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Abstract Ordinary sensations from inside the body are important causes and consequences of our affective states and behaviour, yet the roles of neurotransmitters in interoceptive processing have been unclear. With a within-subjects design, this experiment tested the impacts of acute increases of endogenous extracellular serotonin on the neural processing of attended internal sensations and the links of these effects to anxiety using a selective serotonin reuptake inhibitor (SSRI) (20 mg citalopram) and a placebo. Twenty-one healthy volunteers (fourteen female, mean age 23.9) completed the Visceral Interoceptive Attention (VIA) task while undergoing functional magnetic resonance imaging (fMRI) with each treatment. The VIA task required focused attention on the heart, stomach, or visual sensation. The relative neural interoceptive responses to heart sensation [heart minus visual attention] (heart-IR) and stomach sensation [stomach minus visual attention] (stomach-IR) were compared between treatments. Visual attention subtraction controlled for the general effects of citalopram on sensory processing. Citalopram was associated with lower interoceptive processing in viscerosensory (the stomach-IR of bilateral posterior insular cortex) and integrative/affective (the stomach-IR and heart-IR of bilateral amygdala) components of interoceptive neural pathways. In anterior insular cortex, citalopram reductions of heart-IR depended on anxiety levels, removing a previously known association between anxiety and the region’s response to attended heart sensation observed with placebo. Preliminary post hoc analysis indicated that citalopram effects on the stomach-IR of the amygdalae corresponded to acute anxiety changes. This direct evidence of general and anxiety-linked serotonergic influence on neural interoceptive processes advances our understanding of interoception, its regulation, and anxiety.

Abstract Interoception, the sense of the internal physiological state of the body, theoretically underpins aspects of self-representation. Experimental studies link feelings of body ownership to interoceptive perception, yet few studies have tested for association between the sense of agency and interoceptive processing. Here, we combined an intentional binding paradigm with cardiac measures of interoceptive processing (behavioural performance on a heartbeat discrimination task, and effects of timing within the cardiac cycle) in twenty-six non-clinical participants as an exploratory study. We found performance accuracy on the heartbeat discrimination task correlated positively with the intentional binding effect, an index of sense of agency (β = 0.832, p = 0.005), even after controlling for effects of age, sex, educational level, heart rate, heart rate variability and time accuracy. The intentional binding effect was enhanced during cardiac systole (compared to diastole) in individuals with greater heartbeat discrimination accuracy (β = 0.640, p = 0.047). These findings support the proposal that interoception contributes to mechanisms underlying the emergence of sense of agency.

Abstract The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5–90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Abstract 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

BackgroundSpelling errors in documents lead to reduced trustworthiness, but the mechanism for weighing the psychological assessment (i.e., integrative versus dichotomous) has not been elucidated. We instructed participants to rate content of texts, revealing that their implicit trustworthiness judgments show marginal differences specifically caused by spelling errors.MethodsAn online experiment with 100 English-speaking participants were asked to rate 27 short text excerpts (∼100 words) about multiple sclerosis in the format of unmoderated health forum posts. In a counterbalanced design, some excerpts had no typographic errors, some had two errors, and some had five errors. Each participant rated nine paragraphs with a counterbalanced mixture of zero, two or five errors. A linear mixed effects model (LME) was assessed with error number as a fixed effect and participants as a random effect.ResultsUsing an unnumbered scale with anchors of “completely untrustworthy” (left) and “completely trustworthy” (right) recorded as 0 to 100, two spelling errors resulted in a penalty to trustworthiness of 5.91 ± 1.70 (robust standard error) compared to the reference excerpts with zero errors, while the penalty for five errors was 13.5 ± 2.47; all three conditions were significantly different from each other (P < 0.001).ConclusionParticipants who rated information about multiple sclerosis in a context mimicking an online health forum implicitly assigned typographic errors nearly linearly additive trustworthiness penalties. This contravenes any dichotomous heuristic or local ceiling effect on trustworthiness penalties for these numbers of typographic errors. It supports an integrative model for psychological judgments of trustworthiness.

ObjectivesAutism, 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.MethodsRates 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.ResultsThe 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.ConclusionsIn 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.

