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Background: Dysregulation of fear processing through altered sensitivity to threat is thought to contribute to the development of anxiety disorders and major depressive disorder (MDD). However, fewer studies have examined fear processing in MDD than in anxiety disorders. The current study used propensity matching to examine the hypothesis that comorbid MDD and anxiety (AnxMDD) shows greater neural correlates of fear processing than MDD, suggesting that the co-occurrence of AnxMDD is exemplified by exaggerated defense related processes., Methods: 195 individuals with MDD (N = 65) or AnxMDD (N = 130) were recruited from the community and completed multi-level assessments, including a Pavlovian fear learning task during functional imaging. Visual images paired with threat (conditioned stimuli: CS+) were compared to stimuli not paired with threat (CS-)., Results: MDD and AnxMDD showed significantly different patterns of activation for CS+ vs CS- in the dorsal anterior insula/inferior frontal gyrus (partial eta squared; ηp 2  = 0.02), dorsolateral prefrontal cortex (ηp 2  = 0.01) and dorsal anterior/mid cingulate cortex (ηp 2  = 0.01). These differences were driven by greater activation to the CS+ in AnxMDD versus MDD., Limitations: Limitations include the cross-sectional design, a scream US rather than shock and half the number of MDD as AnxMDD participants., Conclusions: AnxMDD showed a pattern of increased activation in regions identified with fear processing. Effects were consistently driven by threat, further suggesting fear signaling as the emergent target process. Differences emerged in regions associated with salience processing, attentional orienting/conflict, self-relevant processing and executive functioning in comorbid anxiety and depression, thereby highlighting potential treatment targets for this prevalent and treatment resistant group., Competing Interests: Declaration of competing interest This work has been supported in part by The William K. Warren Foundation and the National Institute of General Medical Sciences center grant award number P20GM121312. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Maria Ironside, Rayus Kuplicki, Jennifer Stewart, Robin Aupperle, and Martin Paulus receive funding from the National Institute of General Medical Sciences (NIGMS) center grant P20GM121312; Maria Ironside has additional funding from National Institute of Mental Health (NIMH; R01MH132565). Sahib Khalsa has grant funding from the NIMH (K23MH112949, R01MH127225); Robin Aupperle has additional grant funding from NIMH (K23MH108707; R01MH123691); Jennifer Stewart has additional grant funding from the National Institute of Drug Abuse (NIDA) (R01DA050677), Rayus Kuplicki has additional funding from NIDA (R01DA050677); and Martin Paulus has additional grant funding from the NIDA (U01DA041089, R01DA050677)., (Copyright © 2024. Published by Elsevier B.V.)

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., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

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., (© 2023. The Author(s).)

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.

This study employed a series of heartbeat perception tasks to assess the hypothesis that cardiac interoceptive processing in individuals with depression/anxiety (N = 221), and substance use disorders (N = 136) is less flexible than that of healthy individuals (N = 53) in the context of physiological perturbation. Cardiac interoception was assessed via heartbeat tapping when: (1) guessing was allowed; (2) guessing was not allowed; and (3) experiencing an interoceptive perturbation (inspiratory breath hold) expected to amplify cardiac sensation. Healthy participants showed performance improvements across the three conditions, whereas those with depression/anxiety and/or substance use disorder showed minimal improvement. Machine learning analyses suggested that individual differences in these improvements were negatively related to anxiety sensitivity, but explained relatively little variance in performance. These results reveal a perceptual insensitivity to the modulation of interoceptive signals that was evident across several common psychiatric disorders, suggesting that interoceptive deficits in the realm of psychopathology manifest most prominently during states of homeostatic perturbation.

