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Olfactory modulation of affective touch processing — A neurophysiological investigation
NeuroImage 135 (2016) 135–141
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Olfactory modulation of affective touch processing — A neurophysiological investigation Ilona Croy a,b,d,⁎, Edda Drechsler c, Paul Hamilton d, Thomas Hummel c, Håkan Olausson a,d a
Department of Clinical Neurophysiology, Sahlgrenska University Hospital, University of Gothenburg, Sweden Department of Psychosomatic Medicine and Psychotherapy, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany Smell and Taste Clinic, Department of Otorhinolaryngology, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany d Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine, Linköping University, Sweden b c
a r t i c l e
i n f o
Article history: Received 21 January 2016 Revised 22 March 2016 Accepted 19 April 2016 Available online 30 April 2016 Keywords: C tactile Hedonic fMRI Somatosensory Olfaction
a b s t r a c t Touch can be highly emotional, and depending on the environment, it can be perceived as pleasant and comforting or disgusting and dangerous. Here, we studied the impact of context on the processing of tactile stimuli using a functional magnetic resonance imaging (fMRI) paradigm. This was achieved by embedding tactile stimulation in a variable olfactory environment. Twenty people were scanned with BOLD fMRI while receiving the following stimulus blocks: Slow stroking Touch, Civette odor (feces like), Rose odor, Touch + Civette, and Touch + Rose. Ratings of pleasantness and intensity of tactile stimuli and ratings of disgust and intensity of olfactory stimuli were collected. The impact of the olfactory context on the processing of touch was studied using covariance analyses. Coupling between olfactory processing and somatosensory processing areas was assessed with psychophysiological interaction analysis (PPI). A subjectively disgusting olfactory environment significantly reduced the perceived pleasantness of touch. The touch fMRI activation in the secondary somatosensory cortex, operculum 1 (OP1), was positively correlated with the disgust towards the odors. Decreased pleasantness of touch was related to decreased posterior insula activity. PPI analysis revealed a significant interaction between the OP1, posterior insula, and regions processing the disgust of odors (orbitofrontal cortex and amygdala). We conclude that the disgust evaluation of the olfactory environment moderates neural reactivity in somatosensory regions by upregulation of the OP1 and downregulation of the posterior insula. This adaptive regulation of affective touch processing may facilitate adaptive reaction to a potentially harmful stimulus. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Affective touch perception is of primary importance for human interaction. Touching and stroking can be critical in expressing security and positive attention, and can create bonds between people [for overview (Gallace and Spence, 2010)]. However, interpersonal touch is also fundamentally ambiguous (Major, 1981). A variety of emotions can be communicated via touch (Hertenstein et al., 2006); for example, touch can be comforting, pleasant and arousing, but also aggressive, lecherous, and a means of transferring disease. In threatening contexts touch does not feel pleasant but, rather, evokes negative emotions such as anxiety or disgust (Olausson et al., 2010). Evaluation of contextual information is hence critical for the hedonic perception of touch.
⁎ Corresponding author at: Department of Psychosomatic Medicine and Psychotherapy, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany. E-mail address: [email protected] (I. Croy).
http://dx.doi.org/10.1016/j.neuroimage.2016.04.046 1053-8119/© 2016 Elsevier Inc. All rights reserved.
Moreover, reviews on hedonic perception of touch convey that little is known about the integration of touch and other sensory inputs in generating emotional responses (Gallace and Spence, 2010). The extant body of research on affective touch suggests that this form of touch is a sense of its own and is distinguishable from discriminative touch by involvement of different nerve fibers in the periphery as well as different brain structures (Olausson et al., 2002; McGlone et al., 2014). C-tactile (CT) fibers, a subgroup of the unmyelinated C-fibers innervating the skin, have been found to selectively react to slow stroking stimulation with light force and about 32 °C stimulus temperature – the same stimulus parameters as interpersonal touch (Olausson et al., 2010; Loken et al., 2009; Ackerley et al., 2014). Such gentle touch is processed in several cortical regions including the primary and secondary somatosensory cortex, the posterior insula, and the orbitofrontal cortex (Olausson et al., 2002; Morrison et al., 2011a, 2011b; McCabe et al., 2008; McGlone et al., 2012). Consistent with the formulation that CT transduced touch is socially important, people who score high on autism scales exhibit reduced neural activation to CT targeted touch (Bennett et al., 2013; Kaiser et al., 2015).
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Furthermore, people with reduced C-fiber density experience CT targeted touch as less pleasant (Morrison et al., 2011b). In typical experimental contexts, slow stroking CT targeted touch is experienced as pleasant and calming. This is found for both manual and machine delivered touch (Triscoli et al., 2013), for men and women of different ages (Loken et al., 2009; Morrison et al., 2011b; Triscoli et al., 2013; Croy et al., 2014a; Ellingsen et al., 2014), and in children as young as nine-months old (Fairhurst et al., 2014). Contextual information, however, significantly impacts the pleasantness of touch. For example, the belief that stroking is done in applying a “basic” as opposed to a “rich moisturizing” cream decreases pleasantness (McCabe et al., 2008), as does the belief that stroking is performed by an unattractive male instead of an attractive female (Gazzola et al., 2012), as does viewing angry instead of friendly faces when being stroked (Ellingsen et al., 2014). In everyday life, typically negative odors—such as a bad body odor, the odor of feces or bad breath—affect the appreciation of touch. Odors warn about microbial threats, encouraging us to avoid touch if a microbial threat is in proximity. This olfactory warning function is most likely fulfilled by evoking basic withdrawal reflexes and disgust (Stevenson, 2010). Indeed, unpleasant odors have a high potential of evoking disgust each time they are presented (Croy et al., 2013a). It has been shown, that odors modulate discriminative aspects of touch and odorized fabrics feel different compared to unodorized ones (Dematte et al., 2006). Moreover, we recently found that odors also modulate the affective side of touch – disgusting, but not pleasant, odors influence the pleasantness of affective touch (Croy et al., 2014a), indicating that a negative olfactory environment signals that touch should be avoided. The neural basis of this cross-modal interaction, however, remains to be elucidated. This study aims to investigate the neural underpinnings of olfactory influence on affective touch. To this end, we modified our previous paradigm (Croy et al., 2014a) to be amenable to a functional magnetic resonance imaging (fMRI) setting. Neural activation to touch alone and to touch under the influence of odors was measured. Based on the behavioral data (Croy et al., 2014a), we hypothesized that disgusting odors alter the processing of touch in those neural regions that process affective touch stimuli: primary and secondary somatosensory cortex, posterior insula and orbitofrontal cortex.
2. Materials and methods 2.1. Statement The study followed the Declaration of Helsinki on Biomedical Research Involving Human Subjects and was approved by the Ethics Committee of the TU Dresden (EK 194062013). All participants gave written informed consent.
2.2. Participants Twenty-two participants were scanned using fMRI. All participants were right handed with normal olfactory function as ascertained using the “Sniffin' Sticks” identification test (Hummel et al., 2007). As olfactory processing is altered in depression (Croy et al., 2014b), participants were screened for this disorder. None of the participants suffered from depression as measured using the Beck Depression Inventory (BDI II) questionnaire (Beck and Steer, 1987; Hautzinger et al., 1995)—scores ranged from 0 to 13 (mean 3.6 ± 3.2 SD) and none of the participants was in the range of a “mild depression” or above. Two of the participants were excluded because they rated the intensity of one of the odors (Rose) in the scanner with 0 (“not intense at all”). The remaining group consisted of 20 participants (8 women, 12 men; age ranged from 21 to 37 years, mean age 24.0 years ±3.6 SD).
