Central olfactory pathways (i.e., projection axons of the mitral and tufted cells), and especially olfactory striae, lack common terminology. This is due to their high degree of intra- and interindividual variability, which has been studied in detail over the past century by Beccari, Mutel, Klass, Erhart, and more recently, by Duque Parra et al. These variations led to some confusion about their number and anatomical arrangement. Recent advances in fiber tractography have enabled the precise in vivo visualization of human olfactory striae and the study of their projections. However, these studies require their algorithms to be set up according to the presumed anatomy of the analyzed fibers. A more precise definition of the olfactory striae is therefore needed, not only to allow a better analysis of the results but also to ensure the quality of the data obtained. By studying the various published works on the central olfactory pathways from the first systematic description by Soemmerring to the present, I have traced the different discussions on the olfactory tracts and summarized them here. This review adopts a systematic approach by addressing each stria individually and tracing the historical background of what was known about it in the past, compared to the current knowledge. The chronological and organized approach used provides a better understanding of the anatomy of these essential structures of the olfactory system.

The olfactory centres are the evolutionary oldest and most conservative area of the telencephalon. Olfactory deficiencies are involved in a large spectrum of neurologic disorders and neurodegenerative diseases. The growing interest in human olfaction has been also been driven by COVID-19-induced transitional anosmia. Nevertheless, recent data on the human olfactory centres concerning normal histology and morphogenesis are rare. Published data in the field are mainly restricted to classic studies with non-uniform nomenclature and varied definitions of certain olfactory areas. While the olfactory system in model animals (rats, mice, and more rarely non-human primates) has been extensively investigated, the developmental timetable of olfactory centres in both human prenatal and postnatal ontogeny are poorly understood and unsystemised, which complicates the process of analysing human material, including medical researches. The main purpose of this review is to provide and discuss relevant morphological data on the normal ontogeny of the human olfactory centres, with a focus on the timetable of maturation and developmental cytoarchitecture, and with special reference to the definitions and terminology of certain olfactory areas.

Background: Olfactory functional magnetic resonance imaging (fMRI) of responses to a pleasant odor (PO) (lavender) can objectively evaluate olfactory dysfunction in Alzheimer\'s disease (AD) patients. The brain responses to a PO and unpleasant odor (UPO) were shown to differ in normal young people. Whether AD patients with olfactory dysfunction have the same brain response is not yet known. Objective: Our aim was to explore whether olfactory fMRI with both a PO and UPO can provide more information regarding olfactory impairment in AD than a PO alone. Methods: Twenty-five normal controls (NC), 26 individuals with mild cognitive impairment (MCI), and 22 AD patients underwent olfactory fMRI with lavender and pyridine odorants at three concentrations (0.10, 0.33, and 1.00%) with a 3.0-T MRI scanner. Results: There were no differences in the number of activated voxels in the primary olfactory cortex (POC) between PO and UPO conditions in the NC, MCI, and AD groups (SPM, paired t-test, uncorrected p < 0.001, extent threshold = 70). In the right inferior frontal gyrus, orbital part (F3O), the number of activated voxels was greater with the UPO than with the PO in the NC group (SPM, paired t-test, uncorrected p < 0.001, extent threshold = 70), but there were no differences in the MCI and AD groups. Regardless of PO or UPO conditions, there were significant differences in the number of activated voxels in the POC among the NC, MCI, and AD groups. With increasing odor concentration, the number of activated voxels in the POC decreased in the NC group but increased in the AD group. When 0.10% UPO was presented, the NC group (21/25) showed a lower breathing amplitude and shorter inhalation time, whereas the AD patients (0/22) did not show such changes in breathing. Conclusions: After PO and UPO inhalation, brain activation and respiratory behavior in AD patients were significantly different than in NC patients. Therefore, olfactory fMRI using both PO and UPO stimulation, compared with PO stimulation only, can provide more objective information regarding hyposmia associated with AD based on imaging and behavior.

