The Neural Basis of Self-Touch in a Pain-Free Situation

2Shiseido Global Innovation Center, 2-1-1, Hayabuchi, Tsuzuki-ku, Yokohama, Kanagawa, 224-8558, Japan †Author for correspondence: Professor Yoshiaki Kikuchi, PhD & D Med Science, Department of Frontier Health, Science, Division of Human Health Sciences, Graduate School of Tokyo Metropolitan University, 7-2-10, HigashiOgu, Arakawa-Ku, Tokyo, 116-0012, Japan, Tel & Fax: +81-3-3819-7270; email: ykikuchi@tmu.ac.jp The Neural Basis of Self-Touch in a Pain-Free Situation

Research Professor Yoshiaki Kikuchi regions of the somatosensory cortex (including SI and SII regions) [11][12][13][14] associated with sensory attenuation.In addition to deactivation of SI and SII, the anterior cingulate cortex (ACC) is also deactivated.However, this phenomenon has only been discussed in terms of its role in emotional awareness, without a discussion of its regulatory role in sensory and cortical suppression, for example that self-generated stimuli are less tickly or painful than are externally produced stimuli [11][12][13].Predictive forward models are generally assumed to underlie such attenuation, with the model involving a prediction about the sensory consequences of an action [12,13].
In contrast, studies of pain control have shown that the ACC plays a key role in cortical control of the brainstem opioid system, which comprises the periaqueductal grey (PAG) and the rostral ventromedial medulla (RVM) [14][15][16], during both opioid and placebo analgesia [17,18].These neural structures constitute the descending pain modulatory system (DPMS) [19].In particular, both the ACC and amygdala are opioid-rich.They contribute to and influence the expression of behavioral opioid analgesia via connections with the RVM, which plays a critical role in pain inhibition through interactions with the spinal cord.The RVM shapes spinal processing in a top-down fashion through direct presynaptic actions on the dorsal horn terminals of primary afferent fibers.Based on these, it is suggested that mere self-touch automatically induces the ACC-amygdala-RVM (AAR) system activity not only in painful situations but also in pain-free situations.
Furthermore, stress induces analgesia through descending inhibitory pathways from the amygdala and RVM to the spinal cord [20].This suggests that stress-induced analgesia is modulated by the endogenous opioid system, and this system may play an important role in soothing effects.Indeed, the RVM is thought to be involved in cardiovascular and respiratory regulation [21,22].In animal studies, contexts that induce stress have been described as important for activation of the endogenous opioid system [23].There are indications that the self-soothing effects of certain animal behaviors might result from the release of opioids [24].Moreover, involvement of endogenous opioids and anti-sympathetic effects has also been implicated in human self-soothing behaviors [24,25].These findings suggest that the role of the AAR system is not just to regulate somatosensory perception including pain perception, but also

Introduction
In monkeys, infants deprived of their mothers exhibit a striking decrease in social interactions with others and an increase in self-comforting behaviors [1][2][3].In adults, nonverbal "selfadaptors" are unintentional movements that involve self-touching behaviors such as stroking or rubbing one's own hand, and are associated with a lack of conscious awareness, occurring in response to situational anxiety and stress [4][5][6][7][8].In another example, we often grasp a painful hand with the other hand to reduce the pain.This selftouch is also unintentionally and automatically induced by the painful stimulation.Accordingly, self-touch is considered to be an act of coping with harmful or stressful situations, and is therefore important to the 'survival of the organism' [9].
Experimental studies have shown that self-touch suppresses painful sensations [10,11].Kammers, et al. [10] investigated the influence of touch on paradoxical pain using the thermal grill illusion (TGI), showing that self-touch suppresses thermal pain.They induced the TGI by placing the participant's index and ring fingers in hot water, and the middle finger in cold water.This results in a paradoxical feeling of painful heat in the middle finger.It was shown that the illusioninduced pain is reduced when the fingers of the other hand touched the fingers used to induce the illusion.Even in pain-free tactile perception, many experimental studies provide considerable evidence for sensory attenuation via self-touch in healthy individuals [12,13].These findings support the view that self-touch suppresses not only feelings of pain but also somatosensory perception more generally, with some cooccurring self-soothing (i.e., anti-sympathetic) effects being demonstrated.In addition, this view suggests that inhibitory effects on somatosensory afferents and sympathetic activity commonly underlie these various kinds of selftouch phenomena.

