Interoceptive Threat Research Articles

Sex-specific threat responding and neuronal engagement in carbon dioxide associated fear and extinction: Noradrenergic involvement in female mice

Difficulty in appropriately responding to threats is a key feature of psychiatric disorders, especially fear-related conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD). Most prior work on threat and fear regulation involves exposure to external threatful cues. However, fear can also be triggered by aversive, within-the-body, sensations. This interoceptive signaling of fear is highly relevant to PD and PTSD but is not well understood, especially in the context of sex. Using female and male mice, the current study investigated fear-associated spontaneous and conditioned behaviors to carbon dioxide (CO2) inhalation, a potent interoceptive threat that induces fear and panic. We also investigated whether behavioral sensitivity to CO2 is associated with delayed PTSD-relevant behaviors. CO2 evoked heterogenous freezing behaviors in both male and female animals. However, active, rearing behavior was significantly reduced in CO2-exposed male but not female mice. Interestingly, behavioral sensitivity to CO2 was associated with compromised fear extinction, independent of sex. However, in comparison to CO2-exposed males, females elicited less freezing and higher rearing during extinction suggesting an engagement of active versus passive defensive coping. Persistent neuronal activation marker ΔFosB immuno-mapping revealed attenuated engagement of infralimbic-prefrontal areas in both sexes but higher activation of brain stem locus coeruleus (LC) area in females. Inter-regional co-activation mapping revealed sex-independent disruptions in the infralimbic-amygdala associations but altered LC associations only in CO2-exposed female mice. Lastly, dopamine β hydroxylase positive (DβH + ve) noradrenergic neuronal cell counts in the LC correlated with freezing and rearing behaviors during CO2 inhalation and extinction only in female but not male mice. Collectively, these data provide evidence for higher active defensive responding to interoceptive threat CO2-associated fear in females that may stem from increased recruitment of the brainstem noradrenergic system. Our findings reveal distinct contributory mechanisms that may promote sex differences in fear and panic associated pathologies.

Examining the long-term effects of traumatic brain injury on fear extinction in male rats.

There is a strong association between traumatic brain injuries (TBIs) and the development of psychiatric disorders, including post-traumatic stress disorder (PTSD). Exposure-based therapy is a first-line intervention for individuals who suffer from PTSD and other anxiety-related disorders; however, up to 50% of individuals with PTSD do not respond well to this approach. Fear extinction, a core mechanism underlying exposure-based therapy, is a procedure in which a repeated presentation of a conditioned stimulus in the absence of an unconditioned stimulus leads to a decrease in fear expression, and is a useful tool to better understand exposure-based therapy. Identifying predictors of extinction would be useful in developing alternative treatments for the non-responders. We recently found that CO2 reactivity predicts extinction phenotypes in rats, likely through the activation of orexin receptors in the lateral hypothalamus. While studies have reported mixed results in extinction of fear after TBI, none have examined the long-term durability of this phenotype in the more chronically injured brain. Here we tested the hypothesis that TBI results in a long-term deficit in fear extinction, and that CO2 reactivity would be predictive of this extinction phenotype. Isoflurane-anesthetized adult male rats received TBI (n = 59) (produced by a controlled cortical impactor) or sham surgery (n = 29). One month post-injury or sham surgery, rats underwent a CO2 or air challenge, followed by fear conditioning, extinction, and fear expression testing. TBI rats exposed to CO2 (TBI-CO2) showed no difference during extinction or fear expression relative to shams exposed to CO2 (sham-CO2). However, TBI-CO2 rats, showed significantly better fear expression than TBI rats exposed to air (TBI-air). In contrast to previous findings, we observed no relationship between CO2 reactivity and post-extinction fear expression in either the sham or TBI rats. However, compared to the previously observed naïve sample, we observed more variability in post-extinction fear expression but a very similar distribution of CO2 reactivity in the current sample. Isoflurane anesthesia may lead to interoceptive threat habituation, possibly via action on orexin receptors in the lateral hypothalamus, and may interact with CO2 exposure, resulting in enhanced extinction. Future work will directly test this possibility.

