Setting the stage for pain relief: how treatment setting impacts interdisciplinary multimodal pain treatment for patients with chronic back pain.

ABSTRACT: While interdisciplinary multimodal pain treatment (IMPT) is an effective treatment option for chronic low back pain, it is usually accomplished as an inpatient treatment incurring substantial healthcare costs. Day hospital IMPT could be a resource-saving alternative approach, but whether treatment setting is associated with differences in treatment outcomes has not yet been studied. In a retrospective matched cohort study including data from N = 595 patients diagnosed with chronic back pain and undergoing IMPT at the back pain center in Essen, Germany, we investigated the association between treatment setting (ie, inpatient or day patient of an otherwise identical IMPT) and pain intensity, disability, and self-efficacy after treatment. Outcomes were assessed by questionnaires used in clinical routine, collected at pre-IMPT, post-IMPT, and at 3-, 6-, and 12-month follow-up. The results indicate that day patients showed greater improvements in pain-related disability at 3-month post-IMPT (d = 0.74) and in pain intensity at 6-month post-IMPT (d = 0.79), compared to a matched sample of inpatients. Moreover, day patients achieved higher scores in pain-related self-efficacy at discharge, 3- and 6-month post-IMPT (d = 0.62, 0.99, and 1.21, respectively) and reported fewer incapacity-for-work days than inpatients at 6-month post-IMPT (d = 0.45). These data suggest that day hospital IMPT can be as effective as inpatient treatment and might even be more effective for the less afflicted patients. Further research regarding treatment setting and indication could guide optimized and cost-efficient treatments that are more closely tailored to the individual patient's needs.

Preoperative Anxiolysis and Treatment Expectation (PATE Trial): open-label placebo treatment to reduce preoperative anxiety in female patients undergoing gynecological laparoscopic surgery - study protocol for a bicentric, prospective, randomized-controlled trial.

One of the most common concerns of patients undergoing surgery is preoperative anxiety, with a prevalence of up to 48%. The effects of preoperative anxiety continue beyond the preoperative period and are associated with more severe postoperative pain and poorer treatment outcomes. Treatment options for preoperative anxiety are often limited as sedatives cause side effects and their efficacy remains controversial. Placebo research has shown that optimization of positive treatment expectations, as can be achieved through placebo administration and education, has clinically relevant effects on preoperative anxiety, pain and treatment outcomes. As the administration of masked placebos raises ethical questions, clinical studies have increasingly focused on the use of open, non-deceptive placebo administration (open-label placebo, OLP). The use of OLPs to reduce preoperative anxiety and modify clinically relevant postoperative outcomes has not yet been investigated. This bicentric, prospective, randomized-controlled clinical trial (PATE Trial; German Registry for Clinical Studies DRKS00033221), an associated project of the Collaborative Research Center (CRC) 289 "Treatment Expectation", aims to alleviate preoperative anxiety by optimizing positive treatment expectations facilitated by OLP. Furthermore, this study examines a potential enhancement of these effects through aspects of observational learning, operationalized by a positive expectation-enhancing video. In addition, patient's perspective on the self-efficacy and appropriateness of OLPs prior to surgery will be assessed. To achieve these objectives, female patients will be randomized into three groups before undergoing gynecological laparoscopic surgery. One group receives the OLP with a positive rationale conveyed by a study physician. A second group receives the same intervention, OLP administration and rationale provided by a physician, and additionally watches a video on OLP presenting a satisfied patient. A third group receives standard treatment as usual (TAU). Outcome measures will be effects on preoperative anxiety and postoperative experience, particularly visceral and somatic postoperative pain. As the non-deceptive administration of placebos; when indicated; may yield positive outcomes without side effects, and as current treatment of preoperative anxiety is limited, evidence from clinical placebo research has the potential to improve outcomes and patient experience in the surgical setting.

An externally validated resting-state brain connectivity signature of pain-related learning.

Pain can be conceptualized as a precision signal for reinforcement learning in the brain and alterations in these processes are a hallmark of chronic pain conditions. Investigating individual differences in pain-related learning therefore holds important clinical and translational relevance. Here, we developed and externally validated a novel resting-state brain connectivity-based predictive model of pain-related learning. The pre-registered external validation indicates that the proposed model explains 8-12% of the inter-individual variance in pain-related learning. Model predictions are driven by connections of the amygdala, posterior insula, sensorimotor, frontoparietal, and cerebellar regions, outlining a network commonly described in aversive learning and pain. We propose the resulting model as a robust and highly accessible biomarker candidate for clinical and translational pain research, with promising implications for personalized treatment approaches and with a high potential to advance our understanding of the neural mechanisms of pain-related learning.

