The bookshelf on www.moisesparabebesweb.com.Available from National Library of Medicine, National Institutes of Health. Edited by Carstens E and Akiyama T.Treatment for Itch.The CRC Press/Taylor & Francis Group; 2014. Boca Raton, FL.


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Hideki Mochizuki, Alexandru D.P Papoiu, and Gil Yosipovitch.


23.1. OVERVIEW

The purpose of this chapter is to review the findings of neuroimaging studies that evaluated the processing of itch and scratching in the superior relays of the central nervous system (CNS) when itch was induced experimentally or pathological pruritus was studied as a preexisting condition in chronic diseases.An understanding of the central processing of itch can provide insight into potential altered CNS functioning in diseases such as pruritus as well as identify sources of central sensitization.Brain imaging can detect functional and anatomic changes as a result of chronic itching and can guide treatment by showing how itching can be inhibited.


23.2.1. From Spinal Cord to the Thalamus

Current models for neuronal itch transmission describe distinct pathways for histamine-mediated and nonhistaminergic forms of itch. To date, no consensus has been reached on whether itch is conveyed via a dedicated (“labeled”) line or whether it is encoded by the differential participation of subpopulations of neurons expressing specific pruriceptors. It is possible that itch-specific information is primarily encoded at the spinal level by an interplay of inputs from peripheral afferents, spinal cord interneurons, inhibitory inputs from strictly nociceptive afferents, and top–bottom inhibitory inputs from higher CNS structures (such as the periaqueductal gray formation). It was also proposed that neurons in the thalamus can distinguish nociceptive versus pruriceptive information via a selection mechanism (Davidson and Giesler 2010). Two main neuronal pathways have been described for itch transmission: one mediated by histamine and the other by protease activated receptors PAR2(4) receptors that can be exogenously stimulated by spicules of cowhage (Mucuna pruriens). Upon skin contact cowhage releases a cysteine protease, mucunain, that acts as a ligand for PAR2 receptors. The histamine and cowhage itch modalities are conveyed via distinct peripheral C- and A-delta fibers that synapse in the dorsal horn of the spinal cord. The continuing spinothalamic pathways ascend via the lateral spinothalamic tract and (mostly) maintain their specialization, up to their thalamic (third neuron) stations (Davidson et al. 2009, 2012).

It is now clearly established that a major station for itch transmission is located in the thalamus. Histamine-responsive and cowhage-responsive spinothalamic neurons project in the ventral posterior lateral (VPL), ventral posterior inferior, and posterior nuclei, while cowhage-sensitive neurons additionally end in the suprageniculate and medial geniculate nuclei (Davidson et al. 2012). These studies using antidromic stimulation in nonhuman primates and neuroimaging studies in humans (Papoiu et al. 2012a) were in good agreement showing that cowhage itch evoked a more extensive activation of thalamic nuclei than histamine itch. Functional magnetic resonance imaging (MRI) data also suggested that cowhage itch activated more strongly a thalamic area consistent with the location of the mediodorsal nucleus (Leknes et al. 2007; Papoiu et al. 2012a), which is connected with the orbitofrontal area and the limbic system. Of note, a dysfunction of this circuit was suggested to occur in processing itch in atopic patients (Leknes et al. 2007).


23.2.2. From Thalamus to the Cortex

Because the exact projections of the third (thalamic) neurons conveying itch information from the thalamus to the cerebral cortex have not been identified, they can be inferred from brain imaging studies. Histamine has been the stimulus mostly used as the experimental pruritogen for brain imaging of itch (Hsieh et al. 1994; Darsow et al. 2000; Drzezga et al. 2001; Mochizuki et al. 2003, 2007, 2009; Herde et al. 2007; Valet et al. 2008; Leknes et al. 2007; Schneider et al. 2008; Ishiuji et al. 2009). Considering the lack of effectiveness of antihistamines in pathological forms of itch (e.g., atopic dermatitis and End-Stage-Renal-Disease pruritus) and the involvement of PAR2 in itch of atopic eczema, the PAR2/cowhage model has been proposed as a more suitable experimental model for chronic pruritus. Therefore, more recent neuroimaging studies employed both experimental models of itch induction, using histamine and cowhage for itch stimulation. When the patterns of brain activation evoked by these modalities were compared, common features, but also significant differences were observed (Papoiu et al. 2012a) — vide infra (part 3).


