). Within these groups, seven participants were recommended for both autism and ADHD assessments (7% of total sample). Almost all participants scored ≥ 2 on the 5-point questionnaire (Hakim and Grahame 2003 ) (n = 90, 99% of all participants who completed this measure) – mean score was 3.9/5 (SD = 0.8). 92 (99%) of those assessed met the historical Brighton Criteria for Joint Hypermobility Syndrome, and 53 (57%) met diagnostic criteria for hEDS. Under new classification 43% had HSD. The average number of connective tissue features across participants (measured using Criterion 2A of the hEDS criteria) was 4.6 (SD = 1.9). Table 1 Outcome scores Outcome measure Available data Mean (SD) Met clinical cut-off (where applicable) RAADS-R total /240 (n = 96) 96 (97%) 73.4 (51.5) 45 (47%) RAADS-R Sensory Motor domain /60 (n = 96) 96 (97%) 22.7 (14.3) 58 (60%) RAADS-R Social Relatedness domain /117 (n = 96) 96 (97%) 33.5 (24.5) 45 (47%) RAADS-R Circumscribed Interests domain /42 (n = 96) 96 (97%) 12.7 (10.9) 35 (37%) RAADS-R Language domain /21 (n = 96) 96 (97%) 5.2 (4.7) 52 (54%) WURS total /100 (n = 98) 98 (99%) 30.4 (18.2) 20 (20%) BPQ – Autonomic reactivity score /108 (n = 98) 98 (99%) 59.3 (19.2) N/A Correlation analyses The number of connective tissue features (hEDS criterion 2A) positively correlated with sensory sensitivities, total autistic and ADHD characteristics, and autonomic hyperactivity. Table 2 summarizes correlation results. Table 2 Correlation results Number of connective tissue features in hEDS criterion 2A Autistic Characteristics: RAADS Total Sensory sensitivities: RAADS sensory motor Total ADHD characteristics: WURS Total Autistic Characteristics: RAADS Total .270** Sensory sensitivities: RAADS sensory motor Total .332** .907*** ADHD characteristics: WURS Total .413*** .436*** .488*** BPQ autonomic reactivity Total .451*** .454*** .557*** .489*** * p < 0.05 ** p < 0.01 *** p < 0.001 Mediation analyses The level of autonomic reactivity significantly mediated the relationship between number of connective tissue features and sensory sensitivities, autism and ADHD characteristics (Fig. 1 ). This indicates that reactivity of the autonomic nervous system is a potential mechanism in the relationship between hereditary connective tissue disorders and the presence of (undiagnosed) neurodivergence. These effects remained significant when correcting for anxiety level (GAD-7). Discussion In this study, we showed that in hypermobile people who experience anxiety and have not previously been diagnosed with a neurodivergent condition, a high proportion are likely autistic or have ADHD. Furthermore the number of variant connective tissue features predicted neurodivergent characteristics, autonomic hyperactivity and was particularly relevant for sensory sensitivities. Our findings support previous research showing the relationship between neurodivergence, anxiety, and variant connective tissue, adding a more detailed account of this constitutional relationship, with autonomic reactivity (e.g. heightened sensitivity to interoceptive stimuli) as a potential mechanism. A recent study from our group further highlights the role of sensory processing (Eccles, Quadt et al. 2024 ) in the relationship between neurodivergence, hypermobility and emotion regulation. Autism and ADHD affect approximately 2% (Dietz, Rose et al. 2020 ) and 5% (Song, Zha et al. 2021 ) of the adult general population. Also, it is traditionally, and incorrectly assumed that autism and ADHD are significantly overrepresented in males. Our data suggests that within the adult general population there is a subgroup of people with joint hypermobility, predominantly female, in whom autism and ADHD are over-represented compared to the general population; almost half (47%) met screening threshold criteria for autism, and 20% for ADHD. At the same time, joint hypermobility as measured by the tools used in this study is found more often in females than males, perhaps accounting for the strong female representation in the sample No comparison group of people without anxiety was included because of the nature of the clinical trial, which purposefully advertised for people with anxiety. We can therefore draw no conclusions on whether the same patterns and relationships we found in our data would be similar in people with less or no anxiety. Additionally, since recruitment started during the first COVID-19 lockdown, participants completed the RAADS-R online, and constrained opportunities to ask questions and probe details about individual items with a practitioner. This might have impacted results, although the clinical assessments via video call likely compensated for this shortcoming. Given our sample was mostly female, the screening tools used in this study may not have captured all likely neurodivergent participants. While RAADS-R is usually considered better at picking up female autism traits than traditional screening measures such as the Autism Quotient (Baron-Cohen, Wheelwright et al. 2001 ), a recent study suggests that the RAADS-R may have limited predictive validity for receiving an autism diagnosis (Jones, Johnson et al. 2021 ). Our results support previous research which indicates common neural pathways underlying joint hypermobility, anxiety, and sensory (including interoceptive) processing. Within the brain, the insular cortex is often termed a ‘hub’ for interoception (Craig 2003 , Critchley 2005 , Quadt, Critchley and Nagai 2022 ), receiving afferent bodily information and contributing to efferent autonomic control (Quigley, Kanoski et al. 2021 ). The region is also implicated in normal affective processing (Critchley, Wiens et al. 2004 , Singer, Critchley and Preuschoff 2009 , Zaki, Davis and Ochsner 2012 , Critchley, Eccles and Garfinkel 2013), and emotional symptomatology in psychiatric disorders (Murphy, Brewer et al. 2017 , Nord, Lawson and Dalgleish 2021 , Tran The, Magistretti and Ansermet 2021 ), notably anxiety (Paulus and Stein 2006 , Gray, Harrison et al. 2007 , Ernst, Boker et al. 2014 ). Furthermore, altered insular function may itself reflect the underlying noisy integration of imprecise interoceptive signals in neurodivergent people (Bonaz, Lane et al. 2021 ), perhaps leading to dysautonomic symptoms. In a sample of hypermobile and non-hypermobile participants, sensitivity to interoceptive signals mediated the relationship between anxiety and hypermobility, where hypermobile participants expressed increased neural reactivity to emotional stimuli in insular cortex (Mallorqui-Bague, Garfinkel et al. 2014 ). While the link between neurodivergence, variant connective tissue, and symptoms of dysautonomia is established (Csecs, Iodice et al. 2022 ), the likely mechanistic role of autonomic reactivity observed in this study opens novel pathways for future research and clinical care. Training interoceptive abilities can reduce anxiety in autistic adults (Quadt, Garfinkel et al. 2021 ), and interoception-based interventions are potentially promising for a wider range of mental health conditions (Heim, Bobou et al. 2023 ). New treatment possibilities may thus emerge to decrease autonomic reactivity by training interoceptive accuracy and thereby reducing noisy interoceptive signaling, which likely underlies heightened autonomic reactivity. Our findings emphasize the need for transdiagnostic screening practices to detect co-occurring