Background: Imbalances in approach-avoidance conflict (AAC) decision-making (e.g., sacrificing rewards to avoid negative outcomes) are considered central to multiple psychiatric disorders. We used computational modelling to examine 2 factors that are often not distinguished in descriptive analyses of AAC: decision uncertainty and sensitivity to negative outcomes versus rewards (emotional conflict)., Methods: A previously validated AAC task was completed by 478 participants, including healthy controls ( n = 59), people with substance use disorders ( n = 159) and people with depression and/or anxiety disorders who did not have substance use disorders ( n = 260). Using an active inference model, we estimated individual-level values for a model parameter that reflected decision uncertainty and another that reflected emotional conflict. We also repeated analyses in a subsample (59 healthy controls, 161 people with depression and/or anxiety disorders, 56 people with substance use disorders) that was propensity-matched for age and general intelligence., Results: The model showed high accuracy (72%). As further validation, parameters correlated with reaction times and self-reported task motivations in expected directions. The emotional conflict parameter further correlated with self-reported anxiety during the task ( r = 0.32, p < 0.001), and the decision uncertainty parameter correlated with self-reported difficulty making decisions ( r = 0.45, p < 0.001). Compared to healthy controls, people with depression and/or anxiety disorders and people with substance use disorders showed higher decision uncertainty in the propensity-matched sample ( t = 2.16, p = 0.03, and t = 2.88, p = 0.005, respectively), with analogous results in the full sample; people with substance use disorders also showed lower emotional conflict in the full sample ( t = 3.17, p = 0.002)., Limitations: This study was limited by heterogeneity of the clinical sample and an inability to examine learning., Conclusion: These results suggest that reduced confidence in how to act, rather than increased emotional conflict, may explain maladaptive approach-avoidance behaviours in people with psychiatric disorders., Competing Interests: None declared., (© 2021 Joule Inc. or its licensors)

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., Competing Interests: The authors have declared that no competing interests exist.

Background: Floatation-REST (Reduced Environmental Stimulation Therapy), an intervention that attenuates exteroceptive sensory input to the nervous system, has recently been found to reduce state anxiety across a diverse clinical sample with high levels of anxiety sensitivity (AS). To further examine this anxiolytic effect, the present study investigated the affective and physiological changes induced by Floatation-REST and assessed whether individuals with high AS experienced any alterations in their awareness for interoceptive sensation while immersed in an environment lacking exteroceptive sensation., Methods: Using a within-subject crossover design, 31 participants with high AS were randomly assigned to undergo a 90-minute session of Floatation-REST or an exteroceptive comparison condition. Measures of self-reported affect and interoceptive awareness were collected before and after each session, and blood pressure was measured during each session., Results: Relative to the comparison condition, Floatation-REST generated a significant anxiolytic effect characterized by reductions in state anxiety and muscle tension and increases in feelings of relaxation and serenity (p < .001 for all variables). Significant blood pressure reductions were evident throughout the float session and reached the lowest point during the diastole phase (average reduction >12 mm Hg). The float environment also significantly enhanced awareness and attention for cardiorespiratory sensations., Conclusions: Floatation-REST induced a state of relaxation and heightened interoceptive awareness in a clinical sample with high AS. The paradoxical nature of the anxiolytic effect in this sample is discussed in relation to Wolpe's theory of reciprocal inhibition and the regulation of distress via sustained attention to present moment visceral sensations such as the breath., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

BackgroundBilateral cardiac sympathetic denervation (BCSD) is a surgical treatment for refractory ventricular arrhythmias. Although the procedure has shown efficacy at reducing cardiac arrhythmias, its impact on mental health is unknown. In the current study we examined associations between the BCSD procedure and mental health.Methods10 ventricular arrhythmia patients undergoing BCSD completed assessments of anxiety, depression, and posttraumatic stress symptoms at pre- and post-BCSD time points. Wilcoxon signed rank and Mann-Whitney U tests were used to examine differences in mental health symptoms in the pre- and post-BSCD states. Point biserial correlations were used to explore associations between BCSD response and mental health symptoms.ResultsA significant reduction of anxiety symptoms was observed from pre- to post-BCSD. At the post-BCSD assessment, participants who successfully responded to the BCSD procedure exhibited lower anxiety symptoms compared to non-responders. However, no significant relationships were identified for depressive or PTSD symptoms.ConclusionThe BCSD procedure is associated with reduced anxiety shortly after successful treatment for refractory ventricular arrhythmias in a small sample. Longitudinal surveillance of mental health symptoms after BCSD may be warranted to monitor the impact of this procedure on mental health.