2.3. fMRI procedure A 3-Tesla MR scanner (Trio; Siemens Medical, Erlangen, Germany) was used for data acquisition. Functional data was collected in 200 volumes per session with a 2D GE echo-planar imaging sequence with 36 axial slices (imaging matrix 128 ∗ 128), TR 3000 ms, TE 40 ms, FA 90°, voxel size 3 ∗ 3 ∗ 3.75 mm; no interslice gap) using an eight channel head coil and sagittal acquisition. For anatomical mapping and exclusion of potential brain pathology in participants, a high resolution T1-weighted image (3D IR/GR sequence: TR 2180 ms/TE 3.93 ms) was acquired. Each participant was scanned for five imaging runs, each consisting of 12 on–off stimulation periods (15 s stimulation then 15 s non-stimulation), summing up to 6 min of scanning per run. Participants were asked to rate the stimulation after each run. Therefore each run comprised stimulation of a particular type (Touch, Civette odor, Rose odor, Touch + Civette, and Touch + Rose). The presentation order was randomized across participants; see Fig. 1. 2.3.1. Odor presentation Civette, an animal odor, strongly resembling the odor of feces, and Rose were chosen as olfactory stimuli. Feces are cross-culturally perceived as disgusting (Rozin and Fallon, 1987)and are the most frequently named category when people are asked to pick an disgusting odor (Croy et al., 2011; Seo et al., 2011). In order to be consistent with the previous behavioral study on odor–touch interactions, Rose was used as a second olfactory stimulus. The choice of concentration was based on this previous study (Croy et al., 2014a). The odors were dissolved in propylene glycol at 0.7% or 18.5% v/v, respectively, in order to achieve an equally intense perceptual quality (Civette Base: Fragrance resource, Hamburg, Germany; Rose: Frey and Lau, Henstedt-Ulzburg, Germany). Odors were rated as iso-intense in the scanner (Table S1). A computer-controlled olfactometer (Sommer et al., 2012) was used for bilateral intranasal presentation of odors. For intranasal stimulation, Teflon tubing with an inner diameter of 4 mm was used. In order to avoid odor correlated intranasal mechanical stimulation, odor pulses were embedded in a constant flow of odorless air with a total flow per nostril of 1 l/min. During stimulation, blocks of odors were presented in a pulsed manner with 1 s odor followed by 2 s pause (=5 puff pulses per block) in order to avoid rapid habituation. During non-stimulation (off) blocks, the same airstream was presented but without the odor. Repeated blockwise presentation of odors does not lead to strong habituation effects (Croy et al., 2013b). For affective touch no such data is published. However our unpublished observation shows, that neural response in primary and secondary somatosensory cortices and posterior insula is still present after 30 min of continuous presentation of the very same stroking stimulation, we use here. Potential interference between the timing of odor presentation and respiratory air flow through the nose during inhalation was minimized by teaching participants the breathing technique of velopharyngeal closure (breathing only through the mouth by lifting the soft palate). This technique enables olfactory stimulation to be unaffected by patterns of inhalation and exhalation. This procedure also prevents the participants from “sniffing” of odors which may produce perceptunrelated activation in olfactory–eloquent structures (Mainland and Sobel, 2006). Using biofeedback (displaying the respiratory flow in front of the nostrils on an oscilloscope) the procedure was thoroughly trained prior to scanning with respiratory feedback for each participant until no respiratory nasal airflow was recorded any more in front of the nostrils (2 to 15 min). Respiratory airflow was not controlled in the scanner because experience showed that in healthy participants, once learned, the velopharyngeal closure can be maintained very easily. After each of the Civette only and Rose only runs, the participants verbally rated the pleasantness and intensity and disgust of the odor on three 11-point scales (− 5 to 5: extremely unpleasant–extremely pleasant; 0 to 10: not intense at all–extremely intense; 0 to 10: not disgusting at all–extremely disgusting). The dimensions of disgust and
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Fig. 1. Visualization of the fMRI design. During one run, stimulation was made with either Rose, Civette, Touch, Touch + Rose, or Touch + Civette. Each participant was scanned during five runs in random order. Each stimulus was presented 12 times/run. Within the on blocks, odors were presented pulsed, with 1 s of odor presentation and 2 s of pause. Touch was performed as continuous stroking on the right forearm with a velocity of 3 cm/s. Each stimulation period lasted 15 s and each off period lasted 15 s and was repeated 12 times for each run.
pleasantness have been shown to contribute independent information that describes the odor percepts well (Croy et al., 2013a, 2014a); moreover, inclusion of both ratings, disgust and pleasantness, allowed us to capture more thoroughly the hedonic value of the odors presented.
practiced this entire procedure in a sham scan session in order both to familiarize participants with the procedure and to ensure that they rated the touch only under conditions of combined stimulation. 2.4. fMRI analysis
2.3.2. Touch presentation Slow stroking touch, perceived as pleasant in typical experimental contexts, and effective in activating CT afferents (Loken et al., 2009; Morrison et al., 2011b; Triscoli et al., 2013; Croy et al., 2014a; Ellingsen et al., 2014), was presented on the right dorsal forearm with a velocity of 3 cm/s and a force of approximately 0.4 N at a stroking distance of 10 cm (4 strokes per 15 s block). The touch stimuli were manually applied by the experimenter by means of a 50 mm wide flat, soft watercolor brush made of fine, soft, goat's hair. Before the actual session, the experimenter (author ED) extensively practiced stroking for five days in a row prior to the experiment on a wooden board with a 10 cm marking, which was attached to a fine tuned scale. This practice ensured constant velocity and force; additionally, during fMRI scanning the experimenter's stroking frequency was guided by a computer presentation. With this guidance, manual touch administration is perceptually similar to robot guided administration of tactile stimuli (Triscoli et al., 2013). Synchronization of touch and odor presentation was achieved via the computer presentation, displayed on a screen inside the scanning room. This was visible to the experimenter, but not to the participant. The experimenter was instructed with words (“brush”; “stop”) and color code. In order to allow the experimenter some preparation time, color code always changed 3 s before the beginning of a new instruction. The touch presentation was synchronized with the olfactometer. The experimenter was not informed about whether an odor was presented or not. After each run containing tactile stimulus blocks (Touch, Touch + Civette, Touch + Rose), the participants verbally rated the pleasantness and intensity of the touch stimulation on two 11-point scales (− 5 to 5: extremely unpleasant–extremely pleasant; 0 to 10 not intense at all–extremely intense; compare S1). Participants
