Central mechanisms of itch.

Clinical Neurophysiology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph

Review

Central mechanisms of itch Hideki Mochizuki a,b,⇑, Ryusuke Kakigi a a b

Department of Integrative Physiology, National Institute for Physiological Sciences, Okazaki, Aichi, Japan Department of Dermatology and Temple Itch Center, Temple University School of Medicine, Philadelphia, PA, USA

a r t i c l e

i n f o

Article history: Accepted 18 November 2014 Available online xxxx Keywords: Itch Central itch modulation Contagious itch Scratching-induced pleasurability Functional brain imaging

h i g h l i g h t s This review article discusses functional roles of brain regions activated by itch stimuli, in particular

the primary and secondary somatosensory cortices, the cingulate cortex, and the insular cortex. The central mechanisms of the itch modulation system, contagious itch, and pleasurable sensation

evoked by scratching are also discussed. The cerebral mechanism of itch partly differs between healthy subjects and chronic itch patients.

a b s t r a c t Itch is a complex sensory and emotional experience. Functional brain imaging studies have been performed to identify brain regions associated with this complex experience, and these studies reported that several brain regions are activated by itch stimuli. The possible roles of these regions in itch perception and difference in cerebral mechanism between healthy subjects and chronic itch patients are discussed in this review article. Additionally, the central itch modulation system and cerebral mechanisms of contagious itch, pleasurable sensation evoked by scratching have also been investigated in previous brain imaging studies. We also discuss how these studies advance our understanding of these mechanisms. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . The cerebral representation of itch . . . . . . . . . SI and SII . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cingulate cortex and IC . . . . . . . . . . . . . . . . . . Central itch modulation . . . . . . . . . . . . . . . . . . Contagious Itch. . . . . . . . . . . . . . . . . . . . . . . . . Pleasurable sensation evoked by scratching. . Chronic itch patients versus healthy subjects Conclusion and future directions . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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⇑ Corresponding author at: Department of Dermatology and Temple Itch Center, Temple University School of Medicine, Philadelphia, PA, USA. Tel.: +1 215 707 6394; fax: +1 215 707 9510. E-mail address: [email protected] (H. Mochizuki). http://dx.doi.org/10.1016/j.clinph.2014.11.019 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Mochizuki H, Kakigi R. Central mechanisms of itch. Clin Neurophysiol (2014), http://dx.doi.org/10.1016/ j.clinph.2014.11.019

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H. Mochizuki, R. Kakigi / Clinical Neurophysiology xxx (2014) xxx–xxx

1. Introduction Itch is an unpleasant somatic sensation with the desire to scratch. To the best of our knowledge, the cerebral mechanism of itch in humans was first investigated about 20 years ago (Hsieh et al., 1994). Since then, several brain imaging studies have been conducted to understand this mechanism using positron emission tomography (PET), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and magnetoencephalography (MEG). Most of these studies have investigated the cerebral response to physical itch-inducing stimuli such as histamine, cowhage, and electrical itch stimuli. The authors discussed the cerebral representation of itch and the possible functional roles of the identified brain regions in itch perception. Additionally, other brain imaging studies have investigated interesting phenomena related to itch. For example, itch can be suppressed by scratching or pain stimuli. Viewing itch in others and imaging the itch sensation can induce scratching responses and real itch sensations (Niemeier et al., 2000). This phenomenon is referred to as contagious itch. Moreover, scratching an itch induces a pleasurable sensation (Bin saif et al., 2012). Although the findings obtained from these studies are insufficient to fully elucidate the underlying mechanisms, several interesting findings have been reported. Thus, we also discussed these studies in this review.

2. The cerebral representation of itch Histamine and cowhage are frequently used to induce an itch sensation. This sensation is mainly associated with the excitation of C-fibers (Schmelz et al., 1997, 2003; Namer et al., 2008). The neural signal associated with itch is further transmitted to the brain via the spinothalamic tract (STT) (Andrew and Craig, 2001). However, the itch sensation evoked by histamine and cowhage is transmitted by different populations of C-fibers and STT (Johanek

