Reduced olfactory bulb volume accompanies olfactory dysfunction after mild SARS-CoV-2 infection.

Despite its high prevalence, the determinants of smelling impairment in COVID-19 remain not fully understood. In this work, we aimed to examine the association between olfactory bulb volume and the clinical trajectory of COVID-19-related smelling impairment in a large-scale magnetic resonance imaging (MRI) analysis. Data of non-vaccinated COVID-19 convalescents recruited within the framework of the prospective Hamburg City Health Study COVID Program between March and December 2020 were analyzed. At baseline, 233 participants underwent MRI and neuropsychological testing as well as a structured questionnaire for olfactory function. Between March and April 2022, olfactory function was assessed at follow-up including quantitative olfactometric testing with Sniffin' Sticks. This study included 233 individuals recovered from mainly mild to moderate SARS-CoV-2 infections. Longitudinal assessment demonstrated a declining prevalence of self-reported olfactory dysfunction from 67.1% at acute infection, 21.0% at baseline examination and 17.5% at follow-up. Participants with post-acute self-reported olfactory dysfunction had a significantly lower olfactory bulb volume at baseline than normally smelling individuals. Olfactory bulb volume at baseline predicted olfactometric scores at follow-up. Performance in neuropsychological testing was not significantly associated with the olfactory bulb volume. Our work demonstrates an association of long-term self-reported smelling dysfunction and olfactory bulb integrity in a sample of individuals recovered from mainly mild to moderate COVID-19. Collectively, our results highlight olfactory bulb volume as a surrogate marker that may inform diagnosis and guide rehabilitation strategies in COVID-19.

Olfactory Bulb Volume and Morphology Changes in COVID-19 Patients With Olfactory Disorders Using Magnetic Resonance Imaging.

OBJECTIVES: The aims of the study are to explore the morphological changes of olfactory bulb (OB) and olfactory sulcus in COVID-19 patients with associated olfactory dysfunction (OD) by measuring the OB volume (OBV) and olfactory sulcus depth (OSD) and to compare the measurement values with those of healthy individuals. METHODS: Between March 2020 and January 2022, 31 consecutive hospitalized patients with a diagnosis of COVID-19 with anosmia and hyposmia who underwent brain magnetic resonance imaging and 35 normosmic control individuals were retrospectively included in the study. Bilateral OBV and OSD were measured and shape of the OB was determined based on the consensus by a neuroradiologist and an otorrhynolaryngologist. RESULTS: The mean measurements for the right and the left sides for OBV (38 ± 8.5 and 37.1 ± 8.4, respectively) and OSD (7.4 ± 0.1 and 7.4 ± 1.0 mm, respectively) were significantly lower in COVID-19 patients with OD than those in control group (for the right and the left sides mean OBV 56.3 ± 17.1 and 49.1 ± 13.5, respectively, and mean OSD 9.6 ± 0.8 and 9.4 ± 0.8 mm, respectively). Abnormally shaped OB (lobulated, rectangular, or atrophic) were higher in patient group than those of controls.For the optimal cutoff values, OBV showed sensitivity and specificity values of 90.32% and, 57.14%, for the right, and 87.1% and 62.86% for the left side, respectively (area under the curve, 0.819 and 0.780). Olfactory sulcus depth showed sensitivity and specificity values of 90.32% and 94.29%, for the right, and 96.77% and 85.71%, for the left side, respectively (area under the curve, 0.960 and 0.944). CONCLUSIONS: Decrease in OBV and OSD measurements in COVID-19 patients with OD at the early chronic stage of the disease supports direct damage to olfactory neuronal pathways and may be used to monitor olfactory nerve renewal while returning back to normal function.

Neuroimaging the Development of Olfactory Function in a Woman With No Olfactory Bulbs.

This case report describes a woman with lifelong anosmia in her 20s who presented with the acquisition of unpleasant olfactory phantoms.

Olfactory training with four and eight odors: comparison with clinical testing and olfactory bulb volumetrics.

