Tau propagation in the brain olfactory circuits is associated with smell perception changes in aging.

The direct access of olfactory afferents to memory-related cortical systems has inspired theories about the role of the olfactory pathways in the development of cortical neurodegeneration in Alzheimer's disease (AD). In this study, we used baseline olfactory identification measures with longitudinal flortaucipir and PiB PET, diffusion MRI of 89 cognitively normal older adults (73.82 ± 8.44 years; 56% females), and a transcriptomic data atlas to investigate the spatiotemporal spreading and genetic vulnerabilities of AD-related pathology aggregates in the olfactory system. We find that odor identification deficits are predominantly associated with tau accumulation in key areas of the olfactory pathway, with a particularly strong predictive power for longitudinal tau progression. We observe that tau spreads from the medial temporal lobe structures toward the olfactory system, not the reverse. Moreover, we observed a genetic background of odor perception-related genes that might confer vulnerability to tau accumulation along the olfactory system.

Tractography indicates lateralized differences between trigeminal and olfactory pathways.

Odorous sensations are based on trigeminal and olfactory perceptions. Both trigeminal and olfactory stimuli generate overlapping as well as distinctive activations in the olfactory cortex including the piriform cortex. Orbitofrontal cortex (OFC), an integrative center for all senses, is directly activated in the presence of olfactory stimulations. In contrast, the thalamus, a very important midbrain structure, is not directly activated in the presence of odors, but rather acts as a relay for portions of olfactory information between primary olfactory cortex and higher-order processing centers. The aims of the study were (1) to examine the number of streamlines between the piriform cortex and the OFC and also between the piriform cortex and the thalamus and (2) to explore potential correlations between these streamlines and trigeminal and olfactory chemosensory perceptions. Thirty-eight healthy subjects were recruited for the study and underwent diffusion MRI using a 3T MRI scanner with 67 diffusion directions. ROIs were adapted from two studies looking into olfaction in terms of functional and structural properties of the olfactory system. The "waytotal number" was used which corresponds to number of streamlines between two regions of interests. We found the number of streamlines between the piriform cortex and the thalamus to be higher in the left hemisphere, whereas the number of streamlines between the piriform cortex and the OFC were higher in the right hemisphere. We also found streamlines between the piriform cortex and the thalamus to be positively correlated with the intensity of irritating (trigeminal) odors. On the other hand, streamlines between the piriform cortex and the OFC were correlated with the threshold scores for these trigeminal odors. This is the first studying the correlations between streamlines and olfactory scores using tractography. Results suggest that different chemosensory stimuli are processed through different networks in the chemosensory system involving the thalamus.

Extensive Connections of the Canine Olfactory Pathway Revealed by Tractography and Dissection.

The olfactory sense of the domestic dog is widely recognized as being highly sensitive with a diverse function; however, little is known about the structure of its olfactory system. This study examined a cohort of mixed-sex mesaticephalic canines and used diffusion tensor imaging (DTI), an MRI technique, to map connections from the olfactory bulb to other cortical regions of the brain. The results were validated using the Klingler dissection method. An extensive pathway composed of five white matter tracts connecting to the occipital lobe, cortical spinal tract, limbic system, piriform lobe, and entorhinal pathway was identified. This is the first documentation of a direct connection between the olfactory bulb and occipital lobe in any species and is a step toward further understanding how the dog integrates olfactory stimuli into their cognitive function.SIGNIFICANCE STATEMENT The highly sensitive olfactory system of the domestic dog is largely unexplored. We applied diffusion tractography and dissection techniques to evaluate the white matter connections associated with the olfactory system in a large cohort of dogs. We discovered an extensive white matter network extending from the olfactory bulb to form novel connections directly to other cortices of the brain. This is the first documentation of these novel olfactory connections and provides new insight into how dogs integrate olfactory stimuli in their cognitive functioning.

Changes in Peripheral Olfactory Pathways in Rheumatoid Arthritis.

