Search

ZusammenfassungStörungen der Darm-Gehirn-Achse sind durch komplexe Dysfunktionen auf peripherer und zentralnervöser Ebene gekennzeichnet, die zu viszeraler Hypervigilanz und Hyperalgesie beitragen können und viszeralen Schmerz prägen. An der viszeralen Schmerzmodulation sind zahlreiche kognitive, emotionale und psychoneurobiologische Faktoren beteiligt, die im psychosozialen Therapiekontext das viszerale Schmerzerleben sowohl positiv als auch negativ beeinflussen können. Durch negative Erwartungen vermittelte Noceboeffekte sind bei akuten, aber insbesondere auch bei chronischen viszeralen Schmerzen von hoher klinischer Relevanz; die ihnen zugrunde liegenden Mechanismen sind jedoch bislang unzureichend verstanden. Zur Entstehung und Aufrechterhaltung negativer Erwartungseffekte tragen insbesondere verbale Instruktionen, Vorerfahrungen und Lernprozesse sowie emotionale Faktoren wie Angst und Stress bei. Gezielte Kommunikationsstrategien, ein sensibler Umgang in der Aufklärung und positive Umgebungsbedingungen können in der klinischen Praxis dazu beitragen, ein adäquates Erwartungsmanagement zu etablieren und negative Erwartungseffekte zu minimieren. Zugleich sind translationale Forschungsansätze erforderlich, um tiefere Erkenntnisse bezüglich der Mediatoren und Moderatoren negativer Erwartungseffekte zu erlangen und diese in die Klinik zu übertragen. So kann die Versorgung von Patienten mit Störungen der Darm-Gehirn-Kommunikation verbessert werden.

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.

Vasoactive intestinal polypeptide (VIP) is a neuroendocrine peptide distributed throughout the human body, including the CNS, where it is particularly abundant in brain regions associated with anxiety and depression. Based on earlier studies indicating that peripheral VIP may cross through the blood–brain barrier, we hypothesized plasma VIP levels to be associated with symptoms of anxiety and depression, as well as brain volume and resting-state functional connectivity in the amygdala, hippocampus, parahippocampus, and orbitofrontal cortex. Plasma VIP concentrations and anxiety/depression symptoms were measured in 37 healthy females. Functional and structural magnetic resonance imaging were used to evaluate functional connectivity and brain volume respectively, and their associations with VIP concentrations within brain regions associated with anxiety and depression. Negative correlations were found between VIP levels and symptoms of anxiety (r = − 0.44, p = 0.002) and depression (r = − 0.50, p = 0.001). Functional connectivity demonstrated significant VIP-dependent positive associations between the amygdala seed region with both the right parahippocampus (t(33) = 3.1, pFDR = 0.02) and right lateral orbitofrontal cortex (OFC; t(33) = 2.9, pFDR = 0.02). Moreover, VIP concentrations were significantly, positively correlated with brain volume in the left amygdala (r = 0.28, p = 0.007) and left lateral OFC (r = 0.29, p = 0.004). The present findings highlight a potential role for VIP in the neurobiology of affective symptoms.

Irritable bowel syndrome (IBS) is a symptom-based disorder of gut-brain interactions generating abdominal pain. It is also associated with a vulnerability to develop extraintestinal symptoms, with fatigue often reported as one of the most disturbing. Fatigue is related to brain function and inflammation in several disorders, however, the mechanisms of such relations in IBS remain elusive. This study aimed to elucidate fatigue and its association with a resting state network of mesocorticolimbic regions of known importance in fatigue, and to explore the possible role of circulating TNF-α levels in IBS and healthy controls (HC). Resting state functional magnetic resonance imaging (fMRI) was conducted in 88 IBS patients and 47 HC of similar age and gender to investigate functional connectivity between mesocorticolimbic regions. Further, fatigue impact on daily life and plasma levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α), of known relevance to immune activation in IBS, were also measured. The selected mesocorticolimbic regions indeed formed a functionally connected network in all participants. The nucleus accumbens (NAc), in particular, exhibited functional connectivity to all other regions of interest. In IBS, fatigue impact on daily life was negatively correlated with the connectivity between NAc and dorsolateral prefrontal cortex bilaterally (left p = 0.019; right p = 0.038, corrected for multiple comparisons), while in HC, fatigue impact on daily life was positively correlated to the connectivity between the right NAc and anterior middle insula in both hemispheres (left p = 0.009; right p = 0.011). We found significantly higher levels of TNF-α in IBS patients compared to HC (p = 0.001) as well as a positive correlation between TNF-α and fatigue impact on daily life in IBS patients (rho = 0.25, p = 0.02) but not in HC (rho = −0.13, p = 0.37). There was no association between functional connectivity in the mesocorticolimbic network and plasma levels of TNF-α in either group In summary, this novel multimodal study provides the first evidence that the vulnerability to fatigue in IBS is associated with connectivity within a mesocorticolimbic network as well as immune activation. These findings warrant further investigation, both peripherally and potentially with measurements of central immune activation as well. Additional funding agencies: Lions forskningsfond mot folksjukdomar (AKN; LIU-2019-01190).