et al., 2007, 2008; Davidson et al., 2007; Namer et al., 2008). Thus, to understand the mechanism of cowhage-induced itch is important for the treatment of itch that cannot be inhibited by antihistamines. Several brain imaging studies have been conducted to identify brain regions activated by itch stimuli. As shown in Fig. 1, many brain regions were found to respond to histamineand cowhage-induced itch such as the prefrontal cortex (PFC), supplementary motor area (SMA), premotor cortex (PM), primary motor cortex (MI), primary somatosensory cortex (SI), parietal cortex, cingulate cortex, precuneus, opercular cortex (OPC) including the secondary somatosensory cortex (SII) and insular cortex (IC), claustrum, basal ganglia including the striatum, thalamus, and cerebellum (Hsieh et al., 1994; Darsow et al., 2000; Drzezga et al., 2001; Mochizuki et al., 2003, 2007, 2009; Walter et al., 2005; Leknes et al., 2007; Herde et al., 2007; Ishiuji et al., 2009; Papoiu et al., 2012). Interestingly, a previous brain imaging study reported that brain activation patterns differ between histamine- and cowhage-induced itch (Papoiu et al., 2012), suggesting that the neural mechanism of itch differs between histamine and cowhage not only in the periphery and spinal cord but also in the brain. Because the brain regions observed in the previous itch studies are also activated by pain stimuli (Treede et al., 2000; Apkarian et al., 2005), it appears that there is no brain region specifically activated by itch stimuli. Itch can also be induced by the application of electrical stimuli to the skin (Edwards et al., 1976; Shelley and Arthur, 1957; Tuckett, 1982). It has been reported that electrical stimulation most effectively generates the itch sensation for stimulus durations P2 ms and frequencies P50 Hz (Ikoma et al., 2005). Using this method, the types of peripheral nerve fibers associated with electrically induced itch were investigated using EEG (Mochizuki et al., 2008). As shown in Fig. 2A, the peak latency of the evoked potentials (EPs) to electrical itch stimuli was approximately 900 ms after the onset of these stimuli when the stimuli were applied to the wrists. By contrast, the peak latency of the EPs appeared a few hundred milliseconds earlier when the stimuli

Fig. 1. Representative brain regions activated by itch stimuli. pre-SMA: pre-supplementary motor area, SMA: supplementary motor area, dACC: dorsal part of the anterior cingulate cortex, aMCC: anterior part of the midcingulate cortex, MI: primary motor cortex, SI: primary somatosensory cortex, Th: thalamus, PCC: posterior cingulate cortex, Prec: precuneus, Cb: cerebellum, PFC: prefrontal cortex, PM: premotor cortex, BG: basal ganglia, OPC: opercular cortex, SII: secondary somatosensory cortex, IC: insular cortex.



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Fig. 2. Evoked potential associated with electrical itch stimuli. Evoked potential (EP) when itch stimuli were applied to the wrists (A) and forearms (B). EP was recorded at Cz according to the international 10–20 system. Bold and thick lines were averaged and individual EP, respectively. P1: Peak of amplitude. The figure has been reproduced with the permission of the International Association for the Study of PainÒ (IASP). The figure may not be reproduced for any other purpose without permission.

were applied to the forearms than to the wrists (Fig. 2B). The estimated conduction velocity (CV) calculated using the distance between the wrists and forearms and the difference in peak latencies between them was approximately 1 s. This value was within the range of the CV of C-fibers (0.4– 4 m/s). Thus, electrically evoked itch is mainly associated with C-fibers. Unfortunately, the precise peripheral mechanism of the itch sensation evoked by electrical stimuli is still unclear. An MEG study investigated the temporal profile of the cerebral processing of itch using electrically evoked itch (Mochizuki et al., 2009). As shown in Fig. 3A, magnetic responses to electrical itch stimuli were detected in three different brain regions, including the ipsilateral and contralateral frontotemporal areas and the centroparietal area. The magnetic responses observed in the frontotemporal areas originated from the OPC, including SII and IC, whereas the responses observed in the centroparietal area originated from the precuneus. The peak latencies of magnetic responses in the contralateral OPC were significantly shorter than those in the ipsilateral OPC (contralateral side: 740 ± 76 ms, ipsilateral side: 785 ± 76 ms). This difference in latency may reflect the transmission of neural signals from the contralateral to ipsilateral OPC (Fig. 3B). The timing of activation of the precuneus was between those of the contralateral and ipsilateral OPC. Previous itch studies using PET and fMRI also reported activation of similar regions during itch stimuli (Herde et al., 2007;

