www.elsevier.com/locate/ynimg NeuroImage 30 (2006) 1340 – 1346
A putative social chemosignal elicits faster cortical responses than perceptually similar odorants Johan N. Lundstro¨m,a,* Mats J. Olsson,b Benoist Schaal,c and Thomas Hummel d a
Montreal Nuerogical Institute, McGill University, 3801 University Street, Room 276 Montreal, Que´bec, Canada H3A 2B4 Department of Psychology, Uppsala University, Box 1225, SE-751 42, Uppsala, Sweden c Centre des Sciences du Gouˆt, CNRS-Universite´ de Bourgogne, Dijon, France d Smell and Taste Clinic, Dept. of Otorhinolaryngology, University of Dresden Medical School, Dresden, Germany b
Received 30 April 2005; revised 12 September 2005; accepted 31 October 2005 Available online 18 January 2006
Social chemosignals, so-called pheromones, have recently attracted much attention in that effects on women’s psychophysiology and cortical processing have been reported. We here tested the hypothesis that the human brain would process a putative social chemosignal, the endogenous steroid androstadienone, faster than other odorants with perceptually matched intensity and hedonic characteristics. Chemosensory event-related potentials (ERP) were recorded in healthy women. ERP analyses indicate that androstadienone was processed significantly faster than the control odorants. Androstadienone elicited shorter latencies for all recorded ERP components but most so for the late positivity. This finding indicates that androstadienone is processed differently than other related odorants, suggesting the possibility of a specific neuronal subsystem to the main olfactory pathway akin to the one previously reported in Old-world monkeys and emotional visual stimuli in humans. D 2005 Elsevier Inc. All rights reserved. Keywords: Pheromones; ERP; Olfaction; Androgens; Attention
Introduction Specialized chemicals or chemical mixtures used for communication of social messages between conspecifics, so-called pheromones, were described more than 50 years ago in insects (Karlson and Lu¨scher, 1959). Although several identified compounds have been suggested to act as pheromonal signals among non-primates (Melrose et al., 1971; Schaal et al., 2003), the existence of a specific pheromonal compound in humans has so far been supported only by indirect evidence. Among the first reports on phenomena possibly explainable by pheromonal mediation was the observation that women living in close proximity synchronized their menstrual cycles (McClintock, 1971). However, although studies have shown that the complex * Corresponding author. Fax: +1 514 398 1338. E-mail address:
[email protected] (J. Lundstro¨m). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2005.10.040
odor of axillary sweat carries biological signals (Preti et al., 2003; Russell et al., 1980; Stern and McClintock, 1998) and specific compounds have been suggested (Monti-Bloch and Grosser, 1991), no pheromonal compound in humans has been undisputedly identified so far (Schaal, 2001). Several studies have investigated the psychobiological activity of the endogenous human compound 4, 16-androstadien-3-one (androstadienone) that can, among other places, be found in male axillary secretion (Nixon et al., 1988). Androstadienone is also found in women’s axillary hair, although generally at much smaller concentrations (Brooksbank et al., 1972). Androstadienone has been reported to influence women’s mood (Bensafi et al., 2004; Jacob and McClintock, 2000; Lundstrom et al., 2003a; Lundstrom and Olsson, 2005), psychophysiological variables (Bensafi et al., 2003; Jacob et al., 2001a), and regional cerebral blood flow (rCBF; Gulyas et al., 2004; Jacob et al., 2001b; Savic et al., 2001). Due to the demonstrated sex-specific effects in several of these studies and the higher prevalence of the compound in male secretions, androstadienone has been proposed as a human pheromone (Sobel and Brown, 2001). In line with this notion, Savic et al. (2001, 2005) recently demonstrated in two studies a sex-specific hypothalamic activation to androstadienone exposure. When stimulated by androstadienone, the participating women, but not men, showed an increase of rCBF in the hypothalamic area. Interestingly, this effect seems to be dependent on sexual orientation in that heterosexual men exhibited a hypothalamic activation, whereas their homosexual counterparts did not (Savic et al., 2005). The authors discussed whether a separate neuronal pathway could mediate the sexspecific results: a separate pathway that processes social odorants. Androstadienone has recently been suggested to be a putative ‘‘modulator pheromone’’ (Jacob and McClintock, 2000; McClintock, 2000). Rather than eliciting a stereotypical response, such stimulants are thought to modulate an ongoing psychobiological state in relation to a specific social context, such as an enhancement of attention to relevant stimuli in the environment. Indeed, behavioral evidence indicates that androstadienone affects