We analyzed fMRI time-series data using a standard general linear model approach implemented in SPM8 (Statistical Parametric Mapping; Welcome Department of Imaging Neuroscience, in the Institute of Neurology at University College London [UCL], UK) implemented in Matlab (Matlab 6.5 R3, The MathsWorks IncS., Natick, MA). The data were first preprocessed: realignment with 2nd degree B-spline; temporal filtering with high pass filter cutoff at a period of 128 s; normalization using the segmentation procedure implemented in SPM 8 with affine registration to the ICBM space template (MNI space), bias regularization of 0.0001, and spatial smoothing of functional data with a Gaussian kernel of 8 × 8 × 8 FWHM. The first 5 scans of each sessions were eliminated to allow for equilibration of the longitudinal magnetization vector. The 15 s scans of each stimulation block were used for the first level analysis, where stimulation blocks were compared to non-stimulation blocks using a boxcar covariate reflecting stimulus on–off cycles convolved with SPM's canonical hemodynamic response function. As movement was very limited for all participants (b2 mm translation and 1° rotation for each run for each participant), we did not include motions-based noise regressors in our analysis to preserve degrees of freedom. For subsequent analysis, we first concentrated on data from tactilealone and olfaction-alone blocks, in order to identify neural correlates of tactile and olfactory stimulation, respectively. Neuronal correlates of tactile stimulation were expected in predefined tactile ROIs; correlates of olfactory stimulation in predefined olfactory ROIs (see below). We then focused on the polysensory (tactile plus olfactory stimulation) blocks where we performed a neurobehavioral correlation analysis to examine tactile eloquent regions where response tracked subjective ratings of odor-disgust regardless of odor condition, given that Rose was not always pleasant nor was Civette always aversive to
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our participants. Finally, tactile regions that were sensitive to olfactory disgust were submitted as the seed region of interest (ROI) in a psychophysiological interaction (PPI) analysis. Neural regions responsive to tactile stimulation were identified from the Touch-only (stimulation on versus off) run using a one-sample t-test. This analysis was conducted voxel-wise within a set of four tactile ROIs, a priori defined from publications studying affective touch processing; these regions included contralateral (to the side of stimulation) primary and secondary somatosensory cortices S1 and S2, contralateral posterior insula, mid-anterior and lateral orbitofrontal cortex (Morrison et al., 2011a; McCabe et al., 2008; McGlone et al., 2012), see supplementary methods for more detailed information]. To determine the relation between touch pleasantness perception and tactile activation, covariance analysis was applied with touch pleasantness ratings as a vector of interest on the Touch-only (stimulation on versus off) contrasts. Analysis of olfactory activation was determined from the combined (Civette + Rose) condition (using t-test with a weighted contrast vector: 0.5/0.5) and focused on predefined olfactory ROIs: amygdala, thalamus, hippocampus, piriform cortex, anterior insula, orbitofrontal cortex (please see the supplementary methods section for more details). The anterior insula is not only involved in olfaction, but further sensitive to disgust processing (Hennenlotter et al., 2004). As in our previous study (Croy et al., 2014a), pleasantness ratings did not track perfectly with olfactory condition (i.e., 12 subjects rated Civette most disgusting, 6 subjects rated Rose most disgusting and 2 rated both odors equally disgusting). Given this, we combined Civette- and Rose-only scan data in identifying the relation between olfactory disgust and neuronal response. We determined this relation using covariance analysis with disgust ratings as a vector of interest correlated against Civette and Rose (stimulation on versus off) condition contrasts (vectors: Civette/Rose/Rating Data = 0/0/1). In the polysensory conditions, we first examined tactile ROI activation in the combined Touch Odor (Touch + Civette and Touch + Rose) vs Baseline contrasts using t-test with weighted contrast vectors (Design Matrix: Touch + Civette/Touch + Rose/Touch = 0.5/0.5/0). Activation in the combined Touch Odor contrasts was compared to the Touch only condition, using t-tests (vector: Touch + Civette/Touch + Rose/ Touch = 0.5/0.5/−1). To estimate the relation between olfactory disgust perception and neural response to tactile stimulation, we applied neuralbehavioral covariance analysis at the group level with olfactory disgust ratings as a vector of interest on the contrasts of the Touch + Civette and Touch + Rose (vectors: Touch + Civette/Touch + Rose/Rating data = 0/0/1). Level of significance of the voxel-wise analysis restricted to a set of ROIs was set to p = 0.05 for all tests, Bonferroni corrected for multiple comparisons; thus, statistical maps were thresholded at p = (0.05/4 [4 ROIs]) for tactile search areas and at p = (0.05/6 [6 ROIs]) for olfactory search areas. This modest control is chosen, as olfactory activation in block design sessions is subtle, even when carefully controlled for respiratory influences (Wang et al., 2014). Family wise error based small volume correction at the level of p b 0.1 is additionally reported. We also report results from an exploratory whole-brain analysis for the Touch vs Baseline contrasts. Significant activation clusters were located using the Anatomy toolbox (Eickhoff et al., 2005) and their loci are reported in MNI space. PPI analysis was carried out in order to examine the covariation of experiment-dependent signaling in two brain areas (Gitelman et al., 2003). A seed was placed in the OP1 region, which showed a robust tactile response that was influenced by the disgust perception of odors. Therefore, the cluster obtained from the covariance analysis (olfactory disgust perception on tactile activation) served as ROI and a sphere of 4 mm radius was created around the individual maxima within that ROI of each participant (N = 20) and odor touch condition (N = 2). Choice of the 4 mm radius was guided by a PPI study, with similar voxel-size and smoothing kernel, on the contextual modulation of pain (Wiech et al., 2010). The voxel wise interaction was obtained
for each participant for both polysensory conditions of interest (Touch + Civette, Touch + Rose), and a 192 s high pass filter was applied. Second level analysis was performed in a full factorial design encompassing the individual first level contrasts of the Touch + Odor conditions, treated as non-independent conditions (repeated measurement of odor). Level of significance was set to p = 0.05, Bonferroni corrected for multiple comparisons of the 5 areas found to code the pleasantness of touch and/or the disgust to odors (OFC, S1, post insula, amygdala, thalamus). Statistical maps were accordingly thresholded at p = 0.05/5 [5 ROIs]). 2.5. Statistical analysis of perceptual ratings Rating data was analyzed with SPSS 22 (SPSS Inc., Chicago, Ill., USA). Touch pleasantness and intensity ratings of the conditions Touch, Touch + Civette, and Touch + Rose were compared with a generalized mixed model approach. Each participant served as subject, and the three touch conditions as repeated measurements. In addition, the individual impact of odors on the touch ratings was analyzed in a generalized mixed model approach. Each participant served as subject, the two Touch odor conditions were treated as repeated measurements. The pleasantness rating of Touch under olfactory impact was targeted, and the odor disgust ratings served as fixed main effects. Robust estimation of covariances was used for calculation. 3. Results 3.1. Psychophysical response to affective touch in polysensory conditions On an individual level, disgust towards the odors significantly influenced the perceived pleasantness of touch (F [1,38] = 6.2, p = 0.017, Fig. 2). The more disgusting the odor, the less pleasant touch was perceived. The intensity of touch was not affected by the olfactory environment. 3.2. Neural response to affective touch Touch only, in contrast to baseline, activated all of the tactile ROIs: contralateral S1 and S2, posterior insula and lateral OFC (Table 1; Fig. 3; compare Supplementary Table S2 for whole brain analysis). Covariance analysis revealed that the perceived pleasantness of touch was positively correlated to activation in the OFC (MNI − 32 30 –8, k = 11, T = 3.06; MNI: 52 36 –4, k = 8, T = 3.01).
Fig. 2. Relationship between perceived disgust towards odors and pleasantness of touch. Touch pleasantness decreased significantly with increasing olfactory disgust. The number of participants is indicated by size of the symbols.
