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Panic disorder is characterized by the paroxysmal occurrence and fear of bodily symptoms. In recent years it has been proposed that patients "learn" to fear cardiorespiratory sensations through interoceptive conditioning. This study sought to model the initial stage of this process in healthy volunteers (N=44) using mild cardiac sensations. An additional aim was to explore whether anxiety sensitivity - a known risk factor for panic disorder - modulates such interoceptive learning. Infusions of pentagastrin and saline were used to manipulate the presence versus absence of cardiac sensations, respectively, and served as conditioned stimuli in a differential interoceptive conditioning paradigm. Inhalation of 35% CO 2 -enriched air served as the panicogenic, unconditioned stimulus (UCS). In half of the participants ("prepared" condition), cardiac sensations caused by pentagastrin were followed by inhalation of CO 2 -enriched air (penta CS+), whereas the absence of such sensations (saline) was followed by room air (saline CS-). The reversed combination ("unprepared" condition) was used in the other half of the participants. Conditioning effects showed up for self-reported UCS-expectancy, but not for skin conductance and anxiety ratings. Only participants from the prepared group learned to expect the UCS, and differential learning was impaired with higher scores on anxiety sensitivity. Expectancy learning was more easily established towards the presence compared to the absence of cardiac sensations, whereas the reverse effect was observed for safety learning. Modeling impaired discriminatory learning and the moderating effect of anxiety sensitivity provides new insight in the development of panic disorder., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Fear reduction obtained during a fear extinction procedure can generalize from the extinction stimulus to other perceptually similar stimuli. Perceptual generalization of fear extinction typically follows a perceptual gradient, with increasing levels of fear reduction the more a stimulus resembles the extinction stimulus. The current study aimed to investigate whether perceptual generalization of fear extinction can be observed also after a retention interval of 24h. Fear was acquired to three geometrical figures of different sizes (CS(+), CS1(+) and CS2(+)) by consistently pairing them with a short-lasting suffocation experience (US). Three other geometrical figures that were never followed by the US served as control stimuli (CS(-), CS1(-), CS2(-)). Next, only the CS(+) was extinguished by presenting it in the absence of the US. One day later, fear responses to all stimuli were assessed without any US-presentation. Outcome measures included startle blink EMG, skin conductance, US expectancy, respiratory rate and tidal volume. On day 2 spontaneous recovery of fear was observed in US expectancy and tidal volume, but not in the other outcomes. Evidence for the retention of fear extinction generalization was present in US expectancy and skin conductance, but a perceptual gradient in the retention of generalized fear extinction could not be observed., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Interoceptive fear conditioning (IFC), fear generalization and a lack of safety learning have all been hypothesized to play a role in the pathogenesis of panic disorder, but have never been examined in a single paradigm. The present study aims to investigate whether healthy participants (N=43) can learn both fear and safety to an interoceptive sensation, and whether such learning generalizes to other, similar sensations. Two intensities of inspiratory breathing impairment (induced by two pressure threshold loads of 6 and 25 cm H2O) served as interoceptive conditional stimuli (CSs) in a differential conditioning paradigm. An inspiratory occlusion was used as the unconditioned stimulus (US). Generalization was tested 24h after conditioning, using four generalization stimuli with intensities in-between CS+ and CS- (GSs: 8-10.5-14-18.5 cm H2O). Measures included US-expectancy, startle blink EMG responses, electrodermal activity and respiration. Perceptual discrimination of interoceptive CSs and GSs was explored with a discrimination task prior to acquisition and after generalization. Results indicate that differential fear learning was established for US-expectancy ratings. The group with a low intensity CS+ and a high intensity CS- showed the typical pattern of differential fear responding and a similarity-based generalization gradient. In contrast, the high intensity CS+ and low intensity CS- group showed impaired differential learning and complete generalization of fear. Our findings suggest that interoceptive fear learning and generalization are modulated by stimulus intensity and that the occurrence of discriminatory learning is closely related to fear generalization., (Copyright © 2015. Published by Elsevier Ltd.)