Pain- and Itch-Related Magnetic Fields
Pain and itch are unpleasant somatic sensations, and, in particular, severe problems for patients with chronic pain and itch. It is important to understand how these sensations are perceived/modulated in the brain in order to develop treatments for chronic pain and itch. Magnetoencephalography (MEG) can be used to investigate pain- and itch-related cerebral processing with high temporal resolution (ms). Many pain researchers have investigated the temporal profiles of cortical activities evoked by noxious stimuli and discussed how neural signals associated with pain are processed in the brain. In addition, pain modulation by physical and physiological factors has also been of interest for pain researchers and has been investigated to understand the pain modulation system in the brain. Until recently, it was considered impossible to measure itch-related processing in the brain using MEG, because no itch stimulus was shown to be useful for MEG. However, a new stimulus to evoke the itch sensation by applying electrical stimuli to the skin was developed. This electrical method is reproducible and produces a steep rise in the itch sensation and, therefore, it is suitable for MEG recording. A MEG study using electrical itch stimuli demonstrated that the temporal profile of cortical activity evoked by itch stimuli was partly different from that evoked by pain.
KeywordsPain Itch Pain modulation Magnetic response Oscillation activity Alpha oscillation Gamma oscillation The primary somatosensory cortex The secondary somatosensory cortex The precuneus
Pain and itch are unpleasant somatic sensations. Why do we have such sensations? What happens if these sensations are lost? There are patients who cannot perceive pain sensations, referred to as congenital analgesia and congenital pain insensitivity. Even if a part of the body, for example, the back, is burned, a patient with this disorder cannot perceive it. As a result, these patients can have severe burns, and in a worst case scenario, it can result in death. The itch sensation was also shown to be affected (little or not perceived) in most patients with this disorder (Tomioka et al. 2002). The perception of pain and itch sensations are important warning signals to become aware of dangers that occurred in the body in order to avoid further damage of the body. On the other hand, pain and itch are serious problems for patients with chronic pain and itch (pain: including neuropathic pain, cancer pain, hernia, and cingulum; itch: including allergic diseases, liver diseases, and neuropathic itch). The unpleasantness caused by pain and itch evoke negative emotions and stress, which decrease activities in daily life, work, and education and sometimes lead to depression and suicidal thoughts. Moreover, itch evokes not only unpleasantness but also the desire to scratch. Scratching can cause the skin damage, which in turn exacerbates itch in chronic itch patients. This eventually leads to development of the vicious cycle of itch and scratch. Therefore, it is important to control pain and itch as well as scratching. The unpleasantness of pain and itch and the desire to scratch are generated in the brain. How are these mental events generated in the brain? These issues have been the focus of study for researchers. Positron emission tomography (PET), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and magnetoencephalography (MEG) can noninvasively observe or visualize physiological activity such as neural activity and/or the activity of neurotransmitters in living human brains. Thus, the development of these apparatuses has markedly advanced the understanding of the cerebral mechanisms of itch and pain. The merit of MEG and EEG is higher temporal resolution (unit: ms) than PET and fMRI (unit; min or s). Since neural signals are processed and transmitted in the order of ms, MEG and EEG are strong tools for visualizing information flow in the brain. Pain studies using MEG started in the 1980s (Hari et al. 1983; Huttunen et al. 1986; Kakigi et al. 1995). Since then, many researchers have investigated the cerebral mechanisms of pain sensation. In contrast, itch studies using MEG began in 2009 (Mochizuki et al. 2009). In this chapter, we have introduced what high spatial resolution apparatuses, mainly MEG, have unveiled regarding the cerebral mechanisms of pain and itch.
