Preliminary report: parasympathetic tone links to functional brain networks during the anticipation and experience of visceral pain.

The mechanisms that underpin the anti-nociceptive effect of the parasympathetic nervous system (PNS) on visceral pain remain incompletely understood. We sought to describe the effect of resting parasympathetic tone on functional brain networks during the anticipation and experience of oesophageal pain. 21 healthy participants had their resting cardiac vagal tone (CVT), a validated measure of the PNS, quantified, and underwent functional magnetic resonance imaging during the anticipation and experience of painful oesophageal distention. The relationship between resting CVT and functional brain networks was examined using 11 hypothesis-driven nodes and network-based statistics. A network comprising all nodes was apparent in individuals with high resting CVT, compared to those with low CVT, during oesophageal pain (family wise error rate (FWER)-corrected p < 0.048). Functional connections included the thalamus-amygdala, thalamus-hypothalamus, hypothalamus-nucleus accumbens, amygdala-pallidum, pallidum-nucleus accumbens and insula-pallidum. A smaller network was seen during pain anticipation, comprising the amygdala, pallidum and anterior insula (FWER-corrected p < 0.049). These findings suggest that PNS tone is associated with functional brain networks during the anticipation and experience of visceral pain. Given the role of these subcortical regions in the descending inhibitory modulation of pain, these networks may represent a potential neurobiological explanation for the anti-nociceptive effect of the PNS.

Morphology of subcortical brain nuclei is associated with autonomic function in healthy humans.

The autonomic nervous system (ANS) is a brain body interface which serves to maintain homeostasis by influencing a plethora of physiological processes, including metabolism, cardiorespiratory regulation and nociception. Accumulating evidence suggests that ANS function is disturbed in numerous prevalent clinical disorders, including irritable bowel syndrome and fibromyalgia. While the brain is a central hub for regulating autonomic function, the association between resting autonomic activity and subcortical morphology has not been comprehensively studied and thus was our aim. In 27 healthy subjects [14 male and 13 female; mean age 30 years (range 22-53 years)], we quantified resting ANS function using validated indices of cardiac sympathetic index (CSI) and parasympathetic cardiac vagal tone (CVT). High resolution structural magnetic resonance imaging scans were acquired, and differences in subcortical nuclei shape, that is, 'deformation', contingent on resting ANS activity were investigated. CSI positively correlated with outward deformation of the brainstem, right nucleus accumbens, right amygdala and bilateral pallidum (all thresholded to corrected P < 0.05). In contrast, parasympathetic CVT negatively correlated with inward deformation of the right amygdala and pallidum (all thresholded to corrected P < 0.05). Left and right putamen volume positively correlated with CVT (r = 0.62, P = 0.0047 and r = 0.59, P = 0.008, respectively), as did the brainstem (r = 0.46, P = 0.049). These data provide novel evidence that resting autonomic state is associated with differences in the shape and volume of subcortical nuclei. Thus, subcortical morphological brain differences in various disorders may partly be attributable to perturbation in autonomic function. Further work is warranted to investigate these findings in clinical populations. Hum Brain Mapp 39:381-392, 2018. © 2017 Wiley Periodicals, Inc.

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.

Visually induced nausea causes characteristic changes in cerebral, autonomic and endocrine function in humans.

An integrated understanding of the physiological mechanisms involved in the genesis of nausea remains lacking. We aimed to describe the psychophysiological changes accompanying visually induced motion sickness, using a motion video, hypothesizing that differences would be evident between subjects who developed nausea in comparison to those who did not. A motion, or a control, stimulus was presented to 98 healthy subjects in a randomized crossover design. Validated questionnaires and a visual analogue scale (VAS) were used for the assessment of anxiety and nausea. Autonomic and electrogastrographic activity were measured at baseline and continuously thereafter. Plasma vasopressin and ghrelin were measured in response to the motion video. Subjects were stratified into quartiles based on VAS nausea scores, with the upper and lower quartiles considered to be nausea sensitive and resistant, respectively. Twenty-eight subjects were exposed to the motion video during functional neuroimaging. During the motion video, nausea-sensitive subjects had lower normogastria/tachygastria ratio and cardiac vagal tone but higher cardiac sympathetic index in comparison to the control video. Furthermore, nausea-sensitive subjects had decreased plasma ghrelin and demonstrated increased activity of the left anterior cingulate cortex. Nausea VAS scores correlated positively with plasma vasopressin and left inferior frontal and middle occipital gyri activity and correlated negatively with plasma ghrelin and brain activity in the right cerebellar tonsil, declive, culmen, lingual gyrus and cuneus. This study demonstrates that the subjective sensation of nausea is associated with objective changes in autonomic, endocrine and brain networks, and thus identifies potential objective biomarkers and targets for therapeutic interventions.

