Reduced olfactory performance is associated with changed microbial diversity, oralization, and accumulation of dead biomaterial in the nasal olfactory area.

The partial or complete loss of the sense of smell, which affects about 20% of the population, impairs the quality of life in many ways. Dysosmia and anosmia are mainly caused by aging, trauma, infections, or even neurodegenerative disease. Recently, the olfactory area-a site containing the olfactory receptor cells responsible for odor perception-was shown to harbor a complex microbiome that reflects the state of olfactory function. This initially observed correlation between microbiome composition and olfactory performance needed to be confirmed using a larger study cohort and additional analyses. A total of 120 participants (middle-aged, no neurodegenerative disease) were enrolled in the study to further analyze the microbial role in human olfactory function. Olfactory performance was assessed using the Sniffin' Stick battery, and participants were grouped accordingly (normosmia: n = 93, dysosmia: n = 27). The olfactory microbiome was analyzed by 16S rRNA gene amplicon sequencing and supplemented by metatranscriptomics in a subset (Nose 2.0). Propidium monoazide (PMA) treatment was performed to distinguish between intact and non-intact microbiome components. The gastrointestinal microbiome of these participants was also characterized by amplicon sequencing and metabolomics and then correlated with food intake. Our results confirm that normosmics and dysosmics indeed possess a distinguishable olfactory microbiome. Alpha diversity (i.e., richness) was significantly increased in dysosmics, reflected by an increase in the number of specific taxa (e.g., Rickettsia, Spiroplasma, and Brachybacterium). Lower olfactory performance was associated with microbial signatures from the oral cavity and periodontitis (Fusobacterium, Porphyromonas, and Selenomonas). However, PMA treatment revealed a higher accumulation of dead microbial material in dysosmic subjects. The gastrointestinal microbiome partially overlapped with the nasal microbiome but did not show substantial variation with respect to olfactory performance, although the diet of dysosmic individuals was shifted toward a higher meat intake. Dysosmia is associated with a higher burden of dead microbial material in the olfactory area, indicating an impaired clearance mechanism. As the microbial community of dysosmics (hyposmics and anosmics) appears to be influenced by the oral microbiome, further studies should investigate the microbial oral-nasal interplay in individuals with partial or complete olfactory loss.IMPORTANCEThe loss of the sense of smell is an incisive event that is becoming increasingly common in today's world due to infections such as COVID-19. Although this loss usually recovers a few weeks after infection, in some cases, it becomes permanent-why is yet to be answered. Since this condition often represents a psychological burden in the long term, there is a need for therapeutic approaches. However, treatment options are limited or even not existing. Understanding the role of the microbiome in the impairment of olfaction may enable the prediction of olfactory disorders and/or could serve as a possible target for therapeutic interventions.

Impact of childhood cerebellar tumor surgery on cognition revealed by precuneus hyperconnectivity.

Background: Childhood cerebellar pilocytic astrocytomas harbor excellent overall survival rates after surgical resection, but the patients may exhibit specific cognitive and behavioral problems. Functional MRI has catalyzed insights into brain functional systems and has already been linked with the neuropsychological performance. We aimed to exploit the question of whether resting-state functional MRI can be used as a biomarker for the cognitive outcome assessment of these patients. Methods: We investigated 13 patients (median age 22.0 years; range 14.9-31.3) after a median interval between surgery and examination of 15.0 years (range 4.2-20.5) and 16 matched controls. All subjects underwent functional 3-Tesla MRI scans in a resting-state condition and battery neuropsychological tests. Results: Patients showed a significantly increased functional connectivity in the precuneus compared with controls (P < .05) and at the same time impairments in various domains of neuropsychological functioning such as a lower mean Wechsler Intelligenztest für Erwachsene (WIE) IQ percentile (mean [M] = 48.62, SD = 29.14), lower scores in the Trail Making Test (TMT) letter sequencing (M = 49.54, SD = 30.66), worse performance on the WIE subtest Digit Symbol Coding (M = 38.92, SD = 35.29), subtest Symbol Search (M = 40.75, SD = 35.28), and test battery for attentional performance (TAP) divided attention task (M = 783.92, SD = 73.20). Conclusion: Childhood cerebellar tumor treated by resection only strongly impacts the development of precuneus/posterior cingulate cortex functional connectivity. Functional MRI has the potential to help deciphering the pathophysiology of cerebellar-related cognitive impairments in these patients and could be an additional tool in their individual assessment and follow-up.

An fMRI study of cognitive remediation in drug-naïve subjects diagnosed with first episode schizophrenia.

