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.

Intracranial Recordings of the Human Orbitofrontal Cortical Activity during Self-Referential Episodic and Valenced Self-Judgments.

We recorded directly from the orbital (oPFC) and ventromedial (vmPFC) subregions of the orbitofrontal cortex (OFC) in 22 (9 female, 13 male) epilepsy patients undergoing intracranial electroencephalography (iEEG) monitoring during an experimental task in which the participants judged the accuracy of self-referential autobiographical statements as well as valenced self-judgments (SJs). We found significantly increased high-frequency activity (HFA) in ∼13% of oPFC sites (10/18 subjects) and 16% of vmPFC sites (4/12 subjects) during both of these self-referential thought processes, with the HFA power being modulated by the content of self-referential stimuli. The location of these activated sites corresponded with the location of fMRI-identified limbic network. Furthermore, the onset of HFA in the vmPFC was significantly earlier than that in the oPFC in all patients with simultaneous recordings in both regions. In 11 patients with available depression scores from comprehensive neuropsychological assessments, we documented diminished HFA in the OFC during positive SJ trials among individuals with higher depression scores; responses during negative SJ trials were not related to the patients' depression scores. Our findings provide new temporal and anatomical information about the mode of engagement in two important subregions of the OFC during autobiographical memory and SJ conditions. Our findings from the OFC support the hypothesis that diminished brain activity during positive self-evaluations, rather than heightened activity during negative self-evaluations, plays a key role in the pathophysiology of depression.

Macroscopic resting state model predicts theta burst stimulation response: A randomized trial.

Repetitive transcranial magnetic stimulation (rTMS) is a promising alternative therapy for treatment-resistant depression, although its limited remission rate indicates room for improvement. As depression is a phenomenological construction, the biological heterogeneity within this syndrome needs to be considered to improve the existing therapies. Whole-brain modeling provides an integrative multi-modal framework for capturing disease heterogeneity in a holistic manner. Computational modelling combined with probabilistic nonparametric fitting was applied to the resting-state fMRI data from 42 patients (21 women), to parametrize baseline brain dynamics in depression. All patients were randomly assigned to two treatment groups, namely active (i.e., rTMS, n = 22) or sham (n = 20). The active treatment group received rTMS treatment with an accelerated intermittent theta burst protocol over the dorsomedial prefrontal cortex. The sham treatment group underwent the identical procedure but with the magnetically shielded side of the coil. We stratified the depression sample into distinct covert subtypes based on their baseline attractor dynamics captured by different model parameters. Notably, the two detected depression subtypes exhibited different phenotypic behaviors at baseline. Our stratification could predict the diverse response to the active treatment that could not be explained by the sham treatment. Critically, we further found that one group exhibited more distinct improvement in certain affective and negative symptoms. The subgroup of patients with higher responsiveness to treatment exhibited blunted frequency dynamics for intrinsic activity at baseline, as indexed by lower global metastability and synchrony. Our findings suggested that whole-brain modeling of intrinsic dynamics may constitute a determinant for stratifying patients into treatment groups and bringing us closer towards precision medicine.

Parkinson's disease is characterized by sub-second resting-state spatio-oscillatory patterns: A contribution from deep convolutional neural network.

Deep convolutional neural network (DCNN) provides a multivariate framework to detect relevant spatio-oscillatory patterns in the data beyond common mass-univariate statistics. Yet, its practical application is limited due to the low interpretability of the results beyond accuracy. We opted to use DCNN with a minimalistic architecture design and large penalized terms to yield a generalizable and clinically relevant network model. Our network was trained based on the scalp topology of the electroencephalography (EEG) from an open access dataset, constituting our primary sample of healthy controls (n = 25) and Parkinson's disease (PD) patients (n = 25), with and without medication. Next, we validated the model on another independent, yet comparable open access EEG dataset (healthy controls (n = 20) and PD patients (n = 20)), which was unseen to the network. We applied Gradient-weighted Class Activation Mapping (Grad-CAM) interpretability technique to create a localization map exhibiting the key network predictors, based on the gradients of the classification score flowing into the last convolutional layer. Accordingly, our results indicated that a sub-second of intrinsic oscillatory power pattern in the beta band over the occipitoparietal, gamma band over the left motor cortex as well as theta band over the frontoparietal cluster, had the largest impact on the network score for dissociating the PD patients from age- and gender-matched healthy controls, across the two datasets. We further found that the off-medication motor symptoms were related to the occipitoparietal off-medication beta power whereas the disease duration was associated with the off-medication beta power of the motor cortex. The on-medication theta power of the frontoparietal was related to the improvement of the motor symptoms. In conclusion, our method enabled us to characterize PD patho-electrophysiology according to the multivariate topographic analysis approach, where both spatial and frequency aspects of the oscillations were simultaneously considered. Moreover, our approach was free from common reference problem of the EEG data analyses.

Losing the sense of smell does not disrupt processing of odor words.

