Predrag Petrovic

Pain-related cerebral activation is altered by a distracting cognitive task

Abstract It has previously been suggested that the activity in sensory regions of the brain can be modulated by attentional mechanisms during parallel cognitive processing. To investigate whether such attention‐related modulations are present in the processing of pain, the regional cerebral blood flow was measured using [15O]butanol and positron emission tomography in conditions involving both pain and parallel cognitive demands. The painful stimulus consisted of the standard cold pressor test and the cognitive task was a computerised perceptual maze test. The activations during the maze test reproduced findings in previous studies of the same cognitive task. The cold pressor test evoked significant activity in the contralateral S1, and bilaterally in the somatosensory association areas (including S2), the ACC and the mid‐insula. The activity in the somatosensory association areas and periaqueductal gray/midbrain were significantly modified, i.e. relatively decreased, when the subjects also were performing the maze task. The altered activity was accompanied with significantly lower ratings of pain during the cognitive task. In contrast, lateral orbitofrontal regions showed a relative increase of activity during pain combined with the maze task as compared to only pain, which suggests the possibility of the involvement of frontal cortex in modulation of regions processing pain.

Imaging cognitive modulation of pain processing.

The intensity and unpleasantness of a painful experience is often described as correlating well with the degree of noxious stimulation. However, the perception of pain is not a linear phenomenon, reflecting the signal from the peripheral neuron. Rather, the noxious input may be modulated at every level of the neural axis. One of the most potent sources of modulation is the brain—although these mechanisms have only sparsely been studied. The supraspinal modulatory influences involve both lower order automatic response schemata and higher order dynamic cognitive mechanisms. This organizational pattern has developed as an evolutionary driven adaptation, in which both fast hardwired responses and slower dynamic responses increased the chance for survival. In line with this hypothesis, it has been suggested that the brain is initially processing noxious input in the brainstem supporting the demand for a fast response (Petrovic et al., 2000a; Price, 2000). Apart from autonomic changes and a wide range of defense reactions, the brainstem may induce powerful analgesia in direct response to noxious stimuli (Fanselow, 1994). At a higher level, cognitive processes may dramatically modulate the perception of pain (Melzack and Casey, 1968; Weisenberg et al., 1996). Recently, functional imaging tools, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), have described some of the possible underlying mechanisms that are involved in cognitive modulation of pain perception. Several functional imaging studies have indicated that pain processing may be modulated by cognitive mechanisms (Bantick et al., 2001; Longe et al., 2001; Petrovic et al., 2001a,b; Rainville et al., 1997, 1999; Willoch et al., 2000). Rainville and colleagues used hypnotic suggestion to modulate the perception of unpleasantness during noxious stimulation. When the subjects were suggested to perceive the noxious stimulation as highly unpleasant there was a concomitant increase in the activity in the anterior cingulate cortex (ACC) significantly more than when the subjects were suggested to perceive the same stimulation as less unpleasant (Rainville et al., 1997). However, the activity in the somatosensory areas was unaltered. Since lesion studies and animal studies have indicated that the ACC is involved in processing pain unpleasantness (Vogt et al., 1993) this finding indicates that cognitive mechanisms may specifically modulate sub-systems of the pain network. We used a different but classical approach in order to show that pain networks may be modulated by cognitive demands (Petrovic et al., 2000b). Most people have probably experienced that pain perception can decrease and even disappear when actively engaging the mind in a distracting task. We tested this mechanism by involving the subjects in a highly attention demanding task (computerized perceptual maze test) during noxious stimulation. We were able to show that when subjects solved the maze task and we induced a painful stimulation they perceived less pain as compared with when there was no competition for attentional space. At a neural level, activity was significantly attenuated in somatosensory regions and the PAG in this condition. Recently, it has been shown that cognitive distraction also may attenuate the pain-evoked activity in the ACC, the insula and the thalamus (Bantick et al., 2001; Longe et al., 2001). One intriguing study has demonstrated the opposite cognitive modulation in which the pain network was activated without any noxious stimulation being given (Willoch et al., 2000). In this study, painful perception was induced in patients with phantom-limb pain using hypnotic suggestion that the missing limb was in a painful position. All the regions discussed above are involved in pain processing, and modulation in their activity coincides with the changes in a pain perception. Apart from attention dependent changes in the network processing the perception, another distinct set of structures may act as sources for Pain 95 (2002) 1–5

