Andrew P. Owens

Postural tachycardia syndrome—current experience and concepts

Postural tachycardia syndrome (PoTS) is a poorly understood but important cause of orthostatic intolerance resulting from cardiovascular autonomic dysfunction. PoTS is distinct from the syndromes of autonomic failure usually associated with orthostatic hypotension, such as pure autonomic failure and multiple system atrophy. Individuals affected by PoTS are mainly young (aged between 15 years and 40 years) and predominantly female. The symptoms—palpitations, dizziness and occasionally syncope—mainly occur when the patient is standing upright, and are often relieved by sitting or lying flat. Common stimuli in daily life, such as modest exertion, food ingestion and heat, are now recognized to be capable of exacerbating the symptoms. Onset of the syndrome can be linked to infection, trauma, surgery or stress. PoTS can be associated with various other disorders; in particular, joint hypermobility syndrome (also known as Ehlers–Danlos syndrome hypermobility type, formerly termed Ehlers–Danlos syndrome type III). This Review describes the characteristics and neuroepidemiology of PoTS, and outlines possible pathophysiological mechanisms of this syndrome, as well as current and investigational treatments.

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.

Intermittent Autonomic Disorders and Emotion: A Two-way Street?

Background: Long-term mortality is increased in patients with a history of traumatic brain injury (TBI). Pathophysiology is unknown but might be related to central autonomic dysfunction compromising cardiovascular control. In patients with a history of mild TBI, we found compromised cardiovascular responses to parasympathetic challenge by eyeball-pressure-stimulation (EPS). We hypothesize that EPS also yields abnormal responses in patients with a history of moderate-severe TBI. Methods: In 51 patients with a history of moderate-severe-TBI (32.71 ± 10.49 years, 43.12 ± 33.35 months post-injury, GCS 9.29 ± 4.49), and 30 controls (29.13 ± 9.77 years), we recorded respiration, RR-intervals (RRI), systolic and diastolic blood-pressure (BPsys, BPdia), before and during monocular EPS (120 seconds; 30 mmHg), using an ophthalmologic ocular-pressuredevice. We calculated spectral-powers of mainly sympathetic low (LF: 0.04-0.15Hz) and parasympathetic high (HF: 0.15-0.5Hz) frequency RRI-fluctuations, sympathetically mediated LF-powers of BPsys, normalized RRI-LF- (LFnu-RRI-) powers, normalized RRI-HFpowers (HFnu-RRI-powers), and RRI-LF/HF-ratios. We compared parameters between groups before and during EPS by RANOVA with post-hoc analysis (significance: p b 0.05). Results: At rest, LF-BPsyspowers were lower in patients than controls (11.31 ± 13.23 vs. 15.16 ± 9.56, p = 0.011). During EPS, only controls significantly increased RRIs and HFnu-RRI-powers, and decreased LF-RRI-powers, LFnu-RRI-powers, RRI-LF/HF-ratios, and LF-BPsys-powers. In postTBI-patients, EPS only increased BPsys (132.00 ± 13.13 vs. 129.22 ± 14.52 mmHg, p b 0.001) but changed no other parameter. Conclusions: Already at rest, autonomic BP-modulation is compromised in moderate-severe post-TBI-patients. During EPS, moderate-severe post-TBI-patients fail to activate parasympathetic cardiovascular

Interoceptive inference: From computational neuroscience to clinic

HighlightsHomeostatic interoceptive signal influence efferent autonomic outflow.Predictive coding frameworks can elucidate interoceptive and autonomic symbiosis.We describe interoceptive and autonomic symbiosis using interoceptive inference.We summarise our empirical application of interoceptive inference to dysautonomia.We report preliminary findings linking altered interoception to psychopathology. &NA; The central and autonomic nervous systems can be defined by their anatomical, functional and neurochemical characteristics, but neither functions in isolation. For example, fundamental components of autonomically mediated homeostatic processes are afferent interoceptive signals reporting the internal state of the body and efferent signals acting on interoceptive feedback assimilated by the brain. Recent predictive coding (interoceptive inference) models formulate interoception in terms of embodied predictive processes that support emotion and selfhood. We propose interoception may serve as a way to investigate holistic nervous system function and dysfunction in disorders of brain, body and behaviour. We appeal to predictive coding and (active) interoceptive inference, to describe the homeostatic functions of the central and autonomic nervous systems. We do so by (i) reviewing the active inference formulation of interoceptive and autonomic function, (ii) survey clinical applications of this formulation and (iii) describe how it offers an integrative approach to human physiology; particularly, interactions between the central and peripheral nervous systems in health and disease.

