Variant connective tissue (joint hypermobility) and dysautonomia are associated with multimorbidity at the intersection between physical and psychological health.

The symptoms of joint hypermobility extend beyond articular pain. Hypermobile people commonly experience autonomic symptoms (dysautonomia), and anxiety or related psychological issues. We tested whether dysautonomia might mediate the association between hypermobility and anxiety in adults diagnosed with mental health disorders and/or neurodevelopmental conditions (hereon referred to as patients), by quantifying joint hypermobility and symptoms of autonomic dysfunction. Prevalence of generalized joint laxity (hypermobility) in 377 individuals with diagnoses of mental health disorders and/or neurodevelopmental conditions was compared to prevalence recorded in the general population. Autonomic symptom burden was compared between hypermobile and non-hypermobile patients. Mediation analysis explored relationships between hypermobility, autonomic dysfunction, and anxiety. Patient participants had elevated prevalence of generalized joint laxity (38%) compared to the general population rate of 19% (odds ratio: 2.54 [95% confidence interval: 2.05, 3.16]). Hypermobile participants reported significantly more autonomic symptoms. Symptoms of orthostatic intolerance mediated the relationship between hypermobility and diagnosis of an anxiety disorder. Patients with mental health disorders and/or neurodevelopmental conditions have high rates of joint hypermobility. Accompanying autonomic dysfunction mediates the association between joint hypermobility and clinical anxiety status. Increased recognition of this association can enhance mechanistic understanding and improve the management of multimorbidity expressed in physical symptoms and mental health difficulties.

Subjective embodiment during the rubber hand illusion predicts severity of premonitory sensations and tics in Tourette Syndrome.

In Tourette Syndrome, the expression of tics and commonly preceding premonitory sensations is associated with perturbed subjective feelings of self-control and agency. We compared responses to the Rubber Hand Illusion in 23 adults with TS and 22 controls. Both TS and control participants reported equivalent subjective embodiment of the artificial hand: feelings of ownership, location, and agency were greater during synchronous visuo-tactile stimulation, compared to asynchronous. However, individuals with TS did not manifest greater proprioceptive drift, an objective marker of embodiment observed in controls. An 'embodiment prediction error' index of the difference between subjective embodiment and objective proprioceptive drift correlated with severity of premonitory sensations. Feelings of ownership also correlated with premonitory sensation severity, and feelings of agency with tic severity. These findings suggest that subjective bodily ownership, as measured by the rubber hand illusion, contributes to susceptibility to the premonitory sensations that may be a precipitating factor in tics.

Cardiac interoception in patients accessing secondary mental health services: A transdiagnostic study.

BACKGROUND: Abnormalities in the regulation of physiological arousal and interoceptive processing are implicated in the expression and maintenance of specific psychiatric conditions and symptoms. We undertook a cross-sectional characterisation of patients accessing secondary mental health services, recording measures relating to cardiac physiology and interoception, to understand how physiological state and interoceptive ability relate transdiagnostically to affective symptoms. METHODS: Participants were patients (n = 258) and a non-clinical comparison group (n = 67). Clinical diagnoses spanned affective disorders, complex personality presentations and psychoses. We first tested for differences between patient and non-clinical participants in terms of cardiac physiology and interoceptive ability, considering interoceptive tasks and a self-report measure. We then tested for correlations between cardiac and interoceptive measures and affective symptoms. Lastly, we explored group differences across recorded clinical diagnoses. RESULTS: Patients exhibited lower performance accuracy and confidence in heartbeat discrimination and lower heartbeat tracking confidence relative to comparisons. In patients, greater anxiety and depression predicted greater self-reported interoceptive sensibility and a greater mismatch between performance accuracy and sensibility. This effect was not observed in comparison participants. Significant differences between patient groups were observed for heart rate variability (HRV) although post hoc differences were not significant after correction for multiple comparisons. Finally, accuracy in heartbeat tracking was significantly lower in schizophrenia compared to other diagnostic groups. CONCLUSIONS: The multilevel characterisation presented here identified certain physiological and interoceptive differences associated with psychiatric symptoms and diagnoses. The clinical stratification and therapeutic targeting of interoceptive mechanisms is therefore of potential value in treating certain psychiatric conditions.

Brain structure and joint hypermobility: relevance to the expression of psychiatric symptoms.

