The BTLA-HVEM axis restricts CAR T cell efficacy in cancer.

The efficacy of T cell-based immunotherapies is limited by immunosuppressive pressures in the tumor microenvironment. Here we show a predominant role for the interaction between BTLA on effector T cells and HVEM (TNFRSF14) on immunosuppressive tumor microenvironment cells, namely regulatory T cells. High BTLA expression in chimeric antigen receptor (CAR) T cells correlated with poor clinical response to treatment. Therefore, we deleted BTLA in CAR T cells and show improved tumor control and persistence in models of lymphoma and solid malignancies. Mechanistically, BTLA inhibits CAR T cells via recruitment of tyrosine phosphatases SHP-1 and SHP-2, upon trans engagement with HVEM. BTLA knockout thus promotes CAR signaling and subsequently enhances effector function. Overall, these data indicate that the BTLA-HVEM axis is a crucial immune checkpoint in CAR T cell immunotherapy and warrants the use of strategies to overcome this barrier.

Lateralisation of nasal cycle is not reflected in the olfactory bulb volumes and cerebral activations.

Nasal cycle (NC) is a rhythmic change of lateralised nasal airflow mediated by the autonomous nervous system. Previous studies reported the dependence of NC dominance or more patent side on handedness and hemispheric cerebral activity. We aimed to investigate firstly the possible lateralised effect of NC on olfactory bulb volume and secondly the association of NC with the lateralised cerebral dominance in terms of olfactory processing. Thirty-five subjects (22 women and 13 men, mean age 26 ± 3 years) participated in the study. NC was ascertained using a portable rhino-flowmeter. Structural and functional brain measurements were assessed using a 3T MR scanner. Vanillin odorant was presented during functional scans using a computer-controlled olfactometer. NC was found to be independent of the olfactory bulb volumes. Also, cerebral activations were found independent of the NC during odorant perception. NC potency is not associated with lateralised structural or functional differences in the cerebral olfactory system.

Functional connectivity patterns in parosmia.

OBJECTIVE: Parosmia is a qualitative olfactory dysfunction presenting as "distorted odor perception" in presence of an odor source. Aim of this study was to use resting state functional connectivity to gain more information on the alteration of olfactory processing at the level of the central nervous system level. METHODS: A cross sectional study was performed in 145 patients with parosmia (age range 20-76 years; 90 women). Presence and degree of parosmia was diagnosed on the basis of standardized questionnaires. Participants also received olfactory testing using the "Sniffin' Sticks". Then they underwent resting state scans using a 3 T magnetic resonance imaging scanner while fixating on a cross. RESULTS: Whole brain analyses revealed reduced functional connectivity in salience as well as executive control networks. Region of interest-based analyses also supported reduced functional connectivity measures between primary and secondary olfactory eloquent areas (temporal pole, supramarginal gyrus and right orbitofrontal cortex; dorso-lateral pre-frontal cortex and the right piriform cortex). CONCLUSIONS: Participants with parosmia exhibited a reduced information flow between memory, decision making centers, and primary and secondary olfactory areas.

Exploring brain functional connectivity in patients with taste loss: a pilot study.

PURPOSE: In a previous neuroimaging study, patients with taste loss showed stronger activations in gustatory cortices compared to people with normal taste function during taste stimulations. The aim of the current study was to examine whether there are changes in central-nervous functional connectivity in patients with taste loss. METHODS: We selected 26 pairs of brain regions related to taste processing as our regions of interests (ROIs). Functional magnetic resonance imaging (fMRI) was used to measure brain responses in seven patients with taste loss and 12 healthy controls as they received taste stimulations (taste condition) and water (water condition). The data were analysed using ROI-to-ROI functional connectivity analysis (FCA). RESULTS: We observed weaker functional connectivity in the patient group between the left and right orbitofrontal cortex in the taste condition and between the left frontal pole and the left superior frontal gyrus in the water condition. CONCLUSION: These results suggested that patients with taste loss experience changes of functional connectivity between brain regions not only relevant to taste processing but also to cognitive functions. While further studies are needed, fMRI might be helpful in diagnosing taste loss as an additional tool in exceptional cases.

