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Importance: β-Adrenergic stimulation elicits heart palpitations and dyspnea, key features of acute anxiety and sympathetic arousal, yet no neuroimaging studies have examined how the pharmacologic modulation of interoceptive signals is associated with fear-related neurocircuitry in individuals with generalized anxiety disorder (GAD).Objective: To examine the neural circuitry underlying autonomic arousal induced via isoproterenol, a rapidly acting, peripheral β-adrenergic agonist akin to adrenaline.Design, Setting, and Participants: This crossover randomized clinical trial of 58 women with artifact-free data was conducted from January 1, 2017, to November 31, 2019, at the Laureate Institute for Brain Research in Tulsa, Oklahoma.Exposures: Functional magnetic resonance imaging was used to assess neural responses during randomized intravenous bolus infusions of isoproterenol (0.5 and 2.0 μg) and saline, each administered twice in a double-blind fashion.Main Outcomes and Measures: Blood oxygen level-dependent responses across the whole brain during isoproterenol administration in patients with GAD vs healthy comparators. Cardiac and respiratory responses, as well as interoceptive awareness and anxiety, were also measured during the infusion protocol.Results: Of the 58 female study participants, 29 had GAD (mean [SD] age, 26.9 [6.8] years) and 29 were matched healthy comparators (mean [SD] age, 24.4 [5.0] years). During the 0.5-μg dose of isoproterenol, the GAD group exhibited higher heart rate responses (b = 5.34; 95% CI, 2.06-8.61; P = .002), higher intensity ratings of cardiorespiratory sensations (b = 8.38; 95% CI, 2.05-14.71; P = .01), higher levels of self-reported anxiety (b = 1.04; 95% CI, 0.33-1.76; P = .005), and significant hypoactivation in the ventromedial prefrontal cortex (vmPFC) that was evident throughout peak response (Cohen d = 1.55; P < .001) and early recovery (Cohen d = 1.52; P < .001) periods. Correlational analysis of physiological and subjective indexes and percentage of signal change extracted during the 0.5-μg dose revealed that vmPFC hypoactivation was inversely correlated with heart rate (r56 = -0.51, adjusted P = .001) and retrospective intensity of both heartbeat (r56 = -0.50, adjusted P = .002) and breathing (r56 = -0.44, adjusted P = .01) sensations. Ventromedial prefrontal cortex hypoactivation correlated inversely with continuous dial ratings at a trend level (r56 = -0.38, adjusted P = .051), whereas anxiety (r56 = -0.28, adjusted P = .27) and chronotropic dose 25 (r56 = -0.14, adjusted P = .72) showed no such association.Conclusions and Relevance: In this crossover randomized clinical trial, women with GAD exhibited autonomic hypersensitivity during low levels of adrenergic stimulation characterized by elevated heart rate, heightened interoceptive awareness, increased anxiety, and a blunted neural response localized to the vmPFC. These findings support the notion that autonomic hyperarousal may be associated with regulatory dysfunctions in the vmPFC, which could serve as a treatment target to help patients with GAD more appropriately appraise and regulate signals of sympathetic arousal.Trial Registration: ClinicalTrials.gov Identifier: NCT02615119. [ABSTRACT FROM AUTHOR]

Reduced Environmental Stimulation Therapy (REST) alters the balance of sensory input to the nervous system by systematically attenuating sensory signals from visual, auditory, thermal, tactile, vestibular, and proprioceptive channels. Previous research from our group has shown that REST via floatation acutely reduces anxiety and blood pressure (BP) while simultaneously heightening interoceptive awareness in clinically anxious populations. Anorexia nervosa (AN) is an eating disorder characterized by elevated anxiety, distorted body representation, and abnormal interoception, raising the question of whether REST might positively impact these symptoms. However, this approach has never been studied in eating disorders, and it is unknown whether exposure to floatation REST might worsen AN symptoms. To examine these possibilities, we conducted an open-label study to investigate the safety and tolerability of REST in AN. We also explored the acute impact of REST on BP, affective symptoms, body image disturbance, and interoception. Twenty-one partially weight-restored AN outpatients completed a protocol involving four sequential sessions of REST: reclining in a zero-gravity chair, floating in an open pool, and two sessions of floating in an enclosed pool. All sessions were 90 min, approximately 1 week apart. We measured orthostatic BP before and immediately after each session (primary outcome), in addition to collecting BP readings every 10 min during the session using a wireless waterproof system as a secondary outcome measure. Each participant's affective state, awareness of interoceptive sensations, and body image were assessed before and after every session (exploratory outcomes). There was no evidence of orthostatic hypotension following floating, and no adverse events (primary outcome). Secondary analyses revealed that REST induced statistically significant reductions in BP (p < 0.001; Cohen's d , 0.2–0.5), anxiety (p < 0.001; Cohen's d , >1) and negative affect (p < 0.01; Cohen's d , >0.5), heightened awareness of cardiorespiratory (p < 0.01; Cohen's d , 0.2–0.5) but not gastrointestinal sensations, and reduced body image dissatisfaction (p < 0.001; Cohen's d , >0.5). The findings from this initial trial suggest that individuals with AN can safely tolerate the physical effects of REST via floatation. Future randomized controlled trials will need to investigate whether these initial observations of improved anxiety, interoception, and body image disturbance occur in acutely ill AN populations. Clinical Trial Registration: ClinicalTrials.gov; Identifier: NCT02801084 (April 01, 2016). [ABSTRACT FROM AUTHOR]

