Introduction

Itch has been defined as 'an unpleasant sensation associated with the desire to scratch' since 1660 (Hafenreffer, 1660). This is a desire nearly all of us combat at some time in our lives. In one of the original marriages of body and mind, itch cannot be divorced from scratch, what does scratching achieve? One, is that pain of scratch abolishes itch. The other is that it is a highly rewarding and seemingly addictive behavioral response (Yosipovitch et al., 2007). Previous imaging studies, evaluating the central processing of pruritus, have implicated activity in the premotor and supplementary motor areas to the motor and behavioral response of scratching (Hsieh et al., 1994; Darsow et al., 2000; Drzezga et al., 2001; Mochizuki et al., 2003; Walter et al., 2005; Leknes et al., 2007; Valet et al., 2007). Similar areas have also been implicated in pain imaging (Mochizuki et al., 2003; Apkarian et al., 2005; May, 2007) and therefore it is not clear whether these areas are associated with sensory or motor components of the scratch response. A recent study has also found significant cerebellar hemispheres' activity during itch, and it was suggested that these activations are related to the urge to scratch (Herde et al., 2007). During non-painful vibrotactile somatosensory stimuli, the primary somatosensory (SI) and secondary somatosensory (SII) cortices have been shown to be activated without or minimal activity in non-sensory cortices associated with affect (Coghill et al., 1994; Burton et al., 2004). In contrast, painful stimuli are associated with a much broader activation of SI, SII, anterior cingulate cortex (ACC), and insula. The insula and ACC have important connections with the limbic system associated with the negative affect of pain. To date, no study has examined the neural networks activated by scratching itself. The primary aim of this study was to examine the central sensory effects of repetitive scratching using blood oxygen level-dependent functional magnetic resonance imaging (fMRI) in healthy subjects. To minimize motor-related activation associated with self-scratching, subjects received passive scratching to accurately study the sensory aspects of scratching. A secondary aim was to examine if there is any relationship between perceived scratching intensity and brain areas involved in scratching.

Results

All subjects perceived movement of the cytology brush as scratching. Scratch intensity rating ranged from 2 to 62 mm with the mean intensitySD being 2518.

Repetitive scratching activates sensory and non-sensory brain areas

The scratch stimulus induced brain activation within bilateral portions of SII cortex, insular cortex (left posterior and right anterior), prefrontal cortex (PFC), anterior and posterior cerebellum, inferior parietal lobe, and right frontal operculum. Bilateral temporal operculum, superior temporal gyrus, left dorsal ACC, and left dorsofrontal cortex also exhibited increased activation. It should be noted that scratching did not activate the SI cortex or the thalamus (Figure 1 and Table 1).

Figure 1.

Brain activation during scratching stimuli. These images are located at x_ 2 x_ 28 mm, y_ - 18, y_ - 26, y_ - 64 mm, z_ - 8 mm and z_ 14 and z_ 22 mm in standard stereotaxic space. Red represents brain activation, whereas blue represents brain deactivation.

Full figure and legend (137K)

Table 1 - Talairach coordinates and anatomic substrate of scratching-related activation and deactivation.

Full table

Repetitive scratching deactivates sensory, non-sensory, and motor brain areas

The scratch stimulus induced brain deactivation within bilateral portions of the SI cortex, primary motor cortex, supplementary motor area, perigenual ACC, and dorsal and ventral posterior cingulate cortex (PCC) (Figure 1 and Table 1).

Correlation

All subjects perceived movement of the cytology brush as scratching. Scratch intensity rating ranged from 2 to 62 mm with the mean intensitySD being 2518.

There was a significant correlation between perceived scratch intensity among subjects and bilateral deactivation of the ACC (P=0.02). However, no other significant correlation between perceived scratch intensity and brain activity was seen (Figure 2).

Figure 2.

ACC activity is inversely related to the perceived intensity of scratch. There was a significant correlation between perceived scratch intensity and bilateral deactivation of the ACC (P=0.02). These images are located at x_ 2 mm, y_ 18 mm, and z_ 34 mm in standard stereotaxic space. Blue represents brain deactivation.