OBJECTIVES: We investigated olfactory bulb (OB) volumes and olfactory sulcus (OS) depths in patients with rheumatoid arthritis (RA). METHODS: In this retrospective study, cranial magnetic resonance images of 68 adult patients were included. Group 1 consisted of 34 adult patients with RA. The control group (group 2) consisted of 34 adult patients without RA. In both groups, peripheral odor pathways (OB volumes and OS depths) were measured by magnetic resonance imaging. RESULTS: Our results showed that the OB volumes of the RA group were significantly lower than those in the control group bilaterally (P < 0.05). In each of the RA and control groups, the OS depth of the right side was found to be significantly higher than those on the left side (P < 0.05). On the left side, OS depth values of RA patients who used biological agents were significantly higher than those RA patients who did not use biological agents (P < 0.05). Correlation tests showed that there were positive correlations between OB volumes and OS depths bilaterally. In older patients with RA, bilateral OS depth values were decreased (P < 0.05). CONCLUSIONS: Our study has shown that the peripheral olfactory pathways in patients with RA can be affected to a degree that is reflected in anatomical measurements. The use of biological agents contributes to the protection of odor functions to a certain extent. The importance of evaluating the sense of smell in patients with RA clinically and radiologically should be emphasized.

Cellular bases of olfactory circuit assembly revealed by systematic time-lapse imaging.

Neural circuit assembly features simultaneous targeting of numerous neuronal processes from constituent neuron types, yet the dynamics is poorly understood. Here, we use the Drosophila olfactory circuit to investigate dynamic cellular processes by which olfactory receptor neurons (ORNs) target axons precisely to specific glomeruli in the ipsi- and contralateral antennal lobes. Time-lapse imaging of individual axons from 30 ORN types revealed a rich diversity in extension speed, innervation timing, and ipsilateral branch locations and identified that ipsilateral targeting occurs via stabilization of transient interstitial branches. Fast imaging using adaptive optics-corrected lattice light-sheet microscopy showed that upon approaching target, many ORN types exhibiting "exploring branches" consisted of parallel microtubule-based terminal branches emanating from an F-actin-rich hub. Antennal nerve ablations uncovered essential roles for bilateral axons in contralateral target selection and for ORN axons to facilitate dendritic refinement of postsynaptic partner neurons. Altogether, these observations provide cellular bases for wiring specificity establishment.

Some like it, some do not: behavioral responses and central processing of olfactory-trigeminal mixture perception.

Exploring the potential of eucalyptol as a masking agent for aversive odors, we found that eucalyptol masks the olfactory but not the trigeminal sensation of ammonia in a previous study. Here, we further investigate the processing of a mixture consisting of eucalyptol and ammonia, two olfactory-trigeminal stimuli. We presented the two pure odors and a mixture thereof to 33 healthy participants. The nostrils were stimulated alternately (monorhinal application). We analyzed the behavioral ratings (intensity and pleasantness) and functional brain images. First, we replicated our previous finding that, within the mixture, the eucalyptol component suppressed the olfactory intensity of the ammonia component. Second, mixture pleasantness was rated differently by participants depending on which component dominated their mixture perception. Approximately half of the volunteers rated the eucalyptol component as more intense and evaluated the mixture as pleasant (pleasant group). The other half rated the ammonia component as more intense and evaluated the mixture as unpleasant (unpleasant group). Third, these individual differences were also found in functional imaging data. Contrasting the mixture either to eucalyptol or to both single odors, neural activation was found in the unpleasant group only. Activation in the anterior insula and SII was interpreted as evidence for an attentional shift towards the potentially threatening mixture component ammonia and for trigeminal enhancement. In addition to insula and SII, further regions of the pain matrix were involved when assessing all participant responses to the mixture. Both a painful sensation and an attentional shift towards the unpleasant mixture component complicates the development of an efficient mask because a pleasant perception is an important requirement for malodor coverage.

Volumetric analysis and morphological assessment of the ascending olfactory pathway in an elasmobranch and a teleost using diceCT.

