Childhood neurodivergent traits, inflammation and chronic disabling fatigue in adolescence: a longitudinal case-control study.

OBJECTIVES: To test whether inflammatory processes link the expression of childhood neurodivergent traits to chronic disabling fatigue in adolescence. DESIGN: Longitudinal case-control study. SETTING: We analysed data from The Avon Longitudinal Study of Parents and Children (ALSPAC). PARTICIPANTS: 8115 and 8036 children of the ALSPAC cohort at ages 7 and 9 years, respectively, 4563 of whom also completed self-report measures at age 18 years. PRIMARY AND SECONDARY OUTCOME MEASURES: We assessed if children scoring above screening threshold for autism/attention deficit hyperactivity disorder (ADHD) at ages 7 and 9 years had increased risk of chronic disabling fatigue at age 18 years, computing ORs and CIs for effects using binary logistic regression. Mediation analyses were conducted to test if an inflammatory marker (interleukin 6 (IL-6)) at age 9 years linked neurodivergent traits to chronic disabling fatigue at age 18 years. RESULTS: Children with neurodivergent traits at ages 7 and 9 years were two times as likely to experience chronic disabling fatigue at age 18 years (likely ADHD OR=2.18 (95% CI=1.33 to 3.56); p=0.002; likely autism OR=1.78 (95% CI=1.17 to 2.72); p=0.004). Levels of IL-6 at age 9 were associated with chronic disabling fatigue at age 18 (OR=1.54 (95% CI=1.13 to 2.11); p=0.006). Inflammation at age 9 years mediated effects of neurodivergent traits on chronic disabling fatigue (indirect effect via IL-6: ADHD b=1.08 (95% CI=1.01 to 1.15); autism b=1.06; (95% CI=1.03 to 1.10)). All effects remained significant when controlling for the presence of depressive symptoms. CONCLUSIONS: Our results indicate higher risk of chronic disabling fatigue for children with neurodivergent traits, likely linked to higher levels of inflammation. The implementation of transdiagnostic screening criteria to inform support strategies to counteract risk early in life is recommended.

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.

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.