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The Neural Basis of Self-Touch in a Pain-Free Situation to modulate the general state of the organism.In fact, intrinsic functional connectivity among regions of the DPMS including ACC and RVM has also been demonstrated in even non-painful situations [26].
Based on these considerations, it is suggested that there is a common neural basis underlying various kinds of self-touch in painful, painfree, stressful or stress-free situations, and the AAR system plays a critical role in this process.In addition, it has been suggested that SII is involved in the effects of self-touch [10,27], given that SII plays a critical role in multisensory/motor integration across both hands.In fact, human neuroimaging studies have shown modulation of blood oxygenation level-dependent (BOLD) responses in SII during bimanual self-touch [12].Therefore, synchronous activity of the bilateral SII is also suggested to play an important role in the neural mechanisms underlying self-touch.
Here, we investigated the involvement of the AAR system and synchronous activity of the bilateral SII in simple self-touch (rubbing the back of the left hand with the palm of the right) that is usually observed in everyday situations rather than painful or stressful situations.We investigated two ways of rubbing the hand, which involved either circular (C) or backand-forth (BF) rubbing, and investigated the averaged contrast of (C + BF), focusing on neural activity independent of hand motion as far as possible.Subsequently, we investigated the modulatory effects of the amygdala (source of modulation) on the connection from the rostral ACC (rACC, source of connectivity) to the RVM, and the modulatory effect of coherent bilateral SII activity to the RVM.These effects were investigated with the physio-physiological interaction (PPI) method [28].

Participants
Twelve healthy female participants (31.5 ± 3.7 years) took part in the experiment.All participants were right-handed according to the Chapman test (13.3 ± 0.6) and had no history of neurological or psychiatric disorders.Participants provided informed consent to participate in the present study.The Research Ethics Committee of Tokyo Metropolitan University approved this study and all methods were carried out in accordance with the approved guidelines.