Joint hypermobility is overrepresented among people with anxiety and can be associated with abnormal autonomic reactivity. We tested for associations between regional cerebral grey matter and hypermobility in 72 healthy volunteers using voxel-based morphometry of structural brain scans. Strikingly, bilateral amygdala volume distinguished those with from those without hypermobility. The hypermobility group scored higher for interoceptive sensitivity yet were not significantly more anxious. Our findings specifically link hypermobility to the structural integrity of a brain centre implicated in normal and abnormal emotions and physiological responses. Our observations endorse hypermobility as a multisystem phenotype and suggest potential mechanisms mediating clinical vulnerability to neuropsychiatric symptoms.

Variant connective tissue (joint hypermobility) and its relevance to depression and anxiety in adolescents: a cohort-based case-control study.

OBJECTIVE: To test whether variant connective tissue structure, as indicated by the presence of joint hypermobility, poses a developmental risk for mood disorders in adolescence. DESIGN: Cohort-based case-control study. SETTING: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were interrogated. PARTICIPANTS: 6105 children of the ALSPAC cohort at age 14 years old, of whom 3803 also were assessed when aged 18 years. MAIN OUTCOME MEASURES: In a risk analysis, we examined the relationship between generalised joint hypermobility (GJH) at age 14 years with psychiatric symptoms at age 18 years. In an association analysis, we examined the relationship between presence of symptomatic joint hypermobility syndrome (JHS) and International Classification of Diseases-10 indication of depression and anxiety (Clinical Interview Schedule Revised (CIS-R), Anxiety Sensitivity Index) at age 18 years. RESULTS: GJH was more common in females (n=856, 28%) compared with males (n=319, 11%; OR: 3.20 (95% CI: 2.78 to 3.68); p<0.001). In males, GJH at age 14 years was associated with depression at 18 years (OR: 2.10 (95% CI: 1.17 to 3.76); p=0.013). An index of basal physiological arousal, elevated resting heart rate, mediated this effect. Across genders, the diagnosis of JHS at age 18 years was associated with the presence of depressive disorder (adjusted OR: 3.53 (95% CI: 1.67 to 7.40); p=0.001), anxiety disorder (adjusted OR: 3.14 (95% CI: 1.52 to 6.46); p=0.002), level of anxiety (B=8.08, t(3278)=3.95; p<0.001) and degree of psychiatric symptomatology (B=5.89, t(3442)=5.50; p<0.001). CONCLUSIONS: Variant collagen, indexed by joint hypermobility, is linked to the emergence of depression and anxiety in adolescence, an effect mediated by autonomic factors in males. Recognition of this association may motivate further evaluation, screening and interventions to mitigate development of psychiatric disorders and improve health outcomes.

The challenges of chronic pain and fatigue.

In this review, we explore the challenges of chronic pain and fatigue in clinical practice. Both pain and fatigue are common, troubling and frequently overlapping symptoms, and we describe both the clinical burden and the 'clinical problem'. We explore commonly associated symptoms and possible pathological associations, including variant connective tissue (joint hypermobility), small fibre neuropathy, mast cell activation, dysregulated inflammatory and interoceptive processes, which may inform treatment targets. We suggest a multidisciplinary management approach.

Connecting brain and body: Transdiagnostic relevance of connective tissue variants to neuropsychiatric symptom expression.

The mind is embodied; thoughts and feelings interact with states of physiological arousal and physical integrity of the body. In this context, there is mounting evidence for an association between psychiatric presentations and the expression variant connective tissue, commonly recognised as joint hypermobility. Joint hypermobility is common, frequently under-recognised, significantly impacts quality of life, and can exist in isolation or as the hallmark of hypermobility spectrum disorders (encompassing joint hypermobility syndrome and hypermobile Ehlers-Danlos syndrome). In this narrative review, we appraise the current evidence linking psychiatric disorders across the lifespan, beginning with the relatively well-established connection with anxiety, to hypermobility. We next consider emerging associations with affective illnesses, eating disorders, alongside less well researched links with personality disorders, substance misuse and psychosis. We then review related findings relevant to neurodevelopmental disorders and stress-sensitive medical conditions. With growing understanding of mind-body interactions, we discuss potential aetiopathogenetic contributions of dysautonomia, aberrant interoceptive processing, immune dysregulation and proprioceptive impairments in the context of psychosocial stressors and genetic predisposition. We examine clinical implications of these evolving findings, calling for increased awareness amongst healthcare professionals of the transdiagnostic nature of hypermobility and related disorders. A role for early screening and detection of hypermobility in those presenting with mental health and somatic symptoms is further highlighted, with a view to facilitate preventative approaches alongside longer-term holistic management strategies. Finally, suggestions are offered for directions of future scientific exploration which may be key to further delineating fundamental mind-body-brain interactions.