BackgroundAlthough early adverse life events (EALs) are prevalent among patients with irritable bowel syndrome (IBS), the impact of fear or dissociation experienced during the trauma has not been evaluated. We investigated the prevalence of fear at the time of trauma and its association with IBS status among individuals with early-life trauma before the age of 18.MethodsAmong participants with ≥1 EAL, association of fear and dissociation with IBS status was determined with logistic regression, and improvement in prediction of IBS over ETI score alone was determined with the likelihood ratio test. Controlling for age, sex, and IBS status, we then examined the association of each EAL with reported fear.Key resultsCompared to healthy controls (HCs), IBS subjects reported a higher prevalence of fear (60.4% vs 36.2%, P&nbsp

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.

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.

The role of pain-related fear learning and memory processes, conceptually embedded within the fear-avoidance model of chronic pain, is increasingly recognized. The unique biological salience of interoceptive, visceral pain with its cognitive, emotional, and motivational facets fosters associative learning. Conditioned fear is in principle adaptive but may turn maladaptive and contribute to hypervigilance and hyperalgesia in chronic pain. This review summarizes current knowledge on the formation, extinction, and return of pain-related memories with a focus on visceral pain. It provides a conceptual background, describes experimental approaches, and summarizes findings on behavioral and neural mechanisms in healthy humans and patients with chronic pain. Future directions underscore the potential of refining knowledge on the role of associative learning in the pathophysiology and treatment of chronic visceral pain in disorders of gut–brain interactions such as irritable bowel syndrome.

Visceroception is a complex phenomenon comprising the sensation, interpretation, and integration of sensations along the gut-brain axis, including pain or defecatory urgency. Stress is considered a crucial risk factor for the development and maintenance of disorders of gut-brain signaling, which are characterized by altered visceroception. Although the broad role of stress and stress mediators in disturbed visceroception is widely acknowledged, the putative contribution of chronic stress to variations in normal visceroception remains incompletely understood. We aimed to elucidate the role of chronic stress in shaping different facets of visceroception. From a well-characterized, large sample of healthy men and women (N = 180, 50% female), volunteers presenting with low (n = 57) and elevated (n = 61) perceived chronic stress were identified based on the validated Trier Inventory for Chronic Stress (TICS). Visceral sensitivity together with perceived and recalled intensity and defecatory urgency induced by repeated rectal distensions was experimentally assessed, and compared between low and elevated stress groups. Subgroups were compared regarding state anxiety and salivary cortisol concentrations across experimental phases and with respect to psychological measures. Finally, in the full sample and in chronic stress subgroups, a recall bias in terms of a discrepancy between the perception of experimentally-induced symptoms and their recall was tested. Participants with elevated chronic stress presented with increased state anxiety and higher cortisol concentrations throughout the experimental phases compared to the group with low chronic stress. Group differences in visceral sensitivity were not evident. The elevated stress group perceived significantly higher urgency during the stimulation phase, and recalled substantially higher feelings of urgency induced by rectal distensions, while perceived and recalled intensity were comparable between groups. Volunteers with elevated stress exhibited a recall bias in terms of a higher recall relative to mean perception of urgency, whereas no such bias was observed for the intensity of experimental visceral stimulation. Our findings in healthy men and women provide first evidence that the troublesome symptom of urgency might be particularly modifiable by chronic stress and support the relevance of memory biases in visceroception. These results may help to disentangle the impact of chronic stress on altered visceroception in disturbances of gut-brain communication. CA - Icenhour