Mochizuki et al., 2007; Ishiuji et al., 2009; Bergeret et al., 2011; Papoiu et al., 2012). By contrast, no previous pain or tactile studies using MEG and EEG reported dipoles in the precuneus (e.g., Valeriani et al., 2002; Garcia-Larrea et al., 2003; Cruccu et al., 2003; Forss et al. 2005; Inui et al. 2003; Kakigi et al. 2005; Kanda et al. 2000; Nakata et al. 2008; Opsommer et al. 2001; Ploner et al. 1999, 2000), which implied that some differences may exist in medial parietal processing between itch and other somatic sensations. However, the precuneus is not specific to itch in somatosensory processing, as the response of this region to pain and tactile stimuli was observed in some previous PET and fMRI studies (de Leeuw et al. 2006; Iadarola et al. 1998; Kitada et al. 2005; Niddam et al. 2008). Unfortunately, the precise role of the precuneus in somatosensory processing is unclear. It was reported that pain sensitivity is inversely related to regional gray matter density in the precuneus (Emerson et al., 2014). In addition, it has also been reported that the modulation of pain by hypnosis is partly associated with the precuneus (Schulz-Stübner et al. 2004; Faymonville et al., 2006). An fMRI study of itch reported that activity in the precuneus is significantly and positively correlated with the subjective sensation of itch (Herde et al., 2007). Considering these studies, the precuneus may be associated with the subjective sensations of itch and pain. Several studies have reported that the precuneus is activated when shifting attention in a certain


4


A

OPCc

OPCi

Precuneus

B R Prec OPCi

OPCc

Fig. 3. Magnetic responses to electrical itch stimuli and their source localizations. (A) Magnetic responses to electrical itch stimuli were mainly observed in three different regions (single subject). (B) The mean source localizations of these responses obtained from subjects were estimated in the left and right opercular cortex (OPC) and precuneus (Prec). R: right hemisphere. Black arrow: transition of itch-related signals from the contralateral OPC (OPCc) to ipsilateral OPC (OPCi).

direction and during a motor-imagery task that includes spatial information such as moving eyes, hands, arms, and legs to certain directions (LaBar et al., 1999; Ogiso et al., 2000; Heide et al., 2001; Cavanna and Trimble, 2006; Simon et al., 2002). The itch sensation also induces similar mental processing such as directing attention to the itchy skin and unconsciously or consciously imagining moving one’s hand to the itchy skin (i.e., the desire to scratch). These mental components may be associated with activation of the precuneus during itch stimuli. Further study will be needed to clarify the role of this region in itch perception. 3. SI and SII In pain studies, the SI and SII are considered to be the main regions for the sensory-discriminative component (Fig. 1C). However, their roles seem to differ. Animal and human studies have demonstrated that SI activity bears a linear relationship with stimulus intensity and subjective pain sensation, indicating that the SI plays important roles in the perception of pain intensity (Dong et al., 1989, 1994; Timmermann et al., 2001; Bornhövd et al., 2002; Frot et al., 2007). On the other hand, these studies have also shown that SII activity exhibited an S-shaped function with a sharp increase in amplitude only at a stimulus intensity well above the pain threshold. Based on these observations, it is considered that the SII may subserve the recognition of pain and attention toward painful stimuli. However, a clinical study using intracranial

recordings reported that the S-shaped function is mainly derived from the posterior part of the IC (pIC) (Frot et al., 2007). It is still controversial whether the SII encodes stimulus intensity. In itch research, only one study has investigated the cerebral response to multiple different intensities of itch stimuli (Drzezga et al., 2001). This study demonstrated that SI activity, but not SII activity, was significantly and positively correlated with the stimulus intensity and subjective itch ratings, speculating that the SI plays an important role in the intensity coding of itch (Fig. 4). The location of significant activation of the SI during itch stimuli in this previous study is close to the arm area of the somatosensory homunculus in humans (Nakamura et al., 1998), suggesting that the SI encodes the location of itch (Fig. 4). The role of the SII in itch perception is still unclear. Previous itch studies using PET and fMRI did not observe a significant correlation between SII activity and the stimulus intensity of itch stimuli and subjective itch sensations (Drzezga et al., 2001; Leknes et al., 2007; Mochizuki et al., 2007), except for one fMRI study (Herde et al., 2007). Perhaps, similar to pain, this region may be associated with recognition and attention (Fig. 4). 4. Cingulate cortex and IC The cingulate cortex is activated by itch stimuli. The peak locations of significant activations in the cingulate cortex observed in previous itch studies were mainly located in the dorsal part of the anterior cingulate cortex (dACC), which corresponds to the