Olfactory dysfunction is often the earliest indicator of disease in a range of neurological and psychiatric disorders. One tempting working hypothesis is that pathological changes in the peripheral olfactory system where the body is exposed to many adverse environmental stressors may have a causal role for the brain alteration. Whether and how the peripheral pathology spreads to more central brain regions may be effectively studied in rodent models, and there is successful precedence in experimental models for Parkinson\'s disease. It is of interest to study whether a similar mechanism may underlie the pathology of psychiatric illnesses, such as schizophrenia. However, direct comparison between rodent models and humans includes challenges under light of comparative neuroanatomy and experimental methodologies used in these two distinct species. We believe that neuroimaging modality that has been the main methodology of human brain studies may be a useful viewpoint to address and fill the knowledge gap between rodents and humans in this scientific question. Accordingly, in the present review article, we focus on brain imaging studies associated with olfaction in healthy humans and patients with neurological and psychiatric disorders, and if available those in rodents. We organize this review article at three levels: 1) olfactory bulb (OB) and peripheral structures of the olfactory system, 2) primary olfactory cortical and subcortical regions, and 3) associated higher-order cortical regions. This research area is still underdeveloped, and we acknowledge that further validation with independent cohorts may be needed for many studies presented here, in particular those with human subjects. Nevertheless, whether and how peripheral olfactory disturbance impacts brain function is becoming even a hotter topic in the ongoing COVID-19 pandemic, given the risk of long-term changes of mental status associated with olfactory infection of SARS-CoV-2. Together, in this review article, we introduce this underdeveloped but important research area focusing on its implications in neurological and psychiatric disorders, with several pioneered publications.

Olfactory decline is an early symptom of Alzheimer\'s disease (AD) and is a predictor of conversion from mild cognitive impairment (MCI) to AD. Olfactory decline could reflect AD-related atrophy of structures related to the sense of smell. The aim of this study was to verify whether the presence of a clinical diagnosis of AD or MCI is associated with a volumetric decrease in the olfactory bulbs (OB) and the primary olfactory cortex (POC). We conducted two systematic reviews, one for each region and a meta-analysis. We collected articles from PsychNet, PubMed, Ebsco, and ProQuest databases. Results showed large and heterogeneous effects indicating smaller OB volumes in patients with AD (k = 6, g = -1.21, 95% CI [-2.19, -0.44]) and in patients with MCI compared to controls. There is also a trend for smaller POC in patients with AD or MCI compared to controls. Neuroanatomical structures involved in olfactory processing are smaller in AD and these volumetric reductions could be measured as early as the MCI stage.

The olfactory involvement is an early feature of Alzheimer\'s disease (AD). Olfactory functional MRI (fMRI) is an objective method to evaluate the olfactory function, but might be affected by the individual variation and the magnetic susceptibility artifact of basis cranii. To improve the reliability of olfactory fMRI, we explored the response of primary olfactory cortex (POC) across three different concentrations of odors. Fourty-four normal controls, 46 subjects with mild cognitive impairment (MCI), and 44 patients with AD underwent olfactory fMRI using lavender stimuli of three different (0.10, 0.33, and 1.00%) concentrations during one fMRI sequence with a 3.0T MRI scanner. The numbers of activated voxels in the POC, especially the activation changes during different concentrations were, analyzed. The POC activation pattern of controls showed olfactory adaptation at the higher concentration, whereas the AD patients showed not only increased olfactory threshold but also a lack of olfactory habituation. Five types of activation patterns across different concentrations were summarized to evaluate the olfactory function. The results showed that the activation pattern effectively found 40/44 (90.9%) of the ADs with impaired habituation, whereas 31/44 (70.5%) of the normal controls showed normal olfactory habituation. In MCIs, 29/46 (63.0%) of subjects showed impaired habituation. This finding indicates that the POC activation pattern of olfactory fMRI across different concentrations is useful in evaluating the olfactory function, which is important in the detection of early AD among MCI cases.

The central processing pathways of the human olfactory system are not fully understood. The olfactory bulb projects directly to a number of cortical brain structures, but the distinct networks formed by projections from each of these structures to the rest of the brain have not been well-defined. Here, we used functional magnetic resonance imaging and k-means clustering to parcellate human primary olfactory cortex into clusters based on whole-brain functional connectivity patterns. Resulting clusters accurately corresponded to anterior olfactory nucleus, olfactory tubercle, and frontal and temporal piriform cortices, suggesting dissociable whole-brain networks formed by the subregions of primary olfactory cortex. This result was replicated in an independent data set. We then characterized the unique functional connectivity profiles of each subregion, producing a map of the large-scale processing pathways of the human olfactory system. These results provide insight into the functional and anatomical organization of the human olfactory system.

