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Olfactory dysfunction is associated with aging and the earliest stages of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases; it is thought to be an early biomarker of cognitive decline. In marmosets, a small non-human primate model used in brain research, olfactory pathway activity during olfactory stimulation has not been well studied because of the difficulty in clearly switching olfactory stimuli inside a narrow MRI. Here, we developed an olfactory-stimulated fMRI system using a small-aperture MRI machine. The olfactory presentation system consisted of two tubes, one for supply and one for suction of olfactory stimulants and a balloon valve. A balloon valve installed in the air supply tube controlled the presentation of the olfactory stimulant, which enabled sharp olfactory stimulation within MRI, such as 30 s of stimulation repeated five times at five-minute intervals. The olfactory stimulation system was validated in vivo and in a simulated system. fMRI analysis showed a rapid increase in signal values within 30 s of olfactory stimulation in eight regions related to the sense of smell. As these regions include those associated with Alzheimer's and Parkinson's diseases, olfactory stimulation fMRI may be useful in clarifying the relationship between olfactory dysfunction and dementia in non-human primates., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

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., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2022 the authors.)

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., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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.

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-β 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.

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.

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., (Copyright © 2019 IBRO. All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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 N 1 and P 2 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 N 1 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., (© 2018 The Authors. International Forum of Allergy & Rhinology published by Wiley Periodicals, Inc. on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

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.

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, t 1/2  = 46 min) and manganese-52 (Mn-52, t 1/2  = 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 ([ 52 Mn]Mn 2+ ) was imaged., Results: PET imaging with the divalent radioactive Mn-51 ([ 51 Mn]Mn 2+ ) and [ 52 Mn]Mn 2+ 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 [ 51 Mn]Mn 2+ accumulation in the pancreas after glucose stimulation and showed that [ 52 Mn]Mn 2+ 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 Mn 2+ 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.

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., (© 2018 Wiley Periodicals, Inc.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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., (© 2017 Andrione et al.; Published by Cold Spring Harbor Laboratory Press.)

Objective: The aim of this retrospective study was to perform magnetic resonance imaging assessment of olfactory pathway and skull base abnormalities in Kallmann syndrome (KS) patients with hypogonadotropic hypogonadism and olfaction disorder., Methods: Magnetic resonance brain patterns were retrospectively studied in 19 patients clinically classified as KS. Qualitative assessment of olfactory bulb region comprised bulb atrophy and rectus and medial orbital gyrus ptosis; quantitative assessment measured olfactory fossa depth and width, sulcus depth and ethmoid angle. Results were compared to an age- and sex-matched control population (n=19) with no impairment in the region of interest. Sixteen of the 19 KS patients were genetically screened for mutations associated with KS., Results: On the above qualitative criteria, 15 of the 19 patients presented either unilateral (n=2) or bilateral (n=13) olfactory bulb agenesis; 16 showed tract agenesis and 16 showed gyrus malformation (ptosis or absence). On the quantitative criteria, 18 of the 19 patients showed abnormal sulcus depth and/or olfactory fossa malformation and/or abnormal ethmoid angle., Conclusion: The presence of malformation abnormalities in the olfactory fossae of 18 of the 19 patients appears to be a key factor for etiological diagnosis of hypogonadotropic hypogonadism, and should enable targeted study of genes involved in KS., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: Evidence for olfactory dysfunction in schizophrenia has been firmly established. However, in the typical understanding of schizophrenia, olfaction is not recognized to contribute to or interact with the illness. Despite the solid presence of olfactory dysfunction in schizophrenia, its relation to the rest of the illness remains largely unclear. Here, we aimed to examine functional connectivity of the olfactory bulb, olfactory tract, and piriform cortices and isolate the network that would account for the altered olfaction in schizophrenia., Methods: We examined the functional connectivity of these specific olfactory regions in order to isolate other brain regions associated with olfactory processing in schizophrenia. Using the resting state functional MRI data from the Center for Biomedical Research Excellence in Brain Function and Mental Illness, we compared 84 patients of schizophrenia and 90 individuals without schizophrenia., Results: The schizophrenia group showed disconnectivity between the anterior piriform cortex and the nucleus accumbens, between the posterior piriform cortex and the middle frontal gyrus, and between the olfactory tract and the visual cortices., Conclusions: The current results suggest functional disconnectivity of olfactory regions in schizophrenia, which may account for olfactory dysfunction and disrupted integration with other sensory modalities in schizophrenia., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