23.3.1. General Observations

The multidimensional character of itch experience is reflected in the complexity of itch processing in the brain. The experimental induction of itch leads to simultaneous and long-term activations in multiple brain areas. Itch processing activates somatosensory areas (S1, S2) and interoceptive areas such as insular cortex, and it is accompanied by an invariable emotional-affective response recruiting deep-seated areas of the limbic system, areas connected to craving, pleasure and addiction. Itch is a bothersome, intrusive, acute sensation, requesting an immediate action response; thus major arms of the cerebral itch response are involved in refocusing attention, planning the motor action and seeking itch relief. Numerous brain imaging studies—irrespective of the investigative modalities—agreed in their findings that these interconnected responses occur in the brain almost simultaneously.


23.3.2. Principal Areas Implicated in Itch Processing

The regions most frequently activated in the majority of brain imaging studies, using Positron Emission Tomography (PET) or functional Magnetic Resonance Imaging (MRI) techniques (Blood Oxygen Level Dependent or Arterial Spin Labeling ) were areas specialized in receiving somatosensory inputs: (S1), the associative/secondary somatosensory area S2, areas regulating emotional control and affective responses (pleasantness or unpleasantness), such as the cingulate cortex, in both its anterior and posterior divisions (ACC and PCC), and were linked with evaluative functions and decision-making, such as the dorsolateral prefrontal cortex (DLPFC). Premotor, motor, and supplementary motor areas as well as the cerebellum, which controls an effective/actual or planned response to initiate scratching, are also seen as inseparable from the sensory activations evoked by itch. The activation of premotor cortex and supplementary motor area (SMA) areas are seen in the majority of itch imaging studies, even when scratching itself is not allowed during the brain imaging experiments.

Areas related to memory retrieval, visuospatial processing and self-awareness such as the precuneus (medial parietal cortex) are prominently activated by the sensation of itch. The involvement of this area in itch processing is interesting, because it is not as heavily implicated in the processing of pain. The affective and emotional aspects of itch experience are significantly represented in the activation of ACC, amygdala, and in the subcallosal gray matter–nucleus accumbens (NAcc) (Leknes et al. 2007; Papoiu et al. 2012a, 2013). NAcc has been shown to be involved in itch processing experimentally induced-allergen itch in atopic patients and was found to be activated at rest (in baseline conditions) in ESRD patients on hemodialysis experiencing chronic pruritus.

The insular cortex has a paramount role in processing itch information. Insula is a cortical region linked to salience, self-awareness/interoception and addiction. Insula is considered a major hub for processing visceroceptive and interoceptive inputs, and it is also significantly involved in the processing of pain and especially in assessing stimulus intensity. Bilateral insula has been found to be activated in patients with ESRD pruritus at rest.

A discrete gray matter area whose role has been recently emphasized in itch processing is the claustrum. This area’s functional specialization and connectivity seem very fitting for a region involved with itch sensing, because it has the capability to analyze, compare, and integrate sensory information from various inputs; it is connected to almost all areas of the cortex but especially with the somatosensory cortex, thalamus, and with the limbic structures: cingulate cortex, hippocampus and amygdala. The claustrum is closely linked with insula, anatomically and functionally. It has been shown to be activated more extensively by a complex, transient, fluctuating itch stimulus such as cowhage than by a rather constant stimulus like histamine. The activation of claustrum as well as of insula was largely correlated with the perceived itch intensity, while some discrete areas within the same structures activated irrespective of itch stimulus intensity. It is noteworthy that only very few brain areas insula, claustrum, S2, and the angular gyrus displayed this complex pattern of activations: encompassing regions that were capable to respond either in a manner directly correlated with itch intensity or responding invariably to itch, irrespective of stimulus intensity. Insula and claustrum, in particular, were activated continuously while itch intensity varied (slowly decreased) and were fully activated bilaterally when histamine and cowhage stimuli were administered at the same time. These features suggest a principal role in itch processing for these regions.


