Content » Vol 97, Issue 9

Investigative Report

Distraction From Itch Shows Brainstem Activation Without Reduction in Experimental Itch Sensation

Astrid Stumpf1,2, Bettina Pfleiderer2,3, Gudrun Schneider1,2, Gereon Heuft1,2, Martin Schmelz4, Ngoc Quan Phan2,5, Sonja Ständer2,5 and Markus Burgmer1,2

1Department of Psychosomatics and Psychotherapy, 2Center for Chronic Pruritus (KCP), 3Department of Clinical Radiology and 5Department of Dermatology, University of Münster, Münster, and 4Department of Anesthesiology and Intensive Care Medicine, Karl Feuerstein Professorship, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany


The central processing of itch is not completely understood. This is the first study to use functional magnetic resonance imaging (fMRI) to examine the central modulation by distraction of experimentally induced itch. A total of 33 healthy volunteers were examined with fMRI. Periods of itch induction without distraction and itch with distraction by a Stroop task (psychological test, where the participants have to decide if the colour of the writing corresponds to the written word, for example if “red” is written in red or not) were counterbalanced during the scanning to examine task-specific changes in blood oxygenation level dependent-signal. The intensity of the subjects’ itch sensation, desire to scratch and pain sensation were evaluated. Distraction by a Stroop task did not reduce itch intensity or urge to scratch. However, the Stroop task led to significantly higher activation of the left brainstem when it followed the “pure” itch sensation. Itch and pain seem to have similar inhibition pathways, particularly concerning brainstem activation during distraction. But as itch sensation, in contrast to pain, could not be sufficiently reduced by distraction, both entities might have different modulation systems.

Key words: fMRI; itch; scratch; pain; pain inhibition system.

Acta Derm Venereol 2017; 97: xx–xx.

Accepted Jun 22, 2017; Epub ahead of print Jun 27, 2017

Corr: Astrid Stumpf, Department of Psychosomatics and Psychotherapy, University of Münster, Domagkstrasse 22, DE-48149 Münster, Germany. E-mail:


Itch and pain are unpleasant sensory experiences that have many characteristics in common. Paralleling clinical pain (1, 2), itch leads to a huge reduction in quality of life and thus can provoke comorbidities such as anxiety disorders or depression (3–5). Like chronic pain, the treatment of chronic itch is often insufficient and represents a challenge for the physician (6–9).

During recent years, our knowledge of central processing and modulation of itch has increased. Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) during experimental itch stimulation have revealed activation of brain regions responsible for motor planning, sensory aspects and emotional processes (10–20). The activation patterns of itch and pain overlap to a great extent. However, relative increases in different brain areas may differ. For example, itch-induced activation of the somatosensory areas SI and SII appears to be weaker, whereas activation of motor areas is stronger (21). Moreover, stronger activation of the anterior cingulate cortex (ACC) and insula was observed in experimental pain conditions.

Cognitive attention to, or distraction from, pain are important in pain modulation (22–26) in particular to shift the subject’s attention away from clinical pain (27, 28) and, accordingly, reducing its intensity. On a neurobiological level, pain modulation correlates with a profound interaction between central pain-encoding and pain-inhibiting areas (24, 26, 29). In particular, the frontal lobe, the anterior cingulate cortex, the hypothalamus, the insula and the brainstem (nucleus cuneiformis (NCF), and the periaqueductal grey (PAG)) are involved in the descending modulation of pain (30).

Distraction not only leads to a reduction in the intensity of pain (31, 32), but also of itch (33). The neurobiological background of this phenomenon in itch is unknown. Mochizuki et al. (16) showed that itch can be reduced by painful stimuli, leading to an activation of the PAG. In contrast, Papoiu et al. (34) postulated that itch modulation might be contrary to mechanisms known to suppress pain. They found an activation of the reward system (namely the ventral tegmentum) that led to a deactivation of the PAG. A few studies have examined the effect of drugs on itch modulation. Naltrexone (35) reduced fMRI activity during itch perception induced by histamine or capsaicin, while butorphanol suppressed only histamine-induced itch. In the latter condition, structures of the mesolimbic circuit seemed to play an important role during itch suppression (36). As the PAG seems to play not only an important role in pain modulation (by distraction), but also in itch modulation, we examined the activity of the PAG and the NCF during itch with and without distraction. In line with results from the pain field, we hypothesized that comparable activation of brainstem areas and a decrease in itch sensation during distraction should occur. This paper provides additional analyses based on imaging data published in 2013 from our working group (37). Here, we focus on the effects of distraction on activity in the PAG and NCF. In our previous paper, sex-specific differences were observed in localization and itch perception (37). Since no sex-differences were found for itch sensation and brain activity during distraction, data for male and female subjects were pooled in this paper.