Altering Dynamics of Autonomic Processing Therapy (ADAPT) trial: a novel, targeted treatment for reducing anxiety in joint hypermobility.

BACKGROUND: Hypermobility is a poorly recognised and understood musculoskeletal disorder thought to affect around 20% of the population. Hypermobility is associated with reduced physiological and psychological functioning and quality of life and is a known risk factor for the development of an anxiety disorder. To date, no evidence-based, targeted treatment for anxiety in the context of hypermobility exists. The present intervention (ADAPT-Altering Dynamics of Autonomic Processing Therapy) is a novel therapy combining bio-behavioural training with cognitive approaches from clinical health psychology targeting the catastrophisation of internal sensations, with aim to improve autonomic trait prediction error. METHOD: Eighty individuals with diagnosed hypermobility will be recruited and the efficacy of ADAPT to treat anxiety will be compared to an Emotion-Focused Supportive Therapy (EFST) comparator therapy in a randomised controlled trial. The primary treatment target will be post therapy score on the Beck Anxiety Inventory, and secondary outcomes will also be considered in relation to interoception, depression, alexithymia, social and work adjustment, panic symptoms and dissociation. Due to COVID restrictions, the intervention will be moved to online delivery and qualitative assessment of treatment tolerance to online therapy will also be assessed. DISCUSSION: Online delivery of an intervention targeting anxiety would improve the quality of life for those experiencing anxiety disorder and help to reduce the £11.7 billion that anxiety disorders cost the UK economy annually. TRIAL REGISTRATION: World Health Organization ISRCTN17018615 . Registered on 20th February 2019; trial protocol version 2.

Joint Hypermobility Links Neurodivergence to Dysautonomia and Pain.

OBJECTIVES: Autism, attention deficit hyperactivity disorder (ADHD), and tic disorder (Tourette syndrome; TS) are neurodevelopmental conditions that frequently co-occur and impact psychological, social, and emotional processes. Increased likelihood of chronic physical symptoms, including fatigue and pain, are also recognized. The expression of joint hypermobility, reflecting a constitutional variant in connective tissue, predicts susceptibility to psychological symptoms alongside recognized physical symptoms. Here, we tested for increased prevalence of joint hypermobility, autonomic dysfunction, and musculoskeletal symptoms in 109 adults with neurodevelopmental condition diagnoses. METHODS: Rates of generalized joint hypermobility (GJH, henceforth hypermobility) in adults with a formal diagnosis of neurodevelopmental conditions (henceforth neurodivergent group, n = 109) were compared to those in the general population in UK. Levels of orthostatic intolerance and musculoskeletal symptoms were compared to a separate comparison group (n = 57). Age specific cut-offs for GJH were possible to determine in the neurodivergent and comparison group only. RESULTS: The neurodivergent group manifested elevated prevalence of hypermobility (51%) compared to the general population rate of 20% and a comparison population (17.5%). Using a more stringent age specific cut-off, in the neurodivergent group this prevalence was 28.4%, more than double than the comparison group (12.5%). Odds ratio for presence of hypermobility in neurodivergent group, compared to the general population was 4.51 (95% CI 2.17-9.37), with greater odds in females than males. Using age specific cut-off, the odds ratio for GJH in neurodivergent group, compared to the comparison group, was 2.84 (95% CI 1.16-6.94). Neurodivergent participants reported significantly more symptoms of orthostatic intolerance and musculoskeletal skeletal pain than the comparison group. The number of hypermobile joints was found to mediate the relationship between neurodivergence and symptoms of both dysautonomia and pain. CONCLUSIONS: In neurodivergent adults, there is a strong link between the expression of joint hypermobility, dysautonomia, and pain, more so than in the comparison group. Moreover, joint hypermobility mediates the link between neurodivergence and symptoms of dysautonomia and pain. Increased awareness and understanding of this association may enhance the management of core symptoms and allied difficulties in neurodivergent people, including co-occurring physical symptoms, and guide service delivery in the future.

Beyond bones: The relevance of variants of connective tissue (hypermobility) to fibromyalgia, ME/CFS and controversies surrounding diagnostic classification: an observational study.