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.

Translational aspects of rectal evoked potentials: a comparative study in rats and humans.

Inconsistencies between species has stunted the progress of developing new analgesics. To increase the success of translating results between species, improved comparable models are required. Twelve rats received rectal balloon distensions on 2 different days separated by 24.3 (SD 24.6) days. Rectal balloon distensions were also performed in 18 humans (mean age: 34 yr; range: 21-56 yr; 12 men) on two separate occasions, separated by 9.3 (SD 5.5) days. In rats, cerebral evoked potentials (CEPs) were recorded by use of implanted skull-electrodes to distension pressure of 80 mmHg. In humans surface electrodes and individualized pressure, corresponding to pain detection threshold, were used. Comparison of morphology was assessed by wavelet analysis. Within- and between-day reproducibility was assessed in terms of latencies, amplitudes, and frequency content. In rats CEPs showed triphasic morphology. No differences in latencies, amplitudes, and power distribution were seen within or between days (all P ≥ 0.5). Peak-to-peak amplitude between the first positive and negative potential were the most reproducible characteristic within and between days (evaluated by intraclass correlation coefficients, ICC) (ICC = 0.99 and ICC = 9.98, respectively). In humans CEPs showed a triphasic morphology. No differences in latencies, amplitudes, or power distribution were seen within or between days (all P ≥ 0.2). Latency to the second negative potential (ICC = 0.98) and the second positive potential (ICC = 0.95) was the most reproducible characteristic within and between days. A unique and reliable translational platform was established assessing visceral sensitivity in rats and humans, which may improve the translational process of developing new drugs targeting visceral pain.

Psychophysiological responses to pain identify reproducible human clusters.

Pain is a ubiquitous yet highly variable experience. The psychophysiological and genetic factors responsible for this variability remain unresolved. We hypothesised the existence of distinct human pain clusters (PCs) composed of distinct psychophysiological and genetic profiles coupled with differences in the perception and the brain processing of pain. We studied 120 healthy subjects in whom the baseline personality and anxiety traits and the serotonin transporter-linked polymorphic region (5-HTTLPR) genotype were measured. Real-time autonomic nervous system parameters and serum cortisol were measured at baseline and after standardised visceral and somatic pain stimuli. Brain processing reactions to visceral pain were studied in 29 subjects using functional magnetic resonance imaging (fMRI). The reproducibility of the psychophysiological responses to pain was assessed at year. In group analysis, visceral and somatic pain caused an expected increase in sympathetic and cortisol responses and activated the pain matrix according to fMRI studies. However, using cluster analysis, we found 2 reproducible PCs: at baseline, PC1 had higher neuroticism/anxiety scores (P ≤ 0.01); greater sympathetic tone (P<0.05); and higher cortisol levels (P ≤ 0.001). During pain, less stimulus was tolerated (P ≤ 0.01), and there was an increase in parasympathetic tone (P ≤ 0.05). The 5-HTTLPR short allele was over-represented (P ≤ 0.005). PC2 had the converse profile at baseline and during pain. Brain activity differed (P ≤ 0.001); greater activity occurred in the left frontal cortex in PC1, whereas PC2 showed greater activity in the right medial/frontal cortex and right anterior insula. In health, 2 distinct reproducible PCs exist in humans. In the future, PC characterization may help to identify subjects at risk for developing chronic pain and may reduce variability in brain imaging studies.

Sex differences in brain response to anticipated and experienced visceral pain in healthy subjects.