Despite growing interest in the role of stress mediators in pain chronicity, the effects of the stress hormone cortisol on acute pain remain incompletely understood. In a randomized, double-blind, placebo-controlled study with N = 100 healthy volunteers, we tested the effects of oral hydrocortisone (20 mg) in 2 widely used pain models for the visceral and somatic modality. Salivary cortisol was increased in the hydrocortisone group (time × group: P < 0.001). For the visceral modality, assessed using pressure-controlled rectal distensions, hydrocortisone decreased the pain threshold from before to after treatment (time × group: P = 0.011), an effect primarily driven by women (time × sex: P = 0.027). For the somatic modality, cutaneous heat pain thresholds remained unaffected by hydrocortisone. Hydrocortisone did not alter perceived pain intensity or unpleasantness of either modality. Conditioned pain-related fear in response to predictive cues was only observed for the visceral modality (time × modality: P = 0.026), an effect that was significantly reduced by hydrocortisone compared with placebo (time × group: P = 0.028). This is the first psychopharmacological study to support that acutely increased cortisol enhances pain sensitivity and impairs pain-related emotional learning within the visceral, but not the somatic pain modality. Stress-induced visceral hyperalgesia and deficits in emotional pain-related learning could play a role in the pathophysiology of chronic visceral pain.

n/a Funding Agencies|Region Ostergotland; Bengt-Ihre Fond

Supplemental Digital Content is Available in the Text. Quantitative magnetic resonance spectroscopy of anterior insula reveals decreased glutamatergic neurotransmitter concentrations in patients with irritable bowel syndrome and hemisphere-specific associations with pain severity and pain-related coping., Irritable bowel syndrome (IBS) is a visceral pain condition with psychological comorbidity. Brain imaging studies in IBS demonstrate altered function in anterior insula (aINS), a key hub for integration of interoceptive, affective, and cognitive processes. However, alterations in aINS excitatory and inhibitory neurotransmission as putative biochemical underpinnings of these functional changes remain elusive. Using quantitative magnetic resonance spectroscopy, we compared women with IBS and healthy women (healthy controls [HC]) with respect to aINS glutamate + glutamine (Glx) and γ-aminobutyric acid (GABA+) concentrations and addressed possible associations with symptoms. Thirty-nine women with IBS and 21 HC underwent quantitative magnetic resonance spectroscopy of bilateral aINS to assess Glx and GABA+ concentrations. Questionnaire data from all participants and prospective symptom-diary data from patients were obtained for regression analyses of neurotransmitter concentrations with IBS-related and psychological parameters. Concentrations of Glx were lower in IBS compared with HC (left aINS P < 0.05, right aINS P < 0.001), whereas no group differences were detected for GABA+ concentrations. Lower right-lateralized Glx concentrations in patients were substantially predicted by longer pain duration, while less frequent use of adaptive pain‐coping predicted lower Glx in left aINS. Our findings provide first evidence for reduced excitatory but unaltered inhibitory neurotransmitter levels in aINS in IBS. The results also indicate a functional lateralization of aINS with a stronger involvement of the right hemisphere in perception of abdominal pain and of the left aINS in cognitive pain regulation. Our findings suggest that glutaminergic deficiency may play a role in pain processing in IBS.

BACKGROUND Visceral hypersensitivity plays a key role in the pathophysiology of chronic visceral pain like irritable bowel syndrome (IBS), which is significantly more prevalent in women. Possible sex differences in visceral sensitivity remain poorly studied. We assessed sex differences in visceral sensitivity and their association with subclinical symptoms, trait anxiety, and chronic stress in a large sample of healthy men and women. METHODS In 280 young healthy volunteers (50% female), visceral sensory and pain thresholds were determined using rectal balloon distensions. Gastrointestinal (GI) symptoms, chronic stress, and trait anxiety as IBS-related risk factors were assessed with questionnaires. Men and women were compared regarding visceral sensitivity and multiple regression analyses were conducted to evaluate the predictive value of sex and risk factors for visceral sensitivity. Subgroups with high, intermediate, and low sensitivity were compared regarding psychological and biological characteristics. KEY RESULTS Men and women did not differ in sensory or pain thresholds or in IBS-related risk factors. In multiple regression analyses, no predictor of visceral sensitivity could be identified. While sensitivity subgroups differed in sensory and pain thresholds, the proportions of men and women were comparable, and groups did not differ in IBS-related risk factors. CONCLUSIONS AND INFERENCES Despite the large sample size, we found no evidence supporting sex differences in visceral sensitivity. At least in healthy young volunteers, our findings suggest that sex, GI symptoms, anxiety, or chronic stress do not contribute to altered visceral sensitivity.