Knowledge of brain mechanisms underlying self-regulation can provide valuable insights into how people regulate their thoughts, behaviors, and emotional states, and what happens when such regulation fails. Self-regulation is supported by coordinated interactions of brain systems. Hence, behavioral dysregulation, and its expression as impulsivity, can be usefully characterized using functional connectivity methodologies applied to resting brain networks. The current study tested whether individual differences in trait impulsivity are reflected in the functional architecture within and between resting-state brain networks. Thirty healthy individuals completed a self-report measure of trait impulsivity and underwent resting-state functional magnetic resonance imaging. Using Probabilistic Independent Components Analysis in FSL MELODIC, we identified across participants 10 networks of regions (resting-state networks) with temporally correlated time courses. We then explored how individual expression of these spatial networks covaried with trait impulsivity. Across participants, we observed that greater self-reported impulsivity was associated with decreased connectivity of the right lateral occipital cortex (peak mm 46/-70/16, FWE 1-p = 0.981) with the somatomotor network. No supratheshold differences were observed in between-network connectivity. Our findings implicate the somatomotor network, and its interaction with sensory cortices, in the control of (self-reported) impulsivity. The observed “decoupling” may compromise effective integration of early perceptual information (from visual and somatosensory cortices) with behavioral control programs, potentially resulting in negative consequences.

Individuals who engage in binge drinking behaviors may show evidence of impaired cognitive function and emotional dysregulation. Impaired empathy, characterized by a reduced ability to understand and respond appropriately to feelings of others, is increasingly recognized for its role in Alcohol Use Disorders (AUD). The present study examined a population of young adult social drinkers to compare individuals who show binge drinking behavior to those who do not on measures of empathic processing and associated neural responses. A secondary aim explored similarities and differences between binge drinkers living in the UK and France. Alcohol drinking history and impulsivity ratings were recorded from seventy-one participants [(37 UK (Binge drinkers N = 19); 34 France (Binge drinkers N = 17)], who then underwent a neuroimaging study. During functional magnetic resonance imaging, participants viewed images of bodily pain (vs. no-pain), while adopting the perspective of self (pain recipient) or other (observer of someone else experiencing pain). Anterior midcingulate cortex (aMCC) and insula activation distinguished pain from no-pain conditions. Binge drinkers showed stronger regional neural activation than non-binge drinkers within a cluster spanning fusiform gyrus and inferior temporal gyrus, encompassing the Fusiform Body Area. Binge drinkers compared to non-binge drinkers also took longer to respond when viewing pictures depicting pain, in particular when adopting the perspective of self. Relationships between changes in brain activation and behavioural responses in pain versus no pain conditions (self or other perspective) indicated that whereas non-binge drinkers engage areas supporting self to other distinction, binge drinkers do not. Our findings suggest that alcohol binge drinking is associated with different empathy-related behavioral and brain responses, consistent with the proposed importance of empathy in the development of AUD.

Background: The Cognitive Avoidance Theory of Worry argues that worry is a cognitive strategy adopted to control the physiological arousal associated with anxiety. According to this theory, pathological worry, as in Generalized Anxiety Disorder (GAD), is verbal in nature, negative and abstract, rather than concrete. Neuroimaging studies link the expression of worry to characteristic modes of brain functional connectivity, especially in relation to the amygdala. However, the distinctive features of worry (verbal, abstract, negative), and their relationship to physiological arousal, have not so far been mapped to brain function. Methods: We addressed this omission by undertaking a resting-state functional magnetic resonance neuroimaging study of 19 patients with GAD and 21 controls, before and after induction of perseverative cognitions, while measuring emotional bodily arousal from heart rate (HR). Seed-based analyses quantified brain changes in whole brain functional connectivity from the amygdala. Results: In GAD, the induction increased negative thoughts and their verbal content. In line with predictions, the verbal expression of worry in GAD was associated with higher HR at baseline and attenuated HR increases after induction of perseverative cognitions. Within brain, the increased use of words during worry, and the associated dampening of HR after induction were mediated by the strength of functional connectivity between the amygdala and default mode network ‘hubs’ and the opercular cortex. The negative content of worry was further related to functional communication between amygdala and cingulo-opercular and temporal cortices. Conclusions: Findings provide a neurobiological basis for the impact of verbal worry on HR in GAD. Keywords: Generalized anxiety disorder, Amygdala, Functional connectivity, Worry, Heart rate, New York Cognition Questionnaire

Black individuals are racially stereotyped as threatening but how bodily signals may affect these misperceptions is not known. Here Azevedo and colleagues show that these race-driven responses are affected by the cardiac cycle, being more biased when arterial baroreceptor activation is maximal.

