The testosterone derivative 4,16-androstadien-3-one (AND) and the estrogen-like steroid estra-1,3,5(10),16-tetraen-3-ol (EST) are candidate compounds for human pheromones. AND is detected primarily in male sweat, whereas EST has been found in female urine. In a previous positron emission tomography study, we found that smelling AND and EST activated regions covering sexually dimorphic nuclei of the anterior hypothalamus, and that this activation was differentiated with respect to sex and compound. In the present study, the pattern of activation induced by AND and EST was compared among homosexual men, heterosexual men, and heterosexual women. In contrast to heterosexual men, and in congruence with heterosexual women, homosexual men displayed hypothalamic activation in response to AND. Maximal activation was observed in the medial preoptic area/anterior hypothalamus, which, according to animal studies, is highly involved in sexual behavior. As opposed to putative pheromones, common odors were processed similarly in all three groups of subjects and engaged only the olfactory brain (amygdala, piriform, orbitofrontal, and insular cortex). These findings show that our brain reacts differently to the two putative pheromones compared with common odors, and suggest a link between sexual orientation and hypothalamic neuronal processes.

The sense of smell has been traditionally assumed to be different from other sensory modalities in that odors are encoded perceptually, without a semantic component. Recent findings of improved odor memory upon encoding with verbal cues question this view. Furthermore, familiar odors are easier to remember and discriminate than are unfamiliar ones, and odor familiarity is reported to predict odor naming. To investigate whether familiar odors are processed by different cerebral structures than those that process unfamiliar odors, (15)O H(2)O-positron emission tomography (PET) measurements of cerebral blood flow were carried out in 14 healthy men. The task was passive, birhinal, smelling of familiar odors (FAM), unfamiliar odors (uFAM), and odorless air (AIR). Significant activations (P < 0.05) were calculated using the contrasts FAM-AIR, uFAM-AIR, and FAM-uFAM, and deactivations running these contrasts in the opposite direction. In relation to AIR, both FAM and uFAM activated amygdala, piriform cortex, and parts of anterior cingulate cortex. FAM activated, in addition, left frontal cortex (Brodmann's areas 44,45,47), left parietal cortex incorporating precuneus, and right parahippocampus. Clusters covering parahippocampus and precuneus were observed also in FAM-uFAM. The activation of left frontal cortex and right parahippocampus was positively correlated with familiarity ratings. Smelling of familiar but not unfamiliar odorants seems to engage cerebral circuits mediating memory and language functions, in addition to the engagement of olfactory cortex. Already the most elemental form of odor processing, passive perception thus seems to engage semantic circuits. This is achieved by the ability of odorants to immediately elicit associations and judgments of odor characteristics.

Whether different odorous compounds (odorants) are processed by different cerebral circuits is presently unknown. A first step to address this complicated issue is to investigate how the cerebral regions mediating signals from olfactory (i.e., unimodal) odorants, differ from those mediating the olfactory + trigeminal (i.e., bimodal) odorants. [15O]‐H2O‐PET scans were conducted in 12 healthy females during three separate conditions: birhinal, passive smelling of: 1) the unimodal odorant vanillin; 2) the bimodal odorant acetone; and 3) odorless air. Significant activations were calculated contrasting vanillin to air, acetone to air, and deactivations, running these contrasts in the opposite direction. Smelling of vanillin activated bilaterally the amygdala and piriform cortex. These regions were only engaged slightly by acetone. Instead, strong activations were found in the anterior and central insula and claustrum, the posterior portion of anterior cingulate, the somatosensory cortex (SI for face), cerebellum, ventral medial (VMPo) and dorsal medial (MDvc) thalamus, the lateral hypothalamus, and pons/medulla. In parallel, the somatosensory (SI, below central representation of face), secondary visual and auditory cortices, as well as the supplementary motor area and the parahippocampal gyri were deactivated. No deactivations were observed with vanillin, although the odor components of acetone and vanillin were rated similarly intense (75 ± 17 mm vs. 61 ± 22 mm, NS). The differentiated pattern of cerebral activation during odorant perception seems to be dependent on the signal transducing cranial nerves involved. In contrast to vanillin, which solely activates the olfactory cortex, acetone engages predominantly trigeminal projections from the nasal mucosa. Acetone's limited activation of the olfactory cortex may result from a cross‐modal interaction, with inhibition of acetone's odor component by its trigeminal component. Hum. Brain Mapping 17:17–27, 2002. © 2002 Wiley‐Liss, Inc.

Several studies indicate that women outperform men in olfactory identification tasks. The psychophysical data are more divergent when it comes to gender differences at levels of odor processing which are cognitively less demanding. We therefore compared cerebral activation with H215O PET in 12 females and 11 males during birhinal passive smelling of odors and odorless air. The odorous compounds (odorants) were pure olfactory, or mixed olfactory and weakly trigeminal. Using odorless air as the baseline condition, activations were found bilaterally in the amygdala, piriform and insular cortices in both sexes, irrespective of the odor. No gender difference was detected in the pattern of cerebral activation (random effect analysis SPM99, corrected p < 0.05) or in the subjective perception of odors. Males and females seem to use similar cerebral circuits during the passive perception of odors. The reported female superiority in assessing olfactory information including odor identification is probably an effect of a difference at a cognitive, rather than perceptive level of olfactory processing.

The anatomical pathways for processing of odorous stimuli include the olfactory nerve projection to the olfactory bulb, the trigeminal nerve projection to somatosensory and insular cortex, and the projection from the accessory olfactory bulb to the hypothalamus. In the majority of tetrapods, the sex-specific effects of pheromones on reproductive behavior is mediated via the hypothalamic projection. However, the existence of this projection in humans has been regarded as improbable because humans lack a discernable accessory olfactory bulb. Here, we show that women smelling an androgen-like compound activate the hypothalamus, with the center of gravity in the preoptic and ventromedial nuclei. Men, in contrast, activate the hypothalamus (center of gravity in paraventricular and dorsomedial nuclei) when smelling an estrogen-like substance. This sex-dissociated hypothalamic activation suggests a potential physiological substrate for a sex-differentiated behavioral response in humans.

In a recent PET study on processing of unfamiliar odours we observed that odour discrimination performance was superior during right compared with left nostril presentations, and that mainly the right cerebral hemisphere was activated. In the present study we investigated whether the asymmetric performance is present also during the processing of familiar odours. Seventy-one right-handed healthy subjects (age 21-49 years, 40 females) with normal nasal anatomy and olfactory thresholds participated. Forty pairs of odours (20 familiar and 20 unfamiliar) were presented in the same/different paradigm, alternating nostrils and balancing the order. The number of errors during the discrimination task was compared with respect to nostril and odour familiarity. The overall odour discrimination performance was superior on the right side. However, this difference was valid only for unfamiliar odours, whereas the performance for familiar odours was symmetrical. Familiar odours were easier to discriminate than unfamiliar ones. The present data are congruent with the idea of a semantic influence on odour processing. Odours seem to be processed with a right sided preponderance when not clearly familiar, and symmetrically when language becomes involved. Future studies on odour processing should therefore take into account odour familiarity and side of presentation.