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attention-related mechanisms (Lundstrom and Olsson, 2005; Lundstrom et al., 2003a). Stimuli of high relevance for the individual may have been selected to become triggers of attention and hence processed faster (Tooby and Cosmides, 1990). From these considerations, one would expect that androstadienone, if in fact a human pheromone and in that a social odorant, would be processed faster by a separate neuronal subsystem than other common odorants. Although androstadienone release effects hitherto not seen with other odorants, no study has directly compared cortical responses of androstadienone exposure with responses to other odorants that are similar in both hedonic and intensity percept, two perceptual dimensions that are known to significantly affect measures of mood (Chen and Haviland-Jones, 1999; Knasko, 1995), psychophysiological recordings (Bensafi et al., 2002), and rCBF (Royet et al., 2001; Savic et al., 2000). To examine whether androstadienone is processed differently by the human brain than other perceptually similar but non-social odorants, we recorded chemosensory eventrelated potentials (ERP) for androstadienone and two other odorants matched for intensity and hedonic valence. ERP peak latencies are considered to reflect the time at which certain subroutines in the brain are activated (Kok, 1997), and the amplitude of these peaks is thought to reflect the intensity of the activation (Hummel and Kobal, 2001; Krauel et al., 1998). Olfactory ERPs are commonly divided into the early, more exogenously or sensory evoked potentials (P1 and N1) and the late, more endogenously or psychologically evoked potential (P3), making distinctions between sensory and psychological factors possible (Pause and Krauel, 2000). ERP recordings were selected before other imaging techniques as measurements due to the inherent high temporal resolution which makes the technique uniquely sensitive to the differential information processing of sensory stimuli (Kok, 1997). 5alpha-androst-16en-3-one (androstenone) and hydrogen sulfide (H2S) were used in the present experiment as control odorants. In the popular scientific literature, androstenone has repeatedly been brought forward as a potential human pheromone (cf. Preti and Wysocki, 1999) based on its well recognized pheromonal effect among pigs (Melrose et al., 1971). However, although several interesting psychophysical aspects of androstenone have been reported, such as a high level of specific anosmia, to the best of our knowledge, only one peer-reviewed article claiming meager pheromonal effects has been published (Filsinger et al., 1990; but see also a conference abstract: Kirk-Smith and Booth, 1980). Androstenone was here selected as a control odorant as it is a member of the same chemical group as androstadienone, thus possessing a similarity in chemical structure and hedonic properties, being an odorant of endogenous origin (Gower and Ruparelia, 1993), and a lack of reported reliable pheromonal effects (Cornwell et al., 2004; McClintock, 2003; Preti and Wysocki, 1999). H2S is widely used in human olfactory research due to its lack of trigeminal irritation (Kobal and Hummel, 1998) and is typically rated to have an unpleasant odor, similar to the two androgen odorants used. H2S is also found endogenously but has never been suggested to be a human pheromone. The use of these two chemically dissimilar control odorants further allows us to control for potential effects on processing speed due to chemical structure as previously hypothesized by others (Laing et al., 1994). Based on these previous findings (e.g., Lundstrom and Olsson, 2005; Savic et al., 2001), we hypothesized that the sensory processing of androstadienone, as measured by cortical responses, would be differentiated from these perceptually similar odorants in
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that androstadienone would be processed faster than both androstenone and H2S.
