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.

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.

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.

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

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.

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.

Modulation of activity in swallowing motor cortex following esophageal acidification: a functional magnetic resonance imaging study.

Esophageal acid exposure induces sensory and motility changes in the upper gastrointestinal tract; however, the mechanisms involved and the effects on activity in the brain regions that control swallowing are unknown. The aim of this study was to examine functional changes in the cortical swallowing network as a result of esophageal acidification using functional magnetic resonance imaging (fMRI). Seven healthy volunteers (3 female, age range=20-30 years) were randomized to receive either a 0.1 M hydrochloric acid or (control) saline infusion for 30 min into the distal esophagus. Postinfusion, subjects underwent four 8 min blocks of fMRI over 1 h. These alternated between 1 min swallowing water boluses and 1 min rest. Three-dimensional cluster analysis for group brain activation during swallowing was performed together with repeated-measures ANOVA for differences between acid and saline. After acid infusion, swallowing-induced activation was seen predominantly in postcentral gyrus (p<0.004). ANOVA comparison of acid with saline showed a significant relative reduction in activation during swallowing of the precentral gyrus (M1) BA 4 (p<0.008) in response to acid infusion. No areas of increased cortical activation were identified with acid vs. saline during swallowing. Esophageal acidification inhibits motor and association cortical areas during a swallowing task, probably via changes in vagal afferent or nociceptive input from the esophagus. This mechanism may play a protective role, facilitating acid clearance by reduced descending central motor inhibition of enteric/spinal reflexes, or by preventing further ingestion of injurious agents.

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.

Influence of experimentally induced anxiety on gastric sensorimotor function in humans.

BACKGROUND & AIMS: Unexplained dyspeptic symptoms are associated with changes in gastric sensorimotor function and several psychopathologic dimensions, including anxiety. It is unclear whether this reflects common predisposition or a causal relationship. The aim of this study was to investigate whether experimentally induced anxiety would alter gastric sensorimotor function in health. METHODS: Fourteen subjects underwent a gastric barostat study to assess gastric sensitivity and accommodation. Eighteen subjects underwent a 10-minute satiety drinking test (30 mL/min) with registration of epigastric symptoms on a visual analogue scale (VAS) at 2-minute intervals. Emotional context was modulated for 10 minutes at the start of each experiment by combined projection of validated facial expressions and an audiotape recalling a neutral or an anxious autobiographical experience. Anxiety levels were assessed using a VAS and the Spielberger State-Trait Anxiety Inventory (STAI). RESULTS: VAS and STAI scores confirmed efficacy of anxiety induction. During the anxiety condition, gastric compliance was significantly decreased (57 +/- 5 vs 40 +/- 5 mL/mm Hg; P < .01). Intraballoon pressures inducing discomfort during gastric distention were not altered, but the corresponding volume (630 +/- 47 vs 489 +/- 39 mL; P < .005) was significantly lower. Meal-induced relaxation was inhibited during the anxiety condition and this persisted for the 60-minute measurement (157 +/- 29 vs 100 +/- 24 mL; P < .05). During the satiety drinking test, the anxiety condition was associated with significantly higher scores for satiety, fullness, and bloating. CONCLUSIONS: Experimentally induced anxiety alters gastric sensorimotor function, suggesting that psychological factors may play a causal role in the pathogenesis of some dyspeptic symptoms and mechanisms.

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 neuronal nitric oxide synthase inhibitor, TRIM, as a neuroprotective agent: effects in models of cerebral ischaemia using histological and magnetic resonance imaging techniques.

Most neuroprotective compounds that appear promising in the pre-clinical phase of testing are subsequently dismissed as relatively ineffective when entered into large-scale clinical trials. Many pre-clinical studies of potential neuroprotective candidates evaluate efficacy in only one or possibly two different models of ischaemia. In this study we examined the effects of 1,2-trifluoromethylphenyl imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor, in three models of cerebral ischaemia (global gerbil, global rat and focal rat). In addition, to follow the progression of the pathology, we also compared traditional histology methods with more advanced magnetic resonance imaging (MRI) as endpoint measures for neurological damage and neuroprotection. TRIM (50 mg/kg i.p.) prevented ischaemia-induced hippocampal damage following global ischaemia in gerbils when administered before or immediately post-occlusion, but failed to protect when administration was delayed until 30 min post-occlusion. Further studies indicated that the compound (administered at 50 mg/kg, i.p., immediately after occlusion) also protected in a rat four-vessel occlusion (4-VO) model using both histological and diffusion-weighted (DW) imaging techniques. In a final study, TRIM (50 mg/kg i.p. 30 min after occlusion) provided a significant reduction in infarct volume at 4 and 24 h as measured using diffusion-weighted (DW) and proton density (PD)-weighted magnetic resonance imaging (MRI). This was confirmed using histological techniques. These studies confirm that nNOS inhibitors may have utility in stroke and provide evidence that combined magnetic resonance and histological methods can provide a powerful method of assessing neuronal damage in rodent models of cerebral ischaemia.

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.

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.

Storage of verbal associations is sufficient to activate the left medial temporal lobe.

Neuroimaging studies have shown that memory encoding activates the medial temporal lobe (MTL). Many believe that these activations are related to novelty but it remains unproven which is critical - novelty detection or the rich associative encoding it triggers. We examined MTL activation during verbal associative encoding using functional magnetic resonance imaging. First, associative encoding activated left posterior MTL more than single word encoding even though novelty detection was matched, indicating not only that associative encoding activates the MTL particularly strongly, but also that activation does not require novelty detection. Moreover, it remains to be convincingly shown that novelty detection alone does produce such activation. Second, repetitive associative encoding produced less MTL activation than initial associative encoding, indicating that priming of associative information reduces MTL activation. Third, re-encoding familiar associations in a well-established way had a minimal effect on both memory and MTL activation, indicating that MTL activation reflects storage of associations, not merely their initial representation.