Discrimination of odorous molecules in amniotic fluid occur after 30 weeks' gestation; fetuses exhibit differential responses to maternal diet. Olfactory reflexes enable reliable neonatal testing. Olfactory bulbs can be demonstrated reliably by MRI after 30 weeks' gestation, and their hypoplasia or aplasia also documented by late prenatal and postnatal MRI. Olfactory axons project from nasal epithelium to telencephalon before olfactory bulbs form. Fetal olfactory maturation remains incomplete at term for neuronal differentiation, synaptogenesis, myelination, and persistence of the transitory fetal ventricular recess. Immaturity does not signify nonfunction. Olfaction is the only sensory system without thalamic projection because of its own intrinsic thalamic equivalent. Diverse malformations of the olfactory bulb can be diagnosed by clinical examination, imaging, and neuropathology. Some epileptic auras might be primarily generated in the olfactory bulb. Cranial nerve 1 should be tested in all neonates and especially in patients with brain malformations, endocrinopathies, chromosomopathies, and genetic/metabolic diseases.

Previous studies investigating the differences in olfactory processing and judgments between trained sommeliers and controls have shown increased activations in brain regions involving higher level cognitive processes in sommeliers. However, there is little information about the influence of expertise on causal connectivity and topological properties of the connectivity networks between these regions. Therefore, the current study focuses on addressing these questions in a functional magnetic resonance imaging (fMRI) study of olfactory perception in Master Sommeliers. fMRI data were acquired from Master Sommeliers and control participants during different olfactory and nonolfactory tasks. Mean time series were extracted from 90 different regions of interest (ROIs; based on Automated Anatomical Labeling atlas). The underlying neuronal variables were extracted using blind hemodynamic deconvolution and then input into a dynamic multivariate autoregressive model to obtain connectivity between every pair of ROIs as a function of time. These connectivity values were then statistically compared to obtain paths that were significantly different between the two groups. The obtained connectivity matrices were further studied using graph theoretical methods. In sommeliers, significantly greater connectivity was observed in connections involving the precuneus, caudate, putamen, and several frontal and temporal regions. The controls showed increased connectivity from the left hippocampus to the frontal regions. Furthermore, the sommeliers exhibited significantly higher small-world topology than the controls. These findings are significant, given that learning about neuroplasticity in adulthood in these regions may then have added clinical importance in diseases such as Alzheimer's and Parkinson's where early neurodegeneration is isolated to regions important in smell.

Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [11C]GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [11C]GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [11C]GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [18F]GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics., Competing Interests: G.C. Van de Bittner and J.M. Hooker are inventors on a patent application related to this work (Radiolabeled compounds for imaging – PCT/US2015/040971). M.J. O’Neill, Z. Ahmed, and T.K. Murray receive a salary for their work at Eli Lilly and Co. Ltd.

Background: Olfactory impairment is an early manifestation of Parkinson's disease (PD). Diffusion Tensor Imaging (DTI) and Magnetization Transfer (MT) are two imaging techniques that allow noninvasive detection of microstructural changes in the cerebral white matter., Objective: To assess white matter alterations associated with olfactory impairment in PD, using a binary imaging approach with DTI and MT., Methods: 22 PD patients and 13 healthy controls were examined with DTI, MT and an odor discrimination test. DTI data were first analyzed with tract-based spatial statistics (TBSS) in order to detect differences in fractional anisotropy, mean, radial and axial diffusivity between PD patients and controls. Voxelwise randomized permutation was employed for the MT analysis, after spatial and intensity normalization. Additionally, ROI analysis was performed on both the DTI and MT data, focused on the white matter adjacent to olfactory brain regions., Results: Whole brain voxelwise analysis revealed decreased axial diffusivity in the left uncinate fasciculus and the white matter adjacent to the left olfactory sulcus of PD patients. ROI analysis demonstrated decreased axial diffusivity in the right orbitofrontal cortex, as well as decreased mean diffusivity and axial diffusivity in the white matter of the left entorhinal cortex of PD patients. There were no significant differences regarding fractional anisotropy, radial diffusivity or MT between patients and controls., Conclusions: ROI analysis of DTI could detect microstructural changes in the white matter adjacent to olfactory areas in PD patients, whereas MT imaging could not.

Conclusions: This hospital-based study found a gender differences in Chinese subjects with post-viral olfactory disorder (PVOD). Women appear to face higher susceptibility to PVOD, a finding that appears to be magnified with age and duration of olfactory loss., Objectives: PVOD is one of the most common reasons for acquired olfactory dysfunction, but there is little data in Chinese populations. We analyzed Chinese subjects with PVOD in order to determine demographic risk factors and clinical features in this major population group., Methods: Data from 143 consecutive subjects with PVOD and 117 subjects with other olfactory disorders (controls) were analyzed. This study examined age, duration, and severity of olfactory loss, and compared the differences of subjective and objective olfactory function tests between two groups, using Sniffin' Sticks, Olfactory Event Related Potential (OERP), and olfactory pathway MRI., Results: There were more women in the PVOD group compared to controls (p < 0.001). Older subjects with PVOD were more likely to be women (p = 0.027), and the proportion of women with PVOD increased with the duration of olfactory loss (p = 0.032). There were no differences in the prevalence of abnormal OERP between two groups, although the female-to-male ratio was higher in the PVOD group (p = 0.041). Women with PVOD were less likely to have olfactory pathway abnormalities by MRI compared to controls (p < 0.001).

