Author response: Oxytocin administration enhances pleasantness and neural responses to gentle stroking but not moderate pressure social touch by increasing peripheral concentrations

Abstract

Full text Figures and data Side by side Abstract Editor's evaluation Introduction Methods Results Discussion Data availability References Decision letter Author response Article and author information Metrics Abstract Background: Social touch constitutes a key component of human social relationships, although in some conditions with social dysfunction, such as autism, it can be perceived as unpleasant. We have previously shown that intranasal administration of oxytocin facilitates the pleasantness of social touch and activation of brain reward and social processing regions, although it is unclear if it influences responses to gentle stroking touch mediated by cutaneous C-touch fibers or pressure touch mediated by other types of fibers. Additionally, it is unclear whether endogenous oxytocin acts via direct entry into the brain or by increased peripheral blood concentrations. Methods: In a randomized controlled design, we compared effects of intranasal (direct entry into the brain and increased peripheral concentrations) and oral (only peripheral increases) oxytocin on behavioral and neural responses to social touch targeting C-touch (gentle-stroking) or other (medium pressure without stroking) cutaneous receptors. Results: Although both types of touch were perceived as pleasant, intranasal and oral oxytocin equivalently enhanced pleasantness ratings and responses of reward, orbitofrontal cortex, and social processing, superior temporal sulcus, regions only to gentle-stroking not medium pressure touch. Furthermore, increased blood oxytocin concentrations predicted the pleasantness of gentle stroking touch. The specificity of neural effects of oxytocin on C-touch targeted gentle stroking touch were confirmed by time-course extraction and classification analysis. Conclusions: Increased peripheral concentrations of oxytocin primarily modulate its behavioral and neural responses to gentle social touch mediated by C-touch fibers. Findings have potential implications for using oxytocin therapeutically in conditions where social touch is unpleasant. Funding: Key Technological Projects of Guangdong Province grant 2018B030335001. Clinical trial number: NCT05265806 Editor's evaluation The therapeutic promise of oxytocin to ameliorate deficiencies in social interactions and/or reward circuitry has been confounded by conflicting literature regarding routes of administration and regions of impact (i.e. central or peripheral). This important study systematically compares oral versus nasal administration on the pleasantness of gentle stroking, which is c-fiber mediated, and massage, which is multimodal. The convincing results are unambiguous that either route increases perceived pleasantness only to gentle stroking and that the effects, while perceived in the brain, are likely mediated peripherally. https://doi.org/10.7554/eLife.85847.sa0 Decision letter eLife's review process Introduction Social touch, is of great importance for social interactions and individual development and can promote interpersonal communication (Cascio et al., 2019; Jones and Glover, 2014). In conditions where social dysfunction occurs, such as autism, social touch is often perceived as unpleasant (Baranek et al., 2006; Ujiie and Takahashi, 2022). Touch perception is determined by the stimulation of low-threshold afferent fibers in the skin that innervate distinct classes of mechanoreceptors. While large myelinated Aβ fibers are densely packed in the fingertips and lips and subserve discriminative touch, unmyelinated C-touch (CT) fibers exist in hairy skin and only respond to low force/velocity (caress-like stroking) touch (Croy et al., 2016; McGlone et al., 2014). The latter fibers are specialized for the affective domain of touch and have evolved to signal the rewarding value of physical contact (Liljencrantz and Olausson, 2014; Pawling et al., 2017; Walker et al., 2017). Stimulation of the CT system primarily engages the insula via the spinothalamic tract and brain circuits involved in reward and social-emotional information processing such as the orbitofrontal cortex (OFC) and posterior superior temporal sulcus (pSTS) (Björnsdotter et al., 2014; Davidovic et al., 2016; Gordon et al., 2013; Morrison, 2016; Olausson et al., 2002; Olausson et al., 2010). Medium pressure touch in the form of hugging or massage can also be perceived as pleasant but mainly influences pressure receptors of non-CT fibers (Case et al., 2021; Field, 2010) and primarily targets the somatosensory cortex via the spinothalamic tract (McGlone et al., 2014). While neural substrates of pleasurable gentle stroking and medium pressure touch overlap to some extent they may also involve different parts of the somatosensory cortex and insula (Case et al., 2021). The neuropeptide oxytocin (OT) plays a key role in the regulation of social cognition and the rewarding aspects of social stimuli, including social affective touch (Bartz et al., 2011; Kendrick et al., 2017; Rae et al., 2022; Wigton et al., 2015). There is a close association between OT and CT-targeted social touch (Moberg et al., 2020; Uvnäs-Moberg et al., 2014; Walker et al., 2017) and studies have shown that social touch, particularly administered as gentle stroking touch or medium pressure massage, can activate parvocellular oxytocinergic neurons (Okabe et al., 2015; Tang et al., 2020) and facilitate endogenous OT release in the saliva, blood or urine across species (Crockford et al., 2013; Holt-Lunstad et al., 2008; Li et al., 2019; Morhenn et al., 2012; Portnova et al., 2020; Vittner et al., 2018). Additionally, intranasal administration of OT in humans can modulate processing of social touch at both behavioral and neural levels. More specifically, intranasal OT enhances the perceived pleasantness and activity of the reward system and salience network in response to gentle social touch by a female in men (Scheele et al., 2014), by their partners rather than by an unfamiliar female (Kreuder et al., 2017), or during foot massage administered by a human but not by a machine (Chen et al., 2020b). Intranasal OT also enhances the pleasantness of gentle stroking touch administered indirectly via different materials independent of valence (Chen et al., 2020a). These findings consistently suggest that intranasal OT can enhance the hedonic properties of social touch. While previous studies have interpreted findings in terms of OT potentiating the rewarding effect of CT-targeted social touch, it is less clear whether it does the same for pleasant stimulation of non-CT fiber mechanoreceptors which can also be stimulated by social behaviors such as hugging and during medium pressure massage. Foot massage, for example, incorporates both gentle stroking and medium pressure massage and thus the observed release of OT (Li et al., 2019) and facilitatory effects of intranasal OT (Chen et al., 2020b) may be contributed by CT and non-CT fibers. There is some evidence that receiving frequent hugs can increase OT concentrations (Grewen et al., 2005; Light et al., 2005), although hugging is often accompanied by gentle stroking of the back or neck and so once again both CT and non-CT fibers may be involved. It therefore remains unclear which types of cutaneous afferent fibers are primarily involved in the functional effects of OT on social touch processing. The mechanism(s) whereby intranasal OT produces its functional effects are currently a matter of debate (see Leng and Ludwig, 2016; Yao and Kendrick, 2022). A number of studies have established that intranasally administered OT can directly enter the brain via the olfactory and trigeminal nerves (see Lee et al., 2020; Quintana et al., 2021) and it has been widely assumed to be the main route whereby intranasal OT produces effects on brain and behavior. However, intranasally administered OT also enters the peripheral circulation after absorption by nasal and oral blood vessels and may produce functional effects by entering the brain after binding to the receptor for advanced glycation end products (RAGE) and crossing the blood brain barrier (BBB; Yamamoto and Higashida, 2020), or by vagal stimulation following stimulation of its receptors in the heart and gastrointestinal system (see Carter, 2014; Carter et al., 2020; Yao and Kendrick, 2022) or following stimulation of receptors in other organs. Indeed, in a recent study we have shown that reducing the entry of oxytocin into the peripheral circulation following intranasal administration using a vasoconstrictor prevents its effects on resting state electroencephalographic changes involving cross-frequency coupling (Yao et al., 2023). In the specific context of responses to tactile stimulation peripheral OT could influence OT receptors in keratinocytes in the skin which may act to modulate activity of responses of cutaneous sensory fibers (Baumbauer et al., 2015; Deing et al., 2013; Talagas and Misery, 2019) or in spinal dorsal route ganglion neurons which receive inputs from cutaneous sensory fibers and project to the brain via the spinothalamic tract (González-Hernández et al., 2017; Noguri et al., 2022). Support for peripherally mediated routes have been found in animal model studies reporting functional effects of OT administered subcutaneously or intraperitoneally (see Yao and Kendrick, 2022), and in a previous study, we have shown similar effects of intranasal and oral (lingual) OT on visual attention and state anxiety (Zhuang et al., 2022). There may however also be some administration route-dependent functional effects of OT. For example, in monkeys intranasal and intravenous administration of OT have been reported to produce different patterns of regional perfusion (Lee et al., 2018), although in humans they produced similar neural effects (Martins et al., 2020b). Another recent study in humans has shown that intranasal and oral (lingual) OT have different effects on amygdala and putamen responses to emotional faces and on associated arousal (Kou et al., 2021). Thus, it is unclear whether the reported effects of exogenously administered OT on responses to social touch are mediated via direct entry into the brain or indirectly via increased concentrations in the peripheral circulation which subsequently influence the brain either by crossing the BBB or by acting on receptors in peripheral organs or nerves. Against this background, the present study investigated firstly whether intranasal OT primarily enhanced the pleasantness and associated brain reward responses to touch exclusively targeting CT fibers (using gentle stroking touch) or primarily targeting non-CT fiber pressure mechanoreceptors (medium pressure massage without stroking). Secondly, the effects of intranasal OT were contrasted with those of oral (lingual) OT using the same dose of 24 IU to help establish whether OT was mainly acting via peripherally mediated routes (see Figure 1A for a complete study procedure). While intranasally administered OT can produce functional effects by either directly entering the brain or by increasing peripheral vascular system concentrations, oral OT administration can only do so by the latter. We therefore postulated that if equivalent effects of the two routes of administration are observed then the functional effects of OT are likely to be due to peripheral vascular increases. Behavioral responses to different types of touch were recorded using rating scales and neural responses were acquired using functional near-infrared spectroscopy (fNIRS) measures of oxygenated-hemoglobin chromophore concentration changes in cortical brain regions involved in reward (OFC), social cognition (STS) and somatosensory processing (somatosensory cortex - S1; Figure 1B–C). fNIRS is now widely used in neuroimaging (Pinti et al., 2020) and has the advantage that subjects are more comfortable and can move more than in an MRI scanner and can more easily be catheterized for taking blood samples during recordings. Although, fNIRS only measures activity changes in the superficial cortex it allows recordings to be made from three of the main touch processing regions, the OFC, STS and somatosensory cortex and has therefore often been used in studies investigating touch processing (Bennett et al., 2014; Cruciani et al., 2021; Li et al., 2019). Additionally, physiological measures of autonomic nervous system changes were recorded (skin conductance response - SCR and the electrocardiogram - ECG) and blood samples were taken for measurement of OT concentration changes. We hypothesized firstly that while subjects would find both the gentle stroking touch and medium pressure massage pleasurable, intranasal OT would particularly enhance behavioral and brain reward (OFC) and social processing (STS) region responses to gentle stroking touch targeting the CT fiber system in line with our previous studies (Chen et al., 2020a; Scheele et al., 2014) and not in response to the medium pressure massage targeting non-CT fibers. Secondly, based on recent studies comparing effects of intranasal and oral OT (Xu et al., 2022; Zhuang et al., 2022), we hypothesized that oral OT would have a similar effect to intranasal OT, thereby indicating that its effects were mediated by increased concentrations in the peripheral vasculature rather than by direct entry into the brain. Thirdly, we hypothesized that behavioral and neural effects of OT on social touch would be associated with treatment effects on peripheral plasma concentrations of the peptide, in line with observations in some previous studies (Martins et al., 2020b; Kou et al., 2021). Figure 1 with 1 supplement see all Download asset Open asset The study procedure and layout of fNIRS optodes and channels. (A) The study protocol and sequences of the experimental task. A total of four blood samples (6 ml for each) were collected for each subject before and after the treatment and after each session to measure OT concentration changes. Subjects completed the positive and negative affective schedule (PANAS) before and after the intranasal/oral OT or PLC treatment. During each touch session, neural responses were acquired using functional near-infrared spectroscopy (fNIRS) measures and physiological measures of autonomic nervous system changes including the skin conductance response - SCR and the electrocardiogram - ECG were recorded as well. Subjects were subsequently asked to rate their mood (PANAS) and subjective experience of the massage/touch including the perceived pleasantness, arousal, intensity, and willingness to payment after each session. (B) The array design displayed the locations of the sources (red) and detectors (blue). (C) Channels according to the international 10–20 placement system. A 26-channel array consisting of 12 sources