I. Croy et al. / NeuroImage 135 (2016) 135–141 Table 1 Neural activation in response to touch. Results are presented in predefined tactile ROIs with a height threshold of p b 0.05/4 (Bonferroni corrected for multiple comparison of 4 ROIs). Family wise error correction is reported. Cluster size
T value
MNI coordinates x
y
z
FWE corrected p value
−54 −24 −50 −48 −40 44
−22 −40 −40 −26 −22 48
38 62 54 22 20 −2
0.004 0.011 ns b0.001 b0.001 ns
(Touch + Civette and Touch + Rose) vs Baseline S1 contralateral 76 3.86 −24
−40
62
−46 −40 −46 46
−26 −22 50 44
24 20 −6 −12
0.041 ns b0.001 0.001 ns ns
Touch Only vs (Touch + Civette and Touch + Rose) S2 contralateral 87 3.82 −48
−26
22
0.027
Touch Only vs Baseline S1 contralateral
S2 contralateral posterior insula contralateral OFC
S2 contralateral posterior insula contralateral OFC
70 155 49 404 30 27
297 16 513 260
4.60 4.29 3.09 9.70 5.82 2.93
7.19 4.26 5.10 4.50
139
analysis revealed that the touch activation in OP1 was coupled to processing in the other tactile regions: Negative coupling was observed between OP1 and a cluster encompassing the left posterior insula (MNI: −40 −20 20, k = 41, T = 4.79, puncorr b 0.001;pFWE 0.001) and mixed coupling was observed to the S1 (activation: MNI: − 40 − 24 52, k = 25, T = 3.33, puncorr 0.001; pFWE n.s.; deactivation: MNI: − 26 − 40 60, k = 201, T = 4.07, puncorr b 0.001; pFWE 0.07). Further, OP1 was coupled to olfactory regions coding the disgust of odors: Positive coupling with the OFC was observed (MNI: − 38 36–12, k = 87, T = 3.34, puncorr 0.001;pFWE n.s.; MNI: 46 34–4, k = 14, T = 2.72, puncorr 0.005;pFWE n.s.) and negative coupling with the amygdala (MNI: 36 2–26, k = 13, T = 3.24, puncorr 0.001;pFWE n.s.) (Fig. 4). 4. Discussion
3.3. Neural response to odors The combined odor conditions (Civette + Rose), in contrast to baseline, activated the expected ROIs in olfactory processing areas of amygdala, anterior insula, piriform cortex, thalamus and orbitofrontal cortex (compare Supplementary Table S3 and Fig. S3). The bold signal change varied positively in relation to the perceived disgust towards odors in the olfactory eloquent areas of orbitofrontal cortex (MNI: − 24 38 –4, k = 67, T = 3.47) and in a cluster encompassing hippocampus and amygdala (MNI: −32 −22 −6, k = 90, T = 3.89). 3.4. Neural response to affective touch in polysensory conditions Touch + Odor vs Baseline activated the very same tactile ROIs as Touch only vs baseline. However, activation of S2 diminished in strength and extent (Table 1). The perceived pleasantness of touch in the Touch + Odor conditions was positively correlated to activation in the OFC (MNI: − 50 20 –8, k = 78, T = 2.82) and to activation in the S1 (MNI: − 44 − 18 50, k = 162, T = 3.47; MNI: − 44 − 16 44, k = 80, T = 2.93; MNI: −56 −12 34, k = 36, T = 2.53), S2 (subdivision OP1, OP2 and OP2; MNI: − 40 − 12 22, k = 632, T = 2.91), and the posterior insula (MNI: −34 −24 20, k = 26, T = 2.86) (Fig. 3A). 3.5. Polysensory conditions — coding of olfactory environment in tactile areas The individual perception of the olfactory environment influenced activation in tactile areas. Enhanced disgust towards the olfactory environment in the Touch + Odor conditions was related to activation in the OFC, bilaterally (MNI:− 22 34 –8, k = 17, T = 3.3, puncorr b 0.005; pFWE not significant (n.s.); MNI: 30 33 –8, k = 20, T = 2.91, puncorr b 0.005; pFWE n.s.). This is expected as the OFC is not only responsive to affective touch, but also a secondary olfactory processing area and activation of OFC covaried with olfactory disgust in the Odor only conditions as well. Interestingly however, olfactory disgust was significantly related to enhanced activation in S2, subdivision of the OP1 (MNI:−50 –22 18, k = 18, T = 2.61, puncorr 0.006; pFWE 0.04 Fig. 3B). 3.6. Polysensory conditions — neuronal network of Touch Odor interactions The coding of olfactory disgust in S2, subdivision OP1, was followed in a PPI analyses that focused on the Touch + Odor conditions. This
In line with the hypothesis, an unfavorable olfactory environment modulated the behavioral and neural response to slow stroking, affective touch. Specifically, disgust towards the olfactory environment reduced touch pleasantness and increased response in somatosensory specific regions more associated with coding of discriminative aspects of touch. Hence, the individual evaluation of the context altered touch processing in secondary somatosensory regions. Although fascinating, one should keep the unquantified family wise error control in mind, which may lead to false positive results. However, other researchers found similar impact of context on somatosensory processing areas. For instance, pleasant odors decreased the perception of thermal pain, and they decrease pain related activity within S1 and S2 (Villemure and Bushnell, 2009). A similar experiment has been performed for vision–touch interactions and an augmented response to touch in the S1 region is found if subjects believe the touch is performed by a visually presented attractive (and liberally dressed) woman in contrast to when the touch is believed to be performed by a less attractive male (Gazzola et al., 2012). In our study a disgusting environment enhanced affective touch related S2 processing; in the thermal pain study a pleasant environment reduced the S1 and S2 activity to aversive touch stimuli. In (Gazzola et al., 2012), the sight of an attractive woman increased the affective touch related S1 processing. Taken these studies and ours together, activity of the somatosensory cortices is modulated depending on the environment. The pleasant vs unpleasant nature of the touch environment seems of less importance, but rather salience may change reactivity in the somatosensory regions. The terminology of salience is however vague. We have not asked for evaluation of salience and neither did (Gazzola et al., 2012), but it seems reasonable to speculate that affective touch applied in the context of attractive females (Gazzola et al., 2012) or disgusting odors (our study) warrants more attention than touch perceived in more neutral circumstances. In our study, the environment was modulated by presentation of odors. The Civette odor was perceived as significantly more disgusting and unpleasant compared to the Rose odor and hence it was expected that a Civette environment decreases touch pleasantness more compared to a Rose environment. In a previous psychophysical study with a larger sample size, exactly this was found (Croy et al., 2014a). However, individual perception of odors is highly variable and the individual perception of the olfactory environment seems to be a stronger predictor for odor–touch interactions than the sheer odor quality. The more disgusting the olfactory environment, the less pleasant touch was perceived and – mirroring the behavioral results – the individual disgust to odors was significantly related to the processing of touch in the S2, subdivision OP1. PPI analysis suggested that OP1 is connected to structures involved in the emotional assessment of the environment (OFC, amygdala) as well as to structures involved in the processing of discriminative (S1) and affective touch (posterior insula). This makes OP1 a potential hub for touch processing in relation to environmental needs. Disgusting olfactory stimuli may alter tactile processing via positive OFC-S2 and negative amygdala-S2 connections. In line with previous
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Fig. 3. Neural response to Touch and Coding of emotional assessment in tactile ROIs. A) Touch vs Baseline and Touch + Odor vs Baseline activations in predefined tactile ROIs are shown. Data is thresholded at p b 0.05/4 (Bonferroni corrected by factor4 for multiple comparisons of 4 ROIs) and a cluster threshold of 5 and plotted on the participants mean T1 weighted image. B) Areas significantly co-varying with the perceived touch pleasantness and olfactory disgust are displayed. Areas are extracted from a covariance analysis of the Touch + Odor conditions and relation between Bold Signal and Rating data are visualized for the peak activation voxel of each area. The precise area of activation is displayed above.
studies (Winston et al., 2005; Rolls et al., 2003), both OFC and amygdala code the hedonic perception of odors. The OFC is known to track emotional evaluation of various types of stimuli (Kringelbach et al., 2003; Veldhuizen et al., 2010; Rolls and Grabenhorst, 2008) including pleasantness of touch and the perceived disgust of odors. Positive coupling between the OFC and the OP1 may amplify the S2 reactivity to touch in case of an unfavorable environment. Amygdala-S2 connections were however weak and should be treated with caution. Negative coupling between OP1 and posterior insula suggests inhibitory connections between these regions. Enhanced S2 activation may suppress activation in the posterior insula. The S2 processes the fast, myelinated pathway of touch, related to discriminative perception (Bjornsdotter et al., 2009) and the posterior insula codes for the slow, unmyelinated, C fiber related pathway (Morrison et al., 2011a). In line, the posterior insula, but not the S2, was found to code the pleasantness of stroking. The percept of touch is mediated by afferent input from different nerve fibers, such as A beta and C tactile fibers, and our results suggest a contextual modulation of the cortical processing of this input. A subjectively disgusting context results in a shift from affective to discriminative touch processing. This is potentially of importance for the understanding of mental disorders. For instance, there is an association between impulsivity and addiction (Kreek et al., 2005), which could
potentially be influenced by affective touch processing. High arousal may suppress the influence of C tactile fiber signaling on the touch percept, which would make it hard for drug addicted individuals to experience the beneficial and calming aspects of interpersonal touch. This, in turn, would make them more prone to drug induced states of hedonism. However, more research on the contextual effect of touch processing and on neural processing of touch in mental disorder is warranted. Funding The work was supported by the Swedish Research Council (201502684). IC is founded by a scholarship from the German Research Foundation (DFG; CR 479/1-1). Acknowledgements We would like to thank Cornelia Hummel for her help in preparing the set up of the fMRI experiment. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.neuroimage.2016.04.046.
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Fig. 4. Neural response to Touch and Odors. PPI analysis revealed a positive coupling (red dotted line) between S2, subdivision OP1 and OFC, and a negative (blue dotted line) coupling between S2/OP1 and amygdala and posterior insula. Positive and negative coupling was observed with the S1. Activations from the Touch vs. Baseline contrast (thresholded at p b 0.05/4, Bonferroni corrected) are plotted together with the amygdala ROI on the participants mean T1 weighted image.