neurodivergence and variant connective tissue and to pay particular attention to the role of sensory hypo and hyper-sensitivites. Integrated care for people with both conditions and improved education and awareness among healthcare professionals is needed to provide tailored care for a hitherto neglected population. It was beyond the scope of our study to assess whether participants screening positively for autism and ADHD traits received a diagnosis subsequently. A follow-up study could remedy this and help determine the accuracy of our screening tools. However, given waiting lists in the UK are currently long, and diagnoses are not accessible for many individuals, novel screening instruments that are validated in diverse samples perhaps represents a more realistic strategic goal. Our study highlights the need for research to determine the precise relationships between neurodivergence, variant connective tissue, and autonomic dysfunction. A focus on sensory processing and interoception may particularly offer insight into these relationships and reveal targets for intervention. Declarations Funding Funding for this study came from an MQ Transforming Mental Health and Versus Arthritis Fellowship to JAE (MQF 17/19). Competing interests No competing interests Data Sharing Anonymised datasets and associated material will be available on reasonable request to the corresponding author. Ethical Approval Ethical approval was obtained from London – Bloomsbury Research Ethics Committee on 4 January 2019 (reference: 18/LO/1920, IRAS project ID: 248326). Written, informed consent to participate was obtained from all participants. Author Contribution JAE conceived of and designed this study and acquired funding. GS supported recruitment and set-up of the study. JC and GD collected data. JC and LQ conducted analyses with oversight from JAE. AJH and HC advised on analyses, conceptualisation and the manuscript. JC drafted the initial manuscript. LQ and JAE drafted the final manuscript. All authors approved the final manuscript. Data Availability Anonymised datasets and associated material will be available on reasonable request to the corresponding author. References Asherson, P. (2020). 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Hamonet, C., A. Gompel, Y. Raffray, J. D. Zeitoun, M. Delarue, E. Vlamynck, R. Haidar and G. Mazaltarine (2014). "Les multiples douleurs du syndrome d’Ehlers-Danlos. Description et proposition d’un protocole thérapeutique." Douleurs : Evaluation - Diagnostic - Traitement 15 (6): 264-277. Hayes, A. F. (2017). Introduction to mediation, moderation, and conditional process analysis: A regression-based approach , Guilford publications. Heim, N., M. Bobou, M. Tanzer, P. M. Jenkinson, C. Steinert and A. Fotopoulou (2023). "Psychological interventions for interoception in mental health disorders: A systematic review of randomized‐controlled trials." Psychiatry and Clinical Neurosciences 77 (10): 530-540. Hirvikoski, T., E. Mittendorfer-Rutz, M. Boman, H. Larsson, P. Lichtenstein and S. Bölte (2016). "Premature mortality in autism spectrum disorder." British Journal of Psychiatry 208 (3): 232-238. Hugon-Rodin, J., G. Lebègue, S. Becourt, C. Hamonet and A. Gompel (2016). "Gynecologic symptoms and the influence on reproductive life in 386 women with hypermobility type ehlers-danlos syndrome: a cohort study." Orphanet Journal of Rare Diseases 11 (1). Jones, S. L., M. Johnson, B. Alty and M. Adamou (2021). "The Effectiveness of RAADS-R as a Screening Tool for Adult ASD Populations." Autism Research and Treatment 2021 : 1-6. Malfait, F., C. Francomano, P. Byers, J. Belmont, B. Berglund, J. Black, L. Bloom, J. M. Bowen, A. F. Brady, N. P. Burrows, M. Castori, H. Cohen, M. Colombi, S. Demirdas, J. De Backer, A. De Paepe, S. Fournel-Gigleux, M. Frank, N. Ghali, C. Giunta, R. Grahame, A. Hakim, X. Jeunemaitre, D. Johnson, B. Juul-Kristensen, I. Kapferer-Seebacher, H. Kazkaz, T. Kosho, M. E. Lavallee, H. Levy, R. Mendoza-Londono, M. Pepin, F. M. Pope, E. Reinstein, L. Robert, M. Rohrbach, L. Sanders, G. J. Sobey, T. Van Damme, A. Vandersteen, C. van Mourik, N. Voermans, N. Wheeldon, J. Zschocke and B. Tinkle (2017). "The 2017 international classification of the Ehlers-Danlos syndromes." Am J Med Genet C Semin Med Genet 175 (1): 8-26. Mallorqui-Bague, N., S. N. Garfinkel, M. Engels, J. A. Eccles, G. Pailhez, A. Bulbena and H. D. Critchley (2014). "Neuroimaging and psychophysiological investigation of the link between anxiety, enhanced affective reactivity and interoception in people with joint hypermobility." Front Psychol 5 : 1162. Mulvey, M. R., G. J. Macfarlane, M. Beasley, D. P. Symmons, K. Lovell, P. Keeley, S. Woby and J. McBeth (2013). "Modest Association of Joint Hypermobility With Disabling and Limiting Musculoskeletal Pain: Results From a Large‐Scale General Population–Based Survey." Arthritis care & research 65 (8): 1325-1333. Murphy, J., R. Brewer, C. Catmur and G. Bird (2017). "Interoception and psychopathology: A developmental neuroscience perspective." Dev Cogn Neurosci 23 : 45-56. NICE. (2021). "Autism spectrum disorder in adults: diagnosis and management (Clinical guideline [CG142])." from https://www.nice.org.uk/guidance/CG142/chapter/recommendations. Nord, C. L., R. P. Lawson and T. Dalgleish (2021). "Disrupted Dorsal Mid-Insula Activation During Interoception Across Psychiatric Disorders." American Journal of Psychiatry 178 (8): 761-770. Nyrenius, J., J. Eberhard, M. Ghaziuddin, C. Gillberg and E. Billstedt (2022). "Prevalence of Autism Spectrum Disorders in Adult Outpatient Psychiatry." J Autism Dev Disord 52 (9): 3769-3779. Paulus, M. P. and M. B. Stein (2006). "An insular view of anxiety." Biol Psychiatry 60 (4): 383-387. Pezaro, S., G. Pearce and E. Reinhold (2018). "Hypermobile Ehlers-Danlos Syndrome during pregnancy, birth and beyond." British Journal of Midwifery 26 (4): 217-223. Porges, S. (1993). "Body perception questionnaire." Laboratory of Developmental Assessment, University of Maryland . Proff, I., G. L. Williams, L. Quadt and S. N. Garfinkel (2021). "Sensory processing in autism across exteroceptive and interoceptive domains." Psychology & Neuroscience . Quadt, L., H. Critchley and Y. Nagai (2022). "Cognition, emotion, and the central autonomic network." Autonomic Neuroscience 238 : 102948. Quadt, L., S. N. Garfinkel, J. S. Mulcahy, D. E. O. Larsson, M. Silva, A.