Brandall Y. Suyenobu

The neural correlates of placebo effects: a disruption account.

The neurocognitive pathways by which placebo effects operate are poorly understood. Positron emission tomography (PET) imaging was used to assess the brain response of patients with chronic abdominal pain (irritable bowel syndrome; IBS) to induced intestinal discomfort both before and after a 3-week placebo regimen. A daily symptom diary was used to measure symptom improvement. Increases in right ventrolateral prefrontal cortex (RVLPFC) activity from pre- to post-placebo predicted self-reported symptom improvement, and this relationship was mediated by changes in dorsal anterior cingulate (dACC), typically associated with pain unpleasantness. These results are consistent with disruption theory [Lieberman, M.D., 2003. Reflective and reflexive judgment processes: a social cognitive neuroscience approach. In: Forgas, J.P., Williams, K.R., von Hippel, W. (Eds.), Social Judgments: Explicit and Implicit Processes. Cambridge Univ. Press, New York, pp. 44-67], which proposes that activation of prefrontal regions associated with thinking about negative affect can diminish dACC and amygdala reactivity to negative affect stimuli. This is the first study to identify a neural pathway from a region of the brain associated with placebos and affective thought to a region closely linked to the placebo-related outcome of diminished pain unpleasantness.

Sex-Related Differences in IBS Patients: Central Processing of Visceral Stimuli

BACKGROUND & AIMSnWomen have a higher prevalence of irritable bowel syndrome (IBS) and possible differences in response to treatment, suggesting sex-related differences in underlying pathophysiology. The aim of this study was to determine possible sex-related differences in brain responses to a visceral and a psychological stressor in IBS.nnnMETHODSnRegional cerebral blood flow measurements using H(2)(15)O positron emission tomography were compared across 23 female and 19 male nonconstipated patients with IBS during a visceral stimulus (moderate rectal inflation) and a psychological stimulus (anticipation of a visceral stimulus).nnnRESULTSnIn response to the visceral stimulus, women showed greater activation in the ventromedial prefrontal cortex, right anterior cingulate cortex, and left amygdala, whereas men showed greater activation of the right dorsolateral prefrontal cortex, insula, and dorsal pons/periaqueductal gray. Similar differences were observed during the anticipation condition. Men also reported higher arousal and lower fatigue.nnnCONCLUSIONSnMale and female patients with IBS differ in activation of brain networks concerned with cognitive, autonomic, and antinociceptive responses to delivered and anticipated aversive visceral stimuli.

Differences in brain responses to visceral pain between patients with irritable bowel syndrome and ulcerative colitis

&NA; Patients with mild chronic inflammation of the rectum or ileum have reduced perceptual responses to rectosigmoid distension compared to patients with irritable bowel syndrome (IBS). The current study sought to identify differences in regional cerebral blood flow (rCBF) during rectal distension, which might correspond to these perceptual differences. In 8 male ulcerative colitis (UC) patients with quiescent disease, 7 male IBS patients and 7 healthy male controls, rCBF was assessed using 15O‐water positron emission tomography at baseline and during actual and anticipated but undelivered rectal distensions. No group differences were seen in anterior insula and dorsal anterior cingulate cortex (dACC), two regions consistently activated by painful intestinal stimuli. However, IBS patients showed greater activation of the amygdala, rostroventral ACC, and dorsomedial frontal cortical regions. In contrast, no significant differences were observed between UC and controls. When these two non‐IBS groups were combined, functional connectivity analyses showed that right lateral frontal cortex (RLFC) activation positively correlated with activation of the dorsal pons/periaqueductal gray, a key region involved in endogenous pain inhibition. According to the connectivity analysis, this effect was mediated by inhibition of medial frontal cortex by the RLFC. Chronic colonic inflammation is not necessarily associated with increased visceral afferent input to the brain during rectal distension. In the sample studied, the primary difference between functional and quiescent inflammatory disease of the colon was in terms of greater activation of limbic/paralimbic circuits in IBS, and inhibition of these circuits in UC and controls by the RLFC.

Reduced Brainstem Inhibition during Anticipated Pelvic Visceral Pain Correlates with Enhanced Brain Response to the Visceral Stimulus in Women with Irritable Bowel Syndrome