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NeuroImage journal homepage: www.elsevier.com/locate/ynimg
Olfactory modulation of affective touch processing — A neurophysiological investigation Ilona Croy a,b,d,⁎, Edda Drechsler c, Paul Hamilton d, Thomas Hummel c, Håkan Olausson a,d a
Department of Clinical Neurophysiology, Sahlgrenska University Hospital, University of Gothenburg, Sweden Department of Psychosomatic Medicine and Psychotherapy, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany Smell and Taste Clinic, Department of Otorhinolaryngology, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany d Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine, Linköping University, Sweden b c
a r t i c l e
i n f o
Article history: Received 21 January 2016 Revised 22 March 2016 Accepted 19 April 2016 Available online 30 April 2016 Keywords: C tactile Hedonic fMRI Somatosensory Olfaction
a b s t r a c t Touch can be highly emotional, and depending on the environment, it can be perceived as pleasant and comforting or disgusting and dangerous. Here, we studied the impact of context on the processing of tactile stimuli using a functional magnetic resonance imaging (fMRI) paradigm. This was achieved by embedding tactile stimulation in a variable olfactory environment. Twenty people were scanned with BOLD fMRI while receiving the following stimulus blocks: Slow stroking Touch, Civette odor (feces like), Rose odor, Touch + Civette, and Touch + Rose. Ratings of pleasantness and intensity of tactile stimuli and ratings of disgust and intensity of olfactory stimuli were collected. The impact of the olfactory context on the processing of touch was studied using covariance analyses. Coupling between olfactory processing and somatosensory processing areas was assessed with psychophysiological interaction analysis (PPI). A subjectively disgusting olfactory environment significantly reduced the perceived pleasantness of touch. The touch fMRI activation in the secondary somatosensory cortex, operculum 1 (OP1), was positively correlated with the disgust towards the odors. Decreased pleasantness of touch was related to decreased posterior insula activity. PPI analysis revealed a significant interaction between the OP1, posterior insula, and regions processing the disgust of odors (orbitofrontal cortex and amygdala). We conclude that the disgust evaluation of the olfactory environment moderates neural reactivity in somatosensory regions by upregulation of the OP1 and downregulation of the posterior insula. This adaptive regulation of affective touch processing may facilitate adaptive reaction to a potentially harmful stimulus. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Affective touch perception is of primary importance for human interaction. Touching and stroking can be critical in expressing security and positive attention, and can create bonds between people [for overview (Gallace and Spence, 2010)]. However, interpersonal touch is also fundamentally ambiguous (Major, 1981). A variety of emotions can be communicated via touch (Hertenstein et al., 2006); for example, touch can be comforting, pleasant and arousing, but also aggressive, lecherous, and a means of transferring disease. In threatening contexts touch does not feel pleasant but, rather, evokes negative emotions such as anxiety or disgust (Olausson et al., 2010). Evaluation of contextual information is hence critical for the hedonic perception of touch.
⁎ Corresponding author at: Department of Psychosomatic Medicine and Psychotherapy, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany. E-mail address: [email protected] (I. Croy).
http://dx.doi.org/10.1016/j.neuroimage.2016.04.046 1053-8119/© 2016 Elsevier Inc. All rights reserved.
Moreover, reviews on hedonic perception of touch convey that little is known about the integration of touch and other sensory inputs in generating emotional responses (Gallace and Spence, 2010). The extant body of research on affective touch suggests that this form of touch is a sense of its own and is distinguishable from discriminative touch by involvement of different nerve fibers in the periphery as well as different brain structures (Olausson et al., 2002; McGlone et al., 2014). C-tactile (CT) fibers, a subgroup of the unmyelinated C-fibers innervating the skin, have been found to selectively react to slow stroking stimulation with light force and about 32 °C stimulus temperature – the same stimulus parameters as interpersonal touch (Olausson et al., 2010; Loken et al., 2009; Ackerley et al., 2014). Such gentle touch is processed in several cortical regions including the primary and secondary somatosensory cortex, the posterior insula, and the orbitofrontal cortex (Olausson et al., 2002; Morrison et al., 2011a, 2011b; McCabe et al., 2008; McGlone et al., 2012). Consistent with the formulation that CT transduced touch is socially important, people who score high on autism scales exhibit reduced neural activation to CT targeted touch (Bennett et al., 2013; Kaiser et al., 2015).
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Furthermore, people with reduced C-fiber density experience CT targeted touch as less pleasant (Morrison et al., 2011b). In typical experimental contexts, slow stroking CT targeted touch is experienced as pleasant and calming. This is found for both manual and machine delivered touch (Triscoli et al., 2013), for men and women of different ages (Loken et al., 2009; Morrison et al., 2011b; Triscoli et al., 2013; Croy et al., 2014a; Ellingsen et al., 2014), and in children as young as nine-months old (Fairhurst et al., 2014). Contextual information, however, significantly impacts the pleasantness of touch. For example, the belief that stroking is done in applying a “basic” as opposed to a “rich moisturizing” cream decreases pleasantness (McCabe et al., 2008), as does the belief that stroking is performed by an unattractive male instead of an attractive female (Gazzola et al., 2012), as does viewing angry instead of friendly faces when being stroked (Ellingsen et al., 2014). In everyday life, typically negative odors—such as a bad body odor, the odor of feces or bad breath—affect the appreciation of touch. Odors warn about microbial threats, encouraging us to avoid touch if a microbial threat is in proximity. This olfactory warning function is most likely fulfilled by evoking basic withdrawal reflexes and disgust (Stevenson, 2010). Indeed, unpleasant odors have a high potential of evoking disgust each time they are presented (Croy et al., 2013a). It has been shown, that odors modulate discriminative aspects of touch and odorized fabrics feel different compared to unodorized ones (Dematte et al., 2006). Moreover, we recently found that odors also modulate the affective side of touch – disgusting, but not pleasant, odors influence the pleasantness of affective touch (Croy et al., 2014a), indicating that a negative olfactory environment signals that touch should be avoided. The neural basis of this cross-modal interaction, however, remains to be elucidated. This study aims to investigate the neural underpinnings of olfactory influence on affective touch. To this end, we modified our previous paradigm (Croy et al., 2014a) to be amenable to a functional magnetic resonance imaging (fMRI) setting. Neural activation to touch alone and to touch under the influence of odors was measured. Based on the behavioral data (Croy et al., 2014a), we hypothesized that disgusting odors alter the processing of touch in those neural regions that process affective touch stimuli: primary and secondary somatosensory cortex, posterior insula and orbitofrontal cortex.
2. Materials and methods 2.1. Statement The study followed the Declaration of Helsinki on Biomedical Research Involving Human Subjects and was approved by the Ethics Committee of the TU Dresden (EK 194062013). All participants gave written informed consent.
2.2. Participants Twenty-two participants were scanned using fMRI. All participants were right handed with normal olfactory function as ascertained using the “Sniffin' Sticks” identification test (Hummel et al., 2007). As olfactory processing is altered in depression (Croy et al., 2014b), participants were screened for this disorder. None of the participants suffered from depression as measured using the Beck Depression Inventory (BDI II) questionnaire (Beck and Steer, 1987; Hautzinger et al., 1995)—scores ranged from 0 to 13 (mean 3.6 ± 3.2 SD) and none of the participants was in the range of a “mild depression” or above. Two of the participants were excluded because they rated the intensity of one of the odors (Rose) in the scanner with 0 (“not intense at all”). The remaining group consisted of 20 participants (8 women, 12 men; age ranged from 21 to 37 years, mean age 24.0 years ±3.6 SD).
