Adriane Icenhour

Neural circuitry of abdominal pain‐related fear learning and reinstatement in irritable bowel syndrome

Altered pain anticipation likely contributes to disturbed central pain processing in chronic pain conditions like irritable bowel syndrome (IBS), but the learning processes shaping the expectation of pain remain poorly understood. We assessed the neural circuitry mediating the formation, extinction, and reactivation of abdominal pain‐related memories in IBS patients compared to healthy controls (HC) in a differential fear conditioning paradigm.

Neural circuitry underlying effects of context on human pain-related fear extinction in a renewal paradigm.

The role of context in pain‐related extinction learning remains poorly understood. We analyzed the neural mechanisms underlying context‐dependent extinction and renewal in a clinically relevant model of conditioned abdominal pain‐related fear.

Are there sex differences in placebo analgesia during visceral pain processing? A fMRI study in healthy subjects

We explored sex differences in the neural mechanisms mediating placebo analgesia in an established visceral pain model involving painful rectal distensions in healthy volunteers.

From Pavlov to pain: How predictability affects the anticipation and processing of visceral pain in a fear conditioning paradigm.

Conditioned pain-related fear may contribute to hyperalgesia and central sensitization, but this has not been tested for interoceptive, visceral pain. The underlying ability to accurately predict pain is based on predictive cue properties and may alter the sensory processing and cognitive-emotional modulation of pain thus exacerbating the subjective pain experience. In this functional magnetic resonance imaging study using painful rectal distensions as unconditioned stimuli (US), we addressed changes in the neural processing of pain during the acquisition of pain-related fear and subsequently tested if conditioned stimuli (CS) contribute to hyperalgesia and increased neural responses in pain-encoding regions. N=49 healthy volunteers were assigned to one of two groups and underwent 3T fMRI during acquisition of either differential fear conditioning (predictable) or non-contingent presentation of CS and US (unpredictable). During a subsequent test phase, pain stimuli signaled randomly by the CSs were delivered. For the acquisition, results confirmed differential conditioning in the predictable but not the unpredictable group. With regard to activation in response to painful stimuli, the unpredictable compared to the predictable group revealed greater activation in pain-encoding (somatosensory cortex, insula) and pain-modulatory (prefrontal and cingulate cortices, periaqueductal grey, parahippocampus) regions. In the test phase, no evidence of hyperalgesia or central sensitization was found, but the predictable group demonstrated enhanced caudate nucleus activation in response to CS(-)-signaled pain. These findings support that during fear conditioning, the ability to predict pain affects neural processing of visceral pain and alters the associative learning processes underlying the acquisition of predictive properties of cues signaling pain, but conditioned pain-related fear does not result in visceral hyperalgesia or central sensitization.

Learning by experience? Visceral pain-related neural and behavioral responses in a classical conditioning paradigm

Studies investigating mechanisms underlying nocebo responses in pain have mainly focused on negative expectations induced by verbal suggestions. Herein, we addressed neural and behavioral correlates of nocebo responses induced by classical conditioning in a visceral pain model.

Greater fear of visceral pain contributes to differences between visceral and somatic pain in healthy women

Abstract This functional magnetic resonance imaging study addressed similarities and differences in behavioral and neural responses to experimental visceral compared with somatic pain stimuli and explored the contribution of fear of pain to differences between pain modalities. In N = 22 healthy women, we assessed blood oxygen level–dependent responses to rectal distensions and cutaneous heat stimuli matched for perceived pain intensity. Fear of pain and pain unpleasantness were assessed before and after scanning. Visceral pain was more fear evoking and more unpleasant, and trial-by-trial intensity ratings failed to habituate across trials (all interactions modality × time: P < 0.01). Differences in fear of pain and pain intensity independently contributed to greater visceral pain unpleasantness (combined regression model: R2 = 0.59). We observed joint neural activations in somatosensory cortex and frontoparietal attention network (conjunction analysis: all pFWE <0.05), but distensions induced greater activation in somatosensory cortex, dorsal and ventral anterior insula, dorsal anterior and midcingulate cortices, and brainstem, whereas cutaneous heat pain led to enhanced activation in posterior insula and hippocampus (all pFWE <0.05). Fear of visceral pain correlated with prefrontal activation, but did not consistently contribute to neural differences between modalities. These findings in healthy women support marked differences between phasic pain induced by rectal distensions vs cutaneous heat, likely reflecting the higher salience of visceral pain. More studies with clinically relevant pain models are needed to discern the role of fear in normal interindividual differences in the response to different types of pain and as a putative risk factor in the transition from acute to chronic pain.

Sex differences in cerebellar mechanisms involved in pain-related safety learning.