Study subjects, induction of itch sensation, the experimental and imaging protocol, and the psychophysical measurements have been described in detail previously (37). The following sections give a short summary.


A total of 33 healthy subjects (age 25.5 ± 3.6 years (mean ± standard deviation; SD)) with no history of chronic disease, allergy or mental illness were included in the study. All subjects gave written informed consent. The study was approved by the ethics committee of the Medical Faculty of Münster, Germany, and was conducted in accordance with the principles of the Declaration of Helsinki.

Induction of itch sensation

Itch was induced by applying histamine intradermally via 4 microdialysis fibres (2 in the left forearm and 2 in the left lower leg). Itch stimulation during fMRI scanning was induced by 0.5 ml of 10–4 M sterile histamine solution (Sigma, Deisenhofen, Germany) and terminated by local application of an ice bag and perfusion of 0.7 ml 2% xylocaine-solution (Astra Zeneca, Wedel, Germany).

Experimental and imaging protocol

Magnetic resonance imaging was performed with a 3T-scanner (Gyroscan, Philips, Best, The Netherlands) using a standard receiver head coil. For each subject, 844 echo-planar volumes (EPI) were obtained with the following parameters: TR = 2.5 s, TE = 35 ms, flip angle 90°, matrix dimensions 64 × 64 field of view (FOV) = 210 mm, 36 oblique slices parallel to the AC-PC line; slice thickness: 3.6 mm, pixel size: 3.6×3.6×3.6 mm.

During continuous fMRI scanning the “baseline” condition (50 s with no sensory stimulation) was followed by the histamine perfusion. After 60 s of perfusion a 90 s period of  “itch” was initiated, followed by the “Stroop” condition (90 s). During this distraction condition the subjects had to perform a pseudorandomized colour Stroop task (38). During the “itch” condition the subjects looked at a black cross projected onto the screen. At the end of the experiment, the itch sensation was terminated by local anaesthetics and an ice bag (see above). To avoid habituation, the order of the runs (first “itch” or first “Stroop”) and the localization (lower leg or forearm) were altered. There were 4 runs in total.

The identical experiment was repeated with 10 of the 33 volunteers (5 females, 5 males) of the previous experiment approximately 24 months after the first session. In this control condition histamine and xylocaine were replaced by physiological saline solution (0.9% NaCl solution).

Psychophysical measurements

Subjects were asked to rate their itch intensity, desire to scratch and pain intensity after the “baseline”, “itch” and “Stroop” condition via a numeric rating scale (NRS) ranging from 0 (no itch/no desire to scratch/no pain) to 10 (most intense itch/desire to scratch/pain imaginable) by using a computer mouse held in their right hand. The NRS values under “itch” and “Stroop” condition were calculated as the mean value of each run.

In addition, immediately before and after the experiment, subjects gave information about their mood and their arousal via a self-assessment manikin (SAM) (39).

Statistical calculations were performed with PASW 21.0 (SPSS Inc., Chicago, IL, USA). Corresponding to the fMRI data a 3-factorial analysis of variance (ANOVA) was performed with the factors order (“first” or “second” condition in the stimulation sequence, 2 levels), condition (“itch”, “Stroop”, 2 levels) and localization (“forearm”, “lower leg”, 2 levels). Because of our initial hypothesis of itch reduction by distraction during the Stroop task we focused on the main effect of condition and the interaction of condition×localization or condition×order.

Furthermore, we used t-tests for dependent variables to measure pre- and post-differences of mood and arousal and differences in reaction time and a non-parametric Spearman’s Rho test to calculate correlations between brainstem activity levels and itch intensity during histamine perfusion.

Imaging data analysis

Functional images were analysed using the general linear model (40) for block designs in SPM8 (Welcome Department of Imaging Neuroscience; London, UK; All images were realigned, normalized to an EPI template (resulting voxel size of 2 mm), spatially smoothed (8 mm FWHM kernel), and high-pass filtered (128 s).

First-level analysis

For each subject, data were gathered under 3 conditions: “baseline” condition (20 scans), “itch” condition (36 scans), “Stroop” condition (36 scans) for all runs, resulting in 12 conditions in total (3 conditions×2 runs×2 localizations). Realignment parameters were integrated as regressors into the model. Contrasts were defined as follows: “Stroop”=“Stroop”>“baseline” and “itch”=“itch”>“baseline”. For each subject, 1 BOLD-contrast for each stimulation at each extremity was determined as a function of BOLD-signal changes, so there were 4 BOLD-contrasts in total: first stimulation forearm (A1_itch; A1_Stroop), first stimulation lower leg (B1_itch; B1_Stroop), second stimulation forearm (A2_itch; A2_Stroop) and second stimulation lower leg (B2_itch; B2_Stroop).

