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doi:10.1093/brain/awr011 Brain 2011: 134; 1116–1126 | 1116 BRAIN A JOURNAL OF NEUROLOGY Reduced C-afferent fibre density affects perceived pleasantness and empathy for touch India Morrison,1,2 Line S. Löken,3 Jan Minde,4 Johan Wessberg,2 Irene Perini,2 Inger Nennesmo5 and Håkan Olausson1,2 1 Department of Clinical Neurophysiology, Blå stråket 7, Sahlgrenska University Hospital, S-413 45, Gothenbu
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  BRAIN A JOURNAL OF NEUROLOGY Reduced C-afferent fibre density affectsperceived pleasantness and empathy for touch India Morrison, 1,2 Line S. Lo ¨ken, 3  Jan Minde, 4  Johan Wessberg, 2 Irene Perini, 2 Inger Nennesmo 5 and Ha˚kan Olausson 1,2 1 Department of Clinical Neurophysiology, Bla˚ stra˚ket 7, Sahlgrenska University Hospital, S-413 45, Gothenburg, Sweden2 Institute of Neuroscience and Physiology, University of Gothenburg, S-413 90, Gothenburg, Sweden3 Oxford Centre for functional MRI of the Brain (FMRIB), University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK4 Department of Surgery, Unit of Orthopedics, Perioperative Sciences, Umea˚ University Hospital, S-901 85, Umea˚, Sweden5 Department of Pathology, Karolinska University Hospital, Huddinge, S-141 86, Stockholm, SwedenCorrespondence to: India Morrison,Department of Clinical Neurophysiology,Bla˚ stra˚ket 7,Sahlgrenska University Hospital,S-413 45 Gothenburg, SwedenE-mail: india.morrison@neuro.gu.se We examined patients with a heritable disorder associated with a mutation affecting the nerve growth factor beta gene. Their condition has been classified as hereditary sensory and autonomic neuropathy type V. Carriers of the mutation show a reductionin density of thin and unmyelinated nerve fibres, including C afferents. A distinct type of unmyelinated, low-threshold mech-anoreceptive C fibre, the C-tactile afferent, is present in hairy but not glabrous skin of humans and other mammals. They havebeen implicated in the coding of pleasant, hedonic touch of the kind that occurs in affiliative social interactions. We addressedthe relationship between C fibre function and pleasant touch perception in 10 individuals from a unique population of mutationcarriers in Sweden. We also investigated the effect of reduced C-fibre density on patients’ evaluation of observed interpersonaltouch (empathy). Results showed that patients perceived gentle, slow arm stroking, optimal for eliciting C-tactile afferent responses (1–10cm/s), as less pleasant than did matched controls and also differed in their rating patterns across stimulationvelocities. Further, patients’ blood-oxygen-level-dependent responses in posterior insular cortex—a target for C afferents—werenot modulated by stimulation optimal for activating C-tactile afferents. Hence, perception of the hedonic aspect of dynamictouch likely depends on C-tactile afferent density. Closely similar patterns between individuals’ ratings of felt and seen touchsuggest that appraisal of others’ touch is anchored in one’s own perceptual experience, whether typical or atypical. Keywords:  tactile C afferent; HSAN-V; pleasant touch; nerve growth factor beta gene; empathy Abbreviations:  HSAN = hereditary sensory and autonomic neuropathy; NGFB = nerve growth factor beta Introduction The sense of touch is essential for determining the location of astimulus on the skin surface, for haptic exploration and for objectmanipulation. However, these well-established discriminative as-pects of touch are complemented by an affective aspect thathas only recently begun to be scientifically investigated(McGlone  et al. , 2007). This affective dimension of touch involvesdoi:10.1093/brain/awr011 Brain 2011: 134; 1116–1126  |  1116 Received April 24, 2010. Revised December 7, 2010. Accepted December 8, 2010. Advance Access publication March 4, 2011  The Author (2011). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.For Permissions, please email: journals.permissions@oup.com   b  y g u e  s  t   on O c  t   o b  e r 1  5  ,2  0 1  6 h  t   t   p :  /   /   b r  a i  n . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   inter-individual contact, affiliative behaviour and the formationand maintenance of relationships (Morrison  et al. , 2010;Olausson  et al. , 2010). Such affective aspects may form a func-tional category of touch distinct from the more well-known dis-criminative functions.Evidence that distinct neural pathways play a role in affect-related touch information comes from research both on the per-ipheral and central levels. On the peripheral level, a type ofunmyelinated C fibre, the tactile C afferent, has been shown tobe very sensitive to innocuous tactile stimulation (Nordin, 1990;Vallbo  et al. , 1999; Wessberg  et al. , 2003). Tactile C afferents areslow-conducting, easily fatigued and often show after-discharge,i.e. they may continue to fire for several seconds after stimuluswithdrawal (Vallbo  et al. , 1999). Although