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IC SII · Recognition of itch · Attention to itch · Intensity of itch

SI

aIC · Emotional states (e.g., unpleasantness of itch) · Subjective sensation of itch pIC · Bodily feeling (i.e., itch and its physical intensity)

· Intensity of itch · Location of itch

dACC/aMCC

Thalamus

· Cognition of itch · Motor intention of the desire to scratch

Fig. 4. Possible roles of SI, SII, IC, and cingulate cortex in itch perception. SI: primary somatosensory cortex, SII: secondary somatosensory cortex, aIC: anterior part of the insular cortex, pIC: posterior part of the insular cortex, dACC: dorsal part of the anterior cingulate cortex, and aMCC: anterior part of the midcingulate cortex.

anterior part of the midcingulate cortex (aMCC) (Fig. 1A). This region is associated with cognition rather than emotion (Bush et al., 2000). In addition, the dACC/aMCC is also associated with motivation. For example, electrical stimulation of the MCC can evoke the motivation to act (Vogt and Sikes, 1990). Considering these studies, the activations in the cingulate cortex observed in previous itch studies are likely to be associated with cognition of itch stimuli and motor intentions resulting from the desire to scratch (Fig. 4). The IC is also activated by itch stimuli (Fig. 1D). The anterior and posterior ICs have different roles. The anterior part is considered to be more engaged in the awareness of emotion and subjective feelings, whereas the posterior part is considered to be associated with the awareness of affective body feelings (e.g., pain, cold, and thirst) (Craig, 2010). This concept is partly supported by clinical studies. It was reported that somatic sensations including noxious and innocuous sensations were evoked by applying electrical stimuli to the pIC (Ostrowsky et al., 2002). Lesions in the anterior part of the IC (aIC) lead to deficits of emotional awareness (e.g., alexithymia) (Gu et al., 2013), whereas those in the pIC can induce loss of bodily feeling (e.g., anosognosia) (Jones et al., 2010) and abnormal bodily feeling such as spontaneous pain (Isnard et al., 2011). An fMRI study showed that subjective feelings of perceived thermal sensations and physical stimulus intensity of the thermal stimuli were significantly correlated with activity in the aIC and pIC, respectively (Craig et al., 2000). Previous itch studies observed activations of both parts of the IC (Herde et al., 2007; Leknes et al., 2007; Mochizuki et al., 2007, 2009, 2014; Papoiu et al., 2012). The pIC is one of the major cortical targets of the STT (Dum et al., 2009), and itch signals are transmitted to the brain through the STT (Andrew and Craig, 2001; Davidson et al., 2007). In accordance with this anatomical pathway, only pIC showed a significant correlation between its activity and the physical intensity of itch stimuli (Drzezga et al., 2001). On the other hand, several studies reported that activity in the aIC was significantly and positively correlated with the subjective itch sensation and unpleasantness of itch (Herde et al., 2007; Leknes et al.,

2007; Mochizuki et al., 2007; Bergeret et al., 2011; Papoiu et al., 2012). The same concept may be applicable for the roles of ICs in itch perception (Fig. 4).

5. Central itch modulation Itch can be inhibited by scratching. A previous animal study investigated the neural mechanism of this phenomenon (Davidson et al., 2009). This study observed that neural activity in the spinal cord associated with itch was suppressed during and after scratching, and it proposed two possible mechanisms that explain the itch suppression. One possibility was that scratching inhibits ascending neural signals associated with itch at the spinal level through inhibitory neurons in the spinal cord. The other possibility was a top-down modulation from the supraspinal level. These mechanisms were investigated by another animal study (Akiyama et al., 2011). That study reported that scratching was 50% less effective in reducing neuronal firing after transection of the upper cervical spinal cord, and that scratching still reduced neuronal firing (by 24%), but to a lesser degree than before transection. This finding demonstrated that both mechanisms (i.e., inhibitory neurons and top-down modulation) are associated with scratching-induced itch suppression. A human PET study reported that activity in the periaqueductal gray (PAG) increased while the itch sensation was suppressed by cold pain stimuli (Mochizuki et al., 2003). The PAG is involved in descending inhibitory control, which was identified in the pain research field. As shown in Fig. 5, ascending neural signals associated with pain stimuli are inhibited at the spinal level by descending neural signals from the PAG and the rostral medulla (Millan, 2002). Carstens (1997) reported that excitation of the PAG inhibited neural firing evoked by histamine application at the spinal level. Therefore, an itch modulation system may exist that is similar to descending inhibitory control, and this has been partly supported by an fMRI study showing that the midbrain including the PAG was activated during scratching (Mochizuki et al., 2014). By contrast, another fMRI study reported that activity in the PAG was reduced while the itch sensation was

