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.

Enhancement of offset analgesia during sequential testing.

Interruption of a continuous noxious heat by a relatively greater noxious heat evokes reductions in pain experience when the original noxious heat returns. The reduction is greater than that evoked by continuous delivery of noxious heat. This disproportionate reduction in pain experience, known as offset analgesia, is presumably mediated by a mechanism different to adaptation or habituation. Reduction in pain experience to an equivalent noxious stimulus, however, has also been demonstrated when applying the same stimulus over a number of days. This reduction due to repeated days of stimulation is known as attenuation. In order to distinguish further the mechanisms of offset analgesia and attenuation we applied noxious heat resulting in an experience of low, medium or high pain to the volar forearm of 16 subjects comparing pain intensity ratings for increases and decreases in temperature, repeated over 3 days. Offset analgesia was consistently demonstrated but the effects of attenuation were more complex. There was no attenuation effect for the unchanging stimuli delivered across the 3 days of testing but attenuation effects enhanced the offset analgesia resulting in a larger offset analgesia effect on days 2 and 3. It is possible that offset analgesia and attenuation are mediated by inter-related mechanisms. Further studies might investigate whether offset analgesia involves inhibitory structures such as the PAG-RVM.

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

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.

Attention to pain localization and unpleasantness discriminates the functions of the medial and lateral pain systems.

Functional imaging studies have identified a matrix of structures in the brain that respond to noxious stimuli. Within this matrix, a division of function between sensory-discriminative and affective responses has so far been demonstrated by manipulating either pain intensity or unpleasantness under hypnosis in two different normal volunteer groups studied on separate occasions. Our study used positron emission tomography (PET) to demonstrate this division of function under more natural conditions in a healthy group of volunteers, using a CO(2) laser to provide nociceptive stimuli that selectively activate A-delta and C-fibres without contamination by touch sensations. We measured the differential cerebral responses to noxious and innocuous laser stimuli during conditions of selective attention to either the unpleasantness or location of the stimuli. Attention to location increased responses in the contralateral (right) primary somatosensory and inferior parietal cortices. This result implies that these components of the lateral pain system are concerned mainly with the localization of pain. In contrast, attention to unpleasantness increased responses in bilateral perigenual cingulate and orbitofrontal cortices, contralateral (right) amygdala, ipsilateral (left) hypothalamus, posterior insula, M1 and frontal pole. These areas comprise key components of the medial pain and neuroendocrine systems and the results suggest that they have a role in the affective response to pain. Our results indicate the importance of attentional effects on the pattern of nociceptive processing in the brain. They also provide the first clear demonstration, within a single experiment, of a major division of function within the neural pain matrix.

Pain mechanisms and their disorders.

The purpose of this article is to summarise how functional imaging techniques have changed our understanding of normal and abnormal pain mechanisms, how they inform a change in clinical practice and to speculate on possible future clinical uses.

The effect of the 5-HT3 receptor antagonist, alosetron, on brain responses to visceral stimulation in irritable bowel syndrome patients.

AIM: To conduct a placebo-controlled functional brain imaging study to assess the effect of the 5-hydroxytryptamine-3 receptor antagonist, alosetron, on irritable bowel syndrome symptoms, regional brain activation by rectosigmoid distension and associated perceptual and emotional responses. METHODS: Fifty-two non-constipated irritable bowel syndrome patients (28 female) were enrolled in a randomized, placebo-controlled trial with alosetron (1-4 mg b.d.). Thirty-seven patients completed both brain scans following randomization. Rectosigmoid stimulation was performed with a computer-controlled barostat. Changes in regional cerebral blood flow were assessed using H215O positron emission tomography. Stimulus ratings and changes in gastrointestinal symptoms were assessed using verbal descriptor scales. RESULTS: Alosetron, but not placebo, treatment was associated with a decrease in symptom ratings, and reductions in emotional stimulus ratings. Compared to baseline, alosetron treatment was associated with reduced regional cerebral blood flow in bilateral frontotemporal and various limbic structures, including the amygdala. Compared to placebo, decreases in activity of the amygdala, ventral striatum, hypothalamus and infragenual cingulate gyrus were significantly greater after alosetron. CONCLUSIONS: In non-constipated irritable bowel syndrome patients, 3 weeks of treatment with a 5-hydroxytryptamine-3 receptor antagonist decreases brain activity in response to unanticipated, anticipated and delivered aversive rectal stimuli in structures of the emotional motor system, and this is associated with a decrease in gastrointestinal symptoms.

