The olfactory bulbs (OBs) are the first site of odor representation in the mammalian brain, and their unique ultrastructure is considered a necessary substrate for spatiotemporal coding of smell. Given this, we were struck by the serendipitous observation at MRI of two otherwise healthy young left-handed women, yet with no apparent OBs. Standardized tests revealed normal odor awareness, detection, discrimination, identification, and representation. Functional MRI of these women’s brains revealed that odorant-induced activity in piriform cortex, the primary OB target, was similar in its extent to that of intact controls. Finally, review of a public brain-MRI database with 1,113 participants (606 women) also tested for olfactory performance, uncovered olfaction without anatomically defined OBs in ∼0.6% of women and ∼4.25% of left-handed women. Thus, humans can perform the basic facets of olfaction without canonical OBs, implying extreme plasticity in the functional neuroanatomy of this sensory system.

In turn, a measure of how the world smells is easily obtained from humans, as they can use words to convey their olfactory experience. Whereas human surgical bulbectomy typically occurs in concert with extensive additional damage to peripheral and central olfactory structures (), an isolated lack of OBs is observed in congenital anosmia (). Moreover, reductions in human OB volume may be associated with reductions in olfactory performance (). Given this, we were struck by the initial serendipitous observation at MRI of a woman with an intact sense of smell but without apparent OBs. In this study, we explore this observation in depth.

There have been, however, some controversial exceptions to this rule. One study reported that, after allowing a lengthy recovery from bilateral bulbectomy, mice retained pre-bulbectomy learned olfactory aversions and could learn new olfaction-based tasks (). This study, however, was criticized on a host of methodological considerations, among them a lack of histological verification for bulbectomy (). A second set of studies in rats implied retained olfactory capabilities after extensive OB lesions (). These studies suggested that olfaction survived bulbectomy thanks to ORNs directly targeting the forebrain to form “glomeruli-like structures” in cortex (), a pattern previously observed in mice (). These studies as well, however, were criticized on methodological grounds, primarily suggesting that the lesions spared those aspects of the OB that were critical for the odorants tested (). These histologically based rebuttals notwithstanding, a major limitation of the studies implying retained olfaction following bulbectomy in rodents was in their reliance on performance-based measures of smell. Tasks of odorant detection and discrimination were conducted in animals that are exceptionally keen in all their sensory capabilities and, moreover, highly motivated and solely focused on the tasks at hand. This provides a lot of room for non-olfactory behavioral compensation. Such compensation may arise from any inadvertent non-olfactory information, such as the most minute auditory, visual, or somatosensory cues associated with the task. Moreover, even under the assumption of perfect experimental control with no non-olfactory cues, there are multiple chemosensory subsystems in the mammalian nose beyond the main olfactory system. These include the trigeminal nerve endings, the vomeronasal organ, and the Grueneberg and Septal organs, which can all transduce chemical signals (). Similarly, odorants can also activate taste receptors in the mouth (). It is quite possible that some combination of activation in these subsystems enabled performance in tasks such as odorant detection and discrimination in bulbectomized rodents. In other words, bulbectomized rodents may be able to perform olfactory tasks, but the world may nevertheless smell very differently to them versus their intact conspecifics.

In mammalian olfaction, odorants are first transduced into neural signals at olfactory receptor neurons (ORNs) in the nose. The olfactory neural signal then travels along the axons of these neurons, through perforations in the skull (the cribriform plate), and into the brain where they target the olfactory bulbs (OBs). In rodents, this targeting is highly ordered, and this order is taken to play a critical role in odor coding (). More specifically, rodents have more than 1,000 OR subtypes, each sensitive to a subset of odorant features. The spatial ordering of these ORs in the nose is complex, but in their path to the OB they converge such that all ORNs expressing a specific receptor subtype target one of two common mirror-placed locations in the OB, termed glomeruli. Notably, this organization may follow different rules in humans, as their ∼400 intact OR subtypes () would predict ∼800 glomeruli by this two-glomeruli-to-one-OR principle, yet postmortem studies suggest ∼5,500 glomeruli and more per human OB (). It is widely accepted that odor coding or representation is then reflected in the spatiotemporal activity pattern across these glomeruli (). Moreover, an OB neuroanatomy that is made of intricate intra- () and inter- () OB connectivity forms a highly specialized neural substrate for extended odor coding (). Given this, one would expect that any damage to the OB should damage olfaction and that a lack of an OB altogether should result in a complete loss of the sense of smell.