Orthostatic intolerance and autonomic dysfunction following bariatric surgery: A retrospective study and review of the literature

The prevalence and costs of the obesity epidemic and obesity-related conditions, including diabetes mellitus, is consistently increasing worldwide. Bariatric medicine is attempting to address this with weight loss and exercise programmes, and with increasing frequency, various forms of bariatric surgery. There has been considerable success reported after bariatric surgery but not without. We describe 14 patients with orthostatic intolerance (OI) post bariatric surgery. We report on OI (postural dizziness, palpitations and fainting), the results of cardiovascular autonomic testing and the associated and/or causative findings as well as reviewing the literature to consider the possible mechanisms. Comprehensive autonomic testing revealed that 35.7% (Buchwald et al., 2004) of these patients fulfilled the criteria for the Postural Tachycardia Syndrome (PoTS), 57.1% (Cremieux et al., 2008) had low levels of basal BP and 42.9% (Cammisotto & Bendayan, 2007) patients were presyncopal and 14.3% (Billakanty et al., 2008) experienced syncope. We propose that the incidence of OI post-bariatric surgery is higher than considered, that certain cohorts may be more susceptible to complications, and that further research is needed to identify the prevalence and, ideally anticipate occurrence. With the increasing prevalence of obesity and required clinical interventions, further understanding of the pathophysiological processes causing autonomic dysfunction after bariatric interventions will aid management, which may differ in those with an underlying disposition to autonomic involvement, such as diabetics, in whom such procedures are increasingly used.

Emotional orienting during interoceptive threat in orthostatic intolerance: Dysautonomic contributions to psychological symptomatology in the postural tachycardia syndrome and vasovagal syncope.

Cognitive and emotional processes are influenced by interoception (homeostatic somatic feedback), particularly when physiological arousal is unexpected and discrepancies between predicted and experienced interoceptive signals may engender anxiety. Due to the vulnerability for comorbid psychological symptoms in forms of orthostatic intolerance (OI), this study investigated psychophysiological contributions to emotional symptomatology in 20 healthy control participants (13 females, mean age 36 ± 8 years), 20 postural tachycardia syndrome (PoTS) patients (18 females, mean age 38 ± 13 years) and 20 vasovagal syncope (VVS) patients (15 females, mean age 39 ± 12 years). We investigated indices of emotional orienting responses (OR) to randomly presented neutral, pleasant and unpleasant images in the supine position and during the induced interoceptive threat of symptom provocation of head-up tilt (HUT). PoTS and VVS patients produced greater indices of emotional responsivity to unpleasant images and, to a lesser degree, pleasant images, during interoceptive threat. Our findings are consistent with biased deployment of response-focused emotion regulation (ER) while patients are symptomatic, providing a mechanistic underpinning of how pathological autonomic overexcitation predisposes to anxiogenic traits in PoTS and VVS patients. This hypothesis may improve our understanding of why orthostasis exacerbates cognitive symptoms despite apparently normal cerebral autoregulation, and offer novel therapeutic targets for behavioural interventions aimed at reducing comorbid cognitive-affective symptoms in PoTS and VVS.

Emotion and the Autonomic Nervous System—A Two-Way Street: Insights From Affective, Autonomic and Dissociative Disorders

Brain and body are coupled by the autonomic nervous system. Emotions evoke “top-down” autonomic responses and are shaped by “bottom-up” afferent somatic feedback. This psychophysiological integration is supported by shared autonomic and emotional neuroanatomical pathways. Emotional stress disrupts normative autonomic function, typically through sympathoexcitation. Conversely, in dissociative disorders, emotional stress may suppress sympathoexcitation despite subjective emotional distress. Psychophysiological decoupling is further observed in forms of dysautonomia defined by autonomic overexcitation, resulting in emotional symptoms via interoception of dysautonomic symptoms. The study of these disorders elucidates mechanisms of psychophysiological integration and improves our pathophysiological understanding of affective, autonomic and dissociative disorders.

Abnormal cardiovascular sympathetic and parasympathetic responses to physical and emotional stimuli in depersonalization disorder

Background Depersonalization disorder (DPD) is characterized by a subjective sense of unreality, disembodiment, emotional numbing and reduced psychogenic (sudomotor) sympathoexcitation. Aims Three related experiments utilized escalating physical and emotional challenges in 14 DPD participants and 16 controls aimed to elucidate (i) whether the cardiovascular sympathetic (SNS) and parasympathetic (PNS) nervous systems are implicated in DPD pathophysiology and (ii) if possible, to determine whether the blunted sympathoexcitation in DPD is peripherally or centrally mediated. Method Participants completed the Beck Anxiety Inventory (BAI), Dissociative Experience Scale (DES), and Cambridge Depersonalization Scale (CDS). Study I recorded heart rate (HR) and blood pressure (BP) during 5 min supine baseline, 3 min sustained handgrip (HG), 3 min cold pressor (CP) and 5 min 60° head-up tilt (HUT). In study II, HR, BP, and heart rate variability (HRV) were recorded during 5 min simultaneous 60° HUT and continuous presentation of unpleasant images (5 s per image). Study III examined HR and BP orienting responses (ORs) to simultaneous 60° HUT and pseudorandom presentation of unpleasant, neutral and pleasant images (5 s per image 3 min 25 s). OR data was grouped by image valence post hoc. Results DPD BAI (p = 0.0004), DES (p = 0.0002), and CDS (p ≤ 0.0001) scores were higher than controls. The DPD group produced diminished diastolic BP (DBP) (p = 0.045) increases to HG. Other indices were comparable between groups. DPD participants produced diminished systolic BP (SBP) (p = 0.003) and DBP (p = 0.002) increases, but greater (p = 0.004) HR increases to CP. In study II, DPD high frequency HRV (HF-HRV)—indicating parasympathetic vagal activity–was reduced (p = 0.029). In study III, DPD DBP was higher throughout the 5 s duration of HUT/pseudorandom unpleasant image presentation (1 s, p = 0.002, 2 s p = 0.033, 3 s p = 0.001, 4 s p = 0.009, 5 s p = 0.029). Conclusions Study Is BP pressor data supports previous findings of suppressed sympathoexcitation in DPD. The greater HR increases to CP, decreased HF-HRV in study II, and increased DBP during unpleasant ORs in study III implicates the SNS and PNS in DPD pathophysiology. These studies suggest the cardiovascular autonomic dysregulation in DPD is likely to be centrally-mediated.