Cerebral responses to noxious thermal stimulation in chronic low back pain patients and normal controls.

Changes in regional cerebral blood flow (rCBF) have previously been demonstrated in a number of cortical and subcortical regions, including the cerebellum, midbrain, thalamus, lentiform nucleus, and the insula, prefrontal, anterior cingulate, and parietal cortices, in response to experimental noxious stimuli. Increased anterior cingulate responses in patients with chronic regional pain and depression to noxious stimulation distant from the site of clinical pain have been observed. We suggested that this may represent a generalized hyperattentional response to noxious stimuli and may apply to other types of chronic regional pain. Here these techniques are extended to a group of patients with nonspecific chronic low back pain. Thirty-two subjects, 16 chronic low back pain patients and 16 controls, were studied using positron emission tomography. Thermal stimuli, corresponding to the experience of hot, mild, and moderate pain, were delivered to the back of the subject's right hand using a thermal probe. Each subject had 12 measurements of rCBF, 4 for each stimulus. Correlation of rCBF with subjective pain experience revealed similar responses across groups in the cerebellum, midbrain (including the PAG), thalamus, insula, lentiform nucleus, and midcingulate (area 24') cortex. These regions represented the majority of activations for this study and those recorded by other imaging studies of pain. Although some small differences were observed between the groups these were not considered sufficient to suggest abnormal nociceptive processing in patients with nonspecific low back pain.

Fetal pain: an infantile debate.

The question of whether a fetus can experience pain is an immense challenge. The issue demands consideration of the physical and psychological basis of being and the relation between the two. At the center of this debate is the question of how it is that we are conscious, a question that has inspired the writing of some of our most brilliant contemporary philosophers and scientists, with one commentary suggesting surrender. In my earlier review I attempted to draw together the various strands of thinking that had attacked the question of fetal pain and relate them back to the bigger question of consciousness. In their vituperative response, Benatar and Benatar bite off my finger before looking to where I am pointing. I will examine each of their criticisms.

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 H2(15)O-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.

Exploring the pain "neuromatrix".

A considerable number of functional imaging studies have demonstrated the involvement of multiple central regions during the experience of pain. These regions process information in circuits that can broadly be assumed to process the affective, sensory, cognitive, motor, inhibitory, and autonomic responses stimulated by a noxious event. The concept of a "neuromatrix" for pain processing is, therefore, well supported. There is, however, scant evidence for any particular regional or circuit dysfunction during clinical pain. To be clinically useful, functional imaging may have to step beyond the generalities of the neuromatrix.

Cerebral responses to a continual tonic pain stimulus measured using positron emission tomography.

We have previously demonstrated the localised positron emission tomographic cerebral correlates of the experience of painful phasic heat in the normal human brain. In this study we examine whether these responses are different using a continuous, tonic heat stimulus. The regional cerebral responses to non-painful and painful thermal stimuli in 12 male subjects were studied by monitoring serial measurements of regional cerebral blood flow (rCBF) with positron emission tomography (PET) using H2(15)O. Significantly increased rCBF responses to tonic noxious stimulation compared with non-noxious stimulation were observed bilaterally in the anterior cingulate (Brodmann's area (BA) 24) cortex. Contralateral responses were observed in the lentiform nucleus and posterior insula cortex and ipsilateral responses were observed in the thalamus, cerebellum, prefrontal (BA 10) cortex and anterior insula cortex. These findings demonstrate general agreement between the main areas of cerebral activation during both phasic and tonic pain.

Experiences with functional magnetic resonance imaging at 1 tesla.