2.3. fMRI procedure A 3-Tesla MR scanner (Trio; Siemens Medical, Erlangen, Germany) was used for data acquisition. Functional data was collected in 200 volumes per session with a 2D GE echo-planar imaging sequence with 36 axial slices (imaging matrix 128 ∗ 128), TR 3000 ms, TE 40 ms, FA 90°, voxel size 3 ∗ 3 ∗ 3.75 mm; no interslice gap) using an eight channel head coil and sagittal acquisition. For anatomical mapping and exclusion of potential brain pathology in participants, a high resolution T1-weighted image (3D IR/GR sequence: TR 2180 ms/TE 3.93 ms) was acquired. Each participant was scanned for five imaging runs, each consisting of 12 on–off stimulation periods (15 s stimulation then 15 s non-stimulation), summing up to 6 min of scanning per run. Participants were asked to rate the stimulation after each run. Therefore each run comprised stimulation of a particular type (Touch, Civette odor, Rose odor, Touch + Civette, and Touch + Rose). The presentation order was randomized across participants; see Fig. 1. 2.3.1. Odor presentation Civette, an animal odor, strongly resembling the odor of feces, and Rose were chosen as olfactory stimuli. Feces are cross-culturally perceived as disgusting (Rozin and Fallon, 1987)and are the most frequently named category when people are asked to pick an disgusting odor (Croy et al., 2011; Seo et al., 2011). In order to be consistent with the previous behavioral study on odor–touch interactions, Rose was used as a second olfactory stimulus. The choice of concentration was based on this previous study (Croy et al., 2014a). The odors were dissolved in propylene glycol at 0.7% or 18.5% v/v, respectively, in order to achieve an equally intense perceptual quality (Civette Base: Fragrance resource, Hamburg, Germany; Rose: Frey and Lau, Henstedt-Ulzburg, Germany). Odors were rated as iso-intense in the scanner (Table S1). A computer-controlled olfactometer (Sommer et al., 2012) was used for bilateral intranasal presentation of odors. For intranasal stimulation, Teflon tubing with an inner diameter of 4 mm was used. In order to avoid odor correlated intranasal mechanical stimulation, odor pulses were embedded in a constant flow of odorless air with a total flow per nostril of 1 l/min. During stimulation, blocks of odors were presented in a pulsed manner with 1 s odor followed by 2 s pause (=5 puff pulses per block) in order to avoid rapid habituation. During non-stimulation (off) blocks, the same airstream was presented but without the odor. Repeated blockwise presentation of odors does not lead to strong habituation effects (Croy et al., 2013b). For affective touch no such data is published. However our unpublished observation shows, that neural response in primary and secondary somatosensory cortices and posterior insula is still present after 30 min of continuous presentation of the very same stroking stimulation, we use here. Potential interference between the timing of odor presentation and respiratory air flow through the nose during inhalation was minimized by teaching participants the breathing technique of velopharyngeal closure (breathing only through the mouth by lifting the soft palate). This technique enables olfactory stimulation to be unaffected by patterns of inhalation and exhalation. This procedure also prevents the participants from “sniffing” of odors which may produce perceptunrelated activation in olfactory–eloquent structures (Mainland and Sobel, 2006). Using biofeedback (displaying the respiratory flow in front of the nostrils on an oscilloscope) the procedure was thoroughly trained prior to scanning with respiratory feedback for each participant until no respiratory nasal airflow was recorded any more in front of the nostrils (2 to 15 min). Respiratory airflow was not controlled in the scanner because experience showed that in healthy participants, once learned, the velopharyngeal closure can be maintained very easily. After each of the Civette only and Rose only runs, the participants verbally rated the pleasantness and intensity and disgust of the odor on three 11-point scales (− 5 to 5: extremely unpleasant–extremely pleasant; 0 to 10: not intense at all–extremely intense; 0 to 10: not disgusting at all–extremely disgusting). The dimensions of disgust and
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Fig. 1. Visualization of the fMRI design. During one run, stimulation was made with either Rose, Civette, Touch, Touch + Rose, or Touch + Civette. Each participant was scanned during five runs in random order. Each stimulus was presented 12 times/run. Within the on blocks, odors were presented pulsed, with 1 s of odor presentation and 2 s of pause. Touch was performed as continuous stroking on the right forearm with a velocity of 3 cm/s. Each stimulation period lasted 15 s and each off period lasted 15 s and was repeated 12 times for each run.
pleasantness have been shown to contribute independent information that describes the odor percepts well (Croy et al., 2013a, 2014a); moreover, inclusion of both ratings, disgust and pleasantness, allowed us to capture more thoroughly the hedonic value of the odors presented.
practiced this entire procedure in a sham scan session in order both to familiarize participants with the procedure and to ensure that they rated the touch only under conditions of combined stimulation. 2.4. fMRI analysis
2.3.2. Touch presentation Slow stroking touch, perceived as pleasant in typical experimental contexts, and effective in activating CT afferents (Loken et al., 2009; Morrison et al., 2011b; Triscoli et al., 2013; Croy et al., 2014a; Ellingsen et al., 2014), was presented on the right dorsal forearm with a velocity of 3 cm/s and a force of approximately 0.4 N at a stroking distance of 10 cm (4 strokes per 15 s block). The touch stimuli were manually applied by the experimenter by means of a 50 mm wide flat, soft watercolor brush made of fine, soft, goat's hair. Before the actual session, the experimenter (author ED) extensively practiced stroking for five days in a row prior to the experiment on a wooden board with a 10 cm marking, which was attached to a fine tuned scale. This practice ensured constant velocity and force; additionally, during fMRI scanning the experimenter's stroking frequency was guided by a computer presentation. With this guidance, manual touch administration is perceptually similar to robot guided administration of tactile stimuli (Triscoli et al., 2013). Synchronization of touch and odor presentation was achieved via the computer presentation, displayed on a screen inside the scanning room. This was visible to the experimenter, but not to the participant. The experimenter was instructed with words (“brush”; “stop”) and color code. In order to allow the experimenter some preparation time, color code always changed 3 s before the beginning of a new instruction. The touch presentation was synchronized with the olfactometer. The experimenter was not informed about whether an odor was presented or not. After each run containing tactile stimulus blocks (Touch, Touch + Civette, Touch + Rose), the participants verbally rated the pleasantness and intensity of the touch stimulation on two 11-point scales (− 5 to 5: extremely unpleasant–extremely pleasant; 0 to 10 not intense at all–extremely intense; compare S1). Participants