Tractography indicates lateralized differences between trigeminal and olfactory pathways.

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

Individual variability of olfactory fMRI in normosmia and olfactory dysfunction.

PURPOSE: The diagnosis of olfactory dysfunction is mainly based on psychophysical measurements. The aim of the current study was to investigate how well the olfactory functional magnetic resonance imaging (fMRI) can effectively distinguish between normosmic people and subjects with olfactory dysfunction. METHODS: Thirty-eight participants were recruited for the study. Group 1 consisted of 22 subjects with olfactory dysfunction (mean age = 44.3 years, SD = 18.6), and Group two consisted of 16 participants with normal olfactory function (mean age = 49.6 years, SD = 11.6). Olfactory functions were assessed in great detail for all participants, and brain activation in response to odorous stimulation was assessed using fMRI. RESULTS: The between-group comparison showed stronger odor induced brain activation of the primary olfactory area and the insular cortex among the normosmic group as compared to the dysosmic group. As indicated by the individual analysis, positive responses in the primary olfactory cortex were significantly higher in normosmic people (94%) than in subjects with olfactory dysfunction (41%). However, there was no association between individual fMRI parameters (including the percentage of BOLD signal change, activated cluster size and peak z value), and psychophysical olfactory test scores. Receiver operating characteristic analysis suggested the subjects could not be differentiated from normosmics based on their BOLD signal from the primary olfactory area, orbitofrontal cortex, or the insular cortex. CONCLUSION: There are large inter-individual variabilities for odor-induced brain activation among normosmic subjects and subjects with olfactory dysfunction, due to this variation, at present it appears problematic to diagnose olfactory dysfunction on an individual level using fMRI.

Neural Processing of Odors with Different Well-Being Associations-Findings from Two Consecutive Neuroimaging Studies.

Much is known about the effect of odors on mood, cognition and behavior, but little is known about the relationship between odors and well-being. We investigated the neural processing of odors with different degrees of association with well-being (WB) through two large independent datasets. The study encompassed pre-testing and fMRI. During pre-testing, 100 and 80 (studies 1 and 2) young, healthy subjects participated, rating intensity, valence, and WB association for 14 (study 1) and 8 (study 2) different odors. Pre-testing resulted in the selection of two odors with high WB association (WB-associated) and two odors with lower WB association (neutral odors) for each study. Odors were delivered intranasally to the subjects who underwent fMRI scanning (44 and 41 subjects, respectively, for studies 1 and 2). We assessed brain activity for subjects when they experienced WB-associated versus neutral odors. In study 1, WB-associated odors showed increased activation in the right angular gyrus whereas in study 2, increased activity in the left angular gyrus existed, together with increased activity in the anterior cingulate cortex and posterior orbitofrontal cortex. The increased activity of higher-order cognitive and emotional regions during the processing of WB-associated odors in the two independent studies suggests a role of odors in influencing individual well-being. Moreover, the consistent activation of the angular gyrus might suggest its key role in shifting attention toward relevant emotional stimuli.

Impact of a 12-week olfactory training programme in women with migraine with aura: protocol for a double-blind, randomised, placebo-controlled trial.

INTRODUCTION: Migraine is a leading cause of disability and suffering worldwide. However, conventional pharmacological migraine preventive therapies are often challenging and accompanied by adverse effects. Recently, structured odour exposure has shown to successfully increase pain thresholds in patients with chronic back pain. Despite the importance of the olfactory system in migraine, there are no studies investigating the impact of structured odour exposure in patients with migraine. METHODS AND ANALYSIS: This double-blind randomised placebo-controlled trial will be conducted at the Headache Clinic of the University Pain Center at TU Dresden, Germany and aims at investigating the impact of a 12-week structured exposure to odours in women with migraine. Fifty-four women between 18 and 55 years with migraine with aura will be recruited and randomised to training with odours and odourless training. The primary outcomes are mechanical and electrical pain thresholds. Secondary outcomes comprise olfactory threshold and the number of headache days. Other exploratory measurements are headache associated pain intensity, acute analgesic intake, symptoms of anxiety and depression, and quality of life. Additionally, this protocol assesses neuroanatomical and neurofunctional changes associated with the 12-week olfactory training. Data analysis will be executed on the basis of the general linear model considering repeated measurements. ETHICS AND DISSEMINATION: Ethical approvals were obtained from the Ethics Board of the TU Dresden (Protocol No. BO-EK-353082020). Participation will only be possible after written informed consent is provided. Findings will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER: DRKS00027399.