Unlabelled: Although feedback or centrifugal projections from higher processing centers of the brain to peripheral regions have long been known to play essential functional roles, the anatomical organization of these connections remains largely unknown. Using a virus-based retrograde labeling strategy and 3D whole-brain reconstruction methods, we mapped the spatial organization of centrifugal projections from two olfactory cortical areas, the anterior olfactory nucleus (AON) and the piriform cortex, to the granule cell layer of the main olfactory bulb in the mouse. Both regions are major recipients of information from the bulb and are the largest sources of feedback to the bulb, collectively constituting circuits essential for olfactory coding and olfactory behavior. We found that, although ipsilateral inputs from the AON were uniformly distributed, feedback from the contralateral AON had a strong ventral bias. In addition, we observed that centrifugally projecting neurons were spatially clustered in the piriform cortex, in contrast to the distributed feedforward axonal inputs that these cells receive from the principal neurons of the bulb. Therefore, information carried from the bulb to higher processing structures by anatomically stereotypic projections is likely relayed back to the bulb by organizationally distinct feedback projections that may reflect different coding strategies and therefore different functional roles., Significance Statement: Principles of anatomical organization, sometimes instantiated as "maps" in the mammalian brain, have provided key insights into the structure and function of circuits in sensory systems. Generally, these characterizations focus on projections from early sensory processing areas to higher processing structures despite considerable evidence that feedback or centrifugal projections often constitute major conduits of information flow. Our results identify structure in the organization of centrifugal feedback projections to the olfactory bulb that is fundamentally different from the organization of feedforward circuits. Our study suggests that understanding computations performed in the olfactory bulb, and more generally in the olfactory system, requires understanding interactions between feedforward and feedback "maps" both structurally and functionally., (Copyright © 2016 Padmanabhan et al.)

Unlabelled: A major component of perception is hedonic valence: perceiving stimuli as pleasant or unpleasant. Here, we used early olfactory experiences that shape odor preferences and aversions to explore developmental plasticity in circuits mediating odor hedonics. We used 2-deoxyglucose autoradiographic mapping of neural activity to identify circuits differentially activated by biologically relevant preferred and avoided odors across rat development. We then further probed this system by increasing or decreasing hedonic value. Using both region of interest and functional connectivity analyses, we identified regions within primary olfactory, amygdala/hippocampal, and prefrontal cortical networks that were activated differentially by maternal and male odors. Although some activated regions remained stable across development (postnatal days 7-23), there was a developmental emergence of others that resulted in an age-dependent elaboration of hedonic-response-specific circuitry despite stable behavioral responses (approach/avoidance) to the odors across age. Hedonic responses to these biologically important odors were modified through diet suppression of the maternal odor and co-rearing with a male. This allowed assessment of hedonic circuits in isolation of the specific odor quality and/or intensity. Early experience significantly modified odor-evoked circuitry in an age-dependent manner. For example, co-rearing with a male, which induced pup attraction to male odor, reduced activity in amygdala regions normally activated by the unfamiliar avoided male odor, making this region more consistent with maternal odor. Understanding the development of odor hedonics, particularly within the context of altered early life experience, provides insight into the development of sensory processes, food preferences, and the formation of social affiliations, among other behaviors., Significance Statement: Odor hedonic valence controls approach-avoidance behaviors, but also modulates ongoing behaviors ranging from food preferences and social affiliation with the caregiver to avoidance of predator odors. Experiences can shape hedonic valence. This study explored brain circuitry involved in odor hedonic encoding throughout development using maternal and predator odors and assessed the effects of early life experience on odor hedonic encoding by increasing/decreasing the hedonic value of these odors. Understanding the role of changing brain circuitry during development and its impact on behavioral function is critical for understanding sensory processing across development. These data converge with exciting literature on the brain's hedonic network and highlight the significant role of early life experience in shaping the neural networks of highly biologically relevant stimuli., (Copyright © 2016 the authors 0270-6474/16/366634-17$15.00/0.)