We analyzed fMRI time-series data using a standard general linear model approach implemented in SPM8 (Statistical Parametric Mapping; Welcome Department of Imaging Neuroscience, in the Institute of Neurology at University College London [UCL], UK) implemented in Matlab (Matlab 6.5 R3, The MathsWorks IncS., Natick, MA). The data were first preprocessed: realignment with 2nd degree B-spline; temporal filtering with high pass filter cutoff at a period of 128 s; normalization using the segmentation procedure implemented in SPM 8 with affine registration to the ICBM space template (MNI space), bias regularization of 0.0001, and spatial smoothing of functional data with a Gaussian kernel of 8 × 8 × 8 FWHM. The first 5 scans of each sessions were eliminated to allow for equilibration of the longitudinal magnetization vector. The 15 s scans of each stimulation block were used for the first level analysis, where stimulation blocks were compared to non-stimulation blocks using a boxcar covariate reflecting stimulus on–off cycles convolved with SPM's canonical hemodynamic response function. As movement was very limited for all participants (b2 mm translation and 1° rotation for each run for each participant), we did not include motions-based noise regressors in our analysis to preserve degrees of freedom. For subsequent analysis, we first concentrated on data from tactilealone and olfaction-alone blocks, in order to identify neural correlates of tactile and olfactory stimulation, respectively. Neuronal correlates of tactile stimulation were expected in predefined tactile ROIs; correlates of olfactory stimulation in predefined olfactory ROIs (see below). We then focused on the polysensory (tactile plus olfactory stimulation) blocks where we performed a neurobehavioral correlation analysis to examine tactile eloquent regions where response tracked subjective ratings of odor-disgust regardless of odor condition, given that Rose was not always pleasant nor was Civette always aversive to
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our participants. Finally, tactile regions that were sensitive to olfactory disgust were submitted as the seed region of interest (ROI) in a psychophysiological interaction (PPI) analysis. Neural regions responsive to tactile stimulation were identified from the Touch-only (stimulation on versus off) run using a one-sample t-test. This analysis was conducted voxel-wise within a set of four tactile ROIs, a priori defined from publications studying affective touch processing; these regions included contralateral (to the side of stimulation) primary and secondary somatosensory cortices S1 and S2, contralateral posterior insula, mid-anterior and lateral orbitofrontal cortex (Morrison et al., 2011a; McCabe et al., 2008; McGlone et al., 2012), see supplementary methods for more detailed information]. To determine the relation between touch pleasantness perception and tactile activation, covariance analysis was applied with touch pleasantness ratings as a vector of interest on the Touch-only (stimulation on versus off) contrasts. Analysis of olfactory activation was determined from the combined (Civette + Rose) condition (using t-test with a weighted contrast vector: 0.5/0.5) and focused on predefined olfactory ROIs: amygdala, thalamus, hippocampus, piriform cortex, anterior insula, orbitofrontal cortex (please see the supplementary methods section for more details). The anterior insula is not only involved in olfaction, but further sensitive to disgust processing (Hennenlotter et al., 2004). As in our previous study (Croy et al., 2014a), pleasantness ratings did not track perfectly with olfactory condition (i.e., 12 subjects rated Civette most disgusting, 6 subjects rated Rose most disgusting and 2 rated both odors equally disgusting). Given this, we combined Civette- and Rose-only scan data in identifying the relation between olfactory disgust and neuronal response. We determined this relation using covariance analysis with disgust ratings as a vector of interest correlated against Civette and Rose (stimulation on versus off) condition contrasts (vectors: Civette/Rose/Rating Data = 0/0/1). In the polysensory conditions, we first examined tactile ROI activation in the combined Touch Odor (Touch + Civette and Touch + Rose) vs Baseline contrasts using t-test with weighted contrast vectors (Design Matrix: Touch + Civette/Touch + Rose/Touch = 0.5/0.5/0). Activation in the combined Touch Odor contrasts was compared to the Touch only condition, using t-tests (vector: Touch + Civette/Touch + Rose/ Touch = 0.5/0.5/−1). To estimate the relation between olfactory disgust perception and neural response to tactile stimulation, we applied neuralbehavioral covariance analysis at the group level with olfactory disgust ratings as a vector of interest on the contrasts of the Touch + Civette and Touch + Rose (vectors: Touch + Civette/Touch + Rose/Rating data = 0/0/1). Level of significance of the voxel-wise analysis restricted to a set of ROIs was set to p = 0.05 for all tests, Bonferroni corrected for multiple comparisons; thus, statistical maps were thresholded at p = (0.05/4 [4 ROIs]) for tactile search areas and at p = (0.05/6 [6 ROIs]) for olfactory search areas. This modest control is chosen, as olfactory activation in block design sessions is subtle, even when carefully controlled for respiratory influences (Wang et al., 2014). Family wise error based small volume correction at the level of p b 0.1 is additionally reported. We also report results from an exploratory whole-brain analysis for the Touch vs Baseline contrasts. Significant activation clusters were located using the Anatomy toolbox (Eickhoff et al., 2005) and their loci are reported in MNI space. PPI analysis was carried out in order to examine the covariation of experiment-dependent signaling in two brain areas (Gitelman et al., 2003). A seed was placed in the OP1 region, which showed a robust tactile response that was influenced by the disgust perception of odors. Therefore, the cluster obtained from the covariance analysis (olfactory disgust perception on tactile activation) served as ROI and a sphere of 4 mm radius was created around the individual maxima within that ROI of each participant (N = 20) and odor touch condition (N = 2). Choice of the 4 mm radius was guided by a PPI study, with similar voxel-size and smoothing kernel, on the contextual modulation of pain (Wiech et al., 2010). The voxel wise interaction was obtained
for each participant for both polysensory conditions of interest (Touch + Civette, Touch + Rose), and a 192 s high pass filter was applied. Second level analysis was performed in a full factorial design encompassing the individual first level contrasts of the Touch + Odor conditions, treated as non-independent conditions (repeated measurement of odor). Level of significance was set to p = 0.05, Bonferroni corrected for multiple comparisons of the 5 areas found to code the pleasantness of touch and/or the disgust to odors (OFC, S1, post insula, amygdala, thalamus). Statistical maps were accordingly thresholded at p = 0.05/5 [5 ROIs]). 2.5. Statistical analysis of perceptual ratings Rating data was analyzed with SPSS 22 (SPSS Inc., Chicago, Ill., USA). Touch pleasantness and intensity ratings of the conditions Touch, Touch + Civette, and Touch + Rose were compared with a generalized mixed model approach. Each participant served as subject, and the three touch conditions as repeated measurements. In addition, the individual impact of odors on the touch ratings was analyzed in a generalized mixed model approach. Each participant served as subject, the two Touch odor conditions were treated as repeated measurements. The pleasantness rating of Touch under olfactory impact was targeted, and the odor disgust ratings served as fixed main effects. Robust estimation of covariances was used for calculation. 3. Results 3.1. Psychophysical response to affective touch in polysensory conditions On an individual level, disgust towards the odors significantly influenced the perceived pleasantness of touch (F [1,38] = 6.2, p = 0.017, Fig. 2). The more disgusting the odor, the less pleasant touch was perceived. The intensity of touch was not affected by the olfactory environment. 3.2. Neural response to affective touch Touch only, in contrast to baseline, activated all of the tactile ROIs: contralateral S1 and S2, posterior insula and lateral OFC (Table 1; Fig. 3; compare Supplementary Table S2 for whole brain analysis). Covariance analysis revealed that the perceived pleasantness of touch was positively correlated to activation in the OFC (MNI − 32 30 –8, k = 11, T = 3.06; MNI: 52 36 –4, k = 8, T = 3.01).
Fig. 2. Relationship between perceived disgust towards odors and pleasantness of touch. Touch pleasantness decreased significantly with increasing olfactory disgust. The number of participants is indicated by size of the symbols.