Full figure and legend (44K)

Discussion

Neuroimaging studies assessing the central processing of pruritus have implicated the premotor and supplementary motor areas to the urge to scratch. However, no study has assessed the central effects of scratching itself. This study shows that repetitive scratching induces robust bilateral activation of the SII cortex, insular cortex, PFC, inferior parietal lobe, and cerebellum. In addition, we show that the same stimulus results in robust deactivation of the anterior and posterior cingulate cortices. Results of our study are summarized in schematic form in Figure 3.

Figure 3.

Schematic representation of brain activity during scratching. Red arrows show brain areas that are activated, whereas blue arrows show brain areas that are deactivated by scratching. It is hypothesized that activity in the prefrontal cortex serves to drive the compulsion to continue scratching.

Full figure and legend (142K)

Tactile stimuli, such as application of a brush or rough sponge, as well as vibratory stimuli have both been shown to result in bilateral activation of the SII cortex (Gelnar et al., 1998; Baron et al., 1999; Polonara et al., 1999). However, these stimuli are not entirely reflective of scratching because of differences mainly in frequency (tactile stimulus has a lower frequency than scratching, whereas vibratory stimulus has a higher frequency) and roughness (probes used in experimental studies are typically smooth surfaced). This study used a scratch stimulus with an estimated frequency of 1–5 Hz that has both been validated and described as similar to scratching by our previous studies (Yosipovitch et al., 2007).

We show that repetitive scratching bilaterally activates the SII cortex. The SII cortex has already been shown to respond bilaterally to electrical nerve stimulation (Ferretti et al., 2004), tactile (Zhu et al., 2007) and painful stimuli (Coghill et al., 1994; Ferretti et al., 2003; Koyama et al., 2005). This ipsilateral activation of the SII cortex by scratching and other stimuli may be explained in principle by two neural pathways: (i) direct input from the thalamus or (ii) callosal connections from the SII cortex of the opposite hemisphere. We also show the insular cortex to be robustly activated by repetitive scratching, a similar finding to that elicited by other different sensory stimuli such as pain, touch, sight, and taste (Nagai et al., 2007).

In this study, scratching did not activate the SI cortex, an area of brain heavily involved in the processing of different sensory stimuli, including pain (Oshiro et al., 2007). Both tactile and vibrotactile stimuli have been shown to activate the contralateral SI cortex (Fox et al., 1987; Coghill et al., 1994; Polonara et al., 1999); thus, it is surprising that scratching did not result in activation of this area but in fact caused deactivation. In addition, we show bilateral deactivation of the primary motor cortex following scratching. Tying these observations together, Hlushchuk and Hari (2006) demonstrated phasic suppression of the ipsilateral SI cortex and in the primary motor cortices of both hemispheres in response to tactile stimuli applied to the finger. The authors of this study explained the negative blood oxygen level-dependent response by a decreased neuronal activity as a result of interhemispheric inhibition (Hlushchuk and Hari, 2006). Interestingly, our study did not show activity in the thalamus, a similar finding to other studies assessing vibrotactile stimuli (Fox et al., 1987; Coghill et al., 1994; Polonara et al., 1999).

A unique feature of scratching is activation of the insula and PFC, non-sensory areas likely involved in affect and attention. This activity has not been demonstrated during vibrotactile stimuli (Coghill et al., 1994; Burton et al., 2004). The activation of these areas may be associated with the reward and positive affect of scratching. In the presence of itch, the rewarding aspects of scratching may be amplified. In future studies, it would be of major interest to determine if scratching with itch would be associated with amplification of activity of the insula and PFC.

Repetitive scratching also resulted in bilateral deactivation of the ACC (perigenual region). Neuroimaging studies (and unpublished data from ourselves) have clearly shown experimentally induced itch to activate the ACC (an area of brain involved with emotional and cognitive processing) in healthy subjects (Hsieh et al., 1994; Darsow et al., 2000; Drzezga et al., 2001; Mochizuki et al., 2003; Walter et al., 2005; Leknes et al., 2007). It is thus possible that one mechanism by which scratching mediates its inhibition of itch is through the deactivation of the ACC. A recent study has shown for the first time a limbic deactivation of the subgenual ACC and the amygdala during an on-and-off itch stimulus with histamine and codeine (Herde et al., 2007). The authors further suggest that this downregulation may be related to the preparation for scratching. Our results with scratching support this hypothesis. It should be noted that we show a significant negative correlation between perceived scratch intensity and bilateral deactivation of the ACC. Furthermore, the perigenual region of the ACC has been particularly associated with emotional processing. It is well known that the experience of pruritus is a multidimensional phenomenon consisting of sensory, cognitive, evaluative, and motivational components (Ikoma et al., 2006). Scratching may thus suppress the emotional components of pruritus and thereby bring about its relief.