-M. Jones, C. Strauss and H. D. Critchley (2021). "Interoceptive training to target anxiety in autistic adults (ADIE): A single-center, superiority randomized controlled trial." EClinicalMedicine 39 : 101042. Quigley, K. S., S. Kanoski, W. M. Grill, L. F. Barrett and M. Tsakiris (2021). "Functions of Interoception: From Energy Regulation to Experience of the Self." Trends in Neurosciences 44 (1): 29-38. Ritvo, R. A., E. R. Ritvo, D. Guthrie, M. J. Ritvo, D. H. Hufnagel, W. McMahon, B. Tonge, D. Mataix-Cols, A. Jassi, T. Attwood and J. Eloff (2011). "The Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R): a scale to assist the diagnosis of Autism Spectrum Disorder in adults: an international validation study." J Autism Dev Disord 41 (8): 1076-1089. Sharp, H. E. C., H. D. Critchley and J. A. Eccles (2021). "Connecting brain and body: transdiagnostic relevance of connective tissue variants to neuropsychiatric symptom expression." World Journal of Psychiatry 11 (10): 805. Shaw, S. C. K., M. Doherty, S. Mccowan and J. A. Eccles (2022). "Towards a Neurodiversity-Affirmative Approach for an Over-Represented and Under-Recognised Population: Autistic Adults in Outpatient Psychiatry." Journal of Autism and Developmental Disorders 52 (9): 4200-4201. Shetreat-Klein, M., S. Shinnar and I. Rapin (2014). "Abnormalities of joint mobility and gait in children with autism spectrum disorders." Brain and Development 36 (2): 91-96. Shiari, R., F. Saeidifard and G. Zahed (2013). "Evaluation of the Prevalence of Joint Laxity in Children with Attention Deficit/Hyperactivity Disorder." Annals of Paediatric Rheumatology 2 (2): 78. Singer, T., H. D. Critchley and K. Preuschoff (2009). "A common role of insula in feelings, empathy and uncertainty." Trends Cogn Sci 13 (8): 334-340. Sinibaldi, L., G. Ursini and M. Castori (2015). "Psychopathological manifestations of joint hypermobility and joint hypermobility syndrome/ Ehlers-Danlos syndrome, hypermobility type:The link between connective tissue and psychological distress revised." American Journal of Medical Genetics Part C: Seminars in Medical Genetics 169 (1): 97-106. Song, P., M. Zha, Q. Yang, Y. Zhang, X. Li and I. Rudan (2021). "The prevalence of adult attention-deficit hyperactivity disorder: A global systematic review and meta-analysis." J Glob Health 11 : 04009. Tran The, J., P. J. Magistretti and F. Ansermet (2021). "Interoception Disorder and Insular Cortex Abnormalities in Schizophrenia: A New Perspective Between Psychoanalysis and Neuroscience." Frontiers in Psychology 12 . Voermans, N. C. and H. Knoop (2011). "Both pain and fatigue are important possible determinants of disability in patients with the Ehlers-Danlos syndrome hypermobility type." Disability and rehabilitation 33 (8): 706-707. Ward, M. F., P. H. Wender and F. W. Reimherr (1993). "The Wender Utah Rating Scale: an aid in the retrospective diagnosis of childhood attention deficit hyperactivity disorder." Am J Psychiatry 150 (6): 885-890. Zaki, J., J. I. Davis and K. N. Ochsner (2012). "Overlapping activity in anterior insula during interoception and emotional experience." Neuroimage 62 (1): 493-499. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5563877","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":491219141,"identity":"a5097f2a-bb0b-456c-a077-c00cd3c2c98f","order_by":0,"name":"Jenny Csecs","email":"","orcid":"","institution":"Brighton and Sussex Medical School","correspondingAuthor":false,"prefix":"","firstName":"Jenny","middleName":"","lastName":"Csecs","suffix":""},{"id":491219142,"identity":"f2a5f3bd-4513-44f5-bdd8-b946fc2af754","order_by":1,"name":"Lisa Quadt","email":"","orcid":"","institution":"Brighton and Sussex Medical School","correspondingAuthor":false,"prefix":"","firstName":"Lisa","middleName":"","lastName":"Quadt","suffix":""},{"id":491219143,"identity":"c6320ca0-1d28-4ed6-bef1-ec50843881ae","order_by":2,"name":"Georgia Savage","email":"","orcid":"","institution":"Brighton and Sussex Medical School","correspondingAuthor":false,"prefix":"","firstName":"Georgia","middleName":"","lastName":"Savage","suffix":""},{"id":491219144,"identity":"686b601f-c20b-4638-a534-532ae0eb2f32","order_by":3,"name":"Geoff Davies","email":"","orcid":"","institution":"Brighton and Sussex Medical School","correspondingAuthor":false,"prefix":"","firstName":"Geoff","middleName":"","lastName":"Davies","suffix":""},{"id":491219145,"identity":"201b22d9-df21-47b2-b036-ac3fe333f378","order_by":4,"name":"Parashar Ramanuj","email":"","orcid":"","institution":"Royal National Orthopaedic Hospital","correspondingAuthor":false,"prefix":"","firstName":"Parashar","middleName":"","lastName":"Ramanuj","suffix":""},{"id":491219146,"identity":"94f3a842-55aa-4dad-a55b-6cd03cd03c98","order_by":5,"name":"Alan J Hakim","email":"","orcid":"","institution":"Penn State University","correspondingAuthor":false,"prefix":"","firstName":"Alan","middleName":"J","lastName":"Hakim","suffix":""},{"id":491219147,"identity":"962c501e-c46a-4785-8558-e59b0a8cb9e3","order_by":6,"name":"Hugo D Critchley","email":"","orcid":"","institution":"Brighton and Sussex Medical School","correspondingAuthor":false,"prefix":"","firstName":"Hugo","middleName":"D","lastName":"Critchley","suffix":""},{"id":491219148,"identity":"c2c9ceac-065d-4415-92e0-8168f23efb01","order_by":7,"name":"Jessica A Eccles","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAz0lEQVRIiWNgGAWjYBAC9gb+BwwMBQwM/BJwMTb8WhgbeICkAQOD5AyStRjcIEEL44cfBjb2xrfbn278wWAnzyCRlkBAC/9hyR6DtMRtd86Y3eZhSDZskEg7QMgWNmYGg8MJZjdy2G4zMDAnMEikNxCj5b+98Yz0Zzd/MNQT1iII0XKAcYME0CIehsNALQQcJs3Mwwz0S3LiDLBfDI4btvE8S8CrhY+9/+GHHxV29vyz24EOq6iW52dPM8CrhYEZhWdAMFZGwSgYBaNgFBADANJzPJ0ITN/WAAAAAElFTkSuQmCC","orcid":"","institution":"Brighton and Sussex Medical School","correspondingAuthor":true,"prefix":"","firstName":"Jessica","middleName":"A","lastName":"Eccles","suffix":""}],"badges":[],"createdAt":"2024-12-02 10:53:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5563877/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5563877/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87889011,"identity":"3466b51d-39d0-4b32-95be-6dbfe683c89e","added_by":"auto","created_at":"2025-07-30 06:03:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":165599,"visible":true,"origin":"","legend":"\u003cp\u003eMediation Analyses. Figure 1A shows that autonomic reactivity mediates the relationship between number of connective tissue features and scores on autistic characteristics (RAADS total). Figure 1B shows autonomic reactivity mediates the relationship between number of connective tissue features and RAADS sensory motor sub-scores. Figure 1C shows autonomic reactivity mediates the relationship between number of connective tissue features and Wender-Utah Rating Scale scores as an index of ADHD traits.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5563877/v1/b1fe7de072912e269ec250bb.png"},{"id":87890718,"identity":"92954ca1-2828-4bef-a0c7-83ee7d2369b5","added_by":"auto","created_at":"2025-07-30 06:27:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1025371,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5563877/v1/43a4f670-f34c-4c5d-b1e1-149635b15788.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Beyond bendy joints: number of variant connective tissue features predicts neurodivergent characteristics in hypermobile individuals with anxiety","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeurodivergence (e.g., autism, attention deficit hyperactivity disorder (ADHD)) frequently co-occurs with poor mental and physical health, with potentially devastating consequences for the wellbeing and quality of life of neurodivergent individuals of all ages (Ayres, Parr et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2018\u003c/span\u003e, Asherson \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Neurodivergent individuals have a decreased life expectancy of up to 30 years (Hirvikoski, Mittendorfer-Rutz et al. \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), and experience substantial barriers to effective healthcare (Doherty, Neilson et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Insight into factors that contribute to the poor health status of neurodivergent people is therefore much needed.