PURPOSE: Post-infectious olfactory dysfunction (PIOD) is one of the most common causes of olfactory impairment but has limited treatment options. Recently, olfactory training (OT) has been considered an effective treatment method; however, several questions have arisen regarding its optimal scheme. The aim of this study was to assess whether an OT scheme with 8 odors is more effective than the classic OT scheme with 4 odors by comparing psychophysical test results and olfactory bulb (OB) volumetrics. METHODS: In this prospective cohort study, 72 patients with PIOD were included. The patients followed either the classic 4-odor OT scheme (COT; n = 34 patients) or an extended 8-odor scheme (EOT; n = 38 patients) for 16 weeks. All patients underwent olfactory testing with a Sniffin'Sticks battery test at 0, 8, and 16 weeks. Of the patients, 38 underwent brain magnetic resonance imaging for OB volumetric assessment before and after treatment. RESULTS: The comparison of the olfactory test results did not show any significant difference between the two study groups, in agreement with the OB volumetrics. The convex OB showed better test results than the non-convex OB, with significantly better improvement after treatment regardless of OT type. The EOT group presented significantly better adherence than the COT group. CONCLUSION: The number of odors did not appear to play a significant role in the effect of the OT. However, the training scheme with more than four odors showed better adherence among the patients in a long-term treatment plan. The shape of the OB may have prognostic value in clinical assessment and warrants further investigation.

Functional MRI of murine olfactory bulbs at 15.2T reveals characteristic activation patters when stimulated by different odors.

Thanks to its increased sensitivity, single-shot ultrahigh field functional MRI (UHF fMRI) could lead to valuable insight about subtle brain functions such as olfaction. However, UHF fMRI experiments targeting small organs next to air voids, such as the olfactory bulb, are severely affected by field inhomogeneity problems. Spatiotemporal Encoding (SPEN) is an emerging single-shot MRI technique that could provide a route for bypassing these complications. This is here explored with single-shot fMRI studies on the olfactory bulbs of male and female mice performed at 15.2T. SPEN images collected on these organs at a 108 µm in-plane resolution yielded remarkably large and well-defined responses to olfactory cues. Under suitable T2* weightings these activation-driven changes exceeded 5% of the overall signal intensity, becoming clearly visible in the images without statistical treatment. The nature of the SPEN signal intensity changes in such experiments was unambiguously linked to olfaction, via single-nostril experiments. These experiments highlighted specific activation regions in the external plexiform region and in glomeruli in the lateral part of the bulb, when stimulated by aversive or appetitive odors, respectively. These strong signal activations were non-linear with concentration, and shed light on how chemosensory signals reaching the olfactory epithelium react in response to different cues. Second-level analyses highlighted clear differences among the appetitive, aversive and neutral odor maps; no such differences were evident upon comparing male against female olfactory activation regions.

[Olfactory function and olfactory bulbs in patients with Kallmann syndrome].

BACKGROUND: The majority of Kallmann patients have anosmia or hyposmia. This is how the disease is diagnosed. Some of them don't have such complaints but olfactory dysfunction is diagnosed via olfactometry. Nowadays there is the lack of information about correlation between olfactometry results and subjective complaints. Correlation between olfactory bulbs size and olfactory dysfunction has been little studied. AIM: To explore olfactory bulb size and olfactory function in patients with congenital isolated hypogonadotropic hypogonadism. To correlate olfactory bulb sizes and smell test scores. MATERIALS AND METHODS: Single-centre comparative study. 34 patients were included. The main group consisted of 19 patients with hypogonadotropic (15 -with Kallmann syndrome, 4 - with normosmic hypogonadism). Olfactory bulbs MRI were provided to all the patients, olfactory test (Sniffin' Sticks Test) and molecular-genetic studies were provided in all patients with hypogonadism. Control group consisted of 15 patients who were provided with orbits MRI. Olfactory bulbs were evaluated additionally in them. RESULTS: Normal size of olfactory bulbs were only in 1 patient with hypogonadism. Olfactory bulbs height and width were significantly smaller in patients with hypogonadism in comparison with control group (p<0.01). Height median of right bulb was 1.0 mm [0.2; 1.8] in patients from the main group vs. 3.0 [2.5; 3.2] in controls, width median of right bulb was 1.0 mm [0.2; 1.9] in patients from the main group vs. 2.5 [2.0; 3.0] in controls. Height median of left bulb was 0.8 mm [0.0; 1.2] in patients from the main group vs. 3.0 [2.7; 3.2] in controls, width median of left bulb was 0.8 mm [0.0; 1.2] in patients from the main group vs. 2.5 [2.0; 3.0] in controls. Correlation has been established between left bulb height (r=0.59) and width (r=0.67) and olfactometry results (p<0.05). 4 patients had no anosmia complaints but had olfactory dysfunction according to Sniffin' Sticks Tests. CONCLUSION: Olfactometry was able to diagnose olfactory dysfunction in 78.5% (i.e. in 15 out of 19 patients with congenital isolated hypogonadotropic hypogonadism. However, anosmia complaints had only 11 out of 19 patients. It is the first results of olfactory bulb sizes in patients with hypogonadotropic hypogonadism in Russia. Uni - or bilateral hypoor aplasia were diagnosed in 94.7% patients with hypogonadism regardless of olfactory dysfunction. Bilateral olfactory bulbs hypoplasia were the most common MRI-finding (36.8%). Unilateral hypoor aplasia was diagnosed in 31.6% patients.

