Background and Aims: Anxiety symptoms are elevated among people with joint hypermobility. The underlying neural mechanisms are attributed theoretically to effects of variant connective tissue on the precision of interoceptive representations contributing to emotions. Methods: We used functional magnetic resonance neuroimaging (fMRI) to quantify regional brain responses to emotional stimuli (facial expressions) in patients with generalised anxiety disorder (N=30) and a non-anxious comparison group (N=33). All participants were assessed for joint laxity and were classified (using Brighton Criteria) for the presence and absence of Hypermobility Syndrome (HMS: now considered Hypermobility Spectrum Disorder). Results: HMS participants showed attenuated neural reactivity to emotional faces in specific frontal (inferior frontal gyrus, pre-supplementary motor area), midline (anterior mid and posterior cingulate cortices), and parietal (precuneus and supramarginal gyrus) regions. Notably, interaction between HMS and anxiety was expressed in reactivity of left amygdala (a region implicated in threat processing) and mid insula (primary interoceptive cortex) where activity was amplified in HMS patients with generalised anxiety disorder. Severity of hypermobility in anxious, compared to non-anxious, individuals correlated with activity within anterior insula (implicated as the neural substrate linking anxious feelings to physiological state). Amygdala-precuneus functional connectivity was stronger in HMS, compared to non-HMS, participants. Conclusions: The predisposition to anxiety in people with variant connective tissue reflects dynamic interactions between neural centres processing threat (amygdala) and representing bodily state (insular and parietal cortices). Correspondingly, interventions to regulate of amygdala reactivity while enhancing interoceptive precision may have therapeutic benefit for symptomatic hypermobile individuals.

The authors have declared no competing interest.

Funding for this project came via a fellowship to JAE (MRC MR/K002643/1). JAE was also supported by MQ Transforming Mental Health and Versus Arthritis (MQF 17/19).

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All procedures involving human participants including patients were approved by the National Research Ethics Service - South East Coast (Brighton and Sussex; REC Reference 12/LO/1942; IRAS registration number 115219).

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Analytic Code Availability: The analytic code (SPM batches) that was used for the neuroimaging analysis for this study is available at OSF: DOI 10.17605/OSF.IO/TCEMX. Research Material and Data Availability: The MRI acquisition sequence information, demographic and clinical data, and participant mean FD values are available at OSF: DOI 10.17605/OSF.IO/TCEMX. The neuroimaging data that support the findings of this study (unthresholded statistic images for every contrast reported) are openly available at https://identifiers.org/neurovault.collection:16863/, reference number 16863(31).

https://identifiers.org/neurovault.collection:16863/