Metabolic state modulates neural processing of odors in the human olfactory bulb.

The olfactory and endocrine systems have recently been shown to reciprocally shape the homeostatic processes of energy intake. As demonstrated in animal models, the individual's metabolic state dynamically modulates how the olfactory bulb process odor stimuli using a range of endocrine signals. Here we aimed to determine whether the neural processing of odors in human olfactory bulb is modulated by metabolic state. Participants were exposed to food-associated odors, in separate sessions being hungry and sated, while neural responses from the olfactory bulb was obtained using electrobulbogram. We found significantly higher gamma power activity (51-100 Hz) in the OB's response to odors during the Hunger compared to Sated condition. Specifically, EBG gamma power were elevated while hungry already at 100 ms after odor onset, thereby suggesting intra-bulbar modulation according to metabolic state. These results demonstrate that, akin to other animal models, hunger state affects OB activity in humans. Moreover, we show that the EBG method has the potential to measure internal metabolic states and, as such, could be used to study specificities in olfactory processing of individuals suffering from pathologies such as obesity or anorexia.

Opportunities and Pitfalls of REM Sleep Behavior Disorder and Olfactory Dysfunction as Early Markers in Parkinson's Disease.

During its pre-motor stage, Parkinson's disease (PD) presents itself with a multitude of non-motor symptoms with different degrees of specificity and sensitivity. The most important among them are REM sleep behavior disorder (RBD) and olfactory dysfunction. RBD is a parasomnia characterized by the loss of REM sleep muscle atonia and dream-enacting behaviors. Olfactory dysfunction in individuals with prodromal PD is usually described as hyposmia (reduced sense of smell) or anosmia (complete loss of olfactory function). These symptoms can precede the full expression of motor symptoms by decades. A close comprehension of these symptoms and the underlying mechanisms may enable early screening as well as interventions to improve patients' quality of life. Therefore, these symptoms have unmatched potential for identifying PD patients in prodromal stages, not only allowing early diagnosis but potentially opening a window for early, possibly disease-modifying intervention. However, they come with certain challenges. This review addresses some of the key opportunities and pitfalls of both RBD and olfactory dysfunction as early markers of PD.

Factors influencing olfactory function in an adult general population sample: the CHRIS study.

The sense of smell allows for the assessment of the chemical composition of volatiles in our environment. Different factors are associated with reduced olfactory function, including age, sex, as well as health and lifestyle conditions. However, most studies that aimed at identifying the variables that drive olfactory function in the population suffered from methodological weaknesses in study designs and participant selection, such as the inclusion of convenience sample or only of certain age groups, or recruitment biases. We aimed to overcome these issues by investigating the Cooperative Health Research in South Tyrol (CHRIS) cohort, a population-based cohort, by using a validated odor identification test. Specifically, we hypothesized that a series of medical, demographic and lifestyle variables is associated with odor identification abilities. In addition, our goal was to provide clinicians and researchers with normative values for the Sniffin' Sticks identification set, after exclusion of individuals with impaired nasal patency. We included 6,944 participants without acute nasal obstruction and assessed several biological, social, and medical parameters. A basic model determined that age, sex, years of education, and smoking status together explained roughly 13% of the total variance in the data. We further observed that variables related to medical (positive screening for cognitive impairment and for Parkinson's disease, history of skull fracture, stage 2 hypertension) and lifestyle (alcohol abstinence) conditions had a negative effect on odor identification scores. Finally, we provide clinicians with normative values for both versions of the Sniffin' Sticks odor identification test, i.e. with 16 items and with 12 items.

Behavioural evidence for enhanced olfactory and trigeminal perception in congenital hearing loss.