The potential for clinical application of automatic quantification of olfactory bulb volume in MRI scans using convolutional neural networks.

The olfactory bulbs (OBs) play a key role in olfactory processing; their volume is important for diagnosis, prognosis and treatment of patients with olfactory loss. Until now, measurements of OB volumes have been limited to quantification of manually segmented OBs, which is a cumbersome task and makes evaluation of OB volumes in large scale clinical studies infeasible. Hence, the aim of this study was to evaluate the potential of our previously developed automatic OB segmentation method for application in clinical practice and to relate the results to clinical outcome measures. To evaluate utilization potential of the automatic segmentation method, three data sets containing MR scans of patients with olfactory loss were included. Dataset 1 (N = 66) and 3 (N = 181) were collected at the Smell and Taste Center in Ede (NL) on a 3 T scanner; dataset 2 (N = 42) was collected at the Smell and Taste Clinic in Dresden (DE) on a 1.5 T scanner. To define the reference standard, manual annotation of the OBs was performed in Dataset 1 and 2. OBs were segmented with a method that employs two consecutive convolutional neural networks (CNNs) that the first localize the OBs in an MRI scan and subsequently segment them. In Dataset 1 and 2, the method accurately segmented the OBs, resulting in a Dice coefficient above 0.7 and average symmetrical surface distance below 0.3 mm. Volumes determined from manual and automatic segmentations showed a strong correlation (Dataset 1: r = 0.79, p < 0.001; Dataset 2: r = 0.72, p = 0.004). In addition, the method was able to recognize the absence of an OB. In Dataset 3, OB volumes computed from automatic segmentations obtained with our method were related to clinical outcome measures, i.e. duration and etiology of olfactory loss, and olfactory ability. We found that OB volume was significantly related to age of the patient, duration and etiology of olfactory loss, and olfactory ability (F(5, 172) = 11.348, p < 0.001, R2 = 0.248). In conclusion, the results demonstrate that automatic segmentation of the OBs and subsequent computation of their volumes in MRI scans can be performed accurately and can be applied in clinical and research population studies. Automatic evaluation may lead to more insight in the role of OB volume in diagnosis, prognosis and treatment of olfactory loss.

Reduced olfactory bulb volume and olfactory sulcus depth in obsessive compulsive disorder.

Many studies have shown that limbic system abnormalities are seen in obsessive-compulsive disorder (OCD), but the neurobiological changes in OCD are still unclear. Moreover, olfactory bulb volume (OBV) and its association with symptom severity have not been yet investigated in patients with OCD. This is the first study on OBV and olfactory sulcus depth (OSD) values in OCD patients, to the best of our knowledge. Between January 2018 and March 2022, 25 patients with OCD and 26 healthy controls with brain magnetic resonance imaging (MRI) were included. Detailed disease history of OCD patients was taken, and Yale-Brown obsessive-compulsive scale (YBOCS) was applied. The mean age of the patient group was 33.40±9.58, the mean age of the control group was 32.84±8.01. LOBV, ROBV, TOBV, and LOSD in the patient group were significantly lower than in the control group (p=.013, p=.005, p=.001, p=.015, respectively). ROBV and TOBV were negatively correlated with YBOCS total and subscale scores. A negative correlation was found between ROBV and TOBV and disease duration (r=-0.749 and r=-0.640, respectively). The negative correlation of ROBV and TOBV values with disease duration and disease severity can be used to monitor the neurodegenerative process of OCD disease.

Olfactory bulb volume in cochlear implant candidates as compared to age-matched control subjects: A potential marker of cognitive function for auditory information processing.