23.4. DIFFERENTIAL CEREBRAL PROCESSING OF HISTAMINE AND COWHAGE ITCHES

fn a healthy individual, there was a distinct idea of cowhage itch that was embedded within histamine itch. The difference, however, was that both itch symptoms contained various distinct features. .Contrary to histamine, cowhage induced a more extensive activation of the insular cortex, claustrum, globus pallidum, caudate body, putamen, and thalamic nuclei on the contralateral side of stimulation.This difference may be due not only to differences in cortical projection but also to fluctuations in the quality and associated sensory signals such as stinging and burning that are associated with cowhage.Chronic itch is frequently accompanied by these sensations (Yosipovitch et al. 2002).


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A study of the treatment of cowhage and histamine itches in healthy individuals.The overlap between activations caused by histamine itch (in green) and cowhage itch (in blue) illustrates similar activations in the brain and distinct activations in different areas (more..)


23.5. CHARACTERISTICS OF THE BRAIN PROCESSING OF PRURITUS IN CHRONIC ITCH CONDITIONS

The patterns of associations between activation of various brain areas and the perceived itch intensity appeared to vary with the underlying context of the disease and also to differ in their relationship with disease severity. For example, in atopic dermatitis patients, activation of certain areas such as ACC and dorsolateral prefrontal cortex (DLPFC) was directly correlated with disease severity (as measured by standardized clinical measures such as the EASI score), while histamine itch intensity correlated with activations in the ACC and insula. Overall, the pattern of associations between activations and perceived itch intensity was different than in healthy volunteers (Schneider et al. 2008; Ishiuji et al. 2009; Yosipovitch Group, unpublished).

The distinction between the patterns evoked by histamine and cowhage itches, clearly identified in healthy individuals appears to be blurred in chronic itch diseases (ESRD and AD). Stimulus-specific patterns of activation appear differentially nuanced in a different pathological context. An exact cause for the blurring of this distinction is not apparent at the time of this writing.

An investigation of structural and functional perfusion differences between ESRD patients with chronic pruritus and healthy individuals found a significant thinning of gray matter in the thalamus, insula, ACC, precuneus, and caudate body in ESRD patients (areas involved in itch processing) as well as significant activations (persistent perfusion increases) at baseline in the insula, ACC, claustrum, amygdala, hippocampus and nucleus accumbens. Moreover, the processing of cowhage itch appeared altered in ESRD, while no significant differences could be demonstrated in processing histamine itch. In ESRD pruritus, multiple brain activations appeared to work either directly or inversely correlated with perceived itch intensity, suggesting a dual modulation of itch perception. These unique features could be facilitated by the reduced gray matter thickness in ESRD affecting critical areas involved in itch processing, thus revealing an unprecedented form of neocortical plasticity (and functional reorganization). In this condition, it appeared that the PAR-2 mediated itch pathway was already overstimulated, which could be linked to an overexpression of PAR-2 in the skin. This could lead to a tonic inhibition of the cortical processing of acute cowhage itch, when induced in the preexistent context of ESRD.

A working hypothesis for central top-to-bottom inhibition of itch is drawn from a parallel with the descending pathway for suppression of pain and proposes that the periaqueductal gray matter (PAG) modulates the activity of spinal interneurons. According to this model, descending inputs directed toward itch receptive neurons in the dorsal horn exert an inhibitory action, effectively silencing them (Carstens et al. 1997; Davidson and Giesler 2010). Another possibility is that the cortical projection of itch information into S1/S2 could be inhibited via cortico–cortical inhibitory loops, in a similar fashion with mechanisms that have been known to operate in chronic pain (reviewed in Henry et al. 2011). Our recent findings in ESRD patients on hemodialysis experiencing chronic pruritus suggest that a tonic inhibition may be exerted at the neocortical level to selectively limit the receptive fields for PAR-2-mediated itch processing in S1, precuneus and insula (Papoiu et al. 2013). The activation of these projection areas was significantly limited in contrast with healthy volunteers, although cowhage itch was perceived at a similar intensity. These findings were corroborated by a pattern of inverse correlations between activations in S1, S2, precuneus, and perceived itch intensity, supporting the notion that activation is modulated by negative feedback loops (at least in chronic pruritus of ESRD). These findings are of significant interest because they offer insight into mechanisms the brain may employ to process and modulate itch sensation. Contrary to a widely accepted paradigm in the neuroimaging literature, it is thus possible that a higher intensity itch does not necessarily translate into a higher or more extensive activation of the cerebral cortex. For example, cowhage-induced itch in ESRD patients is significantly more intense than histamine itch, but the cerebral activations evoked by cowhage are less extensive and as mentioned earlier, they are also significantly limited in comparison with healthy volunteers, in the regions of interest related to itch processing.