and 13 detectors were used to record hemodynamic activity of the bilateral lateral orbitofrontal cortex (lOFC: channels 9, 18), medial orbitofrontal cortex (mOFC: channels 12–15) and mediolateral orbitofrontal cortex (mlOFC: channels 10, 11, 16, 17), posterior superior temporal sulcus (pSTS: channels 1–4, 23–26) and the somatosensory area (S1: channels 5–8, 19–22). Methods Participants An a priori sample size calculation using G* power indicated that 159 participants (number of groups: 3, and 53 subjects per group) should be sufficient to reliably detect a medium effect size (ɑ=0.05, f=0.25, 80% power). A total of 180 healthy Chinese subjects (90 males, 21.22±2.77 years) participated in the present study. Exclusion criteria consisted of any self-reported psychiatric/physical illness, alcohol/substance abuse, or other major health concern. Self-reported menstruating information and the luteinizing hormone test were conducted for all female participants. They were asked to participate in the experiment avoiding the menstruation periods. All subjects gave written informed consent prior to any study procedures. All experimental procedures were in accordance with the latest revision of the declaration of Helsinki and approved by the local ethics committee of the University of Electronic Science and Technology of China and registered as a clinical trial (NCT05265806). Five subjects were excluded due to failure to complete the procedures and four subjects were dropped because of technical problems during data acquisition (details see Figure 1—figure supplement 1). Thus data from a final sample of 171 subjects (87 females, 21.58±1.94 years) were analyzed (intranasal OT: N=56; oral OT: N=57; PLC: N=58) (see Table 1). Table 1 Demographic, physiological, and psychometric assessments in the three groups (M±SD). Intranasal OTOral OTPLCvaluepNumber (males)n=56(26)n=57(27)n=58(31)χ2 = 0.670.721Age21.79±1.9621.46±2.0521.50±1.84F=0.480.618ASQ21.43±5.4820.09±5.0521.66±5.84F=1.370.256STQ40.36±8.5141.32±9.6040.79±7.67F=0.180.840SP13.16±5.2812.86±5.5013.38±5.48F=1.130.876SR13.20±4.0714.26±4.2214.16±3.60F=1.240.293SOR22.66±9.4320.88±10.2323.17±9.64F=0.870.421BDI9.21±9.118.39±7.369.79±8.39F=0.420.660TAI42.96±9.3243.47±9.1043.21±9.77F=0.040.959SAI38.59±9.6138.51±8.3739.02±10.33F=0.050.953CBSS39.46±9.5636.21±9.3838.28±8.98F=1.770.173CTQ38.50±8.5736.51±9.0337.97±9.10F=0.760.469IRI48.89±10.9948.95±10.2650.36±11.09F=0.340.710AAS57.84±6.2358.11±6.0457.26±6.02F=0.290.748PANAS Positive affect18.71±0.8019.63±0.7817.42±0.78F=2.040.132 Negative affect11.00±0.3711.31±0.3611.15±0.36F=0.170.840HF Gentle stroking touch47.24±16.6249.32±17.2949.48±16.47Fa = 0.400.878 Medium pressure massage51.89±17.1853.68±16.2052.89±15.74DFAα1 Gentle stroking touch0.92±0.250.89±0.240.88±0.23Fa = 0.330.922 Medium pressure massage0.99±0.250.94±0.270.95±0.25Heart rate Gentle stroking touch72.78±8.2574.47±10.4572.47±9.96Fa = 0.700.653 Medium pressure massage71.73±9.5672.09±8.0970.67±9.48SCR Gentle stroking touch1.45±1.811.20±1.471.09±1.52Fa = 0.430.862 Medium pressure massage2.48±2.152.58±2.392.49±187Basal OT concentrations8.12±0.548.49±0.609.71±0.48F=2.390.105 a: F values of the group x condition interaction analyses. Blood samples and OT assay To measure plasma OT concentrations, before and 30 min after intranasal and oral (lingual) treatments, as well as immediately after each session of social touch/massage condition (see Figure 1A for sampling protocol), 4 blood samples in total (6 ml for each) were collected into EDTA tubes from all subjects by an indwelling venous catheter and were stored after centrifugation at –80°C until assays were performed. Oxytocin concentrations were measured using a commercial ELISA (ENZO, USA, kit no: ADI-901–153). Blood samples were analyzed in duplicate and a standard prior extraction step was performed following the recommended protocol from the manufacturers. Spiked samples (with 100 pg/ml OT added) were included with every assay to calculate extraction efficiency which was 96%. The extraction step incorporated a fourfold concentration of samples using a vacuum concentrator (Concentrator plus, Eppendorf, Germany) resulting in a detection sensitivity of 2 pg/ml. All samples had detectable concentrations. The inter- and intra-assay coefficients of variation were 14 and 11% respectively. The manufacturer’s reported cross-reactivity of the antibody for other neuropeptides, such as vasopressin and vasotocin, is <0.01% (for detailed OT assay methods, see Li et al., 2019). Experimental procedure Participants were first asked to complete Chinese versions of validated questionnaires on personality, traits, mood, attitude toward interpersonal touch and sensitivity to reward to control for possible group differences in potential confounders. Personality trait measures included the Autism Spectrum Quotient (ASQ; Baron-Cohen et al., 2001), the Beck Depression Inventory II (BDI; Beck et al., 1996), the State-Trait Anxiety Inventory (STAI; Spielberger et al., 1983), the Cheek and Buss Shyness Scale (CBSS; Cheek and Buss, 1981), the Interpersonal Reactivity Index (C-IRI; Siu and Shek, 2005), the Childhood Trauma Questionnaire (CTQ; Bernstein et al., 2003), and the Adult Attachment Scale (AAS; Collins and Read, 1990). Individual attitudes and sensitivity to touch and reward were assessed using the Social Touch Questionnaire (STQ; Wilhelm et al., 2001), the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ; Torrubia et al., 2001), and individual levels of sensory over-responsivity (also referred to as defensive responses) toward tactile stimuli were measured by the Sensory Over-Responsivity (SensOR) Scales (Schoen et al., 2008). Additionally, to control for potential confounding effects of treatment on mood, participants completed the Positive and Negative Affect Schedule (PANAS; Watson et al., 1988) immediately before and 30 min after the treatment and after each touch session (details see Figure 1A). Following completion of the questionnaire assessments, participants were randomly assigned to receive the oral (lingual) or intranasal administration of OT spray (24 IU; Oxytocin Spray, Sichuan Defeng Pharmaceutical Co. Ltd, China) or their corresponding placebo (PLC) spray (half received the PLC intranasally and half orally; identical ingredients except the peptide - i.e. glycerine and sodium chloride) in a randomized double-blind placebo-controlled between-subject design. Intranasal and oral spray bottles and OT concentrations per 0.1 ml puff were identical (i.e. 4 IU). For intranasal administration, three puffs were applied to each nostril alternating between them and with 30 s between each puff, for oral administration six puffs were sprayed onto the tongue (i.e. lingual) with 30 s between each puff and the subjects required not to swallow until just before the next puff was applied to allow time for absorption by oral blood vessels (as in Kou et al., 2021). Subjects and experimenters were blind concerning whether PLC or OT was administered. Blinding for the two different routes of administration was not possible although subjects were not informed until they arrived to sign the consent form and take part in the experiment whether they would receive intranasal or oral treatment. In line with our previous findings that oral and intranasal PLC administration do not produce different functional effects either at neural or behavioral levels (Kou et al., 2021; Zhuang et al., 2022), there were also no significant differences in pleasantness ratings of the gentle stroking touch and medium pressure massage between the intranasal and oral PLC groups (ps >0.110) confirming that knowledge of the route of administration had no effects. We therefore combined them into a single PLC group. Participants were unable to guess better than chance whether they had received OT or PLC (χ2=0.43, p=0.512). As a further control for the lack of blinding in the groups receiving different routes of administration initial analyses of blood samples, behavioral and neural data were performed blind by experimenters. In line with previous studies (Paloyelis et al., 2016; Spengler et al., 2017), the task started approximately 35–40 min after the treatment administration. Neural and physiological responses to social touch stimulation were measured via simultaneously acquired fNIRS together with SCR and ECG recording. A professional masseur blinded to the research aim was trained by the experimenter to administer the different social touch stimuli to the calf of each leg as consistently as possible. For gentle touch, the masseur applied only a light stroking touch at the optimum velocity for activating CT fibers (5 cms/s) and at which subjects perceive this form of touch as most pleasant (Löken et al., 2009). For the massage stimulation condition, the masseur applied a medium pressure massage moving discretely up and down the leg at the same velocity but without stroking the skin, designed to primarily target non-CT fibers (Field, 2010). The gentle touch and medium pressure massage were delivered on both legs simultaneously to control for possible preferences for left or right and more importantly to avoid unilateral brain activation. During the experiment, the masseur could simultaneously see a visual cue indicating the type of stimulation on a personal monitor and was instructed to vary the exact start and end point of each stimulation on the calf randomly by a few millimeters in order to minimize receptor fatigue (Cascio et al., 2012). To reduce the possibility that subjects might be uncomfortable with receiving gentle stroking touch from a stranger, subjects were informed that both types of touch stimulation they would receive were forms of professional massage using different amounts of pressure and that they just needed to be relaxed and concentrate on how the administered ‘massage’ made them feel. They were further informed that either a masseur or a masseuse would be