The size (volume or mass) of the olfactory bulbs in relation to the whole brain has been used as a neuroanatomical proxy for olfactory capability in a range of vertebrates, including fishes. Here, we use diffusible iodine-based contrast-enhanced computed tomography (diceCT) to test the value of this novel bioimaging technique for generating accurate measurements of the relative volume of the main olfactory brain areas (olfactory bulbs, peduncles, and telencephalon) and to describe the morphological organisation of the ascending olfactory pathway in model fish species from two taxa, the brownbanded bamboo shark Chiloscyllium punctatum and the common goldfish Carassius auratus. We also describe the arrangement of primary projections to the olfactory bulb and secondary projections to the telencephalon in both species. Our results identified substantially larger olfactory bulbs and telencephalon in C. punctatum compared to C. auratus (comprising approximately 5.2% vs. 1.8%, and 51.8% vs. 11.8% of the total brain volume, respectively), reflecting differences between taxa, but also possibly in the role of olfaction in the sensory ecology of these species. We identified segregated primary projections to the bulbs, associated with a compartmentalised olfactory bulb in C. punctatum, which supports previous findings in elasmobranch fishes. DiceCT imaging has been crucial for visualising differences in the morphological organisation of the olfactory system of both model species. We consider comparative neuroanatomical studies between representative species of both elasmobranch and teleost fish groups are fundamental to further our understanding of the evolution of the olfactory system in early vertebrates and the neural basis of olfactory abilities.

The human olfactory system in two proteinopathies: Alzheimer's and Parkinson's diseases.

Alzheimer's and Parkinson's diseases are the most prevalent neurodegenerative disorders. Their etiologies are idiopathic, and treatments are symptomatic and orientated towards cognitive or motor deficits. Neuropathologically, both are proteinopathies with pathological aggregates (plaques of amyloid-ß peptide and neurofibrillary tangles of tau protein in Alzheimer's disease, and Lewy bodies mostly composed of α-synuclein in Parkinson's disease). These deposits appear in the nervous system in a predictable and accumulative sequence with six neuropathological stages. Both disorders present a long prodromal period, characterized by preclinical signs including hyposmia. Interestingly, the olfactory system, particularly the anterior olfactory nucleus, is initially and preferentially affected by the pathology. Cerebral atrophy revealed by magnetic resonance imaging must be complemented by histological analyses to ascertain whether neuronal and/or glial loss or neuropil remodeling are responsible for volumetric changes. It has been proposed that these proteinopathies could act in a prion-like manner in which a misfolded protein would be able to force native proteins into pathogenic folding (seeding), which then propagates through neurons and glia (spreading). Existing data have been examined to establish why some neuronal populations are vulnerable while others are resistant to pathology and to what extent glia prevent and/or facilitate proteinopathy spreading. Connectomic approaches reveal a number of hubs in the olfactory system (anterior olfactory nucleus, olfactory entorhinal cortex and cortical amygdala) that are key interconnectors with the main hubs (the entorhinal-hippocampal-cortical and amygdala-dorsal motor vagal nucleus) of network dysfunction in Alzheimer's and Parkinson's diseases.

Chemical intolerance: involvement of brain function and networks after exposure to extrinsic stimuli perceived as hazardous.

BACKGROUND: Chemical intolerance (CI) is a chronic condition characterized by recurring and severe symptoms triggered by exposure to low levels of odorous or pungent substances. The etiology of CI has been a controversial subject for a long time. The aim of this review is to summarize findings on the neurological processing of sensory information during and after exposure to low levels of odorous or pungent substances in individuals with CI, focusing on the brain function and networks. METHODS: Scientific studies on CI published between 2000 and 2019 in academic peer-reviewed journals were systematically searched using medical and scientific literature databases. Only peer-reviewed articles reporting original research from experimental human studies directly associated with CI, and involving related neurological responses or brain imaging after exposure to odorous or pungent substances (i.e., in chemical provocation tests), were considered. RESULTS: Forty-seven studies were found to be eligible for a full-text review. Twenty-three studies met the selection criteria and were included in this review. Evidence indicated that differences between subjects with CI and healthy controls were observed by brain imaging during and after exposure to odorous or pungent substances. Differences in brain imaging were also observed between initial exposure and after exposure to these substances. Neurological processing of sensory information after exposure to extrinsic stimuli in the limbic system and related cortices were altered in subjects with CI. A previous documentable exposure event was likely to be involved in this alteration. CONCLUSIONS: This review documents consistent evidence for the altered neurological processing of sensory information in individuals with CI. Further neurophysiological research exploring the processing of extrinsic stimuli and cognition of sensation through the limbic system and related cortices in CI, and the appearance of symptoms in individuals with CI, are required.

