Heartbeat-evoked neural response abnormalities in generalized anxiety disorder during peripheral adrenergic stimulation.

Hyperarousal symptoms in generalized anxiety disorder (GAD) are often incongruent with the observed physiological state, suggesting that abnormal processing of interoceptive signals is a characteristic feature of the disorder. To examine the neural mechanisms underlying interoceptive dysfunction in GAD, we evaluated whether adrenergic modulation of cardiovascular signaling differentially affects the heartbeat-evoked potential (HEP), an electrophysiological marker of cardiac interoception, during concurrent electroencephalogram and functional magnetic resonance imaging (EEG-fMRI) scanning. Intravenous infusions of the peripheral adrenergic agonist isoproterenol (0.5 and 2.0 micrograms, µg) were administered in a randomized, double-blinded and placebo-controlled fashion to dynamically perturb the cardiovascular system while recording the associated EEG-fMRI responses. During the 0.5 µg isoproterenol infusion, the GAD group (n = 24) exhibited significantly larger changes in HEP amplitude in an opposite direction than the healthy comparison (HC) group (n = 24). In addition, the GAD group showed significantly larger absolute HEP amplitudes than the HC group during saline infusions, when cardiovascular tone did not increase. No significant group differences in HEP amplitude were identified during the 2.0 µg isoproterenol infusion. Using analyzable blood oxygenation level-dependent fMRI data from participants with concurrent EEG-fMRI data (21 GAD and 21 HC), we found that the aforementioned HEP effects were uncorrelated with fMRI signals in the insula, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, amygdala, and somatosensory cortex, brain regions implicated in cardiac signal processing in prior fMRI studies. These findings provide additional evidence of dysfunctional cardiac interoception in GAD and identify neural processes at the electrophysiological level that may be independent from blood oxygen level-dependent responses during peripheral adrenergic stimulation.

Hemispheric divergence of interoceptive processing across psychiatric disorders.

Interactions between top-down attention and bottom-up visceral inputs are assumed to produce conscious perceptions of interoceptive states, and while each process has been independently associated with aberrant interoceptive symptomatology in psychiatric disorders, the neural substrates of this interface are unknown. We conducted a preregistered functional neuroimaging study of 46 individuals with anxiety, depression, and/or eating disorders (ADE) and 46 propensity-matched healthy comparisons (HC), comparing their neural activity across two interoceptive tasks differentially recruiting top-down or bottom-up processing within the same scan session. During an interoceptive attention task, top-down attention was voluntarily directed towards cardiorespiratory or visual signals, whereas during an interoceptive perturbation task, intravenous infusions of isoproterenol (a peripherally-acting beta-adrenergic receptor agonist) were administered in a double-blinded and placebo-controlled fashion to drive bottom-up cardiorespiratory sensations. Across both tasks, neural activation converged upon the insular cortex, localizing within the granular and ventral dysgranular subregions bilaterally. However, contrasting hemispheric differences emerged, with the ADE group exhibiting (relative to HCs) an asymmetric pattern of overlap in the left insula, with increased or decreased proportions of co-activated voxels within the left or right dysgranular insula, respectively. The ADE group also showed less agranular anterior insula activation during periods of bodily uncertainty (i.e., when anticipating possible isoproterenol-induced changes that never arrived). Finally, post-task changes in insula functional connectivity were associated with anxiety and depression severity. These findings confirm the dysgranular mid-insula as a key cortical interface where attention and prediction meet real-time bodily inputs, especially during heightened awareness of interoceptive states. Further, the dysgranular mid-insula may indeed be a "locus of disruption" for psychiatric disorders.

Heartbeat-evoked neural response abnormalities in generalized anxiety disorder during peripheral adrenergic stimulation.