From Threat to Fear: The Neural Organization of Defensive Fear Systems in Humans

Postencounter and circa-strike defensive contexts represent two adaptive responses to potential and imminent danger. In the context of a predator, the postencounter reflects the initial detection of the potential threat, whereas the circa-strike is associated with direct predatory attack. We used functional magnetic resonance imaging to investigate the neural organization of anticipation and avoidance of artificial predators with high or low probability of capturing the subject across analogous postencounter and circa-strike contexts of threat. Consistent with defense systems models, postencounter threat elicited activity in forebrain areas, including subgenual anterior cingulate cortex (sgACC), hippocampus, and amygdala. Conversely, active avoidance during circa-strike threat increased activity in mid-dorsal ACC and midbrain areas. During the circa-strike condition, subjects showed increased coupling between the midbrain and mid-dorsal ACC and decreased coupling with the sgACC, amygdala, and hippocampus. Greater activity was observed in the right pregenual ACC for high compared with low probability of capture during circa-strike threat. This region showed decreased coupling with the amygdala, insula, and ventromedial prefrontal cortex. Finally, we found that locomotor errors correlated with subjective reports of panic for the high compared with low probability of capture during the circa-strike threat, and these panic-related locomotor errors were correlated with midbrain activity. These findings support models suggesting that higher forebrain areas are involved in early-threat responses, including the assignment and control of fear, whereas imminent danger results in fast, likely “hard-wired,” defensive reactions mediated by the midbrain.

Effects of oxytocin and prosocial behavior on brain responses to direct and vicariously experienced pain.

In this study, we tested the validity of 2 popular assumptions about empathy: (a) empathy can be enhanced by oxytocin, a neuropeptide known to be crucial in affiliative behavior, and (b) individual differences in prosocial behavior are positively associated with empathic brain responses. To do so, we measured brain activity in a double-blind placebo-controlled study of 20 male participants either receiving painful stimulation to their own hand (self condition) or observing their female partner receiving painful stimulation to her hand (other condition). Prosocial behavior was measured using a monetary economic interaction game with which participants classified as prosocial (N = 12) or selfish (N = 6), depending on whether they cooperated with another player. Empathy-relevant brain activation (anterior insula) was neither enhanced by oxytocin nor positively associated with prosocial behavior. However, oxytocin reduced amygdala activation when participants received painful stimulation themselves (in the nonsocial condition). Surprisingly, this effect was driven by “selfish” participants. The results suggest that selfish individuals may not be as rational and unemotional as usually suggested, their actions being determined by their feeling anxious rather than by reason.

Tickling Expectations: Neural Processing in Anticipation of a Sensory Stimulus

Predictions of the near future can optimize the accuracy and speed of sensory processing as well as of behavioral responses. Previous experience and contextual cues are essential elements in the generation of a subjective prediction. Using a blocked fMRI paradigm, we investigated the pattern of neural activation in anticipation of a sensory stimulus and during the processing of the somatosensory stimulus itself. Tickling was chosen as the somatosensory stimulus rather than simple touch in order to increase the probability to get a high degree of anticipation. The location and nature of the stimulus were well defined to the subject. The state of anticipation was initiated by attributing an uncertainty regarding the time of stimulus onset. The network of activation and deactivation during anticipation of the expected stimulus was similar to that engaged during the actual sensory stimulation. The areas that were activated during both states included the contralateral primary sensory cortex, bilateral areas in the inferior parietal lobules, the putative area SII, the right anterior cingulate cortex and areas in the right prefrontal cortex. Similarly, common decreases were observed in areas of sensorimotor cortex located outside the area representing the target of stimulus, i.e., areas that process information which is irrelevant to the attended process. The overlapping pattern of change, during the somatosensory stimulation and the anticipation, furthers the idea that predictions are subserved by a neuronal network similar to that which subserves the processing of actual sensory input. Moreover, this study indicates that activation of primary somatosensory cortex can be obtained without intra-modal sensory input. These findings suggest that anticipation may invoke a tonic top-down regulation of neural activity.

A PET activation study of dynamic mechanical allodynia in patients with mononeuropathy

The objective of this study was to investigate the central processing of dynamic mechanical allodynia in patients with mononeuropathy. Regional cerebral blood flow, as an indicator of neuronal activity, was measured with positron emission tomography. Paired comparisons were made between three different states; rest, allodynia during brushing the painful skin area, and brushing of the homologous contralateral area. Bilateral activations were observed in the primary somatosensory cortex (S1) and the secondary somatosensory cortex (S2) during allodynia compared to rest. The S1 activation contralateral to the site of the stimulus was more expressed during allodynia than during innocuous touch. Significant activations of the contralateral posterior parietal cortex, the periaqueductal gray (PAG), the thalamus bilaterally and motor areas were also observed in the allodynic state compared to both non-allodynic states. In the anterior cingulate cortex (ACC) there was only a suggested activation when the allodynic state was compared with the non-allodynic states. In order to account for the individual variability in the intensity of allodynia and ongoing spontaneous pain, rCBF was regressed on the individually reported pain intensity, and significant covariations were observed in the ACC and the right anterior insula. Significantly decreased regional blood flow was observed bilaterally in the medial and lateral temporal lobe as well as in the occipital and posterior cingulate cortices when the allodynic state was compared to the non-painful conditions. This finding is consistent with previous studies suggesting attentional modulation and a central coping strategy for known and expected painful stimuli. Involvement of the medial pain system has previously been reported in patients with mononeuropathy during ongoing spontaneous pain. This study reveals a bilateral activation of the lateral pain system as well as involvement of the medial pain system during dynamic mechanical allodynia in patients with mononeuropathy.