In childhood, Attention Deficit Hyperactivity Disorder (ADHD) is reliably associated with reduced volume of the striatum. In contrast, striatal abnormalities are infrequently detected in voxel-based morphometry (VBM) neuroimaging studies of adults with ADHD. This discrepancy has been suggested to reflect normalisation of striatal morphology with age and prolonged treatment of symptoms. If so, this would indicate that while striatal abnormalities are linked to symptom expression in childhood, they cannot explain the persistence of these symptoms in adulthood. However, this may not be case. Instead, we hypothesized that the lack of evidence for striatal abnormalities in adult ADHD may reflect poor sensitivity of typical (T1-weighted) neuroimaging to detect subcortical differences. To address this, we acquired both magnetisation transfer (MT) saturation maps optimised for subcortical contrast, and conventional T1-weighted images in 30 adults with ADHD and 30 age, IQ, gender and handedness-matched controls. Using VBM of both datasets, we demonstrate volumetric reductions within the left ventral striatum on MT that are not observed on identically pre-processed T1-weighted images from the same participants. Nevertheless, both techniques reported similar sensitivity to cortical abnormalities in the right inferior parietal lobe. Additionally, we show that differences in striatal iron may potentially explain this reduced sensitivity of T1-weighted images in adults. Together, these findings indicate that prior VBM studies reporting no abnormalities in striatal volume in adult ADHD might have been compromised by the methodological insensitivity of T1-weighted VBM to subcortical differences, and that structural abnormalities of the striatum in ADHD do indeed persist into adulthood. Keywords: ADHD, Striatum, VBM, MT saturation, T1 weighted MRI, Iron

Tourette Syndrome (TS) is a neurodevelopmental condition characterized by chronic multiple tics, which are experienced as compulsive and ‘unwilled’. Patients with TS can differ markedly in the frequency, severity, and bodily distribution of tics. Moreover, there are high comorbidity rates with attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), anxiety disorders, and depression. This complex clinical profile may account for apparent variability of findings across neuroimaging studies that connect neural function to cognitive and motor behavior in TS.Here we crystalized information from neuroimaging regarding the functional circuitry of TS, and furthermore, tested specifically for neural determinants of tic severity, by applying activation likelihood estimation (ALE) meta-analyses to neuroimaging (activation) studies of TS. Fourteen task-based studies (13 fMRI and one H2O-PET) met rigorous inclusion criteria. These studies, encompassing 25 experiments and 651 participants, tested for differences between TS participants and healthy controls across cognitive, motor, perceptual and somatosensory domains.Relative to controls, TS participants showed distributed differences in the activation of prefrontal (inferior, middle, and superior frontal gyri), anterior cingulate, and motor preparation cortices (lateral premotor cortex and supplementary motor area; SMA). Differences also extended into sensory (somatosensory cortex and the lingual gyrus; V4); and temporo-parietal association cortices (posterior superior temporal sulcus, supramarginal gyrus, and retrosplenial cortex).Within TS participants, tic severity (reported using the Yale Global Tic Severity Scale; YGTSS) selectively correlated with engagement of SMA, precentral gyrus, and middle frontal gyrus across tasks.The dispersed involvement of multiple cortical regions with differences in functional reactivity may account for heterogeneity in the symptomatic expression of TS and its comorbidities. More specifically for tics and tic severity, the findings reinforce previously proposed contributions of premotor and lateral prefrontal cortices to tic expression. Keywords: Activation likelihood estimation (ALE), Meta-analysis, fMRI, Supplementary motor area (SMA), Tic disorder, Tourette Syndrome

Tourette syndrome is a hyperkinetic movement disorder. Characteristic features include tics, recurrent movements that are experienced as compulsive and “unwilled”; uncomfortable premonitory sensations that resolve through tic release; and often, the ability to suppress tics temporarily. We demonstrate how these symptoms and features can be understood in terms of aberrant predictive (Bayesian) processing in hierarchical neural systems, explaining specifically: why tics arise, their “unvoluntary” nature, how premonitory sensations emerge, and why tic suppression works—sometimes. In our model, premonitory sensations and tics are generated through over-precise priors for sensation and action within somatomotor regions of the striatum. Abnormally high precision of priors arises through the dysfunctional synaptic integration of cortical inputs. These priors for sensation and action are projected into primary sensory and motor areas, triggering premonitory sensations and tics, which in turn elicit prediction errors for unexpected feelings and movements. We propose experimental paradigms to validate this Bayesian account of tics. Our model integrates behavioural, neuroimaging, and computational approaches to provide mechanistic insight into the pathophysiological basis of Tourette syndrome.