Hyperarousal symptoms in generalized anxiety disorder (GAD) are often incongruent with the observed physiological state, suggesting that abnormal processing of interoceptive signals is a characteristic feature of the disorder. To examine the neural mechanisms underlying interoceptive dysfunction in GAD, we evaluated whether adrenergic modulation of cardiovascular signaling differentially affects the heartbeat evoked potential (HEP), an electrophysiological marker of cardiac interoception, during concurrent electroencephalogram and functional magnetic resonance imaging (EEG-fMRI) scanning. Intravenous infusions of the peripheral adrenergic agonist isoproterenol (0.5 and 2.0 micrograms, µg) were administered in a randomized, double-blinded and placebo-controlled fashion to dynamically perturb the cardiovascular system while recording the associated EEG-fMRI responses. During the 0.5 µg isoproterenol infusion, the GAD group (n=24) exhibited significantly larger changes in HEP amplitude in an opposite direction than the HC group (n=24). In addition, the GAD group showed significantly larger absolute HEP amplitudes than HC during saline infusions, when cardiovascular tone did not increase. No significant group differences in HEP amplitude were identified during the 2.0 µg isoproterenol infusion. Using analyzable blood oxygenation level dependent fMRI data from participants with concurrent EEG-fMRI data (21 GAD and 21 HC), we found that the aforementioned HEP effects were uncorrelated with fMRI signals in the insula, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, amygdala, and somatosensory cortex, brain regions implicated in cardiac signal processing according to prior fMRI studies. These findings provide additional evidence of dysfunctional cardiac interoception in GAD and identify neural processes at the electrophysiological level that may be independent from blood oxygen level-dependent responses during peripheral adrenergic stimulation.

Reduced vmPFC-insula functional connectivity in generalized anxiety disorder: a Bayesian confirmation study.

Differences in the correlated activity of networked brain regions have been reported in individuals with generalized anxiety disorder (GAD) but an overreliance on null-hypothesis significance testing (NHST) limits the identification of disorder-relevant relationships. In this preregistered study, we applied both a Bayesian statistical framework and NHST to the analysis of resting-state fMRI scans from females with GAD and matched healthy comparison females. Eleven a-priori hypotheses about functional connectivity (FC) were evaluated using Bayesian (multilevel model) and frequentist (t-test) inference. Reduced FC between the ventromedial prefrontal cortex (vmPFC) and the posterior-mid insula (PMI) was confirmed by both statistical approaches and was associated with anxiety sensitivity. FC between the vmPFC-anterior insula, the amygdala-PMI, and the amygdala-dorsolateral prefrontal cortex (dlPFC) region pairs did not survive multiple comparison correction using the frequentist approach. However, the Bayesian model provided evidence for these region pairs having decreased FC in the GAD group. Leveraging Bayesian modeling, we demonstrate decreased FC of the vmPFC, insula, amygdala, and dlPFC in females with GAD. Exploiting the Bayesian framework revealed FC abnormalities between region pairs excluded by the frequentist analysis and other previously undescribed regions in GAD, demonstrating the value of applying this approach to resting-state FC data in clinical investigations.

Null results of oxytocin and vasopressin administration on mentalizing in a large fMRI sample: evidence from a randomized controlled trial.

BACKGROUND: Although potential links between oxytocin (OT), vasopressin (AVP), and social cognition are well-grounded theoretically, most studies have included all male samples, and few have demonstrated consistent effects of either neuropeptide on mentalizing (i.e. understanding the mental states of others). To understand the potential of either neuropeptide as a pharmacological treatment for individuals with impairments in social cognition, it is important to demonstrate the beneficial effects of OT and AVP on mentalizing in healthy individuals. METHODS: In the present randomized, double-blind, placebo-controlled study (n = 186) of healthy individuals, we examined the effects of OT and AVP administration on behavioral responses and neural activity in response to a mentalizing task. RESULTS: Relative to placebo, neither drug showed an effect on task reaction time or accuracy, nor on whole-brain neural activation or functional connectivity observed within brain networks associated with mentalizing. Exploratory analyses included several variables previously shown to moderate OT's effects on social processes (e.g., self-reported empathy, alexithymia) but resulted in no significant interaction effects. CONCLUSIONS: Results add to a growing literature demonstrating that intranasal administration of OT and AVP may have a more limited effect on social cognition, at both the behavioral and neural level, than initially assumed. Randomized controlled trial registrations: ClinicalTrials.gov; NCT02393443; NCT02393456; NCT02394054.

