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Body sensations play a crucial role in the etiology and maintenance of diverse anxiety and health problems (e.g., in panic disorder or respiratory diseases) as they may be perceived as threatening and consequently elicit anxious responses. The factors that may affect the perception of bodily sensations as a threat and thus modulate the anxious response to body sensations have so far rarely been studied. Therefore, the present thesis targeted at elucidating the effect of contextual (i.e., the predictability, expectation, and proximity of a threat) and dispositional factors (i.e., tendency to fear arousal sensations or trait fear of suffocation) on the defensive response to body sensations.
In study 1, it was investigated how a personality factor, that is, fear of suffocation, affects the acquisition of fear to body sensations (i.e., mild dyspnea induced by inspiratory resistive loads) and contexts when faced with a predictable and unpredictable respiratory threat (i.e., severe dyspnea). Study 2 aimed at examining the main and interactive effects of the tendency to fear arousal sensations, again a personality trait factor, and current arousal expectations as varied by situational variables on anxious responding to arousal sensations. In this study, expected and unexpected arousal sensations were induced by administering caffeine in coffee or bitter lemon soda, respectively. Moreover, in study 3, it was explored how subjective anxiety, bodily symptoms, and defensive respiratory responses change and might culminate into active defense behavior (i.e., escape/active avoidance) during increasing dyspnea that was evoked by inspiratory resistive loads increasing in intensity. For a detailed analysis of the factors that contribute to the initiation and maintenance of avoidance of or escape from increasing dyspnea, in study 4 changes in subjective, autonomic, somatic reflex and brain responses were analyzed during repeated avoidance of increasing dyspnea.
In study 1, it was demonstrated that only individuals who fear suffocation learned to fear mild dyspnea preceding the onset of severe dyspnea and developed anxiety during a context of unpredictable respiratory threat. Moreover, the data from study 2 indicate that individuals who fear arousal sensations show an increased attention allocation towards unexpected arousal sensations and higher threat appraisal when expecting arousal sensations. Increasing intensity of dyspnea as provoked in study 3 led to increased defensive respiratory responses that were associated with increased symptom reports in individuals with high compared to low fear of suffocation. Moreover, culminating dyspnea elicited repeated avoidance behavior preceded by increases in defensive respiratory mobilization. The analysis of repeated avoidance of increasing dyspnea in study 4 revealed that physiological fear responses might be involved in the initial initiation of this avoidance behavior while no indication of response preparation and physiological arousal was related to persistent avoidance.
Taken together, the present data suggest that the fear of suffocation, as well as the tendency to fear arousal sensations along with the predictability, expectation, or proximity of interoceptive threat, may increase the perceived threat and thus the anxious response to body sensations. Therefore, contextual and dispositional factors may set the stage for the culmination of body sensations into defensive action and might contribute to the development of pathological anxiety and fear of body sensations. The present findings are integrated into the current literature and discussed in relation to the development and maintenance of pathological anxiety and fear of body sensations.
Dense sensor event-related brain potentials were measured in participants with spider phobia, high anxiety sensitive individuals and non-fearful controls during viewing of medical emergency, spider and standard emotional (pleasant, unpleasant, neutral) pictures. Compared to non-fearful controls spider phobia participants showed a significantly enlarged late positive potential (LPP) during the encoding of phobia-relevant pictures whereas high anxiety sensitive individuals showed a significantly greater Early Posterior Negativity (EPN) during the encoding of medical emergency pictures and a significantly greater Late Positive Potential (LPP) during the encoding of highly arousing unpleasant visual material. Moreover, within group comparisons of the spider phobia group revealed comparable LPP evoked by spider pictures and emotional (unpleasant and pleasant) picture contents indicating that at the level of early stimulus evaluation, the effects of selective attention seem to be related to emotional relevance of the stimulus rather than reflecting a fear-specific response.