PAG

VM

Ascending signal from the periphery

Spinal cord Fig. 5. Descending inhibitory control. PAG: periaqueductal gray, VM: ventral medulla.


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suppressed by scratching (Papoiu et al., 2013). Based on this finding, the study suggested that an opposite effect operates in itch modulation during scratching. That is, the deactivation of PAG may be a key factor in itch modulation by scratching. The PAG sends projections to the rostral medulla (Millan, 2002). There are off- and on-cells in this region, and these cells send descending neural fibers to the spinal cord to inhibit and enhance neural responses in the spinal cord, respectively (Vanegas and Schaible, 2004). Activations of on-cells can enhance behavioral and spinal neuronal responses to noxious stimulation (Porreca et al., 2002). The PAG and ventral medulla play important roles in the transmission of noxious signals (Ghazni et al., 2010). If on-cells are associated with the transmission of itch-related neural signals from the spinal cord to the brain, inhibition of activity in on-cells can inhibit this transmission. The deactivation of the PAG due to scratching observed in the previous fMRI study might inhibit activity in oncells in the rostral medulla to suppress the itch sensation. A more precise investigation using animals will be needed to clarify whether the PAG and rostral medulla are associated with itch modulation during scratching and how these regions contribute to itch modulation.

brain regions activated were similar to those reported in previous fMRI studies of empathy for pain. The aIC is considered to play an important role in empathy for pain (Bird et al., 2010; Lamm and Singer, 2010). This region would also be involved in empathy for itch. However, it remains unclear why itch is contagious. This issue was investigated by comparing brain activity while subjects imagined the itch sensation by viewing pictures depicting itch (e.g., the skin with allergic reactions) with that while they imagined the pain sensation by viewing pictures depicting pain (e.g., burned skin) (Mochizuki et al., 2013). Activation patterns in the brain were similar between itch and pain imagery. On the other hand, a difference was observed in functional connectivity between itch and pain imagery (Figs. 6 and 7). Functional connectivity between the aIC and basal ganglia significantly increased while subjects imagined the itch sensation. The basal ganglia have an anatomical circuit with several cortical areas including the SMA, PM, and MI (Krakauer and Ghez, 2000). This cortico-striatal circuit plays an important role in motor control (Krakauer and Ghez, 2000). The aIC has an anatomical connection with the basal ganglia (Nieuwenhury et al., 1988; Flynn et al., 1999). Interestingly, lesions in the aIC attenuate motivation and craving (Naqvi et al., 2007). A possible mechanism underlying the scratching response due to viewing itch in others may be that activation of the aIC directly or indirectly manipulates (i.e., enhanced) activity in the corticostriatal circuit via the basal ganglia (Fig. 8). As shown in Fig. 6, functional coupling between the aIC and global pallidus (Gp) was higher while viewing itch in others than while viewing pain (Mochizuki et al., 2013). The Gp is associated with the motivation to act and goal-directed behavior (Miller et al., 2006; Adam et al., 2013). This difference in functional coupling could explain why the motor response (i.e., scratching behavior for itch) can be easily evoked by viewing itch in others. Another mystery of contagious itch is that viewing itch in others can induce real itch sensations in observers. However, its cerebral mechanism is still unclear. A previous fMRI study of contagious itch observed significant

6. Contagious Itch When one views others experiencing the pain or itch sensation, one can empathize with them. Viewing itch in others can also induce scratching behavior and real itch sensations in observers (Niemeier et al., 2000; Ikoma et al., 2006; Papoiu et al., 2011). This phenomenon is referred to as contagious itch. It seems that monkeys have a similar capability (Feneran et al., 2013). On the other hand, pain in others is less contagious. Two previous studies investigated the cerebral mechanism underlying contagious itch using fMRI (Holle et al., 2012; Mochizuki et al., 2013) and demonstrated that several brain regions including the IC, SMA, PM, and PFC were activated while viewing others experiencing the itch sensation. The