Second-level analysis

The individual BOLD-contrasts were transferred into a 3 factorial ANOVA (factors order (“first” or “second” position in the stimulation sequence, 2 levels), condition (“Stroop”, “itch”, 2 levels) and localization (“forearm”, “lower leg”, 2 levels)) using SPM8 “full factorial” design. The main effect of condition (and its differential contrast of each condition) and its interactions with order and localization were assessed. Family-wise error correction (p < 0.05) with a minimum cluster size of 20 voxels were defined as levels of significance.

BOLD-Signal in brainstem (PAG, NCF). Because of our initial hypothesis that itch inhibition correlates with brainstem activation during distraction (Stroop task) we determined the condition-dependent course of significant brainstem activations (eigenvariate). The region of interest was chosen according to the analysis of Irene Tracy’s group (41, 42). During whole-brain analysis we found significant brainstem activation (x,y,z-coordinate -8 -26 -10) and the eigenvariates (sphere of 5 mm) of the left (-8 -26 -10) and right (contralateral, 8 -26 -10) cluster were extracted in SPM8. To control whether this activation pattern was based on a pure Stroop-effect (and not itch-related) the eigenvariate of the cluster activation of the 10 participants during our control experiments (saline perfusion) was also evaluated.

Psychophysical data

Stroop”condition. After deleting inconsistent results (participants pushed the button too late or too early), 4,582 tasks were included in the analysis with 4,158 correct answers. The reaction time of the correct answers decreased over the course of the experiment due to a practice effect (A1 = 1,448.9 ± 302.3, n = 993; B1 = 1,362.0 ± 276.0, n = 1,042; A2 = 1,364.2 ± 302.1, n = 1,040; B2 = 1,316.3 ± 274.1, n = 1,083). The low drop-out rate of approximately 3% and an error rate of approximately 10% indicate that subjects performed the task as expected and were distracted. A detailed analysis is given in our previous paper (37).

Valency and arousal. There was no significant difference in the extent of arousal at the beginning and at the end of the experiment (0.8 ± 1.0, 0.9 ± 0.7; p = n.s.). In contrast, at the end of the experiment, the mood of subjects was significantly more negative than at the beginning (2.5 ± 0.9, 2.8 ± 0.8; p = 0.049).

There were no significant differences in arousal (0.7 ± 0.7, 0.6 ± 0.7; p = n.s.) or valency (2.9 ± 0.7, 2.6 ± 1.0; p = n.s.) at the beginning and the end of the experiment during the control experiment.

Itch sensation, desire to scratch and pain. The participants had a mean itch intensity of 3.77 (min–max: 1–8), a mean desire to scratch of 3.46 (min–max: 0–8) and a mean pain intensity of 1.72 (min–max: 0–7). For further details see Fig. 1.

Fig. 1. Mean intensities and standard deviations of psychophysical data (numeric rating scale; NRS) of itch intensity, desire to scratch and pain during each run. ?A1J = first “itch” condition at the forearm; A1S = first “Stroop” condition at the forearm; B1S = first “Stroop” condition at the lower leg; B1J = first “itch” condition at the lower leg; A2S = second “Stroop” condition at the forearm; A2J = second “itch” condition at the forearm; B2J = second “Stroop” condition at the lower leg; B2S = second “Stroop” condition at the lower leg.

In contrast to our hypothesis, the 3-factorial ANOVA revealed that the Stroop task did not reduce itch intensity (F-score = 0.61, p = 0.44), but localization (F-score = 17.12, p < 0.001) and order (F-score = 29.30, p < 0.001) showed significant main effects on itch intensity. The interaction condition×order (F-score = 0.50, p = 0.49) and condition×localization (F-score = 0.16, p = 0.69) revealed no significant effects. Similarly, the Stoop task did not significantly reduce the desire to scratch (F-score = 0.49, p = 0.49).

In contrast, the factors localization (F-score = 24.70, p < 0.001) and order (F-score = 23.50, p < 0.001) showed significant main effects. The interactions condition×order (F-score = 0.72, p = 0.40) or condition×localization (F-score = 0.57, p = 0.46) were not significant. Concerning pain intensity there was neither a significant effect for condition (F-score = 0.47, p = 0.50) nor localization (F-score = 2.75, p = 0.11) but for order (F-score = 5.6, p = 0.024). The interactions condition×order (F-score = 1.01, p = 0.32) and condition×localization (F-score = 0.51, p = 0.48) were not significant.