The identification of NAB2 while scanning controls for NAB1 raises the possibility that an apparent lack of OBs may be more common than we had thought. Moreover, that this encounter occurred while specifically scanning left-handed women further raised the possibility that such lack is somehow associated with a combination of sex and handedness. To get a sense of the possible prevalence of this phenomenon within the general population, we carefully examined the brain MRIs of 1,113 (606F, ages 22–35) participants publicly available through the Human Connectome Project (HCP) (). The HCP also obtained from its participants the NIH Toolbox Odor Identification measure, a 9-item odor identification test scored and normed to have a mean = 100 ± 15. We observed 3 participants, all women (1 left handed), who had no apparent OBs ( Figure 6 A; Figure S10 ) yet, remarkably, above average olfaction scores of 110.45, 110.45, and 111.41 (age adjusted). Notably, the HCP also contained monozygotic twins of all three, and all twins had clear OBs ( Figure 6 B). Amusingly, we note that all three participants without apparent OBs had better olfactory scores in comparison to their intact monozygotic twins (who scored 86.45, 97.19, and 98.04, respectively) ( Figure 6 C). We further observed an additional participant in the HCP, again a left-handed woman, with no apparent OBs, but her MRI was relatively blurry in the ventral frontal areas, leading us to mark this participant with caution ( Figure 6 D; Figure S11 ). We note that an observation of no OBs in four women but no men in this cohort implies a strong trend toward a sex difference (two-tailed chi-square: χ= 3.68, p = 0.055). Notably, if we combine this with the results of the independent study where we serendipitously observed NAB1 (but obviously not with the continued target effort where we scanned only women), this sex difference is significant (two-tailed chi-square: χ= 4.6, p = 0.032). Moreover, we note that the HCP contains data from 47 left-handed women, thus the observation that two of four participants without bulbs were left handed implies significant association with left-handedness (two-tailed chi-square: χ= 10.00, p = 0.0001). Our local data obtained after first identifying NAB1 mirror this: once we started screening left-handed women only, out of 20 left-handed women, we encountered one normosmic woman without OBs (NAB2). Moreover, in recruiting for the normosmic bulbar control group, we encountered a hyposmic left-handed woman who, given her slightly reduced olfaction, was excluded from the intended normosmic bulbar control group. We nevertheless later independently scanned her and found that she too has no OBs (see NAB3 in Figure S12 ). Because unlike NAB1 and NAB2, NAB3 has slightly but significantly impaired olfaction by standardized tests (although she was unaware of this impairment), she was not systematically included in this manuscript. Nevertheless, her presentation joins a previously reported case of significantly impaired but not eradicated olfaction without apparent OBs, also in a woman (). Taken together, we conclude that olfaction without apparent OBs is evident in ∼0.6% of women and in ∼4.25% of left-handed women.

(C) Violin plot of olfactory performance (age-adjusted) in all 602 HCP women participants (those who have both T2 scans and olfactory tests), those without bulbs in purple, and their monozygotic twins with bulbs in yellow.