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.

The Shape of the Olfactory Bulb Predicts Olfactory Function.

The olfactory bulb (OB) plays a key role in the processing of olfactory information. A large body of research has shown that OB volumes correlate with olfactory function, which provides diagnostic and prognostic information in olfactory dysfunction. Still, the potential value of the OB shape remains unclear. Based on our clinical experience we hypothesized that the shape of the OB predicts olfactory function, and that it is linked to olfactory loss, age, and gender. The aim of this study was to produce a classification of OB shape in the human brain, scalable to clinical and research applications. Results from patients with the five most frequent causes of olfactory dysfunction (n = 192) as well as age/gender-matched healthy controls (n = 77) were included. Olfactory function was examined in great detail using the extended "Sniffin' Sticks" test. A high-resolution structural T2-weighted MRI scan was obtained for all. The planimetric contours (surface in mm2) of OB were delineated manually, and then all surfaces were added and multiplied to obtain the OB volume in mm3. OB shapes were outlined manually and characterized on a selected slice through the posterior coronal plane tangential to the eyeballs. We looked at OB shapes in terms of convexity and defined two patterns/seven categories based on OB contours: convex (olive, circle, and plano-convex) and non-convex (banana, irregular, plane, and scattered). Categorization of OB shapes is possible with a substantial inter-rater agreement (Cohen's Kappa = 0.73). Our results suggested that non-convex OB patterns were significantly more often observed in patients than in controls. OB shapes were correlated with olfactory function in the whole group, independent of age, gender, and OB volume. OB shapes seemed to change with age in healthy subjects. Importantly, the results indicated that OB shapes were associated with certain causes of olfactory disorders, i.e., an irregular OB shape was significantly more often observed in post-traumatic olfactory loss. Our study provides evidence that the shape of the OB can be used as a biomarker for olfactory dysfunction.

Neural processing of olfactory-related words in subjects with congenital and acquired olfactory dysfunction.

Olfactory loss can be acquired (patients with a history of olfactory experiences), or inborn (patients without olfactory experiences/life-long inability to smell). Inborn olfactory loss, or congenital anosmia (CA), is relatively rare and there is a knowledge gap regarding the compensatory neural mechanisms involved in this condition. The study aimed to investigate the top-down olfactory processing in patients with CA or idiopathic acquired anosmia (IA) in comparison to normosmia controls (NC) during expectancy and reading of odor-associated words. Functional magnetic resonance imaging was used to assess brain activations in 14 patients with CA, 8 patients with IA, and 16 NC healthy participants during an expectancy and reading task. Words with strong olfactory associations (OW) (e.g. "banana") or with little or no olfactory associations (CW) (e.g. "chair") were used as stimuli and were presented with a block design Analyses were conducted to explore the brain activation in response to OW expectancy or OW reading between groups (CW as baseline). During the expectancy condition of OW, IA and NC groups showed stronger activation in posterior OFC extending to right insula, caudate region and frontal medial OFC respectively. Whereas during the reading condition of OW, CA patients showed stronger activation in posterior OFC extending to the insula. Increased activation of higher-order brain regions related to multisensory integration among CA patients suggests a compensatory mechanism for processing semantic olfactory cues.

Verbal suggestions of nicotine content modulate ventral tegmental neural activity during the presentation of a nicotine-free odor in cigarette smokers.