What is known as an odor object is an integrated representation constructed from physical features, and perceptual attributes mainly mediated by the olfactory and trigeminal systems. The aim of the present study was to comprehend how this multidimensional representation is organized, by deciphering how similarities in the physical, olfactory and trigeminal perceptual spaces of odors are represented in the human brain. To achieve this aim, we combined psychophysics, functional MRI and multivariate representational similarity analysis. Participants were asked to smell odors diffused by an fMRI-compatible olfactometer and to rate each smell along olfactory dimensions (pleasantness, intensity, familiarity and edibility) and trigeminal dimensions (irritation, coolness, warmth and pain). An event-related design was implemented, presenting different odorants. Results revealed that (i) pairwise odorant similarities in anterior piriform cortex (PC) activity correlated with pairwise odorant similarities in chemical properties (P < 0.005), (ii) similarities in posterior PC activity correlated with similarities in olfactory perceptual properties (P <0.01), and (iii) similarities in amygdala activity correlated with similarities in trigeminal perceptual properties (P < 0.01). These findings provide new evidence that extraction of physical, olfactory and trigeminal features is based on specific fine processing of similarities between odorous stimuli in a distributed manner in the olfactory system. Hum Brain Mapp 37:2161-2172, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Post-injury smell disorders., Problems/objectives: Head trauma is the third most common aetioiogy of post-traumatic olfactory loss (PTOL). This literature review aims to report the existing knowledge surrounding this issue, exploring the current understanding of the inducing pathogenesis and the assessment and management standards from the early phases to longer-term considerations., Methodology: Literature search and appraisal in PubMed on the following themes directly associated with PTOL: olfactory disorders, trauma, pathogenesis, examination, recovery and treatment., Results: Scientific evidence was mainly available for epidemiology and exploration tools in cases suffering from PTOL. The current research into obj6ctive batteries of olfactory tests is promising., Conclusions: This paper highlights the importance of an adequate assessment of PTOL for an early start in olfactory training.

The aim of the study was to compare the efficacy of olfactory testing and presynaptic dopamine imaging in diagnosing Parkinson's disease (PD) and atypical parkinsonian syndromes (APS); to evaluate if the combination of these two diagnostic tools can improve their diagnostic value. A prospective investigation of 24 PD patients, 16 APS patients and 15 patients with non-parkinsonian syndromes was performed during an 18-month period. Single photon emission computed tomography with the presynaptic radioligand (123)I-FP-CIT (DaTSCAN(®)) and olfactory testing with the Brief 12-item Smell Identification Test (B-SIT) were performed in all patients. DaTSCAN was analysed semi-quantitatively, by calculating two different striatal uptake ratios, and visually according to a predefined ranking scale. B-SIT score was significantly lower for PD patients, but not significantly different between APS and non-parkinsonism. The visual assessment of DaTSCAN had higher sensitivity, specificity and diagnostic accuracy compared to olfactory testing. Most PD patients (75%) had visually predominant dopamine depletion in putamen, while most APS patients (56%) had visually severe dopamine depletion both in putamen and in caudate nucleus. The combination of DaTSCAN and B-SIT led to a higher rate of correctly classified patients. Olfactory testing can distinguish PD from non-parkinsonism, but not PD from APS or APS from non-parkinsonism. DaTSCAN is more efficient than olfactory testing and can be valuable in differentiating PD from APS. However, combining olfactory testing and DaTSCAN imaging has a higher predictive value than these two methods separately.

During development of the primary olfactory system, axon targeting is inaccurate and axons inappropriately project within the target layer or overproject into the deeper layers of the olfactory bulb. As a consequence there is considerable apoptosis of primary olfactory neurons during embryonic and postnatal development and axons of the degraded neurons need to be removed. Olfactory ensheathing cells (OECs) are the glia of the primary olfactory nerve and are known to phagocytose axon debris in the adult and postnatal animal. However, it is unclear when phagocytosis by OECs first commences. We investigated the onset of phagocytosis by OECs in the developing mouse olfactory system by utilizing two transgenic reporter lines: OMP-ZsGreen mice which express bright green fluorescent protein in primary olfactory neurons, and S100β-DsRed mice which express red fluorescent protein in OECs. In crosses of these mice, the fate of the degraded axon debris is easily visualized. We found evidence of axon degradation at embryonic day (E)13.5. Phagocytosis of the primary olfactory axon debris by OECs was first detected at E14.5. Phagocytosis of axon debris continued into the postnatal animal during the period when there was extensive mistargeting of olfactory axons. Macrophages were often present in close proximity to OECs but they contributed only a minor role to clearing the axon debris, even after widespread degeneration of olfactory neurons by unilateral bulbectomy and methimazole treatment. These results demonstrate that from early in embryonic development OECs are the primary phagocytic cells of the primary olfactory nerve., (© 2014 Wiley Periodicals, Inc.)