We next used fMRI to ask whether we see any evidence for altered odorant-induced brain activity in the NAB group (fMRI signal cannot be measured at the OB). We delivered two generally pleasant (orange and banana) and two generally unpleasant odorants (asafetida and smelly cheese) within an event-related design. In the control cohort, a group image uncovered a typical odorant-induced response, which included pronounced activation in primary (piriform) and secondary (orbitofrontal, inferior frontal gyrus, insula) olfactory regions ( Figure 5 A). Despite variability, a pattern of activation resembling the group image was evident in individual members of the control cohort ( Figure 5 B) and was similarly evident in NAB1 ( Figure 5 C) and NAB2 ( Figure 5 D). Only NAB-CA stood out in this analysis, with no odorant-induced activation at the commonly applied threshold ( Figure 5 E). The primary target of the OBs is piriform cortex. We therefore conducted a ROI analysis of the piriform response () and observed similar odorant-induced responses in NAB1 and NAB2 versus the control group (albeit a trend toward delayed and reduced response in NAB2), and only in NAB-CA did we observe significantly less piriform activation (left piriform parameter estimate [PE]: control = 0.79 ± 0.23, NAB1 = 0.83, two-tailed t(16) = 0.17, p = 0.87, NAB2 = 0.4, two-tailed t(16) = −1.62, p = 0.12, NAB-CA = 0.11, two-tailed t(16) = −2.86, p = 0.01; right piriform PE: control = 0.85 ± 0.26, NAB1 = 1.09, two-tailed t(16) = 0.91, p = 0.37, NAB2 = 0.41, two-tailed t(16) = −1.65, p = 0.12, NAB-CA = 0.2, two-tailed t(16) = −2.47, p = 0.02) ( Figures 5 F and 5G). In other words, activity in the primary cortical target of the OBs was similar in NAB1, NAB2, and the bulbar control cohort, and only NAB-CA significantly differed in this respect. We conducted similar analyses in secondary orbitofrontal and insular regions. The contrast maps revealed a similar outcome of no activation in NAB-CA yet common activation patterns in NAB1, NAB2, and the control cohort ( Figure S7 ). The data from these regions, however, were relatively noisy, such that an ROI analysis in these same structures indeed implied no differences between the group and NAB1 or NAB2 but then only a trend toward reduced activity in NAB-CA ( Figure S7 ). We further investigated the fMRI response as a function of odorant valence ( Figures S8 ) and conducted an investigation of functional connectivity ( Figure S9 ). Like the signal from orbitofrontal cortex, however, these patterns were extremely variable in controls, preventing any decisive statements as to differences in NAB1 and NAB2.

(F and G) Normalized percentage signal change in a ROI delineated in left (F) and right (G) piriform cortex (circle within piriform cortex in A is the ROI). Shaded area reflects SD of the mean. Inlay is a parameter estimate in percentage change values. Error bars are SD. The figure depicts positive betas only (odor > no odor). See also Figures S7–S9