Background: Despite the high prevalence of generalized anxiety disorder (GAD) and its negative impact on society, its neurobiology remains obscure. This study characterizes the neurostructural abnormalities associated with key symptoms of GAD, focusing on indicators of impaired emotion regulation (excessive worry, poor concentration, low mindfulness, and physiological arousal). Methods: These domains were assessed in 19 (16 women) GAD patients and 19 healthy controls matched for age and gender, using questionnaires and a low demand behavioral task performed before and after an induction of perseverative cognition (i.e. worry and rumination). Continuous pulse oximetry was used to measure autonomic physiology (heart rate variability; HRV). Observed cognitive and physiological changes in response to the induction provided quantifiable data on emotional regulatory capacity. Participants underwent structural magnetic resonance imaging; voxel-based morphometry was used to quantify the relationship between gray matter volume and psychological and physiological measures. Results: Overall, GAD patients had lower gray matter volume than controls within supramarginal, precentral, and postcentral gyrus bilaterally. Across the GAD group, increased right amygdala volume was associated with prolonged reaction times on the tracking task (indicating increased attentional impairment following the induction) and lower scores on the ‘Act with awareness’ subscale of the Five Facets Mindfulness Questionnaire. Moreover in GAD, medial frontal cortical gray matter volume correlated positively with the ‘Non-react mindfulness’ facet. Lastly, smaller volumes of bilateral insula, bilateral opercular cortex, right supramarginal and precentral gyri, anterior cingulate and paracingulate cortex predicted the magnitude of autonomic change following the induction (i.e. a greater decrease in HRV). Conclusions: Results distinguish neural structures associated with impaired capacity for cognitive, attentional and physiological disengagement from worry, suggesting that aberrant competition between these levels of emotional regulation is intrinsic to symptom expression in GAD.

Objectives: The consequences of impulsive decisions and actions represent a major source of concern to the health and well-being of individuals and society. It is, therefore, crucial to understand the factors which contribute to impulsive behaviors. Here, we examined how personality traits of behavioral tendencies, interoceptive sensibility as well as transient mood states predict behavioral performance on impulsivity and risk-taking tasks.Method: 574 (121 males; age 18–45) individuals completed self-report personality measures of impulsivity, reward sensitivity, punishment avoidance as well as interoceptive sensibility, undertook a mood assessment and performed a set of cognitive tasks: delay discounting (temporal impulsivity), probability discounting (risk-taking), and reflection impulsivity task. Data were interrogated using principal component analysis, correlations and regression analyses to test mutual relationships between personality traits, interoceptive sensibility, mood state and impulsive behaviors.Results: We observed a clear separation of measures used, both trait and behavioral. Namely, sensation-seeking, reward sensitivity and probability discounting reflected risk-taking. These were separate from measures associated with impulsivity, both trait (negative and positive urgency, premeditation, perseverance) and behavioral (delayed discounting and reflection impulsivity). This separation was further highlighted by their relationship with the current emotional state: positive affect was associated with increased risk-taking tendencies and risky decision-making, while negative emotions were related to heightened impulsivity measures. Interoceptive sensibility was only associated with negative emotions component.Conclusion: Our findings support the proposal that risk-taking and impulsivity represent distinct constructs that are differentially affected by current mood states. This novel insight enhances our understanding of impulsive behaviors.

Around a quarter of the population report “mirror pain” experiences in which bodily sensations of pain are elicited in response to viewing another person in pain. We have shown that this population of responders further fractionates into two distinct subsets (Sensory/localized and Affective/General), which presents an important opportunity to investigate the neural underpinnings of individual differences in empathic responses. Our study uses fMRI to determine how regions involved in the perception of pain interact with regions implicated in empathic regulation in these two groups, relative to controls. When observing pain in others (minor injuries to the hands and feet), the two responder groups show activation in both the sensory/discriminative and affective/motivational components of the pain matrix. The control group only showed activation in the latter. The two responder groups showed clear differences in functional connectivity. Notably, Sensory/Localized responders manifest significant coupling between the right temporo-parietal junction (rTPJ) and bilateral anterior insula. We conclude that conscious experiences of vicarious pain is supported by specific patterns of functional connectivity between pain-related and regulatory regions, and not merely increased activity within the pain matrix itself.