Treatment Expectations-You Get What You Expect-and Depression Plays a Role.

Positive treatment expectations demonstrably shape treatment outcomes regarding pain and disability in patients with chronic low back pain. However, knowledge about positive and negative treatment expectations as putative predictors of interindividual variability in treatment outcomes is sparse, and the role of other psychological variables of interest, especially of depression as a known predictor of long-term disability, is lacking. We present results of the first prospective study considering expectations in concert with depression in a sample of 200 patients with chronic low back pain undergoing an inpatient interdisciplinary multimodal pain therapy. We analyzed the characteristics of pain and disability, treatment expectation, and depression assessed at the beginning (T0), at the end of (T1), and at 3-month follow-up (T2) of interdisciplinary multimodal pain therapy. Treatment expectations did emerge as a significant predictor of changes in pain intensity and disability, respectively, showing that positive expectations were associated with better treatment outcomes. Mediation analyses revealed a partially mediating effect of treatment expectations on the relation between depression and pain outcomes. PERSPECTIVE: These results expand knowledge regarding the role of treatment expectations in individual treatment outcome trajectories in chronic pain patients, paving the way for much-needed efforts toward optimizing patient expectations and personalized approaches in clinical settings.

Disease-specific alterations in central fear network engagement during acquisition and extinction of conditioned interoceptive fear in inflammatory bowel disease.

Interoceptive fear, which is shaped by associative threat learning and memory processes, plays a central role in abnormal interoception and psychiatric comorbidity in conditions of the gut-brain axis. Although animal and human studies support that acute inflammation induces brain alterations in the central fear network, mechanistic knowledge in patients with chronic inflammatory conditions remains sparse. We implemented a translational fear conditioning paradigm to elucidate central fear network reactivity in patients with quiescent inflammatory bowel disease (IBD), compared to patients with irritable bowel syndrome (IBS) and healthy controls (HC). Using functional magnetic resonance imaging, conditioned differential neural responses within regions of the fear network were analyzed during acquisition and extinction learning. In contrast to HC and IBS, IBD patients demonstrated distinctly altered engagement of key regions of the central fear network, including amygdala and hippocampus, during differential interoceptive fear learning, with more pronounced responses to conditioned safety relative to pain-predictive cues. Aberrant hippocampal responses correlated with chronic stress exclusively in IBD. During extinction, differential engagement was observed in IBD compared to IBS patients within amygdala, ventral anterior insula, and thalamus. No group differences were found in changes of cue valence as a behavioral measure of fear acquisition and extinction. Together, the disease-specific alterations in neural responses during interoceptive fear conditioning in quiescent IBD suggest persisting effects of recurring intestinal inflammation on central fear network reactivity. Given the crucial role of interoceptive fear in abnormal interoception, these findings point towards inflammation-related brain alterations as one trajectory to bodily symptom chronicity and psychiatric comorbidity. Patients with inflammatory conditions of the gut-brain axis may benefit from tailored treatment approaches targeting maladaptive interoceptive fear.

Evaluation of a Multimodal Stress Management and Comprehensive Lifestyle Modification Program on Quality of Life and Gastrointestinal Symptoms in Patients with Crohn's Disease: A Randomized Controlled Pilot Trial with 9-Month Follow-Up.