2 Noxious Stimuli-Evoked Magnetic Responses
2.1 Source Localization
SI consists of three cytoarchitectural subdivisions, areas 3, 2, and 1. Anatomical studies have demonstrated that information from the deep body tissues such as muscles and joints reach areas 3a and 2, while areas 3b and 1 receive information from the skin (Hyvärinen and Poranen 1978; Iwamura et al. 1993; Powell and Mountcastle 1959; Kandel 2000). Consistent with these anatomical studies, MEG studies showed that source localizations in SI for tactile stimuli were estimated to be area 3b and 1 (Ploner et al. 2000; Kakigi et al. 2000; Kida et al. 2007). Area 3b responded to innocuous somatosensory stimuli 20–30 ms after the stimulus onset (Wood et al. 1985; Allison et al. 1989a, b; McCarthy et al. 1991) and area 1 responded later than area 3b (Ploner et al. 2000; Inui et al. 2003). In contrast, pain studies using MEG reported that only area 1 responded to noxious stimuli (Ploner et al. 1999; Kanda et al. 2000; Inui et al. 2003). However, single unit recordings in monkeys showed nociceptive SI neurons in areas 3b and 1 (Kenshalo and Isensee 1983). One possibility to explain why the magnetic response in area 3b was not observed in previous MEG studies may be due to the lower number of neurons in area 3b than in area 1 (Chudler et al. 1990). In previous MEG studies that observed area 3b response to tactile stimuli, median nerve stimulation was used as the tactile stimuli. On the other hand, pain studies using MEG used laser stimuli. The area to be stimulated was a tiny spot for laser stimuli, while a much larger skin area was stimulated for the median nerve stimulation. Thus, the total number of neurons in area 3b that responded to the nerve stimulation may have been much higher than that responding to the laser stimuli. This may be another reason for the lack of a clear response in area 3b to noxious stimuli. Unfortunately, there is currently no clear evidence to explain the discrepancy between single unit recordings and pain studies using MEG.
2.2 Peak Latency
The peak latency of painful stimuli-evoked magnetic responses in the contralateral SI, contralateral SII, and ipsilateral SII reported in previous MEG studies were 164–217, 160–212, and 169–213 ms, respectively (Ploner et al. 1999, 2000, 2002; Kanda et al. 2000; Nakata et al. 2004). A human microneurography study demonstrated that the conduction velocity (CV) of Aδ-fibers was about 19 ms (Adriaensen et al. 1983). In a monkey study, the CV of the spinothalamic tract (STT) was found to be 8.0 ms by determining STT neurons with antidromic activation in the contralateral posterior part of the ventral medial nucleus in the thalamus (Dostrovsky and Craig 1996). Similar CVs were reported in a human study in which the CV of the STT using laser-evoked potentials was estimated to be approximately 8–10 ms (Kakigi and Shibasaki 1991). In addition, the CV of thalamocortical fibers was estimated to be 33 ms based on the somatosensory evoked potentials of electric stimulation (Desmedt and Cheron 1980). Based on CVs, it takes over 110 ms for the signals evoked by laser to be transmitted from the hand to the cerebral cortex. On the other hand, the CV of C-fibers and STT associated with C-fibers are 1.2–2.4 m/s (Towell et al. 1996; Magerl et al. 1999; Tran et al. 2001) and 2.9 m/s (Tran et al. 2002), respectively, based on laser-evoked potential studies. Thus, it takes over 500 ms for signals to be transmitted from the hand to the cerebral cortex. The peak latency of the magnetic responses observed in the previous MEG studies was about 200 ms. Thus, magnetic responses are suggested to be derived from the excitation of Aδ-fibers. Kakigi et al. (1995) compared the peak latency and source location (i.e., dipole) of painful stimuli-evoked magnetic responses when a CO2 laser was applied to the arm compared to when it was applied to the leg. They observed that the peak latency for the stimulation of the leg was 50 ms longer than that of the arm. This difference was attributed to the distance between the leg and brain being longer than that between the arm and brain. In all previous pain studies using MEG, peak latency was shorter for the contralateral SII than for the ipsilateral SII (e.g., Yamasaki et al. 1999; Ploner et al. 2000, 2002; Kanda et al. 2000; Nakata et al. 2004, 2008, 2009). The difference in latency between contralateral and ipsilateral SII was 1–25 ms (mean: 13.8 ms) in these studies. Ploner et al. (2000) reported that differences in peak latency between the contralateral and ipsilateral SII for tactile and laser stimuli were 11 and 15 ms, respectively. Similar values were also observed in other MEG studies (e.g., Mauguière et al. 1997). The difference in peak latency has been interpreted to reflect the time to transmit a neural signal from the contralateral SII to the ipsilateral side.
2.3 Intensity Coding of SI and SII
Pain is a complex sensation composed of sensory-discriminative and motivational-affective components. SI and SII are considered to be the main regions for the sensory-discriminative component. Animal studies have demonstrated that there are neurons responsive to nociceptive stimuli in SI and most of the neurons encode the stimulus intensity of noxious stimuli (Chudler et al. 1990; Kenshalo and Isensee 1983; Kenshalo et al. 1988). Unit recoding studies in monkeys have demonstrated that the intensity coding of neurons responsive to noxious stimuli in SII appeared to be poorer than that in SI (Dong et al. 1989, 1994). Analogous to these animal studies, a MEG study observed that the relationship between SI activity and stimulus intensity closely matched the subjects’ pain ratings, while SII activity exhibited an S-shaped function with a sharp increase in amplitude only at stimulus intensity well above the pain threshold (Timmermann et al. 2001). Similar results were also reported in human fMRI and intracranial recoding studies (Bornhövd et al. 2002; Frot et al. 2007). Thus, it has been considered that SI plays more important role in the intensity coding of pain than SII. However, a recent study using noninvasive brain stimulation such as Transcranial Magnetic Stimulation (TMS) reported that when TMS pulses were delivered over S2, participants’ ability to judge pain intensity was disrupted, as compared to S1 and vertex (control) stimulation (Lockwood et al. 2013). Based on this finding, the authors of this study have suggested that early-evoked activity in human SII makes a necessary causal contribution to encoding the intensity of noxious stimuli.