Material and methods Participants Fifteen right-handed, reportedly heterosexual women with a mean age of 28 years (SD = 7.8; range 20 – 45 years) provided written consent to participate in the study. Inclusion criteria were self-reported absence of major head trauma, nasal congestion, pregnancy, lactation, and use of tobacco products. To exclude nasal pathology, participants underwent a detailed otorhinolaryngological examination including nasal endoscopy. Of the participating women, 4 were within days 1 – 5 from menstrual onset, 4 were in the follicular phase (days 6 – 14), and 7 in the luteal phase (days 15 – 30) of their menstrual cycle. Participants were instructed to avoid food or beverages 1 h prior to testing. All aspects of the study were performed in accordance with the declaration of Helsinki and directions from the local ethics committee. Stimuli The steroid compounds were dissolved in propylene glycol (purity 99%; Sigma), a relatively odorless and non-toxic liquid. To produce the stimuli, odorless air was bubbled through solutions of 4 mM androstenone (Sigma, Deisenhofen, Germany) or 4 mM androstadienone (Steraloids Inc., Newport, RI, USA), these odorsaturated airstreams were then diluted to produce stimuli of 15% v/ v androstenone and 40% v/v androstadienone, respectively. H2S was obtained from Air Liquide Deutschland GmbH (Krefeld, Germany) and was presented at a concentration of 4 ppm. The concentrations of the three compounds were chosen since they produce a suprathreshold odor with very little or no trigeminal stimulation (Kobal and Hummel, 1998; Lundstrom et al., 2003b; Wysocki et al., 1987), and they were deemed to be iso-intense in a pilot study where six participants rated intensities of different concentrations of the three odorants in a side-by-side comparison task. Procedure Prior to the electrophysiological measurements, participants were screened for olfactory function using the ‘‘Sniffin’ Sticks’’ 12-item screening test (Hummel et al., 2001). Ten or more correct identifications were needed to fulfil the study’s inclusion criteria. Since previous studies have demonstrated a high rate of specific anosmia to androstenone (Amoore, 1977) and also, at a lesser rate, to androstadienone (Lundstrom et al., 2003b), a three-alternative forced-choice discrimination test was administered for both androstenone and androstadienone, separately. Each discrimination test consisted of seven trials during which the participants were presented with three 50 ml glass jars, placed on the table in front of them in a randomized order. One jar contained 4 ml of the odor in the same concentration that was used for the ERP recordings for that specific compound; the two other jars contained 4 ml of the diluent only. The participants were then asked to sniff each jar once and to identify the odd one. For inclusion in the study, five or more correct identifications were needed on each test, corresponding to a binomial probability of less than 0.04. After the initial psycho-
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physical screening tests, participants completed the Edinburgh Handedness Inventory to ensure that only right-handed individuals were included in the study (Oldfield, 1971). Only right-handed women were included due to a previous report of cortical asymmetries of olfactory processing between right- and lefthanded individuals (Royet et al., 2003). Previous studies have indicated that the sex of the experimenter could be a potential mediator of psychophysiological effects due to androstadienone exposure (Jacob et al., 2001a; Lundstrom and Olsson, 2005). To adhere with the logic of these findings and to ensure consistency in experimenter behavior, the same 31-year-old male experimenter performed all parts of the study, otorhinolaryngological examination excluded, for all participants. Electrophysiological recordings and perceptual ratings Participants were seated comfortably in a secluded area. White noise was used to mask any acoustical stimulation from the switching valves of the olfactory stimulator. In order to keep the participants in an awake and vigilant state during ERP recordings, they were instructed to perform a tracking task on a video monitor (Hummel and Kobal, 2001). Using a mouse, they had to keep a small square inside a larger one that moved in an unpredictable pattern across the screen. To examine participants’ percept of the odors, the tracking task was briefly interrupted after each stimulus presentation, and participants rated stimulus intensity by moving a marker on a visual analogue scale that was presented on the screen in front of them with Fvery weak_ as the left end point and Fvery intense_ as the right end point on the scale. Ratings were automatically transformed to a scale ranging from 0.0 to 10.0. For stimulus presentation, a dynamic olfactometer based on airdilution principles was used (OM6b; Burghart instruments, Wedel, Germany). This delivery