OBJECTIVE: To evaluate magnetic resonance imaging (MRI)-based olfactory bulb (OB) volumes in cochlear implant (CI) candidates with sensorineural hearing loss as compared to age-matched control subjects with normal hearing. METHODS: A total of 31 pediatric CI candidates (mean ± SD age: 7.0 ± 2.5 years, 51.6% were boys) with sensorineural hearing loss and 35 age-matched control subjects (mean ± SD age: 7.1 ± 2.5 years, 54.3% were boys) with normal hearing were included in this study. Data on demographic characteristics (age, gender) and right and left OB volume (mm3) on MRI using planimetric contouring method were recorded in patients and control groups. RESULTS: Median (min-max) values for right OB volume (80(50-120) vs. 90(50-160) mm3, p = 0.006) and left OB volume (70(50-120) vs. 90(50-170) mm3, p = 0.007) were significantly lower in CI candidates vs. controls, regardless of the gender and age. No significant difference was noted between right and left OB volume in CI candidate and control groups. Hearing loss subgroups of CI candidates including hereditary familial (n = 8), hereditary non-familial (n = 14) and mixed syndromic (9) subgroups were also similar in terms of patient demographics and OB volumes. There was a tendency for having lower left OB volume (60(50-120) vs. 80(60-110) mm3) in girls vs. boys in the CI candidate group, along with a tendency for lower left and right OB volume in candidates vs. controls, particularly at age 11 (median 120 vs. 80 mm3 and 120 vs. 60 mm3, respectively). No significant correlation of age was noted with right and left OB volume overall and in the study groups. CONCLUSION: In conclusion, our findings revealed lower left and right OB volumes in CI candidates compared to control subjects, regardless of age and gender, indicating the presence of baseline olfactory dysfunction in patients with hearing loss planned to undergo CI. Accordingly, MRI-based measurement of OB volume in the pre-surgical workup of CI candidates may serve as a marker of cognitive function enabling auditory information processing that may also correlate with post-operative CI outcomes.

Clinical and Imaging Evaluation of COVID-19-Related Olfactory Dysfunction.

BACKGROUND: Olfactory dysfunction has been reported in 47.85% of COVID patients. It can be broadly categorized into conductive or sensorineural olfactory loss. Conductive loss occurs due to impaired nasal air flow, while sensorineural loss implies dysfunction of the olfactory epithelium or central olfactory pathways. OBJECTIVES: The aim of this study was to analyze the clinical and imaging findings in patients with COVID-related olfactory dysfunction. Additionally, the study aimed to investigate the possible mechanisms of COVID-related olfactory dysfunction. METHODS: The study included 110 patients with post-COVID-19 olfactory dysfunction, and a control group of 50 COVID-negative subjects with normal olfactory function. Endoscopic nasal examination was performed for all participants with special focus on the olfactory cleft. Smell testing was performed for all participants by using a smell diskettes test. Olfactory pathway magnetic resonance imaging (MRI) was done to assess the condition of the olfactory cleft and the dimensions and volume of the olfactory bulb. RESULTS: Olfactory dysfunction was not associated with nasal symptoms in 51.8% of patients. MRI showed significantly increased olfactory bulb dimensions and volume competed to controls. Additionally, it revealed olfactory cleft edema in 57.3% of patients. On the other hand, radiological evidence of sinusitis was detected in only 15.5% of patients. CONCLUSION: The average olfactory bulb volumes were significantly higher in the patients' group compared to the control group, indicating significant edema and swelling in the olfactory bulb in patients with COVID-related olfactory dysfunction. Furthermore, in most patients, no sinonasal symptoms such as nasal congestion or rhinorrhea were reported, and similarly, no radiological evidence of sinusitis was detected. Consequently, the most probable mechanism of COVID-related olfactory dysfunction is sensorineural loss through virus spread and damage to the olfactory epithelium and pathways.

The Association Between Depth of the Olfactory Sulcus, Age, Gender and Olfactory Function: An MRI-based Investigation in More Than 1000 Participants.