Whether language is grounded in action and perception has been a key question in cognitive science, yet little attention has been given to the sense of smell. We directly test whether smell is necessary for comprehension of odor language, by comparing language processing in a group of participants with no sense of smell (anosmics) to a group of control participants. We found no evidence for a difference in online comprehension of odor and taste language between anosmics and controls using a lexical decision task and a semantic similarity judgment task, suggesting olfaction is not critical to the comprehension of odor language. Contrary to predictions, anosmics were better at remembering odor words, and rated odor and taste words as more positively valenced than control participants. This study finds no detriment to odor language after losing the sense of smell, supporting the proposal that odor language is not grounded in odor perception.

Loss of olfactory sensitivity is an early and reliable marker for COVID-19.

Detection of early and reliable symptoms is important in relation to limiting the spread of an infectious disease. For COVID-19, the most specific symptom is either losing or experiencing reduced olfactory functions. Anecdotal evidence suggests that olfactory dysfunction is also one of the earlier symptoms of COVID-19, but objective measures supporting this notion are currently missing. To determine whether olfactory loss is an early sign of COVID-19, we assessed available longitudinal data from a web-based interface enabling individuals to test their sense of smell by rating the intensity of selected household odors. Individuals continuously used the interface to assess their olfactory functions and at each login, in addition to odor ratings, recorded their symptoms and results from potential COVID-19 test. A total of 205 COVID-19-positive individuals and 156 pseudo-randomly matched control individuals lacking positive test provided longitudinal data which enabled us to assess olfactory functions in relation to their test result date. We found that odor intensity ratings started to decline in the COVID-19 group as early as 6 days prior to the test result date (±1.4 days). Symptoms, such as sore throat, aches, and runny nose appear around the same point in time; however, with a lower predictability of a COVID-19 diagnosis. Our results suggest that olfactory sensitivity loss is an early symptom but does not appear before other related COVID-19 symptoms. Olfactory loss is, however, more predictive of a COVID-19 diagnosis than other early symptoms.

An olfactory self-test effectively screens for COVID-19.

Background: Key to curtailing the COVID-19 pandemic are wide-scale screening strategies. An ideal screen is one that would not rely on transporting, distributing, and collecting physical specimens. Given the olfactory impairment associated with COVID-19, we developed a perceptual measure of olfaction that relies on smelling household odorants and rating them online. Methods: Each participant was instructed to select 5 household items, and rate their perceived odor pleasantness and intensity using an online visual analogue scale. We used this data to assign an olfactory perceptual fingerprint, a value that reflects the perceived difference between odorants. We tested the performance of this real-time tool in a total of 13,484 participants (462 COVID-19 positive) from 134 countries who provided 178,820 perceptual ratings of 60 different household odorants. Results: We observe that olfactory ratings are indicative of COVID-19 status in a country, significantly correlating with national infection rates over time. More importantly, we observe indicative power at the individual level (79% sensitivity and 87% specificity). Critically, this olfactory screen remains effective in participants with COVID-19 but without symptoms, and in participants with symptoms but without COVID-19. Conclusions: The current odorant-based olfactory screen adds a component to online symptom-checkers, to potentially provide an added first line of defense that can help fight disease progression at the population level. The data derived from this tool may allow better understanding of the link between COVID-19 and olfaction.

The human olfactory bulb processes odor valence representation and cues motor avoidance behavior.

Determining the valence of an odor to guide rapid approach-avoidance behavior is thought to be one of the core tasks of the olfactory system, and yet little is known of the initial neural mechanisms supporting this process or of its subsequent behavioral manifestation in humans. In two experiments, we measured the functional processing of odor valence perception in the human olfactory bulb (OB)-the first processing stage of the olfactory system-using a noninvasive method as well as assessed the subsequent motor avoidance response. We demonstrate that odor valence perception is associated with both gamma and beta activity in the human OB. Moreover, we show that negative, but not positive, odors initiate an early beta response in the OB, a response that is linked to a preparatory neural motor response in the motor cortex. Finally, in a separate experiment, we show that negative odors trigger a full-body motor avoidance response, manifested as a rapid leaning away from the odor, within the time period predicted by the OB results. Taken together, these results demonstrate that the human OB processes odor valence in a sequential manner in both the gamma and beta frequency bands and suggest that rapid processing of unpleasant odors in the OB might underlie rapid approach-avoidance decisions.

A non-invasive olfactory bulb measure dissociates Parkinson's patients from healthy controls and discloses disease duration.