During saline perfusion, the participants had a mean itch intensity over all conditions of 0.36 (min–max: 0–4), a mean of desire to scratch of 0.23 (min–max: 0–3) and a mean pain intensity of 0.88 (min–max: 0–8). This was significantly different from the histamine perfusion for itch intensity and desire to scratch (p ≤ 0.001), but not for pain intensity (p = n.s.). In a 3-factorial ANOVA with order, localization and condition, we found a main effect of order (F-score = 7.3, p = 0.024) for itch sensation, but no main effect for localization and no significant effects for the desire to scratch. Because no itch sensation was experienced in the saline condition no further statistical analysis was performed.

fMRI data

Three-factorial ANOVA. There was widespread activation of the occipital gyrus, certainly due to the visual stimuli during the main effect of condition. Furthermore, there was activation of both frontal gyri (including dorsolateral prefrontal cortex (DLPFC) and pre-supplementary motor area, BA 6, 9, 46), left thalamus, right insula, left brainstem, both lentiform nuclei, left middle temporal gyrus (BA 39) and right parahippocampal gyrus (BA 27) and left precuneus (BA 31) (Table SI).

Differential contrast analyses (t-tests) revealed that these brain activations were mostly driven by the “Stroop” condition (“Stroop”>“itch”) and, most importantly, showed strong brainstem activation during “Stroop”. The reverse contrast (“itch”>“Stroop”) presented activation of the right insula, left precuneus (BA 31), left middle temporal gyrus (BA 39) and right posterior cingulate gyrus (BA 31) and no brainstem activation (Table I, Fig. 2).

Table I. Differential contrasts of “itch” and “Stroop” condition of the 3-factorial analysis of variance (ANOVA) during histamine perfusion

Table I. Differential contrasts of “itch” and “Stroop” condition of the 3-factorial analysis of variance (ANOVA) during histamine perfusion

Fig. 2. Significant functional magnetic resonance imaging (fMRI) signal intensity changes for the differential contrasts of “Stroop”>“itch” (red) and “itch”>“Stroop” (yellow) in the 3-factorial analysis of variance (ANOVA) with the factors order, condition and localization. *The results are family-wise error-corrected (p < 0.05, voxel threshold > 20 voxels).

The interactions condition×order and condition× localization did not present any suprathreshold clusters.

During the control experiment with saline perfusion the main effect of condition revealed activation of the left cerebellum and occipital brain structures (BA 17, 18) as well as right parietal gyrus, right precuneus, left middle frontal gyrus, including DLPFC (BA 9, 46) and left inferior parietal lobule (BA 40) (Table SII).

Concerning the differential contrasts (t-tests) the contrast Stroop”>itch” showed activation of the left cerebellum, left lingual gyrus (BA 17), left cuneus (BA 18), right occipital gyrus (BA 18) and the right superior and left inferior parietal gyrus (BA 7, 40), right precuneus (BA 7) and left inferior and middle frontal gyrus (BA 7, 9) (Table II). The differential contrast of “itch”>Stroop” did not reveal any suprathreshold clusters.

Table II. Differential contrast of “itch” and “Stroop” condition of the 3-factorial analysis of variance (ANOVA) during saline perfusion

The interaction condition×order, as well as the interaction condition×localization, did not reveal any supra-threshold clusters.

BOLD brainstem activity. The eigenvariate as a measure of activation indicates higher activations of the left brainstem cluster during “Stroop” condition compared with the “itch” condition (Fig. 3). Statistical comparison of activation intensities in every single run revealed significant elevated intensities for those runs in which the “itch” condition was first in the sequence (first-run forearm: T-score = –5.67, p-score < 0.001, second-run lower leg: T-score = –3.22, p-score = 0.003). For the other 2 runs, where the Stroop task was first, we could not find any significant differences in brainstem activation pattern (second-run forearm: T-score = –1.10, p-score = 0.28, first-run lower leg: T-score = –0.69, p-score = 0.49).

Fig. 3. Eigenvariates of brainstem activation during “itch” and “Stroop” during histamine perfusion. A significant difference between these 2 conditions can be found only during the first stimulation at the forearm and the second stimulation at the lower leg in the left brainstem. ?*p < 0.05, **p < 0.01, ***p < 0.001. ?A1J = first “itch” condition at the forearm; A1S = first “Stroop” condition at the forearm; B1J = first “itch” condition at the lower leg; B1S = first “Stroop” condition at the lower leg; A2J=second “itch” condition at the forearm; A2S = second “Stroop” condition at the forearm; B2J = second “Stroop” condition at the lower leg; B2S = second “Stroop” condition at the lower leg.

Moreover, the left brainstem activity correlated significantly with itch intensity (r = –0.13, p = 0.035), but not with right brainstem activity ( r =–0.03, p = 0.58).

During saline perfusion without appreciable itch sensation, there was no consistent brainstem activation during the Stroop task (Fig. 4).

Fig. 4. Eigenvariates of brainstem activation during “itch” and “Stroop” during saline perfusion. A significant difference between these 2 conditions can be found only during the second stimulation at the forearm. ?*p < 0.05. ?A1J = first “itch” condition at the forearm; A1S = first “Stroop” condition at the forearm; B1J = first “itch” condition at the lower leg; B1S = first “Stroop” condition at the lower leg; A2J = second “itch” condition at the forearm; A2S = second “Stroop” condition at the forearm; B2J = second “Stroop” condition at the lower leg; B2S = second “Stroop” condition at the lower leg.