Central Autonomic Network Alterations in Anorexia Nervosa Following Peripheral Adrenergic Stimulation.

BACKGROUND: Anorexia nervosa (AN) is characterized by low body weight, disturbed eating, body image disturbance, anxiety, and interoceptive dysfunction. However, the neural processes underlying these dysfunctions in AN are unclear. This investigation combined an interoceptive pharmacological probe, the peripheral ß-adrenergic agonist isoproterenol, with resting-state functional magnetic resonance imaging to examine whether individuals with AN relative to healthy comparison participants show dysregulated neural coupling in central autonomic network brain regions. METHODS: Resting-state functional magnetic resonance imaging was performed in 23 weight-restored female participants with AN and 23 age- and body mass index-matched healthy comparison participants before and after receiving isoproterenol infusions. Whole-brain functional connectivity (FC) changes were examined using central autonomic network seeds in the amygdala, anterior insular cortex, posterior cingulate cortex, and ventromedial prefrontal cortex after performing physiological noise correction procedures. RESULTS: Relative to healthy comparison participants, adrenergic stimulation caused widespread FC reductions in the AN group between central autonomic network regions and motor, premotor, frontal, parietal, and visual brain regions. Across both groups, these FC changes were inversely associated with trait anxiety (State-Trait Anxiety Inventory-Trait), trait depression (9-item Patient Health Questionnaire), and negative body image perception (Body Shape Questionnaire) measures, but not with changes in resting heart rate. These results were not accounted for by baseline group FC differences. CONCLUSIONS: Weight-restored females with AN show a widespread state-dependent disruption of signaling between central autonomic, frontoparietal, and sensorimotor brain networks that facilitate interoceptive representation and visceromotor regulation. Additionally, trait associations between central autonomic network regions and these other brain networks suggest that dysfunctional processing of interoceptive signaling may contribute to affective and body image disturbance in AN.

Association of Generalized Anxiety Disorder With Autonomic Hypersensitivity and Blunted Ventromedial Prefrontal Cortex Activity During Peripheral Adrenergic Stimulation: A Randomized Clinical Trial.

IMPORTANCE: ß-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 ß-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.

The unique face of comorbid anxiety and depression: increased interoceptive fearfulness and reactivity.

Anxiety and depression commonly co-occur, yet the underlying brain and behavioral processes are poorly understood. Here we examined the hypothesis that individuals with comorbid anxiety and depression would show increased fearful reactivity to an aversive interoceptive perturbation relative to depressed-only individuals. One-hundred and eighty anxious and/or depressed participants from the Tulsa 1000 study completed multi-level behavioral or functional magnetic resonance imaging assessments of interoception and nociception including breath-hold and cold-pressor challenges, and heartbeat perception and interoceptive attention tasks. One-hundred and four individuals with comorbid depression and anxiety disorders (Dep+Anx) were propensity matched with 52 individuals with depression-only (Dep). Data were analyzed using mixed-effects linear regression. The Dep+Anx group showed significantly greater self-reported fear of suffocation during breath holding (Wilcoxon r = 0.23) and reduced cold pain tolerance (R 2 = 0.027) signified by hand removal during immersion. However, these groups did not differ with respect to neutrally-valenced behavioral indices of heartbeat perception or neural indices of interoceptive attention. Individuals with comorbid depression and anxiety, vs. those with only depression, show increased respiratory fearfulness and nociceptive reactivity during perturbations of these signals, whilst showing similar interoceptive awareness in the absence of perturbation. Our findings suggest that individuals with comorbid anxiety and depression process aversive interoceptive and nociceptive signals differently than those with depression alone, providing support for a process model of increased threat sensitivity and hyperarousal in anxious depression.

Relative activation patterns associated with self-transcendent and self-enhancement core values: An fMRI study of basic human values theory concepts in males.