Sensory deprivation, especially hearing loss (HL), offers a valuable model for studying neuroplasticity in the human brain and adaptive behaviours that support the daily lives of those with limited or absent sensory input. The study of olfactory function is particularly important as it is an understudied aspect of sensory deprivation. This study aimed to compare the effects of congenital HL on olfactory capacity by using psychophysical tasks. Methodological concerns from previous studies regarding the onset of HL and cognitive assessments were addressed. We recruited 11 individuals with severe-to-profound sensorineural HL (SNHL) since birth and 11 age- and sex-matched typical hearing non-signers. We used standardized neuropsychological tests to assess typical cognition among participants with SNHL. We evaluated olfactory functions by assessing olfactory detection threshold, odour discrimination and odour identification. Hearing-impaired participants outperformed their typical hearing counterparts in olfactory tasks. We further evaluated the accuracy and response time in identifying and localizing odours to disentangle olfactory sensitivity from trigeminal system sensitivity. Participants with SNHL demonstrated higher sensitivity to both the identification and localization tasks. These findings suggest that congenital SNHL is associated with enhanced higher-level olfactory processing and increased trigeminal sensitivity.

Smaller grey matter volume in the central olfactory system in mild cognitive impairment.

One of the major challenges in the diagnosis of Alzheimer's disease (AD) is to increase the specificity of the early diagnosis. While episodic memory impairment is a sensitive AD marker, other measures are needed to improve diagnostic specificity. A promising biomarker might be a cerebral atrophy of the central olfactory processing areas in the early stages of the disease since an impairment of olfactory identification is present at the clinical stage of AD. Our goal was therefore, (1) to evaluate the grey matter volume (GMV) of central olfactory processing regions in prodromal AD and (2) to assess its association with episodic memory. We included 34 cognitively normal healthy controls (HC), 92 individuals with subjective cognitive decline (SCD), and 40 with mild cognitive impairment (MCI). We performed regions of interest analysis (ROI) using two different approaches, allowing to extract GMV from (1) atlas-based anatomical ROIs and from (2) functional and non-functional subregions of these ROIs (olfactory ROIs and non-olfactory ROIs). Participants with MCI exhibited smaller olfactory ROIs GMV, including significant reductions in the piriform cortex, amygdala, entorhinal cortex, and left hippocampus compared to other groups (p ≤ 0.05, corrected). No significant effect was found regarding anatomical or non-olfactory ROIs GMV. The left hippocampus olfactory ROI GMV was correlated with episodic memory performance (p < 0.05 corrected). Limbic/medial-temporal olfactory processing areas are specifically atrophied at the MCI stage, and the degree of atrophy might predict cognitive decline in AD early stages.

Olfaction and declarative memory in aging: a meta-analysis.

Olfactory and declarative memory performances are associated, as both functions are processed by overlapping medial-temporal and prefrontal structures and decline in older adults. While a decline in olfactory identification may be related to a decline in declarative memory, the relationship between olfactory detection threshold and declarative memory remains unclear. In this meta-analysis, we assessed (i) the relationship between olfactory identification/detection threshold and verbal declarative memory in cognitively normal older adults, and (ii) the effect of age on these relationships. We included articles from PsychNet, PubMed, and Academic Search Complete according to the following criteria: (i) inclusion of cognitively normal older adults; (ii) assessment of episodic or semantic memory; and (iii) assessment of olfactory identification or detection threshold. Seventeen studies and 22 effect sizes were eligible and included in this meta-analysis. Olfactory identification was associated with episodic (small effect size: r = 0.19; k = 22) and semantic memory (small effect size: r = 0.16; k = 23). Similarly, the olfactory detection threshold was associated with both episodic (small to medium effect size: r = 0.25; k = 5) and semantic memory (small effect size: r = 0.17; k = 7). Age was found to moderate the relationship between olfactory detection threshold and memory performance. Both olfactory identification and detection threshold performances are associated with declarative memory in older adults, and age only moderates the relationship between olfactory detection threshold and declarative memory performances.

A quick test to objectify smell and taste dysfunction at home: a proof of concept for the validation of the chemosensory perception test.