Women demonstrate higher pain sensitivity and prevalence of chronic visceral pain conditions such as functional gastrointestinal disorders than men. The role of sex differences in the brain processing of visceral pain is still unclear. In 16 male and 16 female healthy subjects we compared personality, anxiety levels, skin conductance response (SCR), and brain processing using functional MRI during anticipation and pain induced by esophageal distension at pain toleration level. There was no significant difference in personality scores, anxiety levels, SCR, and subjective ratings of pain between sexes. In group analysis, both men and women demonstrated a similar pattern of brain activation and deactivation during anticipation and pain consistent with previous reports. However, during anticipation women showed significantly greater activation in the cuneus, precuneus, and supplementary motor area (SMA) and stronger deactivation in the right amygdala and left parahippocampal gyrus, whereas men demonstrated greater activation in the cerebellum. During pain, women demonstrated greater activation in the midcingulate cortex, anterior insula, premotor cortex, and cerebellum and stronger deactivation in the caudate, whereas men showed increased activity in the SMA. The pattern of brain activity suggests that, during anticipation, women may demonstrate stronger limbic inhibition, which is considered to be a cognitive modulation strategy for impending painful stimulation. During pain, women significantly activate brain areas associated with the affective and motivation components of pain. These responses may underlie the sex differences that exist in pain conditions, whereby women may attribute more emotional importance to painful stimuli compared with men.

Fatty acid-induced gut-brain signaling attenuates neural and behavioral effects of sad emotion in humans.

Although a relationship between emotional state and feeding behavior is known to exist, the interactions between signaling initiated by stimuli in the gut and exteroceptively generated emotions remain incompletely understood. Here, we investigated the interaction between nutrient-induced gut-brain signaling and sad emotion induced by musical and visual cues at the behavioral and neural level in healthy nonobese subjects undergoing functional magnetic resonance imaging. Subjects received an intragastric infusion of fatty acid solution or saline during neutral or sad emotion induction and rated sensations of hunger, fullness, and mood. We found an interaction between fatty acid infusion and emotion induction both in the behavioral readouts (hunger, mood) and at the level of neural activity in multiple pre-hypothesized regions of interest. Specifically, the behavioral and neural responses to sad emotion induction were attenuated by fatty acid infusion. These findings increase our understanding of the interplay among emotions, hunger, food intake, and meal-induced sensations in health, which may have important implications for a wide range of disorders, including obesity, eating disorders, and depression.

Neuroticism influences brain activity during the experience of visceral pain.

BACKGROUND & AIMS: One particularly important individual dynamic known to influence the experience of pain is neuroticism, of which little is known about in visceral pain research. Our aim was to study the relationship between neuroticism, psychophysiologic response, and brain processing of visceral pain. METHODS: Thirty-one healthy volunteers (15 male; age range, 22-38 years) participated in the study. The Eysenck Personality Questionnaire was used to assess neuroticism. Skin conductance level, pain ratings, and functional magnetic resonance imaging data were acquired during anticipation of pain and painful esophageal distention. The effect of neuroticism was assessed using correlation analysis. RESULTS: There was a wide spread of neuroticism scores (range, 0-22) but no influence of neuroticism on skin conductance level and pain tolerance or pain ratings. However, a positive correlation between brain activity and neuroticism during anticipation was found in regions associated with emotional and cognitive pain processing, including the parahippocampus, insula, thalamus, and anterior cingulate cortex. These regions showed a negative correlation with neuroticism during pain (P < .001). CONCLUSIONS: This study provides novel data suggesting higher neuroticism is associated with engagement of brain regions responsible for emotional and cognitive appraisal during anticipation of pain but reduced activity in these regions during pain. This may reflect a maladaptive mechanism in those with higher neuroticism that promotes overarousal during anticipation and avoidance coping during pain.

Quantitative prediction of subjective pain intensity from whole-brain fMRI data using Gaussian processes.

Supervised machine learning (ML) algorithms are increasingly popular tools for fMRI decoding due to their predictive capability and their ability to capture information encoded by spatially correlated voxels. In addition, an important secondary outcome is a multivariate representation of the pattern underlying the prediction. Despite an impressive array of applications, most fMRI applications are framed as classification problems and predictions are limited to categorical class decisions. For many applications, quantitative predictions are desirable that more accurately represent variability within subject groups and that can be correlated with behavioural variables. We evaluate the predictive capability of Gaussian process (GP) models for two types of quantitative prediction (multivariate regression and probabilistic classification) using whole-brain fMRI volumes. As a proof of concept, we apply GP models to an fMRI experiment investigating subjective responses to thermal pain and show GP models predict subjective pain ratings without requiring anatomical hypotheses about functional localisation of relevant brain processes. Even in the case of pain perception, where strong hypotheses do exist, GP predictions were more accurate than any region previously demonstrated to encode pain intensity. We demonstrate two brain mapping methods suitable for GP models and we show that GP regression models outperform state of the art support vector- and relevance vector regression. For classification, GP models perform categorical prediction as accurately as a support vector machine classifier and furnish probabilistic class predictions.