Impact of cannabidiol-rich hemp extract oil on reconsolidation disruption of naturalistic interoceptive aversive memory in humans: Protocol for a randomized clinical trial

BackgroundPreclinical experiments with rodents demonstrate that cannabidiol (CBD), the non-psychotomimetic constituent of the Cannabis sativa plant, disrupts reconsolidation of aversive memories conditioned in the laboratory when administered within the memory reconsolidation window (< 6 h. post-retrieval) by indirectly activating cannabinoid type-1 (CB1) receptors in the dorsal anterior cingulate cortex (dACC). Based on these findings, we aim to test whether administration of 300 mg CBD-rich hemp extract oil following fear reactivation of an aversive interoceptive threat memory can disrupt reconsolidation of naturalistic aversive memories in humans. More specifically, naturalistic interoceptive aversive memories, a form of transdiagnostic fear memory that contributes to the pathogenesis of fear-related disorders such as panic disorder, posttraumatic stress disorder (PTSD), and illness anxiety disorder. MethodsFor this proof-of-concept, placebo-controlled double-blind trial, volunteers (n = 99) reporting elevated fears of somatic sensations will be stratified on biological sex and randomized to one of three intervention arms: (a). CBD-rich oil administered within the reconsolidation window, (b) Placebo oil administered within the reconsolidation window; or (c) CBD-rich oil administered outside of the reconsolidation window. Change in emotional reactivity to a 35% CO2 challenge from baseline to two-week follow-up will serve as our primary outcome. ConclusionStudy findings may contribute towards the development of a novel brief transdiagnostic intervention guided by reconsolidation theory for individuals prone to fear-related psychiatric disorders.Trial Registration: ClinicalTrials.gov Identifier: NCT04726475

Subfornical organ interleukin 1 receptor: A novel regulator of spontaneous and conditioned fear associated behaviors in mice

Impaired threat responding and fear regulation is a hallmark of psychiatric conditions such as post-traumatic stress disorder (PTSD) and Panic Disorder (PD). Most studies have focused on external psychogenic threats to study fear, however, accumulating evidence suggests a primary role of homeostatic perturbations and interoception in regulating emotional behaviors. Heightened reactivity to interoceptive threat carbon dioxide (CO2) inhalation associates with increased risk for developing PD and PTSD, however, contributory mechanisms and molecular targets are not well understood. Previous studies from our group suggested a potential role of interleukin 1 receptor (IL-1R1) signaling within BBB-devoid sensory circumventricular organ, the subfornical organ (SFO) in CO2-evoked fear. However, the necessity of SFO-IL-1R1 in regulating CO2-associated spontaneous fear as well as, long-term fear potentiation relevant to PD/PTSD has not been investigated. The current study tested male mice with SFO-targeted microinfusion of the IL-1R1 antagonist (IL-1RA) or vehicle in a recently developed CO2-startle-fear conditioning-extinction paradigm. Consistent with our hypothesis, SFO IL-1RA treatment elicited significant attenuation of freezing and increased rearing during CO2 inhalation suggesting SFO-IL1R1 regulation of spontaneous fear to CO2. Intriguingly, SFO IL-1RA treatment normalized CO2-associated potentiation of conditioned fear and impaired extinction a week later suggesting modulation of long-term fear by SFO-IL-1R1 signaling. Post behavior FosB mapping revealed recruitment of prefrontal cortex-amygdala-periaqueductal gray (PAG) areas in SFO-IL-1RA mediated effects. Additionally, we localized cellular IL-1R1 expression within the SFO to blood vessel endothelial cells and observed CO2-induced alterations in IL-1β/IL-1R1 expression in peripheral mononuclear cells and SFO. Lastly, CO2-evoked microglial activation was attenuated in SFO-IL-1RA treated mice. These observations suggest a peripheral monocyte-endothelial-microglia interplay in SFO-IL-1R1 modulation of CO2-associated spontaneous fear and delayed fear memory. Collectively, our data highlight a novel, “bottom-up” neuroimmune mechanism that integrates interoceptive and exteroceptive threat processing of relevance to fear-related pathologies.

