Large-scale real-world data on a multidisciplinary approach to spinal cord stimulation for persistent spinal pain syndromes: first evaluation of the Neuro-Pain® nationwide screening and follow-up interactive register.

Introduction: Spinal cord stimulation is a common treatment option for neuropathic pain conditions. Despite its extensive use and multiple technological evolutions, long term efficacy of spinal cord stimulation is debated. Most studies on spinal cord stimulation include a rather limited number of patients and/or follow-ups over a limited period. Therefore, there is an urgent need for real-world, long-term data. Methods: In 2018, the Belgian government initiated a nationwide secure platform for the follow-up of all new and existing spinal cord stimulation therapies. This is a unique approach used worldwide. Four years after the start of centralized recording, the first global extraction of data was performed. Results: Herein, we present the findings, detailing the different steps in the centralized procedure, as well as the observed patient and treatment characteristics. Furthermore, we identified dropouts during the screening process, the reasons behind discontinuation, and the evolution of key indicators during the trial period. In addition, we obtained the first insights into the evolution of the clinical impact of permanent implants on the overall functioning and quality of life of patients in the long-term. Discussion: Although these findings are the results of the first data extraction, some interesting conclusions can be drawn. The long-term outcomes of neuromodulation are complex and subject to many variables. Future data extraction will allow us to identify these confounding factors and the early predictors of success. In addition, we will propose further optimization of the current process.

Brain mediators of negative affect-induced physical symptom reporting in patients with functional somatic syndromes.

Functional somatic syndromes (FSS) include fibromyalgia, irritable bowel syndrome (IBS), and others. In FSS patients, merely viewing negative affective pictures can elicit increased physical symptoms. Our aim was to investigate the neural mechanisms underlying such negative affect-induced physical symptoms in FSS patients. Thirty patients with fibromyalgia and/or IBS and 30 healthy controls (all women) watched neutral, positive and negative affective picture blocks during functional MRI scanning and rated negative affect and physical symptoms after every block. We compared brain-wide activation during negative versus neutral picture viewing in FSS patients versus controls using robust general linear model analysis. Further, we compared neurologic pain signature (NPS), stimulus intensity-independent pain signature (SIIPS) and picture-induced negative emotion signature (PINES) responses to the negative versus neutral affect contrast and investigated whether they mediated between-group differences in affective picture-induced physical symptom reporting. More physical symptoms were reported after viewing negative compared to neutral pictures, and this effect was larger in patients than controls (p = 0.025). Accordingly, patients showed stronger activation in somatosensory regions during negative versus neutral picture viewing. NPS, but not SIIPS nor PINES, responses were higher in patients than controls during negative versus neutral pictures (p = 0.026). These differential NPS responses partially mediated between-group differences in physical symptoms. In conclusion, picture-induced negative affect elicits physical symptoms in FSS patients as a result of activation of somatosensory and nociceptive brain patterns, supporting the idea that affect-driven alterations in processing of somatic signals is a critical mechanism underlying FSS.

Common and distinct neural representations of aversive somatic and visceral stimulation in healthy individuals.

Different pain types may be encoded in different brain circuits. Here, we examine similarities and differences in brain processing of visceral and somatic pain. We analyze data from seven fMRI studies (N = 165) and five types of pain and discomfort (esophageal, gastric, and rectal distension, cutaneous thermal stimulation, and vulvar pressure) to establish and validate generalizable pain representations. We first evaluate an established multivariate brain measure, the Neurologic Pain Signature (NPS), as a common nociceptive pain system across pain types. Then, we develop a multivariate classifier to distinguish visceral from somatic pain. The NPS responds robustly in 98% of participants across pain types, correlates with perceived intensity of visceral pain and discomfort, and shows specificity to pain when compared with cognitive and affective conditions from twelve additional studies (N = 180). Pre-defined signatures for non-pain negative affect do not respond to visceral pain. The visceral versus the somatic classifier reliably distinguishes somatic (thermal) from visceral (rectal) stimulation in both cross-validation and independent cohorts. Other pain types reflect mixtures of somatic and visceral patterns. These results validate the NPS as measuring a common core nociceptive pain system across pain types, and provide a new classifier for visceral versus somatic pain.