Several studies have recently suggested that an abnormal processing of respiratory interoceptive and nociceptive (painful) stimuli may contribute to eating disorder (ED) pathophysiology. Mood and anxiety disorders (MA) are also characterized by abnormal respiratory symptoms, and show substantial comorbidity with ED. However, no studies have examined both respiratory and pain processing simultaneously within ED and MA. The present study systematically evaluated responses to perturbations of respiratory and nociceptive signals across the levels of physiology, behavior, and symptom report in a transdiagnostic ED sample (n = 51) that was individually matched to MA individuals (n = 51) and healthy comparisons (HC; n = 51). Participants underwent an inspiratory breath-holding challenge as a probe of respiratory interoception and a cold pressor challenge as a probe of pain processing. We expected both clinical groups to report greater stress and fear in response to respiratory and nociceptive perturbation than HCs, in the absence of differential physiological and behavioral responses. During breath-holding, both the ED and MA groups reported significantly more stress, feelings of suffocation, and suffocation fear than HC, with the ED group reporting the most severe symptoms. Moreover, anxiety sensitivity was related to suffocation fear only in the ED group. The heightened affective responses in the current study occurred in the absence of group differences in behavioral (breath hold duration, cold pressor duration) and physiological (end-tidal carbon dioxide, end-tidal oxygen, heart rate, skin conductance) responses. Against our expectations, there were no group differences in the response to cold pain stimulation. A matched-subgroup analysis focusing on individuals with anorexia nervosa (n = 30) produced similar results. These findings underscore the presence of abnormal respiratory interoception in MA and suggest that hyperreactivity to respiratory signals may be a potentially overlooked clinical feature of ED. [ABSTRACT FROM AUTHOR]

Prominent theories emphasize key roles for the insular cortex in the central representation of interoceptive sensations, but how this brain region responds dynamically to changes in interoceptive state remains incompletely understood. Here, we systematically modulated cardiorespiratory sensations in humans using bolus infusions of isoproterenol, a rapidly acting peripheral beta-adrenergic agonist similar to adrenaline. To identify central neural processes underlying these parametrically modulated interoceptive states, we used pharmacological functional magnetic resonance imaging (phMRI) to simultaneously measure blood-oxygenation-level dependent (BOLD) and arterial spin labelling (ASL) signals in healthy participants. Isoproterenol infusions induced dose-dependent increases in heart rate and cardiorespiratory interoception, with all participants endorsing increased sensations at the highest dose. These reports were accompanied by increased BOLD and ASL activation of the right insular cortex at the highest dose. Different responses across insula subregions were also observed. During anticipation, insula activation increased in more anterior regions. During stimulation, activation increased in the mid-dorsal and posterior insula on the right, but decreased in the same regions on the left. This study demonstrates the feasibility of phMRI for assessing brain activation during adrenergic interoceptive stimulation, and provides further evidence supporting a dynamic role for the insula in representing changes in cardiorespiratory states. This article is part of the themed issue 'Interoception beyond homeostasis: affect, cognition and mental health'. [ABSTRACT FROM AUTHOR]

Disrupted interoception is a prominent feature of the diagnostic classification of several psychiatric disorders. However, progress in understanding the interoceptive basis of these disorders has been incremental, and the application of interoception in clinical treatment is currently limited to panic disorder. To examine the degree to which the scientific community has recognized interoception as a construct of interest, we identified and individually screened all articles published in the English language on interoception and associated root terms in Pubmed, Psychinfo, and ISI Web of Knowledge. This search revealed that interoception is a multifaceted process that is being increasingly studied within the fields of psychiatry, psychology, neuroscience, and biomedical science. To illustrate the multifaceted nature of interoception, we provide a focused review of one of the most commonly studied interoceptive channels, the cardiovascular system, and give a detailed comparison of the most popular methods used to study cardiac interoception. We subsequently review evidence of interoceptive dysfunction in panic disorder, depression, somatic symptom disorders, anorexia nervosa, and bulimia nervosa. For each disorder, we suggest how interoceptive predictions constructed by the brain may erroneously bias individuals to express key symptoms and behaviors, and outline questions that are suitable for the development of neuroscience-based mental health interventions. We conclude that interoception represents a viable avenue for clinical and translational research in psychiatry, with a well-established conceptual framework, a neural basis, measurable biomarkers, interdisciplinary appeal, and transdiagnostic targets for understanding and improving mental health outcomes. [ABSTRACT FROM AUTHOR]