BACKGROUND: Fibromyalgia and myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) are poorly understood conditions with overlapping symptoms, fuelling debate as to whether they are manifestations of the same spectrum or separate entities. Both are associated with hypermobility, but this remains significantly undiagnosed, despite impact on quality of life. OBJECTIVE: We planned to understand the relevance of hypermobility to symptoms in fibromyalgia and ME/CFS. METHOD: Sixty-three patient participants presented with a confirmed diagnosis of fibromyalgia and/or ME/CFS; 24 participants were healthy controls. Patients were assessed for symptomatic hypermobility. RESULTS: Evaluations showed exceptional overlap in patients between fibromyalgia and ME/CFS, plus 81% met Brighton criteria for hypermobility syndrome (odds ratio 7.08) and 18% met 2017 hypermobile Ehlers-Danlos syndrome (hEDS) criteria. Hypermobility scores significantly predicted symptom levels. CONCLUSION: Symptomatic hypermobility is particularly relevant to fibromyalgia and ME/CFS, and our findings highlight high rates of mis-/underdiagnosis. These poorly understood conditions have a considerable impact on quality of life and our observations have implications for diagnosis and treatment targets.

Online psychotherapy: trailblazing digital healthcare.

Advances in digital technology have a profound impact on conventional healthcare systems. We examine the trailblazing use of online interventions to enable autonomous psychological care which can greatly enhance individual- and population-level access to services. There is strong evidence supporting online cognitive-behavioural therapy and more engaging programmes are now appearing so as to reduce user 'attrition'. The next generation of autonomous psychotherapy programmes will implement adaptive and personalised responses, moving beyond impersonalised advice on cognitive and behavioural techniques. This will be a more authentic form of psychotherapy that integrates therapy with the actual relationship experiences of the individual user.

Neurovisceral phenotypes in the expression of psychiatric symptoms.

This review explores the proposal that vulnerability to psychological symptoms, particularly anxiety, originates in constitutional differences in the control of bodily state, exemplified by a set of conditions that include Joint Hypermobility, Postural Tachycardia Syndrome and Vasovagal Syncope. Research is revealing how brain-body mechanisms underlie individual differences in psychophysiological reactivity that can be important for predicting, stratifying and treating individuals with anxiety disorders and related conditions. One common constitutional difference is Joint Hypermobility, in which there is an increased range of joint movement as a result of a variant of collagen. Joint hypermobility is over-represented in people with anxiety, mood and neurodevelopmental disorders. It is also linked to stress-sensitive medical conditions such as irritable bowel syndrome, chronic fatigue syndrome and fibromyalgia. Structural differences in "emotional" brain regions are reported in hypermobile individuals, and many people with joint hypermobility manifest autonomic abnormalities, typically Postural Tachycardia Syndrome. Enhanced heart rate reactivity during postural change and as recently recognized factors causing vasodilatation (as noted post-prandially, post-exertion and with heat) is characteristic of Postural Tachycardia Syndrome, and there is a phenomenological overlap with anxiety disorders, which may be partially accounted for by exaggerated neural reactivity within ventromedial prefrontal cortex. People who experience Vasovagal Syncope, a heritable tendency to fainting induced by emotional challenges (and needle/blood phobia), are also more vulnerable to anxiety disorders. Neuroimaging implicates brainstem differences in vulnerability to faints, yet the structural integrity of the caudate nucleus appears important for the control of fainting frequency in relation to parasympathetic tone and anxiety. Together there is clinical and neuroanatomical evidence to show that common constitutional differences affecting autonomic responsivity are linked to psychiatric symptoms, notably anxiety.

Neuroimaging and psychophysiological investigation of the link between anxiety, enhanced affective reactivity and interoception in people with joint hypermobility.

OBJECTIVE: Anxiety is associated with increased physiological reactivity and also increased "interoceptive" sensitivity to such changes in internal bodily arousal. Joint hypermobility, an expression of a common variation in the connective tissue protein collagen, is increasingly recognized as a risk factor to anxiety and related disorders. This study explored the link between anxiety, interoceptive sensitivity and hypermobility in a sub-clinical population using neuroimaging and psychophysiological evaluation. METHODS: Thirty-six healthy volunteers undertook interoceptive sensitivity tests, a clinical examination for hypermobility and completed validated questionnaire measures of state anxiety and body awareness tendency. Nineteen participants also performed an emotional processing paradigm during functional neuroimaging. RESULTS: We confirmed a significant relationship between state anxiety score and joint hypermobility. Interoceptive sensitivity mediated the relationship between state anxiety and hypermobility. Hypermobile, compared to non-hypermobile, participants displayed heightened neural reactivity to sad and angry scenes within brain regions implicated in anxious feeling states, notably insular cortex. CONCLUSIONS: Our findings highlight the dependence of anxiety state on bodily context, and increase our understanding of the mechanisms through which vulnerability to anxiety disorders arises in people bearing a common variant of collagen.