Recent brain connectome studies have evidenced distinct and overlapping brain regions involved in processing olfactory perception. However, neural correlates of hypo- or anosmia in olfactory disorder patients are poorly known. Furthermore, the bottom-up and top-down processing of olfactory perception have not been well-documented, resulting in difficulty in locating the disease foci of olfactory disorder patients. The primary aim of this study is to characterize the bottom-up process of the neural dynamics across peripheral and central brain regions in anesthetized mice. We particularly focused on the neural oscillations of local field potential (LFP) in olfactory epithelium (OE), olfactory blub (OB), prefrontal cortex (PFC), and hippocampus (HC) during an olfactory oddball paradigm in urethane anesthetized mice. Odorant presentations evoked neural oscillations across slow and fast frequency bands including delta (1-4 Hz), theta (6-10 Hz), beta (15-30 Hz), low gamma (30-50 Hz), and high gamma (70-100 Hz) in both peripheral and central nervous systems, and the increases were more prominent in the infrequently presented odorant. During 5 s odorant exposures, the oscillatory responses in power were persistent in OE, OB, and PFC, whereas neural oscillations of HC increased only for short time at stimulus onset. These oscillatory responses in power were insignificant in both peripheral and central regions of the ZnSO4-treated anosmia model. These results suggest that olfactory stimulation induce LFP oscillations both in the peripheral and central nervous systems and suggest the possibility of linkage of LFP oscillations in the brain to the oscillations in the peripheral olfactory system.

The prepiriform cortex is a part of the phylogenetically oldest pallial division (paleocortex) representing the primary olfactory cortex. While olfactory centers in laboratory animals have been extensively investigated, the developmental timetable of the human prepiriform area is poorly understood. Thus, in the present study we aim to examine the prepiriform cortex in human fetuses from eight postconceptional weeks to birth. Based on cytoarchitecture and immunohistochemistry analysis (NeuN-, SYP-, NSE-, TH-, GFAP-, MBP-) four main periods of the prepiriform cortex fetal development are suggested: the beginning of prefetal stage (the eighth week from conception), the period from the ending of prefetal stage (9-12 postconceptional weeks) to 17 weeks of gestation, 18-27 weeks of gestation and the late fetal period (29-40 gestational weeks). We found that the initial layer differentiation took place before the ninthtenth weeks from conception and by ten weeks the paleocortical plate of the prepiriform cortex was shaped. Both total cell density and NeuN-immunoreactive cell density peaked in the early fetuses and started to decrease after 17 gestational weeks, attaining intermediate values at 18-27 weeks and becoming significantly lower in the late fetuses. In contrast, the NeuN-immunoreactive cell ratio gradually increased over the whole examined period. The prepiriform cortex was defined as approaches the state at birth at 30 gestational weeks. The same developmental periods were observed with SYP- and NSE-assays. No significant distribution of TH immunoreactivity was described in the prepiriform cortex of human fetuses. The prior paleocortex development was demonstrated using glial markers: GFAPimmunoreactivity appeared in the prepiriform cortex at the middle of the early fetal period, ahead of the neocortex and insular cortex. The earlier rates of GFAP-immunoreactivity expansion in the prepiriform cortex, as compared to other pallial regions, persisted in the later fetuses. The first MBP-immunoreactive fibres within pallium were detected in the lateral olfactory tract at 30 weeks. Therefore, the prepiriform cortex approaches a level of maturation similar to that at birth already at the beginning of the late fetal period and matures prior to other pallial regions.

Autism Spectrum Disorder is characterized by sensory anomalies including impaired olfactory identification. Between 5 and 46 percent of individuals with autism have a clinical diagnosis of epilepsy. Primary olfactory cortex (piriform cortex) is central to olfactory identification and is an epileptogenic structure. Cytoarchitectural changes in olfactory cortex may underlie olfactory differences seen in autism. Primary olfactory cortex was sampled from 17 post-mortem autism cases with and without epilepsy, 11 epilepsy cases without autism and 11 typically developed cases. Stereological and neuropathological methods were used to quantify glial, pyramidal and non-pyramidal cell densities in layers of the piriform as well as identify pathological differences in this area and its neighbouring region, the olfactory tubercle. We found increased layer II glial cell densities in autism with and without epilepsy, which were negatively correlated with age and positively correlated with levels of corpora amylacea in layer I. These changes were also associated with greater symptom severity and did not extend to the olfactory tubercle. Glial cell organization may follow an altered trajectory of development with age in autism. The findings are consistent with other studies implicating increased glial cells in the autism brain. Altered cytoarchitecture may contribute to sensory deficits observed in affected individuals. This study provides evidence that autism is linked to alterations in the cytoarchitectural structure that underlies primary sensory processes and is not restricted to heteromodal (\"higher\") cognitive centers.