Resting state functional connectivity of the pain matrix and default mode network in irritable bowel syndrome: a graph theoretical analysis.

Irritable bowel syndrome (IBS) is a functional disorder of brain-gut interactions. Differential brain responses to rectal distention between IBS and healthy controls (HCs) have been demonstrated, particularly in the pain matrix and the default mode network. This study aims to compare resting-state functional properties of these networks between IBS patients and HCs using graph analysis in two independent cohorts. We used a weighted graph analysis of the adjacency matrix based on partial correlations between time series in the different regions in each subject to determine subject specific graph measures. These graph measures were normalized by values obtained in equivalent random networks. We did not find any significant differences between IBS patients and controls in global normalized graph measures, hubs, or modularity structure of the pain matrix and the DMN in any of our two independent cohorts. Furthermore, we did not find consistent associations between these global network measures and IBS symptom severity or GI-specific anxiety but we found a significant difference in the relationship between measures of psychological distress (anxiety and/or depressive symptoms) and normalized characteristic path length. The responses of these networks to visceral stimulation rather than their organisation at rest may be primarily disturbed in IBS.

Endogenous GLP-1 alters postprandial functional connectivity between homeostatic and reward-related brain regions involved in regulation of appetite in healthy lean males: A pilotstudy.

AIMS: Peripheral infusion of glucagon-like peptide-1 (GLP-1) can affect brain activity in areas involved in the regulation of appetite, including hypothalamic and reward-related brain regions. In contrast, the physiological role of endogenous GLP-1 in the central regulation of appetite has hardly been investigated. MATERIALS AND METHODS: This was a randomized, cross-over trial that involved 12 healthy volunteers who received an intragastric (ig) glucose (gluc) load, with or without intravenous (iv) exendin9-39 (ex9-39; specific GLP-1 receptor antagonist). Functional magnetic resonance imaging was used to investigate the effect of endogenous GLP-1 on resting state functional connectivity (rsFC) between homeostatic and reward-related brain regions. Visual analogue scales were used to rate appetite-related sensations. Blood samples were collected for GI hormone measurements. RESULTS: Administration of iv-ex9-39/ig-gluc induced a significantly higher rsFC, relative to ig-gluc administration, between the hypothalamus and the left lateral orbitofrontal cortex (OFC) as well as the left amygdala (P ≤ .001, respectively). Administration of iv-ex9-39/ig-gluc induced a significantly higher rsFC, relative to ig-gluc administration, between the right nucleus accumbens and the right lateral OFC (P < .001). Administration of iv-ex9-39/ig-gluc induced a significantly lower rsFC, relative to ig-gluc administration, between the midbrain and the right caudate nucleus (P = .001). Administration of ig-gluc significantly decreased prospective food consumption and increased sensations of fullness compared to pre-infusion baseline (P = .028 and P = .019, respectively); these effects were not present in the iv-ex9-39/ig-gluc condition. CONCLUSIONS: This pilot trial provides preliminary experimental evidence that glucose-induced endogenous GLP-1 affects central regulation of appetite by modulating rsFC in homeostatic and reward-related brain regions in healthy lean male participants in a GLP-1 receptor-mediated fashion.

Generalizable representations of pain, cognitive control, and negative emotion in medial frontal cortex.

The medial frontal cortex, including anterior midcingulate cortex, has been linked to multiple psychological domains, including cognitive control, pain, and emotion. However, it is unclear whether this region encodes representations of these domains that are generalizable across studies and subdomains. Additionally, if there are generalizable representations, do they reflect a single underlying process shared across domains or multiple domain-specific processes? We decomposed multivariate patterns of functional MRI activity from 270 participants across 18 studies into study-specific, subdomain-specific, and domain-specific components and identified latent multivariate representations that generalized across subdomains but were specific to each domain. Pain representations were localized to anterior midcingulate cortex, negative emotion representations to ventromedial prefrontal cortex, and cognitive control representations to portions of the dorsal midcingulate. These findings provide evidence for medial frontal cortex representations that generalize across studies and subdomains but are specific to distinct psychological domains rather than reducible to a single underlying process.