OBJECTIVE: The purpose of our functional magnetic resonance imaging (fMRI) study was to examine brain activity using a "1-back" paradigm as working memory task in drug-naïve subjects with first episode schizophrenia before and after cognitive remediation training. METHODS: In this study 15 drug-naïve first episode subjects who met DSM-IV criteria for schizophrenia were randomized to receive either atypical antipsychotics (AP, n = 8) or atypical antipsychotics in combination with cognitive remediation therapy (AP + CR, n = 7), 11 subjects had a follow-up fMRI examination after therapy (AP, n = 5; AP + CR, n = 6). RESULTS: In 4 of the 6 AP + CR subjects the number of activation clusters increased, whereas in 4 out of the 5 AP subjects the number of clusters decreased (mean number of clusters: AP + CR = 5.53, SD 12.79, AP = -5.8, SD 6.9). CONCLUSION: In this randomized study the number of activation clusters during a working memory task increased after cognitive remediation training. Our data show that neurobiological effects of cognitive remediation can be identified in the very early course of schizophrenia.

Metabolic Dynamics in the Prefrontal Cortex during a Working Memory Task in Young Adult Smokers.

INTRODUCTION: Cigarette smoking is known to modulate brain metabolism and brain function. How the dynamics of these metabolic alterations influence the active performance of higher order cognitive tasks in smokers, compared to non-smokers, is still unclear. The present exploratory study sought to examine the impact of smoking on the "complete" metabolic profile while the participants performed a working memory (N-back) task. METHODS: The study sample consisted of 40 young male healthy participants (smokers [n = 20] and non-smokers [n = 20]). Functional magnetic resonance spectroscopy data were acquired using a 3 T whole-body MR system. Data analysis was performed using Java-based Magnetic Resonance User Interface software, and metabolite ratios with respect to creatine (Cr) were calculated. RESULTS: On a behavioural level, smokers showed worse performance (measured by d') than non-smokers. However, we observed significant differences in the metabolite concentrations in smokers compared to non-smokers, which also changed over the course of the N-back task. A significant effect of the group was observed with smokers showing lower glutamate/Cr (Glx/Cr) and choline/Cr (Cho/Cr) ratios than non-smokers. Further, N-acetyl aspartate (NAA/Cr) and Cho/Cr ratios were significantly different during the rest and the task conditions. In addition, our results demonstrated the metabolite interactions (NAA and Cho, Glx and myo-inositol [mI], and Cho and mI). CONCLUSION: Further studies are necessary to shed more light on the association between smoking behaviours and metabolic alterations. However, our preliminary findings would assist in this future research to have a complete understanding of the metabolite interactions not only in smoking but also in addiction research.

More Than Smell-COVID-19 Is Associated With Severe Impairment of Smell, Taste, and Chemesthesis.

Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change ±100) revealed a mean reduction of smell (-79.7 ± 28.7, mean ± standard deviation), taste (-69.0 ± 32.6), and chemesthetic (-37.3 ± 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis. The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms.

Sarcopenia in Neurological Patients: Standard Values for Temporal Muscle Thickness and Muscle Strength Evaluation.

Temporal muscle thickness (TMT) was investigated as a novel surrogate marker on MRI examinations of the brain, to detect patients who may be at risk for sarcopenia. TMT was analyzed in a retrospective, normal collective cohort (n = 624), to establish standard reference values. These reference values were correlated with grip strength measurements and body mass index (BMI) in 422 healthy volunteers and validated in a prospective cohort (n = 130) of patients with various neurological disorders. Pearson correlation revealed a strong association between TMT and grip strength (retrospective cohort, ρ = 0.746; p < 0.001; prospective cohort, ρ = 0.649; p < 0.001). A low or no association was found between TMT and age (retrospective cohort, R2 correlation coefficient 0.20; p < 0.001; prospective cohort, ρ = -0.199; p = 0.023), or BMI (retrospective cohort, ρ = 0.116; p = 0.042; prospective cohort, ρ = 0.227; p = 0.009), respectively. Male patients with temporal wasting and unintended weight loss, respectively, showed significantly lower TMT values (p = 0.04 and p = 0.015, unpaired t-test). TMT showed a high correlation with muscle strength in healthy individuals and in patients with various neurological disorders. Therefore, TMT should be integrated into the diagnostic workup of neurological patients, to prevent, delay, or treat sarcopenia.

Human body odor increases familiarity for faces during encoding-retrieval task.