OBJECTIVE: The present study aimed to investigate the relationship between olfactory sulcus (OS) depth and olfactory function considering age and gender and to provide normative data on OS depth in a population with normal olfactory function. MATERIALS AND METHODS: OS depth was obtained using T1 magnetic resonance imaging scans. Participants (mean age ± sd = 57 ± 16 years, ranging from 20 to 80 years) were screened for olfactory function using the Sniffin' Sticks Screening 12 test. They were divided into an olfactory dysfunction group (n = 604) and a normosmia group (n = 493). Participants also completed questionnaires measuring depression, anxiety and quality of life. RESULTS: The right OS was deeper than the left side in all age groups. On the left side, women had deeper OS compared with men, exhibiting a higher degree of symmetry in left and right OS depth in women. Variance of olfactory function was largely determined by age, OS depth explained only minor portions of this variance. Normative data for minimum OS depth was 7.55 mm on the left and 8.78 mm on the right for participants aged between 18 and 35 years (n = 144), 6.47 mm on the left and 6.99 mm on the right for those aged 36-55 years (n = 120), and 5.28 mm on the left and 6.19 mm on the right for participants older than 55 years (n = 222). CONCLUSION: Considering the limited resolution of the presently used T1 weighted MR scans and the nature of the olfactory screening test, OS depth explained only minor portions of the variance of olfactory function, which was largely determined by age. Age-related normative data of OS depth are presented as a reference for future work.

MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms.

BACKGROUND AND OBJECTIVE: Despite olfactory disorders being among the most common neurological complications of coronavirus disease 2019 (COVID-19), their pathogenesis has not been fully elucidated yet. Brain MR imaging is a consolidated method for evaluating olfactory system's morphological modification, but a few quantitative studies have been published so far. The aim of the study was to provide MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms, including olfactory dysfunction. METHODS: 196 COVID-19 patients (median age: 53 years, 56% females) and 39 controls (median age 55 years, 49% females) were included in this cross-sectional observational study; 78 of the patients reported olfactory loss as the only neurological symptom. MRI processing was performed by ad-hoc semi-automatic processing procedures. Olfactory bulb (OB) volume was measured on T2-weighted MRI based on manual tracing and normalized to the brain volume. Olfactory tract (OT) median signal intensity was quantified on fluid attenuated inversion recovery (FLAIR) sequences, after preliminary intensity normalization. RESULTS: COVID-19 patients showed significantly lower left, right and total OB volumes than controls (p < 0.05). Age-related OB atrophy was found in the control but not in the patient population. No significant difference was found between patients with olfactory disorders and other neurological symptoms. Several outliers with abnormally high OT FLAIR signal intensity were found in the patient group. CONCLUSIONS: Brain MRI findings demonstrated OB damage in COVID-19 patients with neurological complications. Future longitudinal studies are needed to clarify the transient or permanent nature of OB atrophy in COVID-19 pathology.

Cholinergic Nucleus 4 Degeneration and Cognitive Impairment in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Cholinergic nucleus 4 (Ch4) degeneration is associated with cognitive impairment in Parkinson's disease and dementia with Lewy bodies, but it is unknown if Ch4 degeneration is also present in isolated rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: The aim was to determine if there is evidence of Ch4 degeneration in patients with iRBD and if it is associated with cognitive impairment. METHODS: We analyzed the clinical and neuropsychological data of 35 iRBD patients and 35 age- and sex-matched healthy controls. Regional gray matter density (GMD) was calculated for Ch4 using probabilistic maps applied to brain magnetic resonance imaging (MRI). RESULTS: Ch4 GMD was significantly lower in the iRBD group compared to controls (0.417 vs. 0.441, P = 0.02). Ch4 GMD was also found to be a significant predictor of letter number sequencing (ß-coefficient = 58.31, P = 0.026, 95% confidence interval [7.47, 109.15]), a measure of working memory. CONCLUSIONS: iRBD is associated with Ch4 degeneration, and Ch4 degeneration in iRBD is associated with impairment in working memory. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Is abnormal metabolism in the olfactory bulb and amygdala associated with bipolar disorder?

Accumulated evidence has demonstrated abnormal amygdala activation in bipolar disorder (BD). The olfactory bulb (OB) has vigorous connections with the amygdala. Although odor-related functions of the OB decreased during the evolutionary process, we hypothesized that an evolved OB with increased activation in emotion regulation may be one of the main factors affecting amygdala functions in BD. Our aim was to investigate metabolism in the OB and amygdala in patients with BD. Twenty-six patients diagnosed with BD according to DSM-5 diagnostic criteria were included in this cross-sectional study. Metabolism in the OB and amygdala was assessed using fluorodeoxyglucose positron emission tomography/CT in patients with BD. The OB and amygdala metabolism was compared with the patients' Z scores. Both OB and amygdala metabolic activities were significantly higher than in the controls. A positive correlation was detected between right/left amygdala metabolism and right OB metabolism (p < 0.05, r:467 and r:662, respectively). This study increased our understanding of the etiopathogenesis of BD. In BD, the main cause of hypermetabolism in the amygdala may be increased metabolism in the OB. During evolution, the OB may have assumed a dominant role in emotional processing rather than olfactory functions.