Altered brain and gut responses to corticotropin-releasing hormone (CRH) in patients with irritable bowel syndrome.

Stress is a known trigger of irritable bowel syndrome (IBS) and exacerbates its gastrointestinal symptoms. However, underlying the physiological mechanism remains unknown. Here, we investigated hypothalamic-pituitary-adrenal (HPA) axis, colonic motility, and autonomic responses to corticotropin-releasing hormone (CRH) administration as well as brain activity alterations in IBS. The study included 28 IBS patients and 34 age and sex-matched healthy control subjects. IBS patients demonstrated greater adrenocorticotropic hormone (ACTH) responses to CRH than control subjects. Male IBS patients had greater increases in colonic motility than male HCs after CRH. Female IBS patients showed altered sympathovagal balance and lower basal parasympathetic tone relative to female control subjects. Brain responses to rectal distention were measured in the same subjects using functional magnetic resonance imaging, and their associations with individual ACTH responses to CRH were tested. A negative association between ACTH response to CRH and activity in the pregenual anterior cingulate cortex (pACC) during rectal distention was identified in controls but not in IBS patients. Impaired top-down inhibitory input from the pregenual ACC to the HPA axis may lead to altered neuroendocrine and gastrointestinal responses to CRH. Centrally acting treatments may dampen the stress induced physical symptoms in IBS.

Brain responses to vestibular pain and its anticipation in women with Genito-Pelvic Pain/Penetration Disorder.

OBJECTIVE: In DSM-5, pain-related fear during anticipation of vaginal penetration is a diagnostic criterion of Genito-Pelvic Pain/Penetration Disorder (GPPPD). We aimed to investigate subjective and brain responses during anticipatory fear and subsequent induction of vestibular pain in women with GPPPD. METHODS: Women with GPPPD (n = 18) and age-matched healthy controls (HC) (n = 15) underwent fMRI scanning during vestibular pain induction at individually titrated pain threshold after a cued anticipation period. (Pain-related) fear and anxiety traits were measured with questionnaires prior to scanning, and anticipatory fear and pain intensity were rated during scanning using visual analog scales. RESULTS: Women with GPPPD reported significantly higher levels of anticipatory fear and pain intensity. During anticipation and pain induction they had stronger and more extensive brain responses in regions involved in cognitive and affective aspects of pain perception, but the group difference did not reach significance for the anticipation condition. Pain-related fear and anxiety traits as well as anticipatory fear ratings were positively associated with pain ratings in GPPPD, but not in HC. Further, in HC, a negative association was found between anticipatory fear ratings and brain responses in regions involved in cognitive and affective aspects of pain perception, but not in women with GPPPD. CONCLUSIONS: Women with GPPPD are characterized by increased subjective and brain responses to vestibular pain and, to a lesser extent, its anticipation, with fear and anxiety associated with responses to pain, supporting the introduction of anticipatory fear as a criterion of GPPPD in DSM-5.

Influence of Uncertain Anticipation on Brain Responses to Aversive Rectal Distension in Patients With Irritable Bowel Syndrome.