In addition, the perception of pruritus is highly influenced by our experiences, memories, and expectations. We show scratching to deactivate the PCC, an area of brain heavily involved with memory. Furthermore, the PCC may mediate interactions of emotional and memory-related processes (Nelson et al., 2004). Scratching may thus suppress activity in this area and, as a result, attenuate the perception of pruritus. Additionally, the PCC has been hypothesized to be involved in a "default-mode network" with increased activity in the resting brain (Greicius et al., 2003). The deactivation in the PCC seen in this study may thus represent a diversion of attention from the resting brain state to the scratching stimulus.

Scratching results in significant activation of the cerebellum, an area of brain activated by other sensory stimuli, including pruritus and pain (Hsieh et al., 1994; Coghill et al., 1999; Walter et al., 2005; Oshiro et al., 2007). Historically, the cerebellum has been associated with motor coordination; however, recent research has implicated this area in sensory coordination as well as certain aspects of cognition and changes in affect (Ellerman et al., 1994; Nitschke et al., 1996; Luft et al., 1998; Rijntjes et al., 1999; Grodd et al., 2001; Habas et al., 2004). Thus, activity in this area induced by scratching may be explained by sensory coordination of these stimuli (Herde et al., 2007). Future studies that assess the central processing of scratching in subjects with cerebellar dysfunction (for example, multiple sclerosis, which interestingly is frequently associated with pruritus; Sandyk, 1994) will facilitate defining the exact role of the cerebellum in response to these stimuli (Derache et al., 2006).

One of the longest-standing enigmas of pruritus research relates to the underlying mechanisms of the "itch–scratch cycle". This study shows bilateral activation of the PFC induced by repetitive scratching. Substantial neurobiological evidence supports the existence of distinct goal-directed and habit-learning systems in rats, with the PFC implicated in such behaviors (Stefani and Moghaddam, 2006). It is thus possible that activity induced by scratching in the PFC may serve to drive the compulsion to continue scratching. It could also account for the highly rewarding aspects of scratching.

Neuroimaging studies assessing the central processing of pruritus have presumed activity in the premotor and supplementary motor areas to the behavioral urge of scratching (Hsieh et al., 1994; Darsow et al., 2000; Drzezga et al., 2001; Mochizuki et al., 2003; Walter et al., 2005; Leknes et al., 2007; Valet et al., 2007). This study, however, showed these areas of brain to be deactivated during repetitive scratching. Previous studies have shown the stimulus of pain to activate the premotor and supplementary motor areas also, implying that these areas can be activated by sensory stimuli alone (Nelson et al., 2004). Importantly, none of the subjects in our study reported scratching as painful. Furthermore, deactivation of the motor areas by scratching may represent a relaxation of muscle tone brought about by the pleasurable and interpersonal aspects of being scratched. It should be noted that scratching was passive in our study and not a true motor response to pruritus. It would be of great interest to examine the effect of different intensities of scratching within the subject on brain imaging of scratch.

Conclusion

Scratching is the fundamental behavioral response to itch, which is both highly rewarding and relieving. This study demonstrates brain areas (motor, sensory, and non-sensory) that are activated and deactivated by repetitive scratching. Future studies that investigate the central effects of scratching in chronic itch conditions will be of high clinical relevance.

Materials And Methods

Subjects

Thirteen healthy subjects (six women, seven men) participated in this study (meanSD: 27.811.8). All procedures were approved by the Institutional Review Board of Wake Forest University School of Medicine. All volunteers provided written informed consent and were free to withdraw from the study at any time. Experiments were performed in accordance with the Declaration of Helsinki Principles.

Experimental task

Subjects underwent functional imaging during scratching of the right lower leg. Scratching stimulus was started 60 seconds after initiation of fMRI acquisition and was cycled between 30-second duration applications of scratching and 30-second duration applications of no stimuli.