these properties render them suboptimal for sensory discrimination, they show many char-acteristics consistent with a role in selectively encoding affectivetouch information. Most notably, they preferentially respond tostroking over the skin surface within a velocity range(1–10cm/s) that is also rated as most hedonically pleasant, asopposed to slower or faster speeds (Lo ¨ ken  et al. , 2009). TactileC afferents are found only in hairy skin and are absent in theglabrous (smooth) skin of the palms (Olausson  et al. , 2010).On the central level, tactile C-afferent pathways project tothe insular cortex (Olausson  et al. , 2002, 2008 a ). Stimulationof tactile C fibres on the arm and thigh also produce somatoto-pically organized activations in posterior insular cortex(Bjo ¨ rnsdotter   et al. , 2009). The response in posterior insular cortex shows a similar velocity selectivity as tactile C fibres(Morrison  et al. , 2008). This cortical region plays an importantrole in representing information relevant to well-being (Craig,2003, 2009).The type of slow, gentle stimulation of hairy skin that activatestactile C receptors is likely to occur during social interactions(Morrison  et al. , 2010). Another aspect of social touch involvesthe recognition of pleasant, affective touch interactions in others.For the social brain, others’ actions and situations supply a richsource of information about objects, contexts and even mentaland emotional states. Recent research suggests that brain areasinvolved in directly experienced touch (Keysers  et al. , 2004;Blakemore  et al. , 2005; Ebisch  et al. , 2008; Morrison  et al. ,2008; Schaefer   et al. , 2009) and pain (Morrison  et al. , 2004,2007 a ; Singer   et al. , 2004; Jackson  et al. , 2006; Morrison andDowning, 2007) can be activated by seeing others undergoingtactile or painful stimulation (empathy). Such responses toobserved touch and pain may underlie recognition of others’ sen-sory states and provide ‘free’ information about objects or situ-ations (Danziger   et al. , 2006; Morrison  et al. , 2007 b ; Morrisonand Downing, 2007).In order to test the relationship between tactile C-fibre functionand directly experienced as well as observed touch, we investi-gated aspects of gentle tactile stimulation in a unique group ofcognitively normal patients with a reduced number of C-afferentfibres. Their condition has been classified as hereditary sensory andautonomic neuropathy type V (HSAN-V) and involves reducedpain and temperature sensitivity (Einarsdottir   et al. , 2004; Minde et al. , 2004). HSAN is a group of rare hereditary neuropathieswith sensory (and to a varying degree autonomic) deficits thathas been further classified into five different types, dependingon mode of inheritance, neuropathology and clinical symptoms(Dyck  et al. , 1983). Gene loci have been identified for most ofthe HSAN subtypes. Our patients with HSAN-V are associatedwith a mutation affecting a gene involved with nerve growthfactor beta (NGFB; Online Mendelian Inheritance in Man608654) (Einarsdottir   et al. , 2004).The mutation (R221W, an arginine to tryptophan changeon amino acid 100 in the mature protein) is located on the b -subunit of the NGF gene (NGFB) (Einarsdottir   et al.,  2004).It has been traced by pedigree to a common ancestor in the17th century (Minde  et al. , 2006). The mutation results not ina complete loss of NGF function but a reduced availability ofactive protein, likely hampering development of sensory fibres(Larsson  et al. , 2009). Carriers exhibit severe to moderate reduc-tion of unmyelinated C fibres and a moderate reduction of thinlymyelinated A   fibres in sural nerve and skin biopsies (Minde  et al. ,2006, 2009; Axelsson  et al. , 2009). The patients have no reduc-tion of large diameter myelinated (A b ) fibres (Minde  et al. , 2006,2009).The group of patients exhibiting the HSAN-V mutation isa population of consanguineous individuals geographically dis-persed in the Norrbotten region in the north of Sweden,along the Tornea River Valley. The HSAN-V haplotype commonto all carriers is located on chromosome 1 (1p11.2-13.2) andis flanked by single nucleotide polymorphism markers rs2490334and rs2275607 (Einarsdottir   et al. , 2004). Carriers presentwith varying degrees of pain insensitivity, particularly deep paininsensitivity, associated with joint deformation and painless bonefractures. Homozygous individuals are severely affected (with joint deformations and disturbances in deep pain sensation),whereas heterozygous carriers present with symptoms tovarying degrees, in some cases showing a progression of thedisease. They have normal cognitive functions (Minde  et al. ,2006, 2009). Unlike in other HSAN disorders, autonomic dysfunc-tion is not a prominent trait, although several individualsdisplay pathological orthostatic tests and diminished sympatheticskin responses (Einarsdottir   et al. , 2004; Minde  et al. , 2004, 2006,2009).Here, we tested the hypothesis that tactile