Recent studies have shown the efficacy of a home test for the self-evaluation of olfactory and gustatory functions in quarantined coronavirus disease-2019 (COVID-19) patients. However, testing was often limited to COVID-19 participants, and the accuracy of home test kits was rarely compared to standardized testing. This study aims at providing proof of concept for the validation of the new Chemosensory Perception Test (CPT) developed to remotely assess orthonasal olfactory, retronasal olfactory, and gustatory functions in various populations using common North American household items. In the 2 experiments, a total of 121 participants irrespective of having olfactory and/or gustatory complaints from various causes (COVID-19, sinunasal, post-viral, idiopathic) were tested first, with one or many of the following tests: (i) a brief chemosensory questionnaire, (ii) an olfactory test-Sniffin' Sticks Test (SST) or University of Pennsylvania Smell Identification Test (UPSIT), and/or (iii) a gustatory test-Brief Waterless Empirical Taste Test (B-WETT). We then applied the CPT which yielded 3 different subscores, namely orthonasal, retronasal, and gustatory CPT scores. The orthonasal CPT score was significantly correlated with SST (ρ = 0.837, P < 0.001) and UPSIT (ρ = 0.364, P < 0.001) scores, and exhibited an excellent accuracy to identify olfactory dysfunction (OD) as compared to SST (area under the curve [AUC]: 0.923 [95% confidence interval {CI}, 0.822-1.000], P < 0.001). The retronasal CPT score but not the gustatory CPT score allowed to distinguish between participants with or without subjective gustatory complaint (AUC: 0.818 [95% CI, 0.726-0.909], P < 0.001). The CPT has the ability to identify OD and to quantify subjective gustatory complaints.

Enhanced maternal behaviors in a mouse model of congenital blindness.

In mammals, mothering is one of the most important prosocial female behavior to promote survival, proper sensorimotor, and emotional development of the offspring. Different intrinsic and extrinsic factors can initiate and maintain these behaviors, such as hormonal, cerebral, and sensory changes. Infant cues also stimulate multisensory systems and orchestrate complex maternal responsiveness. To understand the maternal behavior driven by complex sensory interactions, it is necessary to comprehend the individual sensory systems by taking out other senses. An excellent model for investigating sensory regulation of maternal behavior is a murine model of congenital blindness, the ZRDBA mice, where both an anophthalmic and sighted mice are generated from the same litter. Therefore, this study aims to assess whether visual inputs are essential to driving maternal behaviors in mice. Maternal behaviors were assessed using three behavioral tests, including the pup retrieval test, the home cage maternal behavior test, and the maternal aggression test. Our results show that blind mothers (1) took less time to retrieve their offspring inside the nest, (2) spent more time nursing and licking their offspring in the second- and third-week postpartum, and (3) exhibited faster aggressive behaviors when exposed to an intruder male, compared to the sighted counterparts. This study provides evidence that congenitally blind mothers show more motivation to retrieve the pups, care, and protection towards their pups than sighted ones, likely due to a phenomenon of sensory compensation.

Chemosensation in anxiety: the trigeminal system matters.

The presence of a perceptual bias due to anxiety is well demonstrated in cognitive and sensory task for the visual and auditory modality. Event-related potentials, by their specific measurement of neural processes, have strongly contributed to this evidence. There is still no consensus as to whether such a bias exists in the chemical senses; chemosensory event-related potentials (CSERPs) are an excellent tool to clarify the heterogeneous results, especially since the Late Positive Component (LPC) may be an indicator of emotional involvement after chemosensory stimulation. This research examined the association between state and trait anxiety and the amplitude and latency of pure olfactory and mixed olfactory-trigeminal LPC. In this study, 20 healthy participants (11 women) with a mean age of 24.6 years (SD = 2.6) completed a validated questionnaire to measure anxiety (STAI), and CSERP was recorded during 40 pure olfactory stimulations (phenyl ethanol) and 40 mixed olfactory-trigeminal stimulations (eucalyptol). LPC latency and amplitude were measured at Cz (electrode located at midline central) for each participant. We observed a significant negative correlation between LPC latencies and the state anxiety scores for the mixed olfactory-trigeminal condition (r(18) = -0.513; P = 0.021), but not for the pure olfactory condition. We did not observe any effect on LPC amplitudes. This study suggests that a higher level of state anxiety is related to a more rapid perceptual electrophysiological response for mixed olfactory-trigeminal stimuli but not for pure odors.