The present study is a new analysis of data obtained in a former study (37) in which sex-specific differences in central itch perception and modulation were analysed. In the present study, the effect of distraction by a colour Stroop task on cerebral itch processing was investigated. In contrast to our initial hypothesis, the Stroop task did not reduce any itch-related sensation (intensity, desire to scratch, pain). However, distraction activated, in particular, the DLPFC, brainstem and thalamus, all structures well known to be involved in pain modulation.

Itch sensation and urge to scratch

The analgesic effect of distraction is a well-known phenomenon in experimental (32) and clinical settings (31). Distraction also reduces clinical itch, as shown during experimental distraction in a virtual reality and audiovisual distraction environment (33).

In contrast to the study by Leibovici et al. (33), we did not find distraction to reduce itch intensity or urge to scratch. The difference might be related to the selection of our participants (younger and healthy subjects), different itch stimulation (experimental vs. clinical) and lower itch intensity in our study. Moreover, Leibovici’s distraction via virtual reality might have been a more effective strategy to reduce itch intensity compared with the Stroop task.

Central processing of itch

Analgesic effects of distraction (including Stroop-induced) correlate with increased PAG and NCF activation (26, 30, 42, 43) which emphasizes the importance of brainstem in pain reduction. In our study we found Stroop-related activation of the brainstem with increased activation intensity (eigenvariate) of the left ipsilateral NCF during “Stroop” condition of the 1st and 4th runs (see Fig. 3).

Mochizuki et al. could show that a reduction in experimental itch sensation through an additional painful cold stimulus leads to PAG activation, comparable to diffuse noxious inhibitory control (DNIC) in pain (16). Therefore, the same brainstem areas seem to play a role in pain and itch reduction. The important role is further supported by the observed negative correlation of itch intensity with brainstem activation.

Interestingly, Papoiu et al. (34) hypothesized that itch scratch-evoked reward is linked to deactivation of the PAG. This deactivation was associated with activation of the reward system, especially the ventral tegmentum. Thus, PAG modulation appears to differ between pain-induced reduction in itch (either via a painfully cold stimulus or via distraction) and scratch-induced pleasure.

Moreover, Vierow et al. (35) and Papoiu et al. (36) could reduce itch sensation by naltrexone and butorphanol. While naltrexone reduced the fMRI activity during itch perception induced by histamine and capsaicin, butorphanol led to a reduction in histamine-induced itch only and perfusion changes in the midbrain, thalamus, S1, insula, and cerebellum. During butorphanol infusion, the ventral tegmental area (VTA), periaqueductal gray (PAG), raphé nucleus, thalamus, precuneus and cerebellum were activated. As the PAG is activated in our study, too, it might be feasible to assume that cognitive distraction and drugs lead to corresponding activations of inhibiting systems.

A Stroop task as an instrument of focused attention leads to activation of the anterior cingulate cortex, dorsolateral prefrontal cortex and/or parietal cortex (44–52). However, we assume that the increased DLPFC activation does not merely reflect the effect of attention, but is also involved in pain and itch modulation. Pain studies report that the DLPFC is responsible for anticipation of pain and emotional weighting of pain (53). In itch studies, the DLPFC (with premotor and parietal areas) may reflect the planning of the motor response to itch (scratching) or the attenuation of the desire to scratch (12, 17). Increased DLPFC activity during repetitive scratching has also been reported, suggesting a link with scratch-induced inhibition of itch and induction of pleasure and reward (12, 54). Thus, activation of DLPFC might also be directly linked to modulation of the itch sensation. Furthermore, the DLPFC interacts with the descending pain modulation system, particularly PAG and NCF (43, 55), representing another possible link to itch modulation. These results are supported by our control experiment, in which DLPFC activation was unilateral during “Stroop”>“itch” and not bilateral, as during the histamine experiment.

The activation of thalamus during itch sensation is well known (11, 13). Schneider et al. (20) found a significantly higher activation of an orbito-frontal-pallidum-thalamus circuit for patients with atopic dermatitis, and hypothesized that this circuit could facilitate scratching behaviour. Thus, compared with our study the lentiform nucleus might play a role in modulation of itch and scratching desire by distraction.

Study limitations

First, the intensity of itch sensation might not have been sufficient to distinguish clearly between both conditions (“itch”, “Stroop”) and to decide whether the itch sensation increases or decreases noticeably. As the whole experiment took more than 30 min we cannot rule out that fatigue of our subjects influenced the results.

