A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch

Abstract

Previous PET and fMRI brain imaging studies targeting neural networks processing itch sensation have used histamine as the sole itch inducer. In contrast with histamine, cowhage-induced itch is mediated via proteinase activated receptors PAR2 and is transmitted through a separate spinothalamic pathway, therefore imaging the brain activation evoked by cowhage could provide further insight into central processing of itch. We report for the first time a functional MRI Arterial Spin Labeling (ASL) study of neuronal processing of itch induced by cowhage, analyzed in contrast with histamine-induced itch. We also explored the brain responses induced by histamine and cowhage combined in a tight sequence. The results of our analyses obtained in a group of 15 healthy volunteers suggested that cowhage and histamine co-activated a core group of brain structures, while also revealing notable differences. Core areas activated by both stimuli were found in the thalamus, primary and secondary somatosensory cortices, posterior parietal cortex, superior and middle temporal cortices, PCC, ACC, precuneus and cuneus. Cowhage induced a notably distinct and more extensive involvement of the insular cortex, claustrum, basal ganglia, putamen, thalamic nuclei and pulvinar. The differences observed between these two itch modalities were investigated to determine the impact of quantitative versus qualitative factors, and correlations between itch intensity and the patterns in brain activation were explored. Our analysis revealed that the most significant differences between cowhage and histamine itch were not affected by stimulus intensity, although a subset of regions displayed activations which were intensity-dependent. The combined application of cowhage and histamine highlighted the role of insula and claustrum in the processing of both itch modalities in the same time. The present results suggest the existence of overlapping but also distinct neuronal networks processing these two different types of itch.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1

Figure 1A. The experimental paradigm indicating the sequence of operations: structural scan, T1 map acquisition, ASL scanning series and the order of stimuli used in the induction of itch. Figure 1B. Visual analog scale itch intensity ratings during ASL scans are indicated (average ± standard deviation), as they were reported immediately at the end of each series when itch was induced with histamine, cowhage or their combination. Each ASL scan lasted 390s (6 ½ minutes). Itch ratings are reported on a VAS scale from 0 to 10: 0 = no itch, 10= maximum unbearable itch.

Figure 1

Figure 1A. The experimental paradigm indicating the sequence of operations: structural scan, T1 map acquisition, ASL scanning series and the order of stimuli used in the induction of itch. Figure 1B. Visual analog scale itch intensity ratings during ASL scans are indicated (average ± standard deviation), as they were reported immediately at the end of each series when itch was induced with histamine, cowhage or their combination. Each ASL scan lasted 390s (6 ½ minutes). Itch ratings are reported on a VAS scale from 0 to 10: 0 = no itch, 10= maximum unbearable itch.

Figure 2

The overlap of brain activations maps induced by histamine itch (in green) and by cowhage itch (in blue) illustrates the regions co-activated (in red) and distinct areas activated separately by the two itch pathways. Standard space Talairach coordinates. ACC = anterior cingulate cortex; PCC = posterior cingulate cortex; SPL = superior parietal lobule; M1 = primary motor cortex; S1 = primary somatosensory area; SMG = supramarginal gyrus; MTG= middle temporal gyrus; IPL = inferior parietal lobule; S2 = secondary somatosensory area.

Figure 3

A straight pairwise t test reveals areas activated significantly distinct by cowhage in comparison with histamine itch (in blue). Standard Talairach space coordinates.

Figure 4

A regression analysis reveals activation maps where cowhage activates significantly stronger than histamine (Z > 2.3, p

Figure 5

The overlay of the mapping results from regression analysis and from the paired t test contrasting cowhage with histamine itch, shows that most of the cowhage specific activations (in red) fall outside the map of intensity driven effects (in blue), revealing that distinct cowhage responses are mainly intensity-independent. ACC = anterior cingulate cortex; PCC = posterior cingulate cortex; SPL = superior parietal lobule; S1 = primary somatosensory area; S2 = secondary somatosensory area; BA6 = Brodmann area 6.

Figure 6

Maps of brain activation induced by cowhage itch during two consecutive ASL scans: during the first period of 390s (a), during the second period (b), and the contrast in activation between a and b, recorded in two consecutive scans is depicted in (c). In panel c) stronger activations captured in the first 390s are depicted in red, while activations stronger in the second period (compared to the first) appear in blue. A lower itch intensity during the second scan may not account for the shifts in brain activation observed over time for cowhage itch, since stronger and more extensive activations in rostral ACC, middle frontal gyrus and the paracingulate gyrus occurred during the second interval. ACC = anterior cingulate cortex. SPL = superior parietal lobule; S1 = primary somatosensory area; SMG = supramarginal gyrus.

Figure 7

Illustration of brain activation and deactivations induced by the concurrent stimulation of the two itch pathways using a combination of cowhage & histamine, during the first ASL scan, compared to baseline conditions. Standard space Talairach coordinates. ACC = anterior cingulate cortex; PCC = posterior cingulate cortex; SPL = superior parietal lobule; M1 = primary motor cortex; S1 = primary somatosensory area; SMG = supramarginal gyrus; MDNc = mediodorsal nucleus; Ant Nc = anterior nucleus.

Figure 8

A contrast between activations induced in two consecutive ASL scans by the simultaneous activation of both itch pathways, emphasizes the involvement of insula and claustrum in the processing of dual-mode itch (the combination of cowhage and histamine) at two different intensities. The images show a significantly stronger activation is captured in the first period (6 and ½ minutes), in comparison with the second interval (from minutes 6 ½ to 13). Standard space Talairach coordinates. ACC = anterior cingulate cortex.