Altered neural mechanisms are well-acknowledged in irritable bowel syndrome (IBS), a disorder of brain-gut-communication highly comorbid with anxiety and depression. As a key hub in corticolimbic inhibition, medial prefrontal cortex (mPFC) may be involved in disturbed emotion regulation in IBS. However, aberrant mPFC excitatory and inhibitory neurotransmission potentially contributing to psychological symptoms in IBS remains unknown. Using quantitative magnetic resonance spectroscopy (qMRS), we compared mPFC glutamate + glutamine (Glx) and gamma-aminobutyric acid (GABA+) concentrations in 64 women with IBS and 32 age-matched healthy women (HCs) and investigated their association with anxiety and depression in correlational and subgroup analyses. Applying functional magnetic resonance imaging (fMRI), we explored whether altered neurotransmission was paralleled by aberrant mPFC resting-state functional connectivity (FC). IBS patients did not differ from HCs with respect to mPFC GABA+ or Glx levels. Anxiety was positively associated with mPFC GABA+ concentrations in IBS, whereas Glx was unrelated to psychological or gastrointestinal symptoms. Subgroup comparisons of patients with high or low anxiety symptom severity and HCs revealed increased GABA+ in patients with high symptom severity, and lower mPFC FC with adjacent anterior cingulate cortex (ACC), a crucial region of emotion modulation. Our findings provide novel evidence that altered prefrontal inhibitory neurotransmission may be linked to anxiety in IBS. Funding Agencies|Martinos Center for Biomedical Imaging, MGH (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P41-RR14075, R01 RR16594-01A1, R01 NS052585-01]; Child and Adolescent Neuropsychiatric Research Program, Cambridge Health Alliance (NIH) [K08 MH01573, K01 MH01798]; County Council of Ostergotland; AFA research foundation; Bengt-Ihre fund; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)German Research Foundation (DFG) [IC 81/1-1, 316803389 - SFB 1280]; Kurt and Helena Widens Research Fund; Seeing Organ Function project - Knut and Alice Wallenberg Foundation; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P41 015909, R01 016089]

Changes in brain-gut interactions have been implicated in the pathophysiology of chronic visceral pain in irritable bowel syndrome (IBS). Different mechanisms of sensitization of visceral afferent pathways may contribute to the chronic visceral pain reports and associated brain changes that characterize IBS. They include increased gut permeability and gut associated immune system activation, and an imbalance in descending pain inhibitory and facilitatory mechanisms. In order to study the involvement of these mechanisms, correlations between gut epithelial permeability and live bacterial passage, and structural and functional brain connectivity were measured in women with moderate-to-severe IBS and healthy women. The relationships between gut permeability and functional and anatomical connectivity were significantly altered in IBS compared with the healthy women. IBS participants with lower epithelial permeability reported increased IBS symptoms, which was associated with increased functional and structural connectivity in endogenous pain facilitation regions. The findings suggest that relationships between gut permeability and the brain are significantly altered in IBS and suggest the existence of IBS subtypes based on these interactions., Highlights • Brain-gut interactions are significantly altered in irritable bowel syndrome. • Brain-gut interactions engage pain modulation brain regions in healthy women. • Normal levels of gut permeability in IBS are linked with endogenous pain facilitation.