INTRODUCTION: Stress and lifestyle factors impact the course of Crohn's disease (CD). Our primary objective was to assess whether patients with CD benefit from a mind-body-medicine stress management and lifestyle modification (MBM) program. METHODS: This 9-month two-arm pilot trial was conducted in Bamberg, Germany (2020-2021). Patients (18-75 years) with mild to moderate activity of CD and stable medication were enrolled and randomly assigned to either a 10-week MBM program (intervention group, IG) or a single 90-min education session (waiting list control group, CG). Primary endpoints were quality of life (IBDQ) and disease activity (HBI). Secondary endpoints were emotional distress, core self-evaluation, and inflammatory biomarkers 3 and 9 months after baseline assessment. RESULTS: We analyzed data from 37 patients (IG: n = 19, mean ± SD age 49.6 ± 13.1 years, 68% female; CG: 18, 46.8 ± 11.4, 67% female). Immediately after the intervention, 79% (IG) and 44% (CG) experienced a clinically relevant improvement (IBDQ score ≥16 points). This was similar after 9 months (63% vs. 44%). There was no difference in disease activity (3 months: p = 0.082, 95% CI -1.3 to 2.6; 9 months: p = 0.251, 95% CI -1.2 to 2.5). Secondary outcomes indicated improvements in emotional distress, core self-evaluation, erythrocyte sedimentation rate after three and in emotional distress, T-cell profiling in the blood, and fecal lactoferrin and calprotectin group after 9 months in the IG. CONCLUSION: Our study suggested benefits of a multimodal stress management and lifestyle modification program for patients with CD. Larger trials are needed to determine if the program can supplement or at least partially replace pharmacological treatment approaches.

Hydrocortisone Differentially Affects Reinstatement of Pain-related Responses in Patients With Chronic Back Pain and Healthy Volunteers.

Despite the crucial role of effective and sustained extinction of conditioned pain-related fear in cognitive-behavioral treatment approaches for chronic pain, experimental research on extinction memory retrieval in chronic pain remains scarce. In healthy populations, extinction efficacy of fear memory is affected by stress. Therefore, we investigated the effects of oral hydrocortisone administration on the reinstatement of pain-related associations in 57 patients with non-specific chronic back pain (CBP) and 59 healthy control (HC) participants in a differential pain-related conditioning paradigm within a placebo-controlled, randomized, and double-blind design. Participants' skin conductance responses indicate hydrocortisone-induced reinstatement effects in HCs but no observable reinstatement in HCs receiving placebo treatment. Interestingly, these effects were reversed in patients with CBP, that is, reinstatement responses were only observed in the placebo and not in the hydrocortisone group. Our findings corroborate previous evidence of stress-induced effects on extinction efficacy and reinstatement of fear memory in HCs, extending them into the pain context, and call for more research to clarify the role of stress in fear extinction and return of fear phenomena possibly contributing to treatment failure in chronic pain treatment. PERSPECTIVE: Opposing effects in HCs and patients with non-specific CBP may be associated with changes in the patients' stress systems. These findings could be of relevance to optimizing psychological, extinction-based treatment approaches.

Pre-treatment expectations and their influence on subjective symptom change in Crohn's disease.

BACKGROUND: Treatment expectations reportedly shape treatment outcomes, but have not been studied in the context of multimodal therapy in Crohn's disease (CD). Therefore, the current study investigated the role of treatment expectations for subjective symptom changes in CD patients who have undergone an integrative multimodal therapy program. METHODS: Validated questionnaires were completed at the start of the treatment program and post intervention. Pre-treatment expectations and experienced symptom change were assessed with the Generic Rating Scale for Previous Treatment Experiences, Treatment Expectations, and Treatment Effects (GEEE); stress levels were quantified with the Perceived Stress Scale (PSS-10) and disease specific quality of life was quantified with the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ). We performed multiple linear and Bayesian regression to determine how expectations related to symptom change. RESULTS: N = 71 CD patients (66.2% female) were included. Stronger expectations regarding symptom improvement (b = 0.422, t = 3.70, p < .001) were associated with higher experienced symptom improvement. Additionally, Bayesian analysis provided strong evidence for including improvement expectations as a predictor of improvement experience (BFinclusion = 13.78). CONCLUSIONS: In line with research in other disorders, we found that positive treatment expectations were associated with experienced symptom improvement. In contrast, we found no indication that an experience of symptom worsening was associated with positive or negative baseline treatment expectations. Induction of positive expectations might be a potential avenue for improving treatment outcomes in CD therapy.

Nocebo effects in visceral pain: concept and design of the experimental randomized-controlled pain study 'NoVis'.