The Impact of Acoustic fMRI-Noise on Olfactory Sensitivity and Perception.

Sensory perception is neither static nor simple. The senses influence each other during multisensory stimulation and can be both suppressive and super-additive. As most knowledge of human olfactory perception is derived from functional neuroimaging studies, in particular fMRI, our current understanding of olfactory perception has systematically been investigated in an environment with concurrent loud sounds. To date, the confounding effects of acoustic fMRI-noise during scanning on olfactory perception have not yet been investigated. In this study we investigate how acoustic noise derived from the rapid switching of MR gradient coils, affects olfactory perception. For this, 50 subjects were tested in both a silent setting and an fMRI-noise setting, in a randomised order. We found that fMRI-related acoustic noise had a significant negative effect on the olfactory detection threshold score. No significant effects were identified on olfactory discrimination, identification, identification certainty, hedonic rating, or intensity rating.

FMRI correlates of olfactory processing in typically-developing school-aged children.

Human olfactory processing is understudied relative to other sensory modalities, despite its links to neurodevelopmental and neurodegenerative disorders. To address this limitation, we developed a fast, robust fMRI odor paradigm that is appropriate for all ages and levels of cognitive functioning. To test this approach, thirty-four typically developing children aged 7-12 underwent fMRI during brief, repeated exposure to phenylethyl alcohol, a flower-scented odor. Prior to fMRI scanning, olfactory testing (odor detection and identification) was conducted. During fMRI stimulus presentation, odorant release was synchronized to each participant's inspiratory phase to ensure participants were inhaling during the odorant exposure. Between group differences and correlations between activation and odor detection threshold scores were tested using the FMRIB Software Library. Results demonstrated that our 2-min paradigm significantly activated primary and secondary olfactory regions. In addition, a significant relationship between odor detection threshold and higher activation in the right amygdala and lower activation in the left frontal, insular, occipital, and cerebellar regions was observed, suggesting that this approach is sensitive to individual differences in olfactory processing. These findings demonstrate the feasibility of studying olfactory function in children using brain imaging techniques.

Pepper with and without a sting: Brain processing of intranasal trigeminal and olfactory stimuli from the same source.

Humans have distinct and overlapping brain regions for the processing of intranasal olfactory or trigeminal stimuli. It may be assumed that trigeminal stimulants and "trigeminal-free" odorous stimuli from the same source are processed differently in the human brain. Using functional magnetic resonance imaging (fMRI), this study investigated the question whether the black pepper (Piper nigrum) derived trigeminal active compound piperine and the trigeminal-free pepper essential oil (pepperEO) are processed in relation to their degree of trigeminal stimulation. Twenty-one young healthy adults underwent a fMRI scan where piperine and pepperEO were delivered orthonasally using an olfactometer. Ratings for intensity, irritability, and pleasantness of each stimulus were obtained at the end of the scanning session. Results showed brain activation of the trigeminal network in response to piperine, and olfactory-related areas in response to pepperEO. PepperEO induced larger activations in the trigeminal network as compared to piperine. This was possibly due to the associative learning for the pungent sensations of pepperEO. In addition, conjunction analyses showed that the secondary somatosensory area, insula, and thalamus were involved in the processing of both piperine and pepperEO. In conclusion, the results strongly suggest that the cerebral representations of trigeminal irritants can be evoked by learned associations.

Evaluation of idiopathic olfactory loss with chemosensory event-related potentials and magnetic resonance imaging.