randomly assigned by the experimenter to deliver the ‘massage’, although in fact, they were always given by a same masseur. The paradigm consisted of two sessions and each session comprised 20 blocks of gentle stroking touch or medium pressure massage. Condition-order was counterbalanced across participants. Each block lasted for 30 s alternated with a rest interval of 15 s and each session lasted for 15 min with a 15 min rest interval between each (Figure 1A). Immediately after each session, subjects completed the PANAS and then answered the following four questions: (1) How pleasant did you feel the massage? (1=extremely unpleasant, 9=extremely pleasant). (2) How much did the massage arouse you? (1=drowsy and unresponsive, 9=very arousing). (3) How intense was the massage? (1=extremely light, 9=extremely strong) and (4) How much would you be willing to pay if you had to pay for the applied massage? Please choose from 1 to 100 (1=1 RMB, 9=100 RMB). After the experiment, participants were asked to guess the gender of the massager to control for possible sex-dependent effects. Physiological data acquisition and analyses Physiological measures were collected at a sampling rate of 1000 Hz using a Biopac MP150 system (Biopac Systems, Inc) and recorded using AcqKnowledge (Version 4.4, Biopac Systems Inc, CA, USA). SCR was recorded using a GSR100C module with two electrodes being placed on the tips of participant’s left index and middle fingers. ECG was recorded using an ECG100C module with three electrodes (including the ground electrode) placed relatively close to each other in parallel on the left side of the upper torso (see Niendorf et al., 2012). Physiological data were analyzed using the AcqKnowledge 4.4 software following the manual. To determine different SCR amplitudes in response to the medium pressure massage and the gentle stroking touch, we computed the mean base-to-peak difference within a 15 s time window after the stimulation and rest onset. SCR differences were compared across the three treatment groups for each stimulation condition and rest as well as between the medium pressure massage and the gentle stroking touch. The raw ECG data was band-pass filtered (range: 0.5–35 Hz; 8000 coefficients) to remove baseline drift and high-frequency noise. A template correlation function was used to transform noisy data manually. Next, we extracted R-R intervals from the clean ECG which were next imported into Kubios software (http://kubios.uku.fi) for heart rate (as a sympathetic nervous system measure of arousal) and HRV (indexed by the high-frequency component — HF and the detrended fluctuation scaling exponent — DFAα1, assumed to reflect parasympathetic influence) analyses (Kemp et al., 2012; Martins et al., 2020a). fNIRS data acquisition and analyses Hemodynamic response signals were acquired using the NIRSport2 System (NIRx Medical technologies LLC, Berlin, Germany) operating at two wavelengths (760 and 850 nm) with a sampling frequency of 6.78 Hz. In line with previous studies (Li et al., 2019; Long et al., 2021; Tsuzuki and Dan, 2014), each optode was placed on the surface of skull according to reference points on the head (the nasion, inion, left and right ears, top and back of the head) adjusting for different head size and shapes of different participants. The probe set contains 12 sources and 13 detectors with 3 cm source-detector separation to cover brain regions of interest (ROIs) and allows for 26 different channels to measure the oxyhemoglobin and deoxyhemoglobin concentration changes. The current study focused on the oxyhemoglobin (oxy-Hb) concentration changes because of the higher sensitivity to cerebral blood flow changes and better signal-to-noise ratio. Based on previous studies (e.g., Li et al., 2019; Bennett et al., 2014), five regions engaged in touch processing were selected as a priori ROIs, including the bilateral lateral OFC (lOFC), medial OFC (mOFC), mediolateral OFC (mlOFC), posterior STS (pSTS) and primary somatosensory cortex (medial S1). The optodes were placed in accordance with the international 10–20 system and the lowest lines of the probes were placed at T7 and T8 corresponding to positions of channels 1 and 25, respectively (see Figure 1B–C). The fNIRS raw data were analyzed using the NIRS-KIT software which can be used for both resting-state and task-based fNIRS data analyses (Hou et al., 2021). During preprocessing, raw optical intensity data were firstly converted to concentration changes of oxy-Hb based on the modified Beer-Lambert law. A polynomial regression model was then applied to remove linear detrends from the raw time course. Motion-related artifacts and baseline shifts were removed using the temporal derivative distribution repair (TDDR) method and an infinite impulse response (IIR) Butterworth bandpass filter (0.01–0.08 Hz) was additionally employed to correct for machinery and physiological noise. On the first level, a generalized linear model (GLM)