Stimuli, trial protocol, and procedure
We used two ways of rubbing the hand, which involved either circular (C) or back-and-forth (BF) rubbing of the back of the left hand with the palm of the right.The participant was instructed to relax and close her eyes without thinking about anything specific.Three seconds before condition onset, the researcher let the participant know whether the next condition to be performed was C or BF by placing the participant's right palm softly on the back of her left hand and moving her right hand in the appropriate manner (C or BF) for 2 sec.A session consisted of 8 trials (2 conditions × 4 times), with the trials counterbalanced across participants.A block-design paradigm was applied, with each trial lasting 32 sec and resting for 8 sec.
Each C and BF condition was modeled with a separate regressor.We tested significance in activation/deactivation for the contrast of (C + BF) vs. baseline with a height threshold of p<0.0005 and an extent threshold of p<0.05 (FDR, corrected), to focus on neural activity independent of hand motion as far as possible.Subsequently, among the averaged brain regions showing significant deactivation and activation, we selected regions specifically involved in motor (e.g., left primary motor cortex (MI) and right CB), somatosensory (e.g., right SI and left CB), and emotion (e.g., insula) processing as regions of interest (ROIs, 5 mm radius sphere centered at peak coordinates) for PPI analysis.Moreover, we searched the local maximum points within Research Professor Yoshiaki Kikuchi the nearest 8 mm from the coordinates of the rACC (-10 34 16) [29], right amygdala (16 0 -16) [30,31], and RVM (-6 -35 -39) [31], in the averaged activation/deactivation map.We then selected the spherical regions within a 5 mm radius centered at these points and investigated significant activation/deactivation at p<0.05 (FWE, SVC) as ROIs for the PPI analysis.
We also set additional ROIs that showed significant positive and negative connectivity to the RVM ROI seed for (C + BF) vs. baseline with CONN software (version 13, http://www.web.mit.edu/swg/software.htm).Functional imaging data were first band-pass filtered with a range of 0.01-0.10Hz.Voxel-by-voxel functional time-series data for the whole brain were regressed onto time-series data for the RVM seed region with general linear model (GLM) analysis, removing confounding effects related to white matter and cerebrospinal fluid BOLD signals, head motion (realignment parameters), and the main condition effects (hemodynamic model convolved with the HRF).For each participant, we calculated connectivity between the RVM seed and voxels across the whole brain for the (C + BF) condition.In the second-level between-subjects analysis, we tested whether functional connectivity with the RVM ROI was significant (for each region of positive and negative connectivity, with a height threshold of p<0.0005 and an extent threshold of p<0.05,FDR, corrected).Finally, among the brain regions showing significant connections, we set additional ROIs that are also related to somatosensory processing (e.g., SII and left CB).
We applied a PPI analysis [28] to (C + BF) in SPM8.In this GLM analysis assessing AAR system involvement, the modulatory effects of the amygdala (source of modulation) on the connection from the rACC (source of connectivity) to target regions were calculated across the whole brain for each participant.These effects were modeled as follows.The signal time series for any given voxel (X i ) was regressed on X rACC, denoting the mean-corrected vector containing the activation time series obtained as the first eigenvariate in the rACC ROI, as well as the interaction term X rACC × X amy , wherein X amy contains the activation time series obtained as the first eigenvariate in the ROI for the amygdala.The interaction term equals the element-byelement product of the mean-corrected vectors.To calculate this term, the rACC and amygdala signal time series were deconvolved [32] to compute the underlying neural signal, and then the interaction term was calculated by convolving the product of the neural signals with the HRF.
The parameter estimate (β 1 ) for X rACC × X amy is thought to reflect the amygdala's modulatory effect on connectivity from the rACC.The t-map based on the null hypothesis "β 1 = 0" was created using the following statistical model: (1) Where in β 1 and β 2 are parameter estimates and e i is an error term.Connectivity analysis results from individual participants were subjected to a group analysis with a random effects model.For each of the ROIs except the rACC and right amygdala, we then tested whether the eigenvariate value was significant (p<0.05,FWE, SVC).
To investigate the modulatory effect of coherent bilateral SII activity, we specifically set ROIs (left SII and right SII) and their interaction in the regression model.The subsequent regression model was expressed as follows [28,33]: where X RSII and X LSII denote the time series of the two ROIs.The parameter estimate (β 3 ) for X RSII × X LSII is the effect of the synchronous activity (interaction) of both SIIs on connectivity with X i .The t-map based on the null hypothesis was set as "H 0 : β 3 = 0" For each of the ROIs except for the left and right SII, we then tested whether the eigenvariate value was significant (p<0.05,FWE, SVC).Subsequently, to assess the relationship between activation/deactivation of significantly modulated ROIs and strength of the modulatory effect (β 1 or β 3 ), we conducted a simple linear regression analysis with the eigenvariate value for the ROI as the dependent variable and the modulatory effect as the independent variable (p<0.05).Moreover, we checked the residuals by performing the Shapiro-Wilk (S-W) test of normality (p<0.05), and calculated the Durbin-Watson (D-W) statistic for the null hypothesis of no autocorrelation (using SPSS ver.20, IBM).
Finally, we investigated activation/deactivation relationships between the right SI and the left CB for (C + BF).We conducted a simple linear regression analysis with the eigenvariate value for the right SI ROI as the dependent variable and that of the left CB ROI as the independent variable (p<0.05).Moreover, we checked the residuals by performing the S-W test of normality (p<0.05), and calculated the D-W statistic for the null hypothesis of no autocorrelation.

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The Neural Basis of Self-Touch in a Pain-Free Situation

Relationship between the right SI and left CB
Activity in the right SI was positively correlated with that in the left CB (adjusted R 2 = 0.620, t = 4.355, p = 0.001; S-W statistic = 0.978, p = 0.973; D-W statistic = 2.009).

Research Professor Yoshiaki Kikuchi
rACC.There were no significant modulatory effects on the other ROIs (Figure 3).In addition, the RVM and left TPJ/posterior insula (p = 0.034 and p = 0.044, FWE, respectively) showed significant interaction effects on left and right SII activity (coherent SII activity) (Figure 4), while there were no significant modulatory effects on the other ROIs.