23.6. CONTAGIOUS ITCH

Contagious itch is an intriguing phenomenon that has been reported frequently in daily life and in medical circles and that has been confirmed in no less than four published studies in humans and one study in nonhuman primates (Niemeier et al. 2000; Papoiu et al. 2011; Holle et al. 2012; Lloyd et al. 2012; Feneran et al. 2012). The elucidation of central mechanisms underlying this intriguing phenomenon is of high interest because it could provide invaluable clues for the treatment of itch. It manifests as the endogenous induction of a surreptitious feeling of itch in an observer while looking at other people scratching or in people being presented visual cues merely suggestive of itch. It has been postulated that contagious itch is similar to other socially contagious behaviors (yawning), that it might be correlated with empathy or proneness to neurosis, and that it may work via “mirror neurons.” Contagious itch was significantly easier to induce in atopic dermatitis sufferers (which could be already “sensitized” because they suffer from chronic itch) than in healthy volunteers. Interestingly, the itch induced by visual cues had a scattered, wide body distribution. The exact mechanism of itch “triggered by sight” or by mental suggestion is poorly understood. A recent brain imaging study set out to identify the neural brain networks involved in the generation of “contagious itch” sensation pointed toward Brodmann area 44 (BA44) and the premotor cortex (BA6) as areas activated during the process of “itch induction”. These findings can be seen as a first step in attempting to elucidate this phenomenon (Holle et al. 2012). Just from a fundamental neuroscientific point of view, it is of significant interest to identify the brain centers that can support the generation of a somatic sensation in the absence of peripheral stimulation. In addition, it can provide insight on the specific central areas that can be targeted and used in a therapeutic approach to relieve itch. At this point in time, the existence of a single, specific itch processing center remains elusive, becoming increasingly clear that the complex neuronal processes involved in processing itch cannot be reduced to a single cortical or subcortical area.


23.7. CRAVING FOR ITCH RELIEF AND ITS CEREBRAL MECHANISMS

The sensation of itch and the immediate craving for itch relief manifested as the urge to scratch are inseparable. Reward circuits have been linked with the pleasurability of scratching and could play an important role in itch inhibition, as well in the formation of “vicious” itch scratch cycles, because it is not only the suppression of the sensory aspect of itching but also the quenching of bothersome-irritating emotional feelings that itch evokes, which is equally sought and ultimately rewarding. Novel findings suggest that the reward system of the midbrain, more specifically the ventral tegmentum (VTA), and substantia nigra, as well as nc. accumbens (NAcc), may play a role in the urge to scratch and the subsequent satisfaction (pleasure) derived from scratching, via their connections with the insula, ACC, and putamen. The implication of VTA and NAcc underscores the addictive nature of the itch–scratch cycle and also suggests a role for the dopaminergic system in itch relief (Papoiu et al. 2013). A possible mechanistic link to the alterations of sleep/wakefulness cycle—leading to depression, mood changes frequently reported in chronic pruritus—could be explained by the connections of nucleus accumbens with thalamocortical circuits. An activation of NAcc was observed at rest in ESRD pruritus (Figure 23.2).


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Brain activations in patients with ESRD pruritus at baseline. Cerebral perfusion was higher at baseline in ESRD patients with chronic pruritus compared to healthy individuals in the insula, claustrum, ACC, amygdala, enthorinal cortex, subcallosal gray (more..)


23.8. BRAIN PROCESSING OF SCRATCHING

In this section, we review neuroimaging studies that looked at the brain mechanisms of scratching and discuss possible mechanisms of itch inhibition that might be accomplished with scratching.Additionally, we talk about the connection between scratching and pleasantness.In chronic itchy patients, areas of the brain that are engaged by scratching appear to work excessively.Brain networks activated by scratching can lead to an amplification of behavior.There is a possibility that the pleasant sensations evoked by scratching induce and reinforce the uncontrollable urge to scratch. There have been a number of hypotheses proposed to account for the cathartic effect of scratching (Davidson and Giesler 2010).They generally imply a regulatory mechanism at the spinal level, involving interneuronal interference in the inhibition of itching.These spinal relays are controlled in a "state-dependent" manner, such that scratching exerts an inhibitory effect only when sensory itch fibers are concomitantly stimulated (Davidson et al. 2009).It is much less understood what is happening in the supraspinal (cortical) areas that inhibit itching.A reliable way to visualize in terms of neuroimaging the successful treatment of itch would be to observe a reduction in activity in ACC and insular cortex.