Individuals with anorexia nervosa (AN) typically display anxious traits prior to the onset of food avoidance and weight loss that characterize the disorder. Meal associated anxiety is an especially common clinical feature in these patients, and heightened sensitivity to sympathetically mediated interoceptive sensations has also been observed. However, it remains unclear how heightened interoceptive sensitivity relates to experiences of anxiety before and after meals. To investigate this relationship, we experimentally induced anxiety and panic symptoms with isoproterenol, a peripheral sympathetic agonist similar to adrenaline, across several different conditions: during panic provocation, during anticipation of a 1,000 Calorie meal, and after meal consumption. Fifteen AN and 15 age- and sex-matched healthy comparisons received bolus infusions of isoproterenol and saline in a double-blinded, randomized design. Participants rated anxiety symptoms after each infusion, completed panic rating scales, and traced the location of perceived palpitations on a manikin to index interoceptive "body map" representation. The AN group reported significantly elevated anxiety relative to healthy comparisons during infusions before and after the meal, but surprisingly, not during panic provocation. These symptoms were accompanied by geographical differences in patterns of perceived heartbeat sensations across each condition. In particular, the AN group localized heartbeat sensations disproportionately to the chest during meal related saline infusions, when no cardiorespiratory modulation actually occurred. The AN group also showed a trend toward higher panic attack rates during the meal anticipation period. Correcting for anxiety levels reported during saline infusions abolished group differences in anxiety change across all conditions, suggesting a significant contribution of anxious traits in AN. The observation of meal related "visceral illusions" provides further evidence that AN is associated with abnormal interoceptive representation of the heartbeat and suggests that meal consumption, particularly when anticipated, preferentially alters the processing of interoception related signals in AN.

We report here, for the first time, two cases demonstrating a synergistic application of bilateral cardiac sympathetic decentralization and multimodal psychiatric treatment for the assessment and management of anxiety following recurrent Implantable Cardioverter Defibrillator (ICD) shocks. In a first case the combination of bilateral cardiac sympathetic decentralization (BCSD), cognitive behavioral psychotherapy and anxiolytic medication was sufficient to attenuate the patient's symptoms and maladaptive behaviors, with a maintained benefit at 1 year. Among the more prominent subjective changes in the post-lesion state we observed a decrease in aversive interoceptive sensations, particularly of the heartbeat. The patient continued to experience cognitive threat appraisals on a frequent basis, although these were no longer incapacitating. In a second case, we report the effect of BCSD on autonomic tone and subjective state. In the post-lesion state we observed attenuated sympathetic responses to the valsalva maneuver, isometric handgrip and mental arithmetic stressor, including decreased systolic and diastolic blood pressure and, decreased skin conductance. Collectively, these preliminary findings suggest that an integrative, multidisciplinary approach to treating anxiety disorders in the setting of ventricular arrhythmias and recurrent ICD shocks can result in sustained improvements in physical, psychological, and functional status. These findings raise the possibility of a potential role for the stellate ganglion in the modulation of emotional experience and afferent transmission of interoceptive information to the central nervous system.

Electroencephalography (EEG) measures the brain's electrophysiological spatio-temporal activities with high temporal resolution. Multichannel and broadband analysis of EEG signals is referred to as EEG microstates (EEG-ms) and can characterize such dynamic neuronal activity. EEG-ms have gained much attention due to the increasing evidence of their association with mental activities and large-scale brain networks identified by functional magnetic resonance imaging (fMRI). Spatially independent EEG-ms are quasi-stationary topographies (e.g., stable, lasting a few dozen milliseconds) typically classified into four canonical classes (microstates A through D). They can be identified by clustering EEG signals around EEG global field power (GFP) maxima points. We examined the EEG-ms properties and the dynamics of cohorts of mood and anxiety (MA) disorders subjects (n = 61) and healthy controls (HCs; n = 52). In both groups, we found four distinct classes of EEG-ms (A through D), which did not differ among cohorts. This suggests a lack of significant structural cortical abnormalities among cohorts, which would otherwise affect the EEG-ms topographies. However, both cohorts' brain network dynamics significantly varied, as reflected in EEG-ms properties. Compared to HC, the MA cohort features a lower transition probability between EEG-ms B and D and higher transition probability from A to D and from B to C, with a trend towards significance in the average duration of microstate C. Furthermore, we harnessed a recently introduced theoretical approach to analyze the temporal dependencies in EEG-ms. The results revealed that the transition matrices of MA group exhibit higher symmetrical and stationarity properties as compared to HC ones. In addition, we found an elevation in the temporal dependencies among microstates, especially in microstate B for the MA group. The determined alteration in EEG-ms temporal dependencies among the cohorts suggests that brain abnormalities in mood and anxiety disorders reflect aberrant neural dynamics and a temporal dwelling among ceratin brain states (i.e., mood and anxiety disorders subjects have a less dynamicity in switching between different brain states). [ABSTRACT FROM AUTHOR]

