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The human brain is organized as a hierarchical global network. Functional connectivity research reveals that sensory cortices are connected to corresponding association cortices via a series of intermediate nodes linked by synchronous neural activity. These sensory pathways and relay stations converge onto central cortical hubs such as the default‐mode network (DMN). The DMN regions are believed to be critical for representing concepts and, hence, language acquisition and use. Although prior research has established that major senses are placed at a similar distance from the DMN—five to six connective steps—it is still unknown how the olfactory system functionally connects to the large‐scale cortical hubs of the human brain. In this study, we investigated the connective distance from olfactory seed areas to the DMN. The connective distance involves a series of three to four intermediate steps. Furthermore, we parcellated the olfactory cortical subregions and found evidence of two distinct olfactory pathways. One emerges from the anterior olfactory nucleus and olfactory tubercle; it involves early access to the orbitofrontal cortex, known for processing reward and multisensory signals. The other emerges from the frontal and temporal regions of the piriform cortex, involving the anterior insula, intermediate frontal sulcus, and parietal operculum. The results were confirmed in a replication cohort. Our results provide evidence that olfaction has unique early access to the central cortical networks via dual pathways. Olfaction has unique early access to central cortical networks via dual connectivity pathways: evidence from a resting functional magnetic resonance imaging approach.

Subjective cognitive decline (SCD) is a high‐risk population in the preclinical stage of Alzheimer's disease (AD), and olfactory dysfunction is a risk factor for dementia progression. The present study aimed to explore the patterns of functional connectivity (FC) changes in the olfactory neural circuits during olfactory stimulation in SCD subjects. A total of 56 SCD subjects and 56 normal controls (NCs) were included. All subjects were assessed with a cognitive scale, an olfactory behavior test, and olfactory task‐based functional magnetic resonance imaging scanning. The FC differences in olfactory neural circuits between the two groups were analyzed by the generalized psychophysiological interaction. Additionally, we calculated and compared the activation of brain regions within the olfactory neural circuits during odor stimulation, the volumetric differences in brain regions showing FC differences between groups, and the correlations between neuroimaging indicators and olfactory behavioral and cognitive scale scores. During odor stimulation, the FC between the bilateral primary olfactory cortex (bPOC) and the right hippocampus in the SCD group was significantly reduced; while the FC between the right hippocampus and the right frontal cortex was significantly increased in the SCD group. The bPOC of all subjects showed significant activation, but no significant difference in activation between groups was found. No significant differences were observed in the volume of the brain regions within the olfactory neural circuits or in olfactory behavior between groups. The volume of the bPOC and right frontal cortex was significantly positively correlated with olfactory identification, and the volume of the right frontal cortex and right hippocampus was significantly correlated with cognitive functions. Furthermore, a significant correlation between the activation of bPOC and the olfactory threshold was found in the whole cohort. These results suggested that while the structure of the olfactory neural circuits and olfactory behavior in SCD subjects remained stable, there were significant changes observed in the FC of the olfactory neural circuits (specifically, the POC‐hippocampus‐frontal cortex neural circuits) during odor stimulation. These findings highlight the potential of FC alterations as sensitive imaging markers for identifying high‐risk individuals in the early stage of AD. Our findings showed that during odor stimulation, the subjective cognitive decline group exhibited significantly reduced functional connectivity (FC) between the bilateral primary olfactory cortex and the right hippocampus compared to the normal control group. Conversely, there was a significantly enhanced FC between the right hippocampus and the right frontal cortex.

Abstract Background and Hypothesis Persistent auditory verbal hallucinations (pAVHs) and olfactory identification impairment are common in schizophrenia (SCZ), but the neuroimaging mechanisms underlying both pAVHs and olfactory identification impairment are unclear. This study aimed to investigate whether pAVHs and olfactory identification impairment in SCZ patients are associated with changes in cortical thickness. Study Design In this study, cortical thickness was investigated in 78 SCZ patients with pAVHs (pAVH group), 58 SCZ patients without AVHs (non-AVH group), and 83 healthy controls (HC group) using 3T magnetic resonance imaging. The severity of pAVHs was assessed by the Auditory Hallucination Rating Scale. Olfactory identification deficits were assessed using the Odor Stick Identification Test for Japanese (OSIT-J). In addition, the relationship between the severity of pAVHs and olfactory identification disorder and cortical thickness abnormalities was determined. Study Results Significant reductions in cortical thickness were observed in the right medial orbital sulcus (olfactory sulcus) and right orbital sulcus (H-shaped sulcus) in the pAVH group compared to both the non-AVH and HC groups (P < .003, Bonferroni correction). Furthermore, the severity of pAVHs was found to be negatively correlated with the reduction in cortical thickness in the olfactory sulcus and H-shaped sulcus. Additionally, a decrease in cortical thickness in the olfactory sulcus showed a positive correlation with the OSIT-J scores (P < .05, false discovery rate correction). Conclusions Cortical thickness abnormalities in the olfactory sulcus may be a common neuroimaging mechanism for pAVHs and olfactory identification deficits in SCZ patients.