23.8.1. Brain Regions Associated with the Desire to Scratch

Itch promptly evokes the desire to scratch. The responses elicited in the brain are strongly manifested in multiple regions that have a motor specialization. The activation of supplementary motor area (SMA) and premotor cortex (PM) during itch stimulation was frequently observed in most of the previous studies, irrespective of the particular neuroimaging techniques used (PET or fMRI) (Hsieh et al. 1994; Darsow et al. 2000; Drzezga et al. 2001; Mochizuki et al. 2003, 2007, 2009; Herde et al. 2007; Valet et al. 2008; Leknes et al. 2007; Schneider et al. 2008; Ishiuji et al. 2009; Papoiu et al. 2012a). The location of these regions in the brain is shown in Figure 23.3. In animal studies, it was reported that monkeys with lesions in the SMA and PM cortices showed a significant deterioration of task performances when the tasks required complex movement, such as reaching out their hands to target items, while avoiding obstacles and moving their hands and arms in a correct order (e.g., Brinkman 1984; Thaler et al. 1995; Moll and Kuypers 1979; Halsband and Passingham 1985). Thus, SMA and PM are considered to be associated with planning movement. In fact, neurons in SMA and PMC begin to activate before motor execution (Kurata and Wise 1988; Tanji and Shima 1994). Evidently, the cerebral processes of motor planning need to be performed before motor execution. Interestingly, functional neuroimaging studies in humans reported that SMA and PM were also activated when subjects just imagined moving their hands and arms, without execution (e.g., Lotze et al. 1999; Naito et al. 2002; Ehrsson et al. 2003; Meister et al. 2004; Ueno et al. 2010). Considering these previous findings, the activation of SMA and PM during itch stimulation may reflect the preparation for scratching. SMA and PM are anatomically and functionally connected to the striatum, which is also activated by itch (Herde et al. 2007; Leknes et al. 2007; Mochizuki et al. 2007; Papoiu et al. 2012a). The striatum may also play additional roles in itch perception and motivation. Motivation is an important factor in triggering actions and improving performance (Apicella et al. 1991; Schultz et al. 1992; Bowman et al. 1996; Breiter et al. 2001; Delgado et al. 2004; Harsay et al. 2011). Moreover, if the activation of the striatum during itch stimulation would reflect only motor planning, this region would be activated during an imagery task such as the imagination of finger movement. However, evidence showed that the striatum was not activated during motor imagery (e.g., Lotze et al. 1999; Naito et al. 2002; Ehrsson et al. 2003; Meister et al. 2004; Ueno et al. 2010). Therefore, the activation of the striatum during itch stimulation may reflect the motivation to scratch. The activity in the striatum in atopic dermatitis patients was significantly higher than in healthy subjects (Schneider et al. 2008; Ishiuji et al. 2009). In other words, the neural circuits associated with motivation and motor planning of scratching were more strongly activated in atopic dermatitis patients when they perceived itch. Atopic patients are indeed troubled by severe skin damage and exacerbation of itch, since they scratch excessively and repeatedly. This phenomenon could be associated with the “excessive” activation of the striatum.


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Top view of MNI template of the human brain. PFC, prefrontal cortex; SMA, supplementary motor area; PM, premotor cortex; Motor cortex, primary motor cortex.


Previous PET and fMRI studies of itch have noted the activation of the primary motor cortex (M1) in the hemisphere contralateral to itch stimulation (Darsow et al. 2000; Drzezga et al. 2001; Ishiuji et al. 2009). A possible interpretation of this observation is that motor control was voluntarily exerted to refrain from moving the involved arm (Figure 23.3).


