Stuart W.G. Derbyshire

Cerebral activation in patients with irritable bowel syndrome and control subjects during rectosigmoid stimulation.

Objective Patients with irritable bowel syndrome (IBS) show evidence of altered perceptual responses to visceral stimuli, consistent with altered processing of visceral afferent information by the brain. In the current study, brain responses to anticipated and delivered rectal balloon distension were assessed. Methods Changes in regional cerebral blood flow were measured using H215O-water positron emission tomography in 12 nonconstipated IBS patients and 12 healthy control subjects. Regional cerebral blood flow responses to moderate rectal distension (45 mm Hg) and anticipated but undelivered distension were assessed before and after a series of repetitive noxious (60-mm Hg) sigmoid distensions. Results Brain regions activated by actual and simulated distensions were similar in both groups. Compared with control subjects, patients with IBS showed lateralized activation of right prefrontal cortex; reduced activation of perigenual cortex, temporal lobe, and brain stem; but enhanced activation of rostral anterior cingulate and posterior cingulate cortices. Conclusions IBS patients show altered brain responses to rectal stimuli, regardless of whether these stimuli are actually delivered or simply anticipated. These alterations are consistent with reported alterations in autonomic and perceptual responses and may be related to altered central noradrenergic modulation.

The necessity of animal models in pain research.

&NA; There exists currently a fair degree of introspection in the pain research community about the value of animal research. This review represents a defense of animal research in pain. We discuss the inherent advantage of animal models over human research as well as the crucial complementary roles animal studies play vis‐à‐vis human imaging and genetic studies. Finally, we discuss recent developments in animal models of pain that should improve the relevance and translatability of findings using laboratory animals. We believe that pain research using animal models is a continuing necessity–to understand fundamental mechanisms, identify new analgesic targets, and inform, guide and follow up human studies–if novel analgesics are to be developed for the treatment of chronic pain.

Fibromyalgia pain and its modulation by hypnotic and non-hypnotic suggestion: an fMRI analysis.

The neuropsychological status of pain conditions such as fibromyalgia, commonly categorized as ‘psychosomatic’ or ‘functional’ disorders, remains controversial. Activation of brain structures dependent upon subjective alterations of fibromyalgia pain experience could provide an insight into the underlying neuropsychological processes. Suggestion following a hypnotic induction can readily modulate the subjective experience of pain. It is unclear whether suggestion without hypnosis is equally effective. To explore these and related questions, suggestions following a hypnotic induction and the same suggestions without a hypnotic induction were used during functional magnetic resonance imaging to increase and decrease the subjective experience of fibromyalgia pain. Suggestion in both conditions resulted in significant changes in reported pain experience, although patients claimed significantly more control over their pain and reported greater pain reduction when hypnotised. Activation of the midbrain, cerebellum, thalamus, and midcingulate, primary and secondary sensory, inferior parietal, insula and prefrontal cortices correlated with reported changes in pain with hypnotic and non‐hypnotic suggestion. These activations were of greater magnitude, however, when suggestions followed a hypnotic induction in the cerebellum, anterior midcingulate cortex, anterior and posterior insula and the inferior parietal cortex. Our results thus provide evidence for the greater efficacy of suggestion following a hypnotic induction. They also indicate direct involvement of a network of areas widely associated with the pain ‘neuromatrix’ in fibromyalgia pain experience. These findings extend beyond the general proposal of a neural network for pain by providing direct evidence that regions involved in pain experience are actively involved in the generation of fibromyalgia pain.

Pain sensation evoked by observing injury in others.

&NA; Observing someone else in pain produces a shared emotional experience that predominantly activates brain areas processing the emotional component of pain. Occasionally, however, sensory areas are also activated and there are anecdotal reports of people sharing both the somatic and emotional components of someone elses pain. Here we presented a series of images or short clips depicting noxious events to a large group of normal controls. Approximately one‐third of this sample reported an actual noxious somatic experience in response to one or more of the images or clips. Ten of these pain responders were subsequently recruited and matched with 10 non‐responders to take part in an fMRI study. The subjects were scanned while observing static images of noxious events. In contrast with emotional images not containing noxious events the responders activated emotional and sensory brain regions associated with pain while the non‐responders activated very little. These findings provide convincing evidence that some people can readily experience both the emotional and sensory components of pain during observation of others pain resulting in a shared physical pain experience.

