So far, no controlled study investigated the effect of short-term alternating temperature modulation on experimentally induced itch in patients with atopic eczema. It is also the first study to investigate the differences in the cerebral processing of histamine-induced itch in lesional and nonlesional skin. With the new stimulus paradigm, characterizations of different skin conditions and their effects on the cerebral processing were possible. This means that results of a brain scan under controlled stimulus conditions can differentiate lesional from nonlesional skin areas in atopic eczema.
In spite of the common knowledge that intensive cold inhibits itch (34, 44, 45), but in accordance with two previous studies in healthy volunteers (29, 30), the results of our study show a reproducible, significant enhancement of histamine-induced itch by a short-term moderate temperature decrease in lesional as well as in nonlesional skin of patients with atopic eczema. When taking into account the definition of itch as a sensation provoking the desire to scratch, the stimulus paradigm shows an ‘on/off’ phenomenon: Mean itch intensity was above scratch threshold during the whole cold blocks, while more than half of the warm blocks remained below the scratch threshold level. Patients were also able to correctly discriminate the warm from the cold stimulation according to the ratings of the qualitative EIQ-items.
Although histamine is not the main itch mediator in atopic dermatitis it is so far the only reliable and evaluated experimental stimulus model for experimental itch (32); so far studies on the cerebral processing of itch in healthy volunteers have all been carried out with histamine (30, 35, 38–43, 46–48).
However, in another study in healthy volunteers, thermal stimuli failed to modulate experimental itch (49). This discrepancy might be explained by methodical differences, such as the use of histamine iontophoresis (instead of the skin prick test), which has been shown to induce only a moderate initial itch intensity compared to our skin puncture stimulus model (32). Different (noxious) temperature ranges, thermode sizes and thermode localization might be other reasons for differences between studies.
Mean itch intensity was perceived as more intense in lesional skin compared to nonlesional as well as healthy control skin. These findings confirm previous results of other groups (21, 28, 50).
One new finding is the fact that patients with atopic eczema (NLS as well as LS) have a delay in their itch response reaching their highest peak of itch intensity (slightly) later than healthy volunteers.
Concerning the EIQ, patients with atopic eczema in comparison to healthy controls showed the highest significance level for items which have previously been shown to be disease specific (‘unbearable’, ‘severe’, ‘uncontrollable’, ‘I only feel the itch’, ‘my only desire: no itch’, ‘bothersome’, ‘wearing’, ‘unpleasant’, ‘stubborn’). These results underline the validity and specificity of the EIQ for atopic eczema (10).
Interestingly, the emotional quality ratings of itch perception of the EIQ differed strongly between all three groups, while descriptive itch quality ratings showed no significant differences between groups. Itchy lesional skin areas resulted in the highest ratings; and although mean itch intensity was perceived as slightly higher in healthy control skin compared to nonlesional atopic skin, emotional itch questionnaire ratings were significantly higher for nonlesional skin pointing out the emotional extra-component of itch in atopic eczema even in nonaffected areas.
Possible underlying mechanisms
A possibly underlying cutaneous mechanism for the biphasic itch induction by short-term alternating temperature modulation of histamine could be that high tissue concentrations of histamine lead to increased activation of itch fibers by influencing the threshold of itch specific receptors (18). Cooling is sensed by peripheral thermoreceptors, the main transduction mechanism of which is probably a cold- and menthol-activated ion channel, transient receptor potential (melastatin)-8 (TRPM8) (51, 52). TRPM8 is activated by chemical cooling agents (such as menthol or eucalyptol) or when ambient temperature drops below 26°C and depolarises sensory neurons (51, 53, 54); it can adapt to long-term variations in baseline temperature to sensitively detect small temperature changes and is selectively expressed on a certain subpopulation of A and C-type sensory afferents (55). The process between ion channel closure and reopening after depolarization occurs within seconds (56). TRPM8 is not the only thermosensitive element in cold receptors and interacts with other ionic currents to shape cold receptor activity, but seems to play an essential and predominant role in thermosensation over a wide range of cold temperatures (51). Temperature change from 25 to 32°C also enhances the sensitivity and efficacy of voltage activation for TRPV1 (57), which undergoes changes in ion selectivity upon channel activation with a maximum potential shift 21 seconds after activation (58). Pruritogens such as histamine could act on these receptors (34, 59, 60), their pruritic effect might, however, intermittently be overlapped or even enhanced when the receptors are at threshold temperature of activation, e.g. with the described short-term alternating temperature modulation.