Associative learning and extinction of conditioned threat predictors across sensory modalities

The formation and persistence of negative pain-related expectations by classical conditioning remain incompletely understood. We elucidated behavioural and neural correlates involved in the acquisition and extinction of negative expectations towards different threats across sensory modalities. In two complementary functional magnetic resonance imaging studies in healthy humans, differential conditioning paradigms combined interoceptive visceral pain with somatic pain (study 1) and aversive tone (study 2) as exteroceptive threats. Conditioned responses to interoceptive threat predictors were enhanced in both studies, consistently involving the insula and cingulate cortex. Interoceptive threats had a greater impact on extinction efficacy, resulting in disruption of ongoing extinction (study 1), and selective resurgence of interoceptive CS-US associations after complete extinction (study 2). In the face of multiple threats, we preferentially learn, store, and remember interoceptive danger signals. As key mediators of nocebo effects, conditioned responses may be particularly relevant to clinical conditions involving disturbed interoception and chronic visceral pain.

Vagal control of the heart decreases during increasing imminence of interoceptive threat in patients with panic disorder and agoraphobia

Theoretically, panic disorder and agoraphobia pathology can be conceptualized as a cascade of dynamically changing defensive responses to threat cues from inside the body. Guided by this trans-diagnostic model we tested the interaction between defensive activation and vagal control as a marker of prefrontal inhibition of subcortical defensive activation. We investigated ultra-short-term changes of vagally controlled high frequency heart rate variability (HRV) during a standardized threat challenge (entrapment) in n = 232 patients with panic disorder and agoraphobia, and its interaction with various indices of defensive activation. We found a strong inverse relationship between HRV and heart rate during threat, which was stronger at the beginning of exposure. Patients with a strong increase in heart rate showed a deactivation of prefrontal vagal control while patients showing less heart rate acceleration showed an increase in vagal control. Moreover, vagal control collapsed in case of imminent threat, i.e., when body symptoms increase and seem to get out of control. In these cases of defensive action patients either fled from the situation or experienced a panic attack. Active avoidance, panic attacks, and increased sympathetic arousal are associated with an inability to maintain vagal control over the heart suggesting that teaching such regulation strategies during exposure treatment might be helpful to keep prefrontal control, particularly during the transition zone from post-encounter to circa strike defense.Trial Registration Number: ISRCTN80046034.

Decreased defensive reactivity to interoceptive threat after successful exposure-based psychotherapy in patients with panic disorder

Panic disorder (PD) is characterized by a dysfunctional defensive responding to panic-related body symptoms that is assumed to contribute to the persistence of panic symptomatology. The present study aimed at examining whether this dysfunctional defensive reactivity to panic-related body symptoms would no longer be present following successful cognitive behavior therapy (CBT) but would persist when patients show insufficient symptom improvement. Therefore, in the present study, effects of CBT on reported symptoms and defensive response mobilization during interoceptive challenge were investigated using hyperventilation as a respiratory symptom provocation procedure. Changes in defensive mobilization to body symptoms in the course of CBT were investigated in patients with a primary diagnosis of PD with or without agoraphobia by applying a highly standardized hyperventilation task prior to and after a manual-based CBT (n = 38) or a waiting period (wait-list controls: n = 20). Defensive activation was indexed by the potentiation of the amygdala-dependent startle eyeblink response. All patients showed a pronounced defensive response mobilization to body symptoms at baseline. After treatment, no startle reflex potentiation was found in those patients who showed a clinically significant improvement. However, wait-list controls and treatment non-responders continued to show increased defensive responses to actually innocuous body symptoms after the treatment/waiting period. The present results indicate that the elimination of defensive reactivity to actually innocuous body symptoms might be a neurobiological correlate and indicator of successful CBT in patients with PD, which may help to monitor and optimize CBT outcomes.

High Behavioral Sensitivity to Carbon Dioxide Associates with Enhanced Fear Memory and Altered Forebrain Neuronal Activation