Negative mood affects brain processing of visceral sensation.

BACKGROUND & AIMS: A link between negative emotional state and abnormal visceral sensation has been frequently reported. However, the influence of negative emotion on brain processing of painful visceral sensations has not been investigated. We used functional magnetic resonance imaging (fMRI) and negative emotional stimuli to investigate the effects of negative emotion on brain processing of esophageal sensation. METHODS: Twelve healthy male volunteers (age range, 21-32 years) participated in the study. Negative emotion was induced using emotionally valent music. fMRI images were acquired during 2 experimental runs; throughout these, volunteers received randomized nonpainful and painful distentions to the esophagus during neutral and negative emotion. Subjective perception of each stimulus was acquired, as were mood ratings. RESULTS: Sadness ratings increased significantly following negative mood induction (P < .01). There was no significant effect of emotion on subjective perception of painful and nonpainful stimulation (P > .05). Following painful stimulation, brain activity increased in the right hemisphere during negative emotion and was localized to the anterior cingulate cortex (ACC; BA24/32), anterior insula, and inferior frontal gyrus. Following nonpainful stimulation during negative emotion, brain activity increased in the right anterior insula and ACC (BA24 and 32). CONCLUSIONS: This study provides new information about the influence of negative affect on central processing of visceral pain. Evidence of right hemispheric dominance during negative emotion indicates this hemisphere is predominately associated with sympathetic activity (arousal, negative affect) and that the right insula and right ACC are integral to subjective awareness of emotion through interoception.

Effects of attention on visceral stimulus intensity encoding in the male human brain.

BACKGROUND & AIMS: Hypervigilance is considered important in pain perception in functional gastrointestinal disorders. Nonetheless, a comprehensive assessment of the influence of attention on brain processing of visceral sensation has not been performed. We investigated the effects of attention on esophageal pain perception and brain activity. METHODS: Twelve healthy male volunteers (age range, 21-32 years) underwent 4 functional magnetic resonance imaging scans incorporating 4 levels of esophageal stimulation (ES), ranging from nonpainful to painful, during which they completed a task aimed at distracting them from the esophageal stimulus. The volunteers were then scanned a fifth time, during painful stimulation without distraction. RESULTS: Following ES during distraction, there was a significant linear trend (P < .05) in which the intensity of cerebral activation in the primary somatosensory cortex (SI) (bilateral) and left mid-anterior cingulate cortex (ACC) increased with stimulation intensity. When pain was delivered during distraction, there was a significant reduction in pain ratings, accompanied by significant decreases (P < .05) in brain activity in the right ACC and right prefrontal cortex. There was no effect of distraction on SI activity (P < .05). CONCLUSIONS: Our results suggest that the SI is involved in processing sensory-discriminative aspects of visceral sensation. In contrast, activity in the mid-ACC suggests that this region is multifunctional because it appears to be involved in sensory and cognitive appraisal of visceral pain; the right prefrontal cortex seems to be involved in only cognitive responses to pain.

Functional brain imaging of gastrointestinal sensation in health and disease.

It has since long been known, from everyday experience as well as from animal and human studies, that psychological processes-both affective and cognitive-exert an influence on gastrointestinal sensorimotor function. More specifically, a link between psychological factors and visceral hypersensitivity has been suggested, mainly based on research in functional gastrointestinal disorder patients. However, until recently, the exact nature of this putative relationship remained unclear, mainly due to a lack of non-invasive methods to study the (neurobiological) mechanisms underlying this relationship in non-sleeping humans. As functional brain imaging, introduced in visceral sensory neuroscience some 10 years ago, does provide a method for in vivo study of brain-gut interactions, insight into the neurobiological mechanisms underlying visceral sensation in general and the influence of psychological factors more particularly, has rapidly grown. In this article, an overview of brain imaging evidence on gastrointestinal sensation will be given, with special emphasis on the brain mechanisms underlying the interaction between affective & cognitive processes and visceral sensation. First, the reciprocal neural pathways between the brain and the gut (brain-gut axis) will be briefly outlined, including brain imaging evidence in healthy volunteers. Second, functional brain imaging studies assessing the influence of psychological factors on brain processing of visceral sensation in healthy humans will be discussed in more detail. Finally, brain imaging work investigating differences in brain responses to visceral distension between healthy volunteers and functional gastrointestinal disorder patients will be highlighted.

Reproducibility of human brain activity evoked by esophageal stimulation using functional magnetic resonance imaging.