The learning theory of panic disorder differs between panic attacks and anxious apprehension as distinct emotional states. Acute panic is accompanied by extreme fear, experience of strong body symptoms reflecting autonomic surge and flight tendencies. In contrast, anxious apprehension is associated with hypervigilance towards bodily sensations and increased distress when subtle somatic symptoms are identified. Following animal models, these clinical entities reflect different stages of defensive reactivity depending upon the imminence of interoceptive or exteroceptive threat cues with lowest distance to threat during panic attacks. We tested this model by investigating the dynamics of defensive reactivity in a large group of patients suffering from panic disorder and agoraphobia (PD/AG) prior to a multicenter controlled clinical trial. Three hundred forty-five patients participated in a standardized behavioral avoidance test (being entrapped in a small, dark chamber for 10 minutes). Defensive 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 the exposure period of the behavioral avoidance test. While 125 patients showed strong anxious apprehension during the task (as indexed by increased reports of anxiety, elevated physiological arousal, and startle potentiation), 72 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 were observed during 34 reported panic attacks as well. 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. Importantly, the patients differed quite substantially according defensive reactivity during the behavioral avoidance test despite all patients received the same principal diagnosis. These differences can be explained in part by differences in the disposition according to two genetic variants previously associated with panic disorder. Patients carrying the risk variant of a polymorphism in the neuropeptide S receptor gene showed an overall increased heart rate during the whole behavioral avoidance test reflecting an enhanced sympathomimetic activation and consequently arousal level. During the entrapment situation in which heart rate further increased over an already elevated baseline level, risk variant carriers were prone to experience more panic symptoms. This is in line with the learning perspective of panic disorder, postulating that internal cues of elevated arousal increase the chance of experiencing another panic attack once they have been associated with aversive responses. Furthermore, the risk variant of a polymorphism in the monoamine oxidase A gene was observed to augment the occurrence of panic attacks and escape behavior preparation. In addition, we find evidence that suggest an enhanced resistance to corrective learning experiences as indicated by a lack of a reduction of avoiding and escaping behavior during repeated test chamber exposures in wait-list control patients carrying the risk gene variant. Both effects may strengthen the learning mechanism hypothesized to be involved in the pathogenesis of panic disorder. Exteroceptive and interoceptive cues previously associated with the initial panic attack might trigger subsequent attacks in risk allele carriers more rapidly while simultaneously the opportunity to dissolve once established associations due to contradictory experiences is limited. Now, differential dispositions regarding defensive reactivity in PD/AG patients has to be linked to mechanisms supposed to be involved in exposure based therapy. First outcome evaluations of the clinical trial indicated that a behavioral therapy variant suggested to be linked with higher fear activation during exposure exercises is more effective than another. Further analyses have to proof whether those patients showing a clear specific fear response during the behavioral avoidance test benefit more than others from exposure based therapy.
Fear is an emotional state, characterized by the activation of a defense system that is designed to ensure the organism’s survival. This system enables a rapid recognition of threats and organizes defensive response patterns in order to adaptively cope with the threatening environment. Yet, to ensure its flexibility under changing environmental conditions, inhibitory pathways exist that modulate the activation of this defense system, if a previously threatening cue no longer predicts any harm – a memory-formatting process referred to as fear extinction, leading to a reduction of defensive responding. Fear extinction is presumed to at least partially underlie exposure treatment of anxiety disorders, which is why the facilitation of this learning process may promote such treatment’s efficacy. Animal models suggested, that the stimulation of the vagus nerve or the superior colliculus (SC) – a midbrain structure mediating visual attentional processing – target these inhibitory extinction pathways and, thus, facilitate fear extinction. However, as it is unclear whether similar mechanisms exist in humans, this thesis manuscript examined how non-invasive stimulation of these inhibitory pathways by transcutaneous vagus nerve stimulation (tVNS) or SC-recruiting visual attentional manipulation impact on human fear extinction.
To this end, we conducted three studies using multiple-day single-cue fear conditioning and extinction paradigms. First, we elaborated on fear that is established in these paradigms by examining defensive responding that is elicited by an innocuous conditioned stimulus, which has either been paired (fear learning group) with an aversive unconditioned stimulus (US; an electric shock) or was unpaired (control group; study 1). During the following extinction training, either tVNS vs. sham stimulation was applied (study 1, study 2) or participants were instructed, to either generate saccadic eye movements (strong SC activation) vs. smooth eye pursuits (low SC activation; study 3). During subsequent sessions, extinction consolidation as well as the short- and long-term extinction recall was tested (study 2, study 3).
Conditioned fear in the fear learning group was characterized by elevated cognitive risk assessments (US-expectancy ratings), as well as increased cardiac deceleration and startle reflex potentiation compared to controls. Cardiac deceleration was positively correlated to startle potentiation, but was decoupled from cognitive risk assessments (study 1). Initial, short- and long-term extinction of these defensive responses was facilitated by tVNS on all three response levels (cognitive, physiological, behavioral; study 1, study 2). In contrast, saccades facilitated initial extinction only for physiological and behavioral elements of the defensive response pattern, while extinction consolidation and recall was impaired by any eye movement manipulation (study 3) for physiological and behavioral indicators of defensive responding.
Taken together, the data of the experimental series suggest, that on a behavioral level, conditioned fear may best be conceived as attentive immobility – a defense strategy elicited by inevitable distal threats, that is uniformly expressed across species and is accompanied by cardiac deceleration and startle reflex potentiation. In addition, it was shown that such rather automatic defensive adaptations are independent from verbally expressed threat expectancies. As expected, tVNS impacted on fear extinction on both levels, strongly in line with the suggestion, that vagal stimulation activates cortical and subcortical neural pathways involved in extinction learning, consolidation and recall. TVNS may, thus, be a promising adjuvant for exposure treatment of mental disorders. In contrast, SC-recruiting visual attentional manipulation only affected subcortically mediated defensive responding, in line with rodent findings, indicating that the SC specifically inhibits subcortical parts of the neural defense system. However, as extinction recall was impaired by any type of visual attentional manipulation, this appeared to have functioned as a form of avoidance, initially attenuating fear but preventing extinction consolidation and, thus, impairing sustained fear reduction. Both non-invasive stimulation techniques may therefore increase initial defensive flexibility in the face of no-longer threat-signaling stimuli, but only tVNS may achieve long-term effects on multiple response levels.