Cognitive factors such as fear of pain and symptom-related anxiety play an important role in chronic pain states. The current study sought to characterize abnormalities in preparatory brain response before aversive pelvic visceral distention in irritable bowel syndrome (IBS) patients and their possible relationship to the consequences of distention. The brain functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) response to anticipated and delivered mild and moderate rectal distention was recorded from 14 female IBS patients and 12 healthy controls. During cued anticipation of distention, activity decreased in the insula, supragenual anterior cingulate cortex (sACC), amygdala, and dorsal brainstem (DBS) of controls. IBS patients showed less anticipatory inactivation. Group differences were significant in the right posterior insula and bilateral DBS. Self-rated measures of negative affect during scanning were higher in patients than controls (p < 0.001), and the anticipatory BOLD decreases in DBS were inversely correlated with these ratings. During subsequent distention, both groups showed activity increases in insula, dorsal ACC, and DBS and decreases in the infragenual ACC. The increases were more extensive in patients, producing significant group differences in dorsal ACC and DBS. The amplitude of the anticipatory decrease in the pontine portion of DBS was associated with greater activation during distention in right orbitofrontal cortex and bilateral sACC. Both regions have been associated previously with corticolimbic inhibition and cognitive coping. Deficits in preparatory inhibition of DBS, including the locus ceruleus complex and parabrachial nuclei, may interfere with descending corticolimbic inhibition and contribute to enhanced brain responsiveness and perceptual sensitivity to visceral stimuli in IBS.

Impact of mindfulness-based stress reduction training on intrinsic brain connectivity

The beneficial effects of mindful awareness and mindfulness meditation training on physical and psychological health are thought to be mediated in part through changes in underlying brain processes. Functional connectivity MRI (fcMRI) allows identification of functional networks in the brain. It has been used to examine state-dependent activity and is well suited for studying states such as meditation. We applied fcMRI to determine if Mindfulness-Based Stress Reduction (MBSR) training is effective in altering intrinsic connectivity networks (ICNs). Healthy women were randomly assigned to participate in an 8-week Mindfulness-Based Stress Reduction (MBSR) training course or an 8-week waiting period. After 8 weeks, fMRI data (1.5T) was acquired while subjects rested with eyes closed, with the instruction to pay attention to the sounds of the scanner environment. Group independent component analysis was performed to investigate training-related changes in functional connectivity. Significant MBSR-related differences in functional connectivity were found mainly in auditory/salience and medial visual networks. Relative to findings in the control group, MBSR subjects showed (1) increased functional connectivity within auditory and visual networks, (2) increased functional connectivity between auditory cortex and areas associated with attentional and self-referential processes, (3) stronger anticorrelation between auditory and visual cortex, and (4) stronger anticorrelation between visual cortex and areas associated with attentional and self-referential processes. These findings suggest that 8 weeks of mindfulness meditation training alters intrinsic functional connectivity in ways that may reflect a more consistent attentional focus, enhanced sensory processing, and reflective awareness of sensory experience.

Effect of Abuse History on Pain Reports and Brain Responses to Aversive Visceral Stimulation: An fMRI Study

BACKGROUND & AIMSnAbuse history is common in irritable bowel syndrome (IBS) and is associated with greater pain reporting, psychologic distress, and poorer health outcome. These effects may be mediated by enhanced responses to aversive visceral stimuli. We investigated the effects of IBS and abuse history on pain reporting and brain activation in response to rectal distentions.nnnMETHODSnTen female patients with IBS and 10 controls were included. Half of patients in each group reported a history of abuse. Brain functional magnetic resonance imaging (fMRI) images and pain ratings were obtained during rectal distentions. Statistical parametric mapping identified activation in subregions of the dorsal cingulate cortex and covariation with rated pain.nnnRESULTSn(1) Distention-elicited pain correlated with anxiety and activation of the posterior (PCC) and middle (MCC) dorsal cingulate subregions. (2) Subjects with a history of abuse showed greater activation in the left MCC (P = .022; t = 5.61) and PCC (P = .033; t = 5.00) than subjects without abuse. (3) Those with IBS and abuse reported greater pain than all others (P = .004), had more activity in the left MCC (P = .021; t = 5.29) and PCC (P = .049; t = 4.81), and had less activity in the left supragenual anterior cingulate (sACC) (P = .01; t = 4.86).nnnCONCLUSIONSnPain ratings during rectal distention are associated with activation of dorsal cingulate regions implicated in homeostatic afferent processing, and prior abuse enhances this activation. Patients with IBS and abuse report more pain, greater MCC/PCC activation, and reduced activity of a region implicated in pain inhibition and arousal (sACC). These findings suggest a possible explanation for the clinical observation of greater pain reporting and poorer outcome in IBS patients with a history of abuse.

Brain responses to visceral and somatic stimuli in patients with irritable bowel syndrome with and without fibromyalgia

OBJECTIVE:Symptoms of irritable bowel syndrome (IBS) and fibromyalgia (FM) commonly coexist. We hypothesized that one of the mechanisms underlying this comorbidity is increased activation of brain regions concerned with the processing and modulation of visceral and somatic afferent information, in particular subregions of the anterior cingulate cortex (ACC).METHODS:Regional cerebral blood flow (rCBF) was assessed in age-matched female IBS (n = 10) and IBS + FM (n = 10) subjects using H215O positron emission tomography during noxious visceral (rectal) and somatic pressure stimuli.RESULTS:GI symptom severity was significantly higher in the IBS patients compared with the IBS + FM patients (p < 0.05). In addition, IBS + FM patients rated somatic pain as more intense than their abdominal pain (p < 0.05). Whereas the somatic stimulus was less unpleasant than the visceral stimulus for IBS patients without FM, the somatic and visceral stimuli were equally unpleasant in the IBS + FM group. Group differences in regional brain activation were entirely within the middle subregion of the ACC. There was a greater rCBF increase in response to noxious visceral stimuli in IBS patients and to somatic stimuli in IBS + FM patients.CONCLUSION:Chronic stimulus-specific enhancement of ACC responses to sensory stimuli in both syndromes may be associated with cognitive enhancement of either visceral (IBS) or somatic (IBS + FM) sensory input and may play a key pathophysiologic role in these chronic pain syndromes.