Brain regions increased connectivity with the right aIC during imagery of pain x = -34

z = 30

x = 36

z = 40 ACC

Occipital

Intensity of connectivity (parameter estimates)

pOPC

1.0

z = 54

z = 61 pre-SMA / SMA

MI/PM

PM/DLPFC

p = 0.002

0.5

0.0

-0.5

Itch

Pain

-1.0

Fig. 6. Functional connectivity during pain imagery. Brain regions that showed significant connectivity in activity with the right anterior insular cortex (aIC) during pain imagery are shown (blue color regions). The green region is where functional connectivity was significantly stronger for pain imagery than for itch imagery. pOPC: posterior opercular cortex, ACC: anterior cingulate cortex, MI: primary motor cortex, PM: premotor cortex, DLPFC: dorsolateral prefrontal cortex, (pre-) SMA:(pre-) supplementary motor area. The figure has been reproduced with the permission of the International Association for the Study of PainÒ (IASP). The figure may not be reproduced for any other purpose without permission.


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Brain regions increased connectivity with the left aIC during imagery of itch z=4

x=6

z = 13

BG

z = 33 ACC

TA Parietal

Intensity of connectivity (parameter estimates)

Left Gp 1.0

Right Gp p = 0.004

p = 0.007 1.0

0.5

0.5

0.0

0.0

Itch

Pain

-0.5

-0.5

-1.0

-1.0

Fig. 7. Functional connectivity during itch imagery. Brain regions that showed significant connectivity in activity with the left anterior insular cortex (aIC) during pain imagery are shown (red color regions). The green regions are where functional connectivity was significantly stronger for itch imagery than for pain imagery. TA: tegmental area, BG: basal ganglia, Gp: globus pallidus, ACC: anterior cingulate cortex. The figure has been reproduced with the permission of the International Association for the Study of PainÒ (IASP). The figure may not be reproduced for any other purpose without permission.

(e. Contagious itch

aIC

I) ex Cort PM, M , A M g., S Cortico-striatal circuit

BG Pleasure of scratching

Th

DA Fig. 8. A potential neural circuit associated with scratching. The cortico-striatal circuit may play an important role for scratching behavior and the desire to scratch. The anterior insular cortex (aIC) and dopaminergic neurons (DA) in the brain may affect activity in this circuit to drive the scratching response due to contagious itch and induce excessive scratching caused by the pleasure of scratching, respectively.

activation of the SI while subjects watched others scratching the body (Holle et al., 2012). This activation would be independent of empathy for tactile sensation caused by viewing scratching the body, because the effect of empathy for tactile sensation on brain activity was cancelled out by comparing brain activity between viewing scratching and tapping the body in their study. Interestingly, activation of the SI has not been observed in most previous brain imaging studies of empathy for pain. Additionally, an fMRI study with a schizophrenia patient reported that the SI is partly associated with somatic hallucinations (Shergill et al., 2001). The SI may be partly associated with itch perception due to contagious itch. Alternatively, brain regions that have not been observed in previous fMRI studies of contagious itch may play important roles.

In these previous fMRI studies, subjects were asked to report the intensity of feeling of itch or imagined itch sensation. Thus, it was uncertain whether the subjects actually perceived the itch sensation. Perhaps, real itch sensation was not evoked in the previous studies. If so, these studies failed to observe key brain regions associated with itch perception due to contagious itch. There were two brain imaging studies that investigated somatic hallucination such as tactile and pain hallucinations. Both studies observed a significant activation of the medial parietal cortex including the posterior cingulate cortex and precuneus (Shergill et al., 2001; Bär et al. 2002). This region is also associated with memory (Cavanna and Trimble, 2006). Memory of past experience of itch may be a key factor of the itch sensation evoked by viewing itch in others. The medial parietal cortex could be another potential region associated with the itch sensation due to contagious itch.