Objectives 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. Experimental design: In this functional magnetic resonance imaging study, two groups of healthy volunteers underwent differential fear conditioning with painful rectal distensions as unconditioned stimuli (US) and visual conditioned stimuli (CS+; CS−). The extinction context was changed in an experimental group (context group), which was subsequently returned into the original learning context to test for renewal. No context changes occurred in the control group. Group differences in CS-induced differential neural activation were analyzed along with skin conductance responses (SCR), CS valence and CS-US contingency ratings. Principal observations: During extinction, group differences in differential neural activation were observed in dorsolateral (dlPFC) and ventromedial (vmPFC) prefrontal cortex and amygdala, mainly driven by enhanced activation in response to the CS− in the control group. During renewal, observed group differences in activation of dlPFC and orbitofrontal cortex (OFC) resulted primarily from differential modulation of the CS− in the absence of group differences in response to CS+ or SCR. Conclusion The extinction context affects the neural processing of nonpain predictive safety cues, supporting a role of safety learning in pain-related memory processes. Hum Brain Mapp 36:3179–3193, 2015. © 2015 Wiley Periodicals, Inc.

Objective The aim of this study was to compare behavioral and neural anticipatory responses to cues predicting either somatic or visceral pain in an associative learning paradigm. Methods Healthy women (N = 22) underwent functional magnetic resonance imaging. During an acquisition phase, two different visual cues repeatedly signalled either experimental visceral or somatic pain. In a subsequent extinction phase, identical cues were presented without pain. Before and after each phase, cue valence and contingency awareness were assessed on visual analog scales. Results Visceral compared to somatic pain-predictive cues were rated as more unpleasant after acquisition (visceral, 32.18 ± 13.03 mm; somatic, -18.36 ± 10.36 mm; p = .021) with similarly accurate cue-pain contingencies. After extinction, cue valence returned to baseline for both modalities (visceral, 1.55 ± 9.81 mm; somatic, -18.45 ± 7.12; p = .41). During acquisition, analyses of cue-induced neural responses revealed joint neural activation engaging areas associated with attention processing and cognitive control. Enhanced deactivation of posterior insula to visceral cues was observed, which correlated with enhanced responses within the salience network (anterior cingulate cortex, anterior insula) during visceral compared to somatic pain stimulation. During extinction, both pain modalities induced anticipatory neural activation in the extinction and salience network (all pFWE values Conclusions Conditioned emotional responses to pain-predictive cues are modality specific and enhanced for the visceral modality, suggesting that pain anticipation is shaped by the salience of painful stimuli. Common but also modality-specific neural mechanisms are involved during cue-pain learning, whereas extinction of cued responses seems unaffected by modality. Future research should examine potential implications for the pathophysiology of chronic pain conditions, especially chronic visceral pain.

Background 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. Methods In two independent studies, a total of 40 healthy volunteers underwent classical conditioning, consisting of repeated pairings of one visual cue (CSHigh) with rectal distensions of high intensity, while a second cue (CSLow) was always followed by low-intensity distensions. During subsequent test, only low-intensity distensions were delivered, preceded by either CSHigh or CSLow. Distension intensity ratings were assessed in both samples and functional magnetic resonance imaging data were available from one study (N=16). As a consequence of conditioning, we hypothesized CSHigh-cued distensions to be perceived as more intense and expected enhanced cue- and distension-related neural responses in regions encoding sensory and affective dimensions of pain and in structures associated with pain-related fear memory. Key Results During test, distension intensity ratings did not differ depending on preceding cue. Greater distension-induced neural activation was observed in somatosensory, prefrontal, and cingulate cortices and caudate when preceded by CSHigh. Analysis of cue-related responses revealed strikingly similar activation patterns. Conclusions & Inferences We report changes in neural activation patterns during anticipation and visceral stimulation induced by prior conditioning. In the absence of behavioral effects, markedly altered neural responses may indicate conditioning with visceral signals to induce hypervigilance rather than hyperalgesia, involving altered attention, reappraisal, and perceptual acuity as processes contributing to the pathophysiology of visceral pain.