Scratching stimulus

Scratching was accomplished by study personnel repetitively moving a cytology brush (Medi-Pak 7-inch cytology brush; General Medical Corporation, Elkridge, MD) over the left leg. Uniformity was controlled by applying sufficient pressure to bend skin-facing brush bristles, so that the brush handle touched the skin surface. The bending force of the cytology brush was equivalent to approximately 29 g on a digital scale. The cytology brush includes approximately 1,000 individual bristles, and the diameter of the brush was 7.5 mm. In addition, the same member of the research team (MIH) applied the cytology brush for all subjects. Scratching was started 60 seconds after initiation of fMRI acquisition and was cycled between 30-second duration applications of scratching and 30-second duration applications of no stimuli. Each examinee underwent a training session in which study personnel applied the cytology brush. The examinee was asked whether the procedure was similar to their experience when they scratch their skin. All subjects reported that they perceived this procedure as closely simulating scratching. In addition, this scratching stimulus has been shown to inhibit itch in a previous psychophysical study in healthy subjects (Yosipovitch et al., 2007). None of the examinees perceived application of the cytology brush as a painful, pricking, or burning sensation.

Subjects used a 100-mm visual analog scale (ranging from 0 to 100 mm) to report perceived intensity of scratching once at the end of each series of fMRI. Thus, two ratings of scratching were obtained.

Image acquisition and image processing

fMRI data were acquired on a 1.5-T General Electric Twin-Speed LX Scanner with a birdcage quadrature head coil (General Electric Healthcare, Milwaukee, WI). For functional imaging, two-dimensional blood oxygenation level-dependent images of the entire brain were acquired continuously by using single-shot echo planar imaging (echo time, 40 milliseconds; repetition time, 2 seconds; 28 5-mm-thick slices; in-plane resolution, 3.75 3.75 mm; flip angle, 90°; no slice gap) (Ogawa et al., 1990). The total acquisition time for each fMRI experiment was 320 seconds. The first 20 seconds of the fMRI experiment is used to establish steady state. The data acquired during this time are discarded in post-processing. Two fMRI series with a scratch stimulus were acquired for each subject. During the fMRI acquisition, subjects were requested to close their eyes. High-resolution structural scans were acquired using an inversion recovery three-dimensional spoiled gradient echo with inversion preparation sequence (inversion time, 600 milliseconds; repetition time, 9.1 milliseconds; flip angle, 20°; echo time, 1.98 milliseconds; matrix, 256 196; slice thickness, 1.5 mm; 124 slices with an in-plane resolution, 0.9375 0.9375 mm; field of view, 24.0 18.4 cm).

The functional image analysis package FSL (Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (Center for FMRIB, University of Oxford, Oxford, UK)) was used for image processing and statistical analysis. The functional data were motion corrected, spatially smoothed with a 5-mm three-dimensional isotropic Gaussian kernel, and temporally filtered by a nonlinear high-pass filter with a cutoff period of 100 seconds. Each functional image was scaled by its mean global intensity (intensity normalization). Next, each subject's functional images were registered to their structural data using a seven-parameter linear three-dimensional transformation and transformed into standard stereotaxic space (as defined by the Montreal Neurological Institute) using a 12-parameter linear three-dimensional transformation (Talairach and Tournoux, 1988; Jenkinson et al., 2002).

Statistical analysis of regional signal changes within the brain

Brain activity during scratching was compared with that during rest using a regressor, where scratch was given an arbitrary value of 1, rest - 1, and the prescratch period was 0. This regression was corrected for the hemodynamic response of scratch stimuli. Using these regressors, interseries group analyses across 13 subjects were performed separately for scratch, with a fixed-effects model within series and within subject and random-effects model between subjects (Woolrich et al., 2001).

We used psychophysical ratings of scratch as a covariate of interest in between-subject analyses to identify brain activation that was significantly related to perceived scratch intensity. Clusters of voxels exceeding a Z-score >2.3 and P<0.05 were considered statistically significant (Worsley et al., 1992).

Conflict Of Interest

The authors state no conflict of interest.

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Acknowledgments

This study was supported by the Center for Biomolecular Imaging of Wake Forest University Health Sciences. Dr Robert C Coghill was supported by the National Institutes of Health Grant RO1 NS39426.