Voxel-based morphometry and arterial spin labeling fMRI reveal neuropathic and neuroplastic features of brain processing of itch in end-stage renal disease

Pruritus of end-stage renal disease (ESRD) is a multifactorial symptom of complex etiology not yet fully understood. In this study we have investigated the cerebral perfusion patterns at rest in ESRD patients on hemodialysis, compared with those in healthy volunteers. We have also studied the brain responses evoked by experimental itch induction in ESRD, after stimulating the two distinct histamine and cowhage itch pathways, and compared them with the responses evoked in healthy volunteers. To identify potential structural alterations in ESRD patients compared with a group of age-matched healthy volunteers, we calculated the density of gray matter for the entire brain using a voxel-based morphometric analysis. Our results indicated that gray matter density was significantly reduced in ESRD patients in the frontal, parietal, temporal, and occipital cortices, as well as in the S1, precuneus, and insula, whereas the brain stem, hippocampus, amygdala, midcingulate cortex, and nucleus accumbens displayed an increased gray matter density. Functionally, we found a significantly higher brain perfusion at baseline associated with ESRD pruritus in the anterior cingulate, insula, claustrum, hippocampus, and nucleus accumbens. The brain responses evoked by cowhage itch, which are mediated by protease-activated receptors (PAR2), displayed significant differences compared with responses in healthy individuals and were correlated with perceived itch intensity in a dual, complex manner. The inverse correlations in particular suggested that a negative feedback mechanism modulated itch intensity, when elicited in a preexistent chronic itch background.