Anthony K.P. Jones

Pain processing during three levels of noxious stimulation produces differential patterns of central activity

&NA; Previous functional imaging studies have demonstrated a number of discrete brain structures that increase activity with noxious stimulation. Of the commonly identified central structures, only the anterior cingulate cortex shows a consistent response during the experience of pain. The insula and thalamus demonstrate reasonable consistency while all other regions, including the lentiform nucleus, somatosensory cortex and prefrontal cortex, are active in no more than half the current studies. The reason for such discrepancy is likely to be due in part to methodological variability and in part to individual variability. One aspect of the methodology which is likely to contribute is the stimulus intensity. Studies vary considerably regarding the intensity of the noxious and non‐noxious stimuli delivered. This is likely to produce varying activation of central structures coding for the intensity, affective and cognitive components of pain. Using twelve healthy volunteers and positron emission tomography (PET), the regional cerebral blood flow (rCBF) responses to four intensities of stimulation were recorded. The stimulation was delivered by a CO2 laser and was described subjectively as either warm (not painful), pain threshold (just painful), mildly painful or moderately painful. The following group subtractions were made to examine the changing cerebral responses as the stimulus intensity increased: (1) just painful − warm; (2) mild pain − warm; and (3) moderate pain − warm. In addition, rCBF changes were correlated with the subjective stimulus ratings. The results for comparison ‘1’ indicated activity in the contralateral prefrontal (area 10/46/44), bilateral inferior parietal (area 40) and ipsilateral premotor cortices (area 6), possibly reflecting initial orientation and plans for movement. The latter comparisons and correlation analysis indicated a wide range of active regions including bilateral prefrontal, inferior parietal and premotor cortices and thalamic responses, contralateral hippocampus, insula and primary somatosensory cortex and ipsilateral perigenual cingulate cortex (area 24) and medial frontal cortex (area 32). Decreased rCBF was observed in the amygdala region. These responses were interpreted with respect to their contribution to the multidimensional aspects of pain including fear avoidance, affect, sensation and motivation or motor initiation. It is suggested that future studies examine the precise roles of each particular region during the central processing of pain.

Temporal difference models describe higher-order learning in humans

The ability to use environmental stimuli to predict impending harm is critical for survival. Such predictions should be available as early as they are reliable. In pavlovian conditioning, chains of successively earlier predictors are studied in terms of higher-order relationships, and have inspired computational theories such as temporal difference learning. However, there is at present no adequate neurobiological account of how this learning occurs. Here, in a functional magnetic resonance imaging (fMRI) study of higher-order aversive conditioning, we describe a key computational strategy that humans use to learn predictions about pain. We show that neural activity in the ventral striatum and the anterior insula displays a marked correspondence to the signals for sequential learning predicted by temporal difference models. This result reveals a flexible aversive learning process ideally suited to the changing and uncertain nature of real-world environments. Taken with existing data on reward learning, our results suggest a critical role for the ventral striatum in integrating complex appetitive and aversive predictions to coordinate behaviour.

Identification of human brain loci processing esophageal sensation using positron emission tomography

BACKGROUND & AIMS Brain loci that process human esophageal sensation remain unidentified. The aim of this study was to identify the brain loci that process nonpainful and painful human esophageal sensation. METHODS In 8 healthy subjects (7 men; age range, 24-47 years), distal esophageal stimulation was performed by repeatedly inflating a balloon at volumes that produced either no sensation, definite sensation, or pain. Two positron emission tomography scans were performed for each sensation using H2(15)O. Magnetic resonance brain scans were also performed in each subject, and the positron emission tomography data were coregistered with magnetic resonance scans. Analysis of covariance-corrected t images showing the contrasts definite sensation-baseline, pain-baseline, and pain-definite sensation were created. RESULTS Nonpainful stimulation elicited bilateral activations along the central sulcus, insular cortex, and frontal/parietal operculum (P < 0.01). Painful stimulation produced more intense activations of the same areas and additional activation of the right anterior insular cortex and the anterior cingulate gyrus. Multiple areas of decreased activation were also observed; prominent among these was the right prefrontal cortex, which was inhibited during both nonpainful and painful stimulation. CONCLUSIONS Esophageal sensation activates bilaterally the insula, primary somatosensory cortex, and operculum. The right anterior insular cortex and anterior cingulate gyrus process esophageal pain.

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

Abstract 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.

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 CO2 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.

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

&NA; 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 15O. Significantly increased rCBF responses to tonic noxious stimulation compared with non‐noxious stimulation were observed bilaterally in the anterior cingulate (Brodmanns 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.