Odors can increase memory performance when presented as context during both encoding and retrieval phases. Since information from different sensory modalities is integrated into a unified conceptual knowledge, we hypothesize that the social information from body odors and faces would be integrated during encoding. The integration of such social information would enhance retrieval more so than when the encoding occurs in the context of common odors. To examine this hypothesis and to further explore the underlying neural correlates of this behavior, we have conducted a functional magnetic resonance imaging study in which participants performed an encoding-retrieval memory task for faces during the presentation of common odor, body odor or clean air. At the behavioral level, results show that participants were less biased and faster in recognizing faces when presented in concomitance with the body odor compared to the common odor. At the neural level, the encoding of faces in the body odor condition, compared to common odor and clean air conditions, showed greater activation in areas related to associative memory (dorsolateral prefrontal cortex), odor perception and multisensory integration (orbitofrontal cortex). These results suggest that face and body odor information were integrated and as a result, participants were faster in recognizing previously presented material.

Noninvasive Differentiation of Meningiomas and Dural Metastases Using Intratumoral Vascularity Obtained by Arterial Spin Labeling.

PURPOSE: Using conventional magnetic resonance imaging (MRI) techniques, the imaging features of meningiomas and dural metastases overlap and a differentiation between these tumor entities therefore remains difficult, particularly in patients with a known primary neoplasm. The purpose of this study was to explore the potential role of normalized vascular intratumoral signal intensity values (nVITS) obtained from pulsed arterial spin labeling (PASL) to differentiate between meningiomas and dural metastases. METHODS: In this study PASL was performed in 46 patients with meningiomas (n = 30) and dural metastases (n = 16) on a 3T scanner, in addition to the routine diagnostic imaging protocol. The ratio between the vascular signal intensity of the tumor and the contralateral normal white matter obtained by PASL images was defined as nVITS. RESULTS: Meningiomas showed significantly higher nVITS values compared to dural metastases (p < 0.001). The optimal nVITS cut-off value to differentiate between the 2 tumor entities was 1.989, with 100% sensitivity and 81.2% specificity. CONCLUSION: The nVITS values obtained by PASL provide a fast and noninvasive MRI technique with which to differentiate between meningiomas and dural metastases in a routine clinical setting based on tumor vascularity.

Exploring the Archaeome: Detection of Archaeal Signatures in the Human Body.

Due to their fundamentally different biology, archaea are consistently overlooked in conventional microbiome surveys. Using amplicon sequencing, we evaluated methodological set-ups to detect archaea in samples from five different body sites: respiratory tract (nasal cavity), digestive tract (mouth, appendix, and stool) and skin. With optimized protocols, the detection of archaeal ribosomal sequence variants (RSVs) was increased from one (found in currently used, so-called "universal" approach) to 81 RSVs in a representative sample set. The results from this extensive primer-evaluation led to the identification of the primer pair combination 344f-1041R/519F-806R which performed superior for the analysis of the archaeome of gastrointestinal tract, oral cavity and skin. The proposed protocol might not only prove useful for analyzing the human archaeome in more detail but could also be used for other holobiont samples.

The microbiome of the upper respiratory tract in health and disease.

The human upper respiratory tract (URT) offers a variety of niches for microbial colonization. Local microbial communities are shaped by the different characteristics of the specific location within the URT, but also by the interaction with both external and intrinsic factors, such as ageing, diseases, immune responses, olfactory function, and lifestyle habits such as smoking. We summarize here the current knowledge about the URT microbiome in health and disease, discuss methodological issues, and consider the potential of the nasal microbiome to be used for medical diagnostics and as a target for therapy.

When to collect resting-state data: The influence of odor on post-task resting-state connectivity.

The human brain networks at rest represent spontaneous activity that is highly correlated between different brain regions. Previous studies have shown that these resting-state networks are flexible and dynamic, and they can be affected by performance of different types of tasks. Moreover, it has been suggested that the re-activation of a task-related brain network during rest promotes learning and improves the expertise on that task. However, it is still unclear whether the presence of different sensory information in the on-task state affects functional connectivity in subsequent resting-state fMRI even though the perception of the sensory information did not induce significant behavioral effects. To clarify this issue, we compared pre- and post-task resting-state fMRI of two groups of participants performing the same task either with an odor context (ODOR group) or without an odor context (AIR group). Seed-based functional connectivity analyses were performed with orbitofrontal cortex, piriform cortex and working-memory core network as seeds. The results showed that an odor context presented during an encoding task induced significant changes in the functional connectivity only within the olfactory network of the post-task resting-state compared to the same post-task situation without previous odor context. No significant difference in functional connectivity were found for the working-memory core network. This evidence emphasizes how the sensory context, in which a task is performed, is relevant for understanding the observed changes of functional connectivity during rest.