method allows the embedding of odorous stimuli in a constant flow of odorless air (Kobal, 1981). For each odorant, 20 stimulations grouped in blocks of four were presented pseudo-randomized to prevent that the same odor block would be presented twice in a row, comprising a total of 60 stimulations within a session. The odorants were presented non-synchronously to breathing with an average inter-stimulus interval of 40 s with 250 ms stimulus duration. Stimuli were presented monorhinally to either the left or right nostril in a counterbalanced order. Participants were instructed and trained to use the technique of velopharyngeal closure during the whole session (Kobal, 1981). Velopharyngeal closure restricts airflow to the oral cavity which eliminates the need for presenting the stimuli synchronized to the participant’s breathing; this procedure reduces potential expectation-related effects such as the contingent negative variation (Loveless, 1983). After completion of the ERP recordings, participants were once again stimulated with the three odorants and asked to rate their hedonic valence by indicating how pleasant or unpleasant they perceived each of them. Ratings were performed on a visual analogue scale similar to the one described above with the difference that the left end of the scale was marked Fvery unpleasant_, the middle of the scale as Fneutral_, and the right side as Fvery pleasant_. ERPs were recorded at 3 midline scalp positions according to the international 10 – 20 system (Fz, Cz, and Pz) using an 8-channel amplifier (SIR, Ro¨ttenbach, Germany), referenced to linked earlobes (A1 + A2). Vertical eye movements were monitored at the Fp2 lead. The sampling frequency was 250 Hz; the pre-trigger period was 500 ms with a recording time of 2048 ms (band pass
0.02 – 30 Hz). Recordings were additionally filtered off-line (lowpass 15 Hz). Eye blink-contaminated recordings with artifacts larger than 50 AV in the Fp2 lead were discarded. Recordings were averaged off-line separately for each recording site, yielding late near-field ERPs (Hummel and Kobal, 2001). Peaks of the ERP were defined as P1, N1, and P3. Mean base-to-peak amplitudes, peak latencies, and peak-to-peak amplitudes (P1 – N1 and N1 – P3) were measured (software BOMPE 4.1; Kobal, Erlangen, Germany). Means and standard deviations for the ERP at recording site Cz for each compound are given in Table 1. Statistical analyses ERP data were submitted to repeated-measures analyses of variance (repeated-measures (rm)-ANOVA) for each ERP peak (P1, N1, and P3) separately, with Fodorant_ (androstadienone, androstenone, and H2S) and Felectrodes_ (Fz, Cz, and Pz) as within-subject factors. Differences in hedonic and intensity ratings were analyzed with rm-ANOVAs with Fodorant_ (androstadienone, androstenone, and H2S) as a within-subject factor. Alpha values below 0.05 are here reported as significant differences, and alpha values below 0.10 are reported as statistical tendencies.
Results Perception Rm-ANOVAs with Fodorants_ as a within-subject factor indicated that there were no significant differences in participants’ intensity ratings, F(2,28) = 0.75, ns, or hedonic ratings among odorants [ F(2,28) = 1.86, ns; see Fig. 1]. As indicated by Fig. 1, androstadienone was nominally rated as more pleasant than the two other odorants. To explore this potential difference further, separate paired Student’s t tests were performed, demonstrating no differences in the participant’s hedonic ratings between any of the odorants, all P’s ns. Cortical responses There were significant differences among odorants for all peak latencies as indicated by rm-ANOVAs with Fodorants_ and Felectrodes_ as within-subject factors [P1, F(2,28) = 4.00, P < 0.05; N1, F(2,28) = 3.45, P < 0.05; P3, F(2,28) = 7.00, P < 0.01]. Fisher PLSD post-hoc tests, corrected for multiple comparisons, showed that androstadienone was processed faster than both
Table 1 Means and standard deviations (SD) for each peak’s amplitude (AV) and latency (ms) at the Cz electrode Androstadienone
Androstenone
H2S
Mean
SD
Mean
Mean
2.97 3.17 6.37 2.91 5.47 141 158 157
1.94 2.62 2.58 2.07 3.18 2.16 1.94 2.77 5.65 3.66 7.18 3.71 5.12 2.59 4.52 2.60 8.84 3.43 9.13 4.51 512 117 479 120 609 135 559 129 817 162 818 145
Amplitude P1 1.26 N1 3.48 P3 7.30 P1 – N1 4.74 N1 – P3 10.78 Latency P1 430 N1 522 P3 701
SD
SD
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Fig. 1. Perception of the odorants. Mean (TSEM) psychophysical ratings of the odorants’ stimulus intensity and hedonic value for androstadienone (ANDI), androstenone (AND), and hydrogen sulfide (H2S). Units expressed as distances on a visual analogue scale. For intensity, zero represents Fvery weak_, and ten represents Fvery intense_; for hedonic, zero represents Fvery unpleasant_, five represents Fneutral_, and ten represents Fvery pleasant_. (A) Rm-ANOVAs with Fodorant_ as within-subject factor, (B) separate paired Student’s t test.