There is considerable interest in pre-trauma individual differences that may contribute to increased risk for developing post-traumatic stress disorder (PTSD). Identification of underlying vulnerability factors that predict differential responses to traumatic experiences is important. Recently, the relevance of homeostatic perturbations in shaping long-term behavior has been recognized. Sensitivity to CO2 inhalation, a homeostatic threat to survival, was shown to associate with the later development of PTSD symptoms in veterans. Here, we investigated whether behavioral sensitivity to CO2 associates with PTSD-relevant behaviors and alters forebrain fear circuitry in mice. Mice were exposed to 5% CO2 or air inhalation and tested one week later on acoustic startle and footshock contextual fear conditioning, extinction and reinstatement. CO2 inhalation evoked heterogenous freezing behaviors (high freezing CO2-H and low freezing CO2-L) that significantly associated with fear conditioning and extinction behaviors. CO2-H mice elicited potentiated conditioned fear and delayed extinction while behavioral responses in CO2-L mice were similar to the air group. Persistent neuronal activation marker ΔFosB immunostaining revealed altered regional neuronal activation within the hippocampus, amygdala and medial pre-frontal cortex that correlated with conditioned fear and extinction. Inter-regional co-activation mapping revealed disruptions in the coordinated activity of hippocampal dentate-amygdala-infralimbic regions and infralimbic-prelimbic associations in CO2-H mice that may explain their enhanced fear phenotype. In conclusion, our data support an association of behavioral sensitivity to interoceptive threats such as CO2 with altered fear responding to exteroceptive threats and suggest that “CO2-sensitive” individuals may be susceptible to developing PTSD.

Recruitment of central angiotensin II type 1 receptor associated neurocircuits in carbon dioxide associated fear

Individuals with fear-associated conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD) display increased emotional responses to interoceptive triggers, such as CO2 inhalation, that signal a threat to physiological homeostasis. Currently, effector systems and mechanisms underlying homeostatic modulation of fear memory are not well understood. In this regard, the renin angiotensin system (RAS), particularly the angiotensin receptor type 1 (AT1R), a primary homeostatic regulatory target, has gained attention. RAS polymorphisms have been reported in PD and PTSD, and recent studies report AT1R-mediated modulation of fear extinction. However, contribution of AT1Rs in fear evoked by the interoceptive threat of CO2 has not been investigated. Using pharmacological, behavioral, and AT1R/ACE gene transcription analyses, we assessed central AT1R recruitment in CO2-associated fear. CO2 inhalation led to significant AT1R and ACE mRNA upregulation in homeostatic regulatory regions, subfornical organ (SFO) and paraventricular nucleus (PVN), in a temporal manner. Intracerebroventricular infusion of selective AT1R antagonist, losartan, significantly attenuated freezing during CO2 inhalation, and during re-exposure to CO2 context, suggestive of AT1R modulation of contextual fear. Regional Fos mapping in losartan-treated mice post-behavior revealed significantly attenuated labeling in areas regulating defensive behavior, contextual fear, and threat responding; such as, the bed nucleus of stria terminalis, dorsal periaqueductal gray, hypothalamic nuclei, hippocampus, and prefrontal areas such as the prelimbic, infralimbic, and anterior cingulate cortices. Sub-regions of the amygdala did not show CO2-associated AT1R regulation or altered Fos labeling. Collectively, our data suggests central AT1R recruitment in modulation of fear behaviors associated with CO2 inhalation via engagement of neurocircuits regulating homeostasis and defensive behaviors. Our data provides mechanistic insights into the interoceptive regulation of fear, relevant to fear related disorders such as PD and PTSD.

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.

Cue and context conditioning to respiratory threat: Effects of suffocation fear and implications for the etiology of panic disorder

Interoceptive threats play a crucial role in the etiology of panic disorder (PD). While body sensations may become conditioned stimuli (CS) when paired with such interoceptive threats (cue conditioning), the environment in which such interoceptive threats occur may also be learned as a predictor of threat (context conditioning). Suffocation fear (SF) might facilitate these associative learning processes if threats of suffocation become relevant as unconditioned stimuli (US). To investigate whether SF affects associative learning during such respiratory threat, we used mild dyspnea as CS that predicted the occurrence of strong dyspnea (US) in one context (predictable), was not related to the occurrence of the US in another context (unpredictable) or was presented in a different context (safe) in which no US was delivered. Startle eyeblink responses and subjective reports were assessed in 34 participants during learning. Individuals reporting high SF showed a clear potentiation of the startle response during the interoceptive CS predicting the occurrence of interoceptive threat (US). Such startle potentiation was not observed when the CS remained unpaired (safe or unpredictable context). Moreover, high SF persons also showed a significant startle potentiation to the threatening context, when the CS did not predict the onset of the US. No such learning effects were observed for low SF individuals. The data support the view that defensive response mobilization can be triggered by cues but also by contexts that predict the occurrence of interoceptive threats if these threats are relevant for the individuals, supporting learning accounts for the development of PD.

