It has been shown repeatedly that perceiving itch-related pictures or listening to a lecture on itch can enhance itch sensation and scratching behaviour (Niemeier and Gieler, 2000; Holle et al., 2012; Lloyd et al., 2013), indicating that itch is strongly influenced by expectations. Using fMRI, we investigated the neural correlates of the itch-related nocebo effect in healthy male and female human subjects. Itch sensation on the left forearm was induced by cutaneous histamine application and thermally modulated, with cooling leading to higher itch. Nocebo-induced aggravation of histaminergic itch was achieved by ostensibly treating volunteers with "transcutaneous electrical nerve stimulation (TENS)" about which subjects were instructed that it would increase itch. During a conditioning phase subjects indeed experienced stronger itch due to slightly altered cooling and histamine concentrations, but attributed it to the alleged "TENS stimulation". Importantly, in the subsequent test phase where no "TENS" or electrical stimulation was applied, volunteers significantly reported stronger itch during the nocebo as compared to the control condition. Comparing BOLD responses during nocebo in contrast to control, we observed increased activity in contralateral (right) rolandic operculum. Opercular involvement was repeatedly reported in studies related to the expectation of stimulus intensification and might thus represent an early area integrating expectation information with somatosensory information. Finally, functional coupling between the insula and the periaqueductal gray (PAG) was enhanced specifically in the nocebo condition. This cortex-PAG interaction indicates that context-dependent top-down modulation during itch might represent a shared mechanism with other modalities such as pain.