Recent studies have suggested that the cerebellum contributes to the central processing of pain, including pain-related learning and memory processes. As a complex experience with multiple emotional and cognitive facets, the response to pain and its underlying neural correlates differ between men and women. However, it remains poorly understood whether and to what extent sex differences exist in the cerebellar contribution to pain-related associative learning processes. In the present conditioning study with experimental abdominal pain as unconditioned stimuli (US), we assessed sex-dependent differences in behavioral and neural responses to conditioned warning and safety cues in healthy volunteers. The results revealed that in response to visual stimuli signaling safety from abdominal pain (CS(-)), women showed enhanced cerebellar activation in lobules I-IV, V, VI, VIIIa, IX and X as well as Crus II and the dentate nucleus, which are mostly representative of somatomotor networks. On the other hand, men showed enhanced neural activation in lobules I-IV, VI, VIIb, VIIIb, IX as well as Crus I and II in response to CS(-), which are representative of frontoparietal and ventral attention networks. No sex differences were observed in response to pain-predictive warning signals (CS(+)). Similarly, men and women did not differ in behavioral measures of conditioning, including conditioned changes in CS valence and contingency awareness. Together, we could demonstrate that the cerebellum is involved in associative learning processes of conditioned anticipatory safety from pain and mediates sex differences in the underlying neural processes. Given the high prevalence of chronic pain conditions in women, these results may contribute to improve our understanding of the acquisition and manifestation of chronic abdominal pain syndromes.

Contingency Awareness Shapes Acquisition and Extinction of Emotional Responses in a Conditioning Model of Pain-Related Fear

As a fundamental learning process, fear conditioning promotes the formation of associations between predictive cues and biologically significant signals. In its application to pain, conditioning may provide important insight into mechanisms underlying pain-related fear, although knowledge especially in interoceptive pain paradigms remains scarce. Furthermore, while the influence of contingency awareness on excitatory learning is subject of ongoing debate, its role in pain-related acquisition is poorly understood and essentially unknown regarding extinction as inhibitory learning. Therefore, we addressed the impact of contingency awareness on learned emotional responses to pain- and safety-predictive cues in a combined dataset of two pain-related conditioning studies. In total, 75 healthy participants underwent differential fear acquisition, during which rectal distensions as interoceptive unconditioned stimuli (US) were repeatedly paired with a predictive visual cue (conditioned stimulus; CS+) while another cue (CS−) was presented unpaired. During extinction, both CS were presented without US. CS valence, indicating learned emotional responses, and CS-US contingencies were assessed on visual analog scales (VAS). Based on an integrative measure of contingency accuracy, a median-split was performed to compare groups with low vs. high contingency accuracy regarding learned emotional responses. To investigate predictive value of contingency accuracy, regression analyses were conducted. Highly accurate individuals revealed more pronounced negative emotional responses to CS+ and increased positive responses to CS− when compared to participants with low contingency accuracy. Following extinction, highly accurate individuals had fully extinguished pain-predictive cue properties, while exhibiting persistent positive emotional responses to safety signals. In contrast, individuals with low accuracy revealed equally positive emotional responses to both, CS+ and CS−. Contingency accuracy predicted variance in the formation of positive responses to safety cues while no predictive value was found for danger cues following acquisition and for neither cue following extinction. Our findings underscore specific roles of learned danger and safety in pain-related acquisition and extinction. Contingency accuracy appears to distinctly impact learned emotional responses to safety and danger cues, supporting aversive learning to occur independently from CS-US awareness. The interplay of cognitive and emotional factors in shaping excitatory and inhibitory pain-related learning may contribute to altered pain processing, underscoring its clinical relevance in chronic pain.

Viszeraler Schmerz – eine biopsychologische Perspektive

Zusammenfassung Der von inneren Organen ausgehende, viszerale Schmerz unterscheidet sich in entscheidenden Aspekten von somatischen Schmerzen, sodass sich aus der somatischen Schmerzforschung gewonnene Erkenntnisse nur begrenzt übertragen lassen. Zugleich sind insbesondere zentralnervöse Mechanismen der bidirektionalen Kommunikation zwischen Darm und Gehirn bislang nur unzureichend verstanden. Diese Übersichtsarbeit beleuchtet den viszeralen Schmerz aus einer biopsychologischen Perspektive mit Schwerpunkt auf neurowissenschaftlichen Erkenntnissen. Die Bedeutung von Stress und weiteren psychologischen Einflussfaktoren auf die bidirektionale Signalvermittlung entlang der Gehirn-Darm-Achse steht dabei im Fokus. Zudem werden Befunde zu möglichen geschlechtsbezogenen Unterschieden bei viszeralen Schmerzen diskutiert. An der Schnittstelle von biologischer Psychologie, Neurogastroenterologie und den Neurowissenschaften soll so ein Einblick in ein faszinierendes, interdisziplinäres Forschungsgebiet eröffnet werden.

Visceral pain – a biopsychological perspective

Abstract Visceral pain arising from inner organs differs from somatic pain in crucial aspects, limiting the possibility to transfer knowledge derived from somatic pain research. The neurobiological mechanisms involved in the bidirectional communication between the brain and the gut along the brain-gut axis remain incompletely understood. This review addresses visceral pain from a biopsychological perspective, with an emphasis on psychological aspects and neuroimaging findings. It focuses on the role of stress and other psychological factors involved in the pathophysiology of chronic visceral pain in functional gastrointestinal disorders such as irritable bowel syndrome and summarizes findings on possible sex-related differences. Together, this overview aims to provide insights into a fascinating, interdisciplinary field of research at the interface between biological psychology, neurogastroenterology and the neurosciences.