Abstract

Fear conditioning is relevant for elucidating the pathophysiology of anxiety, but may also be useful in the context of chronic pain syndromes which often overlap with anxiety. Thus far, no fear conditioning studies have employed aversive visceral stimuli from the lower gastrointestinal tract. Therefore, we implemented a fear conditioning paradigm to analyze the conditioned response to rectal pain stimuli using fMRI during associative learning, extinction and reinstatement.In N = 21 healthy humans, visual conditioned stimuli (CS+) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS−) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, conditioned anticipatory neural activation was assessed along with perceived CS-US contingency and CS unpleasantness.Fear conditioning resulted in significant contingency awareness and valence change, i.e., learned unpleasantness of a previously neutral stimulus. This was paralleled by anticipatory activation of the anterior cingulate cortex, the somatosensory cortex and precuneus (all during early acquisition) and the amygdala (late acquisition) in response to the CS+. During extinction, anticipatory activation of the dorsolateral prefrontal cortex to the CS− was observed. In the reinstatement phase, a tendency for parahippocampal activation was found.Fear conditioning with rectal pain stimuli is feasible and leads to learned unpleasantness of previously neutral stimuli. Within the brain, conditioned anticipatory activations are seen in core areas of the central fear network including the amygdala and the anterior cingulate cortex. During extinction, conditioned responses quickly disappear, and learning of new predictive cue properties is paralleled by prefrontal activation. A tendency for parahippocampal activation during reinstatement could indicate a reactivation of the old memory trace. Together, these findings contribute to our understanding of aversive visceral learning and memory processes relevant to the pathophysiology of chronic abdominal pain.

Highlights

  • Fear conditioning is well-established to elucidate the mechanisms mediating associative learning and memory processes [1], [2], very little is known in the context of visceral pain

  • Participants A total of 21 healthy subjects participated (71.4%, N = 15 male; 28.6%, N = 6 female); due to technical errors (N = 1) and movement artifacts (N = 1) full fMRI data sets were available for N = 19 subjects

  • We implemented the first Pavlovian conditioning study in which the conditioned anticipatory brain responses to painful rectal pain stimuli as unconditioned stimuli (US) were analyzed with fMRI in healthy subjects during associative learning, extinction and reinstatement

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Summary

Introduction

Fear conditioning is well-established to elucidate the mechanisms mediating associative learning and memory processes [1], [2], very little is known in the context of visceral pain. Fear conditioning with aversive visceral stimuli as US has not been accomplished far, with the exception of a single esophageal distension study [6]. There is evidence to support that associative learning processes could be important in the aetiology of clinical conditions associated with chronic abdominal pain and/or visceral hyperalgesia. Learned associations between predictive contextual cues and painful stimuli were reportedly relevant for the development of visceral hypersensitivity [7] and for the retrieval of visceral pain-conditioned passive avoidance in rats [8]. Classical trace eyeblink conditioning was altered in fibromyalgia [11], a condition which often overlaps with IBS [12]

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