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Interoceptive mismatch is a perceptual discrepancy between ascending bodily signals and higher-order representation of anticipated physiological state. This mismatch is implicated in emotion inference within predictive coding models. We present autonomic perceptual mismatch as a novel in vivo measure of the discrepancy between actual and perceived autonomic signals, for clinical application to brain-body interactions, specifically in the expression of anxiety. Joint hypermobility is disproportionately found in individuals with anxiety disorders, revealing an underexplored link between the mind and body. Atypical autonomic reactivity represents a likely mediating mechanism consequent of altered connective tissue within the vasculature and nervous system. The present fMRI study determined neural substrates of autonomic perceptual mismatch on affective processing in the hypermobility-anxiety interaction. We compared regional brain activity during emotional face processing in participants with and without hypermobility and generalized anxiety disorder diagnosis, then tested association with perceptual mismatch. In the brain, autonomic perceptual mismatch correlated with enhanced activation in emotion processing and autonomic control regions, notably anterior cingulate cortex. Anxious individuals exhibited increased mid-insula cortex activity in relation to perceptual mismatch. Activity was decreased within the inferior frontal gyrus, a region implicated in cognitive control. Dysautonomia mediated the link between hypermobility and anxiety. Together, these findings support a neural basis of an autonomic perceptual mismatch model in a clinical sample. This is supported by the engagement of neural systems for emotion-cognition and interoception. This work highlights convergent aspects of neurodiversity, mental health, connective tissue disorders and brain-body interactions relevant to precision healthcare.

ObjectiveEmotional states are expressed in body and mind through subjective experience of physiological changes. In previous work, subliminal priming of anger prior to lexical decisions increased systolic blood pressure (SBP). This increase predicted the slowing of response times (RT), suggesting that baroreflex-related autonomic changes and their interoceptive (feedback) representations, influence cognition. Alexithymia is a subclinical affective dysfunction characterized by difficulty in identifying emotions. Atypical autonomic and interoceptive profiles are observed in alexithymia. Therefore, we sought to identify mechanisms through which SBP fluctuations during emotional processing might influence decision-making, including whether alexithymia contributes to this relationship.MethodsThirty-two male participants performed an affect priming paradigm and completed the Toronto Alexithymia Scale. Emotional faces were briefly presented (20ms) prior a short-term memory task. RT, accuracy and SBP were recorded on a trial-by-trial basis. Generalized mixed-effects linear models were used to evaluate the impact of emotion, physiological changes, alexithymia score, and their interactions, on performances.ResultsA main effect of emotion was observed on accuracy. Participants were more accurate on trials with anger primes, compared to neutral priming. Greater accuracy was related to increased SBP. An interaction between SBP and emotion was observed on RT: Increased SBP was associated with RT prolongation in the anger priming condition, yet this relationship was absent under the sadness priming. Alexithymia did not significantly moderate the above relationships.ConclusionsOur data suggest that peripheral autonomic responses during affective challenges guide cognitive processes. We discuss our findings in the theoretical framework proposed by Lacey and Lacey (1970).

Empathy-for-pain states are underpinned by interoception, i.e the central representation of internal states. Cardiac signals occur in a phasic manner; baroreceptor discharges at systole communicate the heartbeats’ strength. These signals modulate pain and emotion processing. We tested whether these phasic interoceptive signals modulate empathy-for-pain. As oxytocin (OT) enhances empathy and modulates interoceptive signals’ precision, we also tested if OT administration impacts empathy-for-pain via interoceptive mechanisms.Male subjects (N=32) attended three sessions to perform psychometric tests and an fMRI empathy-for-pain task, after intranasal administration of OT or placebo (40IU). Pictures of hands in painful or non-painful context were presented at systole or diastole. Effects of drug, emotion and cardiac timing on behaviour and brain activity was tested using general and mixed-effects linear models.Across conditions, activation was observed within regions implicated in pain and empathy-for-pain, with insula activation greater in the right than left hemisphere. OT administration, compared to placebo, attenuated the reactivity of some regions, including anterior cingulate cortex, but presentation of stimuli at systole blocked the OT attenuating effect.Our data suggest that OT alters the processing of motivationally-salient social cues, interacting with interoceptive signals. Our findings may inform targeted use of OT in psychiatric conditions linked to aberrant interoceptive processing.