Neurophysiology, Neuropsychology, Epilepsy, 2022: Hills We Have Climbed and the Hills Ahead. Cognition and Sensory Systems in Healthy and Diseased Subjects.

This article summarizes selected presentations from a session titled "Cognition and Sensory Systems in Healthy and Diseased Subjects", held to highlight and honor the work of Dr. Marilyn Jones-Gotman. The session was part of a two-day symposium, "Neurophysiology, Neuropsychology, Epilepsy, 2022: Hills We Have Climbed and the Hills Ahead". The session presented research on epilepsy and sensory systems by colleagues and former trainees of Dr. Jones-Gotman. The extended summaries provide an overview of historical and current work in the neuropsychology of epilepsy, neuropsychological and neuroimaging approaches to understanding brain organization, sex differences in brain mechanisms underlying neurological disorders, dietary influences on brain function and cognition, and expertise in olfactory training and language experiences and their implications for brain organization and structure.

Olfactory Training Impacts Olfactory Dysfunction Induced by COVID-19: A Pilot Study.

INTRODUCTION: Olfactory dysfunction is one of the main symptoms of COVID-19 and may last beyond resolution of the infection. The most promising intervention for post-viral olfactory dysfunction is olfactory training (OT), which involves exposing the olfactory system to a range of odors daily. This approach is thought of promoting the regeneration of olfactory receptor cells, but its effectiveness in patients with post-COVID-19 olfactory dysfunction has yet to be confirmed. METHODS: This double-blind randomized pilot study compared the effectiveness of OT versus placebo in the treatment of post-COVID-19 olfactory dysfunction. Twenty-five participants were recruited in each group. OT protocol consisted of sniffing 4 scents (rose, orange, clove, and eucalyptus) for 5 min twice daily for 12 weeks. Olfactory function was assessed before and after the training using (1) a validated odor identification test (UPSIT-40) and (2) a 10-point visual analog scale; we further assessed the presence of (3) parosmia. RESULTS: While we did not observe any effect of OT on olfactory test scores, we observed a significant improvement of subjective olfactory function in the intervention group, while no such effect was observed in the placebo group. Finally, the frequency of parosmia was significantly lower in the intervention group. CONCLUSIONS: This study highlights an increase in subjective but not objective olfactory function when performing OT for 12 weeks. Further, parosmia seems to be positively affected by OT. These results may serve as a starting point for larger scale studies to assess the efficacy of OT for treatment of post-COVID-19 olfactory dysfunction.

Olfactory perception in patients with a mild traumatic brain injury: a longitudinal study.

OBJECTIVE: This longitudinal study aimed to evaluate olfactory perception in patients with first time mild traumatic brain injury (mTBI) 2-4 weeks (baseline) and 6 months (follow-up) following their trauma. METHODS: At baseline, we enrolled 107 participants (54 healthy controls; 53 patients with mTBI). Thirty-nine healthy controls and 32 patients with mTBI returned for follow-up. We assessed odor detection (yes/no paradigm) and odor perception with a self-reported evaluation of intensity and pleasantness of four common odorants, by using an olfactometer, i.e., a computer controlled automated odor presentation device. RESULTS: At baseline, patients with mTBI showed significantly more difficulty detecting odors; however, they perceived them as more intense and less pleasant. These effects vanished at follow-up. CONCLUSION: These results suggest that patients with mTBI suffer from altered olfactory detection and perception in the first weeks following their trauma. This may have an impact on eating behavior and quality of life. Further, our data suggest recovery of olfactory function within the first six months following a head trauma.

Altered morphological traits along central olfactory centres in congenitally blind subjects.

It is well documented that early sensory loss typically alters brain morphology in the areas associated with the lost sense. However, much less is known about the impact of early sensory loss on the remainder of the sensory regions. Therefore, we investigated whether congenitally blind (CB) individuals show brain alterations in the olfactory system by comparing cortical morphology and olfactory bulb (OB) volume between 16 congenitally blind individuals and 16 sighted matched controls. Our results showed that not only CB blind individuals exhibited smaller OB but also alterations of cortical density in some higher olfactory processing centres, but unchanged cortical thickness. Our current findings suggest that a lifelong absence of visual input leads to morphological alterations in olfactory processing areas.