Influence of 4-week multi-strain probiotic administration on resting-state functional connectivity in healthy volunteers.

PURPOSE: Experimental investigations in rodents have contributed significantly to our current understanding of the potential importance of the gut microbiome and brain interactions for neurotransmitter expression, neurodevelopment, and behaviour. However, clinical evidence to support such interactions is still scarce. The present study used a double-blind, randomized, pre- and post-intervention assessment design to investigate the effects of a 4-week multi-strain probiotic administration on whole-brain functional and structural connectivity in healthy volunteers. METHODS: Forty-five healthy volunteers were recruited for this study and were divided equally into three groups (PRP: probiotic, PLP: placebo, and CON: control). All the participants underwent resting-state functional MRI and diffusion MRI brain scans twice during the course of study, at the beginning (time point 1) and after 4 weeks (time point 2). MRI data were acquired using a 3T whole-body MR system (Magnetom Skyra, Siemens, Germany). RESULTS: Functional connectivity (FC) changes were observed in the default mode network (DMN), salience network (SN), and middle and superior frontal gyrus network (MFGN) in the PRP group as compared to the PLP and CON groups. PRP group showed a significant decrease in FC in MFGN (in frontal pole and frontal medial cortex) and in DMN (in frontal lobe) as compared to CON and PLP groups, respectively. Further, significant increase in FC in SN (in cingulate gyrus and precuneus cortex) was also observed in PRP group as compared to CON group. The significance threshold was set to p < 0.05 FWE corrected. No significant structural differences were observed between the three groups. CONCLUSIONS: This work provides new insights into the role of a multi-strain probiotic administration in modulating the behaviour, which is reflected as changes in the FC in healthy volunteers. This study motivates future investigations into the role of probiotics in context of major depression and stress disorders.

High correlation of temporal muscle thickness with lumbar skeletal muscle cross-sectional area in patients with brain metastases.

OBJECTIVES: This study aimed to assess the correlation of temporal muscle thickness (TMT), measured on routine cranial magnetic resonance (MR) images, with lumbar skeletal muscles obtained on computed tomography (CT) images in brain metastasis patients to establish a new parameter estimating skeletal muscle mass on brain MR images. METHODS: We retrospectively analyzed the cross-sectional area (CSA) of skeletal muscles at the level of the third lumbar vertebra on computed tomography scans and correlated these values with TMT on MR images of the brain in two independent cohorts of 93 lung cancer and 61 melanoma patients (overall: 154 patients) with brain metastases. RESULTS: Pearson correlation revealed a strong association between mean TMT and CSA in lung cancer and melanoma patients with brain metastases (0.733; p<0.001). The two study cohorts did not differ significantly in patient characteristics, including age (p = 0.661), weight (p = 0.787), and height (p = 0.123). However, TMT and CSA measures differed significantly between male and female patients in both lung cancer and melanoma patients with brain metastases (p<0.001). CONCLUSION: Our data indicate that TMT, measured on routine cranial MR images, is a useful surrogate parameter for the estimation of skeletal muscle mass in patients with brain metastases. Thus, TMT may be useful for prognostic assessment, treatment considerations, and stratification or a selection factor for clinical trials in patients with brain metastases. Further studies are needed to assess the association between TMT and clinical frailty parameters, and the usefulness of TMT in patients with primary brain tumors.

Modulation of resting-state network connectivity by verbal divergent thinking training.

A growing body of evidence suggests that creativity is associated with functional connectivity across widespread neural networks, including regions associated with executive processes and cognitive control, along with regions linked to the default mode network (DMN) of the brain. This study investigated whether a three-week verbal divergent thinking training modulates functional connectivity in networks that have been related to creativity. In a task-based functional imaging study (Fink et al., 2015), the employed creativity training was found to modulate brain activity in regions closely associated with semantic memory demands. Hence, the specific aim of this study was to assess whether the observed task-related brain changes relate to changes in functional connectivity patterns of the brain at rest, as assessed by independent component analysis. The participants were tested at three time points with an inter-test interval of four weeks each, and randomly assigned to two groups which received the verbal creativity training time-delayed. Findings revealed that successful training of verbal creativity was mirrored by functional connectivity changes in the DMN, sensorimotor and auditory network, and the attention network. These rather global changes in resting-state functional connectivity supplement the findings of task-based fMRI, where changes in more task specific brain regions were found.

Investigating Sex-Specific Characteristics of Nicotine Addiction Using Metabolic and Structural Magnetic Resonance Imaging.