Functional magnetic resonance imaging (fMRI) has been performed on a standard 1 T system using a pulse sequence developed to utilize blood oxygen level dependent (BOLD) contrast and an off-line analysis routine using correlation techniques. The sequence and the data analysis routine have been validated by reproducing the conventional hand movement paradigm studies reported by numerous other workers. Our work has then been extended to investigate cerebral foci for a tonic pain stimulus and the cortical representation of oesophageal stimulation. Both these studies relate to paradigms where the expected BOLD signal is significantly less than that encountered for motor or visual cortex paradigms. The results show good agreement with other modalities (positron emission tomography, magnetoencephalography and cortical evoked potentials). Performing fMRI at 1 T is slightly controversial. However, our successful study of demanding paradigms, using a standard clinical 1 T imaging system, has important implications for many other users operating at this field strength.

Pain and Stroop interference tasks activate separate processing modules in anterior cingulate cortex.

Investigations of pain using functional imaging techniques have revealed an extensive central network associated with nociception. This network includes the thalamus, insula, prefrontal cortex and anterior cingulate cortex (ACC) as well as the somatosensory cortices. Positron emission tomography (PET) of regional cerebral blood flow (rCBF) has demonstrated activation of the ACC during cognitively challenging tasks such as the Stroop interference task and divided attention. One interpretation of this research is that ACC is involved in the general features of attention and that it does not play a specific role in pain processing per se. Three-dimensional PET imaging provides a method for assessments of rCBF in a single individual during multiple tasks. In addition, coregistration of PET and magnetic resonance (MR) images allows for better localisation of the PET signals so that differences in cortical activation sites can be more accurately determined. This approach was used to assess rCBF during the experience of pain by subtracting images collected during heat from those during noxious heat stimulation. Two regions of the ACC had elevated rCBF, one in the perigenual region and one in the mid-rostrocaudal region (i.e. midcingulate cortex). During the execution of the Stroop task, the group result showed the midcingulate region overlapping with the site seen during the experience of pain. This group result, however, was not confirmed in the individual subject analysis, which revealed widespread and independent areas of ACC response to pain and Stroop. It is concluded that the ACC contributes to multiple cognitive procedures. It is inadequate to describe the primary contribution of ACC to pain processing as "attention" because it is unlikely that the multiple small and independent activation sites produced by pain and Stroop subserve attentive processing throughout the brain.

Reduced cortical responses to noxious heat in patients with rheumatoid arthritis.

OBJECTIVES: To test the hypothesis that patients with chronic inflammatory pain develop adaptive cortical responses to noxious stimulation characterised by reduced anterior cingulate responses. METHODS: Positron emission tomography was used to measure changes in regional cerebral blood flow (rCBF) in response to an acute experimental pain stimulus in six patients with rheumatoid arthritis (RA) in comparison to six age and sex matched controls. A standardised and reproducible non-painful and painful phasic heat stimulus was delivered by a thermal probe to the back of the right hand during six two minute periods during which time rCBF measurements were made. The effects of non-painful heat were subtracted from those of painful heat to weight the analysis towards the non-discriminatory or 'suffering' components of pain processing. Significance maps of pain processing were generated and compared in each group and contrasted with results obtained in a group of patients with atypical facial pain (AFP) that have been previously published. RESULTS: The RA patients showed remarkably damped cortical and subcortical responses to pain compared with the control group. Significant differences between the two groups were observed in the prefrontal (BA 10) and anterior cingulate (BA 24) and cingulofrontal transition cortical (BA 32) areas. The reduced anterior cingulate responses to standardised heat pain were compared with the increased cingulate responses seen in patients with psychogenically maintained pain (AFP) who had both lower pain tolerance and mood than the RA group. CONCLUSIONS: Major cortical adaptive responses to standardised noxious heat can be measured and contrasted in patients with different types of chronic pain. The different pattern of cingulate and frontal cortical responses in the patients with inflammatory and non-nociceptive pain suggest that different mechanisms are operating, possibly at a thalamocortical level. Implications for treatment strategies for chronic pain are discussed.