Floatation-REST (Reduced Environmental Stimulation Therapy) reduces sensory input to the nervous system through the act of floating supine in a pool of water saturated with Epsom salt. The float experience is calibrated so that sensory signals from visual, auditory, olfactory, gustatory, thermal, tactile, vestibular, gravitational and proprioceptive channels are minimized, as is most movement and speech. This open-label study aimed to examine whether Floatation-REST would attenuate symptoms of anxiety, stress, and depression in a clinical sample. Fifty participants were recruited across a spectrum of anxiety and stress-related disorders (posttraumatic stress, generalized anxiety, panic, agoraphobia, and social anxiety), most (n = 46) with comorbid unipolar depression. Measures of self-reported affect were collected immediately before and after a 1-hour float session, with the primary outcome measure being the pre- to post-float change score on the Spielberger State Anxiety Inventory. Irrespective of diagnosis, Floatation-REST substantially reduced state anxiety (estimated Cohen’s d > 2). Moreover, participants reported significant reductions in stress, muscle tension, pain, depression and negative affect, accompanied by a significant improvement in mood characterized by increases in serenity, relaxation, happiness and overall well-being (p < .0001 for all variables). In reference to a group of 30 non-anxious participants, the effects were found to be more robust in the anxious sample and approaching non-anxious levels during the post-float period. Further analysis revealed that the most severely anxious participants reported the largest effects. Overall, the procedure was well-tolerated, with no major safety concerns stemming from this single session. The findings from this initial study need to be replicated in larger controlled trials, but suggest that Floatation-REST may be a promising technique for transiently reducing the suffering in those with anxiety and depression. Trial registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

The article describes how a transdiagnostic process called interoception may help to advance the understanding and treatment of eating disorders. Topics discussed include overview of interoception, interoception in anorexia nervosa, and developmental importance of interoception in eating disorders. Treating dysfunctional interoceptive awareness in eating disorders is also mentioned.

ABSTRACT Objective Impaired interoceptive awareness (IA), the subjective perception of internal body sensations, has been proposed as a vulnerability or maintaining factor in anorexia nervosa (AN). We examined whether IA of heartbeat and breathing sensations was impaired in AN across a range of arousal levels, and whether it was influenced by meal anticipation and consumption. Method: IA was assessed using randomized, double-blinded, bolus intravenous infusions of isoproterenol, a peripheral beta-adrenergic sympathetic agonist, and saline. Fifteen women with AN and 15 age-, and sex- matched healthy comparisons (HC) were evaluated before and after consumption of a 1,000 Calorie meal. During each infusion participants rated their moment-to-moment intensity of heartbeat and breathing sensations with a dial. To measure IA we evaluated interoceptive detection thresholds, retrospective ratings of palpitation and dyspnea intensity, and interoceptive accuracy via correlations between subjective dial ratings and observed heart rate responses. Results: Contrary to prediction the AN group was more likely to report detection of interoceptive sensations across all conditions, an effect driven by false discriminations at low arousal levels. Concordant with prediction, meal anticipation was associated with intensified interoceptive sensations, particularly dyspnea. There were no differences in interoceptive accuracy. Discussion: This represents the first demonstration of interoceptive prediction errors in AN. Although IA is unimpaired at high arousal levels in AN, prediction signals are abnormal at low arousal levels, especially during meal anticipation. Altered interoceptive prediction signaling during meal anticipation could contribute to phenotypes of high anxiety in AN or alternatively, might be explained by enhanced meal associated anxiety. © 2015 Wiley Periodicals, Inc. (Int J Eat Disord 2015; 48:889-897) [ABSTRACT FROM AUTHOR]

