For most healthy subjects, both subjective pain ratings and pain-evoked potentials are attenuated under conditioned pain modulation (CPM; formerly termed diffuse noxious inhibitory controls, or DNIC). Although essentially spinal-bulbar, this inhibition is under cortical control. This is the first study to observe temporal as well as spatial changes in cortical activations under CPM. Specifically, we aimed to investigate the interplay of areas involved in the perception and processing of pain and those involved in controlling descending inhibition. We examined brief consecutive poststimulus time windows of 50 ms using a method of source-localization from pain evoked potentials, sLORETA. This enabled determination of dynamic changes in localized cortical generators evoked by phasic noxious heat stimuli to the left volar forearm in healthy young males, with and without conditioning hot-water pain to the right hand. We found a CPM effect characterized by an initial increased activation in the orbitofrontal cortex (OFC) and amygdala at 250-300 ms poststimulus, which was correlated with the extent of psychophysical pain reduction. This was followed by reduced activations in the primary and secondary somatosensory cortices, supplementary motor area, posterior insula, and anterior cingulate cortex from 400 ms poststimulus. Our findings show that the prefrontal pain-controlling areas of OFC and amygdala increase their activity in parallel with subjective pain reduction under CPM, and that this increased activity occurs prior to reductions in activations of the pain sensory areas. In conclusion, achieving pain inhibition by the CPM process seems to be under control of the OFC and the amygdala.

This study aimed to identify the cortical mechanisms underlying the processes of interictal dishabituation to experimental pain in subjects suffering from migraine with aura (MWA). In 21 subjects with MWA and 22 healthy controls, cortical responses to two successive trials of noxious contact-heat stimuli were analyzed using EEG-tomography software. When compared with controls, MWA patients showed significantly increased pain-evoked potential amplitudes accompanied by reduced activity in the orbitofrontal cortex (OFC) and increased activity in the pain matrix regions, including the primary somatosensory cortex (SI) (p < .05). Similarly to controls, MWA subjects displayed an inverse correlation between the OFC and SI activities, and positive interrelations between other pain-specific regions. The activity changes in the OFC negatively correlated with lifetime headache duration and longevity (p < .05). Reduced inhibitory functioning of the prefrontal cortex is a possible cause for disinhibition of the pain-related sensory cortices in migraine. The finding of OFC hypofunction over the disease course is in keeping with current concepts of migraine as a progressive brain disorder.

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Our findings of impaired modulation of anticipated pain in migraine suggest a heightened state of anticipatory readiness combined with ineffective recruitment of prefrontal inhibitory pathways during experience of pain; the latter might account for the former, at least partially. In line, less efficient inhibitory capability is a plausible mechanistic explanation for patients' high concern about their upcoming migraine attacks.

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