Jessica Eccles

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.

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.

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.

Sensations of skin infestation linked to abnormal frontolimbic brain reactivity and differences in self-representation

Some patients experience skin sensations of infestation and contamination that are elusive to proximate dermatological explanation. We undertook a functional magnetic resonance imaging study of the brain to demonstrate, for the first time, that central processing of infestation-relevant stimuli is altered in patients with such abnormal skin sensations. We show differences in neural activity within amygdala, insula, middle temporal lobe and frontal cortices. Patients also demonstrated altered measures of self-representation, with poorer sensitivity to internal bodily (interoceptive) signals and greater susceptibility to take on an illusion of body ownership: the rubber hand illusion. Together, these findings highlight a potential model for the maintenance of abnormal skin sensations, encompassing heightened threat processing within amygdala, increased salience of skin representations within insula and compromised prefrontal capacity for self-regulation and appraisal.

Pre-treatment waking cortisol response and vulnerability to interferon α induced depression

Depressive disorder is a common consequence of interferon α treatment. An understanding of the aetiological processes involved is evolving. HPA axis abnormalities are clearly described in community depressive disorder and represent vulnerability to depression development. We explored whether pre-treatment HPA axis abnormalities influence depression emergence during interferon α treatment. We examined waking HPA axis response via salivary cortisol sampling in 44 non-depressed, chronic hepatitis C infected patients due to commence standard interferon α treatment. Hamilton depression scales and the structured clinical interview for DSM-IV major depressive disorder status were administered monthly during treatment. Major depressive disorder developed in 26 of 44 subjects during interferon-α treatment. The pre-treatment waking cortisol response over 1h was significantly greater in the subsequent switch to depression group (F=4.23, p=0.046). The waking cortisol response pre-treatment with interferon α appears greater in those subsequently switching to depressive disorder during treatment. This waking response may join other vulnerability factors for depression emergence in this group. This model could prove a valuable tool in understanding non-iatrogenic depressive disorder in the general population and notably the role of cytokines.

Psychomotor retardation and vulnerability to interferon alpha induced major depressive disorder: Prospective study of a chronic hepatitis C cohort

BACKGROUND Major depressive disorder (MDD) is a common consequence of interferon alpha (IFNα) treatment and important supporting evidence of a role of inflammation in the aetiology of depression. OBJECTIVE This study aimed to expand the knowledge of baseline clinical vulnerability characteristics to IFNα induced MDD, particularly exploring sub-threshold depressive symptoms. METHODS A prospective cohort of chronic HCV patients undergoing treatment with pegylated-IFNα and ribavirin was studied. MDD was assessed using the Structured Clinical Interview for DSM-IV (SCID-I). Depressive symptoms and severity were assessed at baseline and monthly with the Hamilton Depression Rating Scale (HAMD). Subjects with MDD or taking antidepressant treatment at baseline were excluded. RESULTS 278 patients were assessed for this cohort with a final study sample of 190. 94.2% had contracted HCV through intravenous drug use. During six months IFNα treatment, 53.2% of patients transitioned to DSM-IV threshold MDD. In the multivariate logistic analysis, independent factors significantly associated with development of MDD were younger age (OR 0.96, 95% CI 0.93-1.00, p=0.028), past history of MDD (OR 3.82, 95% CI 1.63-8.92, p=0.002), baseline HAMD items psychomotor retardation (OR 15.21, 95% CI 1.33-173.41, p=0.032) and somatic symptoms (general) (OR 2.96, 95% CI 1.44-6.08, p=0.003), and HCV genotype 2 (OR 2.27, 95% CI 1.07-4.78, p=0.032). CONCLUSIONS During IFNα treatment, the rate of transition to MDD was high in this cohort. Psychomotor retardation and somatic symptoms may represent a greater inflamed state pre-treatment. This iatrogenic model of MDD may offer important insights into wider depression aetiology.

The Heart, the Brain, and the Regulation of Emotion

Muller and colleagues1 present a study showing that an electroencephalographic signature of the brain’s representation of internal bodily responses (the amplitude of heartbeat evoked potential) is abnormally attenuated in patients with borderline personality disorder (BPD). This deficit predicts symptoms, including the degree of emotional instability, and correlates with structural differences in the gray matter volume in the insula and the anterior cingulate cortex, brain regions engaged during emotional regulation and implicated in the integrative control of mind and body. Patients with BPD in remission show a more normative heartbeat evoked potential, suggesting that strategies to improve mental and physiological integration may enhance psychotherapeutic interventions for this patient group.

