A transcranial direct current stimulation over the sensorimotor cortex modulates the itch sensation induced by histamine
Introduction
An itch is an unpleasant sensation that is accompanied by the desire to scratch, which is the easiest way to suppress this sensation (Davidson et al., 2009, Vierow et al., 2009, Mochizuki et al., 2014). However, it often causes skin damage and exacerbates the itch. Therefore, scratching represents a significant problem in patients with chronic itch sensations such as atopic dermatitis. Thus, other approaches for the relief of itching need to be identified.
Although an itch is a distinct sensation from pain, they share several features. Itch sensations are transmitted to the brain through C-fibers (Schmelz et al., 1997) and the spinothalamic tract (Andrew and Craig, 2001). The common brain regions activated by itch and pain stimuli include the insula, cingulate cortex, prefrontal cortex, inferior parietal cortex, pre-/supplementary motor cortex, somatosensory cortex, and basal ganglia (Drzezga et al., 2001, Mochizuki et al., 2007). Furthermore, some endogenous inhibitory mechanisms have also been detected in both processes. A previous study suggested that the periaqueductal gray matter in the midbrain was related to the modulation of itch, which is known to be a component of the pain modulation system (Mochizuki et al., 2003). Another study showed that strong stress-induced antinociception attenuated itch-related scratching in rats as well as nociceptive behaviors (Spradley et al., 2012).
A top-down approach by stimulating the primary somatosensory cortex (SI) or primary motor cortex (MI) has recently been investigated for the treatment of pain. Non-invasive brain stimulation techniques using a repetitive transcranial magnetic stimulation, theta burst stimulation, or transcranial direct current stimulation (tDCS) have been applied as useful options (Song et al., 2011, Mylius et al., 2012, Vaseghi et al., 2014). The intervention of tDCS has some advantages over other brain stimulation techniques because the device is portable, inexpensive, easy to apply, and safe in the setting of clinical practice (Poreisz et al., 2007, Tanaka and Watanabe, 2009). Previous studies demonstrated that tDCS interventions modulated experimentally-induced pain sensations in healthy subjects (Antal et al., 2008, Boggio et al., 2008, Terney et al., 2008, Csifcsak et al., 2009, Hansen et al., 2011, Reidler et al., 2012). One possible mechanism is that widespread changes in pain-related subcortical and cortical brain regions; however, this is still being debated because some studies failed to find positive effects (Jürgens et al., 2012, Ihle et al., 2014). The effects of the repeated application of tDCS to suppress various types of chronic pain such as fibromyalgia (Fregni et al., 2006b, Valle et al., 2009), spinal cord injury (Fregni et al., 2006a), multiple sclerosis (Mori et al., 2010), and migraine (Dasilva et al., 2012) have been investigated in clinical studies.
On the other hand, only one study has been reported for itch relief. This study examined the effects of a sustained tDCS intervention on neuropathic pain and itch sensations, and found that the tDCS intervention reduced the itch sensation (Knotkova et al., 2013). However, this investigation was only performed on a single patient. Thus, a quantitative evaluation with more subjects needs to be performed in order to verify whether tDCS has positive effects on itch relief. This issue was investigated in the present study.
The SI area is considered to play an important role in the intensity coding of itch sensations (Drzezga et al., 2001), and was previously shown to be activated with contralateral hemisphere predominance (Darsow et al., 2000, Ishiuji et al., 2009, Mochizuki et al., 2009). Thus, we targeted the contralateral SI area to modulate itch sensations. Recent tDCS studies that targeted SI or MI reported that a bi-hemispheric intervention represented a more powerful strategy for modulating sensory or motor functions than a uni-hemispheric stimulation (Vines et al., 2008, Fujimoto et al., 2014, Koyama et al., 2015). These findings suggested that the bi-hemispheric intervention yielded the combined effects of increased excitability from anodal tDCS and decreased inter-hemispheric inhibition from cathodal tDCS over the ipsilateral side. Therefore, we here in addressed the efficacy of bi-hemispheric tDCS interventions over the SI for itch sensations in healthy subjects using a double-blind, Sham-controlled, and cross-over experimental design.
Section snippets
Participants
Fourteen healthy volunteers (2 females and 12 males, mean age: 30.9 ± 6.9 years, 13 right-handed and 1 left-handed) participated in the present study. Before measurements were taken, we confirmed that participants did not use anti-histaminic or anti-inflammatory drugs or have immunological and dermatological diseases. This study was approved by the Ethics Committee at the National Institute for Physiological Sciences (NIPS). Written informed consent was obtained from each participant in every
Results
As shown in Fig. 1C, the itch sensation peaked immediately after the electrical stimulus for the histamine-induced itch and decreased over time. The means ± SD of rNRS scores before the tDCS intervention were 1.2 ± 0.2 for R-A/L-C, 1.2 ± 0.3 for L-A/R-C, and 1.3 ± 0.4 for Sham. No significant differences were observed before the tDCS intervention (F(2, 20) = 1.36, p = 0.28, partial η2 = 0.12).
Discussion
The present study demonstrated histamine-induced itch modulation during bi-hemispheric tDCS interventions over the SMC using a double-blind, Sham-controlled, and cross-over design. We revealed that the R-A/L-C intervention (anodal electrode placed over the SMC of the contralateral side to the stimulated hand and cathodal electrode placed over that of the ipsilateral one) significantly decreased the peak and lasting subjective itch sensation, whereas the inhibitory effects of the reverse layout
Conclusions
We confirmed the antipruritic effects of experimentally-induced itch sensations in healthy participants. By combining the results obtained in the present study with the findings of a previous case report, we suggest that a SMC stimulation using tDCS is useful for the treatment of itching. Further studies are needed to explore more effective stimulus conditions for this method for future clinical applications.
Acknowledgments
The authors are grateful to Dr. K. Inui for his helpful comments on the manuscript and Mr. Y. Takeshima for his technical support. This work was supported by the Strategic Research Foundation Grant-aided Project for Private Universities (S1311011), the Center of Innovation Science and Technology based Radical Innovation and Entrepreneurship Program (COI STREAM), and a Grant-in-Aid for Young Scientists (B) (24790584) from Ministry of Education, Culture, Sports, Sciences, and Technology (MEXT),
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