ObjectiveAutism, attention deficit hyperactivity disorder (ADHD), and tic disorder (Tourette syndrome; TS) are neurodevelopmental conditions that frequently co-occur and impact psychological, social and emotional functioning. Vulnerability to chronic physical symptoms, including fatigue and pain, are also recognised. The expression of joint hypermobility, reflecting a constitutional variant in connective tissue, predicts vulnerability to psychological symptoms alongside recognised physical symptoms. Here, we tested for increased rates of joint hypermobility, autonomic dysfunction and pain in 109 adults with neurodevelopmental diagnoses.MethodRates of generalized joint laxity in those individuals with neurodevelopmental conditions were compared to those in the general population in UK. Levels of orthostatic intolerance and musculoskeletal symptoms were compared to a neurotypical control group.ResultsAdults with neurodevelopmental diagnoses manifest elevated rates of joint hypermobility (50%) compared to the general population rate of 20% and a matched control population of 10%. Odds ratio for hypermobility in individuals with neurodevelopmental diagnoses, compared to the general population was 4.51 (95%CI 2.17-9.37), with greater odds in females rather than males. Neurodevelopmental patients reported significantly more symptoms of orthostatic intolerance and musculoskeletal skeletal pain than controlsConclusionsIn adults with neurodevelopmental conditions, there is a strong link between the expression of joint hypermobility, autonomic dysfunction and pain, more so than in healthy controls. Increased awareness and understanding of this association may enhance the management of core symptoms and allied difficulties including comorbid stress-sensitive physical symptoms.

ImportanceDepression and anxiety are common mood disorders that show higher prevalence in adults with joint hypermobility, a consequence of a constitutional variant of connective tissue structure. In adolescents, an association between mood disorder and hypermobility may enhance the potential understanding of risk factors for emotional disorder and provide opportunities for early intervention approaches.ObjectiveTo test the hypothesis that joint hypermobility, a consequence of constitutional variant of connective tissue, is associated with common mental illness in adolescents.DesignThis was a longitudinal prospective study.SettingThe Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective ongoing general population birth cohort study based in Avon County, England.ParticipantsThe original data set comprised 6105 individuals from the cohort with data available on joint hypermobility at age 14 years; a sub-sample (n=3803) had later psychiatric assessments.Measurement of ExposureJoint hypermobility was measured by physical examination at age 14 and 18 years, using the Beighton ScaleMain Outcome and MeasuresParticipants were assessed at age 18 years. ICD-10 diagnoses of Depression and Anxiety were obtained using the Clinical Interview Schedule-Revised (CIS-R) and levels of anxiety quantified using the Anxiety Sensitivity Index (ASI)ResultsPresence of generalized joint hypermobility (GJH) at age 14 years predicted depression at 18 years in males (Odds Ratio (OR) 2.10; 95%CI, 1.17-3.76) but not females After accounting for missing data it was determined that this relationship was mediated by heart rate, a potential measure of physiological arousal. Symptomatic hypermobility ((GJH plus chronic widespread pain (CWP)) at age 18 years was further associated with the presence of anxiety disorder (OR 3.13; 95% CI 1.52-6.46) and level of anxiety (Beta = 0.056, t(3315)=3.27), depressive disorder (adjusted OR 3.52; 95%CI, 1.67 – 7.40) and degree of psychiatric symptomatology (Beta 0.096, t(2064)=4.38)Conclusions and relevanceGeneralized joint hypermobility and symptomatic hypermobility are associated with common mental disorders in adolescence. Consideration of hypermobility may provide important opportunities for intervention to mitigate psychiatric disorder.KEY POINTSQuestionIs joint hypermobility related to depression and anxiety in adolescence?FindingsIn this longitudinal study presence of generalized joint hypermobility at 14 predicted subsequent adolescent depression in males only and this relationship was mediated by heart rate. At age 18 symptomatic hypermobility was associated with both presence of anxiety and depression and psychiatric symptom severity.MeaningGeneralized joint hypermobility and symptomatic hypermobility are associated with common mental disorders in adolescence.

Interoception is the signalling, perception, and interpretation of internal physiological states. Much of the psychopharmacology of interoception is still undiscovered. However, psychiatric disorders associated with changes of interoception, including depressive, anxiety, and eating disorders are often treated with selective serotonin reuptake inhibitors (SSRIs). The causal effect of acute changes of serotonergic signaling on interoceptive cognition was tested by a within-participant, crossover, placebo-controlled study. Forty-seven healthy human volunteers (31 female, 16 male) were tested both on and off a 20mg oral dose of the commonly prescribed SSRI citalopram. For each randomly ordered session, participants made judgments on the synchrony of their heartbeat to auditory tones and expressed confidence in each of these judgments. Citalopram enhanced insight into the likelihood that one's interoceptive judgment had been correct, driven primarily by enhanced confidence for correct responses. This effect was independent of measured cardiac and subjective effects of the drug. This novel result is evidence that acute serotonin changes can alter metacognitive insight into the reliability of inferences based on interoceptive information, which is a foundation for considering effects of serotonin on cognition and emotion in terms of effective top-down regulation of interoceptive influence on mental states.