Sex differences in brain activity during aversive visceral stimulation and its expectation in patients with chronic abdominal pain: A network analysis

Differences in brain responses to aversive visceral stimuli may underlie previously reported sex differences in symptoms as well as perceptual and emotional responses to such stimuli in patients with irritable bowel syndrome (IBS). The goal of the current study was to identify brain networks activated by expected and delivered aversive visceral stimuli in male and female patients with chronic abdominal pain, and to test for sex differences in the effective connectivity of the circuitry comprising these networks. Network analysis was applied to assess the brain response of 46 IBS patients (22 men and 24 women) recorded using [15O] water positron emission tomography during rest/baseline and expected and delivered aversive rectal distension. Functional connectivity results from partial least squares analyses provided support for the hypothesized involvement of 3 networks corresponding to: 1) visceral afferent information processing (thalamus, insula and dorsal anterior cingulate cortex, orbital frontal cortex), 2) emotional-arousal (amygdala, rostral and subgenual cingulate regions, and locus coeruleus complex) and 3) cortical modulation (frontal and parietal cortices). Effective connectivity results obtained via structural equation modeling indicated that sex-related differences in brain response are largely due to alterations in the effective connectivity of emotional-arousal circuitry rather than visceral afferent processing circuits. Sex differences in the cortico-limbic circuitry involved in emotional-arousal, pain facilitation and autonomic responses may underlie the observed differences in symptoms, and in perceptual and emotional responses to aversive visceral stimuli.

Multiband topographic EEG analysis of a simulated visuomotor aviation task.

Topographic EEG spectral magnitudes from 19 cortical sites were compared in 15 adult male subjects during performance of a simulated flight task and during control conditions which attempted to separately evaluate functional components of this task. Four conditions were studied, including eyes closed, a visual control, a motor control and a simulated landing task requiring integration of both visual and motor components. Each condition was repeated twice in a counterbalanced replicated measures design. A linked-ear EEG reference was used and spectral magnitudes calculated for 6 frequency bands. Decisions concerning band width and spectral transform were empirically determined. Findings indicated no significant differences between replications. A broad posterior cortical suppression of all frequencies was observed in the visual control condition. Anterior sites were affected only in the 7-12 Hz range. Additional suppression was seen during the motor control condition but limited to frontocentral sites in the 11-13 Hz band. The flight task, however, produced a further suppression at centroparietal cortex in the 9-13 Hz range. The extraction of both attentional and motor components from this task suggests that the parietal EEG activation was specific to cognitive processing.

Corticotropin-releasing factor receptor 1 antagonist alters regional activation and effective connectivity in an emotional-arousal circuit during expectation of abdominal pain.

Alterations in corticotropin-releasing factor (CRF) signaling pathways have been implicated in irritable bowel syndrome (IBS) pathophysiology. We aimed to (1) determine the effect of the selective CRF receptor 1 antagonist (CRF1) GW876008 relative to placebo, on regional activation and effective connectivity of a stress-related emotional–arousal circuit during expectation of abdominal pain using functional magnetic resonance imaging in human subjects with a diagnosis of IBS and healthy controls (HCs), and (2) examine GW876008 effects on state–trait anxiety and hypothalamic–pituitary–adrenal (HPA) axis response. Although there were no drug-related effects on peripheral HPA activity, significant central effects were observed in brain regions associated with the stress response. Effective connectivity analysis showed drug-induced normalizations between key regions of the emotional–arousal circuit in patients. During pain expectation, orally administered GW876008 relative to placebo produced significant blood oxygen level-dependent (BOLD) signal reductions in the amygdala, hippocampus, insula, anterior cingulate, and orbitomedial prefrontal cortices across groups. Patients showed significantly greater BOLD responses in the left locus coeruleus and hypothalamus after placebo compared with HCs, and BOLD signal decreases in the left hypothalamus after drug. The inhibitory effects of GW876008 in the hypothalamus in patients were moderated by anxiety; patients having average and high levels of state anxiety showed drug-related BOLD decreases. GW876008 represents a novel tool for elucidating the neuronal mechanisms and circuitry underlying hyperactivation of CRF/CRF1 signaling and its role in IBS pathophysiology. The unique state anxiety effects observed suggest a potential pathway for therapeutic benefit of CRF1 receptor antagonism for patients with stress-sensitive disorders.