All of the above tests reflect olfactory performance-based measures. As noted in the Introduction , odorant detection and discrimination, however, may be accomplished using chemosensory subsystems beyond the olfactory system alone (). Hence, a potentially more important question is how does the world smell to these individuals without OBs? To address this, NAB1, NAB2, and 140 age-matched women used visual analog scales (VASs) to rate 10 odorants along each of 11 descriptors. These data can be examined in two ways: the first way is at face value, namely, the raw ratings across odorants and descriptors. We can represent each participant as a 110-value vector reflecting the 11 descriptors applied to each of the 10 odorants. For each participant, we Z scored this vector and calculated the Euclidean distance with all other participants. We observed that NAB1 and NAB2 do not stand out in this measure (mean Euclidean distance across participants = 12 ± 1.3, NAB1 = 13.22, two-tailed t(139) = 0.96, p = 0.33; NAB2 = 12.62, two-tailed t(139) = 0.5, p = 0.61), yet NAB-CA was significantly different (NAB-CA = 14.7, two-tailed t(139) = 2.1, p = 0.036) ( Figure 4 A). This similarity between NAB1, NAB2, and the group, in application of verbal descriptors to odorants, is further retained when examining each odorant and descriptor separately ( Figure S6 ). In other words, NAB1 and NAB2 apply raw verbal descriptors to odorants as do 140 age-matched women controls. Rather than using the raw language-based representation, we can also represent each person’s olfactory perception as a matrix of perceptual similarities between all odorant pairs (). We can precisely derive the pairwise perceptual similarity from the pairwise application of descriptors (). Ten odorants provide for 45 pairwise perceptual similarity values. Such a similarity matrix makes for a measure referred to as an olfactory perceptual fingerprint (), which provides for a semantics-free representation of how the world smells to an individual (). Such olfactory perceptual fingerprints remain reasonably stable over time and are linked to genetic makeup (). Using this approach, we can again for each participant calculate the Euclidean distance of this vector with all other participants. We again observe that NAB1 and NAB2 do not stand out in their mean distance (mean Euclidean distance across participants: 331.3 ± 77.2, NAB1 = 334.15, two-tailed t(139) = 0.037, p = 0.97; NAB2 = 353.72, two-tailed t(139) = 0.29, p = 0.77), yet NAB-CA was again significantly different (mean distance = 764.8, two-tailed t(139) = 5.6, p = 1.15 × 10) ( Figure 4 B). To visualize this, we used principal-component analysis (PCA) to project all participants into a space reflecting olfactory perception ( Figure 4 C). We observe that the perceptual fingerprints of NAB1 and NAB2 are indeed interspersed with the perceptual fingerprints of the group, yet NAB-CA stands separately ( Figure 4 C), but we are also impressed that NAB1 and NAB2 may be closer to each other than expected by chance. To test this impression, we measured all the pairwise distances between all participants within the PCA space. We observed that, whereas the average distance across all 9,730 pairwise comparisons provided by the 140 participants was 288.1 ± 110.4, the difference between NAB1 and NAB2 was 130.85, which is indeed closer than 96% of all comparison (p = 0.04) ( Figure 4 C, inlay). Taken together, these analyses imply that NAB1 and NAB2 smell the world as does an average woman of their age, yet they are more similar to each other than expected by chance. Phrased differently, there may be a typical perception of the olfactory world without OBs, and this typical perception is within the range of normal perception.

In addition to the above internationally standardized and validated tests, we conducted in-lab detection threshold estimations for four odorants. NAB-CA was unable to detect even the highest concentrations we used for limonene, and phenyl ethyl alcohol (PEA) but was able to detect the highest concentrations (only) of menthol (2.5%) and isovaleric acid (10%), reflecting an overwhelming difference from controls (menthol (−log10): control = 5.68 ± 1.24, NAB-CA = 1.75, two-tailed t(22) = −3.19, p = 0.004; isovaleric (−log10): control = 6.1 ± 0.91, NAB-CA = 1.5, two-tailed t(22) = −4.9, p = 6.5 × 10) ( Figure 3 E). NAB-CA detection of these high concentrations presumably reflects trigeminal responses (). In contrast, NAB1 and NAB2 were not significantly different from controls at detecting menthol, isovaleric acid, and limonene (menthol (−log10): control = 5.68 ± 1.24, NAB1 = 5.97, two-tailed t(22) = 0.23, p = 0.82, NAB2 = 3.86, two-tailed t(22) = −1.48, p = 0.15. isovaleric (−log10): control = 6.1 ± 0.91, NAB1 = 6.67, two-tailed t(22) = 0.62, p = 0.54, NAB2 = 6.29, two-tailed t(22) = 0.22, p = 0.83. Limonene (−log10): control = 5.17 ± 0.44, NAB1 = 5.04, two-tailed t(22) = −0.28, p = 0.78, NAB2 = 4.67, two-tailed t(22) = −1.11, p = 0.27) ( Figure 3 E). Only for PEA, we observed that although NAB1 and NAB2 clearly detected it (detecting the 9and 10dilution steps, respectively, orders of magnitude above chance and above NAB-CA), they were nevertheless significantly poorer than controls (PEA (−log10): control = 7.1 ± 0.67, NAB1 = 4.8, two-tailed t(21) = −3.35, p = 0.003, Z-CC = −3.45, NAB2 = 5.64, two-tailed t(21) = −2.15, p = 0.043, Z-CC = −2.19) ( Figure 3 E). Finally in this series, we tested the ability to discriminate between enantiomers, namely, structural mirror images of the same molecular species (). We used a particularly difficult version of the triangle paradigm, where participants were allowed only one sniff for each of three stimuli, two containing the same enantiomer and a third containing the mirror image enantiomer, and their task is to select the odd odorant. We observed that NAB1 and NAB2 were not significantly different from the control mean (control = 48% ± 15.7%, NAB1 = 41.8%, two-tailed t(21) = −0.41, p = 0.68; NAB2 = 25%, two-tailed t(21) = −1.46, p = 0.16) ( Figure 3 F). The value of this final test, however, may be limited by its difficulty: chance at this task is 33% and just significant discrimination or a d-prime (d′) score of 1 is associated with 41.8% accuracy (). Thus, we observe that 5 of 22 bulbar participants, as well as NAB2, had d′ <1 or, in other words, could not make the discrimination. In contrast, NAB1 had a score of d′ = 1 and, along with 17 bulbar participants, could make the discrimination ( Figure 3 F). Taken together, the set of lab tests again implied that NAB1 and NAB2 clearly have a sense of smell, and, with the exception of reduced detection threshold for PEA, they are not significantly different from bulbar controls.