\u003c/p\u003e\u003cp\u003eOne potential factor is the overrepresentation of hereditary connective tissue disorders in this population (Doğan, Taner and Evcik \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2011\u003c/span\u003e, Cederlöf, Larsson et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2016\u003c/span\u003e, Casanova, Baeza-Velasco et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Variant connective tissue, often expressed as joint hypermobility, may be present in approximately 20% of the general population (Mulvey, Macfarlane et al. \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2013\u003c/span\u003e), and in up to 51% of the neurodivergent population (Csecs, Iodice et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). When joint hypermobility is experienced in combination with medical symptoms a diagnosis of hypermobility spectrum disorder (HSD) (previously known as joint hypermobility syndrome (JHS)) or Ehlers-Danlos Syndrome (EDS) (of which hypermobile EDS (hEDS) is by far the most common) may be present (Malfait, Francomano et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2017\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eA population-based matched cohort study (nationwide registry) in Sweden (n = 1771), showed that individuals with EDS are 7.4 times more likely to be autistic than a comparison group, and 5.6 times more likely to have an ADHD diagnosis than those without EDS (Cederlöf, Larsson et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Moreover, autistic children have a greater frequency of presence of generalised joint hypermobility compared to a matched group of non-autistic children (Shetreat-Klein, Shinnar and Rapin \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) and the frequency of presence of generalised joint hypermobility in children with ADHD (n = 86) is 74% compared to 13% of a comparison group (Shiari, Saeidifard and Zahed \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e2013\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eVariant connective tissue often underlies poor physical and mental health, including chronic pain and fatigue (Voermans and Knoop \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e2011\u003c/span\u003e, Mulvey, Macfarlane et al. \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2013\u003c/span\u003e, Hakim, De Wandele et al. \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2017\u003c/span\u003e), gastrointestinal difficulties (Fikree, Chelimsky et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2017\u003c/span\u003e), gynaecological and obstetric problems (Hugon-Rodin, Lebègue et al. \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2016\u003c/span\u003e, Pezaro, Pearce and Reinhold \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) and psychological health difficulties, particularly anxiety (Cederlöf, Larsson et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2016\u003c/span\u003e, Bulbena, Baeza-Velasco et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2017\u003c/span\u003e, Sharp, Critchley and Eccles \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eVariant connective tissue also affects the function of the autonomic nervous system, and has been shown to link neurodivergence and dysautonomia mechanistically (Csecs, Iodice et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Neural interactions that support autonomic regulation include homeostatic reflexes and allostatic control, which are both tightly coupled to viscerosensory feedback signals from internal bodily organs; i.e., interoception (Quadt, Critchley and Nagai \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). A hallmark of neurodivergence is a difference in sensory processing, and this includes interoceptive differences (Proff, Williams et al. \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Joint hypermobility is also associated with differences in sensory processing, which include paraesthesia, hyperaesthesia, hyperacusis and hyperosmia (Hamonet, Gompel et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2014\u003c/span\u003e, Colombi, Dordoni et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2015\u003c/span\u003e, Baeza-Velasco, Grahame and Bravo \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Interoception therefore offers a window into the link between autonomic dysregulation, neurodivergence and variant connective tissue, where autonomic reactivity may be conceptualized as heightened sensitivity to interoceptive signals. While associations are apparent in the aforementioned research and case studies (Sinibaldi, Ursini and Castori \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2015\u003c/span\u003e), the relationship between joint hypermobility, autonomic and interoceptive dysfunction, and neurodivergence requires further investigation and understanding (Bulbena, Baeza-Velasco et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn the current study, we used screening data from a sample of potential participants for a clinical trial of an interoceptive therapy for people with joint hypermobility and anxiety (Davies, Csecs et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). None of the participants had formal diagnoses of neurodivergent conditions. We aimed, first; to estimate the frequency of autism and ADHD by establishing in this cohort who scored above threshold for screening criteria for these neurodivergent conditions and, second; to test whether autonomic reactivity was a potential mechanistic factor in the relationship between variant connective tissue and neurodivergence.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eStudy design and participants\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis study used screening data gathered during the assessment phase of the Altering Dynamics of Autonomic Processing Therapy (ADAPT) trial (ISRCTN17018615), which was a randomised controlled trial comparing two non-drug therapies for anxiety in joint hypermobility (Davies, Csecs et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). We assessed 99 adults (age ≥ 18 years) interested in taking part in the ADAPT trial. Initial inclusion criteria were a score of ≥ 2 points on a five-part joint hypermobility questionnaire (Hakim and Grahame \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2003\u003c/span\u003e) at screening, or having a hypermobility related diagnosis: Joint Hypermobility Syndrome (JHS), Hypermobility Spectrum Disorder (HSD), Ehlers-Danlos Syndrome (EDS), and having anxiety (scored ≥ 16 on the Beck Anxiety Inventory at screening). Exclusion criteria for the ADAPT trial included major psychiatric disorders (except co-occurring depression, as it is commonly seen in anxiety) and previously confirmed diagnosis of a neurodevelopmental condition (e.g., autism or ADHD). For this sub-study, we used data from the full screening interview. All inclusion and exclusion criteria for the ADAPT trial are available in the published protocol (Davies, Csecs et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eProcedure\u003c/b\u003e\u003c/p\u003e\u003cp\u003eParticipants were initially screened for eligibility via phone by a research assistant. If they met initial criteria, they were referred to a research clinical psychologist to obtain informed consent and conduct the full screening interview, alongside the research assistant. Due to COVID-19 restrictions, this assessment was conducted by completing questionnaires online via Qualtrics and meeting researchers over video-conferencing software. See published protocol (Davies, Csecs et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) for complete list of assessment measures.