Heightened Functional Neural Activation to Psychological Stress Covaries With Exaggerated Blood Pressure Reactivity

Individuals who show exaggerated blood pressure reactions to psychological stressors are at increased risk for hypertension, atherosclerosis, and stroke. We tested whether individuals who show exaggerated stressor-induced blood pressure reactivity also show heightened stressor-induced neural activation in brain areas involved in controlling the cardiovascular system. In a functional MRI study, 46 postmenopausal women (mean age: 68.04; SD: 1.35 years) performed a standardized Stroop color-word interference task that served as a stressor to increase blood pressure. Across individuals, a larger task-induced rise in blood pressure covaried with heightened and correlated patterns of activation in brain areas implicated previously in stress-related cardiovascular control: the perigenual and posterior cingulate cortex, bilateral prefrontal cortex, anterior insula, and cerebellum. Entered as a set in hierarchical regression analyses, activation values in these brain areas uniquely predicted the magnitude of task-induced changes in systolic (&Dgr;R2=0.54; P<0.001) and diastolic (&Dgr;R2=0.27; P<0.05) blood pressure after statistical control for task accuracy and subjective reports of task stress. Heightened stressor-induced activation of cingulate, prefrontal, insular, and cerebellar brain areas may represent a functional neural phenotype that characterizes individuals who are prone to show exaggerated cardiovascular reactivity.

The rebirth of neuroscience in psychosomatic medicine, Part II: clinical applications and implications for research.

During the second half of the last century, biopsychosocial research in psychosomatic medicine largely ignored the brain. Neuroscience has started to make a comeback in psychosomatic medicine research and promises to advance the field in important ways. In this paper we briefly review select brain imaging research findings in psychosomatic medicine in four key areas: cardiovascular regulation, visceral pain in the context of functional gastrointestinal disorders, acute and chronic somatic pain and placebo. In each area, there is a growing literature that is beginning to define a network of brain areas that participate in the functions in question. Evidence to date suggests that cortical and subcortical areas that are involved in emotion and emotion regulation play an important role in each domain. Neuroscientific research is therefore validating findings from previous psychosomatic research and has the potential to extend knowledge by delineating the biological mechanisms that link mind and body more completely and with greater specificity. We conclude with a discussion of the implications of this work for how research in psychosomatic medicine is conducted, the ways in which neuroscientific advances can lead to new clinical applications in psychosomatic contexts, the implications of this work for the field of medicine more generally, and the priorities for research in the next 5 to 10 years. ACC = anterior cingulate cortex; aMCC = anterior midcingulate cortex; CAD = coronary artery disease; CVD = cardiovascular diseases; DBS = deep brain stimulation; DLPFC = dorsolateral prefrontal cortex; ECG = electrocardiographic; FGID = functional gastrointestinal disorder; fMRI = functional magnetic resonance imaging; IBS = irritable bowel syndrome; MCC = midcingulate cortex; MEG = magnetoencephalography; MPFC = medial prefrontal cortex; NAC = nucleus accumbens; OFC = orbitofrontal (or orbital prefrontal) cortex; pACC = pregenual anterior cingulate cortex; PAG = periacqueductal gray; PET = positron emission tomography; PCC = posterior cingulate cortex; PI-IBS = post infectious irritable bowel syndrome; S1 = primary somatosensory cortex; S2 = secondary somatosensory cortex; sACC = subgenual anterior cingulate cortex; sTMS = slow transcranial magnetic stimulation; TMS = transcranial magnetic stimulation; VNS = vagus nerve stimulation.