Secondly, we do not have a “pure” itch sensation, but a certain mixture with pain sensation. The pain sensation might be provoked by the histamine solution, which has a specific “burning” effect. However, the pain sensation is much lower than the itch sensation, so we assume that pain sensation plays only a minor role. Moreover, the low drop-out rate of 2.9% and an error rate of 9.8% indicate that subjects performed the task as expected and were distracted.

Finally, we did not perform a single study analysis on brainstem level. We cannot rule out that our minimum cluster size was too large and PAG brain activity measurements may have been influenced by signals from neighbouring structures. Furthermore, we did not perform a separate normalization procedure of the brainstem, besides the normalization in SPM in accordance with the MNI template during pre-processing, which might have influenced the localization of our brainstem cluster.

In conclusion, distraction paradigms have been shown to reduce itch and pain via activation of overlapping brain regions, especially by the brainstem. However, our data suggest that even a clear activation of DLPFC, brainstem and thalamus by a Stroop task is not sufficient to reduce histamine-induced itch sensation.


The authors would like to thank Hermann Schillers, Department of Physiology, University of Münster for technical support, and Stefanie Schelzig and Özkan Genc, Department of Clinical Radiology, University of Münster for fMRI measurements.

The authors acknowledge support from the Open Access Publication Fund of the University of Münster.

The authors declare no conflicts of interest.