The aim of this article is to investigate the cortical metabolic arrangements in olfactory processing by using F fluorodeoxyglucose (FDG) positron emission tomography/computed tomography.Twenty-six normosmic individuals (14 women and 12 men; mean age 46.7 ± 10 years) were exposed to a neutral olfactory condition (NC) and, after 1 month, to a pure olfactory condition (OC) in a relatively ecological environment, that is, outside the scanner. All the subjects were injected with 185-210 megabecquerel of F FDG during both stimulations. Statistical parametric mapping version 2 was used in order to assess differences between NC and OC.As a result, we found a significant higher glucose consumption during OC in the cuneus, lingual, and parahippocampal gyri, mainly in the left hemisphere. During NC, our results show a relative higher glucose metabolism in the left superior, inferior, middle, medial frontal, and orbital gyri as well as in the anterior cingulate cortex.The present investigation, performed with a widely available functional imaging clinical tool, may help to better understand the neural responses associated to olfactory processing in healthy individuals and in patients with olfactory disorders by acquiring data in an ecologic, noise-free, and resting condition in which possible cerebral activations related to unwanted attentional processes might be avoided.

Unlabelled: Olfactory dysfunction is an early feature of Alzheimer disease. This study used multimodal imaging of PET and (18)F-FDG combined with diffusion tensor imaging (DTI) to investigate the association of fiber tract integrity in the olfactory tract with cortical glucose metabolism in subjects with mild cognitive impairment (MCI) and normal controls. We hypothesized that MCI subjects would show loss of olfactory tract integrity and may have altered associations with glucose metabolism., Methods: Subjects diagnosed with amnestic MCI (n = 12) and normal controls (n = 23) received standard brain (18)F-FDG PET and DTI with 32 gradient directions on a 3-T MR imaging scanner. Fractional anisotropy (FA) maps were generated. Voxelwise correlation analysis of olfactory tract FA values with (18)F-FDG PET images was performed., Results: Integrated analysis over all subjects indicated a positive correlation between white matter integrity in the olfactory tract and metabolic activity in olfactory processing structures, including the rostral prefrontal cortex, dorsomedial thalamus, hypothalamus, orbitofrontal cortex, and uncus, and in the superior temporal gyrus, insula, and anterior cingulate cortex. Subjects with MCI, compared with normal controls, showed differential associations of olfactory tract integrity with medial temporal lobe and posterior cortical structures., Conclusion: These findings indicate that impairment of axonal integrity or neuronal loss may be linked to functional metabolic changes and that disease-specific neurodegeneration may affect this relationship. Multimodal imaging using (18)F-FDG PET and DTI may provide better insights into aging and neurodegenerative processes.

Background: So far, an overall view of olfactory structures activated by natural biologically relevant odors in the awake rat is not available. Manganese-enhanced MRI (MEMRI) is appropriate for this purpose. While MEMRI has been used for anatomical labeling of olfactory pathways, functional imaging analyses have not yet been performed beyond the olfactory bulb. Here, we have used MEMRI for functional imaging of rat central olfactory structures and for comparing activation maps obtained with odors conveying different biological messages., Methodology/principal Findings: Odors of male fox feces and of chocolate flavored cereals were used to stimulate conscious rats previously treated by intranasal instillation of manganese (Mn). MEMRI activation maps showed Mn enhancement all along the primary olfactory cortex. Mn enhancement elicited by male fox feces odor and to a lesser extent that elicited by chocolate odor, differed from that elicited by deodorized air. This result was partly confirmed by c-Fos immunohistochemistry in the piriform cortex., Conclusion/significance: By providing an overall image of brain structures activated in awake rats by odorous stimulation, and by showing that Mn enhancement is differently sensitive to different stimulating odors, the present results demonstrate the interest of MEMRI for functional studies of olfaction in the primary olfactory cortex of laboratory small animals, under conditions close to natural perception. Finally, the factors that may cause the variability of the MEMRI signal in response to different odor are discussed.

Objectives: Experiments in animal models have identified specific subcortical anatomic circuits, which are critically involved in the pathogenesis and control of seizure activity. However, whether such anatomic substrates also exist in human epilepsy is not known., Methods: We studied 2 separate groups of patients with focal epilepsies arising from any cortical location using either simultaneous EEG-fMRI (n = 19 patients) or [¹¹C]flumazenil PET (n = 18)., Results: Time-locked with the interictal epileptiform discharges, we found significant hemodynamic increases common to all patients near the frontal piriform cortex ipsilateral to the presumed cortical focus. GABA(A) receptor binding in the same area was reduced in patients with more frequent seizures., Conclusions: Our findings of cerebral blood flow and GABAergic changes, irrespective of where interictal or ictal activity occurs in the cortex, suggest that this area of the human primary olfactory cortex may be an attractive new target for epilepsy therapy, including neurosurgery, electrical stimulation, and focal drug delivery.