androstenone and H2S in the P1 peak (all corrected P < 0.05). No difference was found between H2S and androstenone (corrected P ns). Although not significant, there were statistical tendencies for androstadienone to be processed faster than both androstenone and H2S in the N1 peak (all corrected P < 0.10). Again, no difference was found between H2S and androstenone (corrected P ns). In the P3 peak, no difference was found between H2S and androstenone (corrected P ns). However, androstadienone was on average processed over 100 ms faster than both androstenone and H2S [all corrected P < 0.01, (see Fig. 2)]. There were no significant differences in base-to-peak amplitudes among these odorants for any of the peaks as indicated by rm-
ANOVAs with Fodorants_ and Felectrodes_ as within-subject variables [P1, F(2,28) = 0.33, ns; N1, F(2,28) = 0.80, ns; P3, F(2 28) = 0.77, ns]. Finally, there were no significant differences in peakto-peak amplitudes among these odorants for neither P1 – N1 nor N1 – P3 as indicated by rm-ANOVAs with Fodorants_ and Felectrodes_ as within-subject factors [P1 – N1, F(2,28) = 0.52, ns; N1 – P3, F(2,28) = 1.75, ns]. A visual comparison of the participants’ ratings of odor hedonics and the difference in P3 latencies between odorants suggests a functional relationship. To investigate whether the large difference in P3 latency between androstadienone and the two control odors is dependent on the participants’ hedonic ratings of
Fig. 2. Electrophysiological responses. Mean (TSEM) latencies of the averaged means of the Fz, Cz, and Pz electrodes separated by ERP components. In figure, * denotes a significant difference ( P < 0.05) and . denotes a statistical tendency ( P > 0.10) as deemed by post-hoc tests with Bonferroni corrections. Cartoon indicates ERP components and electrode locations.
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androstadienone, participants were split into two groups based on their hedonic ratings, forming the factor Fhedonic rating_ [Flow rater_ (n 8); Fhigh rater_ (n 7)]. An rm-ANOVA with Fodorants_ and Felectrodes_ as within-subject factors and Fhedonic rating_ as between-subject factor indicated that there was no main effect of Fhedonic rating_ on the P3 latencies [ F(1,13) = 0.17, ns] nor was there an interaction effect between Fodorants_ and Fhedonic rating_ on the P3 latencies [ F(2,26) = 0.39, ns]. The nominal difference in hedonic ratings between androstadienone and the two control odors thus had no impact on the differences in latencies between odorants.