Poststroke shoulder pain: a prospective study of the association and risk factors in 152 patients from a consecutive cohort of 205 patients presenting with stroke

BACKGROUND AND PURPOSE Shoulder pain is known to retard rehabilitation after stroke. Its causes and prognosis are uncertain. This study describes the incidence of poststroke shoulder pain prospectively, in an unselected stroke population in the first 6 months after stroke and identifies risk factors for developing pain.

Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception

ABSTRACT The neural mechanisms whereby placebo conditioning leads to placebo analgesia remain unclear. In this study we aimed to identify the brain structures activated during placebo conditioning and subsequent placebo analgesia. We induced placebo analgesia by associating a sham treatment with pain reduction and used fMRI to measure brain activity associated with three stages of the placebo response: before, during and after the sham treatment, while participants anticipated and experienced brief laser pain. In the control session participants were explicitly told that the treatment was inactive. The sham treatment group reported a significant reduction in pain rating (p = 0.012). Anticipatory brain activity was modulated during placebo conditioning in a fronto‐cingulate network involving the left dorsolateral prefrontal cortex (DLPFC), medial frontal cortex and the anterior mid‐cingulate cortex (aMCC). Identical areas were modulated during anticipation in the placebo analgesia phase with the addition of the orbitofrontal cortex (OFC). However, during altered pain experience only aMCC, post‐central gyrus and posterior cingulate demonstrated altered activity. The common frontal cortical areas modulated during anticipation in both the placebo conditioning and placebo analgesia phases have previously been implicated in placebo analgesia. Our results suggest that the main effect of placebo arises from the reduction of anticipation of pain during placebo conditioning that is subsequently maintained during placebo analgesia.

Cerebral decreases in opioid receptor binding in patients with central neuropathic pain measured by [11C]diprenorphine binding and PET

Central neuropathic pain (CNP) is pain resulting from damage to the central nervous system. Up till now, it has not been possible to identify a common lesion or pharmacological deficit in these patients. This preliminary study in a group of patients with CNP with predominantly post‐stroke pain, demonstrates that there is significantly less opioid receptor binding in a number of cortical and sub‐cortical structures that are mostly, but not exclusively, within the medial pain system in patients compared to age‐matched pain‐free controls. The reductions in opioid receptor binding within the medial system were observed mainly in the dorsolateral (Brodman area 10) and anterior cingulate (Brodman area 24 with some extension into area 23) and insula cortices and the thalamus. There were also reductions in the lateral pain system within the inferior parietal cortex (Brodman area 40). These changes in binding could not be accounted for by the cerebral lesions shown by CT or MRI, which were outside the areas of reduced binding and the human pain system. To our knowledge this is the first systematic demonstration of a reduction in opioid receptor‐binding capacity in neurones within the human nociceptive system in patients with CNP. This may be a key common factor resulting in undamped nociceptor activity within some of the structures that are predominantly within the medial nociceptive system. If confirmed, these findings may explain why certain patients with CNP require high doses of synthetic opiates to achieve optimum analgesia. The findings also raise the possibility of new pharmacological approaches to treatment.

Modulation of pain ratings by expectation and uncertainty: Behavioral characteristics and anticipatory neural correlates.

&NA; Expectations about the magnitude of impending pain exert a substantial effect on subsequent perception. However, the neural mechanisms that underlie the predictive processes that modulate pain are poorly understood. In a combined behavioral and high‐density electrophysiological study we measured anticipatory neural responses to heat stimuli to determine how predictions of pain intensity, and certainty about those predictions, modulate brain activity and subjective pain ratings. Prior to receiving randomized laser heat stimuli at different intensities (low, medium or high) subjects (n = 15) viewed cues that either accurately informed them of forthcoming intensity (certain expectation) or not (uncertain expectation). Pain ratings were biased towards prior expectations of either high or low intensity. Anticipatory neural responses increased with expectations of painful vs. non‐painful heat intensity, suggesting the presence of neural responses that represent predicted heat stimulus intensity. These anticipatory responses also correlated with the amplitude of the Laser‐Evoked Potential (LEP) response to painful stimuli when the intensity was predictable. Source analysis (LORETA) revealed that uncertainty about expected heat intensity involves an anticipatory cortical network commonly associated with attention (left dorsolateral prefrontal, posterior cingulate and bilateral inferior parietal cortices). Relative certainty, however, involves cortical areas previously associated with semantic and prospective memory (left inferior frontal and inferior temporal cortex, and right anterior prefrontal cortex). This suggests that biasing of pain reports and LEPs by expectation involves temporally precise activity in specific cortical networks.