Almost every odor we encounter in daily life has the capacity to produce a trigeminal sensation. Surprisingly, few functional imaging studies exploring human neuronal correlates of intranasal trigeminal function exist, and results are to some degree inconsistent. We utilized activation likelihood estimation (ALE), a quantitative voxel-based meta-analysis tool, to analyze functional imaging data (fMRI/PET) following intranasal trigeminal stimulation with carbon dioxide (CO(2)), a stimulus known to exclusively activate the trigeminal system. Meta-analysis tools are able to identify activations common across studies, thereby enabling activation mapping with higher certainty. Activation foci of nine studies utilizing trigeminal stimulation were included in the meta-analysis. We found significant ALE scores, thus indicating consistent activation across studies, in the brainstem, ventrolateral posterior thalamic nucleus, anterior cingulate cortex, insula, precentral gyrus, as well as in primary and secondary somatosensory cortices-a network known for the processing of intranasal nociceptive stimuli. Significant ALE values were also observed in the piriform cortex, insula, and the orbitofrontal cortex, areas known to process chemosensory stimuli, and in association cortices. Additionally, the trigeminal ALE statistics were directly compared with ALE statistics originating from olfactory stimulation, demonstrating considerable overlap in activation. In conclusion, the results of this meta-analysis map the human neuronal correlates of intranasal trigeminal stimulation with high statistical certainty and demonstrate that the cortical areas recruited during the processing of intranasal CO(2) stimuli include those outside traditional trigeminal areas. Moreover, through illustrations of the considerable overlap between brain areas that process trigeminal and olfactory information; these results demonstrate the interconnectivity of flavor processing.

Background: Whether pheromone signaling exists in humans is still a matter of intense discussion. In the present study we tested if smelling of Androstenol, a steroid produced by the human body and reported to affect human behavior, may elicit cerebral activation. A further issue was to evaluate whether the pattern of activation resembles the pattern of common odors., Methodology: PET measurements of regional cerebral blood flow (rCBF) were conducted in 16 healthy heterosexual women during passive smelling of Androstenol, four ordinary odors (OO), and odorless air (the base line condition)., Principal Findings: Smelling Androstenol caused activation of a portion of the hypothalamus, which according to animal data mediates the pheromone triggered mating behavior. Smelling of OO, on the other hand, engaged only the classical olfactory regions (the piriform cortex, lateral amygdala, anterior insular and anterior cingulate cortex)., Conclusions: The observed pattern of activation is very similar to the pattern previously detected with 4,16-androstadien-3-one in heterosexual females. It suggests that several compounds released by human body may activate cerebral networks involved in human reproduction.

Multiple Chemical Sensitivity (MCS) is a chronic acquired disorder of unknown pathogenesis. The aim of this study was to ascertain whether MCS patients present brain single photon emission computed tomography (SPECT) and psychometric scale changes after a chemical challenge. This procedure was performed with chemical products at non-toxic concentrations in 8 patients diagnosed with MCS and in their healthy controls. In comparison to controls, cases presented basal brain SPECT hypoperfusion in small cortical areas of the right parietal and both temporal and fronto-orbital lobes. After chemical challenge, cases showed hypoperfusion in the olfactory, right and left hippocampus, right parahippocampus, right amygdala, right thalamus, right and left Rolandic and right temporal cortex regions(p

Extranigral neuropathological changes may precede the degeneration of nigrostriatal dopaminergic neurones in Parkinson's disease (PD). Therefore, non-motor disturbances are an interesting target for the development of tests aimed at identifying individuals with premotor PD. An impaired sense of smell occurs with high prevalence in the clinical motor stages of PD patients and has also been reported in first-degree relatives of PD patients. In a prospective study in 361 asymptomatic first-degree relatives of PD patients, we studied the value of a two-step approach, combining olfactory testing and dopamine transporter (DAT) SPECT imaging, in detecting patients in the premotor phase of PD. Unexplained hyposmia alone was associated with a 12.5% risk of developing PD within a five year period. Cox regression analysis revealed that odour discrimination performance was most strongly correlated with the risk of future PD. Furthermore, all relatives that later developed PD had both hyposmia and abnormally reduced striatal DAT binding at baseline. The results of our studies provide the proof-of-principle that a two-step approach of olfactory testing and DAT SPECT imaging may serve to diagnose PD in its premotor phase. Yet, the low positive predictive value of hyposmia indicates that a wider application of this approach for screening purposes would require too many DAT SPECT scans in healthy individuals. Therefore, future studies in larger populations are necessary to further characterize premotor PD and identify additional genetic and/or clinical susceptibility markers to be used in conjunction with olfactory testing as additional screening steps toward diagnosing PD in its earliest stages.