C fibres play a cen-tral role in pleasant touch perception by assessing subjective re-sponses to skin stroking at five different velocities (0.3–30cm/s) inthe thin fibre denervated patient group. Since thinly myelinated A  fibres do not signal light touch in humans (Olausson  et al. , 2002,2008 b ), any differences in tactile perception would be related totactile C-afferent function. We predicted that the patients’ reduc-tion in thin C-afferent density would be associated with a reduc-tion in perceived pleasantness of dynamic touch but not indiscriminative touch capacity. Further, we tested whether anysuch altered perception of touch pleasantness would influencethe evaluation of touch pleasantness in others during touch ob-servation (touch empathy). We predicted that the individual ratingpatterns for visually observed touch would closely match those for directly experienced touch, indicating that evaluation of others’touch interactions draws on information from affect-related tactilepathways.Tactile C afferents, pleasant touch and empathy Brain 2011: 134; 1116–1126  |  1117   b  y g u e  s  t   on O c  t   o b  e r 1  5  ,2  0 1  6 h  t   t   p :  /   /   b r  a i  n . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   Materials and methods Participants Patients and controls gave informed consent approved by theUniversity of Gothenburg ethics committee and in accordance withthe Declaration of Helsinki, and received financial compensation for their participation.Ten individuals (age 17–73 years, mean age 45; five female) sharinga missense mutation of the NGFB gene, resulting in HSAN type V,were included in the study (Supplementary Table 1). Three (Cases 1–3,Supplementary Table 1) were homozygous (having the mutation onboth alleles) and the rest heterozygous (having the mutation on oneallele). The patients have, to different degrees, reduced temperatureand pain sensations, notably deep pain insensitivity (Minde  et al. ,2004, 2006, 2009). The most affected suffer from painless fractures,bone necrosis, osteochondritis and joint destruction leading to severeCharcot arthropathy (Einarsdottir   et al. , 2004; Minde  et al. , 2004,2006, 2009). One patient (Case 2) suffers from orthostatic hypoten-sion and in two patients (Cases 2 and 3) sympathetic skin responsescould not be recorded. They all have normal cognitive functions andconsider themselves to have normal touch sensibility with no history ofallodynia or hyperalgesia. All patients for whom data are available(7/10) show a moderate to severe reduction in A   and C fibres innerve and skin biopsies. They have normal motor and sensory neuro-graphy (except for median nerve compression at the level of the carpaltunnel in Cases 5, 6 and 8) indicating intact function of A b  fibres, andno other neurological disease besides the HSAN-V neuropathy(Supplementary Table 1). They did not take any drugs that influenceneurological function.The patients’ shared NGFB mutation was maintained in the popula-tion through consanguineous marriages (e.g. among cousins) over sev-eral generations following the lifetime of the common ancestor in the17th century. The population is now geographically dispersed over thelarge Norrbotten region north of the Arctic Circle in Sweden. Thereforethe carriers do not necessarily know each other and can be separatedfrom one another by several generations.The disease shows a progressive trend, with mildly or unaffectedcarriers developing symptoms with increasing age in some cases andworsening symptoms in others (Minde  et al.,  2004). However, itshould be emphasized that all patients with HSAN-V shared thesame mutation haplotype on the NGFB gene (Einarsdottir   et al. , 2004).Ten neurologically healthy individuals (ages 18–77, mean age 45;five female) participated in the study. Individuals were matched tothe patient participants on the basis of age, sex and length ofeducation. Stimuli and procedures Discriminative touch Tactile directional sensibility was tested on the left dorsal forearmusing a hand-held stimulator that was moved with a speed of1cm/s (Supplementary Fig. 1, for details see online SupplementaryMaterial). A forced-choice method was used and the stimulator wasmoved over a predetermined distance in either proximal or distal dir-ection in a pseudorandom order (Norrsell  et al. , 2001; Lo ¨ ken  et al. ,2011). The participant was instructed to have his/her eyes closed andverbally report the direction of the movement. The result was sum-marized in a response profile area (theoretical range 18–90) that pro-vided a quantitative measure of the directional sensibility of thesubject’s forearm (the lower the response profile area value thebetter the directional sensibility). Pleasant touch Stimuli to assess participants’ responses to gentle touch consisted ofsingle brush strokes over 10cm of left forearm skin using a soft 70mmwide goat-hair artist’s brush. Brush strokes were delivered manually ina proximal to distal direction at five