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The Neural Basis of Self-Touch in a Pain-Free Situation  Research Professor Yoshiaki Kikuchi there was no significant correlation for the other ROI.

Discussion
We observed modulation of neural connectivity to the RVM from the rACC by the right amygdala, with RVM activity decreasing in proportion to the strength of the modulatory effect (β 1 ).This suggests that the rACC suppresses RVM activity, which may successively suppress somatosensory afferent signals through interactions with the spinal cord via the right amygdala.
The rACC plays a key role in cortical control of the brainstem during both opioid and placebo analgesia [17,18].The brainstem opioid system consists of a network of regions, including the PAG and RVM [15,16].The ACC has one of the highest levels of opioid receptor binding in the cortex [34], and positron emission tomography (PET) studies indicate that the binding potential is specifically highest in the rACC [35,36].A positive correlation has been shown between behavioral opioid analgesia and opioid-induced suppression of neuronal responses to noxious stimuli in the right amygdala and the RVM, which are the key DPMS structures [20].The RVM plays a critical role in both inhibition and facilitation of pain through interactions with the spinal cord.Both off-and on-cells in the RVM project to the spinal dorsal horn, indicating that they exert modulatory influences on nociceptive/ non-nociceptive inputs [37].RVM on-cells are directly inhibited by opioids, and it is suggested that these cells express mu-opioid receptors [38].Moreover, increased RVM neuronal responses to noxious stimuli observed in human imaging studies indicate on-cell activity [39,40].Therefore, we suggest that decreased responses in the RVM observed in the present study reflect inhibited on-cell activity through the AAR system activation.In fact, the AAR system can function even in the absence of painful/ stressful stimulation, because intrinsic functional connectivity among the DPMS regions including ACC and RVM has been demonstrated in such situations [26].In addition, anatomical evidence that RVM neurons directly project to medullary and spinal cord cardiovascular sites suggests that RVM neurons elicit increases in arterial pressure by inhibiting parasympathetic control of the heart at the level of the medulla, and by activating direct descending pathways to spinal cord sympathetic preganglionic neurons [22,41,42].Moreover, the RVM may also function in the control of respiration through direct connections to the phrenic nucleus [43,44].Based on these facts, the present results suggest the possibility that self-touch regulates the autonomic nervous system, producing an antisympathetic effect in even a pain-free and stress-free situation.As with a possible input pathway to the AAR system in self-touch, sensory/motor-related information processed in the SII may be conveyed to the ACC and amygdala which are major regions in the AAR system, via the insula which directly connects to the SII.