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eVariant connective tissue\u003c/b\u003e\u003c/p\u003e\u003cp\u003eVariant connective tissue was assessed using the 5-part questionnaire (5PQ) for joint hypermobility, (Hakim and Grahame \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2003\u003c/span\u003e) (scores of ≥ 2), the Brighton Criteria for JHS, and the 2017 hEDS criteria (Castori, Tinkle et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2017\u003c/span\u003e) – see Supplementary Table\u0026nbsp;1 for full diagnostic criteria. The hEDS diagnostic checklist has 3 criteria which need to be met: Criterion 1 – Generalised Joint Hypermobility (i.e. Beighton score ≥ 5 in pubertal men and women to age 50 or ≥ 4 if over age 50), Criterion 2 – two or more features (A, B or C) must be present (i.e. ≥ 5/12 of feature A, e.g. ‘unusually soft or velvety skin’; feature B: positive family history of hEDS; ≥ 1 of feature C: 3 items e.g. ‘chronic, widespread pain for ≥ 3 months) and Criterion 3 – all 3 prerequisites must be met (e.g. ‘absence of unusual skin fragility, which should prompt consideration of other types of EDS’). It was not possible to determine the last item of Criterion 2A (aortic root dilatation with Z-score \u0026gt; + 2) as participants did not undergo echocardiography as part of the study protocol (Eccles, Thompson et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). The hypermobility assessments were administered as clinical examinations by a trained clinician/researcher. hEDS Criterion 2A items were used to quantify the number of connective tissue features (Eccles, Thompson et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003eAutism\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R, (Ritvo, Ritvo et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2011\u003c/span\u003e), (endorsed by NICE Clinical guideline [CG142] (NICE \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)) was used in combination with a clinical interview, as part of a screening process for autism; this involved assessing autistic characteristics across 4 domains: Social Relatedness, Circumscribed Interests, Language and Sensory Motor. It consists of 80 self-report statements (e.g. ‘I often use words and phrases from movies and television in conversations’), with four options to choose from per statement (i.e. ‘true now and when I was young’, ‘true now only’, ‘true only when I was younger than 16’ and ‘never true’). Scores range from 0-240 and the threshold of likely autism is ≥ 65 (sensitivity = 97%, specificity = 100%) (Ritvo, Ritvo et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). The study’s patient and public involvement group considered the RAADS-R to be a more acceptable screening tool for a sample that was likely to include mostly people who identified as female. Scores from the RAADS-R were subsequently used in conjunction with the clinical interview with Clinical Psychologists as part of the trial eligibility assessment; autistic characteristics which warranted further investigation (i.e. total RAADS-R score ≥ 65) (Nyrenius, Eberhard et al. \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2022\u003c/span\u003e, Shaw, Doherty et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) were explored and, if appropriate, participants were recommended to be referred for full autism assessments.\u003c/p\u003e\u003cp\u003e\u003cb\u003eADHD\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe Wender Utah Rating Scale (WURS, designed for adults to rate their own childhood behaviour; (Ward, Wender and Reimherr \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e1993\u003c/span\u003e) was used to assess ADHD characteristics. This was combined with a clinical interview with a Clinical Psychologist, as part of our screening process for ADHD. The WURS has 61 self-report items which are rated in relation to presence and severity during childhood (e.g. ‘acting without thinking, impulsive’ is rated on a 5-point Likert scale from ‘0 = not at all or very slightly’ to ‘4 = very much’), 25 of the items are totalled to produce an overall score. Scoring 46/100 or more is suggestive of ADHD (sensitivity = 86%, specificity = 99%, (Ward, Wender and Reimherr \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e1993\u003c/span\u003e)), and further explored in the clinical interview. Where appropriate, participants were recommended to be referred for full ADHD assessments.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAutonomic reactivity\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe Body Perception Questionnaire (BPQ (Porges \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e1993\u003c/span\u003e)) subscale ‘Autonomic Nervous System Reactivity’ was used as a self-report measure for autonomic reactivity. The scale contains 27 items of sensations related to autonomic nervous system reactivity, e.g., “My heart often beats irregularly”, that are rated in terms of frequency on a five-point scale ranging from ‘never’ to ‘always’. Scores range between 27 and 108.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStatistical Analyses\u003c/b\u003e\u003c/p\u003e\u003cp\u003eParticipants were assessed as to whether they met criteria for generalised joint hypermobility, JHS, and hEDS (including number of connective tissue features in Criterion 2A (Castori, Tinkle et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2017\u003c/span\u003e)). Total scores from the RAADS-R (including from the 4 domains and as an overall score) and from the relevant 25 items on the WURS were evaluated against the clinical cut-offs. The ‘Autonomic Reactivity’ subscale was also totalled as part of the BPQ.\u003c/p\u003e\u003cp\u003eWe ran separate bivariate correlation analyses of differential relationships between number of connective tissue features (hEDS Criterion 2A), RAADS total and RAADS sensory motor scores, WURS total scores, and autonomic reactivity. Missing data were handled by excluding cases pairwise\u003c/p\u003e\u003cp\u003eTo examine potential causal associations between neurodivergence, connective tissue features, and autonomic reactivity, we performed separate mediation analyses using PROCESS macro v3.5 for SPSS by Hayes (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). The 95% bootstrapped confidence interval for the indirect effect was based on 5,000 samples and considered significant if the bootstrapped confidence intervals do not cross zero. We ran two separate mediation analyses with RAADS sensory motor scores and WURS scores as outcome variables. In both models, the predictor variable was number of connective tissue features, and the mediator variable was autonomic reactivity scores. In an additional analysis anxiety level was used as a co-variate.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMissing data\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAll participants self-reported they had hypermobility and data were available for the RAADS (n = 96, 97%), WURS (n = 98, 99%) and BPQ (n = 98, 99%) as part of screening before the full clinical assessment. The majority of the sample completed full hypermobility assessments as part of the clinical assessment; a small number of participants did not complete the full hypermobility assessments due to being ineligible at screening before further assessment (i.e., Beck Anxiety Inventory score \u0026lt; 16, \u003cem\u003en\u003c/em\u003e = 6). Given the low numbers of missing data, we used listwise exclusion.