4.1 The piriform cortex: the first cytoarchitectonic map
The piriform cortex belongs to the paleocortex — a three-layered type of cortex, unlike the six-layered neocortex. Not until 2024 was the first cytoarchitectonic map of the human piriform produced, built on 10 post-mortem brains (20 hemispheres) Human. The map divides the medial piriform region into four areas:
- Two areas of true three-layered paleocortex, each only about 32–114 mm³ and 34–74 mm³ (extreme values across brains).
- Two areas of five-layered transitional cortex, the largest of which reaches 215–626 mm³.
The volume of each area varies two- to threefold between brains. And one finding has methodological consequences: the anatomical landmark that MRI protocols use as the anterior border of the piriform was crossed by the three-layered area in 8/20 hemispheres. This suggests that MRI protocols using this landmark may cut off part of the true piriform while also including transitional cortex.
Cross-species comparison yields an interesting scaling law Animal: across six species, the number of layer 2 neurons in the piriform increases as the 3/2 power of the number of glomeruli, and each glomerulus–neuron pair has on average almost exactly one synapse. In mice, neuron density beneath each mm² of piriform surface is about 59,000, compared with about 100,000 in neocortex; and piriform neurons do not fall into discrete transcriptomic groups as in neocortex but vary continuously. In humans there is as yet no neuron count or single-nucleus transcriptomic atlas for the piriform; the structure of its sublayers is currently inferred from rodents.
4.2 “Piriform volume” depends on the definition
For the same structure, studies report volumes differing by up to about sevenfold. Segmentation on 3T MRI (automated or combined with manual tracing) gives about 460–510 mm³ per hemisphere; manual segmentation on 7T MRI gives frontal plus temporal piriform of about 228–252 mm³ (conference abstract, n = 11); whereas the true three-layered part by histology is only about 66–188 mm³. The main cause is differing regional definitions — whether or not the endopiriform nucleus, the periamygdaloid region and transitional cortex are included — together with partial-volume effects where a thin structure lies next to cerebrospinal fluid. Overlap between automated and manual segmentation reaches a Jaccard coefficient of only 0.5 in healthy people, and lower still in patients.
Practical significance: any conclusion of the kind “the piriform is smaller in group X” is meaningful only within the same measurement protocol.
4.3 Evidence from epilepsy surgery
In animals, the piriform is a site where seizures are very readily initiated Animal. In humans, surgical evidence shows a close association: in an observational cohort of 107 temporal lobectomy patients (further validated in 31 people; only the abstract could be read), the proportion of piriform resected was strongly associated with outcome: the seizure-free group had a median of 83% of the piriform resected against 52% in the group with continuing seizures; resecting 50% or more of the piriform increased the odds of seizure freedom by about 16-fold (95% confidence interval: 5–47). The extent of resection of the hippocampus, amygdala and entorhinal cortex was not associated with outcome Human.
4.4 Other primary olfactory cortical areas
The human olfactory tubercle has been cytoarchitectonically mapped in 10 brains (conference abstract), showing striatum-like medium spiny neurons and high inter-individual variability. The amygdala has a probabilistic map of 10 subdivisions based on cytoarchitecture, supplemented by measurement of 15 neurotransmitter receptor types. Parcellation based on structural connectivity in 100 people shows the amygdala separating from the piriform, and the piriform splitting into frontal and temporal parts. But there is no standard human volume for the olfactory tubercle, the cortical nuclei of the amygdala or the part of the entorhinal cortex receiving olfactory input; and we have not found direct measurements in humans of the projections from the olfactory bulb to these areas.
4.5 The orbitofrontal cortex and the insula
The olfactory area of the orbitofrontal cortex has never had its borders defined cytoarchitectonically; it is defined only by functional activation. A 2013 coordinate meta-analysis (45 studies, 594 coordinates) did find a cluster in this region, but a 2023 meta-analysis for food odours did not — possibly because of MRI signal loss in the region next to the sinuses. Grey-matter volume in the right orbital sulcus correlates with olfactory function in 90 healthy people. A case of right orbitofrontal lesion showed loss of conscious awareness of odour while unconscious responses remained — the phenomenon of “blind smell” Human.
The insula plays a smaller olfactory role than is usually thought: on electrical stimulation of the insula, only about 1% of responses are olfactory sensations Human.