Because humans seem to lack neuronal elements in the vomeronasal organ (VNO), many scientists believe that humans are unable to detect pheromones. This view is challenged by the observations that pheromone-like compounds, 4,16-androstadien-3-one (AND) and oestra-1,3,5(10),16-tetraen-3-ol (EST), activate the human hypothalamus. Whether these activations are mediated via VNO, venous blood or olfactory mucosa is presently unknown. To disentangle between the three alternatives, we conducted activation studies in 12 heterosexual males with chronic anosmia because of nasal polyps. Polyposis hampers signal transduction via the olfactory mucosa without interfering with the VNO or the pheromone transport via venous blood. Twelve healthy men served as controls. Subjects were investigated with (15)O-H(2)O PET during smelling of odorless air (base line), AND, EST, vanillin, and acetone. Smelling of EST activated the anterior hypothalamus in controls, but not anosmics. Neither did the anosmics display cerebral activations with AND or vanillin. Clusters were detected only with the trigeminal odorant acetone, and only in the thalamus, brainstem, the anterior cingulate, and parts of the sensorimotor cortex. Direct comparisons with controls (controls-anosmics) showed clusters in the olfactory cortex (amygdala and piriform cortex) with AND, vanillin, and acetone, and in the anterior hypothalamus with EST. The observed absence of olfactory and presence of trigeminal activations in anosmics indicates that polyposis primarily affected signal processing via the olfactory mucosa. The anosmics inability to activate the hypothalamus with EST, therefore, suggests that in healthy men EST signals were primarily transmitted via the olfactory system., (2009 Wiley-Liss, Inc.)

Olfactory hypersensitivity (OHS) may occur during migraine attacks and seems to be very specific to this form of headache. OHS is also observed during migraine-free periods and is associated with the presence of odour-triggered attacks. Yet the pathophysiology of OHS remains unknown. The aim of our study was to evaluate olfactory processing in migraineurs with OHS and to investigate whether regional cerebral blood flow (rCBF) associated with olfactory stimulation is modified in these patients compared with controls. Eleven migraineurs with OHS and 12 controls participated in a H(2)(15)O-positron emission tomography study, including three scans in which odours were delivered and three scans where only odourless air was delivered. rCBF during olfactory condition was compared with that for the odourless baseline condition. Between-group analyses were performed using voxel-based and region-of-interest analyses. During both olfactory and non-olfactory conditions, we observed higher rCBF in the left piriform cortex and antero-superior temporal gyrus in migraineurs compared with controls. During odour stimulation, migraineurs also showed significantly higher activation than controls in the left temporal pole and significantly lower activation in the frontal (left inferior as well as left and right middle frontal gyri) and temporo-parietal (left and right angular, and right posterior superior temporal gyri) regions, posterior cingulate gyrus and right locus coeruleus. These results could reflect a particular role of both the piriform cortex and antero-superior temporal gyrus in OHS and odour-triggered migraine. Whether these rCBF changes are the cause or a consequence of odour-triggered migraines and interictal OHS remains unknown. Further comparisons between migraineurs with and without OHS are warranted to address this issue. The abnormal cerebral activation patterns during olfactory stimulation might reflect altered cerebrovascular response to olfactory stimulation due to the migraine disease, or an abnormal top-down regulation process related to OHS.

In recent years the Drosophila olfactory system, with its unparalleled opportunities for genetic dissection of development and functional organization, has been used to study the development of central olfactory neurons and the molecular basis of olfactory coding. The results of these studies have been interpreted in the absence of a detailed understanding of the steps in maturation of glial cells in the antennal lobe. Here we present a high-resolution study of the glia associated with olfactory glomeruli in adult and developing antennal lobes. The study provides a basis for comparison of findings in Drosophila with those in the moth Manduca sexta that indicate a critical role for glia in antennal lobe development. Using flies expressing GFP under a Nervana2 driver to visualize glia for confocal microscopy, and probing at higher resolution with the electron microscope, we find that glial development in Drosophila differs markedly from that in moths: glial cell bodies remain in a rind around the glomerular neuropil; glial processes ensheathe axon bundles in the nerve layer but likely contribute little to axonal sorting; their processes insinuate between glomeruli only very late and then form only a sparse, open network around each glomerulus; and glial processes invade the synaptic neuropil. Taking our results in the context of previous studies, we conclude that glial cells in the developing Drosophila antennal lobe are unlikely to play a strong role in either axonal sorting or glomerulus stabilization and that in the adult, glial processes do not electrically isolate glomeruli from their neighbors., ((c) 2008 Wiley-Liss, Inc.)