\u003c/p\u003e\u003cp\u003e\u003cb\u003ePatient and Public Involvement\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis specific sub-study of the ADAPT trial was motivated by our ongoing Patient and Public Involvement (PPI) work. We regularly correspond with patients and members of the public who express the wish for more research on the intersection of connective tissue disorders/joint hypermobility and neurodivergence. For the ADAPT trial, a Lived Experience Advisory Panel (LEAP) was formed via Sussex Partnership NHS Trust to engage patients and public in the design of the study, design of materials for ethical approval, and strategies for recruitment and dissemination (Davies, Csecs et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Meetings were held regularly with the LEAP group and informed the choice of assessment questionnaires used in this sub-study. LEAP members and other PPI contacts will support the dissemination of findings among interested members of the public in an accessible manner. The authorship team includes individuals with lived experience of hypermobility and neurodivergence.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eParticipants\u003c/b\u003e\u003c/p\u003e\u003cp\u003eNinety-nine participants were assessed as part of the ADAPT trial. Most participants identified as female (n\u0026thinsp;=\u0026thinsp;90, 91%), six identified as male (6%), one participant identified as non-binary, one participant identified as gender fluid, and one participant identified as transgender male. The mean age of participants was 38.6 years (SD\u0026thinsp;=\u0026thinsp;12). At screening, participants who disclosed a formal diagnosis of autism or ADHD were excluded, as per the original trial protocol which was focussed on anxiety alone.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcome measures \u0026ndash; screening thresholds for hypermobility, autism and ADHD\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes outcome scores and number and percentage of participants scoring above threshold for JHS, hEDS, autism, and ADHD. Almost half of participants scored above the clinical cut-off for likely autism (n\u0026thinsp;=\u0026thinsp;45, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Following further assessment as part of the clinical interview, Clinical Psychologists recommended that 34 participants were referred for full autism assessments (34% of total sample). One-fifth of participants scored above the clinical cut-off for likely ADHD (n\u0026thinsp;=\u0026thinsp;20). Following further assessment as part of the clinical interview, Clinical Psychologists recommended that 14 participants were referred for full ADHD assessments (14% of total sample). Within these groups, seven participants were recommended for both autism and ADHD assessments (7% of total sample).\u003c/p\u003e\u003cp\u003eAlmost all participants scored\u0026thinsp;\u0026ge;\u0026thinsp;2 on the 5-point questionnaire (Hakim and Grahame \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2003\u003c/span\u003e) (n\u0026thinsp;=\u0026thinsp;90, 99% of all participants who completed this measure) \u0026ndash; mean score was 3.9/5 (SD\u0026thinsp;=\u0026thinsp;0.8). 92 (99%) of those assessed met the historical Brighton Criteria for Joint Hypermobility Syndrome, and 53 (57%) met diagnostic criteria for hEDS. Under new classification 43% had HSD. The average number of connective tissue features across participants (measured using Criterion 2A of the hEDS criteria) was 4.6 (SD\u0026thinsp;=\u0026thinsp;1.9).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eOutcome scores\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutcome measure\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAvailable data\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMean (SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMet clinical cut-off (where applicable)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRAADS-R total /240 (n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96 (97%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e73.4 (51.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e45 (47%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRAADS-R Sensory Motor domain /60 (n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96 (97%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e22.7 (14.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e58 (60%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRAADS-R Social Relatedness domain /117 (n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96 (97%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e33.5 (24.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e45 (47%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRAADS-R Circumscribed Interests domain /42 (n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96 (97%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12.7 (10.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e35 (37%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRAADS-R Language domain /21 (n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96 (97%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.2 (4.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e52 (54%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWURS total /100 (n\u0026thinsp;=\u0026thinsp;98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98 (99%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e30.4 (18.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20 (20%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBPQ \u0026ndash; Autonomic reactivity score /108 (n\u0026thinsp;=\u0026thinsp;98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98 (99%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e59.3 (19.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eN/A\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eCorrelation analyses\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe number of connective tissue features (hEDS criterion 2A) positively correlated with sensory sensitivities, total autistic and ADHD characteristics, and autonomic hyperactivity. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes correlation results.