23.8.2. Brain Imaging and Processing of Scratching Reveal Itch Modulation Mechanisms

A couple of fMRI studies have investigated the cerebral processing of the responses evoked by passive scratching, when investigators scratched the subjects’ skin using small plastic brushes or copper plates (Yosipovitch et al. 2008; Vierow et al. 2009). The brain regions commonly observed in these studies were the prefrontal cortex (PFC), the anterior cingulate cortex (ACC), the insula, the secondary somatosensory cortex (S2), and the cerebellum (Figure 23.4). The significant activations of PFC and insula during scratching are interesting because these regions, in particular PFC, are less sensitive to vibrotactile stimuli (Gelnar et al. 1999; Coghill et al. 2000; Burton et al. 2004; Golaszewski et al. 2002; Seitz and Roland 1992; Hagen and Pardo 2002). The PFC was associated with the motivational aspects of action. Clinical studies in individuals suffering with addiction have also demonstrated the role of PFC in motivation, reporting that activity in PFC increased during craving (Brody et al. 2002; Olbrich et al. 2006; Franklin et al. 2007). Electrical stimulation of PFC using transcranial magnetic stimulation and transcranial direct current stimulation modulated craving reactions in these patients (Camprodon et al. 2007; Boggio et al. 2008; Amiaz et al. 2009), demonstrating that PFC plays a crucial role in controlling motivation-based actions. Thus, scratching may increase the motivation to scratch further by enhancing PFC activity.


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The skin can be scratched to activate certain areas of the brain.As seen in the red and blue regions, neural activity increased during scratching and decreased during scratching, respectively.(more..) On the ACC, we find a posterior cingulate cortex, a secondary somatosensory cortex, and an anterior prefrontal cortex.


The activity of the medial parietal cortex, including the posterior cingulate cortex and precuneus, was significantly decreased by scratching, while a significant activation of this region by itch was frequently observed (Herde et al. 2007; Mochizuki et al. 2007, 2009; Ishiuji et al. 2009; Papoiu et al. 2012a). In addition, the activity of this region was significantly correlated with itch intensity (Mochizuki et al. 2007). The medial parietal cortex is associated with memory and attention (Cavanna and Trimble 2006), and memory and attention can modulate perceptions.

Ruscheweyh and colleagues (2009) reported that pain evoked by physical stimuli such as heat, pinprick, or pressure was higher in subjects with a higher ability to imagine pain, an ability considered to be partly associated with memory. It was reported that itch and pain were reduced when subjects shifted their attention away (Leibovici et al. 2009; Schlereth et al. 2003). In addition, the medial parietal cortex is part of the brain network active during the resting state, known as the default mode network. It was reported that pain modulation depends on the strength of connectivity within the default mode network (Napadow et al. 2012). Activity in the medial parietal cortex significantly increased when pain hallucination was evoked in a coenesthesia patient (Bär et al. 2002). These studies suggest that the medial parietal cortex may have a role in modulating itch and pain. The reduced activity in the medial parietal cortex, which is induced by scratching, could diminish itch perception.

Scratching-induced reduction of activity was also observed in other brain regions such as the primary somatosensory cortex (S1), ACC, and motor areas such as SMA and PM (Figure 23.2) (Yosipovitch et al. 2008). S1 is considered to be associated with the sensory-discriminative aspects of itch (intensity, location, quality and duration), while ACC is linked with affective-motivational aspects, such as unpleasantness and the urge to scratch. Activity in these regions was significantly correlated with itch intensity (Darsow et al. 2000; Drzezga et al. 2001; Mochizuki et al. 2003, 2007; Leknes et al. 2007). However, not all fMRI studies of scratching observed significant activations in these regions. This discrepancy may have stemmed from differences in the pressure exerted during scratching. The scratching force applied in these studies was substantially different (0.29 and 2.65 N). However, even if the scratching was “less forceful,” it was still effective to inhibit itch (Yosipovitch et al. 2007). Future studies examining active (self) scratching performed by healthy subjects and chronic itch patients themselves will enable us to better understand the brain mechanisms underlying the inhibition of itch.