BACKGROUND: Idiopathic olfactory loss (IOL) accounts for a sizable fraction of olfactory dysfunction, but very little is known about its etiology and electrophysiological changes in the olfactory pathway. METHODS: We analyzed the physiology of IOL using chemosensory event-related potentials (ERPs) (olfactory and trigeminal: oERP and tERP) and olfactory pathway magnetic resonance imaging (MRI) measured in adult patients with IOL and healthy controls. Subjective olfactory function was measured by Toyota and Takagi (T&T) olfactometry and Sniffin' Sticks (SS). RESULTS: Olfactory function was worse in patients with IOL compared to controls (T&T, p < 0.001; SS, p < 0.001). oERPs could be evoked in 17 IOL patients. Signals in these patients showed lower amplitude in the N1 and P2 waves than controls (p < 0.05 for both), but there were no difference in latency between the 2 groups (p > 0.05). tERP were detected in all patients and controls; there were no differences in latency and nor amplitude between the 2 groups (p > 0.05). The olfactory bulb (OB) volume was significantly smaller in the IOL group than controls (p < 0.001), but there was no difference in the olfactory sulcus depth between groups (p > 0.05). Better olfactory function was associated with increasing magnitude of N1 amplitude in oERPs (p < 0.05) and increasing OB volume (p < 0.05). CONCLUSION: IOL patients show neurophysiologic deficits and some anatomic differences compared to healthy controls.

Severity of olfactory deficits is reflected in functional brain networks-An fMRI study.

Even though deficits in olfactory function affect a considerable part of the population, the neuronal basis of olfactory deficits remains scarcely investigated. To achieve a better understanding of how smell loss affects neural activation patterns and functional networks, we set out to investigate patients with olfactory dysfunction using functional magnetic resonance imaging (fMRI) and olfactory stimulation. We used patients' scores on a standardized olfactory test as continuous measure of olfactory function. 48 patients (mean olfactory threshold discrimination identification (TDI) score = 16.33, SD = 6.4, range 6 - 28.5) were investigated. Overall, patients showed piriform cortex activation during odor stimulation compared to pure sniffing. Group independent component analysis indicated that the recruitment of three networks during odor stimulation was correlated with olfactory function: a sensory processing network (including regions such as insula, thalamus and piriform cortex), a cerebellar network and an occipital network. Interestingly, recruitment of these networks during pure sniffing was related to olfactory function as well. Our results support previous findings that sniffing alone can activate olfactory regions. Extending this, we found that the severity of olfactory deficits is related to the extent to which neural networks are recruited both during olfactory stimulation and pure sniffing. This indicates that olfactory deficits are not only reflected in changes in specific olfactory areas but also in the recruitment of occipital and cerebellar networks. These findings pave the way for future investigations on whether characteristics of these networks might be of use for the prediction of disease prognosis or of treatment success.

Anatomy, Functionality, and Neuronal Connectivity with Manganese Radiotracers for Positron Emission Tomography.

PURPOSE: Manganese ion has been extensively used as a magnetic resonance imaging (MRI) contrast agent in preclinical studies to assess tissue anatomy, function, and neuronal connectivity. Unfortunately, its use in human studies has been limited by cellular toxicity and the need to use a very low dose. The much higher sensitivity of positron emission tomography (PET) over MRI enables the use of lower concentrations of manganese, potentially expanding the methodology to humans. PROCEDURES: PET tracers manganese-51 (Mn-51, t1/2 = 46 min) and manganese-52 (Mn-52, t1/2 = 5.6 days) were used in this study. The biodistribution of manganese in animals in the brain and other tissues was studied as well as the uptake in the pancreas after glucose stimulation as a functional assay. Finally, neuronal connectivity in the olfactory pathway following nasal administration of the divalent radioactive Mn-52 ([52Mn]Mn2+) was imaged. RESULTS: PET imaging with the divalent radioactive Mn-51 ([51Mn]Mn2+) and [52Mn]Mn2+ in both rodents and monkeys demonstrates that the accumulation of activity in different organs is similar to that observed in rodent MRI studies following systemic administration. Furthermore, we demonstrated the ability of manganese to enter excitable cells. We followed activity-induced [51Mn]Mn2+ accumulation in the pancreas after glucose stimulation and showed that [52Mn]Mn2+ can be used to trace neuronal connections analogous to manganese-enhanced MRI neuronal tracing studies. CONCLUSIONS: The results were consistent with manganese-enhanced MRI studies, despite the much lower manganese concentration used for PET (100 mM Mn2+ for MRI compared to ~ 0.05 mM for PET). This indicates that uptake and transport mechanisms are comparable even at low PET doses. This helps establish the use of manganese-based radiotracers in both preclinical and clinical studies to assess anatomy, function, and connectivity.

fMRI-based Neuronal Response to New Odorants in the Newborn Brain.