different velocities: 0.3, 1, 3,10 and 30cm/s. All stimulations were performed by I.M. who wastrained in the delivery of the stimuli and during the experiment wasguided regarding brushing velocity by a visual meter (on a monitor notvisible to the subject).Stimuli were presented in three blocks with two repetitions of eachvelocity, for a total of six trials/velocity. Participants were seated infront of a laptop monitor showing a visual-analogue scale, with theanchor points ‘unpleasant’ (  10) and ‘pleasant’ (10). In each trialinstructions appeared above the visual-analogue scale to ‘rate howpleasant the touch feels to you’ followed by a 4–6s response interval.Participants were wearing goggles flanked by occluders that ensuredthat their arm and the experimenter were out of view. Pleasant touch observation Short videos depicting strokes on another person’s forearm skin wererandomly intermixed with the tactile stimulus trials within the threeblocks. The same velocities were used in videos and tactile trials. Aswith tactile trials, two visual trials were delivered per block, for a totalof six trials/velocity. The video clips showed a hand moving over 10cm of a model’s skin against a neutral black background(Fig. 2B). As with the tactile trials, participants registered their ratingson the visual-analogue scale after each trial, with the instruction‘rate how pleasant you think the touch feels to the person in thevideo’. It was made clear to participants that the ‘person in thevideo’ referred to the recipient of the stroking (the model) rather than the person performing the stroking. The models were either male or female and arms were presented from either an allocentricor egocentric viewpoint (gender and viewpoint were randomized butnot considered as factors, as pilot data showed no effect of either variable on ratings). TACTYPE questionnaire At the end of the testing session, participants were administered aSwedish translation of the 15-item TACTYPE questionnaire(Deethardt and Hines, 1983). Most questions focused on the affectiveaspect of interpersonal touch behaviour in social situations, particu-larly in opposite-sex relationships (participants were instructed to an-swer as they would if they were in such a relationship). An exampleitem is: ‘I enjoy touching my girlfriend/boyfriend when greeting thatperson’. Participants reported their degree of agreement with eachitem using a 5-point scale ranging from ‘totally disagree’ to ‘totallyagree’. Statistics All data were analysed using Statistical Package for the Social Sciences(SPSS Inc., Chicago, IL, USA) and R (R Foundation for StatisticalComputing, Vienna, Austria). Data were first analysed by averagingthe visual-analogue scale scores given by each participant for eachvelocity and these average ratings were used in the reportedANOVA and multiple linear regression analyses for single sets ofdata (that is, patients or controls; visual or tactile modality). Thiswas the same approach used to investigate tactile C discharge and 1118  |  Brain 2011: 134; 1116–1126 I. Morrison  et al .   b  y g u e  s  t   on O c  t   o b  e r 1  5  ,2  0 1  6 h  t   t   p :  /   /   b r  a i  n . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   visual-analogue scale pleasantness rating patterns in Lo ¨ ken  et al. (2009). An extensive analysis that allowed for the repeated measuresat each velocity was then implemented using mixed random and fixedeffects modelling (Littel  et al. , 2009). This model also allowed directstatistical tests for differences between groups (patients, controls) andmodalities (tactile, visual). The models were fitted using RestrictedMaximum Likelihood and an unstructured covariance matrix, similar to multiple linear regression. The findings reported in the presentstudy were robust with regard to assumptions about covariance struc-ture and various types of mixed effect models were extensivelyexplored without altering the significance levels of the reported find-ings. We also fitted the same models using ranks of all visual-analoguescale ratings instead of visual-analogue scale values, hence limitingvisual-analogue scale to an ordinal scale. The reported findings andsignificance levels were the same for visual-analogue scale ranks as for visual-analogue scale scores. Cortical correlates of tactile Cstimulation The posterior insular cortex is a target for tactile C-afferent projections(Olausson  et al ., 2002; Bjo ¨ rnsdotter   et al ., 2009). A separate experi-ment aimed to rule out the possibility that patients’ low density oftactile C afferents is sufficient to activate posterior insula.Blood-oxygen-level-dependent responses to brush stroking on theforearm at a tactile C-optimal stroking velocity (3cm/s) and at anon-optimal stroking velocity (30cm/s) were assessed in five patientsusing functional MRI. We performed a search for voxels showing thegreatest signal change for 3cm/s, the stroking speed most likely toelicit tactile C activation and a pleasant percept