Lloyd J. Gregory

Exploring relationships for visceral and somatic pain with autonomic control and personality

ABSTRACT The autonomic nervous system (ANS) integrates afferent and motor activity for homeostatic processes including pain. The aim of the study was to compare hitherto poorly characterised relations between brainstem autonomic control and personality in response to visceral and somatic pain. Eighteen healthy subjects (16 females, mean age 34) had recordings during rest and pain of heart rate (HR), cardiac vagal tone (CVT), cardiac sensitivity to baroreflex (CSB), skin conductance level (SC), cardiac sympathetic index (CSI) and mean blood pressure (MBP). Visceral pain was induced by balloon distension in proximal (PB) and distal (DB) oesophagus and somatic pain by nail‐bed pressure (NBP). Eight painful stimuli were delivered at each site and unpleasantness and intensity measured. Personality was profiled with the Big Five inventory. (1) Oesophageal intubation evoked “fight‐flight” responses: HR and sympathetic (CSI, SC, MBP) elevation with parasympathetic (CVT) withdrawal (p < 0.05). (2) Pain at all sites evoked novel parasympathetic/sympathetic co‐activation with elevated HR but vasodepression (all p < 0.05). (3) Personality traits correlated with slope of distal oesophageal pain‐related CVT changes wherein more neurotic‐introvert subjects had greater positive pain‐related CVT slope change (neuroticism r 0.8, p < 0.05; extroversion r −0.5, p < 0.05). Pain‐evoked heart rate increases were mediated by parasympathetic and sympathetic co‐activation – a novel finding in humans but recently described in mammals too. Visceral pain‐related parasympathetic change correlated with personality. ANS defence responses are nuanced and may relate to personality type for visceral pain. Clinical relevance of these findings warrants further exploration.

Neuroimaging correlates of negative priming

Many theoretical accounts of selective attention and memory retrieval include reference to active inhibitory processes, such as those argued to underlie the negative priming effect. fMRI was used in order to investigate the areas of cortical activation associated with Stroop interference, Stroop facilitation and Stroop negative priming tasks. The most significant activation within the negative priming task was within the inferior parietal lobule, left temporal lobe and frontal lobes. Areas of cortical activation are discussed with reference to theoretical accounts of the negative priming effect.

Cognitive Modulation of the Cerebral Processing of Human Oesophageal Sensation using Functional Magnetic Resonance Imaging

Background: While cortical processing of visceral sensation has been described, the role that cognitive factors play in modulating this processing remains unclear. Aim: To investigate how selective and divided attention modulate the cerebral processing of oesophageal sensation. Methods: In seven healthy volunteers (six males, mean age 33 years; ranging from 24 to 41 years old) from the general community, phasic visual and oesophageal (non-painful balloon distension) stimuli were presented simultaneously. During the selective attention task, subjects were instructed to press a button either to a change in frequency of oesophageal or visual stimuli. During a divided attention task, subjects received simultaneous visual and oesophageal stimuli and were instructed to press a button in response to a change in frequency of both stimuli. Results: Selectively focussing attention on oesophageal stimuli activated the visceral sensory and cognitive neural networks (primary and secondary sensory cortices and anterior cingulate cortex respectively) while selective attention to visual stimuli primarily activated the visual cortex. When attention was divided between the two sensory modalities, more brain regions in the sensory and cognitive domains were utilised to process oesophageal stimuli in comparison to those employed to process visual stimuli (p = 0.003). Conclusion: Selective and divided attention to visceral stimuli recruits more neural resources in both the sensory and cognitive domains than attention to visual stimuli. We provide neurobiological evidence that demonstrates the biological importance placed on visceral sensations and demonstrate the influence of cognitive factors such as attention on the cerebral processing of visceral sensation.

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.

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.

Defining the role of cholecystokinin in the lipid-induced human brain activation matrix.

BACKGROUND & AIMS In human beings, as in most vertebrates, the release of the intestinal peptide cholecystokinin (CCK) by ingested food plays a major role both in digestion and the regulation of further food intake, but the changes in brain function and their underlying activation mechanisms remain unknown. Our aim was to explore, using a novel physiologic magnetic resonance imaging approach, the temporospatial brain activation matrix, in response to ingestion of a lipid meal and, by use of a CCK-1 receptor antagonist, to define the role of CCK in this activation. METHODS We studied, in 19 healthy subjects, the brain activation responses to ingested lipid (dodecanoic acid) or saline (control) with magnetic resonance imaging. Gallbladder volume, plasma CCK levels, and subjective hunger and fullness scores were also recorded. The experiment was then repeated, with and without prior administration of the CCK-1 receptor antagonist dexloxiglumide (600 mg orally) with a controlled, randomized order, latin-square design. RESULTS Ingested lipid activated bilaterally a matrix of brain areas, particularly the brain stem, pons, hypothalamus, and also cerebellum and motor cortical areas. These activations were abolished by dexloxiglumide, indicating a CCK-mediated pathway, independent of any nutrient-associated awareness cues. CONCLUSION The identification of these activations now defines the lipid-activated brain matrix and provides a means by which the gut-derived homeostatic mechanisms of food regulation can be distinguished from secondary sensory and hedonic cues, thereby providing a new approach to exploring aberrant human gastrointestinal responses and eating behavior.

Novelty-related activation within the medial temporal lobes.