Dynamics of Defensive Response Mobilization to Approaching External Versus Interoceptive Threat

BackgroundExcessive fear and anxiety are core features of anxiety disorders. Defensive response mobilization varies dynamically with threat proximity. MethodsWe analyzed defensive responses in 48 healthy students to an approaching external, predator-like threat (an electric shock resembling a predator attack) versus an approaching threat from inside the body (feeling of dyspnea as evoked by forced breath-holding). Threats either were inevitable or could be avoided by button press. ResultsAutonomic changes (heart rate, skin conductance), defensive reflex priming (startle eyeblink response), respiratory responses, and event-related potentials were assessed. Regardless of its source, when an approaching threat was inevitable, a defensive pattern emerged characterized by an increase in skin conductance, a potentiation of the startle reflex, and bradycardia. Minute ventilation increased only with approaching dyspnea. In preparation for active avoidance of either threat, startle magnitudes were inhibited and probe-elicited P3 wave amplitudes were reduced. Moreover, generation of avoidant action resulted in heart rate acceleration. ConclusionsThis study demonstrates common and specific defensive activation patterns for approaching external and respiratory threats. The specific modulation in respiration in response to an inevitable respiratory threat may have important implications for our understanding of the etiology of anxiety disorders, especially panic disorder.

Dynamics of defensive response mobilization during repeated terminations of exposure to increasing interoceptive threat

Resistant avoidance behaviors play a crucial role in the maintenance of anxiety disorders and are therefore central targets of therapeutic interventions. In the present study, the development of avoidance behavior was investigated in 24 healthy participants who repeatedly prematurely terminated the exposure to increasing interoceptive threat, i.e., the feeling of dyspnea induced by increasing inspiratory resistive loads that were followed by the ultimate threat, a short breathing occlusion. Physiological responses and subjective anxiety preceding terminations were compared to matched intervals of a matched control group (N=24) who completed the exposure. Initially, participants terminated during the ultimate threat, i.e., during occlusion. This first termination was preceded by a strong surge in autonomic arousal and reported anxiety. Startle reflex and the P3 component of event-related brain potentials to startle probes were strongly inhibited, indicating preparation for defensive action. With repetitive terminations, individuals successively terminated earlier, avoiding exposure to the occlusion. This avoidant behavior was accompanied by alleviated autonomic arousal as compared to the first termination. In addition, no indication of physiological response preparation was found implying that the avoidance behavior was performed in a rather habitual way. Matched controls did not show any indication of a defensive response surge in the matched intervals. In matched controls, no changes in physiological response patterns were detected while anxiety levels increased with repetitions. The present results shed new light on our understanding of the motivational basis of avoidance behavior and may help to refine etiological models, behavioral analysis and therapeutic strategies in treating anxiety disorders.

Chronic stress load in air rescue teams: CAR and HRV at different assignments

Resistant avoidance behaviors play a crucial role in the maintenance of anxiety disorders and are therefore central targets of therapeutic interventions. In the present study, the development of avoidance behavior was investigated in 24 healthy participants who repeatedly prematurely terminated the exposure to increasing interoceptive threat, i.e., the feeling of dyspnea induced by increasing inspiratory resistive loads that were followed by the ultimate threat, a short breathing occlusion. Physiological responses and subjective anxiety preceding terminations were compared to matched intervals of a matched control group (N = 24) who completed the exposure. Initially, participants terminated during the ultimate threat, i.e., during occlusion. This first termination was preceded by a strong surge in autonomic arousal and reported anxiety. Startle reflex and the P3 component of event-related brain potentials to startle probes were strongly inhibited, indicating preparation for defensive action. With repetitive terminations, individuals successively terminated earlier, avoiding exposure to the occlusion. This avoidant behavior was accompanied by alleviated autonomic arousal as compared to the first termination. In addition, no indication of physiological response preparation was found implying that the avoidance behavior was performed in a rather habitual way. Matched controls did not show any indication of a defensive response surge in the matched intervals. In matched controls, no changes in physiological response patterns were detected while anxiety levels increased with repetitions. The present results shed new light on our understanding of the motivational basis of avoidance behavior and may help to refine etiological models, behavioral analysis and therapeutic strategies in treating anxiety disorders.