in healthy individuals(Lo ¨ ken  et al.,  2009). Differences in blood-oxygen-level-dependant re-sponse between 3 and 30cm/s stimulation, likely reflecting signallingfrom tactile C-afferent projections to cortex, were compared in thepatient sample ( n  = 5) and in a sample of healthy volunteers ( n  = 5).Statistical maps for both patient and healthy participant groups werethresholded at  P  = 0.0005, with a family-wise-error corrected cluster threshold of 20 voxels ( P 5 0.05). See online Supplementary Materialfor details of the stimuli, data acquisition and data analysis.All participants gave informed consent approved by the University ofGothenburg and Sahlgrenska University Hospital, in accordance withthe Declaration of Helsinki. Travel expenses for patients’ travel fromthe far north of Sweden to Gothenburg were paid. Eight patients(three homozygotes) were recruited for the study but data for twoof them were excluded due to excessive motion in one case and in-sufficient wakefulness in the other. No data were acquired from onepatient who became panicked in the scanner. The final patient groupconsisted of five individuals: one homozygous female, one homozy-gous male, two heterozygous males and one heterozygous female(mean age 52; see online Supplementary material). The healthygroup consisted of five gender-matched volunteers recruited fromthe University of Gothenburg (three female; mean age 25).Participation was compensated at 200 Swedish crowns (  20 Euro)per session. Results Discriminative touch The directional sensibility test used to measure discriminative touchis very sensitive in detecting dysfunction of myelinated A b  fibres(Olausson  et al. , 1997; Norrsell  et al. , 2001) (SupplementaryFig. 1). C-fibre denervated patients ( n  = 10, SupplementaryTable 1) and age-, sex- and education-matched healthy controlsubjects ( n  = 10) performed equally well on the test (Wilcoxonsigned ranks test,  P  = 0.47; patients’ median response profilearea = 18, range 18–38; healthy controls’ median response profilearea = 18, range 18–25), and all results were well within the ear-lier established normal range (Olausson  et al. , 1997; Norrsell et al. , 2001). Evaluation of touch pleasantness For brush stroking on the forearm, the control group’sratings were consistent with previously published results fromanother group of healthy subjects (Lo ¨ ken  et al. , 2009). Themean pleasantness ratings for each velocity for patients andhealthy participants were compared using a two-way ANOVAwith factors group (patient, healthy control) and velocity. Post hoc t  -tests revealed that patients rated brush stroking as sig-nificantly less pleasant compared with controls [ F  (1,94) = 14.5, P 5 0.001; Fig. 1]. Patients’ ratings also had a higher coefficientof variance compared with controls ( P 5 0.001, independent sam-ples  t  -test).To determine the effect of stroking velocity on the pattern ofpleasantness ratings between groups, regression analyses specific-ally assessing the shape of rating curves were performed on thepatient and control groups separately. The independent variable‘velocity’ was logarithm-transformed and entered as linear andquadratic terms in a regression model. A negative quadraticterm in the regression captures the unique, inverted U-shapedrating pattern correlated with tactile C-afferent discharge inhealthy subjects (Lo ¨ ken  et al. , 2009). For the control group, thenegative quadratic term provided a significantly better fit than alinear term ( P 5 0.001), as in earlier research (Lo ¨ ken  et al. , 2009).In contrast, for the patient group the negative quadratic term didnot supply a significantly better fit than a linear term ( P  = 0.13;test for comparison of regression models) (Chatterjee and Hadi,2006).As a direct test between the shapes of the regression (reflect-ing rating patterns across velocities) for patients and controls,we performed an extended mixed random- and fixed-effectsmodel for repeated measures in which all the visual-analoguescale ratings from the two groups were taken into account(Littel  et al. , 2009). This involves performing a standard signifi-cance test of the quadratic term, then performing a statisticalcomparison between groups using a model implementedin SPSS. Statistical analysis of this model showed that the quad-ratic regression term for velocity was significantly negativefor healthy controls but non-significant for patients( P  = 0.022 for the difference in quadratic term). The visual-analogue scale intercept was also significantly lower for patientscompared with controls ( P  = 0.019). We found no other statisticaldifferences in visual-analogue scale ratings between patients andcontrols.Tactile C afferents, pleasant touch and empathy Brain 2011: 134; 1116–1126  |  1119   b  y g u e  s  t   on O c  t   o b  e r 1  5  ,2  0 1  6 h  t   t   p :  /   /   b r  a i  n . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om 
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