A conceivable explanation on a spinal level for the increase of itch sensation is that the stimulation of A-delta fibers by cooling on a fast but low intensity level (temperature decrease of 5°C per second from 32 to 25°C) might lead to a temporary central disinhibition of pruritoceptive neurons, thereby enhancing pruritoceptive responses.
Central mechanisms of disinhibition have been discussed for the paradoxical heat sensation, where the perception of heat is reported when the skin temperature is innocuously cooled (61). Here the insular cortex, an important area for thermosensory perception, is thought to play a major role (62). We have recently described the insular cortex to be involved in itch processing (30).
As mentioned above, the psychophysical data revealed that in nonlesional skin, patients have a delayed itch sensation in response to the temperature decrease as compared to lesional skin or to the skin of healthy volunteers. Peripheral mechanisms with a heightened threshold of pruriceptors (sub-population of C-fiber neurons) might contribute to this observation, but central mechanisms are in our view more likely to explain this phenomenon. The neuroimaging results support this hypothesis.
In a previous investigation of our group, histamine-induced itch in healthy control skin produced an activation of brain regions, such as the thalamus, pre-SMA, anterior insular, inferior parietal and dorsolateral prefrontal cortex and a decreased activation of the orbitofrontal, medial frontal, mid-cingulate and primary motor cortex as compared to the saline condition (30) (Fig. 4C). These regions are known to be involved in the encoding of sensory, attentive, emotional, evaluative and motivational aspects of itch (30, 35, 39, 40, 42, 43, 47, 63).
In the current study, a very similar activation pattern was observed in lesional skin (Fig. 4B). In contrast to healthy control and lesional skin, a profound deactivation pattern occurred when provoking itch in nonlesional skin (Fig. 4A). These different itch-specific brain activation/deactivation patterns are striking. In our view, the deactivation pattern during the provocation of itch in nonlesional skin reflects a neurobiological attempt to suppress the perception of itch (somatosensory areas) as well as the desire to scratch (premotor and supplementary motor areas). This hypothesis would explain why the initial itch sensation is delayed in nonlesional skin (Interval six and seven, Fig. 2).
In the course of stimulation the itch intensity ratings are increasing (Interval 8–10, Fig. 2), which is in accordance with our neuroimaging results (Fig. 4A), where the initial deactivation pattern changes to an increasing activation in the basal ganglia and lateral prefrontal areas. A feasible explanation might be related to temporal summation processes: when the amount of pruriceptive input reaches a critical threshold, the firing of itch specific neurons cannot further be suppressed by central mechanisms (24). Moreover, after exceeding the inhibition threshold of pruriceptive input, the firing seems to be prolonged in the patient group, which is reflected by the delayed decline of itch responses during the warm blocks (Interval 1–2, Fig. 2).
Although deactivations (negative fMRI BOLD signal) have been observed in many fMRI studies, its interpretation remains controversial. Recent studies suggest that the negative fMRI BOLD signal response reflects both an active inhibitory role as well as neuronal deactivation depending on the interplay between hemodynamics and metabolism (64–66). This is not the first study reporting cerebral deactivations in itch processing: Deactivation of limbic structures in itch processing of healthy controls has been observed previously, which has been attributed to the stressful character of the itch stimulation and the urge to scratch (43) as well as the process of scratching itself (48).
A possible explanation for the differences in brain activation between nonlesional skin and lesional skin could be related to the magnitude of inflammation induced by histamine in lesional skin vs nonlesional skin. As a matter of intensity central processing may be ‘prioritized’.
As this is the first study comparing lesional with nonlesional atopic eczema skin as well as healthy control skin, comparisons to other studies are difficult. Leknes et al. (42) were the first to investigate the cerebral processing of allergen-induced itch postulating a dysfunction of striato-thalamo-orbitofrontal circuits, which are believed to underlie the failure to regulate the motivational drive in disorders associated with strong urges, e.g., addiction and obsessive compulsive disorder. Schneider et al. (67) demonstrated significant differences in central imaging of histamine-induced itch between patients with atopic dermatitis in nonlesional skin and healthy subjects in a study correlating itch intensity with cerebral activation using positron emission tomography.
Our study supports a peripheral as well as a central component in the pathophysiology of chronic itch in patients suffering from atopic eczema. On the one hand, pathological skin conditions, such as a skin barrier abnormality and local inflammation processes in atopic eczema patients (68, 69) point to a peripherally increased sensitivity to itch stimuli. On the other hand, central filter mechanisms might counteract this pathological skin condition to a certain point when the threshold of the pruriceptive input is exceeded.