Although the amygdala plays an important part in the pathogenesis of anxiety and generation of exteroceptive fear, recent discoveries have challenged the directionality of this brain-behavior relationship with respect to interoceptive fear. Here we highlight several paradoxical findings including: (1) amygdala lesion patients who experience excessive fear and panic following inhalation of carbon dioxide (CO 2), (2) clinically anxious patients who have significantly smaller (rather than larger) amygdalae and a pronounced hypersensitivity toward CO 2 , and (3) epilepsy patients who exhibit apnea immediately following stimulation of their amygdala yet have no awareness that their breathing has stopped. The above findings elucidate an entirely novel role for the amygdala in the induction of apnea and inhibition of CO 2 -induced fear. Such a role is plausible given the strong inhibitory connections linking the central nucleus of the amygdala with respiratory and chemoreceptive centers in the brainstem. Based on this anatomical arrangement, we propose a model of Apnea-induced Anxiety (AiA) which predicts that recurring episodes of apnea are being unconsciously elicited by amygdala activation, resulting in transient spikes in CO 2 that provoke fear and anxiety, and lead to characteristic patterns of escape and avoidance behavior in patients spanning the spectrum of anxiety. If this new conception of AiA proves to be true, and activation of the amygdala can repeatedly trigger states of apnea outside of one's awareness, then it remains possible that the chronicity of anxiety disorders is being interoceptively driven by a chemoreceptive system struggling to maintain homeostasis in the midst of these breathless states. • The causal role of the amygdala with regard to fear and anxiety remains controversial. • Research is reviewed across lesion studies, intracranial stimulation, and volumetric MRI. • The amygdala inhibits fear evoked by elevations in CO 2. • Stimulation of the amygdala triggers a state of apnea outside of one's awareness. • We propose a model of apnea-induced anxiety that can be tested in future studies. [ABSTRACT FROM AUTHOR]

Background: Electroencephalography (EEG) studies suggest that major depressive disorder (MDD) is associated with lower left than right frontal brain activity (asymmetry), a pattern appearing stronger in women than men, and when elicited during emotionally-relevant paradigms versus an uncontrolled resting state. However, it is unclear whether this asymmetry pattern generalizes to the common presentation of MDD with co-occurring anxiety. Moreover, asymmetry may differ for anxiety subtypes, wherein anxious apprehension (AnxApp: worry characteristic of generalized anxiety disorder) appears left-lateralized, but anxious arousal (AnxAro: panic characteristic of social anxiety, posttraumatic stress, and panic disorders) may be right-lateralized.Methods: This analysis attempted to replicate frontal EEG asymmetry patterns using functional magnetic resonance imaging (fMRI). Participants completed clinical interviews and a monetary incentive delay (MID) task during fMRI recording. We compared five groups of right-handed women from the Tulsa 1000 study, MDD (n=40), MDD-AnxApp (n=26), MDD-AnxAro (n=34), MDD-Both (with AnxApp and AnxAro; n=26), and healthy controls (CTL; n=24), as a function of MID anticipation condition (no win/loss, win, loss) and hemisphere on frontal blood oxygen-level-dependent (BOLD) signal.Results: CTL exhibited higher bilateral superior, middle, and inferior middle frontal gyrus BOLD signal than the four MDD groups for high arousal (win and loss) conditions. However, frontal attenuations were unrelated to current depression/anxiety symptoms, suggestive of a trait as opposed to a state marker.Limitations: This was a cross-sectional analysis restricted to women.Conclusions: Reduced prefrontal cortex recruitment during processing of both positively and negatively valenced stimuli is consistent with the emotion context insensitivity theory of MDD. [ABSTRACT FROM AUTHOR]