The role of psychological factors in the pathophysiology and treatment of chronic visceral pain in disorders of gut-brain interactions (DGBI) is increasingly appreciated. Placebo research has underscored that expectations arising from the psychosocial treatment context and from prior experiences shape treatment responses. However, effects of negative expectations, i.e., nocebo effects, as they are likely crucial elements of DGBI patients' clinical reality, have thus far only rarely been investigated in the context of visceral pain, with untapped potential for improved prevention and treatment. The experimental randomized-controlled pain study "NoVis," carried out within the Collaborative Research Center (CRC) 289 ("Treatment Expectation"), aims to close gaps regarding the generation and persistence of nocebo effects in healthy volunteers. It is designed to elucidate effects of negative expectations in a multiple-threat paradigm with intensity-matched rectal distensions and cutaneous thermal stimuli, allowing to test nocebo effects in the visceral and somatic pain modalities. Negative expectations are experimentally induced by elements of doctor-patient communication (i.e., instruction) and/or by surreptitious amplification of symptom intensity (i.e., experience/learning) within a treatment context. Accordingly, the repeated measures between-subject design contains the between-group factors "treatment instruction" (negative vs. control) and "treatment experience" (negative vs. control), with volunteers randomized into four experimental groups undergoing several pain stimulation phases (repeated factor). This allows to compare the efficacy of instruction vs. experience, and more importantly, their combined effects on the magnitude of negative expectations and their impact on pain responses, which we expect will be greatest for the visceral modality. After a Baseline, short-term effects are assessed during a test phase accomplished on study day 1 (Test-1 Phase). To explore the persistence of effects, a second test phase is accomplished 1 week later (Test-2 Phase). Effects of negative expectations within and across pain modalities are assessed at the subjective and objective levels, with a focus on psychophysiological and neuroendocrine measures related to stress, fear, and anxiety. Since nocebo effects can play a considerable role in the generation, maintenance, or worsening of chronic visceral pain, and may even constitute risk factors for treatment failure, knowledge from experimental nocebo research has potential to improve treatment outcomes in DGBI and other clinical conditions associated with chronic visceral pain.

Amplified gut feelings under inflammation and depressed mood: A randomized fMRI trial on interoceptive pain in healthy volunteers.

BACKGROUND: Inflammation and depressed mood constitute clinically relevant vulnerability factors for enhanced interoceptive sensitivity and chronic visceral pain, but their putative interaction remains untested in human mechanistic studies. We tested interaction effects of acute systemic inflammation and sad mood on the expectation and experience of visceral pain by combining experimental endotoxemia with a mood induction paradigm. METHODS: The double-blind, placebo-controlled, balanced crossover fMRI-trial in N = 39 healthy male and female volunteers involved 2 study days with either intravenous administration of low-dose lipopolysaccharide (LPS, 0.4 ng/kg body weight; inflammation condition) or saline (placebo condition). On each study, day two scanning sessions were conducted in an experimentally induced negative (i.e., sad) and in a neutral mood state, accomplished in balanced order. As a model of visceral pain, rectal distensions were implemented, which were initially calibrated to be moderately painful. In all sessions, an identical series of visceral pain stimuli was accomplished, signaled by predictive visual conditioning cues to assess pain anticipation. We assessed neural activation during the expectation and experience of visceral pain, along with unpleasantness ratings in a condition combining an inflammatory state with sad mood and in control conditions. All statistical analyses were accomplished using sex as covariate. RESULTS: LPS administration led to an acute systemic inflammatory response (inflammation X time interaction effects for TNF-α, IL-6, and sickness symptoms, all p <.001). The mood paradigm effectively induced distinct mood states (mood X time interaction, p <.001), with greater sadness in the negative mood conditions (both p <.001) but no difference between LPS and saline conditions. Significant main and interaction effects of inflammation and negative mood were observed for pain unpleasantness (all p <.05). During cued pain anticipation, a significant inflammation X mood interaction emerged for activation of the bilateral caudate nucleus and right hippocampus (all pFWE < 0.05). Main effects of both inflammation and mood were observed in multiple regions, including insula, midcingulate cortex, prefrontal gyri, and hippocampus for inflammation, and midcingulate, caudate, and thalamus for mood (all pFWE < 0.05). CONCLUSIONS: Results support an interplay of inflammation and sad mood on striatal and hippocampal circuitry engaged during visceral pain anticipation as well as on pain experience. This may reflect a nocebo mechanism, which may contribute to altered perception and interpretation of bodily signals. At the interface of affective neuroscience and the gut-brain axis, concurrent inflammation and negative mood may be vulnerability factors for chronic visceral pain.