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCorrelation results\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of connective tissue features in hEDS criterion 2A\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAutistic Characteristics: RAADS Total\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSensory sensitivities: RAADS sensory motor Total\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eADHD characteristics: WURS Total\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAutistic Characteristics: RAADS Total\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e.270**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSensory sensitivities: RAADS sensory motor Total\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e.332**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e.907***\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eADHD characteristics: WURS Total\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e.413***\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e.436***\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.488***\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBPQ autonomic reactivity Total\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e.451***\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e.454***\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.557***\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e.489***\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e* p\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e** p\u0026thinsp;\u0026lt;\u0026thinsp;0.01\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e*** p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eMediation analyses\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe level of autonomic reactivity significantly mediated the relationship between number of connective tissue features and sensory sensitivities, autism and ADHD characteristics (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This indicates that reactivity of the autonomic nervous system is a potential mechanism in the relationship between hereditary connective tissue disorders and the presence of (undiagnosed) neurodivergence. These effects remained significant when correcting for anxiety level (GAD-7).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we showed that in hypermobile people who experience anxiety and have not previously been diagnosed with a neurodivergent condition, a high proportion are likely autistic or have ADHD. Furthermore the number of variant connective tissue features predicted neurodivergent characteristics, autonomic hyperactivity and was particularly relevant for sensory sensitivities. Our findings support previous research showing the relationship between neurodivergence, anxiety, and variant connective tissue, adding a more detailed account of this constitutional relationship, with autonomic reactivity (e.g. heightened sensitivity to interoceptive stimuli) as a potential mechanism. A recent study from our group further highlights the role of sensory processing (Eccles, Quadt et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) in the relationship between neurodivergence, hypermobility and emotion regulation.\u003c/p\u003e\u003cp\u003eAutism and ADHD affect approximately 2% (Dietz, Rose et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2020\u003c/span\u003e) and 5% (Song, Zha et al. \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) of the adult general population. Also, it is traditionally, and incorrectly assumed that autism and ADHD are significantly overrepresented in males. Our data suggests that within the adult general population there is a subgroup of people with joint hypermobility, predominantly female, in whom autism and ADHD are over-represented compared to the general population; almost half (47%) met screening threshold criteria for autism, and 20% for ADHD. At the same time, joint hypermobility as measured by the tools used in this study is found more often in females than males, perhaps accounting for the strong female representation in the sample\u003c/p\u003e\u003cp\u003eNo comparison group of people without anxiety was included because of the nature of the clinical trial, which purposefully advertised for people with anxiety. We can therefore draw no conclusions on whether the same patterns and relationships we found in our data would be similar in people with less or no anxiety. Additionally, since recruitment started during the first COVID-19 lockdown, participants completed the RAADS-R online, and constrained opportunities to ask questions and probe details about individual items with a practitioner. This might have impacted results, although the clinical assessments via video call likely compensated for this shortcoming.\u003c/p\u003e\u003cp\u003eGiven our sample was mostly female, the screening tools used in this study may not have captured all likely neurodivergent participants. While RAADS-R is usually considered better at picking up female autism traits than traditional screening measures such as the Autism Quotient (Baron-Cohen, Wheelwright et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2001\u003c/span\u003e), a recent study suggests that the RAADS-R may have limited predictive validity for receiving an autism diagnosis (Jones, Johnson et al. \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eOur results support previous research which indicates common neural pathways underlying joint hypermobility, anxiety, and sensory (including interoceptive) processing. Within the brain, the insular cortex is often termed a \u0026lsquo;hub\u0026rsquo; for interoception (Craig \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2003\u003c/span\u003e, Critchley \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2005\u003c/span\u003e, Quadt, Critchley and Nagai \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), receiving afferent bodily information and contributing to efferent autonomic control (Quigley, Kanoski et al. \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). The region is also implicated in normal affective processing (Critchley, Wiens et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2004\u003c/span\u003e, Singer, Critchley and Preuschoff \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2009\u003c/span\u003e, Zaki, Davis and Ochsner \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2012\u003c/span\u003e, Critchley, Eccles and Garfinkel 2013), and emotional symptomatology in psychiatric disorders (Murphy, Brewer et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2017\u003c/span\u003e, Nord, Lawson and Dalgleish \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2021\u003c/span\u003e, Tran The, Magistretti and Ansermet \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), notably anxiety (Paulus and Stein \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2006\u003c/span\u003e, Gray, Harrison et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2007\u003c/span\u003e, Ernst, Boker et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Furthermore, altered insular function may itself reflect the underlying noisy integration of imprecise interoceptive signals in neurodivergent people (Bonaz, Lane et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), perhaps leading to dysautonomic symptoms. In a sample of hypermobile and non-hypermobile participants, sensitivity to interoceptive signals mediated the relationship between anxiety and hypermobility, where hypermobile participants expressed increased neural reactivity to emotional stimuli in insular cortex (Mallorqui-Bague, Garfinkel et al. \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWhile the link between neurodivergence, variant connective tissue, and symptoms of dysautonomia is established (Csecs, Iodice et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), the likely mechanistic role of autonomic reactivity observed in this study opens novel pathways for future research and clinical care. Training interoceptive abilities can reduce anxiety in autistic adults (Quadt, Garfinkel et al. \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), and interoception-based interventions are potentially promising for a wider range of mental health conditions (Heim, Bobou et al. \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). New treatment possibilities may thus emerge to decrease autonomic reactivity by training interoceptive accuracy and thereby reducing noisy interoceptive signaling, which likely underlies heightened autonomic reactivity.