When dyspnea gets worse: Suffocation fear and the dynamics of defensive respiratory responses to increasing interoceptive threat.

In patients with anxiety and/or respiratory diseases, body sensations, particularly from the respiratory system, may increase in intensity and aversiveness and thus lead into defensive action (e.g., escape) or panic. The processes, however, that might contribute to the culmination of symptoms and the switch into defensive action have not been well understood yet. The current study aimed at evaluating an experimental paradigm to characterize the dynamics of defensive mobilization to body sensations increasing in intensity and aversiveness. Persons reporting low and high suffocation fear (SF; N = 69) were exposed to increasingly unpleasant feelings of dyspnea induced by inspiratory resistive loads and a breathing occlusion requiring voluntary breath holding. Respiratory responses were assessed along with subjective reports of anxiety and panic symptoms. Presentation of respiratory loads with increasing physical resistance led to increasingly unpleasant feelings of dyspnea. Twenty-eight participants terminated the exposure prematurely at least once. When dyspnea was severe, high compared to low SF persons exhibited an increased respiratory rate that was accompanied by reports of more intense panic symptoms. Premature terminations of exposure were preceded by a surge in anxiety, breathing frequency, and mouth pressure, and a decrease in tidal volume. We successfully established an experimental paradigm to assess changes in defensive responding with increasing intensity of an interoceptive threat. The current data foster our understanding of behavioral expression patterns observed in patients with anxiety and/or respiratory diseases and the processes involved in the culmination of bodily sensations and anxiety into panic.

Defensive activation to (un)predictable interoceptive threat: The NPU respiratory threat test (NPUr).

Potentially life-threatening interoceptive sensations easily engage the behavioral defensive system. Resulting fear and anxiety toward interoceptive threat are functionally distinct states that are hypothesized to play a prominent role in the etiology of panic disorder. The present study aimed to investigate whether fear- and anxiety-potentiated startle responses occur to predictable and unpredictable interoceptive threat, respectively. Therefore, we modified the NPU threat test (Schmitz & Grillon, ) and replaced the aversive electrocutaneous stimulus with an aversive interoceptive stimulus (a breathing occlusion, making it briefly impossible to breathe). Healthy participants (N = 48) underwent three instructed conditions. A visual cue signaled the occlusion in the predictable condition (P), whereas another cue was unrelated to the occurrence of the occlusion in the unpredictable condition (U). The safe condition (N) also had a visual cue, but no occlusion. Both fear- and anxiety-potentiated startle blink responses were observed in response to predictable and unpredictable respiratory threat, respectively. The current study presents and validates the NPU respiratory threat test (NPUr) as an ecologically valid paradigm to study both anxiety and fear in response to a panic-relevant interoceptive threat. The paradigm allows future testing of contextual generalization, investigation of different clinical groups, and more explicit comparisons of defensive responding to interoceptive versus exteroceptive threats.

Why Do Anxiety Sensitive Smokers Perceive Quitting as Difficult? The Role of Expecting “Interoceptive Threat” During Acute Abstinence

There is a growing literature that documents the direct and indirect effects of anxiety sensitivity in terms of the maintenance of cigarette smoking and cessation problems, as maintained, at least in part, by affective-regulatory expectancies effects and motives for smoking. Yet, the role of expectancies about the interoceptive-specific consequences of smoking abstinence has yet to be empirically examined. Participants (N = 110) were daily tobacco smokers recruited as part of a self-guided tobacco cessation study. Baseline (pre-treatment) data were utilized. A structural equation model was constructed to examine the relations between anxiety sensitivity in terms of interoceptively-relevant smoking abstinence expectancies (somatic symptoms and harmful consequences) in regard to perceived barriers to smoking cessation, number of problematic symptoms experienced during past quit attempts, and the number of prior quit attempts. Anxiety sensitivity was significantly related to interoceptive threat abstinence expectancies (β = .56, p < .001). Expectancies were directly related to perceived barriers to smoking cessation (β = .39, p < .001) and number of problematic symptoms experienced during past quit attempts (β = .41, p < .001), but not the number of prior quit attempts. Mediational results indicated indirect (but not direct) effects of anxiety sensitivity on perceived barriers to smoking cessation and problems during prior quit attempts; effects that occurred through interoceptive threat smoking abstinence expectancies. The present findings suggest that one’s expectancies about the negative interoceptive consequences of smoking abstinence may be an explanatory mechanism between anxiety sensitivity and certain quit-relevant smoking processes.