Olfactory system measurements in COVID-19: a systematic review and meta-analysis.

PURPOSE: The neurotropism of SARS-CoV-2 and the consequential damage to the olfactory system have been proposed as one of the possible underlying causes of olfactory dysfunction in COVID-19. We aimed to aggregate the results of the studies which reported imaging of the olfactory system of patients with COVID-19 versus controls. METHODS: PubMed and EMBASE were searched to identify relevant literature reporting the structural imaging characteristics of the olfactory bulb (OB), olfactory cleft, olfactory sulcus (OS), or olfactory tract in COVID-19 patients. Hedge's g and weighted mean difference were used as a measure of effect size. Quality assessment, subgroup analyses, meta-regression, and sensitivity analysis were also conducted. RESULTS: Ten studies were included in the qualitative synthesis, out of which seven studies with 183 cases with COVID-19 and 308 controls without COVID-19 were enrolled in the quantitative synthesis. No significant differences were detected in analyses of right OB volume and left OB volume. Likewise, right OS depth and left OS depth were also not significantly different in COVID-19 cases compared to non-COVID-19 controls. Also, we performed subgroup analysis, meta-regression, and sensitivity analysis to investigate the potential effect of confounding moderators. CONCLUSION: The findings of this review did not confirm alterations in structural imaging of the olfactory system, including OB volume and OS depth by Covid-19 which is consistent with the results of recent histopathological evaluations.

Deficits in peripheric and central olfactory measurements in smokers: evaluated by cranial MRI.

OBJECTIVES: Cigarette smoking remains a serious health problem all over the world. We investigated the peripheral and central olfactory pathways in young male smokers to determine whether there is a relationship between the amount of cigarettes smoked and duration of smoking and the dimensions of the olfactory areas. METHODS: In this retrospective study, cranial Magnetic Resonance Imaging (MRI) images of adult male smokers aged ≤ 40 years (n = 51) and 50 healthy male adults were analyzed. The olfactory bulbus (OB) volumes and olfactory sulcus (OS) depths, insular gyrus, and corpus amygdala areas were measured via cranial MRI. In the smoker group, the number of cigarettes smoked and duration of smoking were noted and the Brinkmann index was calculated. RESULTS: OB volume, OS depth, and the insular gyrus areas of the smokers were lower than in the control group (p < 0.05). There were no differences between the groups in terms of the corpus amygdala measurements (p > 0.05). No significant correlations were found between the number of cigarettes smoked daily, smoking duration, and the Brinkmann index and the peripheral and central olfactory measurements in our study (p > 0.05). CONCLUSIONS: In smokers, OB volumes, the OS, and the central areas decrease bilaterally, regardless of smoking duration and number of cigarettes smoked daily. This could be related to inflammatory mediators that may be harmful to the olfactory neuroepithelium, gray matter atrophy in the brain, or endothelial damage related to smoking and its effects on blood support to the brain and olfactory regions.

Effects of COVID-19 on the Human Central Olfactory System: A Natural Pre-Post Experiment.

BACKGROUND AND PURPOSE: Reduced olfactory function is the symptom with the highest prevalence in coronavirus disease 2019 (COVID-19) with nearly 70% of infected individuals experiencing partial or total loss of their sense of smell at some point during the disease. The exact cause is not known, but beyond peripheral damage, studies have demonstrated insults to both the olfactory bulb and central olfactory brain areas. However, these studies often lack both baseline pre-COVID-19 assessments and control groups, and the effects could, therefore, simply reflect pre-existing risk factors. MATERIALS AND METHODS: Shortly before the COVID-19 outbreak, we completed an olfactory-focused study, which included structural MR brain images and a full clinical olfactory test. Opportunistically, we invited participants back 1 year later, including 9 participants who had experienced mild-to-moderate COVID-19 (C19+) and 12 who had not (C19-), creating a natural pre-post experiment with a control group. RESULTS: Despite C19+ participants reporting subjective olfactory dysfunction, few showed signs of objectively altered function. Critically, all except 1 individual in the C19+ group had reduced olfactory bulb volume (average reduction, 14.3%), but this did not amount to a significant statistical difference compared with the control group (2.3%) using inference statistics. We found no morphologic differences in olfactory brain areas but stronger functional connectivity between olfactory brain areas in the C19+ group at the postmeasure. CONCLUSIONS: Our data suggest that COVID-19 might cause long-term reduction in olfactory bulb volume and altered functional connectivity but with no discernible morphologic differences in cerebral olfactory regions.