  1. Reme SE, Tangen T, Moe T, Eriksen HR. Prevalence of psychiatric disorders in sick listed chronic low back pain patients. Eur J Pain 2011; 15: 1075–1080.
    View article    Google Scholar
  2. Tunks ER, Crook J, Weir R. Epidemiology of chronic pain with psychological comorbidity: prevalence, risk, course, and prognosis. Can J Psychiatry 2008; 53: 224–234.
    View article    Google Scholar
  3. Jordan JM, Whitlock FA. Atopic dermatitis anxiety and conditioned scratch responses. J Psychosom Res 1974; 18: 297–299.
    View article    Google Scholar
  4. Schneider G, Driesch G, Heuft G, Evers S, Luger TA, Ständer S. Psychosomatic cofactors and psychiatric comorbidity in patients with chronic itch. Clin Exp Dermatol 2006; 31: 762–767.
    View article    Google Scholar
  5. Gupta MA, Gupta AK, Schork NJ, Ellis CN. Depression modulates pruritus perception: a study of pruritus in psoriasis, atopic dermatitis, and chronic idiopathic urticaria. Psychosom Med 1994; 56: 36–40.
    View article    Google Scholar
  6. Ong PY, Boguniewicz M. Investigational and unproven therapies in atopic dermatitis. Immunol Allergy Clin North Am 2010; 30: 425–439.
    View article    Google Scholar
  7. Patel T, Yosipovitch G. The management of chronic pruritus in the elderly. Skin Therapy Lett 2010; 15: 5–9.
    View article    Google Scholar
  8. Metz M, Ständer S. Chronic pruritus – pathogenesis, clinical aspects and treatment. J Eur Acad Derm Venereol 2010; 24: 1249–1260.
    View article    Google Scholar
  9. Ständer S, Streit M, Darsow U, Niemeier V, Vogelgsang M, Ständer H, et al. Diagnostic and therapeutic procedures in chronic pruritus. J Dtsch Dermatol Ges 2006; 4: 350–370.
    View article    Google Scholar
  10. Hsieh JC, Hagermark O, Stahle-Backdahl M, Ericson K, Eriksson L, Stone-Elander S, et al. Urge to scratch represented in the human cerebral cortex during itch. J Neurophysiol 1994; 72: 3004–3008.
    View article    Google Scholar
  11. Herde L, Forster C, Strupf M, Handwerker HO. Itch induced by a novel method leads to limbic deactivations a functional MRI study. J Neurophysiol 2007; 98: 2347–2356.
    View article    Google Scholar
  12. Ishiuji Y, Coghill RC, Patel TS, Oshiro Y, Kraft RA, Yosipovitch G. Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis. Br J Dermatol 2009; 161: 1072–1080.
    View article    Google Scholar
  13. Leknes SG, Bantick S, Willis CM, Wilkinson JD, Wise RG, Tracey I. Itch and motivation to scratch: an investigation of the central and peripheral correlates of allergen – and histamine-induced itch in humans. J Neurophysiol 2007; 97: 415–422.
    View article    Google Scholar
  14. Mochizuki H, Inui K, Tanabe HC, Akiyama LF, Otsuru N, Yamashiro K, et al. Time course of activity in itch-related brain regions: a combined MEG-fMRI study. J Neurophysiol 2009; 102: 2657–2666.
    View article    Google Scholar
  15. Mochizuki H, Sadato N, Saito DN, Toyoda H, Tashiro M, Okamura N, et al. Neural correlates of perceptual difference between itching and pain: a human fMRI study. NeuroImage 2007; 36: 706–717.
    View article    Google Scholar
  16. Mochizuki H, Tashiro M, Kano M, Sakurada Y, Itoh M, Yanai K. Imaging of central itch modulation in the human brain using positron emission tomography. Pain 2003; 105: 339–346.
    View article    Google Scholar
  17. Valet M, Pfab F, Sprenger T, Woller A, Zimmer C, Behrendt H, et al. Cerebral processing of histamine-induced itch using short-term alternating temperature modulation – an FMRI study. J Invest Dermatol 2008; 128: 426–433.
    View article    Google Scholar
  18. Darsow U, Drzezga A, Frisch M, Munz F, Weilke F, Bartenstein P, et al. Processing of histamine-induced itch in the human cerebral cortex: a correlation analysis with dermal reactions. J Invest Dermatol 2000; 115: 1029–1033.
    View article    Google Scholar
  19. Drzezga A, Darsow U, Treede RD, Siebner H, Frisch M, Munz F, et al. Central activation by histamine-induced itch: analogies to pain processing: a correlational analysis of O-15 H2O positron emission tomography studies. Pain 2001; 92: 295–305.
    View article    Google Scholar
  20. Schneider G, Ständer S, Burgmer M, Driesch G, Heuft G, Weckesser M. Significant differences in central imaging of histamine-induced itch between atopic dermatitis and healthy subjects. Eur J Pain 2008; 12: 834–841.
    View article    Google Scholar
  21. Ständer S, Schmelz M. Chronic itch and pain – similarities and differences. Eur J Pain 2006; 10: 473–478.
    View article    Google Scholar
  22. Bantick SJ, Wise RG, Ploghaus A, Clare S, Smith SM, Tracey I. Imaging how attention modulates pain in humans using functional MRI. Brain 2002; 125: 310–319.
    View article    Google Scholar
  23. Seminowicz DA, Mikulis DJ, Davis KD. Cognitive modulation of pain-related brain responses depends on behavioral strategy. Pain 2004; 112: 48–58.
    View article    Google Scholar
  24. Tracey I, Ploghaus A, Gati JS, Clare S, Smith S, Menon RS, et al. Imaging attentional modulation of pain in the periaqueductal gray in humans. J Neurosci 2002; 22: 2748–2752.
    View article    Google Scholar
  25. Chaves JF, Dworkin SF. Hypnotic control of pain: historical perspectives and future prospects. Int J Clin Exp Hypn 1997; 45: 356–376.
    View article    Google Scholar
  26. Valet M, Sprenger T, Boecker H, Willoch F, Rummeny E, Conrad B, et al. Distraction modulates connectivity of the cingulo-frontal cortex and the midbrain during pain – an fMRI analysis. Pain 2004; 109: 399–408.
    View article    Google Scholar
  27. Eccleston C. Chronic pain and distraction: an experimental investigation into the role of sustained and shifting attention in the processing of chronic persistent pain. Behav Res Ther 1995; 33: 391–405.
    View article    Google Scholar
  28. Miron D, Duncan GH, Bushnell MC. Effects of attention on the intensity and unpleasantness of thermal pain. Pain 1989; 39: 345–352.
    View article    Google Scholar
