Hideki Mochizuki

Scratching Induces Overactivity in Motor-Related Regions and Reward System in Chronic Itch Patients

Scratching evokes a rewarding and pleasurable sensation, particularly in chronic itch patients. To date, no study has investigated the cerebral activity during scratching in chronic itch patients and whether it differs from that in healthy subjects. Using arterial spin labeling functional magnetic resonance imaging, we analyzed and compared the cerebral mechanism of self-scratching and its correlation with pleasurability in 10 patients with chronic itch and in 10 healthy controls. Cowhage was applied to the right forearm to induce itch. Scratching significantly attenuated the itch sensation (P<0.001) and evoked an associated pleasurability. Scratching-induced pleasurability significantly activated the reward system in the chronic itch and healthy groups, confirming that this reward system has a crucial role in scratching-induced pleasurability. A higher activity during scratching in chronic itch patients, versus healthy controls, was noted in brain regions related to motor control and motivation to act, including the supplementary motor area, premotor cortex, primary motor cortex, and midcingulate cortex, as well as the caudate nucleus involved in the reward system. This overactivity may be associated with the addictive scratching and/or neural hypersensitization.

Central mechanisms of itch

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.

A transcranial direct current stimulation over the sensorimotor cortex modulates the itch sensation induced by histamine

OBJECTIVEnItching can be suppressed by scratching. However, scratching may aggravate itch symptoms by damaging the skin. Therefore, identifying an alternative approach to suppress itching is of clinical importance. The aim of the present study was to determine whether a transcranial direct current stimulation (tDCS) was useful for itch relief.nnnMETHODSnThe present study was performed on a double-blind, Sham-controlled, and cross-over experimental design. A histamine-induced itch was evoked on the left dorsal forearms of healthy participants, who were asked to report the subjective sensation of itching every 30s for 23 min. tDCS was applied over the sensorimotor cortex (SMC) according to a bi-hemispheric stimulation protocol during the itch stimuli; one electrode was placed over the right SMC, while the other was placed over the left SMC. The peak and lasting sensations of itching were compared between R-A/L-C (anodal electrode placed over the right and cathodal electrode over the left), L-A/R-C (anodal electrode placed over the left and cathodal electrode over the right), and Sham interventions.nnnRESULTSnThe peak and lasting itch sensation were significantly suppressed during the R-A/L-C intervention than during the Sham intervention. On the other hand, the L-A/R-C intervention suppressed the peak itch sensation, but the effects did not last for more than a few minutes.nnnCONCLUSIONSnThese results suggest that a bi-hemispheric tDCS intervention, especially when the anodal electrode was placed over the SMC of the contralateral side, was a potentially useful method for relieving lasting itch sensations.nnnSIGNIFICANCEnThe present study demonstrated that a tDCS intervention may be an alternative approach for suppressing unpleasant itch sensations in healthy participants. Since tDCS has some advantages, namely, its easy application and safety in a clinical setting, it may become a useful method for the treatment of itching.

Neuroimaging of Itch as a Tool of Assessment of Chronic Itch and Its Management

Chronic itch is a multidimensional physical state strongly associated with emotional and cognitive aspects of suffering that causes the urge to scratch. Pathophysiology, psychological stress, and social milieu can influence itch. Here, we review brain neuroimaging research in humans that detects functional and anatomic changes in health and disease states. New data are emerging that are shaping our understanding of itch mechanisms and scratching-the behavioral response as well as the effect of treatments and brain dynamics during itch. Future developments will continue to expand our knowledge of itch mechanisms, allowing translation to clinical assessment and novel therapies focused on the brain, the final relay of itch transmission.

Brain mechanism of itch in atopic dermatitis and its possible alteration through non-invasive treatments

Atopic dermatitis (AD) is a common chronic skin disease that is characterized by intense pruritus and has high impairment of quality of life. AD is often described as the itch that rashes, rather than the rash that itches. Several studies suggest that mechanisms of central modulation play an important role in the development and maintenance of chronic itch. Therefore, treating the neurosensory aspects of itch is an important part in the management of chronic itch. However, little attention has been paid to the role of the central nervous system in the processing of itch in AD. Targeting itch-related anatomical structures in the brain with non-invasive treatments such as psychological interventions and transcranial Direct Current Stimulation (tDCS) could have an antipruritic effect in AD. Therefore, in this review article, we discuss the current progress in brain imaging research of itch, as well as the efficacy of non-invasive interventions for itch relief in this patient group.