Distinct Alterations in Central Pain Processing of Visceral and Somatic Pain in Quiescent Ulcerative Colitis Compared to Irritable Bowel Syndrome and Health.

BACKGROUND AND AIMS: Despite relevance to pain chronicity, disease burden, and treatment, mechanisms of pain perception for different types of acute pain remain incompletely understood in patients with inflammatory bowel disease [IBD]. Building on experimental research across pain modalities, we herein addressed behavioural and neural correlates of visceral versus somatic pain processing in women with quiescent ulcerative colitis [UC] compared to irritable bowel syndrome [IBS] as a patient control group and healthy women [HC]. METHODS: Thresholds for visceral and somatic pain were assessed with rectal distensions and cutaneous thermal pain, respectively. Using functional magnetic resonance imaging, neural and behavioural responses to individually calibrated and intensity-matched painful stimuli from both modalities were compared. RESULTS: Pain thresholds were comparable across groups, but visceral thresholds correlated with gastrointestinal symptom severity and chronic stress burden exclusively within UC. Upon experience of visceral and somatic pain, both control groups demonstrated enhanced visceral pain-induced neural activation and greater perceived pain intensity, whereas UC patients failed to differentiate between pain modalities at both behavioural and neural levels. CONCLUSIONS: When confronted with acute pain from multiple bodily sites, UC patients' responses are distinctly altered. Their failure to prioritise pain arising from the viscera may reflect a lack of adaptive behavioural flexibility, possibly resulting from long-lasting central effects of repeated intestinal inflammatory insults persisting during remission. The role of psychological factors, particularly chronic stress, in visceral sensitivity and disease-specific alterations in the response to acute pain call for dedicated mechanistic research as a basis for tailoring interventions for intestinal and extraintestinal pain symptoms in IBD.

Inflammation shapes neural processing of interoceptive fear predictors during extinction learning in healthy humans.

Inflammation could impact on the formation and persistence of interoceptive fear and hypervigilance, with relevance to psychiatric disorders and chronic pain. To systematically analyze effects of inflammation on fear learning and extinction, we performed two complementary randomized, double-blind, placebo-controlled functional magnetic resonance imaging (fMRI) studies combining experimental endotoxemia as a translational model of acute systemic inflammation with a two-day multiple-threat fear conditioning paradigm involving interoceptive and exteroceptive unconditioned stimuli (US). Healthy volunteers (N = 95) were randomized to receive intravenous injections of either endotoxin (lipopolysaccharide, LPS; 0.4 ng/kg) or placebo prior to fear acquisition (study 1) or extinction training (study2). Treatment effects on behavioral and neural responses to conditioned stimuli (CS) predicting interoceptive or exteroceptive threat were assessed during fear learning and extinction phases, along with US valence ratings. Despite robust inflammatory and emotional responses triggered by LPS, no direct effects of inflammation on US ratings or on the formation or extinction of conditioned fear, as assessed with CS valence ratings, were observed. However, in the group treated with LPS prior to acquisition (i.e., study 1), we found enhanced neural responses to the interoceptive but not the exteroceptive CS in key regions of the central fear circuitry during extinction learning. After extinction, this group further showed enhanced negative valence ratings selectively for the interoceptive US during unexpected US re-exposure when compared to the placebo group. Together, inflammation during fear acquisition may promote the establishment of a more robust neural signature of the interoceptive fear memory trace, which may contribute to altered interoceptive pain perception. The fear extinction circuitry engaged during interoceptive fear memory processing may be particularly vulnerable to inflammation, with transdiagnostic implications for gut-brain mechanisms underlying disturbed interoception in psychiatric conditions and chronic visceral pain.

Placebo response in pharmacological trials in patients with functional dyspepsia-A systematic review and meta-analysis.