Offset analgesia is mediated by activation in the region of the periaqueductal grey and rostral ventromedial medulla

Interrupting a continuous noxious heat by a greater noxious heat causes rapid and disproportionate pain reduction when the original noxious heat returns. This reduction in pain experience, known as offset analgesia, is believed to be the consequence of active descending inhibitory control of pain originating in the periaqueductal grey (PAG) and rostral ventromedial medulla (RVM). To test this possibility, brain activation was measured using fMRI in twelve healthy controls during an offset procedure. Each subject experienced six second periods of noxious heat followed by an equal period of more intense heat before returning to the original temperature for a further 6 s. Subjects were also scanned during control trials involving continuous, unchanging, noxious heat for 18 s or involving 6 s of noxious heat followed by an equal period of more intense heat before returning to the non-noxious baseline for a further 6 s. Brain activation during the final 6 s of each trial was compared with activation during the first 6 s and this difference was contrasted across trials. PAG/RVM activation was observed during the final 6 s of offset trials but not during either of the control trials and this difference across trials was significant. Activation throughout the pain neuromatrix was inhibited during the final 6 s of the offset trials and was comparable to the activation observed when the heat returned to a non-noxious baseline. These findings provide strong evidence that offset analgesia engages an endogenous inhibitory mechanism originating in the PAG/RVM region, which inhibits pain experience and activation of the pain neuromatrix.

Blunted cardiac stress reactivity relates to neural hypoactivation

The present study compared neural activity in participants with blunted (N = 9) or exaggerated (N = 8) cardiac stress reactions. Neural activity was recorded with fMRI while participants performed a validated stress task and control task. Exaggerated reactors exhibited significant increases in heart rate from control to stress task, whereas blunted reactors had no change in heart rate. Blunted reactors also had reduced activation in the anterior midcingulate cortex and insula compared to exaggerated reactors during the stress condition, and a greater deactivation in the amygdala and posterior cingulate. The biological differences between groups in response to the stress task could not be explained by subjective measures of engagement, stressfulness, or difficulty. This study supports the notion that blunted peripheral physiological stress reactivity may be a marker of a corresponding under-recruitment of brain systems during behavioral states requiring motivated action.

Increased bias to report heat or pain following emotional priming of pain-related fear.

&NA; Emotional and attentional factors have been identified to play a significant role in modulating pain perception with negative emotions increasing pain sensitivity. Recent studies suggest that fearful images may activate the attentional components of fear driven behaviours and facilitate an attentional bias or sensitivity toward noxious stimuli. The current investigation examines whether priming of pain‐related fear will affect performance by increasing sensitivity to punctuate heat stimuli. A modified version of the visual dot probe task was employed to provide priming of pain‐related fear and a heat detection task was used to measure the effects of priming on sensitivity. The results indicated a significant facilitation of heat and pain perception at varying temperatures following emotional priming. In particular, there was an increase in the bias toward reporting a heat stimulus following emotional priming. The findings emphasise the efficacy of the visual dot probe task as a method of priming and provide a possible method for probing hypervigilance in chronic pain patients.

Intrinsic variability in the human response to pain is assembled from multiple, dynamic brain processes

The stimulus-evoked response is the principle measure used to elucidate the timing and spatial location of human brain activity. Brain and behavioural responses to pain are influenced by multiple intrinsic and extrinsic factors and display considerable, natural trial-by-trial variability. However, because the neuronal sources of this variability are poorly understood the functional information it contains is under-exploited for understanding the relationship between brain function and behaviour. We recorded simultaneous EEG-fMRI during rest and noxious thermal stimulation to characterise the relationship between natural fluctuations in behavioural pain-ratings, the spatiotemporal dynamics of brain network responses and intrinsic connectivity. We demonstrate that fMRI response variability in the pain network is: dependent upon its resting-state functional connectivity; modulated by behaviour; and correlated with EEG evoked-potential amplitude. The pre-stimulus default-mode network (DMN) fMRI signal predicts the subsequent magnitude of pain ratings, evoked-potentials and pain network BOLD responses. Additionally, the power of the ongoing EEG alpha oscillation, an index of cortical excitability, modulates the DMN fMRI response to pain. The complex interaction between alpha-power, DMN activity and both the behavioural report of pain and the brains response to pain demonstrates the neurobiological significance of trial-by-trial variability. Furthermore, we show that multiple, interconnected factors contribute to both the brains response to stimulation and the psychophysiological emergence of the subjective experience of pain.