We next examined UPSIT results. Given that several of the 40 UPSIT odor-objects are culturally specific to the US, we first estimated a local norm (n = 88F, age 20–39; norm = 33.59 ± 2.48, i.e., 83.97% accuracy). Unsurprisingly, NAB-CA obtained a score of 20%, which is significantly worse than the norm (two-tailed t(87) = −10.3, p < 0.00001, Z-CC = −10.32) and not different from chance (chance = 25%, p = 0.82) ( Figure 3 D). In contrast, whereas NAB1 obtained a score of 82.5%, which is squarely within local norms (two-tailed t(87) = −0.24, p = 0.81) ( Figure 3 D), NAB2 obtained a lower score of 65%, which is on par with two other members of the norm cohort, still far better than chance (p = 1.1 × 10) yet significantly lower than the norm cohort average (two-tailed t(87) = −3.05, p = 0.003, Z-CC = −3.06) ( Figure 3 D). However, given that using Sniffin Sticks, the very same NAB2 obtained an unusually high identification score (15 of 16 in an identical 4-alternative identification task), her lower identification score at UPSIT may reflect odorant familiarity issues. As noted, many of the UPSIT odorants are unfamiliar to non-American cohorts. The creators of the UPSIT recognized this limitation and published a short-version UPSIT consisting of a subset of 12 out of the 40 UPSIT odorants, which they labeled as culturally independent (). We observe that NAB2 correctly scored 10 out of these 12 odorants (chance = 3, difference from chance p = 3.7 × 10), which renders her normosmic under this UPSIT culturally independent version ().