BACKGROUND: Pharmacological trials in functional dyspepsia (FD) are associated with high placebo response rates. We aimed to identify the magnitude and contributing factors to the placebo response. METHODS: We conducted a systematic review and meta-analysis including randomized controlled trials (RCTs) with a dichotomous outcome in adult patients with FD that compared an active pharmacotherapeutic treatment with placebo. Our main outcome was identification of the magnitude of the pooled placebo response rate for the following endpoints: symptom responder, symptom-free responder, adequate relief responder, and combined endpoint responder (i.e., the primary endpoint of each specific trial regarding treatment response). Several putative moderators (i.e., patient, disease, and trial characteristics) were examined. KEY RESULTS: We included 26 RCTs in our analysis. The pooled placebo response rate was 39.6% (95% CI 30.1-50.0) using the symptom responder definition, 20.5% (12.8-31.0) using the symptom-free responder definition, 38.5% (33.8-43.6) using the adequate relief responder definition, and 35.5% (31.6-39.7) using the combined endpoint responder definition. A lower overall baseline symptom score was significantly associated with a higher placebo response rate. No other moderators were found to significantly impact the placebo response rate. Due to the lack of data, no analyses could be performed according to individual FD subtypes or symptoms. CONCLUSIONS AND INFERENCES: The pooled placebo response rate in pharmacological trials in FD is about 39%, depending on which responder definitions is used. Future trials should consider applying an entry criterion based on minimal level of symptom severity to decrease the placebo response. We also suggest separate reporting of core FD symptoms pending more concrete harmonization efforts in FD trials.

Circulating Pro-inflammatory Cytokines Do Not Explain Interindividual Variability in Visceral Sensitivity in Healthy Individuals.

A role of the immune system in the pathophysiology of pain and hyperalgesia has received growing attention, especially in the context of visceral pain and the gut-brain axis. While acute experimental inflammation can induce visceral hyperalgesia as part of sickness behavior in healthy individuals, it remains unclear if normal plasma levels of circulating pro-inflammatory cytokines contribute to interindividual variability in visceral sensitivity. We herein compiled data from a tightly screened and well-characterized sample of healthy volunteers (N = 98) allowing us to assess associations between visceral sensitivity and gastrointestinal symptoms, and plasma concentrations of three selected pro-inflammatory cytokines (i.e., TNF-α, IL-6, and IL-8), along with cortisol and stress-related psychological variables. For analyses, we compared subgroups created to have distinct pro-inflammatory cytokine profiles, modelling healthy individuals at putative risk or resilience, respectively, for symptoms of the gut-brain axis, and compared them with respect to rectal sensory and pain thresholds and subclinical GI symptoms. Secondly, we computed multiple regression analyses to test if circulating pro-inflammatory markers predict visceral sensitivity in the whole sample. Despite pronounced subgroup differences in pro-inflammatory cytokine and cortisol concentrations, we observed no differences in measures of visceroception. In regression analyses, cytokines did not emerge as predictors. The pain threshold was predicted by emotional state and trait variables, especially state anxiety, together explaining 10.9% of the variance. These negative results do not support the hypothesis that systemic cytokine levels contribute to normal interindividual variability in visceroception in healthy individuals. Trajectories to visceral hyperalgesia as key marker in disorders of gut-brain interactions likely involve complex interactions of biological and psychological factors in keeping with a psychosocial model. Normal variations in systemic cytokines do not appear to constitute a vulnerability factor in otherwise healthy individuals, calling for prospective studies in at risk populations.

Greater interruption of visual processing and memory encoding by visceral than somatic pain in healthy volunteers - An fMRI study.

Visceral pain is regarded as more salient than somatic pain. It has greater affective and emotional components, i.e., it elicits higher levels of pain-related fear and is perceived as more unpleasant than somatic pain. In this fMRI study, we examined the neural effects of painful visceral as compared to painful somatic stimulation on visual processing and memory encoding in a visual categorization and surprise recognition task in healthy volunteers. During the categorization task, participants received either rectal distensions or heat stimuli applied to the forearm, with stimuli being individually matched for unpleasantness. Behaviorally, visceral pain reduced memory encoding as compared to somatic pain (Kleine-Borgmann et al., 2021). Imaging analyses now revealed that visceral pain was associated with reduced activity (i.e., greater pain-related interruption) in neural areas typically involved in visual processing and memory encoding. These include the parahippocampal gyrus, fusiform gyrus, striatum, occipital cortex, insula, and the amygdala. Moreover, reduced engagement of the lateral occipital complex during visual categorization under visceral pain was associated with higher visceral pain-related fear. These findings obtained in healthy volunteers shed light on the neural circuitry underlying the interruptive effect of visceral pain and pave the way for future studies in patient samples.

Positive Treatment Expectations Shape Perceived Medication Efficacy in a Translational Placebo Paradigm for the Gut-Brain Axis.