Persisting chemosensory impairments in 366 healthcare workers following COVID-19: an 11-month follow-up.

Olfactory and gustatory dysfunctions (OD, GD) are prevalent symptoms following COVID-19 and persist in 6%-44% of individuals post-infection. As only few reports have described their prognosis after 6 months, our main objective was to assess the prevalence of OD and GD 11-month post-COVID-19. We also aimed to determine intraclass correlation coefficients (ICC) of chemosensory self-ratings for the follow-up of chemosensory sensitivity. We designed an observational study and distributed an online questionnaire assessing chemosensory function to healthcare workers with a RT-PCR-confirmed SARS-CoV-2 infection 5- and 11-month post-COVID-19. Specifically, we assessed olfaction, gustation, and trigeminal sensitivity (10-point visual analog scale) and function (4-point Likert scale). We further measured clinically relevant OD using the Chemosensory Perception Test, a psychophysical test designed to provide a reliable remote olfactory evaluation. We included a total of 366 participants (mean [SD] age of 44.8 (11.7) years old). They completed the last online questionnaire 10.6 months (0.7) after the onset of COVID-19 symptoms. Of all participants, 307 (83.9%) and 301 (82.2%) individuals retrospectively reported lower olfactory or gustatory sensitivity during the acute phase of COVID-19. At the time of evaluation, 184 (50.3%) and 163 (44.5%) indicated reduced chemosensory sensitivity, 32.2% reported impairment of olfactory function while 24.9% exhibited clinically relevant OD. Olfactory sensitivity had a high test-retest reliability (ICC: 0.818; 95% CI: 0.760-0.860). This study suggests that chemosensory dysfunctions persist in a third of COVID-19 patients 11 months after COVID-19. OD appears to be a common symptom of post-COVID-19 important to consider when treating patients.

Effects of Congenital Blindness on Ultrasonic Vocalizations and Social Behaviors in the ZRDBA Mouse.

Mice produce ultrasonic vocalizations (USVs) at different ages and social contexts, including maternal-pup separation, social play in juveniles, social interactions, and mating in adults. The USVs' recording can be used as an index of sensory detection, internal state, and social motivation. While sensory deprivation may alter USVs' emission and some social behaviors in deaf and anosmic rodents, little is known about the effects of visual deprivation in rodents. This longitudinal study aimed to assess acoustic communication and social behaviors using a mouse model of congenital blindness. Anophthalmic and sighted mice were assayed to a series of behavioral tests at three different ages, namely, the maternal isolation-induced pup USV test and the home odor discrimination and preference test on postnatal day (PND) 7, the juvenile social test on PND 30-35, and the female urine-induced USVs and scent-marking behavior at 2-3 months. Our results evidenced that (1) at PND 7, USVs' total number between both groups was similar, all mice vocalized less during the second isolation period than the first period, and both phenotypes showed similar discrimination and preference, favoring exploration of the home bedding odor; (2) at PND 30-35, anophthalmic mice engaged less in social behaviors in the juvenile play test than sighted ones, but the number of total USVs produced is not affected; and (3) at adulthood, when exposed to a female urine spot, anophthalmic male mice displayed faster responses in terms of USVs' emission and sniffing behavior, associated with a longer time spent exploring the female urinary odor. Interestingly, acoustic behavior in the pups and adults was correlated in sighted mice only. Together, our study reveals that congenital visual deprivation had no effect on the number of USVs emitted in the pups and juveniles, but affected the USVs' emission in the adult male and impacted the social behavior in juvenile and adult mice.

Olfactory bulb volume and cortical thickness evolve during sommelier training.