There is evidence to support a role of the cerebellum in emotional learning processes, which are demonstrably altered in patients with chronic pain. We tested if cerebellar activation is altered during visceral pain-related fear conditioning and extinction in irritable bowel syndrome (IBS). Cerebellar blood oxygenation level-dependent (BOLD) data from N = 17 IBS patients and N = 21 healthy controls, collected as part of a previous fMRI study, was reanalyzed utilizing an advanced normalizing method of the cerebellum. The differential fear conditioning paradigm consisted of acquisition, extinction, and reinstatement phases. During acquisition, two visual conditioned stimuli (CS) were presented either paired (CS+) or unpaired (CS-) with painful rectal distension as unconditioned stimulus (US). In the extinction phase, the CS+ and CS- were presented without US. For reinstatement, unpaired US presentations were followed by unpaired CS+ and CS- presentations. Group differences in cerebellar activation were analyzed for the contrasts CS+ CS- and CS- CS+. During acquisition, IBS patients revealed significantly enhanced cerebellar BOLD responses to pain-predictive (CS+) and safety (CS-) cues compared to controls (p 0.05, family-wise error corrected). Increased activation was found in three main clusters, including the vermis (maximum in vermal lobule VI), intermediate cerebellum (maximum in lobule VIII), and the posterolateral cerebellar hemisphere (maximum in lobule VI). Areas overlapped for the contrasts CS+ CS- and CS- CS+. Group differences were most prominent in the contrast CS- CS+. During extinction and reinstatement, no significant group differences were found. During visceral pain-related fear conditioning, IBS patients showed increased activations in circumscribed areas of the medial, intermediate, and lateral cerebellum. These areas are involved in autonomic, somatosensory, and cognitive functions and likely contribute to the different aspects of pain-related fear. The cerebellum contributes to altered pain-related fear learning in IBS.

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.

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.

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.

Zusammenfassung Epidemiologische Studien dokumentieren, dass Frauen deutlich haufiger von chronischen Schmerzen betroffen sind als Manner. Die Ursachen und Mechanismen, die diesen Geschlechtsunterschieden zugrunde liegen, werden jedoch erst seit einigen Jahren systematisch untersucht. Aktuell geht man von einem multifaktoriellen Schmerzmodell aus, dem zufolge biologische, psychologische und soziale Faktoren bei der Entstehung und Aufrechterhaltung von Schmerzen zusammenwirken und auf die Geschlechtsunterschiede potenziell zuruckfuhrbar sind. In diesem Beitrag wird auf der Basis des bio-psychosozialen Krankheitsmodells die aktuelle, sehr komplexe Befundlage zu Geschlechtsdifferenzen bei Schmerzen dargestellt. Am Beispiel des Reizdarmsyndroms wird das Zusammenwirken biologischer und psychosozialer Einflusse verdeutlicht und es werden offene Fragen thematisiert, aus denen zentrale Erkenntnisse fur ein tieferes Verstandnis des komplexen Themenbereichs geschlechtsbezogener Unterschiede bei Schmerzen gewonnen werden konnen. Schlusselworter: chronische Schmerzen, Geschlechtsdifferenzen, Gender, Reizdarmsyndrom, bio-psychosoziales Krankheitsmodell ----- Biological and psychosocial influences on sex-/gender-associated differences in pain. Summary Epidemiological studies document distinctly higher prevalence rates for chronic pain in women compared to men. However, the causes of these differences have only recently started to be systematically investigated and the findings are proving to be very complex. A multifactorial pain model is currently postulated, whereby biological, psychological and social factors interact in the development and persistence of pain. Based on a bio-psychosocial model, results of sex/gender differences in pain and their potential causes and mechanisms are reviewed. Taking irritable bowel syndrome as an example in the field of chronic pain, further insight into the interaction between biological and psychosocial factors is provided and open questions are raised to gain a deeper understanding of the complex field of sex-/gender-associated differences in pain. Keywords: chronic pain, sex differences, gender, irritable bowel syndrome, bio-psychosocial model ----- Bibliographie: Icenhour, Adriane/Elsenbruch, Sigrid/Benson, Sven: Biologische und psychosoziale Einflussfaktoren auf geschlechterbezogene Unterschiede beim Schmerz, GENDER, 2-2015, S. 11-28. https://doi.org/10.3224/gender.v7i2.19310