Placebo research has established the pivotal role of treatment expectations in shaping symptom experience and patient-reported treatment outcomes. Perceived treatment efficacy constitutes a relevant yet understudied aspect, especially in the context of the gut-brain axis with visceral pain as key symptom. Using a clinically relevant experimental model of visceral pain, we elucidated effects of pre-treatment expectations on post-treatment perceived treatment efficacy as an indicator of treatment satisfaction in a translational placebo intervention. We implemented positive suggestions regarding intravenous treatment with a spasmolytic drug (in reality saline), herein applied in combination with two series of individually calibrated rectal distensions in healthy volunteers. The first series used distension pressures inducing pain (pain phase). In the second series, pressures were surreptitiously reduced, modeling pain relief (pain relief phase). Using visual analog scales (VAS), expected and perceived treatment efficacy were assessed, along with perceived pain intensity. Manipulation checks supported that the induction of positive pre-treatment expectations and the modeling of pain relief were successful. Generalized Linear Models (GLM) were implemented to assess the role of inter-individual variability in positive pre-treatment expectations in perceived treatment efficacy and pain perception. GLM indicated no association between pre-treatment expectations and perceived treatment efficacy or perceived pain for the pain phase. For the relief phase, pre-treatment expectations (p = 0.024) as well as efficacy ratings assessed after the preceding pain phase (p < 0.001) were significantly associated with treatment efficacy assessed after the relief phase, together explaining 54% of the variance in perceived treatment efficacy. The association between pre-treatment expectations and perceived pain approached significance (p = 0.057) in the relief phase. Our data from an experimental translational placebo intervention in visceral pain support that reported post-treatment medication efficacy is shaped by pre-treatment expectations. The observation that individuals with higher positive expectations reported less pain and higher treatment satisfaction after pain relief may provide first evidence that perceived symptom improvement may facilitate treatment satisfaction. The immediate experience of symptoms within a given psychosocial treatment context may dynamically change perceptions about treatment, with implications for treatment satisfaction, compliance and adherence of patients with conditions of the gut-brain axis.

Temporal dynamics of fMRI signal changes during conditioned interoceptive pain-related fear and safety acquisition and extinction.

Associative learning and memory mechanisms drive interoceptive signaling along the gut-brain axis, thus shaping affective-emotional reactions and behavior. Specifically, learning to predict potentially harmful, visceral pain is assumed to succeed within very few trials. However, the temporal dynamics of cerebellar and cerebral fMRI signal changes underlying early acquisition and extinction of learned fear signals and the concomitant evolvement of safety learning remain incompletely understood. 3 T fMRI data of healthy individuals from three studies were uniformly processed across the whole brain and the cerebellum. All studies employed differential delay conditioning (N = 94) with one visual cue (CS+) being repeatedly paired with visceral pain as unconditioned stimulus (US) while a second cue remained unpaired (CS-). During subsequent extinction (N = 51), all CS were presented without US. Behavioral results revealed increased CS+-aversiveness and CS--pleasantness after conditioning and diminished valence ratings for both CS following extinction. During early acquisition, the CS- induced linearly increasing neural activation in the insula, midcingulate cortex, hippocampus, precuneus as well as cerebral and cerebellar somatomotor regions. The comparison between acquisition and extinction phases yielded a CS--induced linear increase in the posterior cingulate cortex and precuneus during early acquisition, while there was no evidence for linear fMRI signal changes for the CS+ during acquisition and for both CS during extinction. Based on theoretical accounts of discrimination and temporal difference learning, these results suggest a gradual evolvement of learned safety cues that engage emotional arousal, memory, and cortical modulatory networks. As safety signals are presumably more difficult to learn and to discriminate from learned threat cues, the underlying temporal dynamics may reflect enhanced salience and prediction processing as well as increasing demands for attentional resources and the integration of multisensory information. Maladaptive responses to learned safety signals are a clinically relevant phenotype in multiple conditions, including chronic visceral pain, and can be exceptionally resistant to modification or extinction. Through sustained hypervigilance, safety seeking constitutes one key component in pain and stress-related avoidance behavior, calling for future studies targeting the mechanisms of safety learning and extinction to advance current cognitive-behavioral treatment approaches.