\u003c/p\u003e\u003cp\u003eOur findings emphasize the need for transdiagnostic screening practices to detect co-occurring neurodivergence and variant connective tissue and to pay particular attention to the role of sensory hypo and hyper-sensitivites. Integrated care for people with both conditions and improved education and awareness among healthcare professionals is needed to provide tailored care for a hitherto neglected population. It was beyond the scope of our study to assess whether participants screening positively for autism and ADHD traits received a diagnosis subsequently. A follow-up study could remedy this and help determine the accuracy of our screening tools. However, given waiting lists in the UK are currently long, and diagnoses are not accessible for many individuals, novel screening instruments that are validated in diverse samples perhaps represents a more realistic strategic goal.\u003c/p\u003e\u003cp\u003eOur study highlights the need for research to determine the precise relationships between neurodivergence, variant connective tissue, and autonomic dysfunction. A focus on sensory processing and interoception may particularly offer insight into these relationships and reveal targets for intervention.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eFunding for this study came from an MQ Transforming Mental Health and Versus Arthritis Fellowship to JAE (MQF 17/19).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eNo competing interests\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eData Sharing\u003c/h2\u003e\u003cp\u003eAnonymised datasets and associated material will be available on reasonable request to the corresponding author.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eEthical Approval\u003c/h2\u003e\u003cp\u003e Ethical approval was obtained from London \u0026ndash; Bloomsbury Research Ethics Committee on 4 January 2019 (reference: 18/LO/1920, IRAS project ID: 248326). Written, informed consent to participate was obtained from all participants.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJAE conceived of and designed this study and acquired funding. GS supported recruitment and set-up of the study. JC and GD collected data. JC and LQ conducted analyses with oversight from JAE. AJH and HC advised on analyses, conceptualisation and the manuscript. JC drafted the initial manuscript. LQ and JAE drafted the final manuscript. All authors approved the final manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAnonymised datasets and associated material will be available on reasonable request to the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAsherson, P. 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Ochsner (2012). \u0026quot;Overlapping activity in anterior insula during interoception and emotional experience.\u0026quot; \u003cu\u003eNeuroimage\u003c/u\u003e \u003cstrong\u003e62\u003c/strong\u003e(1): 493-499.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-mental-health-research","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"npjmentalhealth","sideBox":"Learn more about [npj Mental Health Research](https://www.nature.com/npjmentalhealth/)","snPcode":"44184","submissionUrl":"https://mts-npjmentalhealth.nature.com/cgi-bin/main.p...","title":"npj Mental Health Research","twitterHandle":"@npjmentalhealth\n","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"npj","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Autism, ADHD, autonomic nervous system, joint hypermobility, Ehlers Danlos Syndrome","lastPublishedDoi":"10.21203/rs.3.rs-5563877/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5563877/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe goal of this study was to determine whether the number of connective tissue features in hypermobility is associated with level of neurodivergent characteristics and establish whether autonomic reactivity is a mechanistic factor in the relationship between variant connective tissue and neurodivergent characteristics. 99 adult participants were assessed for joint hypermobility syndrome/hypermobile Ehlers-Danlos-Syndrome and filled out screening questionnaires for autism and ADHD. 99% of participants met criteria for generalized joint hypermobility, and 57% for hypermobile Ehlers-Danlos-Syndrome. 47% of participants scored above screening threshold for autism and 20% for ADHD. All measures were significantly correlated. Level of autonomic reactivity (as measured by the Body Perception Questionnaire) mediated the relationship between number of connective tissue features and neurodivergence, even after controlling for anxiety level. This shows that autonomic reactivity has a potential mechanistic role in the established link between variant connective tissue and neurodivergence, opening novel pathways for research and clinical care.\u003c/p\u003e","manuscriptTitle":"Beyond bendy joints: number of variant connective tissue features predicts neurodivergent characteristics in hypermobile individuals with anxiety","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-30 06:03:54","doi":"10.21203/rs.3.rs-5563877/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-20T19:24:49+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-13T20:41:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"28476207760673403898407861225820662263","date":"2025-09-23T14:19:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-09T21:46:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"271769728111245540960942752963899313310","date":"2025-08-07T16:20:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-25T09:55:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-21T04:27:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-15T17:10:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Mental Health Research","date":"2024-12-02T10:45:26+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-mental-health-research","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"npjmentalhealth","sideBox":"Learn more about [npj Mental Health Research](https://www.nature.com/npjmentalhealth/)","snPcode":"44184","submissionUrl":"https://mts-npjmentalhealth.nature.com/cgi-bin/main.p...","title":"npj Mental Health Research","twitterHandle":"@npjmentalhealth\n","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"npj","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e2ea561f-682c-4c74-b923-8129be03a14b","owner":[],"postedDate":"July 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":52160689,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Anxiety"},{"id":52160690,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Autism spectrum disorders"},{"id":52160691,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Chronic pain"},{"id":52160692,"name":"Health sciences/Medical research/Translational research"}],"tags":[],"updatedAt":"2026-05-04T16:24:43+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-30 06:03:54","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5563877","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5563877","identity":"rs-5563877","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}