Another mechanism of itch inhibition by scratching could be exerted by descending inhibitory pathways (Basbaum and Fields 1984; Millan et al. 2002). Descending pathways from the brain reach the dorsal horn of the spinal cord via the PAG, the raphe nuclei, and locus coeruleus. Neural signals conducted by the descending pathways inhibit nociceptive ascending signals at the spinal level. Electrical stimulation of PAG inhibited the neural responses in spinothalamic neurons evoked by application of pruritogens, such as histamine (Carstens et al. 1997). A human PET study reported that PAG activity increased while itch intensity was reduced, when pain stimuli were applied (Mochizuki et al. 2003). Thus, it is likely that the descending inhibitory control could inhibit itch. Previous fMRI studies of scratching did not show activation of PAG. It is conceivable that the intensity of activity (or the extent of the activated areas) engaged during pain or itch modulation could have been below the detection threshold. However, recent data from our group using a new ASL fMRI technique (3-D Grase Propeller) identified a significant deactivation of ventral tegmentum and of the raphe nucleus (interconnected with PAG) during itch inhibition by scratching (Papoiu et al. 2013, PLoS One, in press). Thus, further investigations using electrophysiological techniques and fMRI with a higher spatial and functional resolution at higher magnetic fields will be necessary to clarify in what way exactly the descending inhibitory control is associated with itch inhibition by scratching.


23.8.3. Pleasantness and Scratching

Why are pleasant sensations evoked by scratching an itch? This is one of the great mysteries of itch. The pleasant sensations evoked by scratching are considered an exacerbating factor that could play an important role in the induction of the addictive itch–scratching cycle. A few neurophysiology or neuroimaging studies have addressed this phenomenon. It was speculated that the PFC and the orbitofrontal cortex are associated with the hedonic experience (Ikoma et al. 2006), because the medial PFC and the orbitofrontal cortex were previously linked with pleasure (Kringelback 2005; Ursu and Carter 2005; Kim et al. 2006). A couple of reports identified the striatum as one of the brain regions associated with the relief of itch associated with scratching (Vierow et al. 2009; Napadow et al. 2012). The striatum maintained a higher activity during scratching an itch, compared to scratching in the absence of itch. In addition, the activity in the striatum reached a maximum when itch was at a minimum, implying that the activation of the striatum was associated with scratching an itch, rather than with perceiving itch alone. This area was also found to play an important role in the pleasantness induced by pain relief (Leknes et al. 2011). Therefore, it is possible that the activation of the striatum during itch relief may have reflected hedonic aspects of scratching. A recently completed functional neuroimaging study addressed the question of why scratching is pleasurable and discovered that the activity of brain’s reward circuits, especially in discrete formations of the midbrain including the ventral tegmental area, substantia nigra, and the raphe nucleus, was strongly correlated with itch relief (Papoiu et al. 2013).


23.9. INSIGHTS FOR A THERAPEUTIC STRATEGY TO RELIEVE ITCH DERIVED FROM BRAIN IMAGING STUDIES

Addressing the emotional and psychological suffering associated with itch are cornerstones for building a successful therapy for pruritus. The amplification of a vicious itch–scratch cycle is well known to aggravate the symptoms and the evolution of skin conditions marred by chronic pruritus, such as atopic eczema or psoriasis. Thus, an overactive limbic system (ACC-amygdala-nc. accumbens) may reflect a more intense, unbalanced craving for itch relief, accompanied by activations in the insular cortex (as seen in ESRD pruritus at baseline) that can lead only to the amplification of compulsive scratching behavior and more distress. It is not only the organic source of the problem that needs to be addressed according to its etiology, depending on the respective diagnosis, but also the subjective, profound impact that itch experience has upon the affected individuals “inner world.” We surmise that neuroimaging studies provide insight not only on the physiological responses (or their dysfunction) but also serves as a window into the supramodal functions of the mind and psyche. Cognitive and emotional aspects of itch experience influence the higher level integration of physical stimuli. Brain areas involved in self-awareness (precuneus) and self-perception (insula) are getting immediately involved, confirming the observation that itch is a very intrusive and disturbing sensation, perturbing the well-being of the person. A successful treatment would need to target and interrupt the vicious itch–scratching cycle and offer a solution for the intense, “amplified” craving for relief. This raises the possibility that cognitive behavioral techniques could be helpful in limiting the emotional and affective impact of this bothersome symptom. Refocusing attention on tasks unrelated to itch could be one avenue worth exploring, because these approaches have been shown to be effective in diminishing the perception of pain (Zeidan et al. 2011). These “mindfulness” reframing techniques may prove to be even more effective for the subjective relief of itch, because itch (contrary to pain) can be easily generated via a central induction mechanism (the “contagious itch” phenomenology). Therefore, if there is a central “source” that is capable of producing itch sensation (in the absence of external pruritogenic stimuli), it must be a way to reverse the mechanism, turning it into a cure.