Two standardized tests of olfactory performance are widely applied: “Sniffin Sticks” () and the University of Pennsylvania Smell Identification Test (UPSIT) (). In Sniffin Sticks, we compared the NAB group to the age- and sex-matched norms for odorant threshold (T), discrimination (D), identification (I), and a combined score (TDI). Norm values were originally obtained from a group of ∼700 women age 16–35 (). We observed that NAB-CA could not detect even the highest concentration of n-butanol (4%) (difference from norm: T= 1, T= 9.39 ± 2.56, two-tailed t(759) = −3.27, p = 0.001, Z-CC = −3.28) and was at chance in discrimination (D= 7, difference from chance: p = 0.08, difference from norm: D= 12.91 ± 1.92, two-tailed t(740) = −3.07, p = 0.003, Z-CC = −3.08) and identification (I= 6, difference from chance: p = 0.19, I= 13.68 ± 1.62, difference from norm: two-tailed t(826) = −4.73, p < 0.00001, Z-CC = −4.74) ( Figure 3 B), achieving a total TDI score of 14, which is significantly lower than the norm (TDI= 36.06 ± 4.17, two-tailed t(703) = −5.29, p < 0.00001, Z-CC = −5.29) ( Figure 3 C) and is indeed considered anosmic (). In contrast, NAB1 registered a very low (good) detection threshold (T= 9.75, difference from norm: two-tailed t(759) = 0.14, p = 0.89) and normal discrimination (D= 13, difference from chance: p = 3.8 × 10, difference from norm: two-tailed t(740) = 0.05, p = 0.96) and identification (I= 12, difference from chance: p = 3.8 × 10, difference from norm: two-tailed t(826) = −1.04, p = 0.3) ( Figure 3 B), combining for a totally normosmic score of TDI = 34.75 (difference from norm: two-tailed t(703) = −0.31 p = 0.75) ( Figure 3 C). Similarly, NAB2 registered a normal detection threshold (T= 8.5, difference from norm: two-tailed t(759) = −0.35, p = 0.73), normal discrimination (D= 12, difference from chance: p = 3.8 × 10, difference from norm: two-tailed t(740) = −0.47, p = 0.64), and very high (good) identification (I= 15, difference from chance: p = 1.14 × 10, difference from norm: two-tailed t(826) = 0.81, p = 0.42) ( Figure 3 B), combining for a totally normosmic score of TDI = 35.5 (difference from norm: two-tailed t(703) = 0.13, p = 0.9) ( Figure 3 C). In other words, according to the widely validated TDI scores, NAB-CA is indeed anosmic, yet NAB1 and NAB2, despite having no apparent OBs, are completely normosmic ( Figures 3 B and 3C).

Both NAB1 and NAB2 self-proclaimed highly acute olfaction. The subjective role of olfaction in one’s life can be estimated using the standardized Subjective Importance of the Sense of Smell Questionnaire (SISSQ) (). Given that the SISSQ is culturally variable (), we first estimated a local norm (n = 150F, age 22–36; norm = 2.98 ± 0.37). We then observed that, unsurprisingly, NAB-CA was significantly lower than norm (NAB-CA = 1, two-tailed t(149) = −5.33, p < 0.00001, Z-CC = −5.35), yet NAB1 and NAB2 were not different from the norm (NAB1 = 3.22, two-tailed t(149) = 0.65, p = 0.52; NAB2 = 2.44, two-tailed t(149) = −1.45, p = 0.15) ( Figure 3 A). In other words, despite no apparent OBs, a standardized test verified a significant subjective role for olfaction in the lives on NAB1 and NAB2. We next set out to test whether this subjective sense was reflected in objective capabilities.

Although human OBs are prominent at MRI ( Figure 1 A; Figure S1 ), one may suggest that these participants may have OBs that are radically smaller than normal, and which we therefore failed to see. To estimate this, we scanned NAB2 two more times, now using an ultra-high-definition 3D imaging paradigm once at 600 × 600 × 600 μmresolution, and once at 470 × 470 × 470 μmresolution. At this resolution, we obtain very clear images of intact OBs in controls but still no apparent OBs in NAB2 ( Figure S5 Data S3 ). We note that a typical human OB is ∼58 mmand contains ∼5,500 glomeruli (). Thus, an OB that we would be unable to see at the resolution we used (i.e., an OB of less than one voxel) is ∼0.18% of a typical OB and would contain ∼10 glomeruli. Figure S5 C contains depictions of what 1-voxel, 3-voxel, and 9-voxel OBs would look like and illustrates the unlikeliness of us failing to observe such structures. Thus, we conclude that in the expected location of the OBs these participants have either no OBs at all or rudimentary microscopic structures that may contain tens of glomeruli rather than the expected 5,500 glomeruli and more (more on this in the Discussion ). We next continue to ask what are the olfactory capabilities of these participants with no apparent OBs.