MRI tractography reveals the human olfactory nerve map connecting the olfactory epithelium and olfactory bulb.

The olfactory nerve map describes the topographical neural connections between the olfactory epithelium in the nasal cavity and the olfactory bulb. Previous studies have constructed the olfactory nerve maps of rodents using histological analyses or transgenic animal models to investigate olfactory nerve pathways. However, the human olfactory nerve map remains unknown. Here, we demonstrate that high-field magnetic resonance imaging and diffusion tensor tractography can be used to visualize olfactory sensory neurons while maintaining their three-dimensional structures. This technique allowed us to evaluate the olfactory sensory neuron projections from the nasal cavities to the olfactory bulbs and visualize the olfactory nerve maps of humans, marmosets and mice. The olfactory nerve maps revealed that the dorsal-ventral and medial-lateral axes were preserved between the olfactory epithelium and olfactory bulb in all three species. Further development of this technique might allow it to be used clinically to facilitate the diagnosis of olfactory dysfunction.

Deep Learning-Based Segmentation of Post-Mortem Human's Olfactory Bulb Structures in X-ray Phase-Contrast Tomography.

The human olfactory bulb (OB) has a laminar structure. The segregation of cell populations in the OB image poses a significant challenge because of indistinct boundaries of the layers. Standard 3D visualization tools usually have a low resolution and cannot provide the high accuracy required for morphometric analysis. X-ray phase contrast tomography (XPCT) offers sufficient resolution and contrast to identify single cells in large volumes of the brain. The numerous microanatomical structures detectable in XPCT image of the OB, however, greatly complicate the manual delineation of OB neuronal cell layers. To address the challenging problem of fully automated segmentation of XPCT images of human OB morphological layers, we propose a new pipeline for tomographic data processing. Convolutional neural networks (CNN) were used to segment XPCT image of native unstained human OB. Virtual segmentation of the whole OB and an accurate delineation of each layer in a healthy non-demented OB is mandatory as the first step for assessing OB morphological changes in smell impairment research. In this framework, we proposed an effective tool that could help to shed light on OB layer-specific degeneration in patients with olfactory disorder.

Olfactory Bulb Integrity in Frontotemporal Dementia and Alzheimer's Disease.

BACKGROUND: Olfactory dysfunction is highly prevalent in dementia syndromes, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). The structural integrity of the olfactory bulb (OB) is thought to play a critical role in odor detection and identification, but no MRI study has measured OB volume in FTD, or measured OB volume longitudinally in AD. OBJECTIVE: To measure OB volume in FTD and AD patients longitudinally using MRI. METHODS: This study measured OB volumes using MRI in patients diagnosed with behavioral-variant FTD (n = 55), semantic dementia (n = 34), progressive non-fluent aphasia (n = 30), AD (n = 50), and healthy age-matched controls (n = 55) at their first visit to a dementia research clinic ('baseline'). Imaging data in patients 12-months later were analyzed where available (n = 84) for longitudinal assessment. Volumes of subcortical and cortical olfactory regions ('olfactory network') were obtained via surface-based morphometry. RESULTS: Results revealed that in AD and FTD at baseline, OB volumes were similar to controls, whereas volumes of olfactory network regions were significantly reduced in all patient groups except in progressive non-fluent aphasia. Longitudinal data revealed that OB volume became significantly reduced (10-25% volume reduction) in all dementia groups with disease progression. CONCLUSION: Olfactory dysfunction is common in patients diagnosed with AD or FTD, but our results indicate that there is no detectable volume loss to the OBs upon first presentation to the clinic. Our findings indicate that the OBs become detectably atrophied later in the disease process. OB atrophy indicates the potential usefulness for OBs to be targeted in interventions to improve olfactory function.