The Good, the Bad, and the Ugly-Chances, Challenges, and Clinical Implications of Avoidance Research in Psychosomatic Medicine.

Avoidance behaviors are shaped by associative learning processes in response to fear of impending threats, particularly physical harm. As part of a defensive repertoire, avoidance is highly adaptive in case of acute danger, serving a potent protective function. However, persistent or excessive fear and maladaptive avoidance are considered key factors in the etiology and pathophysiology of anxiety- and stress-related psychosomatic disorders. In these overlapping conditions, avoidance can increase the risk of mental comorbidities and interfere with the efficacy of cognitive behavioral treatment approaches built on fear extinction. Despite resurging interest in avoidance research also in the context of psychosomatic medicine, especially in conditions associated with pain, disturbed interoception, and disorders of the gut-brain axis, current study designs and their translation into the clinical context face significant challenges limiting both, the investigation of mechanisms involved in avoidance and the development of novel targeted treatment options. We herein selectively review the conceptual framework of learning and memory processes, emphasizing how classical and operant conditioning, fear extinction, and return of fear shape avoidance behaviors. We further discuss pathological avoidance and safety behaviors as hallmark features in psychosomatic diseases, with a focus on anxiety- and stress-related disorders. Aiming to emphasize chances of improved translational knowledge across clinical conditions, we further point out limitations in current experimental avoidance research. Based on these considerations, we propose means to improve existing avoidance paradigms to broaden our understanding of underlying mechanisms, moderators and mediators of avoidance, and to inspire tailored treatments for patients suffering from psychosomatic disorders.

Impaired pain-related threat and safety learning in patients with chronic back pain.

ABSTRACT: Pain-related learning mechanisms likely play a key role in the development and maintenance of chronic pain. Previous smaller-scale studies have suggested impaired pain-related learning in patients with chronic pain, but results are mixed, and chronic back pain (CBP) particularly has been poorly studied. In a differential conditioning paradigm with painful heat as unconditioned stimuli, we examined pain-related acquisition and extinction learning in 62 patients with CBP and 61 pain-free healthy male and female volunteers using valence and contingency ratings and skin conductance responses. Valence ratings indicate significantly reduced threat and safety learning in patients with CBP, whereas no significant differences were observed in contingency awareness and physiological responding. Moreover, threat learning in this group was more impaired the longer patients had been in pain. State anxiety was linked to increased safety learning in healthy volunteers but enhanced threat learning in the patient group. Our findings corroborate previous evidence of altered pain-related threat and safety learning in patients with chronic pain. Longitudinal studies exploring pain-related learning in (sub)acute and chronic pain are needed to further unravel the role of aberrant pain-related learning in the development and maintenance of chronic pain.

Evidence for engagement of the nucleus of the solitary tract in processing intestinal chemonociceptive input irrespective of conscious pain response in healthy humans.

ABSTRACT: Neuroimaging studies have revealed important pathomechanisms related to disorders of brain-gut interactions, such as irritable bowel syndrome and functional dyspepsia. More detailed investigations aimed at neural processing in the brainstem, including the key relay station of the nucleus of the solitary tract (NTS), have hitherto been hampered by technical shortcomings. To ascertain these processes in more detail, we used multiecho multiband 7T functional magnetic resonance imaging and a novel translational experimental model based on a nutrient-derived intestinal chemonociceptive stimulus. In a randomized cross-over fashion, subjects received duodenal infusion of capsaicin (the pungent principle in red peppers) and placebo (saline). During infusion, functional magnetic resonance imaging data and concomitant symptom ratings were acquired. Of 26 healthy female volunteers included, 18 were included in the final analysis. Significantly increased brain activation over time during capsaicin infusion, as compared with placebo, was observed in brain regions implicated in pain processing, in particular the NTS. Brain activation in the thalamus, cingulate cortex, and insula was more pronounced in subjects who reported abdominal pain (visual analogue scale > 10 mm), as compared with subjects who experienced no pain. On the contrary, activations at the level of the NTS were independent of subjective pain ratings. The current experimental paradigm therefore allowed us to demonstrate activation of the principal relay station for visceral afferents in the brainstem, the NTS, which was engaged irrespective of the conscious pain response. These findings contribute to understanding the fundamental mechanism necessary for developing novel therapies aimed at correcting disturbances in visceral afferent pain processing.