Brain plasticity is essential for experts to acquire the abilities they need. Sommeliers are olfaction experts who display differences in olfactory regions in the brain that correlate with greater olfactory abilities. While most studies on this topic are cross-sectional, we used a longitudinal design and invited 17 sommelier students at the start and end of their training then to compare them to 17 control students to study the effects of training-related brain plasticity. After a year and a half, 5 sommelier students and 4 control students dropped out, leading to 12 sommelier students versus 13 controls. We used magnetic resonance imaging to measure cortical thickness and olfactory bulb volume, as this structure plays a crucial role in olfactory processing. We used the Sniffin' Sticks test to evaluate olfactory performance. During training, olfactory bulb volume increased in sommelier students while there was no significant change in the control group. We also observed that thickness of right entorhinal cortex increased, and cortical thickness decreased in other cerebral regions. Our olfactory tests did not reveal any significant changes in sommelier students. In conclusion, this is the first longitudinal study to report an increase in olfactory bulb volume in olfaction experts in line with the notion of effects of ecological training-related brain plasticity. The mixed results about cortical thickness might be explained by a "overproduction-pruning" model of brain plasticity, according to which the effects of training-related plasticity are non-linear and simultaneously involve different processes.

Cortical network and connectivity underlying hedonic olfactory perception.

Objective.The emotional response to olfactory stimuli implies the activation of a complex cascade of events triggered by structures lying in the limbic system. However, little is known about how this activation is projected up to cerebral cortex and how different cortical areas dynamically interact each other.Approach.In this study, we acquired EEG from human participants performing a passive odor-perception task with odorants conveying positive, neutral and negative valence. A novel methodological pipeline integrating global field power (GFP), independent component analysis (ICA), dipole source localization was applied to estimate effective connectivity in the challenging scenario of single-trial low-synchronized stimulation.Main results.We identified the brain network and the neural paths, elicited at different frequency bands, i.e.θ(4-7Hz),α(8-12Hz)andß(13-30Hz), involved in odor valence processing. This brain network includes the orbitofrontal cortex (OFC), the cingulate gyrus (CgG), the superior temporal gyrus (STG), the posterior cingulate cortex/precuneus (PCC/PCu) and the parahippocampal gyrus (PHG). It was analyzed using a time-varying multivariate autoregressive model to resolve time-frequency causal interactions. Specifically, the OFC acts as the main node for odor perception and evaluation of pleasant and unpleasant stimuli, whereas no specific path was observed for a neutral stimulus.Significance.The results introduce new evidences on the role of the OFC during hedonic perception and underpin its specificity during the odor valence assessment. Our findings suggest that, after the odor onset different, bidirectional interactions occur between the OFC and other brain regions associated with emotion recognition/categorization and memory according to the stimulus valence. This outcome unveils how the hedonic olfactory network dynamically changes based on odor valence.

Quantifying neural efficiency and neural capacity across the brain during a working memory task using a quadratic model of neural-cognitive relationships.

Task-based functional magnetic resonance imaging (MRI) neuroimaging for the study of cognitive neuroscience provides insight into how the brain responds to increasing cognitive demands. Theoretical models of neural-cognitive relationships define neural efficiency and neural capacity as two parameters to describe the rate of gain of brain activity and the upper limits of the increases, respectively. Although qualitatively well described, there are limited discussions and demonstrations of estimating these parameters from data. The current work presents a method using a quadratic equation model of cognitive demands. The methods were applied to 21 healthy young adults while engaging in four levels of the verbal n-back working memory task (0, 1, 2 and 3-back). Measures of the area under the curve captured both linear and curvilinear responses to quantify the locations and amounts of task-related increases in brain activity. In addition, we calculated voxel-wise maps of neural efficiency and neural capacity. Results showed increases in brain activation in regions typically involved in working memory. The relationships between increasing cognitive demands and brain activity also differed across the brain within and between individuals, as indicated by differential neural efficiency and neural capacity values. This approach provides tools for evaluating current theories about the relationships between brain activity and cognition. Neural efficiency and neural capacity provide physiological measures of brain activity, which will help evaluate how age, disease and intervention processes affect brain activity. Finally, all presented methods are readily applicable using standard current software packages for neuroimaging.

Volumetry of Olfactory Structures in Mild Cognitive Impairment and Alzheimer's Disease: A Systematic Review and a Meta-Analysis.

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