Multisensory integration is particularly important in the human olfactory system, which is highly dependent on non-olfactory cues, yet its underlying neural mechanisms are not well understood. In this study, we use intracranial electroencephalography techniques to record neural activity in auditory and olfactory cortices during an auditory-olfactory matching task. Spoken cues evoke phase locking between low frequency oscillations in auditory and olfactory cortices prior to odor arrival. This phase synchrony occurs only when the participant’s later response is correct. Furthermore, the phase of low frequency oscillations in both auditory and olfactory cortical areas couples to the amplitude of high-frequency oscillations in olfactory cortex during correct trials. These findings suggest that phase synchrony is a fundamental mechanism for integrating cross-modal odor processing and highlight an important role for primary olfactory cortical areas in multisensory integration with the olfactory system. Humans integrate sensory cues across multiple modalities to guide behaviour. Here, the authors report long-range phase synchronization between auditory and olfactory cortices prior to odor arrival, in a task where sound cues predict odors.

Humans naturally integrate signals from the olfactory and intranasal trigeminal systems. A tight interplay has been demonstrated between these two systems, and yet the neural circuitry mediating olfactory–trigeminal (OT) integration remains poorly understood. Using functional magnetic resonance imaging (fMRI), combined with psychophysics, this study investigated the neural mechanisms underlying OT integration. Fifteen participants with normal olfactory function performed a localization task with air‐puff stimuli, phenylethyl alcohol (PEA; rose odor), or a combination thereof while being scanned. The ability to localize PEA to either nostril was at chance. Yet, its presence significantly improved the localization accuracy of weak, but not strong, air‐puffs, when both stimuli were delivered concurrently to the same nostril, but not when different nostrils received the two stimuli. This enhancement in localization accuracy, exemplifying the principles of spatial coincidence and inverse effectiveness in multisensory integration, was associated with multisensory integrative activity in the primary olfactory (POC), orbitofrontal (OFC), superior temporal (STC), inferior parietal (IPC) and cingulate cortices, and in the cerebellum. Multisensory enhancement in most of these regions correlated with behavioral multisensory enhancement, as did increases in connectivity between some of these regions. We interpret these findings as indicating that the POC is part of a distributed brain network mediating integration between the olfactory and trigeminal systems. Practitioner Points Psychophysical and neuroimaging study of olfactory–trigeminal (OT) integration. Behavior, cortical activity, and network connectivity show OT integration. OT integration obeys principles of inverse effectiveness and spatial coincidence. Behavioral and neural measures of OT integration are correlated. Behavior, cortical activity and network connectivity show olfactory–trigeminal (OT) integration. OT integration obeys principles of inverse effectiveness and spatial coincidence. Behavioral and neural measures of OT integration are correlated.

Olfactory function, and specifically semantic olfactory memory (i.e., odor identification), has frequently been shown to predict cognitive functioning across multiple domains in old age. This observation suggests that olfactory function can serve as a marker for the integrity of temporolimbic cortical networks, but a clear delineation of this association is still missing. To address this issue, the present study employed voxel-based morphometry in a region of interest-based design to determine the extent to which gray matter volumes of core olfactory and memory areas are associated with olfactory memory performance in an aging population free from neurodegenerative disease. We further aimed to determine potential overlap in structural anatomical correlates, and differences in association strength, for semantic and episodic olfactory memory. Structural magnetic resonance imaging (MRI), episodic and semantic odor memory and episodic and semantic verbal memory data were collected in 422 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), all aged ​≥ ​60 years. Controlling for age and education, semantic, but not episodic, olfactory memory was positively related to gray matter volume in a cluster extending from the anterior hippocampus and amygdala into the posterior piriform cortex. The observed associations remained even when verbal memory performance was controlled for, supporting a link between the olfactory memory domain and cortical volume over and above more generalized memory abilities. As such, our data provide evidence for distinct functional-structural associations for semantic odor memory, supporting the idea of temporolimbic integrity as a neurobiological substrate linking olfactory function to cognitive health in old age. •Olfactory semantic memory performance was linked to frontotemporal gray matter volume.•Associations remained significant when verbal memory performance was controlled for.•No significant correlates of olfactory episodic memory were found.