Functional magnetic resonance imaging (fMRI) was used to examine whether (1) verbal associative encoding activates the medial temporal lobes (MTL) and related regions more than non-associative encoding, (2) verbal associative novelty is related to enhanced MTL activation, and (3) verbal item novelty is related to enhanced MTL activation and, if so, whether these activations are in different or overlapping sites. No increase in MTL activation was found during verbal associative encoding relative to non-associative encoding, although associative encoding was related to a relative increase in activation in the posterior cingulate cortex. In contrast, verbal associative novelty was found to activate the MTL and posterior cingulate cortex. Verbal item novelty did not significantly activate any brain region. The verbal associative novelty-related effect occurred despite subjects having little awareness of associative novelty. The verbal associative novelty-related activation in the MTL may be related either to unconscious novelty detection or to a priming effect at encoding. We argue that if the priming explanation is correct then this may account for our failure to observe an associative encoding MTL activation.

Anxiety increases acid-induced esophageal hyperalgesia.

Objective: Anxiety at the time of gastrointestinal injury or inflammation increases the risk of developing visceral hyperalgesia. Distal esophageal acidification induces hyperalgesia in the non-acid exposed proximal esophagus, due to the sensitization of spinal dorsal horn neurones. The objective was to determine whether anxiety influences acid-induced hyperalgesia. Methods: A total of 19 healthy volunteers (n = 12 females; age, 22–57 years; mean, 35.7 years) completed a 10-minute mood induction paradigm (anxiety or neutral) with autonomic monitoring (visit 1). On visits 2 and 3, pain thresholds to electrical stimulation, in milliamperes (mA), were determined in the proximal esophagus and foot (control) before and after a 30-minute infusion of 0.15 M of hydrochloric acid. During esophageal acid infusion, the subjects randomly received anxiety or neutral mood induction with autonomic monitoring, in a crossover design. Anxiety and pain ratings were recorded pre and post infusion. Results: Visit 1: Anxiety induction increased anxiety scores (p < .001), mean arterial pressure (p < .001), and cardiac sympathetic index (p = .007), and reduced parasympathetic measures (cardiac vagal tone [p = .05] and cardiac sensitivity to baroreflex [p = .006)]). Visit 2: Anxiety induction conferred greater acid-induced hyperalgesia compared with neutral (−4.9 mA versus 2.7 mA, p = .009, analysis of covariance). No differences in autonomic measures were found during acid infusion with anxiety or neutral mood induction. Conclusions: Anxiety induction increases acid-induced esophageal hyperalgesia; anxiety, thus, facilitates central sensitization in the esophagus. Our studies provide a new model for studying the effects of anxiety on esophageal hyperalgesia and may allow testing of therapeutic strategies to reduce this effect. CS = central sensitization; SSAI = Spielberger State Anxiety Inventory; CVT = cardiac vagal tone; CSB = cardiac sensitivity to baroreflex; CSI = Cardiac Sympathetic Index.

Personality differences affect brainstem autonomic responses to visceral pain

Abstract  Brainstem autonomic nuclei integrate interoceptive inputs including pain, with descending modulation, to produce homeostatic and defence outputs. Cardiac Vagal Control is especially implicated in psychophysiological processes for both health and disease and is indexed non‐invasively by heart rate variability. The study aim was to determine the nature of psychophysiological response profiles for visceral pain. Nineteen healthy subjects had electrocardiographic recordings at rest and during 10 painful oesophageal balloon distensions. Cardiac Vagal Control originating from nucleus ambiguus (CVCNA) was determined by polynomial filter application to the electrocardiogram inter‐beat interval series. Heart rate and ‘Cardiac Sympathetic Index (CSI)’ were also determined. Psychological state and trait, including neuroticism and extroversion, were assessed. Subjects who increased CVCNA to pain were more neurotic, anxious and sensory sensitive than those who decreased CVCNA. Cluster analysis identified two psychophysiological groups: Group 1 (n = 11) demonstrated lower baseline CVCNA (P = 0.0001), higher heart rate (P = 0.02) and CSI (P = 0.015), pain tolerance at lower balloon volumes (P = 0.04), but attenuated heart rate response to pain (P = 0.01). Group 2 (n = 8) had the converse profile. Neuroticism scores were higher (P = 0.0004) and extroversion lower (P = 0.01) for group 1 than group 2. Two distinct psychophysiological response profiles to visceral pain exist that are influenced by personality. These may reflect different psychobiological bases for active and passive defence repertoires. Prevalence and clinical relevance of these endophenotypes as vulnerability factors for pain and emotion disorders warrant further exploration.

Diminished Neural and Cognitive Responses to Facial Expressions of Disgust in Patients with Psoriasis: A Functional Magnetic Resonance Imaging Study

Psoriasis produces significant psychosocial disability; however, little is understood about the neurocognitive mechanisms that mediate the adverse consequences of the social stigma associated with visible skin lesions, such as disgusted facial expressions of others. Both the feeling of disgust and the observation of disgust in others are known to activate the insula cortex. We investigated whether the social impact of psoriasis is associated with altered cognitive processing of disgust using (i) a covert recognition of faces task conducted using functional magnetic resonance imaging (fMRI) and (ii) the facial expression recognition task (FERT), a decision-making task, conducted outside the scanner to assess the ability to recognize overtly different intensities of disgust. Thirteen right-handed male patients with psoriasis and 13 age-matched male controls were included. In the fMRI study, psoriasis patients had significantly (P<0.005) smaller signal responses to disgusted faces in the bilateral insular cortex compared with healthy controls. These data were corroborated by FERT, in that patients were less able than controls to identify all intensities of disgust tested. We hypothesize that patients with psoriasis, in this case male patients, develop a coping mechanism to protect them from stressful emotional responses by blocking the processing of disgusted facial expressions.