Functional MRI is a popular tool for investigating central processing of visceral pain in healthy and clinical populations. Despite this, the reproducibility of the neural correlates of visceral sensation by use of functional MRI remains unclear. The aim of the present study was to address this issue. Seven healthy right-handed volunteers participated in the study. Blood oxygen level-dependent contrast images were acquired at 1.5 T while subjects received nonpainful and painful phasic balloon distensions ("on-off" block design, 10 stimuli per "on" period, 0.3 Hz) to the distal esophagus. This procedure was repeated on two further occasions to investigate reproducibility. Painful stimulation resulted in highly reproducible activation over three scanning sessions in the anterior insula, primary somatosensory cortex, and anterior cingulate cortex. A significant decrease in strength of activation occurred from session 1 to session 3 in the anterior cingulate cortex, primary somatosensory cortex, and supplementary motor cortex, which may be explained by an analogous decrease in pain ratings. Nonpainful stimulation activated similar brain regions to painful stimulation, but with greater variability in signal strength and regions of activation between scans. Painful stimulation of the esophagus produces robust activation in many brain regions. A decrease in subjective perception of pain and brain activity from the first to the final scan suggests that serial brain imaging studies may be affected by habituation. These findings indicate that for brain imaging studies that require serial scanning, development of experimental paradigms that control for the effect of habituation is necessary.

Brain response to visceral aversive conditioning: a functional magnetic resonance imaging study.

BACKGROUND & AIMS: Brain-imaging studies to date have confounded visceral pain perception with anticipation. We used functional magnetic resonance imaging of the human brain to study the neuroanatomic network involved in aversive conditioning of visceral pain and, thus, anticipation. METHODS: Eight healthy volunteers (5 male) participated in the study. We used a classic conditioning paradigm in which 3 neutral stimuli (differently colored circles) that acted as conditioned stimuli were paired with painful esophageal distention, air puff to the wrist, or nothing, which acted as unconditioned stimuli. Neural activity was measured during learning, anticipation (pairing only 50% of conditioned stimuli with their unconditioned stimuli), and extinction (unpaired conditioned stimuli) phases. For magnetic resonance imaging, axial slices depicting blood oxygen level-dependent contrast were acquired with a 1.5-T system. RESULTS: Neural responses during the learning phase included areas commonly associated with visceral pain (anterior cingulate cortex, insula, and primary and secondary somatosensory cortices) and innocuous somatosensory perception (primary and secondary somatosensory cortices and insula). During the anticipation and extinction phases of aversive stimulation, brain activity resembled that seen during actual painful esophageal stimulation. In contrast, anticipation and extinction of the innocuous somatic stimulus failed to show that effect. CONCLUSIONS: We have shown that actual and anticipated visceral pain elicit similar cortical responses. These results have implications for the design and interpretation of brain-imaging studies of visceral pain. They not only contribute to our understanding of the processing of visceral pain, but also have clinical implications for the management of chronic pain states.

The effect of negative emotional context on neural and behavioural responses to oesophageal stimulation.

Sensory experience is influenced by emotional context. Although perception of emotion and unpleasant visceral sensation are associated with activation within the insula and dorsal and ventral anterior cingulate gyri (ACG), regions important for attention to and perception of sensory and emotional information, the neural mechanisms underlying the effect of emotional context upon visceral sensation remain unexplored. Using functional MRI, we examined neural responses to phasic, non-painful oesophageal sensation (OS) in eight healthy subjects (seven male; age range 27-36 years) either during neutral or negative emotional contexts produced, respectively, by presentation of neutral or fearful facial expressions. Activation within right insular and bilateral dorsal ACG was significantly greater (P < 0.01) during OS with fearful than with neutral faces. In a second experiment, we measured anxiety, discomfort and neural responses in eight healthy male subjects (age range 22-41 years) to phasic, non-painful OS during presentation of faces depicting either low, moderate or high intensities of fear. Significantly greater (P < 0.01) discomfort, anxiety and activation predominantly within the left dorsal ACG and bilateral anterior insulae occurred with high-intensity compared with low-intensity expressions. Clusters of voxels were also detected in this region, which exhibited a positive correlation between subjective behaviour and blood oxygenation level-dependent effect (P < 0.05). We report the first evidence for a modulation of neural responses, and perceived discomfort during, non-painful visceral stimulation by the intensity of the negative emotional context in which the stimulation occurs, and suggest a mechanism for the effect of negative context on symptoms in functional pain disorders.