7. Pleasurable sensation evoked by scratching The desire to scratch is evoked when one perceives the itch sensation. Scratching itchy skin suppresses the itch sensation, while simultaneously evoking the pleasurable sensation. This sensation can induce excessive scratching. However, the underlying cerebral mechanisms for these phenomena remain unclear. To the best of our knowledge, two studies investigated this issue (Papoiu et al., 2013; Mochizuki et al., 2014). These studies reported activations of the reward system such as the midbrain, striatum, medial PFC (mPFC), ACC, and OFC while the pleasurable sensation was evoked (Fig. 9C). These regions play an important role in pleasure (Fig. 10) (de Araujo et al., 2003; McCabe and Rolls, 2007; Filbey et al., 2008; Izuma et al., 2008; Salimpoor et al., 2011; Kühn and Gallinat, 2012). Thus, it is suggested that scratching-induced pleasurability is also associated with the reward system. In the previous fMRI studies investigating the pleasurable sensation evoked by


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z = -29

z = -13

z = -8

z=0

z = 10

z = 36

z = 52

R

A. Pleasant

B. Control Striatum

IC

IFG/PM

MCC PM SMA

C. P > C Cb

Midbrain

Thalamus

S1

Fig. 9. Scratching-related activations in the brain. Brain regions significantly activated while scratching stimuli were applied in the pleasant (A) and control (B) conditions. R: right hemisphere. (C) Brain regions that showed significantly higher activity in the pleasant condition compared with the control condition (P > C) within the brain regions significantly activated in the pleasant condition. Cb: cerebellum, IC: insular cortex, IFG: inferior frontal gyrus, PM: premotor cortex, MCC: medial cingulate cortex, SMA: supplementary motor area, SI: primary somatosensory cortex.

Fig. 10. The reward system. mPFC: medial prefrontal cortex, ACC: anterior cingulate cortex, OFC: orbitofrontal cortex, DA: dopaminergic neurons in the midbrain, Str: striatum. The mPFC, ACC, OFC, and striatum are innervated by DA through nerve fibers (purple arrows).

scratching, scratching was performed by experimenters and not by subjects themselves (passive scratching). Thus, subjects did not move their hand during scratching. However, motor-related regions such as the SMA, PM, and cerebellum were activated during passive scratching (Fig. 9A and B). Interestingly, activity in these regions during scratching with pleasure was significantly higher than that during scratching without pleasure (Fig. 9C). One possible interpretation of this enhanced activity would be that scratching itchy skin unconsciously or consciously induces a different type of desire such as the desire to scratch to get further pleasurability. This interpretation is partly supported by animal and

clinical studies. For example, an animal study reported that motivation to act caused by expected reward enhances activity in the SMA and PM (Roesch and Olson, 2003). Electrical stimulation of the SMA can induce an urge to act (Fried et al., 1991), while reducing excitability of the SMA can suppress a compulsive urge for a certain behavior (obsessive–compulsive disorder) (Mantovani et al., 2013). The midbrain is rich in dopaminergic neurons (Saper, 2000), which send projections to several areas including the striatum, mPFC, ACC, and OFC and regulate activity in these areas (Fig. 10) (Saper, 2000; Björklund and Dunnett, 2007; Salimpoor et al., 2011). The findings of human and animal studies directly and indirectly demonstrated that dopaminergic neurons were activated by pleasurable stimuli (Wise and Rompre, 1989; Berke and Hyman, 2000; Myrick et al., 2000; Drevets et al., 2004; Small et al., 2003; Boileau et al., 2003; de Araujo et al., 2003: Barrett et al., 2004; Pelchat et al., 2004; Filbey et al., 2008; McClernon et al., 2009; Wang et al., 1999, 2004; Salimpoor et al., 2011). Unfortunately, there is no study investigating the relationship between dopamine and pleasurable sensation evoked by scratching. However, considering that activity in the midbrain increases with increment of scratching-induced pleasurability (Papoiu et al., 2013; Mochizuki et al., 2014), dopamine release is likely to be increased by the pleasurable sensation evoked by scratching. 8. Chronic itch patients versus healthy subjects Chronic itch is a major symptom in dermatological diseases such as atopic eczema, and it is a frequent symptom in other Table 1 Classification of chronic itch. Causes

Examples of diagnoses

Dermatologic Systemic

Atopic eczema, psoriasis, xerosis Chronic kidney disease, cholestasis, human immunodeficiency virus infection Brachioradial pruritus, notalgia paresthesia, postherpetic itch Obsessive–compulsive disorder, delusions of parasitosis, substance abuse