4.6 The thalamic route: for attention, not for smelling
Olfaction is famous for not needing the thalamus to reach the cortex. But there is still a second route through the mediodorsal thalamus to the orbitofrontal cortex. Human evidence is limited, but suggests that this route serves attention rather than perception:
- In a sample of 6 patients with mediodorsal thalamic lesions, sensitivity, discrimination, naming, recognition and pleasantness ratings were normal, but attention to odours was impaired; another sample of 4 patients confirmed the attentional impairment Human.
- In fMRI in 12 people, when attending to odours, effective connectivity from the mediodorsal thalamus to the orbitofrontal cortex increased (parameter 0.033 versus −0.006 when attending to sounds), and the indirect route via the thalamus was modulated more strongly than the direct route Human.
Note: all human data on mediodorsal thalamic lesions taken together amount to only about 10 cases, and another study reported impairment of discrimination, identification and pleasantness ratings as well.
4.7 Tractography: a weak tool for small structures
Reconstructing axonal pathways with diffusion MRI faces major difficulties in the olfactory system because the structures are very small. Three examples: the medial olfactory stria is not a stable white-matter bundle when compared against post-mortem dissection; a connection “to the thalamus” is found in 88–94% of people but disappears when only grey-matter regions are used as seed points; and one study failed to reconstruct the anterior commissure whereas multi-shell protocols succeeded. Conclusion: olfactory connectivity diagrams built from tractography in humans should be read as hypotheses, not as maps.
4.8 Laterality: how true is “right-hemisphere dominance”?
| Structure / measure | Direction | Notes |
|---|---|---|
| Orbitofrontal cortex (PET 1992; a single lesion case; volume correlation n = 90) | Right dominant | The most consistent evidence |
| Insula (lesions) | Left dominant | Olfactory impairment after left lesions 6/7, after right lesions 2/8 |
| Temporal lobectomy (31 patients) | No difference | Identification impaired equally whichever side was resected |
| Piriform volume | Conflicting | Right larger by 17.7%; by about 5%; left larger; on histology, one three-layered area lateralised to the right at uncorrected level, the other areas not lateralised |
| Tractography | Both directions | Piriform–thalamus pathway lateralised left, piriform–orbitofrontal lateralised right |
| fMRI with unilateral nasal stimulation (non-peer-reviewed preprint) | Complex | Temporal piriform bilateral; frontal piriform right only; entorhinal left only |
In brief: olfactory laterality depends on the region and is not a general property of the system. People with defects of interhemispheric connection show the role of the pathways linking the two sides: 3/6 people could not localise which nostril an odour came from. In the anterior commissure — a pathway between the two hemispheres — the largest group of fibres in humans comes from the inferior temporal lobe, with targets including the amygdala; we have not found a direct measurement of its olfactory component in humans.
4.9 Ageing, Alzheimer’s disease and COVID-19
- Tau, not amyloid. In 155 people with tau PET scans, tau explained decline in odour identification even after adjustment for amyloid (T = 2.80; p = 0.006); a spreading model showed tau moving from the medial temporal lobe into the olfactory system. Tau in the piriform was already elevated in cognitively normal amyloid-positive people, rose further in mild cognitive impairment and Alzheimer’s disease, but did not rise in Parkinson’s disease Human.
- The olfactory bulb in Alzheimer’s disease. A meta-analysis of 6 studies found clearly smaller olfactory bulb volume (Hedges g = −1.21), but with high heterogeneity (I² = 88%). For primary olfactory cortex there are only 3 independent samples — not enough to pool.
- A warning about atlas labels. Many ageing studies use the region labelled “olfactory” in a popular atlas; this region may not coincide with the true piriform, so conclusions based on it should be read with caution.
- COVID-19. In 785 people scanned twice (401 infected cases, 384 controls), the infected group lost an additional ~0.7% of grey matter in olfaction-related regions, and 1.3–1.8% in the parahippocampal and entorhinal regions; this study did not separate the olfactory bulb or piriform Human.
A monograph compiled from 259 sourced facts collected under a common protocol. Practical-implication sections are the compilers’ inferences. Diagrams are newly drawn from published data. Scientific reference material, not medical advice.