Effects of satiety on cerebral processing of pain and on resting state of the brain.

RATIONALE: The experience of pain is widespread and is estimated to be around 10-15% in UK population. Inadequate nutrition or irregular eating behaviour may explain the occurrence of spontaneous episodes of visceral or musculo-sketal pain occurring in non-clinical populations. Notably, functional and affective effects of satiety involve pleasure, well-being and facilitation of cognitive function. In contrast, the negative consequences of fasting include over-alertness, irritability, and nervousness. Thus, we may hypothesize that fasting, in contrast to satiety, would increase the cerebral processing of noxious stimuli. However, surprisingly little is known about benefits of satiety on pain perception. Besides being of scientific interest, the studentship will examine a potentially important psychological benefit of healthy nutrition. Thus, if we would be able to show that satiety reduces cerebral processing of noxious stimulus and in turn decrease the sensitivity to these nociceptive stimuli, this would open up an exiting new therapeutic avenue to pain reduction by promoting regular eating and managing hunger as a means to reduce pain sensitivity. EVIDENCE SUBSTANTIATING SATIETY-PAIN INTERACTION: The links between satiety/fasting and pain are well established in animal studies. Firstly, stimulation of the lateral hypothalamus, the cerebral hunger centre, is associated with decreased pain sensitivity that may be mediated by hypothalamic orexin. Secondly, stimulation of vagal afferent fibres originating from subgastric region increases nociception in rats during fasting period. This fasting-induced increase in pain sensitivity is not related to hypoglycemia but with hyperxcitability of vagal afferent nerves targetting opioid receptors in the brain. Thirdly, vagal afferents from the guts and stomach feed into the solitary tract nucleus and the parabrachial nucleus. The parabrachial nucleus in turn projects to the posterior insula, hypothalamus and amygdala. The posterior insula is the cortical centre for interoception evaluating information from the glucostats, and from peripheral warm, cold, and pain receptors indicating shared cortical representation of satiety and pain. In humans, overlapping brain regions participate both in food reward and pain processing. Specifically, neuroimaging studies have shown these overlapping regions to include the anterior and posterior insula, medial frontal cortex, and less consistently amygdala. Nevertheless, in humans, only indirect evidence is available for a relationship between cerebral processing of pain and satiety. These findings suggest that regular eating, rather than over or under consumption per se, mediate a balance between nutrition and pain. For example, eating disorders such as anorexia nervosa or binge eating obesity are associated with elevation of pain thresholds suggesting dysbalance of a satiety-pain system. Fasting is also precipitating factor in headache yet obesity is associated with migraine. Moreover, managed dietary restriction can produce therapeutic benefits alleviating the pain in arthritic patients. GOALS: In addition to merely establishing brain areas associated with both pain and satiety the studentship will demonstrate that 1) the default mode networks of the brain will be less active during fasted as compared to the satiated state, and that the functional connectivity between different brain regions during fasting will also involve regions participating in pain processing, 2) the fasted (compared to satiated) state is associated with a steeper slope of temporal summation of pain, and that this difference will be encoded in the posterior insula, and 3) pain responses will be stronger in fasted than satiated states but only in the presence of non-edible objects as edible objects would activate the competing food-reward circuits. These goals will be realized in a series of experiments involving functional MR and high-resolution EEG recordings.