Finally, congenital anosmia, which is associated with no apparent OBs, is also associated with changes in brain anatomy beyond the olfactory system alone (). With this in mind, we applied whole-brain voxel-based morphometry, as well as region-of-interest-based measurements of subcortical volume and cortical thickness, yet found no brain differences in NAB1 and NAB2 beyond the olfactory system ( Figure S4 ). The same analyses applied to NAB-CA uncovered a thicker left lateral orbitofrontal cortex in comparison to controls (control = 2.79 ± 0.11, NAB-CA = 3.05, two-tailed t(17) = 2.32, p = 0.033), yet we treat this finding with caution, as it would not survive correction for multiple comparisons had this not been a targeted region of interest (ROI). Indeed, we acknowledge that the power of this claim, namely, no additional brain differences between the NAB group and controls, is limited by the inherent limitations of comparing an individual to a group using these particular MR structural methods. Thus, minute yet significant differences may have gone unnoticed.

To further explore structure at microscopic scale, we acquired diffusion MRI (dMRI). Although acquired using a voxel size of 2.1 × 2.1 × 2.1 mm, dMRI is sensitive to anisotropic microstructure smaller than the voxel size itself (). These data provide for white matter (WM)-like tissue fiber orientation distributions (FODs) reflecting tightly packed tracts of axons (). In controls, we observed clear FODs running the full length from primary olfactory (piriform) cortex to within the entire length of the OB ( Figure 2 A). In contrast, in NAB1 ( Figure 2 B) and NAB2 ( Figure 2 C), structure was substantially diminished, with only trace FODs, and in NAB-CA, almost all structure was lost ( Figure 2 D).

Review of structural T2-weighted MRIs revealed that the NAB group indeed had no measurable OBs (bulbar controls OB volume: left = 58.4 ± 13.1 mm, right = 57.1 ± 13.6 mm, NAB group left and right volume was zero) ( Figure 1 E). The NAB group also had a significantly shallower left olfactory sulcus (bulbar control: mean = 8.68 ± 1.05 mm, NAB1 = 2.45 mm, NAB2 = 1.65 mm, NAB-CA = 3.7 mm, all two-tailed t(17) < -4.6, all p < 0.001, all Z-CC < −4.74) (two-tailed Crawford and Howell’s modified t test, see STAR Methods ) ( Table S1 ). The right olfactory sulcus was completely absent in NAB-CA, trended toward shallower in NAB1 (bulbar control: mean = 9.05 ± 1.36 mm, NAB1 = 6.37 mm, two-tailed t(17) = −1.91, p = 0.07) but was typical in NAB2 (NAB2 = 9.6 mm, two-tailed t(17) = 0.41, p = 0.7) ( Figure 1 F). NAB-CA also had no apparent olfactory tracts, yet these were evident at T2 in NAB1 and NAB2. Reexamination of these findings at T1-weighted MRI revealed similar lack of OBs in the NAB group, yet poorer than T2 OB-border delineation in controls ( Figure S3 ). Finally, we note that the NAB group had normal epithelial structures at endoscopy (see STAR Methods ).

During MRI scanning of normosmic controls for a different study, we noticed that, in contrast to the very prominent OBs of a typical participant ( Figures 1 A, S1 , and S2 ), one 29-year-old woman (“NAB1”) had no apparent OBs ( Figures 1 B and S2 Data S1 ). To probe this serendipitous observation, we set out to recruit controls for two types of comparisons: the first was a 33-year-old woman with congenital anosmia (“NAB-CA”), who as expected in congenital anosmia (), also has no apparent OBs ( Figures 1 C and S2 ). As a second comparison for NAB1, and particularly for functional imaging, we set out to recruit a cohort of similarly aged and similarly left-handed normosmic women with intact OBs (“bulbar controls”) ( Figure S1 ). Remarkably, at the ninth control scan, we encountered an additional participant without apparent OBs (“NAB2,” age 26 years) ( Figures 1 D and S2 Data S2 ). Thus, from here on we will characterize NAB1, NAB2, and NAB-CA (“NAB group”) side by side, using imaging to compare them to bulbar controls (n = 18, left-handed women age 25.9 ± 3.1 years) ( Table S1 ), and using olfactory psychophysics to compare them to large cohorts of age-matched women.