Excessive and uncontrollable worry is a defining feature of Generalized Anxiety Disorder. An important endeavor in the treatment of pathological worry is to understand why some people are unable to stop worrying once they have started. Worry perseveration is associated with a tendency to deploy goal-directed worry rules (known as ‘as many as can’ worry rules; AMA). These require attention to the goal of the worry task and continuation of worry until the aims of the ‘worry bout’ are achieved. This study examined the association between the tendency to use AMA worry rules and neural and autonomic responses to a perseverative cognition induction. To differentiate processes underlying AMA worry rule use from trait worry, we also examined the relationship between scores on the Penn State Worry Questionnaire and neural and autonomic responses following the same induction. We used resting-state functional magnetic resonance brain imaging while measuring emotional bodily arousal from heart rate variability (where decreased HRV indicates stress-related parasympathetic withdrawal) in 19 patients with GAD and 21 control participants. Seed-based analyses were conducted to quantify brain changes in functional connectivity with the amygdala. The tendency to adopt an AMA worry rule was associated with validated measures of worry, anxiety, depression, and rumination. AMA worry rule endorsement predicted a stronger decrease in HRV and was positively associated with increased connectivity between right amygdala and locus coeruleus, a brainstem noradrenergic projection nucleus. Higher AMA scores were also associated with increased connectivity between amygdala and rostral superior frontal gyrus. Higher PSWQ scores amplified decreases in functional connectivity between right amygdala and subcallosal cortex, bilateral inferior frontal gyrus, middle frontal gyrus, and areas of parietal cortex. Our results identify neural mechanisms underlying the deployment of AMA worry rules. We propose that the relationship between AMA worry rules and increased connectivity between the amygdala and prefrontal cortex represents attempts by high worriers to maintain arousal and distress levels in order to feel prepared for future threats. Furthermore, we suggest that neural mechanisms associated with the PSWQ represent effortful inhibitory control during worry. These findings provide unique information about the neurobiological processes that underpin worry perseveration.

We describe a theoretical model of the neurocognitive mechanisms underlying conscious presence. The model is based on interoceptive prediction error and is informed by predictive models of agency, general models of hierarchical predictive coding and dopaminergic signalling in cortex, the role of the anterior insular cortex in interoception and emotion, and cognitive neuroscience evidence from studies of virtual reality and of psychiatric disorders of presence, specifically depersonalization/derealization disorder. The model associates presence with successful ‘explaining away’ by top-down predictions of informative interoceptive signals evoked by autonomic control signals and, indirectly, by visceral responses to afferent sensory signals. The model connects presence to agency by allowing that predicted interoceptive signals will depend on whether afferent sensory signals are determined, by a parallel predictive-coding mechanism, to be self-generated or externally caused. Anatomically, we identify the anterior insular cortex as the likely locus of key neural comparator mechanisms. Our model integrates a broad range of previously disparate evidence, makes predictions for conjoint manipulations of agency and presence, offers a new view of emotion as interoceptive inference, and represents a step towards a mechanistic account of a fundamental phenomenological property of consciousness.

Objectives This study sought to explore whether generalised joint hypermobility (GJH, a common marker of variant connective tissue) was a risk factor for self-reported non-recovery from COVID-19 infection.Design Prospective observational study.Setting COVID Symptom Study Biobank (https://cssbiobank.com/) UKParticipants Participants were surveyed in August 2022. 3064 (81.4%) reported at least one infection with COVID-19. These individuals self-reported on recovery and completed a self-report questionnaire to detect GJH (Hakim and Grahame 5-part questionnaire, 5PQ).Main outcome measures The primary outcome was the presence of self-reported non-recovery from COVID-19 infection at the time of the survey. Additional outcomes included scores on 5PQ and self-reported fatigue level (Chalder Fatigue Scale).Results The presence of GJH was not specifically associated with reported COVID-19 infection risk per se. However, it was significantly associated with non-recovery from COVID-19 (OR 1.43 (95% CI 1.20 to 1.70)). This association remained after sequential models adjusting for age, sex, ethnic group, education level and index of multiple deprivation (OR 1.33 (95% CI 1.10 to 1.61)) and further adjustment for vaccination status and number of vaccinations (OR 1.33 (95% CI 1.10 to 1.60)). Additionally, including in a model adjusting for all covariates, hypermobility significantly predicted higher fatigue levels (B=0.95, SE=0.25, t=3.77, SE, p=0.002). Fatigue levels mediated the link between GJH and non-recovery from COVID-19 (estimate of indirect effect=0.18, 95% bootstrapped CI 0.08 to 0.29).Conclusions Individuals with GJH were approximately 30% more likely not to have recovered fully from COVID-19 infection at the time of the questionnaire, and this predicted the fatigue level. This observation is clinically important through its potential impact for understanding and identifying sub-phenotypes of long COVID for screening and personalised targeted interventions. More generally, greater awareness of GJH and its extra-articular associations is needed for effective patient stratification and implementation of personalised medicine.