Objective: Memory for odors is often associated with highly emotional experiences, and odors have long been noted by clinicians to be precipitants of trauma symptoms in posttraumatic stress disorder (PTSD). Primitive brain systems involved in fear responsivity and survival also mediate smell, including the olfactory cortex and amygdala. The purpose of this study was to measure neural correlates of olfaction in PTSD., Methods: We exposed male combat veterans with PTSD (N = 8) and without PTSD (N = 8) to a set of smells, including diesel (related to traumatic memories of combat), and three other types of smells: odorless air, vanilla/coconut, and hydrogen sulfide (H2S) (respectively, a neutral, positive, and negative hedonic nontraumatic smell) in conjunction with PET imaging of cerebral blood flow and assessment of psychophysiological and behavioral symptoms. All subjects also underwent a baseline of olfactory acuity., Results: PTSD patients rated diesel as unpleasant and distressing, resulting in increased PTSD symptoms and anxiety in PTSD versus combat controls. Exposure to diesel resulted in an increase in regional blood flow (rCBF) in amygdala, insula, medial prefrontal cortex, and anterior cingulate cortex, and decreased rCBF in lateral prefrontal cortex in PTSD in comparison to combat controls. Combat controls showed less rCBF changes on any smell, and did not show amygdala activation upon diesel exposure., Conclusions: These data support the hypothesis that in PTSD trauma-related smells can serve as strong emotional reminders. The findings indicate the involvement of a neural circuitry that shares olfactory elements and memory processing regions when exposed to trauma-related stimuli.

Background: In vivo imaging of the dopamine transporter with [99mTc]TRODAT-1 (TRODAT) and olfactory testing have both been proposed as potential biomarkers in Parkinson disease (PD)., Objective: To evaluate the relationship between TRODAT SPECT imaging, odor identification skills, and motor function in patients with early PD., Methods: Twenty-four patients with a clinical diagnosis of early-stage PD (mean Hoehn & Yahr stage = 1.4) underwent TRODAT imaging, Unified PD Rating Scale (UPDRS) ratings of motor function, and administration of the University of Pennsylvania Smell Identification Test (UPSIT). Brain images were obtained using a standardized processing protocol and specific uptake ratios for striatal regions of interest were calculated. Partial correlations between the imaging indices, disease duration, UPSIT scores, and UPDRS motor scores were then calculated., Results: UPSIT scores were correlated with TRODAT uptake in the striatum as a whole (r = 0.66, p = 0.001). The putamen showed the strongest correlation with the UPSIT (r = 0.74; p < 0.001). The correlation between dopamine transporter density in the caudate and UPSIT was moderate (r = 0.36, p = 0.11), but was not significant., Conclusions: Olfactory function is highly correlated with dopamine transporter imaging abnormalities in early Parkinson disease (PD). Further studies are warranted to determine whether changes over time in these two measures are also correlated in early PD.

We used positron emission tomography (PET) to investigate brain regions associated with odor imagery. Changes in regional cerebral blood flow (CBF) during odor imagery were compared with changes during nonspecific expectation of olfactory stimuli and with those during odor perception. Sixty-seven healthy volunteers were screened for their odor imagery (with a paradigm developed in a previous study), and 12 of them, assessed to be "good odor imagers," participated in the neuroimaging part of the study. Imagination of odors was associated with increased activation in several olfactory regions in the brain: the left primary olfactory cortical (POC) region including piriform cortex, the left secondary olfactory cortex or posterior orbitofrontal cortex (OFC), and the rostral insula bilaterally. Furthermore, blood flow in two regions within the right orbitofrontal cortex correlated significantly with the behavioral measure of odor imagery during scanning. Overall, the findings indicated that neural networks engaged during odor perception and imagery overlap partially.

Neuroimaging studies suggest that piriform cortex is activated at least in part by sniffing. We used H(2)(15)O positron emission tomography (PET) to study 15 healthy volunteers while they participated in four conditions, two of which were sniffing odorants and odorless air. The remaining two conditions involved a constant, very low flow of either odorized or odorless air during velopharyngeal closure (VPC), a technique that prevents subject-induced airflow through the nasal passages. Contrary to expectation, sniffing under odorless conditions did not induce significant piriform and surrounding cortical (PC+) activity when compared to odorless VPC, even at a liberal statistical threshold. However, a small correlation emerged in PC+ between the difference signal of [odorless sniffing - odorless VPC] and peak rate of nasal pressure change. PC+ activity was, however, strongly evoked by odorant exposure during sniffing and VPC, with neither technique showing greater activation. Activity in orbitofrontal (olfactory association) cortex was absent during odorant stimulation (OS) with VPC, but present during odorant sniffing. Sniffing may therefore play an important role in facilitating the higher-order analysis of odors. A right orbitofrontal region was also activated with odorless sniffing, which suggests a possible orbitofrontal role in guided olfactory exploration.

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., (Copyright 2004 Wiley-Liss, Inc.)