Itch and brain.

Itch is an unpleasant somatic sensation that evokes the urge to scratch. Chronic itch is a severe problem that diminishes quality of life. There are many patients suffering from chronic itch across the world. The brain is the final terminal to receive itch‐related signals from the body and plays an important role in perceiving the itch sensation. Thus, to understand the cerebral mechanism of itch perception and how this mechanism differs between healthy subjects and chronic itch patients is important for advancing our understanding on the pathophysiology of chronic itch. Itch is suppressed by scratching or applying painful stimuli. The pleasurable sensation evoked by scratching an itch increases the urge to scratch. Viewing others in itch or imagining the itch sensation may evoke real itch sensations and the scratching response. To understand the mechanisms responsible for these phenomena may provide useful information for the development of treatment of itch and advance our understanding of the cerebral mechanism of itch and scratch. Several functional brain imaging studies have addressed these issues and reported interesting findings. In this review article, the authors discussed the findings of previous studies and how they have advanced our understanding of the central mechanisms of itch, scratch and chronic itch.

Suppression of scratching-induced pleasurable sensation by compression nerve blocking and its association with itch relief

Itch can be suppressed by scratching. At the same time, scratching evokes a pleasurable sensation. In the present study, we investigated the peripheral mechanism of scratching-induced pleasurability and its association with itch relief using compression nerve block. We found that myelinated nerve fibers (A&bgr;-fibers and possibly A&dgr;-fibers), are involved in transmission of scratching-induced pleasurability. We observed that itch relief effect was the same regardless of whether the pleasurable sensation was evoked by scratching an itch, indicating that pleasure is not a necessary component to induce itch relief. This is the first study to investigate the peripheral mechanism of scratching-induced pleasurability and itch relief.

Brain Processing of Contagious Itch in Patients with Atopic Dermatitis

Several studies show that itch and scratching cannot only be induced by pruritogens like histamine or cowhage, but also by the presentation of certain (audio-) visual stimuli like pictures on crawling insects or videos showing other people scratching. This phenomenon is coined “Contagious itch” (CI). Due to the fact that CI is more profound in patients with the chronic itchy skin disease atopic dermatitis (AD), we believe that it is highly relevant to study brain processing of CI in this group. Knowledge on brain areas involved in CI in AD-patients can provide us with useful hints regarding non-invasive treatments that AD-patients could profit from when they are confronted with itch-inducing situations in daily life. Therefore, this study investigated the brain processing of CI in AD-patients. 11 AD-patients underwent fMRI scans during the presentation of an itch inducing experimental video (EV) and a non-itch inducing control video (CV). Perfusion based brain activity was measured using arterial spin labeling functional MRI. As expected, the EV compared to the CV led to an increase in itch and scratching (p < 0.05). CI led to a significant increase in brain activity in the supplementary motor area, left ventral striatum and right orbitofrontal cortex (threshold: p < 0.001; cluster size k > 50). Moreover, itch induced by watching the EV was by trend correlated with activity in memory-related regions including the temporal cortex and the (pre-) cuneus as well as the posterior operculum, a brain region involved in itch processing (threshold: p < 0.005; cluster size k > 50). These findings suggest that the fronto-striatal circuit, which is associated with the desire to scratch, might be a target region for non-invasive treatments in AD patients.

Central Representation of Itch

Chronic itch is multidimensional phenomenon associated with emotional and cognitive aspects of suffering that causes the urge to scratch. The brain is the final terminal to receive itch-related neural signals from the body and to process them. Thus, it is important to better understand the mechanism of itch and its behavioral response of scratching in the brain. Brain imaging studies using positron emission tomography, functional MRI, electroencephalography, and magnetoencephalography have been conducted to understand the cerebral mechanism of itch mainly in healthy subjects using experimental itch models. Several brain imaging studies have investigated this mechanism in chronic itch patients to better understand the pathophysiology of chronic itch in the central nervous system. Pharmacological functional MRI studies add to our understanding of drug-effects on brain systems. Recently, this technique was used to investigate how a kappa opioid drug butoprhanol, modulates the processing of itch in the brain. Other promising treatments targeting the brain such as non-invasive transcranial Direct Current Stimulation that has been used for treatments of chronic pain has been reported for itch relief. In this chapter, we review the current progress in neuroimaging research of itch and scratch and its treatments.