Discussion The odor of androstadienone was here processed faster than both androstenone and H2S, although the participants rated the three compounds as iso-intense and as having a similar hedonic tone. The perceptual similarity among these odorants was supported by the lack of differences in amplitudes among responses to the three odorants. The large difference in processing speed between androstadienone and the two other odorants presented in the current study is unique. Androstadienone was here processed between 13 and 20% faster than the two control odorants in all ERP components. Differences in chemosensory ERP have previously only been demonstrated between perceptually very dissimilar compounds (cf. Hummel and Kobal, 2001). This large difference in processing speed between perceptually similar odorants has not previously been reported and supports the hypothesis that androstadienone is processed differently by the cortex than the other odorants. Savic et al. (2001, 2005) recently proposed that androstadienone could be processed by a separate neuronal pathway. Such a separate subcortical olfactory pathway has indeed previously been demonstrated in Old-world monkeys (Takagi, 1989; Tazawa et al., 1987) that, similar to humans, appear to miss a functional receptor organ for an accessory olfactory system (Zhang and Webb, 2003). Little is known about potential pheromonal pathways in humans (Meredith, 2001) and the separate question of which specific anatomical sensory system could be responsible for mediating the above effects is beyond the scope of this study. However, the large differences in latency between odors on both the early and late positive components of the ERP indeed suggest that androstadienone may be processed by a separate neuronal subcortical circuit. Such a separate circuitry has previously been demonstrated in the visual system for both arousing emotional and social stimuli by behavioral (Ohman et al., 2001a,b; Zihl and von Cramon, 1979), imaging (Morris et al., 1999; Sahraie et al., 1997), and lesion studies (Tomaiuolo et al., 1997). These stimuli are processed by a separate subcortical pathway, rendering a faster and more automatic processing than non-relevant stimuli (Morris et al., 1999; Ohman and Mineka, 2001). If androstadienone is a human pheromone in some sense, its relevance as a social signal should be evident. It is thus conceivable that androstadienone is processed by a similar subsystem of the main olfactory pathway as previously demonstrated in the visual system, a subsystem that processes emotional and social stimuli of high relevance. This preliminary study sets the stage for further work on the differential processing of putative social chemical signals. Future studies employing connectivity analyses, possibly in relation with receptor organ manipulation, will be helpful to establish the potential differences in neural pathways.
As a putative human modulator pheromone, androstadienone is expected to enhance attention to relevant stimuli (Jacob and McClintock, 2000; McClintock, 2000). In the present study, the latency of the P3 component showed the greatest difference between androstadienone and the two other odorants. Previous studies have demonstrated that latencies of the late component are considerably reduced when subjects are performing automatic processing of stimuli in comparison with non-automatic processing (Hoffman et al., 1983; Kramer et al., 1986, 1991), a phenomenon that may reflect an automatic attention response (Kok, 1997). It is thus conceivable that this significant difference in response latencies for the late positive component between androstadienone and the two control odorants indicates that androstadienone receives more rapid and more automatic processing, implying pheromonal properties (Gulyas et al., 2004; Lundstrom and Olsson, 2005; Lundstrom et al., 2003a). One might argue that the difference in latencies among odorants is due to a difference in speed of mucus absorption in the olfactory mucosa as previously hypothesized for odorants in mixtures (Laing et al., 1994). However, this is an unlikely explanation. Androstadienone was processed faster than both the perceptually and chemically similar androstenone and the perceptually similar but chemically dissimilar H2S. If mucus transfer processes are mediating the above-reported effects, androstadienone and androstenone should be processed in a similar temporal fashion due to their chemical similarity (Jinks et al., 2001; Schild and Restrepo, 1998). In fact, when temporal differences in processing between odorants have previously been demonstrated, less pleasant and more intense stimuli are processed faster (Jinks and Laing, 1999; Kobal et al., 1992; Laing et al., 1994). In this context, the participants’ hedonic and intensity ratings of the odorants argue that androstadienone should be processed slower rather than faster than the two control odorants. However, we demonstrate here that the large difference in processing speed for androstadienone is not dependent on differences in perception between the odorants. Moreover, since comparisons to both a chemically similar and a chemically dissimilar odorant were made, we argue that the large difference in processing speed demonstrated here cannot be explained by a difference in mucus transduction process. Of special interest is the difference in latencies between androstadienone and androstenone. These odorants are not only both endogenously produced with a similar musky odor quality, the participating women could also be expected to have similar lifetime exposure to both compounds. The demonstrated difference in speed of processing between these odorants could thus not readily be explained by amount of exposure or learned responses. In conclusion, this study demonstrates a difference in cortical activity between odorants similar in intensity and hedonic value. The participating women had shorter latencies on all ERP components when exposed to androstadienone as compared to the perceptually similar odors of androstenone and H2S. This difference in latencies suggests that androstadienone is processed by a neural subsystem to the main olfactory system which would make it unique among odorants.
Acknowledgments We thank Dr. Michael Knecht for help with the ENT examinations and Julie Boyle and Dr. Marilyn Jones-Gotman for helpful comments on previous versions of the manuscript.
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The authors declare that they have no competing financial interest.
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