Core values have been shown to influence a variety of social behaviors, but research on the brain networks supporting their effects is sparse. While undergoing fMRI scanning, twenty male participants evaluated descriptions of real-world activities according to how worthwhile they were and how likely they were to participate in them. Each activity was categorized according to contexts conceptualized in the Basic Human Values Theory (BHVT) model of core values. We investigated two Self-enhancement values (Power and Achievement) and two Self-transcendent values (Benevolence and Universalism). Behavioral results indicated that Achievement and Benevolence activities were rated higher on both worthiness and participation willingness than Power and Universalism activities. Neuroimaging results revealed that self-transcendence activities elicited greater medial prefrontal cortex and anterior cingulate activation relative to self-enhancement activities during participation rated trials. Contrasting Power, Benevolence, and Universalism activities against Achievement activities during participation rated trials revealed a network of regions critical for moral processing, suggesting that activities corresponding to these three values were considered within a moral framework. No brain regions demonstrated activity that tracked behavioral ratings associated with specific values. This study expands upon previous core values research by demonstrating that real-world contexts related to different BHVT values elicit different brain regions.

Null results of oxytocin and vasopressin administration across a range of social cognitive and behavioral paradigms: Evidence from a randomized controlled trial.

Research examining oxytocin and vasopressin in humans has the potential to elucidate neurobiological mechanisms underlying human sociality that have been previously unknown or not well characterized. A primary goal of this work is to increase our knowledge about neurodevelopmental and psychiatric disorders characterized by impairments in social cognition. However, years of research highlighting wide-ranging effects of, in particular, intranasal oxytocin administration have been tempered as the fields of psychology, neuroscience, and other disciplines have been addressing concerns over the reproducibility and validity of research findings. We present a series of behavioral tasks that were conducted using a randomized, double-blind, placebo controlled, between-subjects design, in which our research group found no main effects of oxytocin and vasopressin on a host of social outcomes. In addition to null hypothesis significance testing, we implemented equivalence testing and Bayesian hypothesis testing to examine the sensitivity of our findings. These analyses indicated that 47-83% of our results (depending on the method of post-hoc analysis) had enough sensitivity to detect the absence of a main effect. Our results add to evidence that intranasal oxytocin may have a more limited direct effect on human social processes than initially assumed and suggest that the direct effects of intranasal vasopressin may be similarly limited. Randomized controlled trial registration: NCT01680718.

The influence of oxytocin and vasopressin on men's judgments of social dominance and trustworthiness: An fMRI study of neutral faces.

Cues signaling trust and dominance are crucial for social life. Previous studies on the effects of oxytocin (OT) nasal sprays on trustworthiness evaluations have been inconsistent and its influence on dominance is unknown. Vasopressin (AVP) may also influence social cue perception, but even fewer investigations have evaluated this possibility. We evaluated the effects of intranasal OT and AVP compared to placebo control during three double-blinded functional magnetic resonance imaging sessions. Twenty males received a pseudo-randomized order of nasal spray conditions and rated the trustworthiness and dominance of neutral faces. OT increased facial dominance ratings compared to placebo. Neuroimaging results revealed an inverse relationship between brain activation and face ratings for OT compared to placebo in regions involved in processing emotional expressions. Specifically, the right superior temporal gyrus was attenuated as ratings increased and the left precuneus selectively diminished with increasing dominance ratings. Additionally, OT increased functional connectivity between frontoparietal regions and the right amygdala for faces rated as highly dominant, but OT increased connectivity between the fusiform gyrus, hippocampus, and bilateral ventral tegmental area (VTA) for faces perceived as highly trustworthy. Overall, OT increased the perception of dominance but did not influence trustworthiness judgments. However, we observed regional neural effects for OT that differed between judgments of trustworthiness and dominance. AVP attenuated left temporoparietal junction activity as face ratings increased, a result consistent with AVP influencing mentalization. AVP also led to increased left amygdala and right VTA connectivity with the putamen, which is consistent with cue-driven, habitual responses.