OBJECTIVE: We investigated whether certainty and uncertainty of impending aversive visceral sensation differently modulate regional brain activity, both during anticipation and visceral sensation in irritable bowel syndrome (IBS) patients compared with healthy controls. METHODS: Twenty-six IBS patients (14 women) and 29 healthy controls (15 women) were enrolled in a functional magnetic resonance imaging study. Participants received rectal distention at an individually titrated severe discomfort level that was preceded by visual cues to induce certain (100% chance of distention), uncertain (50% chance), and safe (0% chance) anticipation. RESULTS: Subjective ratings of anticipatory fear before and discomfort during distention were similar between IBS and control participants under cued certainty and uncertainty (p > .05). Uncertain anticipation compared with certain anticipation induced greater activation of anterior midcingulate cortex, thalamus, and visual processing areas in IBS patients compared with controls. Rectal distention after the uncertain, but not certain, cue induced higher activity in the posterior- and midcingulate cortices and the precuneus in IBS compared with controls. Controls exhibited bilateral insula activation during the nondistention period after the uncertain cue compared with the safe cue. IBS patients failed to produce this response, which was possibly due to elevated bilateral insular responses during nondistention after the safe cue. Brain data were significant at a voxel-level threshold of puncorrected value of less than .005 combined with a cluster-level threshold of pFWE-corrected value of less than .05. CONCLUSIONS: Preceding uncertainty differentially modulates the brain processing of physiologically identical rectal stimulation in IBS patients. Cue-dependent alterations in brain responses may underlie hypervigilance to visceral sensations in IBS patients.

Biased Intensity Judgements of Visceral Sensations After Learning to Fear Visceral Stimuli: A Drift Diffusion Approach.

A growing body of research has identified fear of visceral sensations as a potential mechanism in the development and maintenance of visceral pain disorders. However, the extent to which such learned fear affects visceroception remains unclear. To address this question, we used a differential fear conditioning paradigm with nonpainful esophageal balloon distensions of 2 different intensities as conditioning stimuli (CSs). The experiment comprised of preacquisition, acquisition, and postacquisition phases during which participants categorized the CSs with respect to their intensity. The CS+ was always followed by a painful electrical stimulus (unconditioned stimulus) during the acquisition phase and in 60% of the trials during postacquisition. The second stimulus (CS-) was never associated with pain. Analyses of galvanic skin and startle eyeblink responses as physiological markers of successful conditioning showed increased fear responses to the CS+ compared with the CS-, but only in the group with the low-intensity stimulus as CS+. Computational modeling of response times and response accuracies revealed that differential fear learning affected perceptual decision-making about the intensities of visceral sensations such that sensations were more likely to be categorized as more intense. These results suggest that associative learning might indeed contribute to visceral hypersensitivity in functional gastrointestinal disorders. PERSPECTIVE: This study shows that associative fear learning biases intensity judgements of visceral sensations toward perceiving such sensations as more intense. Learning-induced alterations in visceroception might therefore contribute to the development or maintenance of visceral pain.

Differential brain responses to gradual intragastric nutrient infusion and gastric balloon distension: A role for gut peptides?

BACKGROUND: Rapid gastric balloon distension to discomfort threshold activates the "pain neuromatrix" and deactivates exteroceptive sensory and "default mode network" regions. However, little is known about brain mechanisms underlying tolerance of meal-induced gastric distension. We aimed to directly compare brain responses to gradual balloon distension and intragastric nutrient infusion and to explore the role of differential gut peptide release in these responses. MATERIALS AND METHODS: Brain responses to balloon- and nutrient-induced distension (to individually titrated pain or maximal satiation threshold) were measured in 15 healthy volunteers using H215O-PET on 2 separate days in counterbalanced order. The effects of increasing gastric distension and plasma levels of ghrelin and peptide YY3-36 (PYY3-36) on neural activity were assessed. RESULTS: Balloon distension progressively activated pain-responsive regions and deactivated exteroceptive sensory and "default mode network" areas. During nutrient infusion, "pain neuromatrix" regions and the orbitofrontal cortex were progressively deactivated, while the midbrain was activated. Plasma levels of PYY3-36 and ghrelin increased and decreased, respectively, during nutrient infusion only; decreasing ghrelin levels correlated with increasing midbrain activity. CONCLUSION: Different brain responses to gastric balloon distension and intragastric nutrient infusion are associated with nutrient-induced gut-brain signals, particularly to the midbrain, where these signals may interfere with both descending pain modulatory and mesolimbic reward processes. Deactivation of the "pain neuromatrix" during nutrient infusion may constitute the neurophysiological mechanism underlying the tolerance of normal meal volumes in health without induction of (painful) symptoms. Nutrient-induced deactivation of the orbitofrontal cortex may represent a key interoceptive meal termination signal.