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The Neural Basis of Self-Touch in a Pain-Free Situation In addition to the RVM, neural connectivity to the left CB from the rACC was also modulated by the right amygdala, and this activity decreased in proportion to the strength of the modulatory effect (β 1 ), suggesting that the rACC suppresses left CB activity via the right amygdala.Moreover, right SI activity was positively correlated with left CB activity.Therefore, deactivation of both the RVM and left CB, interactively modulated by the rACC via the right amygdala, and may contribute to suppression of right SI activity.This suggests that the AAR system is involved in effective suppression of somatosensory cortex activity during self-touch.However, this suppression mechanism has only ever been discussed in terms of the internal forward model without discussion of its regulatory role in sensory and cortical suppression.In addition, neural connectivity to each of the left and right SII from the rACC was modulated by the right amygdala, suggesting that SII activity is synchronized with interactive activity between the rACC and right amygdala.This suggests that sensory/motor interactive processing in both SII regions is specifically important for the AAR system activation.Moreover, the SII region has significantly higher BP opiate receptor activity than SI/MI, a level comparable to the ACC, suggesting that the cortical anti-nociceptive effects of opiates are mediated not only by the rACC, right amygdala, and RVM, but also by SII, if it can be assumed that opioid binding mediates anti-nociception in this structure [44].
The amygdala receives information about the external environment from the sensory thalamus and sensory cortices.The basolateral cortex of the amygdala is reciprocally connected with cortical regions, particularly the midline prefrontal cortices (including the rACC and VMPFC), as well as sensory areas such as SI and SII [45].The amygdala plays a central role in encoding and maintaining sensory associations with potential threat [46].Therefore, deactivation of the right amygdala may reflect reduced threat value, suggesting that even mere self-touch can create a certain safe internal state for the self.
It has been suggested that autonomic control and efference copy signals [47] originate in the rACC, which can be interpreted as the "visceromotor cortex" given its function in the autonomic modulation of bodily arousal to meet behavioral demands [48][49][50][51].The neural basis of interoceptive prediction signals is thought to be an output from the VMPFC, which has robust connections with limbic regions, including the amygdala, hypothalamus, midbrain, brainstem (including the RVM), and spinal cord areas, which are involved in regulation of the internal bodily state (physiological state) [52,53].This is complemented by a parallel and partly reciprocal system of anti-sympathetic efferent drive operating through the VMPFC [48,54,55].Moreover, the VMPFC connects certain categories of events based on memory records to somatosensory units in the somatosensory cortex (SI, SII) and to interoceptive units in the insula.In addition, VMPFC processes may use the self as a point of reference.The internal body representation may ultimately provide the primary reference, a material self, for interaction with the environment.The significant functional connectivity between the VMPFC and the RVM suggests that self-touch regulates the internal state based on the self as a reference.
The SII sub-region , which we observed to be correlated with the RVM, is part of the parietal operculum (OP4), which is associated with sensory/motor integration, including incorporating sensory feedback into motor actions, unlike the other sub-regions [56,57].In addition, early interhemispheric somatosensory integration primarily occurs in SII, and therefore has behavioral importance in terms of bimanual object manipulation and exploration.While SII neurons are predominantly contralateral dominant, they have moderate to well-defined bilateral receptive fields that are usually larger than the receptive fields for SI neurons [58].
Coherent SII activity is thought to be actuated as a corresponding bodily state induced and maintained by temporally synchronous sensory/ motor signals from both hands, which are spatially symmetrical with respect to the body axis.Furthermore, this coherence is important for the maintenance of the body schema [59].Moreover, coherent SII activity significantly modulated the left TPJ, which is involved in body ownership [60].This suggests that the bodily self is specifically important for the effects observed, together with VMPFC involvement.
In addition, synchronous SII activity is shown to bias the routing of signals towards the ACC [61].In our study, stronger bilateral SII activity coherence was associated with more RVM deactivation.Accordingly, coherent SII activity is thought to be an important factor for inducing the AAR system activity based on the bodily self.Our study suggested that this mechanism depends not only on the AAR system but also that bilateral coherence is associated with an Research Professor Yoshiaki Kikuchi enhanced sense of self-awareness.
The present study indicated the possibility that mere self-touch induces activation of the AAR system, which suppresses somatosensory afferents from the touched hand and regulates the sympathetic nervous system, in a pain-free and stress-free situation.It should be noted here that the neural mechanism observed in the present study, which exerts control over the RVM through modulatory effects of the rACC and amygdala, and bilateral SII activity, could be activated by mere self-touching behaviors, i.e., touching and rubbing the back of the left hand with the palm of the right in pain-free/ stress-free normal situations.Therefore, this mechanism is expected to be activated under the same self-touch situations, potentially explaining the effects of self-soothing behaviors, as well as attenuation of somatosensory perception and somatosensory cortex activity in pain-free/stressfree situations.
are some limitations in the present study.First, simultaneous measurements of the autonomic responses were not performed in the present study, although we discussed the possibility that the AAR system activation is involved in antisympathetic effects associated with self-touch.To confirm it, simultaneous recording of the autonomic information such as heart rate and respiration should be performed.Second, it was not confirmed how opioid is actually involved in the effects associated with self-touching, in the present study.Some PET studies might be useful to confirm it.

Figure 4 :
Figure 4:The RVM and left temporoparietal junction/posterior insula (p = 0.034 and p = 0.044, FWE, respectively) showed significant interaction effects on the left and right SII activity (B).Moreover, the modulatory effect for the left and right SII was negatively correlated with the betas for the RVM (adjusted R 2 = 0.329, t = -2.528,p = 0.030) (B).