Nicotine addiction is known to modulate neurotransmission and alter the brain structure. The detrimental effect of nicotine is more prominent in females as compared to males. This study sought to examine the sex-specific influence of nicotine addiction on gamma amino butyric acid (GABA) and the white matter (WM) microstructure. Sixty healthy subjects (smokers/non-smokers) underwent structural and metabolic magnetic resonance imaging scans. Results showed alterations in WM integrity (measured as changes in fractional anisotropy [FA] and GABA in smokers versus non-smokers and females versus males. No overall significant smoking and sex-specific interactions were observed in this study. However, on comparing female smokers with female non-smokers, significantly higher GABA and FA values were observed in female smokers. However, GABA and FA values did not differ significantly when male smokers were compared against male non-smokers. Our results provide a further rationale to investigate the impact of nicotine on central GABAergic function and WM integrity, in particular due to the potential risk for females to experience depressive/anxiety symptoms during smoking cessation.

Temporal muscle thickness is an independent prognostic marker in melanoma patients with newly diagnosed brain metastases.

OBJECTIVES: The purpose of this study was to evaluate the prognostic relevance of temporal muscle thickness (TMT) in melanoma patients with newly diagnosed brain metastases. METHODS: TMT was retrospectively assessed in 146 melanoma patients with newly diagnosed brain metastases on cranial magnetic resonance images. Chart review was used to retrieve clinical parameters, including disease-specific graded prognostic assessment (DS-GPA) and survival times. RESULTS: Patients with a TMT > median showed a statistically significant increase in survival time (13 months) compared to patients with a TMT < median (5 months; p < 0.001; log rank test). A Cox regression model revealed that the risk of death was increased by 27.9% with every millimeter reduction in TMT. In the multivariate analysis, TMT (HR 0.724; 95% 0.642-0.816; < 0.001) and DS-GPA (HR 1.214; 95% CI 1.023-1.439; p = 0.026) showed a statistically significant correlation with overall survival. CONCLUSION: TMT is an independent predictor of survival in melanoma patients with brain metastases. This parameter may aid in patient selection for clinical trials or to the choice of different treatment options based on the determination of frail patient populations.

MRI-based quantification of residual fibroglandular tissue of the breast after conservative mastectomies.

PURPOSE: Skin-sparing and nipple-sparing mastectomies (SSM; NSM) remove the breast's fibroglandular tissue (FGT), thereby reducing breast cancer risk. The postoperative presence of residual FGT (RFGT) is associated with remaining cancer risk. This study evaluated the role of MRI in the quantitative assessment of RFGT and its impact on the estimation of the remaining breast cancer risk. METHODS: The postoperative MRI scans (following EUSOMA recommendations) of 58 patients who had undergone SSM or NSM between 2003 and 2013, as well as preoperative MRI scans that were available in 25 of these patients, were retrospectively evaluated for the presence and location of RFGT by three radiologists. Two different observers quantitatively assessed the volume and percentage of retromamillary and other RFGT (RFGTrm and RFGTother) were assessed. The Fisher's exact test, the Student's t-test, and intraclass coherence were used to compare patient groups and to assess reproducibility. RESULTS: RFGT was found in 20% of all breasts and significantly more frequently after NSM than SSM (50% vs. 13%, p = .003). RFGTrm and RFGTother were more prevalent after NSM (p < 0.001; p = .127). RFGT ranged from 0.5 to 26% of the preoperative FGT, with higher percentages after NSM than SSM (p = .181). CONCLUSIONS: The prevalence and percentage of RFGT found on MRI indicate a considerable remaining postoperative breast cancer risk in some women.

Probiotics drive gut microbiome triggering emotional brain signatures.

Experimental manipulation of the gut microbiome was found to modify emotional and cognitive behavior, neurotransmitter expression and brain function in rodents, but corresponding human data remain scarce. The present double-blind, placebo-controlled randomised study aimed at investigating the effects of 4 weeks' probiotic administration on behavior, brain function and gut microbial composition in healthy volunteers. Forty-five healthy participants divided equally into three groups (probiotic, placebo and no intervention) underwent functional MRI (emotional decision-making and emotional recognition memory tasks). In addition, stool samples were collected to investigate the gut microbial composition. Probiotic administration for 4 weeks was associated with changes in brain activation patterns in response to emotional memory and emotional decision-making tasks, which were also accompanied by subtle shifts in gut microbiome profile. Microbiome composition mirrored self-reported behavioral measures and memory performance. This is the first study reporting a distinct influence of probiotic administration at behavioral, neural, and microbiome levels at the same time in healthy volunteers. The findings provide a basis for future investigations into the role of the gut microbiota and potential therapeutic application of probiotics.