Differential Activation in Amygdala and Plasma Noradrenaline during Colorectal Distention by Administration of Corticotropin-Releasing Hormone between Healthy Individuals and Patients with Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) often comorbids mood and anxiety disorders. Corticotropin-releasing hormone (CRH) is a major mediator of the stress response in the brain-gut axis, but it is not clear how CRH agonists change human brain responses to interoceptive stimuli. We tested the hypothesis that brain activation in response to colorectal distention is enhanced after CRH injection in IBS patients compared to healthy controls. Brain H215O- positron emission tomography (PET) was performed in 16 male IBS patients and 16 age-matched male controls during baseline, no distention, mild and intense distention of the colorectum using barostat bag inflation. Either CRH (2 µg/kg) or saline (1:1) was then injected intravenously and the same distention protocol was repeated. Plasma adrenocorticotropic hormone (ACTH), serum cortisol and plasma noradrenaline levels were measured at each stimulation. At baseline, CRH without colorectal distention induced more activation in the right amygdala in IBS patients than in controls. During intense distention after CRH injection, controls showed significantly greater activation than IBS patients in the right amygdala. Plasma ACTH and serum cortisol secretion showed a significant interaction between drug (CRH, saline) and distention. Plasma noradrenaline at baseline significantly increased after CRH injection compared to before injection in IBS. Further, plasma noradrenaline showed a significant group (IBS, controls) by drug by distention interaction. Exogenous CRH differentially sensitizes brain regions of the emotional-arousal circuitry within the visceral pain matrix to colorectal distention and synergetic activation of noradrenergic function in IBS patients and healthy individuals.

Influence of Interoceptive Fear Learning on Visceral Perception.

OBJECTIVES: Interoceptive fear learning and generalization have been hypothesized to play a key role in unexplained abdominal and esophageal pain in patients with functional gastrointestinal disorders. However, there is no experimental evidence demonstrating that fear learning and generalization to visceral sensations can be established in humans and alter visceral perception. METHODS: In a novel fear learning-generalization paradigm, an innocuous esophageal balloon distension served as conditioned stimulus (CS), and distensions at three different pressure levels around the pain detection threshold were used as generalization stimuli. During fear learning, the CS was paired with a painful electrical stimulus (unconditioned stimulus) in the conditioning group (n = 30), whereas in the control group (n = 30), the unconditioned stimulus was delivered alone. Before and after fear learning, visceral perception thresholds for first sensation, discomfort, and pain and visceral discrimination sensitivity were assessed. RESULTS: Fear learning was established in the conditioning group only (potentiated eye-blink startle to the CS (t(464.06) = 3.17, p = .002), and fear generalization to other stimulus intensities was observed (t(469.12) = 2.97, p = .003; t(464.29) = 4.17, p < .001). The thresholds for first sensation habituated in the control group, whereas it remained constant in the conditioning group (F(1,43) = 9.77, p = .003). CONCLUSIONS: These data show that fear learning using visceral stimuli induces fear generalization and influences visceral perception. These findings support the idea that in functional gastrointestinal disorder, fear learning and generalization can foster gastrointestinal-specific anxiety and contribute to visceral hypersensitivity.

Efficacy of Mirtazapine in Patients With Functional Dyspepsia and Weight Loss.