I. Croy et al. / NeuroImage 135 (2016) 135–141 Table 1 Neural activation in response to touch. Results are presented in predefined tactile ROIs with a height threshold of p b 0.05/4 (Bonferroni corrected for multiple comparison of 4 ROIs). Family wise error correction is reported. Cluster size
T value
MNI coordinates x
y
z
FWE corrected p value
−54 −24 −50 −48 −40 44
−22 −40 −40 −26 −22 48
38 62 54 22 20 −2
0.004 0.011 ns b0.001 b0.001 ns
(Touch + Civette and Touch + Rose) vs Baseline S1 contralateral 76 3.86 −24
−40
62
−46 −40 −46 46
−26 −22 50 44
24 20 −6 −12
0.041 ns b0.001 0.001 ns ns
Touch Only vs (Touch + Civette and Touch + Rose) S2 contralateral 87 3.82 −48
−26
22
0.027
Touch Only vs Baseline S1 contralateral
S2 contralateral posterior insula contralateral OFC
S2 contralateral posterior insula contralateral OFC
70 155 49 404 30 27
297 16 513 260
4.60 4.29 3.09 9.70 5.82 2.93
7.19 4.26 5.10 4.50
139
analysis revealed that the touch activation in OP1 was coupled to processing in the other tactile regions: Negative coupling was observed between OP1 and a cluster encompassing the left posterior insula (MNI: −40 −20 20, k = 41, T = 4.79, puncorr b 0.001;pFWE 0.001) and mixed coupling was observed to the S1 (activation: MNI: − 40 − 24 52, k = 25, T = 3.33, puncorr 0.001; pFWE n.s.; deactivation: MNI: − 26 − 40 60, k = 201, T = 4.07, puncorr b 0.001; pFWE 0.07). Further, OP1 was coupled to olfactory regions coding the disgust of odors: Positive coupling with the OFC was observed (MNI: − 38 36–12, k = 87, T = 3.34, puncorr 0.001;pFWE n.s.; MNI: 46 34–4, k = 14, T = 2.72, puncorr 0.005;pFWE n.s.) and negative coupling with the amygdala (MNI: 36 2–26, k = 13, T = 3.24, puncorr 0.001;pFWE n.s.) (Fig. 4). 4. Discussion
3.3. Neural response to odors The combined odor conditions (Civette + Rose), in contrast to baseline, activated the expected ROIs in olfactory processing areas of amygdala, anterior insula, piriform cortex, thalamus and orbitofrontal cortex (compare Supplementary Table S3 and Fig. S3). The bold signal change varied positively in relation to the perceived disgust towards odors in the olfactory eloquent areas of orbitofrontal cortex (MNI: − 24 38 –4, k = 67, T = 3.47) and in a cluster encompassing hippocampus and amygdala (MNI: −32 −22 −6, k = 90, T = 3.89). 3.4. Neural response to affective touch in polysensory conditions Touch + Odor vs Baseline activated the very same tactile ROIs as Touch only vs baseline. However, activation of S2 diminished in strength and extent (Table 1). The perceived pleasantness of touch in the Touch + Odor conditions was positively correlated to activation in the OFC (MNI: − 50 20 –8, k = 78, T = 2.82) and to activation in the S1 (MNI: − 44 − 18 50, k = 162, T = 3.47; MNI: − 44 − 16 44, k = 80, T = 2.93; MNI: −56 −12 34, k = 36, T = 2.53), S2 (subdivision OP1, OP2 and OP2; MNI: − 40 − 12 22, k = 632, T = 2.91), and the posterior insula (MNI: −34 −24 20, k = 26, T = 2.86) (Fig. 3A). 3.5. Polysensory conditions — coding of olfactory environment in tactile areas The individual perception of the olfactory environment influenced activation in tactile areas. Enhanced disgust towards the olfactory environment in the Touch + Odor conditions was related to activation in the OFC, bilaterally (MNI:− 22 34 –8, k = 17, T = 3.3, puncorr b 0.005; pFWE not significant (n.s.); MNI: 30 33 –8, k = 20, T = 2.91, puncorr b 0.005; pFWE n.s.). This is expected as the OFC is not only responsive to affective touch, but also a secondary olfactory processing area and activation of OFC covaried with olfactory disgust in the Odor only conditions as well. Interestingly however, olfactory disgust was significantly related to enhanced activation in S2, subdivision of the OP1 (MNI:−50 –22 18, k = 18, T = 2.61, puncorr 0.006; pFWE 0.04 Fig. 3B). 3.6. Polysensory conditions — neuronal network of Touch Odor interactions The coding of olfactory disgust in S2, subdivision OP1, was followed in a PPI analyses that focused on the Touch + Odor conditions. This
In line with the hypothesis, an unfavorable olfactory environment modulated the behavioral and neural response to slow stroking, affective touch. Specifically, disgust towards the olfactory environment reduced touch pleasantness and increased response in somatosensory specific regions more associated with coding of discriminative aspects of touch. Hence, the individual evaluation of the context altered touch processing in secondary somatosensory regions. Although fascinating, one should keep the unquantified family wise error control in mind, which may lead to false positive results. However, other researchers found similar impact of context on somatosensory processing areas. For instance, pleasant odors decreased the perception of thermal pain, and they decrease pain related activity within S1 and S2 (Villemure and Bushnell, 2009). A similar experiment has been performed for vision–touch interactions and an augmented response to touch in the S1 region is found if subjects believe the touch is performed by a visually presented attractive (and liberally dressed) woman in contrast to when the touch is believed to be performed by a less attractive male (Gazzola et al., 2012). In our study a disgusting environment enhanced affective touch related S2 processing; in the thermal pain study a pleasant environment reduced the S1 and S2 activity to aversive touch stimuli. In (Gazzola et al., 2012), the sight of an attractive woman increased the affective touch related S1 processing. Taken these studies and ours together, activity of the somatosensory cortices is modulated depending on the environment. The pleasant vs unpleasant nature of the touch environment seems of less importance, but rather salience may change reactivity in the somatosensory regions. The terminology of salience is however vague. We have not asked for evaluation of salience and neither did (Gazzola et al., 2012), but it seems reasonable to speculate that affective touch applied in the context of attractive females (Gazzola et al., 2012) or disgusting odors (our study) warrants more attention than touch perceived in more neutral circumstances. In our study, the environment was modulated by presentation of odors. The Civette odor was perceived as significantly more disgusting and unpleasant compared to the Rose odor and hence it was expected that a Civette environment decreases touch pleasantness more compared to a Rose environment. In a previous psychophysical study with a larger sample size, exactly this was found (Croy et al., 2014a). However, individual perception of odors is highly variable and the individual perception of the olfactory environment seems to be a stronger predictor for odor–touch interactions than the sheer odor quality. The more disgusting the olfactory environment, the less pleasant touch was perceived and – mirroring the behavioral results – the individual disgust to odors was significantly related to the processing of touch in the S2, subdivision OP1. PPI analysis suggested that OP1 is connected to structures involved in the emotional assessment of the environment (OFC, amygdala) as well as to structures involved in the processing of discriminative (S1) and affective touch (posterior insula). This makes OP1 a potential hub for touch processing in relation to environmental needs. Disgusting olfactory stimuli may alter tactile processing via positive OFC-S2 and negative amygdala-S2 connections. In line with previous
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Fig. 3. Neural response to Touch and Coding of emotional assessment in tactile ROIs. A) Touch vs Baseline and Touch + Odor vs Baseline activations in predefined tactile ROIs are shown. Data is thresholded at p b 0.05/4 (Bonferroni corrected by factor4 for multiple comparisons of 4 ROIs) and a cluster threshold of 5 and plotted on the participants mean T1 weighted image. B) Areas significantly co-varying with the perceived touch pleasantness and olfactory disgust are displayed. Areas are extracted from a covariance analysis of the Touch + Odor conditions and relation between Bold Signal and Rating data are visualized for the peak activation voxel of each area. The precise area of activation is displayed above.
studies (Winston et al., 2005; Rolls et al., 2003), both OFC and amygdala code the hedonic perception of odors. The OFC is known to track emotional evaluation of various types of stimuli (Kringelbach et al., 2003; Veldhuizen et al., 2010; Rolls and Grabenhorst, 2008) including pleasantness of touch and the perceived disgust of odors. Positive coupling between the OFC and the OP1 may amplify the S2 reactivity to touch in case of an unfavorable environment. Amygdala-S2 connections were however weak and should be treated with caution. Negative coupling between OP1 and posterior insula suggests inhibitory connections between these regions. Enhanced S2 activation may suppress activation in the posterior insula. The S2 processes the fast, myelinated pathway of touch, related to discriminative perception (Bjornsdotter et al., 2009) and the posterior insula codes for the slow, unmyelinated, C fiber related pathway (Morrison et al., 2011a). In line, the posterior insula, but not the S2, was found to code the pleasantness of stroking. The percept of touch is mediated by afferent input from different nerve fibers, such as A beta and C tactile fibers, and our results suggest a contextual modulation of the cortical processing of this input. A subjectively disgusting context results in a shift from affective to discriminative touch processing. This is potentially of importance for the understanding of mental disorders. For instance, there is an association between impulsivity and addiction (Kreek et al., 2005), which could
potentially be influenced by affective touch processing. High arousal may suppress the influence of C tactile fiber signaling on the touch percept, which would make it hard for drug addicted individuals to experience the beneficial and calming aspects of interpersonal touch. This, in turn, would make them more prone to drug induced states of hedonism. However, more research on the contextual effect of touch processing and on neural processing of touch in mental disorder is warranted. Funding The work was supported by the Swedish Research Council (201502684). IC is founded by a scholarship from the German Research Foundation (DFG; CR 479/1-1). Acknowledgements We would like to thank Cornelia Hummel for her help in preparing the set up of the fMRI experiment. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.neuroimage.2016.04.046.
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Fig. 4. Neural response to Touch and Odors. PPI analysis revealed a positive coupling (red dotted line) between S2, subdivision OP1 and OFC, and a negative (blue dotted line) coupling between S2/OP1 and amygdala and posterior insula. Positive and negative coupling was observed with the S1. Activations from the Touch vs. Baseline contrast (thresholded at p b 0.05/4, Bonferroni corrected) are plotted together with the amygdala ROI on the participants mean T1 weighted image.
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