Discussion

We found that two women without apparent OBs can nevertheless perform the basic facets of olfaction. Moreover, in a large public database we found evidence for definitely three, and possibly four, additional such women. This implies that this phenomenon, although rare, was not unique to our cohort and may be evident in ∼0.6% of women, and more particularly in ∼4.25% of left-handed women. This result may have implications for the basic and clinical neuroscience of olfaction.

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et al. The age of olfactory bulb neurons in humans. Human olfaction without apparent OBs poses two types of questions: First, is there any facet of olfaction for which intact typical human OBs are absolutely necessary? Second, how do humans achieve the olfactory facets we observed without typical intact OBs? As to the former question, one can speculate on various facets such as olfactory learning and memory, spatial olfaction, social chemosignaling, and more, that may be more significantly impaired in these individuals, yet we did not exhaustively test. Thus, here we can only concentrate on those facets that we did test and for which intact typical OBs are apparently not absolutely necessary, namely, odorant detection, discrimination, identification, and perceptual representation. How could these facets of olfaction be achieved without apparent OBs? We see five possible explanations for our results: first, a complete intact OB may have migrated in altered development to a different brain location in the NAB participants. Although we think such a large structure would have been uncovered by the voxel-based morphometry (VBM) analysis, VBM lacks power when comparing an individual to a group, and this remains a possibility. Second, and a more likely extension of the above, is that through some process of altered development, a reshaped glomerular space sufficient to support olfaction may have formed somewhere in cortex, as implied in bulbectomized mice () and rats (). This interpretation can account for our results in conjunction with current notions on olfactory coding. Third, these women may have in-place OBs that are just too tiny for us to see, even with our high-resolution scans. Although we cannot rule out this possibility, it would remain a near-equally meaningful result for the functional neuroanatomy of olfaction if humans can perform normally with OBs of ∼1.6% (i.e., 9 voxels; bulbs we are very unlikely to miss, see Figure S5 ) the volume of typical OBs. A fourth alternative is that humans somehow use trigeminal and perhaps other chemosensory nerve endings in order to compensate for their OB loss. Although we can see how this alternative can account for task performance, if it also accounts for perceptual representation, this is truly remarkable. Finally, a fifth alternative is that coding mechanisms of human olfaction differ from those in rodents, allowing for basic olfactory facets without OBs. This is consistent with three non-rodent-like aspects in human olfactory neurobiology: (1) ratio of receptor subtypes to glomeruli (), (2) placement of the OB within the brain (), and (3) lack of OB regeneration (). Our methods could not decidedly favor any particular one of the above five interpretations, and therefore we are forced to conclude in this respect that humans can retain olfaction without apparent OBs, and we don’t know how they achieve this.

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Nordin S.

Hummel T. Olfactory disorders and quality of life--an updated review. As to the implications for clinical neuroscience of olfaction, congenital anosmia is associated with a lack of OBs (). Given that missing OBs is probably an irreversible state, there has not been much effort directed at early detection of congenital anosmia, which, remarkably, is typically first diagnosed only in teens (). Indeed, why bother diagnosing anosmia early if there is nothing to be done about it? However, our observations suggest that humans can develop olfaction without apparent OBs. Assuming NAB1 and NAB2 developed olfaction through some developmental compensatory mechanisms, whether altered shaping of the olfactory system or increased capabilities of secondary chemosignaling subsystems, perhaps such compensatory mechanisms can be promoted early in life, when neural plasticity is at its highest. Currently in the West, newborns are tested for vision, audition, and more, all within the first hours or days after birth. It is perhaps time to start screening children, or perhaps even babies, using non-verbal measures of olfaction (). Early identification of reduced olfaction could then perhaps be addressed within an odor enrichment program () in the aim of triggering compensatory mechanisms such as those possibly in action in NAB1 and NAB2. This could potentially prevent the many deleterious, yet widely underappreciated, outcomes associated with anosmia ().