BACKGROUND & AIMS: A subset of patients with functional dyspepsia (FD) present with early satiation and weight loss, for which there are no established therapeutic options. We investigated the efficacy of mirtazapine (an antidepressant and antagonist of the histamine receptor H1, the α2 adrenergic receptor, and the serotonin receptors 5-HT2C and 5-HT-3) in patients with FD and weight loss. METHODS: We conducted a randomized, placebo-controlled pilot trial that studied 34 patients with FD (29 women; mean age, 35.9 ± 2.3 years) with weight loss >10% of original body weight (mean loss, 12.4 ± 2.3 kg) without depression or anxiety. After a run-in period, patients were randomly assigned to groups given placebo (n = 17) or mirtazapine 15 mg each day for 8 weeks (n = 17) in a double-blind manner. Subjects were evaluated during a 2-week baseline and 8-week treatment for dyspepsia symptom severity, quality of life (on the basis of the Nepean Dyspepsia Index), and gastrointestinal-specific anxiety; they were given a nutrient challenge test and weighed. Data were analyzed by using linear mixed models, followed by planned contrasts with adaptive step-down Bonferroni multiple testing correction. RESULTS: Two patients in each group dropped out. At weeks 4 and 8, mirtazapine significantly reduced mean dyspepsia symptom severity scores compared with week 0 (P = .003 and P = .017, respectively); there was no significant reduction in the placebo group (P > .37 for weeks 4 and 8). The difference in change from week 0 between mirtazapine and placebo showed a trend with a large effect size at week 4 (P = .059) that was not significant at week 8 (P = .55). However, improvements from week 0 to weeks 4 and 8 were significantly larger in the mirtazapine group than placebo group for early satiation, quality of life, gastrointestinal-specific anxiety, weight, and nutrient tolerance (mostly with large effect sizes). CONCLUSIONS: In a randomized, placebo-controlled trial, mirtazapine significantly improved early satiation, quality of life, gastrointestinal-specific anxiety, nutrient tolerance, and weight loss in patients with FD. ClinicalTrials.gov number: NCT01240096.

Startle responding in the context of visceral pain.

This study aimed to investigate affective modulation of eye blink startle by aversive visceral stimulation. Startle blink EMG responses were measured in 31 healthy participants receiving painful, intermittent balloon distentions in the distal esophagus during 4 blocks (positive, negative, neutral or no pictures), and compared with startles during 3 'safe' blocks without esophageal stimulations (positive, negative or neutral emotional pictures). Women showed enhanced startle during blocks with distentions (as compared with 'safe' blocks), both when the balloon was in inflated and deflated states, suggesting that fear and/or expectations may have played a role. Men's startle did not differ between distention and non-distention blocks. In this particular study context affective picture viewing did not further impose any effect on startle eye blink responses. The current results may contribute to a better understanding of emotional reactions to aversive interoceptive stimulation.

Acute Anxiety and Anxiety Disorders Are Associated With Impaired Gastric Accommodation in Patients With Functional Dyspepsia.

BACKGROUND & AIMS: Functional dyspepsia (FD) is associated with impaired gastric accommodation, as well as gastric hypersensitivity, delayed emptying, and psychosocial comorbidities. In healthy people, acute anxiety impairs gastric accommodation, which is traditionally quantified as the average increase in gastric volume after a meal over 1 hour. However, this quantification approach does not address the complex time course of the gastric accommodation response to a meal. We modeled gastric accommodation in patients with FD as a function of postprandial time, to investigate whether it is associated with psychosocial factors (state anxiety, anxiety disorder, depression) and gastric sensorimotor function (sensitivity, emptying). METHODS: We studied gastric sensorimotor function in 259 consecutive patients diagnosed with FD based on Rome II at the University Hospitals Leuven from January 2002 through February 2009. Subjects underwent a gastric barostat and breath test; psychiatric comorbidity was assessed by questionnaires. Subjects completed the State-Trait Anxiety Inventory to measure levels of state anxiety immediately before and after gastric barostat analysis. The time course of the accommodation response was analyzed using mixed models. Psychological and sensorimotor variables were added to the model as continuous (state anxiety) or dichotomous (gastric sensitivity and emptying, anxiety disorders, depression) covariates, including their interaction with the time effects. RESULTS: In subjects with FD, delayed emptying (ß = 50.3 ± 15.9; P = .002) and lower state anxiety (ß = -1.7 ± 0.7; P = .012) were associated with an upward shift of the accommodation curve. There was a significant interaction between comorbid anxiety disorder and linear (ß = 8.2 ± 3.5; P = .02), quadratic (ß = -0.4 ± 0.1; P = .004), and cubic (ß = 0.005 ± 0.002; P = .002) effects of time: patients with a comorbid anxiety disorder had significantly slower initial increases in gastric volume to a lower maximum, and a slower return to baseline, compared with patients without anxiety disorder. Depression and gastric sensitivity were not associated significantly with gastric accommodation. CONCLUSIONS: In patients with FD, state anxiety and comorbid anxiety disorders are associated with impaired accommodation; gastric emptying also is associated with accommodation in these patients. These findings help elucidate the complex interactions between psychological processes and disorders, gastric sensorimotor dysfunction, and symptom reporting in patients with FD.