Joint hypermobility and autonomic hyperactivity: an autonomic and functional neuroimaging study

Abstract Background Joint hypermobility is a common connective tissue variant. Surprisingly, people with this disorder are especially vulnerable to anxiety. Recent imaging studies suggest that non-anxious individuals with hypermobility express structural and functional differences in emotional brain regions. Autonomic dysregulation, typically postural tachycardia, is often found. Our aim was to test the hypothesis that joint hypermobility increases the expression of anxiety through aberrant central autonomic control. Methods The study had a 2×2 factorial design (presence or absence of hypermobility×presence or absence of generalised anxiety disorder). Adults with generalised anxiety disorder and healthy controls were prospectively recruited so that half of each group had hypermobility. Autonomic testing was done before measurement by functional MRI of brain responses to emotional stimuli. Between-group analyses tested for differences in autonomic function and patterns of brain activation. Presence of generalised anxiety disorder was assessed with DSM-IV criteria (MINI, MINI International Neuropsychiatric Interview). Anxiety was quantified with the Beck Anxiety Inventory. All neuroimaging findings are presented at a significance threshold of p(FWE corrected) Findings 70 adults were recruited (32 with generalised anxiety disorder, of whom 16 had hypermobility; 38 controls of whom 19 had hypermobility). An increase in sympathetic reactivity (proportional change in heart rate on active standing) was observed in individuals with hypermobility (n=35) versus those without hypermobility (n=35) (mean change from baseline 22·4% [SE 2·7] vs 14·2 [2·1], p=0·024) and in those with generalised anxiety disorder (n=32) versus those without anxiety (n=38) (24·0 [2·9] vs 13·9 [1·9], p=0·005), correlating with hypermobility ( r =0·34, p=0·024) and anxiety scores ( r =0·38, p=0·004). There was an interaction between the effects of hypermobility and anxiety on sympathetic reactivity (p=0·001). Within the brain, individuals with hypermobility showed increased reactivity to emotional stimuli within brain areas implicated in emotional processing and autonomic control, notably amygdala (p[FWE corrected] Interpretation This study shows that joint hypermobility is associated with the expression of anxiety through autonomic hyper-reactivity linked to aberrant engagement of the amygdala and insula. This study is the first, to our knowledge, to provide a mechanistic understanding of the association between joint hypermobility and anxiety; the findings will enhance recognition across medical disciplines of extra-articular features and vulnerabilities of joint hypermobility, offering possibilities for optimum personalised medicine. Funding Medical Research Council.

Orthostatic Intolerance and Autonomic Dysfunction following Bariatric Surgery: A case series and review of the literature

Introduction: The prevalence and costs of the obesity epidemic and obesity-related conditions including diabetes mellitus is relentlessly increasing worldwide. Bariatric medicine is attempting to address this with weight loss and exercise programmes, and with increasing frequency, various forms of bariatric surgery. There has been considerable success reported after bariatric surgery but not without complications (1, 2, 3). Methods: We describe 13 patients referred in the last 5 years with orthostatic intolerance, who had undergone bariatric surgery. We report on orthostatic intolerance and the results of cardiovascular autonomic testing and the associated and/or causative findings. Results: Autonomic testing using established protocols (4) revealed 4 patients exhibiting PoTS, 6 patients with pre-syncope/syncope and 9 patients with low resting blood pressure. Conclusions: We have reviewed the literature and speculate on the possible mechanisms. We propose that the incidence of orthostatic intolerance due to autonomic dysfunction is higher than considered, that certain cohorts may be more susceptible to complications, and that further research is needed to identify the prevalence, and ideally anticipate occurrence. Further understanding of the pathophysiological processes causing autonomic dysfunction with different bariatric interventions will aid management, which may differ in those with an underlying disposition to autonomic involvement, such as diabetics in whom such procedures are increasingly used.