Dynamics of Defensive Reactivity in Patients with Panic Disorder and Agoraphobia: Implications for the Etiology of Panic Disorder

The learning perspective of panic disorder distinguishes between acute panic and anxious apprehension as distinct emotional states. Following animal models, these clinical entities reflect different stages of defensive reactivity depending upon the imminence of interoceptive or exteroceptive threat cues. The current study tested this model by investigating the dynamics of defensive reactivity in a large group of patients with panic disorder and agoraphobia (PD/AG). Three hundred forty-five PD/AG patients participated in a standardized behavioral avoidance test (being entrapped in a small, dark chamber for 10 minutes). Defense reactivity was assessed measuring avoidance and escape behavior, self-reports of anxiety and panic symptoms, autonomic arousal (heart rate and skin conductance), and potentiation of the startle reflex before and during exposure of the behavioral avoidance test. Panic disorder and agoraphobia patients differed substantially in their defensive reactivity. While 31.6% of the patients showed strong anxious apprehension during this task (as indexed by increased reports of anxiety, elevated physiological arousal, and startle potentiation), 20.9% of the patients escaped from the test chamber. Active escape was initiated at the peak of the autonomic surge accompanied by an inhibition of the startle response as predicted by the animal model. These physiological responses resembled the pattern observed during the 34 reported panic attacks. We found evidence that defensive reactivity in PD/AG patients is dynamically organized ranging from anxious apprehension to panic with increasing proximity of interoceptive threat. These data support the learning perspective of panic disorder.

Brain activation during anticipation of interoceptive threat

The current study investigated the neural networks activated during the anticipation of potentially threatening body symptoms evoked by a guided hyperventilation task in a group of participants reporting either high or low fear of unexplained somatic sensations. 15 subjects reporting high and 14 subjects reporting low fear of somatic symptoms first learned that one of two cues predicted the occurrence of a hyperventilation task reliably producing body symptoms in all participants that were rated as more intense and unpleasant in the high fear group. During anticipation of unpleasant symptoms, high fear participants reported more intense body symptoms and showed potentiation of the startle reflex. After this learning session, participants were taken into the fMRI where the same cues either predicted the occurrence of hyperventilation or normoventilation, although the task was never performed in the scanner. During anticipation of hyperventilation all participants showed an increased activation of anterior insula/orbitofrontal cortex and rostral parts of the dorsal anterior cingulate cortex/dorsomedial prefrontal cortex (dACC/dmPFC). Brain activation of high compared to low fear participants differed in two ways. First, high fear participants showed an overall stronger activation of this network during threat and safe conditions indexing stronger anxious apprehension during the entire context. Second, while low fear participants no longer responded with stronger activation to the threat cue after experiencing that the hyperventilation challenge did not follow this cue, high fear participants continued to show stronger activation of the network to this cue. Activation of the rostral dACC/dmPFC was significantly correlated with reported fear of somatic symptoms. These data demonstrate that anticipation of interoceptive threat activates the same network that has been found to be active during anticipation of exteroceptive threat cues. Thus, the current paradigm might provide an innovative method to study anxious apprehension and treatment effects in patients with panic disorder.

Attentional Control Moderates Fearful Responding to a 35% CO2 Challenge

Attentional control (AC) is an individual difference variable indexing the ability to voluntarily focus attention and shift attention when desired. AC is thought to impact the experience of fear by facilitating the disengagement of attention from threat and promoting the deployment of attentional resources toward regulatory or coping strategies. Whereas previous research has focused on visual threat cues, in the current study we examined whether this model also applies to interoceptive threat by evaluating the extent to which individual differences in AC moderated the relationship between trait anxiety and self-reported fear in response to a single vital capacity inhalation of a 35% CO2, 65% balanced O2 gas mixture. The sample comprised a large nonclinical group of young adults (N=128). Results indicated that AC moderated the relationship between trait anxiety and fearful responding to the challenge. Findings suggest that AC plays a significant and clinically important role in modulating self-reported fear.