Increased cerebral cannabinoid-1 receptor availability is a stable feature of functional dyspepsia: a [F]MK-9470 PET study.

BACKGROUND: Functional dyspepsia (FD) is a prevalent functional gastrointestinal disorder (FGID) defined by chronic epigastric symptoms in the absence of organic abnormalities likely to explain them. Comorbidity with mood and anxiety disorders as well as with other FGIDs and functional somatic syndrome (FSS) is high. FD is characterized by abnormal regional cerebral activity in cognitive/affective pain modulatory circuits, but it is unknown which neurotransmitter systems are involved. The authors aimed to assess and compare in vivo cerebral cannabinoid-1 (CB1) receptor availability between FD patients and age-, gender- and BMI-matched healthy controls (HC). METHODS: Twelve FD patients and 12 matched HC were investigated using positron emission tomography (PET) with the CB1 receptor radioligand [(18)F]MK-9470. Nine of the patients received a second PET scan after a naturalistic follow-up period of 36 ± 9.6 months (range: 25.2-50.4 months). RESULTS: FD patients had significantly higher CB1 receptor availability in the cerebral regions involved in (visceral) nociception (brainstem, insula, anterior cingulate cortex) as well as in the homeostatic and hedonic regulation of food intake [hypothalamus, (ventral) striatum] (p < 0.05 corrected for multiple testing, region of interest analysis), which persisted after a follow-up period of 36 ± 9.6 months. CONCLUSIONS: Although these findings need replication in larger samples, they suggest that the abnormal brain activity in several of these regions, previously demonstrated in FD, may be due to a sustained endocannabinoid system dysfunction, identifying it as a potential novel target for treatment and warranting further studies to elucidate whether it is also a feature of other FGIDs or FSSs.

Uncertainty in anticipation of uncomfortable rectal distension is modulated by the autonomic nervous system--a fMRI study in healthy volunteers.

The human brain responds both before and during the application of aversive stimuli. Anticipation allows the organism to prepare its nociceptive system to respond adequately to the subsequent stimulus. The context in which an uncomfortable stimulus is experienced may also influence neural processing. Uncertainty of occurrence, timing and intensity of an aversive event may lead to increased anticipatory anxiety, fear, physiological arousal and sensory perception. We aimed to identify, in healthy volunteers, the effects of uncertainty in the anticipation of uncomfortable rectal distension, and the impact of the autonomic nervous system (ANS) activity and anxiety-related psychological variables on neural mechanisms of anticipation of rectal distension using fMRI. Barostat-controlled uncomfortable rectal distensions were preceded by cued uncertain or certain anticipation in 15 healthy volunteers in a fMRI protocol at 3T. Electrocardiographic data were concurrently registered by MR scanner. The low frequency (LF)-component of the heart rate variability (HRV) time-series was extracted and inserted as a regressor in the fMRI model ('LF-HRV model'). The impact of ANS activity was analyzed by comparing the fMRI signal in the 'standard model' and in the 'LF-HRV model' across the different anticipation and distension conditions. The scores of the psychological questionnaires and the rating of perceived anticipatory anxiety were included as covariates in the fMRI data analysis. Our experiments led to the following key findings: 1) the subgenual anterior cingulate cortex (sgACC) is the only activation site that relates to uncertainty in healthy volunteers and is directly correlated to individual questionnaire score for pain-related anxiety; 2) uncertain anticipation of rectal distension involved several relevant brain regions, namely activation of sgACC and medial prefrontal cortex and deactivation of amygdala, insula, thalamus, secondary somatosensory cortex, supplementary motor area and cerebellum; 3) most of the brain activity during anticipation, but not distension, is associated with activity of the central autonomic network. This approach could be applied to study the ANS impact on brain activity in various pathological conditions, namely in patients with chronic digestive conditions characterized by visceral discomfort and ANS imbalance such as irritable bowel syndrome or inflammatory bowel diseases.