Neuropathic Psychogenetic



diseases as well (Yosipovitch and Bernhard, 2013) (Table 1). Severe itch and scratch due to diseases affect the quality of life of patients similar to chronic pain. Therefore, it is important to understand the pathophysiology of chronic itch. Even though there are many chronic itch patients, few functional brain imaging studies have been conducted as yet. Two studies previously investigated similarities and differences in brain activation patterns associated with itch between patients with atopic eczema and healthy subjects. One study reported significantly higher activity in the basal ganglia for patients with atopic eczema (Schneider et al., 2008). The other study showed a similar trend (Ishiuji et al., 2009). Moreover, one other study observed enhanced baseline activity and higher density of the gray matter in a similar region in patients with endstage renal disease pruritus (Papoiu et al., 2014). The basal ganglia play an important role in motor control, motivation to act, and craving. One significant problem for chronic itch patients is scratching. Scratching damages the skin, which, in turn, exacerbates the itch symptoms. However, excessive scratching and habitual scratching are frequently seen in chronic itch patients (Allen and Harris, 1966; Zschocke et al., 2000; Rishe et al., 2008). The enhanced activity and increased gray matter in the basal ganglia observed in chronic itch patients may be associated with these behaviors. Future study will be needed to evaluate this possibility, which will advance our understanding of the pathophysiology of chronic itch.

9. Conclusion and future directions Brain research on itch began just about 20 years ago. About 20 studies have been published during this period. Most studies have investigated the cerebral response to itch stimuli. Multiple brain regions are activated by itch stimuli. The SI is suggested to be associated with the sensory and discriminative aspect of itch, whereas the SII may have higher order of functions such as cognition of itch and attention to itch. The aIC and dACC/aMCC are engaged in the affective and motivational aspects of itch. The pIC is likely to be associated with the awareness of bodily feeling (e.g., itch and its physical intensity). However, the findings of previous itch studies are not sufficient to support these interpretations. Thus, more precise investigations will be needed to evaluate the roles of these regions in itch perception. For example, manipulating neural activity in local brains will give us more direct evidence to understand the role of each brain region. In this point of view, animal studies or human studies using transcranial magnetic stimulation and transcranial direct current stimulation that can manipulate neural activity in the brain in living humans will be useful and play important roles in advancing the understanding of the cerebral mechanism of itch. Scratching is a significant component of itch. In particular, it is one of the severe problems for chronic itch patients, because it damages the skin and this damage aggravates the itch symptom. Based on previous itch studies, we speculate that the cortico-striatal circuit plays an important role in the scratching behavior (Fig. 8). Interestingly, a part of this circuit (i.e., the basal ganglia) showed enhanced activity and increased gray matter in chronic itch patients. This circuit may become a target for inhibiting excessive and habitual scratching behavior seen in chronic itch patients. Previous studies have clearly demonstrated that the descending itch modulation system exists. To understand this mechanism will lead to development of novel treatments for itch relief. Thus, it is important to identify whether and how the PAG and ventral medulla are associated with itch suppression. It would also be important to investigate whether this modulation system affects only itch sensation and, if so, whether there are specific descending pathways or chemical agents to inhibit itch. From a clinical point of view, it is also interesting that psychological interventions (e.g.,

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Central Mechanisms of Itch.

The peripheral and central mechanisms underlying itch.

Peripheral Mechanisms of Itch.

Itch mechanisms and circuits.

Understanding itch: an update on mediators and mechanisms of pruritus.

Neuroimmune interactions in itch: Do chronic itch, chronic pain, and chronic cough share similar mechanisms?

PI3Kγ: Partners in Central Transmission of Itch.

Molecular and cellular mechanisms that initiate pain and itch.

Phantom itch, pseudophantom itch, and senile pruritus.

Neuroimaging of central breathlessness mechanisms.

Enhanced itch elicited by capsaicin in a chronic itch model.

Itch itch with not a wink of sleep.

Mechanisms of central tolerance for B cells.

Some methods for evaluating clinical itch and their application for studying pathophysiological mechanisms.

Dhobies' Itch.

The epistolary itch.

A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch.

Erratum to: Molecular and cellular mechanisms that initiate pain and itch.

Referred itch (Mitempfindungen).

Cholinergic mechanisms in central thermoregulation in pigeons.

Neuropathic pain and injured nerve: central mechanisms.

Trp channels and itch.

Breaking the itch cycle.

Protease-activated receptors and itch.