2.4 Parallel or Serial Processing?
2.5 Magnetic Responses to Noxious Stimuli Associated with C-Fibers
The peak latencies of the magnetic responses in SI and SII were longer than 700 ms when the stimuli were applied to the hand (Kakigi et al. 2003), which was clearly a different latency from noxious stimuli associated with Aδ-fibers. A microneurographic study confirmed that the novel method selectively excited C-fibers (Qiu et al. 2003). Forss et al. (2005) compared cortical processing between Aδ-fiber- and C-fiber-related pain. They reported that the peak latencies of the magnetic response to laser stimuli were much shorter for Aδ-fiber pain than for C-fiber pain, while the source localizations were not significantly different. Thus, they suggested that nociceptive inputs mediated by Aδ- and C-fibers are processed in a common cortical network in different time windows. A pain study using fMRI reported significant differences in the activities in the anterior cingulate cortex (ACC) and IC between Aδ- and C-fibers (Qiu et al. 2006). These different perceptions between Aδ- and C-fibers may contribute to motivational-affective components such as ACC and IC rather than sensory-discriminative components such as SI and SII.
3 Pain Modulation
4 Oscillatory Activity and Pain
It has recently been demonstrated that time frequency information (i.e., oscillatory activity) encodes or reflects several mental states such as cognition, emotion, perception, and thought. For example, several researchers reported an association between alpha oscillation (around 10 Hz) and pain perception. Kakigi et al. (2005a, b) reported that the power of the alpha band increased while a Yoga master in meditation did not feel the pain sensation. Nir et al. (2010) reported that subjects with higher frequency, which was maximum in power within the alpha range (i.e., 8–12 Hz) during the resting state, perceived noxious stimuli as being more intense. Other studies demonstrated that the gamma frequency range (40–100 Hz) reflected pain perception. Gross et al. (2007) showed that gamma power at a frequency between 60 and 95 Hz in the contralateral SI (i.e., SI in the left hemisphere) increased when laser stimuli were applied to the right hand. Pain-induced gamma oscillations were observed around 100–300 ms after the stimulus onset, indicating the excitation of Aδ-fibers. The power of gamma oscillations increased with increments in stimulus intensity and subjective pain sensation. Interestingly, they reported that laser-evoked magnetic responses in SI were observed regardless of whether subjects perceived stimuli as painful or not, whereas the power of gamma oscillations in the region was observed only when stimuli were painful for subjects. It was reported that the power of gamma oscillations was modulated by the manipulation of subjects’ attention to pain (Hauck et al. 2007). Alpha and gamma oscillations are not specific to pain. These oscillations are also observed in other modalities. However, at least, these oscillations may be useful for the evaluation of subjective pain sensation and assessment of chronic pain.
5 Itch Stimuli-Evoked Magnetic Responses
MEG is a strong tool to investigate information flow in the brain with high temporal resolution. Several aspects of the cerebral processing of pain have been unveiled. For example, SI and SII respond to noxious stimuli mediated by Aδ-fibers about 100–200 ms after the stimulus onset, while those mediated by C-fibers respond much later. Pain inhibition by tactile stimuli occurs not only in the spinal cord (i.e., the gate control theory) but also in the brain. The intensities of the responses of SI and SII to noxious stimuli are closely related to the stimulus intensity and subjective pain rating, which supported these regions being associated with the sensory-discriminative component of pain. Oscillation studies have reported that oscillation activity is a good indicator to evaluate subjective pain sensation. At the same time, new questions have also been raised. For example, it is still unclear whether SI and SII have a serial or parallel pathway, what mechanism underlies pain inhibition by tactile stimuli, and why is subjective pain sensation reflected by oscillation activity? Studies investigating the itch sensation using MEG have been too few to discuss the cerebral processing of itch. There are still many questions that remain to be answered in the pain and itch research fields.
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