Expectancies of nicotine content have been shown to impact smokers' subjective responses and smoking behaviors. However, little is known about the neural substrates modulated by verbally induced expectancies in smokers. In this study we used functional magnetic resonance imaging (fMRI) to investigate how verbally induced expectations, regarding the presence or absence of nicotine, modulated smokers' neural response to a nicotine-free odor. While laying in the scanner, all participants (N = 24) were given a nicotine-free odor, but whereas one group was correctly informed about the absence of nicotine (control group n = 12), the other group was led to believe that the presented odor contained nicotine (expectancy group n = 12). Smokers in the expectancy group had significantly increased blood-oxygen-level-dependent (BOLD) responses during the presentation of the nicotine-free odor in the left ventral tegmental area (VTA), and in the right insula, as compared to smokers in the control group (Regions of interest analysis with pFWE-corrected p ≤ 0.05). At a more liberal uncorrected statistical level (p-unc ≤ 0.001), increased bilateral reactivity in the dorsolateral prefrontal cortex (dlPFC) was also observed in the expectancy group as compared with the control group. Our findings suggest that nicotine-expectancies induced through verbal instructions can modulate nicotine relevant brain regions, without nicotine administration, and provide further neural support for the key role that cognitive expectancies play in the cause and treatment of nicotine dependence.

Reduced Olfactory Bulb Volume in Obesity and Its Relation to Metabolic Health Status.

Smell perception plays an important role in eating behavior and might be involved in body weight gain. Since a body of literature implies that olfactory perception and function is hampered in obesity, we here investigate neuroanatomical correlates of this phenomenon. We assessed olfactory bulb (OB) volume with magnetic resonance imaging in 67 healthy participants with a body mass index (BMI) from 18.9 to 45.4 kg/m2 (mean = 28.58 ± 6.64). Moreover, we obtained psychophysiological data on olfactory ability (Sniffin' Sticks, Food associated odor test) and self-report measurements on eating behavior. Additionally, we collected parameters associated with metabolic health in obesity (waist-hip ratio, waist-height ratio, leptin levels, body fat percentage, fat mass index, insulin resistance) to investigate recently proposed mechanistic explanatory models of why olfaction may be altered in obesity. We showed that OB volume was significantly lower in participants with obesity when compared to those of normal weight. Moreover, we found weak to moderate negative correlations between OB volume and BMI and related measures of metabolic health, especially leptin, body fat percentage, waist-height ratio and insulin resistance. However, neither OB volume nor BMI were related to olfactory function in our young and healthy sample. Nevertheless, our results provide first indications that obesity is associated with brain anatomical changes in the OBs.

A novel technique for olfactory bulb measurements.

BACKGROUND: To introduce new ways to calculate OB volumes, checking their validity and comparing them to already established technique i.e. OB volumetric based on manual segmentation of OB boundaries. METHODS: Two approaches were used to calculate OB volumes (1) Manual Segmentation using planimetric manual contouring; (2) Box-frame method, calculating the parameters based on a box placed around the OB. RESULTS: We calculated OB volumes using both techniques and found comparable outcomes. High inter-observer reliability was found for volumes calculated by both observers. For manual segmentation, Cronbach's alpha (α) was 0.91 and 0.93 for right and left OB volume, respectively, whereas for the box-frame method α was 0.94 and 0.90 for right and left OB, respectively. CONCLUSIONS: The simple box-frame method of OB volume calculation appears reliable. Its results are comparable to an established technique.

Global study of variability in olfactory sensitivity.

Variability in human olfactory sensitivity has been attributed to individual-level factors such as genetics, age, sex, medical history of infections and trauma, neurogenerative diseases, and emotional disorders. Scarce evidence exists on the cross-cultural variation in olfactory sensitivity. Hence, we performed 2 studies to estimate the variability in olfactory threshold as a function of location and environment. Study 1 involved 11 laboratories from 4 continents (N = 802). In each location, in a designated laboratory, approximately 80 subjects underwent olfactory sensitivity testing with custom-made tests with eucalyptol and phenylethanol (PEA) odors. Tests were based on the Threshold subtest of the Sniffin' Sticks battery. In Study 2, we compared olfactory sensitivity and suprathreshold perception of PEA and eucalyptol in 2 Chinese (N = 160) and 2 Indian (N = 92) populations-one based in their native country and the other in Germany. Both studies present large-scale evidence that olfactory sensitivity varies as a function of geographical location and suggest that environmental factors play an important role in shaping olfactory sensitivity and suprathreshold olfactory perception. We delineate further steps necessary to identify specific factors underlying uncovered variability and the relationship between olfactory sensitivity and suprathreshold odor perception. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

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.