How the number of learning trials affects placebo and nocebo responses

&NA; Conditioning procedures are used in many placebo studies because evidence suggests that conditioning‐related placebo responses are usually more robust than those induced by verbal suggestions alone. However, it has not been shown whether there is a causal relation between the number of conditioning trials and the resistance to extinction of placebo and nocebo responses. Here we test the effects of either one or four sessions of conditioning on the modulation of both non‐painful and painful stimuli delivered to the dorsum of the foot. Placebo and nocebo manipulations were obtained by pairing green or red light to a series of stimuli that were made lower or higher with respect to a yellow light associated with a series of control stimuli. Subjects were told that the lights would indicate a treatment that would reduce or increase non‐painful and painful stimuli to the foot. They were randomly assigned to either Group 1 or 2. Group 1 underwent one session of conditioning and Group 2 received four sessions of conditioning. We found that one session of conditioning (Group 1) induced nocebo responses, but not placebo responses in no pain condition. After one session of conditioning, we observed both nocebo and placebo responses to painful stimulation. However, these effects extinguished over time. Conversely, four sessions of conditioning (Group 2) induced robust placebo and nocebo responses to both non‐painful and painful stimuli that persisted over the entire experiment. These findings suggest that the strength of learning may be clinically important for producing long‐lasting placebo effects.

Predictability modulates the affective and sensory-discriminative neural processing of pain

Knowing what is going to happen next, that is, the capacity to predict upcoming events, modulates the extent to which aversive stimuli induce stress and anxiety. We explored this issue by manipulating the temporal predictability of aversive events by means of a visual cue, which was either correlated or uncorrelated with pain stimuli (electric shocks). Subjects reported lower levels of anxiety, negative valence and pain intensity when shocks were predictable. In addition to attenuate focus on danger, predictability allows for correct temporal estimation of, and selective attention to, the sensory input. With functional magnetic resonance imaging, we found that predictability was related to enhanced activity in relevant sensory-discriminative processing areas, such as the primary and secondary sensory cortex and posterior insula. In contrast, the unpredictable more aversive context was correlated to brain activity in the anterior insula and the orbitofrontal cortex, areas associated with affective pain processing. This context also prompted increased activity in the posterior parietal cortex and lateral prefrontal cortex that we attribute to enhanced alertness and sustained attention during unpredictability.

A prefrontal non-opioid mechanism in placebo analgesia

&NA; Behavioral studies have suggested that placebo analgesia is partly mediated by the endogenous opioid system. Expanding on these results we have shown that the opioid‐receptor‐rich rostral anterior cingulate cortex (rACC) is activated in both placebo and opioid analgesia. However, there are also differences between the two treatments. While opioids have direct pharmacological effects, acting on the descending pain inhibitory system, placebo analgesia depends on neocortical top‐down mechanisms. An important difference may be that expectations are met to a lesser extent in placebo treatment as compared with a specific treatment, yielding a larger error signal. As these processes previously have been shown to influence other types of perceptual experiences, we hypothesized that they also may drive placebo analgesia. Imaging studies suggest that lateral orbitofrontal cortex (lObfc) and ventrolateral prefrontal cortex (vlPFC) are involved in processing expectation and error signals. We re‐analyzed two independent functional imaging experiments related to placebo analgesia and emotional placebo to probe for a differential processing in these regions during placebo treatment vs. opioid treatment and to test if this activity is associated with the placebo response. In the first dataset lObfc and vlPFC showed an enhanced activation in placebo analgesia vs. opioid analgesia. Furthermore, the rACC activity co‐varied with the prefrontal regions in the placebo condition specifically. A similar correlation between rACC and vlPFC was reproduced in another dataset involving emotional placebo and correlated with the degree of the placebo effect. Our results thus support that placebo is different from specific treatment with a prefrontal top‐down influence on rACC.

Context-dependent Deactivation of the Amygdala during Pain

The amygdala has been implicated in fundamental functions for the survival of the organism, such as fear and pain. In accord with this, several studies have shown increased amygdala activity during fear conditioning and the processing of fear-relevant material in human subjects. In contrast, functional neuroimaging studies of pain have shown a decreased amygdala activity. It has previously been proposed that the observed deactivations of the amygdala in these studies indicate a cognitive strategy to adapt to a distressful but in the experimental setting unavoidable painful event. In this positron emission tomography study, we show that a simple contextual manipulation, immediately preceding a painful stimulation, that increases the anticipated duration of the painful event leads to a decrease in amygdala activity and modulates the autonomic response during the noxious stimulation. On a behavioral level, 7 of the 10 subjects reported that they used coping strategies more intensely in this context. We suggest that the altered activity in the amygdala may be part of a mechanism to attenuate pain-related stress responses in a context that is perceived as being more aversive. The study also showed an increased activity in the rostral part of anterior cingulate cortex in the same context in which the amygdala activity decreased, further supporting the idea that this part of the cingulate cortex is involved in the modulation of emotional and pain networks.