The majority of interoceptive tasks (i.e. measuring the sensitivity to bodily signals) are based upon the heartbeat sensations perception. However, temporal perception of heartbeats varies among individuals and confidence and spatial perception of heartbeats in relation to temporal judgements have not yet been systematically investigated. This study examined the perception of heartbeat sensations in both time and spatial domains, using a multi-interval heartbeat discrimination task. The relationship between these domains was investigated, as well as the contribution of mental health conditions and cardiovascular parameters. Heartbeat sensations occurred on average ~250ms after the ECG R-wave and were more frequently sampled from the left part of the chest. Participants’ confidence in their experience of heartbeat sensations was maximal for the 0 ms interval. Interestingly, higher confidence was related to reduced dispersion of sampling locations but we found evidence toward the absence of relationship between temporal and spatial heartbeat sensations perception, using Bayesian statistics. Finally, we found evidence toward a relationship between spatial precision of heartbeat sensations and state anxiety score, which seems independent from the cardiovascular parameters. This systematic investigation of heartbeat sensations perception provides important fresh insights, informing the mechanistic understanding of the interoceptive signaling contribution to emotion, cognition and behaviour.

ObjectivesTo understand the relevance of symptomatic hypermobility and related connective tissue variants to the expression of symptoms in Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). The study further tested if specific subfactors within the diagnostic classification of hypermobility predict clinical presentations.DesignWe report part of a larger case-control study exploring mechanisms of chronic pain and fatigue in Fibromyalgia and ME/CFS (https://doi.org/10.1186/ISRCTN78820481)Settingan NHS Clinical Research Facility.ParticipantsA subsample of 87 participants were assessed for symptomatic hypermobility by a trained clinician: 63 presented with a clinical diagnosis of either Fibromyalgia and or ME/CFS confirmed at screening; 24 participants were confirmed as healthy controls.Main outcome measures1) Brighton Criteria for joint hypermobility syndrome and 2017 hEDS diagnostic criteria. 2) ACR 2010 Diagnostic Criteria for Fibromylagia and Canadian and Fukada diagnostic criteria for ME/CFS. 3) Self report measures of subjective pain, fatigue and interoceptive sensibility.ResultsTwenty of the 63 patients (32%) presented with a clinical diagnosis of Fibromyalgia; 24 (38%) with a clinical diagnosis of ME/CFS and 19 (30%) with dual diagnoses of fibromyalgia and ME/CFS. After evaluation using clinical research tools, 56 patients (89%) met ACR diagnostic criteria for fibromyalgia; 59 (94%) Canadian Criteria for ME/CFS; and 61 (97%) Fukada Criteria for ME/CFS. After research evaluation 52 patients (85%) in fact met diagnostic criteria for Fibromyalgia and ME/CFS on all three sets of tools (ACR, Canadian, Fukada). In addition, 51 patients (81%) and 9 (37.5%) healthy controls met Brighton Criteria for joint hypermobility syndrome and 11 (18%) and 2 (8%) of patients and controls respectively, on the 2017 hEDS criteria. Of these patient participants with symptomatic hypermobility only 12 (23.5%) had received a prior diagnosis of hypermobility.Across all participants meeting Brighton Criteria, 13 (22%) also endorsed a hEDS diagnosis. Membership of the patient group was predicted by meeting the Brighton Criteria for joint hypermobility syndrome (p=ConclusionsSymptomatic joint hypermobility is relevant to symptoms and diagnosis in Fibromyalgia and ME/CFS. These conditions are poorly understood yet have a considerable impact on quality of life. Further work is needed to determine the prevalence of hEDS within the general population and define the critical clinical dimensions within symptomatic hypermobility. It is important to note the high rates of mis/underdiagnosis of symptomatic hypermobility in this group. Moreover, we need to clarify the role of variant connective tissue in dysautonomic and inflammatory mechanisms implicated in the expression of pain and fatigue in fibromyalgia and ME/CFS. Our observations have implications for diagnosis and treatment targets.Study registrationISCRTN78820481

BackgroundFibromyalgia is characterised by chronic widespread pain. Quality of life is further reduced by autonomic and cognitive symptoms, including subjective ‘brain-fog’ and dissociative experiences. Although an association with joint hypermobility suggests variant connective tissue is a factor in both fibromyalgia and dysautonomia, the mechanisms underlying the neuropsychiatric symptoms are poorly understood.Methods21 fibromyalgia patients and 21 healthy controls were assessed for joint hypermobility dissociative experiences, autonomic symptoms and interoceptive sensibility. Mediation analyses were conducted according to the method of Baron and Kenny.ResultsPatients with fibromyalgia reported greater dissociative experiences and autonomic symptoms. The relationship between fibromyalgia and dissociative experiences was fully mediated by symptoms of orthostatic intolerance. Fibromyalgia, dissociative experiences and orthostatic intolerance all were associated with joint hypermobility and interoceptive sensibility.ConclusionsThis exploratory investigation highlights the relationship between dissociative experiences in the context of fibromyalgia and subjective experience of aberrant physiological responses. These findings can enhance the recognition and management of neuropsychiatric symptoms in patients with fibromyalgia, wherein dissociative experiences reflect disturbance of self-representation that can arise through abnormalities in internal agency, autonomic (dys)control and interoceptive prediction errors.