  29. Apkarian AV, Bushnell MC, Treede R-D, Zubieta J-K. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 2005; 9: 463–484.
    View article    Google Scholar
  30. Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron 2007; 55: 377–391.
    View article    Google Scholar
  31. Choudhury N, Amer I, Daniels M, Wareing MJ. Audiovisual distraction reduces pain perception during aural microsuction. Ann R Coll Surg Engl 2013; 95: 34–36.
    View article    Google Scholar
  32. Kohl A, Rief W, Glombiewski JA. Acceptance, cognitive restructuring, and distraction as coping strategies for acute pain. J Pain 2013; 14: 305–315.
    View article    Google Scholar
  33. Leibovici V, Magora F, Cohen S, Ingber A. Effects of virtual reality immersion and audiovisual distraction techniques for patients with pruritus. Pain Res Manag 2009; 14: 283–286.
    View article    Google Scholar
  34. Papoiu ADP, Nattkemper LA, Sanders KM, Kraft RA, Chan Y-H, Coghill RC, et al. Brain’s reward circuits mediate itch relief. a functional MRI study of active scratching. PloS One 2013; 8: e82389.
    View article    Google Scholar
  35. Vierow V, Forster C, Vogelgsang R, Dorfler A, Handwerker HO. Cerebral networks linked to itch-related sensations induced by histamine and capsaicin. Acta Derm Venereol 2015; 95: 645–652.
    View article    Google Scholar
  36. Papoiu ADP, Kraft RA, Coghill RC, Yosipovitch G. Butorphanol suppression of histamine itch is mediated by nucleus accumbens and septal nuclei: a pharmacological fMRI study. J Invest Dermatol 2015; 135: 560–568.
    View article    Google Scholar
  37. Stumpf A, Burgmer M, Schneider G, Heuft G, Schmelz M, Phan NQ, et al. Sex differences in itch perception and modulation by distraction – an FMRI pilot study in healthy volunteers. PloS One 2013; 8: e79123.
    View article    Google Scholar
  38. Stroop JR. Studies of interference in serial verbal reactions. Journal of Experimental Psychology 1935; 18: 643–662.
    View article    Google Scholar
  39. Bradley MM, Lang PJ. Measuring emotion: the self-assessment manikin and the semantic differential. Behav Ther Exp Psychiatry 1994; 25: 49–59.
    View article    Google Scholar
  40. Friston KJ, Ashburner J, Kiebel SJ, Nichols TE, Penny WD. Statistical parametric mapping: the analysis of functional brain images. 2007.
    View article    Google Scholar
  41. Wiech K, Jbabdi S, Lin CS, Andersson J, Tracey I. Differential structural and resting state connectivity between insular subdivisions and other pain-related brain regions. Pain 2014; 155: 2047–2055.
    View article    Google Scholar
  42. Tracey I, Ploghaus A, Gati JS, Clare S, Smith S, Menon RS, et al. Imaging attentional modulation of pain in the periaqueductal gray in humans. J Neurosci 2002; 22: 2748–2752.
    View article    Google Scholar
  43. Dunckley P, Wise RG, Fairhurst M, Hobden P, Aziz Q, Chang L, et al. A comparison of visceral and somatic pain processing in the human brainstem using functional magnetic resonance imaging. J Neurosci 2005; 25: 7333–7341
    View article    Google Scholar
  44. Milham MP, Banich MT, Webb A, Barad V, Cohen NJ, Wszalek T, et al. The relative involvement of anterior cingulate and prefrontal cortex in attentional control depends on nature of conflict. Brain Res Cogn Brain Res 2001; 12: 467–473.
    View article    Google Scholar
  45. Liu X, Banich MT, Jacobson BL, Tanabe JL. Functional dissociation of attentional selection within PFC: response and non-response related aspects of attentional selection as ascertained by fMRI. Cereb Cortex 2006; 16: 827–834.
    View article    Google Scholar
  46. Banich MT, Milham MP, Atchley RA, Cohen NJ, Webb A, Wszalek T, et al. Prefrontal regions play a predominant role in imposing an attentional ‘set’: evidence from fMRI. Brain research. Cogn Brain Res 2000; 10: 1–9.
    View article    Google Scholar
  47. Banich MT, Milham MP, Atchley R, Cohen NJ, Webb A, Wszalek T, et al. fMri studies of Stroop tasks reveal unique roles of anterior and posterior brain systems in attentional selection. J Cogni Neurosci 2000; 12: 988–1000.
    View article    Google Scholar
  48. Bench CJ, Frith CD, Grasby PM, Friston KJ, Paulesu E, Frackowiak RS, et al. Investigations of the functional anatomy of attention using the Stroop test. Neuropsychol 1993; 31: 907–922.
    View article    Google Scholar
  49. MacDonald AW, Cohen JD, Stenger VA, Carter CS. Dissociating the role of the dorsolateral prefrontal and anterior cingulate cortex in cognitive control. Science 2000; 288: 1835–1838.
    View article    Google Scholar
  50. Coderre EL, Filippi CG, Newhouse PA, Dumas JA. The Stroop effect in kana and kanji scripts in native Japanese speakers: an fMRI study. Brain Lang 2008; 107: 124–132.
    View article    Google Scholar
  51. Polk TA, Drake RM, Jonides JJ, Smith MR, Smith EE. Attention enhances the neural processing of relevant features and suppresses the processing of irrelevant features in humans: a functional magnetic resonance imaging study of the Stroop task. J Neurosci 2008; 28: 13786–13792.
    View article    Google Scholar
  52. Carter CS, Mintun M, Cohen JD. Interference and facilitation effects during selective attention: an H215O PET study of Stroop task performance. NeuroImage 1995; 2: 264–272.
    View article    Google Scholar
  53. Lorenz J, Minoshima S, Casey KL. Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation. Brain 2003; 126: 1079–1091.
    View article    Google Scholar
  54. Yosipovitch G, Ishiuji Y, Patel TS, Hicks MI, Oshiro Y, Kraft RA, et al. The brain processing of scratching. J Invest Dermatol 2008; 128: 1806–1811.
    View article    Google Scholar
  55. Hadjipavlou G, Dunckley P, Behrens TE, Tracey I. Determining anatomical connectivities between cortical and brainstem pain processing regions in humans: a diffusion tensor imaging study in healthy controls. Pain 2006; 123: 169–178.
    View article    Google Scholar
Supplementary content
Table SI
Table SII