Background 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. Methods During fear acquisition, predictive visual cues (CS+) were paired with rectal distensions (US), while control cues (CS−) were presented unpaired. During extinction, only CSs were presented. Subsequently, memory reactivation was assessed with a reinstatement procedure involving unexpected USs. Using functional magnetic resonance imaging, group differences in neural activation to CS+ vs CS− were analyzed, along with skin conductance responses (SCR), CS valence, CS-US contingency, state anxiety, salivary cortisol, and alpha-amylase activity. The contribution of anxiety symptoms was addressed in covariance analyses. Key Results Fear acquisition was altered in IBS, as indicated by more accurate contingency awareness, greater CS-related valence change, and enhanced CS+-induced differential activation of prefrontal cortex and amygdala. IBS patients further revealed enhanced differential cingulate activation during extinction and greater differential hippocampal activation during reinstatement. Anxiety affected neural responses during memory formation and reinstatement. Conclusions & Inferences Abdominal pain-related fear learning and memory processes are altered in IBS, mediated by amygdala, cingulate cortex, prefrontal areas, and hippocampus. Enhanced reinstatement may contribute to hypervigilance and central pain amplification, especially in anxious patients. Preventing a ‘relapse’ of learned fear utilizing extinction-based interventions may be a promising treatment goal in IBS.

There exists converging evidence to support a role of pain-related fear in the pathophysiology and treatment of chronic pain conditions. Pain-related fear is shaped by associative learning and memory processes, which remain poorly characterized especially in the context of abdominal pain such as in irritable bowel syndrome (IBS). Therefore, using event-related functional magnetic resonance imaging (fMRI), we assessed the neural mechanisms mediating the formation, extinction and reinstatement of abdominal pain-related fear in healthy humans. Employing painful rectal distensions as clinically-relevant unconditioned stimuli (US), in this fear conditioning study we tested if differential excitatory and inhibitory learning is evocable after very few CS-US learning trials ("rapid conditioning"), and explored the underlying neural substrates of these learning and memory processes.In N=24 healthy men and women, "rapid" fear acquisition was accomplished by pairing visual conditioned stimuli (CS(+)) with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS(-)) were presented without US (differential delay conditioning with five CS(+) and five CS(-) presentations and a 80% reinforcement ratio). During extinction, all CS were presented without US. Subsequently, a reinstatement procedure was implemented, defined as the retrieval of an extinguished memory after unexpected and unpaired exposure to the US, followed by CS presentations. For each phase, changes in perceived CS-US contingency and CS unpleasantness were assessed with visual analogue scales and compared with analyses of variance. fMRI data were analyzed using whole-brain analyses (at p.001 uncorrected) and in regions-of-interest analyses with familywise error correction of alpha (pFWE.05). Differential neural activation in response to the CS during each experimental phase (i.e., CS(+)CS(-); CS(+)CS(-)) was analyzed without and subsequently also with a linear parametric modulation including trial number as a regressor.A significant valence change (i.e. increased CS(+) unpleasantness) was observed following acquisition, indicating successful differential aversive learning. On the other hand, CS-US contingency awareness was not fully established. These behavioral results were paralleled by differential activation of the putamen (pFWE.05), insula (pFWE.05) and secondary somatosensory cortex (S2, p.001 uncorrected) in response to the CS(+) during acquisition. The same analysis with a linear parametric modulation confirmed but also strengthened the resulting activations, which were all highly significant in ROI analyses at pFWE.05. Extinction and reinstatement involved differential activation in response to the CS(-), involving the cingulate cortex and primary motor cortex (M1) during extinction and the posterior cingulate cortex (PCC) during reinstatement (all p.001 uncorrected), without obvious effects upon linear parametric modulation analysis.Abdominal pain stimuli are effective US that elicit conditioned pain-related fear even after very few learning experiences without full contingency awareness. These findings extend similar evidence of "rapid learning" in response to interoceptive US (e.g., conditioned taste aversion, conditioned nausea), and have implications for the pathophysiology and treatment of chronic abdominal pain such as in IBS.

Background We explored sex differences in the neural mechanisms mediating placebo analgesia in an established visceral pain model involving painful rectal distensions in healthy volunteers. Methods N = 15 men and N = 15 women underwent three consecutive functional magnetic resonance imaging sessions during which cued painful rectal distensions were delivered. After an adaptation session, positive expectations were induced with deceptive instructions regarding administration of an analgesic drug (placebo session). In the other session (control), truthful information about an inert substance was given. Sex differences in placebo-induced modulation of neural activation during anticipation and pain were analyzed along with ratings of expected and perceived pain intensity. Key Results Placebo-induced reductions in pain ratings were comparable between men and women. At the level of the brain, group comparisons with respect to differences between the placebo and control conditions revealed greater modulation of the posterior insula (regions-of-interest analysis: pFWE