The sense of smell is one of the oldest and the most primitive senses mammals possess, it helps to evaluate the surrounding environment. From birth, smell is an important sensory modality, highly relevant for neonatal behavioral adaptation. Even though human newborns seem to be able to perceive and react to olfactory stimuli, there is still a lack of knowledge about the ontogeny of smell and the underlying central processing involved in odor perception in newborns. Brain networks involved in chemosensory perception of odorants are well described in adults, however in newborns there is no evidence that central olfaction is functional given the largely unmyelinated neonatal central nervous system. To examine this question, we used functional magnetic resonance imaging (fMRI) in the newborn to characterize cortical response to olfactory and trigeminal odorants. Here we show that brain response to odors can be measured and localized using functional MRI in newborns. Furthermore, we found that the developing brain, only few days after birth, processes new artificial odorants in similar cortical areas than adults, including piriform cortex, orbitofrontal cortex and insula. Our work provides evidence that human olfaction at birth relies on brain functions that involve all levels of the cortical olfactory system.

Structural anomalies of the peripheral olfactory system in psychosis high-risk subjects.

BACKGROUND: Olfactory impairments are prominent in both schizophrenia and the preceding at-risk state. Their presence prior to illness predicts poor functional outcome. In schizophrenia, these impairments reflect peripheral olfactory structural abnormalities, which are hypothesized to arise during early embryonic development. If this is correct, then similar structural anomalies should be apparent among clinical high-risk subjects. METHODS: Thirty-nine clinical high-risk (CR) subjects (24M/15F) were compared to 36 low-risk (LR) subjects (19M/17F). Olfactory measures derived from 3T MRI scans included olfactory bulb volume, primary olfactory cortical gray matter volume, and the depth of the olfactory sulcus overlying the bulb. Additionally, nasal cavity volumes were assessed with acoustic rhinometry. RESULTS: Male CR subjects exhibited bilateral reductions in olfactory bulb volume and abnormal asymmetries of the posterior nasal cavities and olfactory sulci (left reduced relative to right). Post-hoc contrasts also indicated reduced left, but not right, olfactory cortical gray matter volume. Female CRs had no significant abnormalities, although they exhibited similar trend effects. Left olfactory bulb volume correlated, across all CR subjects, with negative, but not positive, symptoms. In a classification analysis, with 80% target specificity, olfactory measurements distinguished male CR from male LR subjects with 93% sensitivity. Among females, the comparable sensitivity was 69%. CONCLUSION: Psychosis-risk youths exhibit an array of sexually dimorphic and laterally asymmetric anomalies of the peripheral olfactory system. These are consistent with a developmental disruption primarily affecting male fetuses. These structural biomarkers may enhance the identification of at-risk subjects with poor prognosis, before their clinical trajectory is apparent.

Morphofunctional experience-dependent plasticity in the honeybee brain.

Repeated or prolonged exposure to an odorant without any positive or negative reinforcement produces experience-dependent plasticity, which results in habituation and latent inhibition. In the honeybee (Apis mellifera), it has been demonstrated that, even if the absolute neural representation of an odor in the primary olfactory center, the antennal lobe (AL), is not changed by repeated presentations, its relative representation with respect to unfamiliar stimuli is modified. In particular, the representation of a stimulus composed of a 50:50 mixture of a familiar and a novel odorant becomes more similar to that of the novel stimulus after repeated stimulus preexposure. In a calcium-imaging study, we found that the same functional effect develops following prolonged odor exposure. By analyzing the brains of the animals subjected to this procedure, we found that such functional changes are accompanied by morphological changes in the AL (i.e., a decrease in volume in specific glomeruli). The AL glomeruli that exhibited structural plasticity also modified their functional responses to the three stimuli (familiar odor, novel odor, binary mixture). We suggest a model in which rebalancing inhibition within the AL glomeruli may be sufficient to elicit structural and functional correlates of experience-dependent plasticity.