fMRI measurement of CNS responses to naloxone infusion and subsequent mild noxious thermal stimuli in healthy volunteers.

The aims of this study were to assess the effects of a mu-opioid antagonist, naloxone, on endogenous opioid systems and to evaluate the effect of naloxone on the CNS response to mild noxious heat. Doubled-blinded experiments were performed in a cross-over design in 10 healthy male volunteers. Functional magnetic resonance imaging (fMRI) data were collected before and during the infusion and also during thermal stimuli. Increased signal was observed in a number of cortical and subcortical brain regions for naloxone versus saline infusion. Cortical activation was induced in regions including cingulate, prefrontal cortex, and insula. Subcortical regions showing increased signal change included hippocampus and entorhinal cortex. A 46 degrees C stimulus delivered to the back of the hand induced an overall increase in activation in a number of regions in the naloxone group that were not seen in the saline group (e.g., insula, orbitofrontal cortex, thalamus, and hippocampus). These results show that naloxone, even in the absence of psychophysical effects, produces activation in several brain regions that are known to have high levels of mu-opioid receptors and may be involved in endogenous analgesia. Our study is an example of how fMRI can measure subtle changes in brain activation induced by pharmacological agents without cognitive effects.

Cerebellar responses during anticipation of noxious stimuli in subjects recovered from depression. Functional magnetic resonance imaging study.

BACKGROUND: Subjects recovered from depression have a substantial risk for recurrence of depression, suggesting persistent abnormalities in brain activity. AIMS: To test whether women recovered from depression show abnormal brain activity in functional magnetic resonance imaging (fMRI) during a conditioning paradigm with a noxious pain stimulus. METHOD: Ten unmedicated women who had recovered from major depression and eight healthy control women each received either noxious hot or non-noxious warm stimuli, the onset of which was signalled by a specific coloured light during 3-tesla echo planar imaging-based fMRI. RESULTS: Similar patterns of brain activation were found during painful stimulation for both patients and healthy controls. However, relative to healthy controls, subjects recovered from depression showed a reduced response in the cerebellum during anticipation of the noxious stimulus compared with anticipation of the non-noxious stimulus. CONCLUSIONS: Our data suggest that abnormal cerebellar function could be a marker of vulnerability to recurrent depression. This could provide a new target for therapeutic interventions.

Exacerbation of pain by anxiety is associated with activity in a hippocampal network.

It is common clinical experience that anxiety about pain can exacerbate the pain sensation. Using event-related functional magnetic resonance imaging (FMRI), we compared activation responses to noxious thermal stimulation while perceived pain intensity was manipulated by changes in either physical intensity or induced anxiety. One visual signal, which reliably predicted noxious stimulation of moderate intensity, came to evoke low anxiety about the impending pain. Another visual signal was followed by the same, moderate-intensity stimulation on most of the trials, but occasionally by discriminably stronger noxious stimuli, and came to evoke higher anxiety. We found that the entorhinal cortex of the hippocampal formation responded differentially to identical noxious stimuli, dependent on whether the perceived pain intensity was enhanced by pain-relevant anxiety. During this emotional pain modulation, entorhinal responses predicted activity in closely connected, affective (perigenual cingulate), and intensity coding (mid-insula) areas. Our finding suggests that accurate preparatory information during medical and dental procedures alleviates pain by disengaging the hippocampus. It supports the proposal that during anxiety, the hippocampal formation amplifies aversive events to prime behavioral responses that are adaptive to the worst possible outcome.

Learning about pain: the neural substrate of the prediction error for aversive events.

Associative learning is thought to depend on detecting mismatches between actual and expected experiences. With functional magnetic resonance imaging (FMRI), we studied brain activity during different types of mismatch in a paradigm where contrasting-colored lights signaled the delivery of painful heat, nonpainful warmth, or no stimulation. When painful heat stimulation was unexpected, there was increased FMRI signal intensity in areas of the hippocampus, superior frontal gyrus, cerebellum, and superior parietal gyrus that was not found with mismatch between expectation and delivery of nonpainful warmth stimulation. When painful heat stimulation was unexpectedly omitted, the FMRI signal intensity decreased in the left superior parietal gyrus and increased in the other regions. These contrasting activation patterns correspond to two different mismatch concepts in theories of associative learning (Rescorla-Wagner, temporal difference vs. Pearce-Hall, Mackintosh). Searching for interventions to specifically modulate activation of these brain regions therefore offers an approach to identifying new treatments for chronic pain, which often has a substantial associative learning component.

Dissociating pain from its anticipation in the human brain.

The experience of pain is subjectively different from the fear and anxiety caused by threats of pain. Functional magnetic resonance imaging in healthy humans was applied to dissociate neural activation patterns associated with acute pain and its anticipation. Expectation of pain activated sites within the medial frontal lobe, insular cortex, and cerebellum distinct from, but close to, locations mediating pain experience itself. Anticipation of pain can in its own right cause mood changes and behavioral adaptations that exacerbate the suffering experienced by chronic pain patients. Selective manipulations of activity at these sites may offer therapeutic possibilities for treating chronic pain.