Subjective hyperosmia refers to a self-reported olfactory ability that is superior to a normal, intact sense of smell (normosmia), and is associated with olfactory emotional experience. The current study used voxel-based morphometry to investigate the gray matter volume (GMV) in people with self-rated hyperosmia (subjective hyperosmia, SH, N = 18) in comparison to people with self-rated normal olfaction (subjective normosmia, SN, N = 14). Participants’ olfactory function were assessed by the extensive olfactory test battery, the “Sniffin’ Sticks” test. Within the predicted brain regions (regions-of-interest analyses), the SH participants showed larger GMV of the left hippocampus as compared to SN participants (FWE corrected p  < 0.05). Further, the whole-brain search indicated that SH had larger GMV of the bilateral hippocampus, the right hypothalamus, the left precuneus, and the left superior frontal gyrus as compared to the SN group. ROI analyses showed positive correlations between the left hippocampal GMV and odor threshold or discrimination scores across all participants. In addition, the whole-brain analysis suggested that the self-rated olfactory ability was positively associated with GMV in the cerebellum, superior frontal gyrus and the precentral gyrus among SH participants. In conclusion, the current results suggest that SH was associated with increased GMV in several brain regions that were previously shown to be involved in the processing of cognitive aspects of odors.

Studies in rodents show that olfactory processing in the principal neurons of olfactory bulb (OB) and piriform cortex (PC) is controlled by local inhibitory interneurons, and glutamate NMDA receptor plays a role in this inhibitory control. It is not clear if findings from studies in rodents translate to olfactory processing in nonhuman primates (NHPs). In this study, the effect of the glutamate NMDA receptor antagonist MK801 on odorant-induced olfactory responses in the OB and PC of anesthetized NHPs (rhesus monkeys) was investigated by cerebral blood volume (CBV) fMRI. Isoamyl-acetate was used as the odor stimulant. For each NHP, sixty fMRI measurements were made during a 4-h period, with each 4-min measurement consisting of a 1-min baseline period, a 1-min odor stimulation period, and a 2-min recovery period. MK801 (0.3 mg/kg) was intravenously delivered 1 hour after starting fMRI. Before MK801 injection, olfactory fMRI activations were observed only in the OB, not in the PC. After MK801 injection, olfactory fMRI activations in the OB increased, and robust olfactory fMRI activations were observed in the PC. The data indicate that MK801 enhances the olfactory responses in both the OB and PC. The enhancement effects of MK801 are most likely from its blockage of NMDA receptors on local inhibitory interneurons and the attenuation of the inhibition onto principal neurons. This study suggests that the mechanism of local inhibitory control of principal neurons in the OB and PC derived from studies in rodents translates to NHPs.

To investigate the differences in brain glucose consumption during olfactory stimulation between subjects affected by multiple chemical sensitivity (MCS) and a group of healthy individuals. Two (18)F-FDG PET/CT scans were performed in 26 subjects (6 men and 20 women; mean age 46.7 ± 11 years) with a clinical diagnosis of MCS and in 11 healthy controls (6 women and 5 men; mean age 45.7 ± 11 years), the first scan after a neutral olfactory stimulation (NS) and the second after a pure olfactory stimulation (OS). Differences in (18)F-FDG uptake were analysed by statistical parametric mapping (SPM2). In controls OS led to an increase in glucose consumption in BA 18 and 19 and a reduction in glucose metabolism in BA 10, 11, 32 and 47. In MCS subjects, OS led to an increase in glucose consumption in BA 20, 23, 18 and 37 and a reduction in glucose metabolism in BA 8, 9 and 10. The results of our study suggest that cortical activity in subjects with MCS differs from that in healthy individuals during olfactory stimulation.

Introduction Olfactory deficits are prevalent in early Alzheimer's disease (AD) and are predictive of progressive memory loss and dementia. However, direct neural evidence to relate AD neurodegeneration to deficits in olfaction and memory is limited. Methods We combined the University of Pennsylvania Smell Identification Test (UPSIT) with olfactory functional magnetic resonance imaging (fMRI) to investigate links between neurodegeneration, the olfactory network (ON) and the default mode network (DMN) in AD. Results Behaviorally, olfactory and memory scores showed a strong positive correlation in the study cohorts. During olfactory fMRI, the ON showed reduced task‐related activation and the DMN showed reduced task‐related suppression in mild cognitive impairment (MCI) and AD subjects compared to age‐matched cognitively normal subjects. Conclusions The results provide in vivo evidence for selective vulnerability of ON and DMN in AD and significantly improves the viable clinical applications of olfactory testing. A network‐based approach, focusing on network integrity rather than focal pathology, seems beneficial to olfactory prediction of dementia in AD. Olfactory and memory scores can differentiate Alzheimer's disease (AD) from mild cognitive impairment (MCI). Neurodegeneration, as measured by hippocampus and primary olfactory cortex (POC) volume is similar in AD and MCI. Patterns of ON activation support compensatory mechanisms in MCI and not in AD. DMN suppression during olfactory processing is impaired in AD. Effective connectivity between DMN and ON, in a model of causal influence, is impaired in AD.