Normal values and reproducibility of the real-time index of vagal tone in healthy humans: a multi-center study.

BACKGROUND: The parasympathetic nervous system has been implicated in the pathogenesis of a number of gastrointestinal disorders including irritable bowel syndrome. Within the field, cardiometric parameters of parasympathetic/vagal tone are most commonly derived from time, or frequency, domain analysis of heart rate variability (HRV), yet it has limited temporal resolution. Cardiac vagal tone (CVT) is a non-invasive beat-to-beat measure of brainstem efferent vagal activity that overcomes many of the temporal limitations of HRV parameters. However, its normal values and reproducibility in healthy subjects are not fully described. The aim of this study was to address these knowledge gaps. METHODS: 200 healthy subjects (106 males, median age 28 years, range 18-59 years) were evaluated across three study centers. After attachment of CVT recording equipment, 20 min of data (resting/no stimulation) was acquired. 30 subjects, selected at random, were restudied after 1 year. RESULTS: The mean CVT was 9.5±4.16 linear vagal scale (LVS). Thus, the normal range (mean±2 standard deviations) for CVT based on this data was 1.9-17.8 LVS. CVT correlated negatively with heart rate (r=-0.6, P=0.001). CVT reproducibility over 1 year, as indexed by an intra-class correlational coefficient of 0.81 (95% confidence interval 0.64-0.91), was good. CONCLUSIONS: In healthy subjects, the normal range for CVT should be considered to be 1.9-17.8 LVS and is reproducible over 1 year. Future research utilizing CVT should refer to these values although further study is warranted in patient groups.

Lack of endogenous opioid release during sustained visceral pain: a [11C]carfentanil PET study.

Opioidergic neurotransmission in the central nervous system is involved in somatic pain, but its role in visceral pain remains unknown. We aimed to quantify endogenous opioid release in the brain during sustained painful gastric distension. Therefore, 2 dynamic [11C]carfentanil positron emission tomography scans were performed in 20 healthy subjects during 2 conditions: sustained (20 minutes) painful proximal gastric balloon distension at predetermined individual discomfort threshold (PAIN) and no distension (NO PAIN), in counterbalanced order. Pain levels were assessed during scanning using visual analogue scales and after scanning using the McGill Pain Questionnaire. Emotional state was rated after scanning using the Positive and Negative Affect Schedule. Distribution volume ratios in 21 volumes of interest in the pain matrix were used to quantify endogenous opioid release. During the PAIN compared to the NO PAIN condition, volunteers reported a significantly higher increase in negative affect (5.50±1.29 versus 0.10±1.08, P=.0147) as well as higher pain ratings (sensory: 74.05±9.23 versus 1.50±0.95, P<.0001; affective: 91.42±8.13 versus 4.33±6.56, P<.0001). No difference in endogenous opioid release was demonstrated in any of the volumes of interest. Thus, contrary to its somatic counterpart, no opioid release is detected in the brain during sustained visceral pain, despite similar pain intensities. Endogenous opioids may play a less important role in visceral compared to somatic pain.