Cyberball3D+: A 3D Serious Game for fMRI Investigating Social Exclusion and Empathy

This paper presents a 3D interactive gaming paradigm for the secluded space of an fMRI scanner. The Cyberball3D+ game is a virtual ball-toss game in which the participant is either excluded or not from ball tossing played by three virtual players and the subject in the scanner. It has been used in simple sketch mode by neuroscientists for research on ostracism, social exclusion or rejection as well as discrimination and prejudice. The game proposed is designed to render an interactive Virtual Environment (VE) on an fMRI display, enabling the conduct of formal neuroscientific experiments and investigating the effects of social exclusion, empathy and different level of anthropomorphism on human brain activity. Although, here, the focus is on the technical implementation of the system, the goal is to use this system to explore whether the pain felt by someone when socially excluded is the same when observing other people get socially excluded and whether there are differences in relation to empathy for friends and strangers. Moreover, for the first time, we propose a validated neuroscientific measure of character believability and emotional engagement. The system was developed in close collaboration between the Technical University of Crete where the technical implementation took place and the Brighton and Sussex Medical School where the initial fMRI experiments were conducted using the system proposed. A broader aim of this work is to assess whether such powerful social-psychological studies could be usefully carried out within VEs advancing cognitive neuroscience and computer graphics as well as serious gaming research.

Imaging abnormal skin sensations: a novel functional MRI study

Abstract Background A subgroup of patients present to dermatological services with unexplained skin sensations, usually ascribing them to infestation; however, no medical cause can be found. This condition is referred to as delusional infestation, a rare and difficult to treat disorder with considerable impact on psychosocial functioning. The neurobiological mechanisms underlying this condition are unclear. We undertook the first functional MRI (fMRI) study in this group of patients. Methods Five patients presenting with medically unexplained skin sensations were recruited from the specialist psychodermatology service at The Royal London Hospital, UK (mean age 52·8 years, four women, one man). Five healthy controls were matched for age and gender. Whole brain fMRI data were acquired with a 1·5 T scanner. In an event-related design, participants were randomly shown six classes of images: insects on skin, insects on leaf, other objects on skin, other objects on leaf, neutral images, and disgusting and fearful images. Functional images were analysed with statistical parametric mapping, version 8. A full factorial model was used to analyse the results with two factors—group and stimulus type. Findings Results are reported at the significance threshold p Interpretation We have shown for the first time that brain activity differs between patients with abnormal skin sensations and controls when viewing pictures. This activity is in regions of brain supporting emotional awareness. Funding UK Medical Research Council.

20 Dissociative experiences in patients with fibromyalgia are mediated by symptoms of autonomic dysfunction

Objective The aim of this study was to determine the basis of dissociative experiences in patients with fibromyalgia, testing a hypothesised link to ‘internal agency’ through interoception and autonomic control. Fibromyalgia is a complex polysymptomatic musculoskeletal disorder affecting 5% of the population. Common neuropsychiatric features include emotional fatigue, subjective cognitive dysfunction (e.g. ‘brain-fog’) and dissociation. The combination of brain-fog and dissociation is linked to higher levels of pain symptom intensity and decreased mental well-being. Patients describe such disturbances are as ‘nearly universal’ and important, yet the mechanisms underlying neuropsychiatric symptoms in fibromyalgia are poorly understood. Interestingly fibromyalgia is associated with dysautonomia, notably orthostatic intolerance. Moreover, fibromyalgia and dysautonomia (e.g. Postural Tachycardia Syndrome; PoTS) are both associated with connective tissue disorders, specifically joint hypermobility syndromes (Ehlers Danlos Syndrome hypermobile type; EDS-HT). Method Twenty-one patients with fibromyalgia (20 female; mean age 41.86 years) and twenty-two healthy controls (16 female; mean age 44.00 years) were recruited. Each participant completed the Dissociative Experiences Scale and the ASQoLS, which measures symptoms of autonomic dysfunction including orthostatic intolerance. All participants underwent assessment for joint hypermobility/EDS-HT using Brighton Criteria. Statistical comparison between groups was performed using independent samples t test. Mediation analyses were conducted according to the method of Baron and Kenny. Results Patients with fibromyalgia reported greater (mean, SEM) dissociative experiences (48.67, 9.99) than the control group (18.14, 2.72), (t40=2.95, p=0.005) and greater symptoms of orthostatic intolerance (41.90, 4.93) than controls (8.64, 1.02), (t41=6.611, p<0.001). The relationship between fibromyalgia (independent variable) and dissociation (dependent variable) remained significant after adjusting for the gender (r=0.391, p=0.011). This relationship was rendered non-significant when adjusted for symptoms of orthostatic intolerance (r=0.175, p=0.281), indicating full mediation. Interestingly all three variables (fibromyalgia, dissociative experiences and orthostatic intolerance) correlated significantly with the presence of joint hypermobility syndrome/EDS-HT. Conclusion In a patient population vulnerable to neuropsychiatric symptoms, we found that dissociative experiences are fully mediated by symptoms of orthostatic intolerance. This is also the first study, to our knowledge, to explore dissociation and orthostatic intolerance in the context of fibromyalgia. Moreover, dissociation and brain-fog appear closely linked and are frequently reported by both patients with fibromyalgia and those with PoTS. Our observations are consistent with the hypothesised basis to dissociative symptoms in abnormalities in self-representation and internal agency linked to autonomic control and interoceptive prediction, revealed by subjective symptoms of orthostatic intolerance. This study suggests possibilities for recognition and treatment of neuropsychiatric symptoms.