Olfactory dysfunction is a prevalent non-motor symptom of Parkinson's disease (PD). This dysfunction is a result of neurodegeneration within the olfactory bulb (OB), the first processing area of the central olfactory system, and commonly precedes the characteristic motor symptoms in PD by several years. Functional measurements of the OB could therefore potentially be used as an early biomarker for PD. Here, we used a non-invasive method, so-called electrobulbogram (EBG), to measure OB function in PD and age-matched healthy controls to assess whether EBG measures can dissociate PDs from controls. We estimated the spectrogram of the EBG signal during exposure to odor in PD (n = 20) and age-matched controls (n = 18) as well as identified differentiating patterns of odor-related synchronization in the gamma, beta, and theta frequency bands. Moreover, we assessed if these PD-EBG components could dissociate PD from control as well as their relationship with PD characteristics. We identified six EBG components during the initial and later stages of odor processing which dissociated PD from controls with 90% sensitivity and 100% specificity with links to PD characteristics. These PD-EBG components were related to medication, disease duration, and severity, as well as clinical odor identification performance. These findings support using EBG as a tool to experimentally assess PD interventions, potentially aid diagnosis, and the potential development of EBG into an early biomarker for PD.

Acquired olfactory loss alters functional connectivity and morphology.

Removing function from a developed and functional sensory system is known to alter both cerebral morphology and functional connections. To date, a majority of studies assessing sensory-dependent plasticity have focused on effects from either early onset or long-term sensory loss and little is known how the recent sensory loss affects the human brain. With the aim of determining how recent sensory loss affects cerebral morphology and functional connectivity, we assessed differences between individuals with acquired olfactory loss (duration 7-36 months) and matched healthy controls in their grey matter volume, using multivariate pattern analyses, and functional connectivity, using dynamic connectivity analyses, within and from the olfactory cortex. Our results demonstrate that acquired olfactory loss is associated with altered grey matter volume in, among others, posterior piriform cortex, a core olfactory processing area, as well as the inferior frontal gyrus and angular gyrus. In addition, compared to controls, individuals with acquired anosmia displayed significantly stronger dynamic functional connectivity from the posterior piriform cortex to, among others, the angular gyrus, a known multisensory integration area. When assessing differences in dynamic functional connectivity from the angular gyrus, individuals with acquired anosmia had stronger connectivity from the angular gyrus to areas primary responsible for basic visual processing. These results demonstrate that recently acquired sensory loss is associated with both changed cerebral morphology within core olfactory areas and increase dynamic functional connectivity from olfactory cortex to cerebral areas processing multisensory integration.

Odor identity can be extracted from the reciprocal connectivity between olfactory bulb and piriform cortex in humans.

Neuronal oscillations route external and internal information across brain regions. In the olfactory system, the two central nodes-the olfactory bulb (OB) and the piriform cortex (PC)-communicate with each other via neural oscillations to shape the olfactory percept. Communication between these nodes have been well characterized in non-human animals but less is known about their role in the human olfactory system. Using a recently developed and validated EEG-based method to extract signals from the OB and PC sources, we show in healthy human participants that there is a bottom-up information flow from the OB to the PC in the beta and gamma frequency bands, while top-down information from the PC to the OB is facilitated by delta and theta oscillations. Importantly, we demonstrate that there was enough information to decipher odor identity above chance from the low gamma in the OB-PC oscillatory circuit as early as 100 ms after odor onset. These data further our understanding of the critical role of bidirectional information flow in human sensory systems to produce perception. However, future studies are needed to determine what specific odor information is extracted and communicated in the information exchange.

No Evidence That Hormonal Contraceptives Affect Chemosensory Perception.

The use of oral contraceptives (OC) in the form of a hormonal pill has been widespread for decades. Despite its popularity and long-time use, there is still much ambiguity and anecdotal reports about a range of potential side effects. Here, we addressed the potential effect of OC use on chemosensory perception. Previous research has almost exclusively focused on olfaction, but we expanded this to the trigeminal system and the sense of taste. We used Bayesian statistics to compare the olfactory, trigeminal, and taste detection abilities between a group of 34 normal cycling women and a group of 26 women using OC. Our results indicated that odor, trigeminal, and taste thresholds were not affected by the use of OC. Moreover, neither odor perception, nor taste perception was affected; all with Bayes factors consistently favoring the null hypothesis. The only exception to these results was odor identification where Bayes factors indicated inconclusive evidence. We conclude that effects of OC use on chemosensory perception are unlikely, and if present, likely are of no to little behavioral relevance.

Whole-brain modelling of resting state fMRI differentiates ADHD subtypes and facilitates stratified neuro-stimulation therapy.

Recent advances in non-linear computational and dynamical modelling have opened up the possibility to parametrize dynamic neural mechanisms that drive complex behavior. Importantly, building models of neuronal processes is of key importance to fully understand disorders of the brain as it may provide a quantitative platform that is capable of binding multiple neurophysiological processes to phenotype profiles. In this study, we apply a newly developed adaptive frequency-based model of whole-brain oscillations to resting-state fMRI data acquired from healthy controls and a cohort of attention deficit hyperactivity disorder (ADHD) subjects. As expected, we found that healthy control subjects differed from ADHD in terms of attractor dynamics. However, we also found a marked dichotomy in neural dynamics within the ADHD cohort. Next, we classified the ADHD group according to the level of distance of each individual's empirical network from the two model-based simulated networks. Critically, the model was mirrored in the empirical behavior data with the two ADHD subgroups displaying distinct behavioral phenotypes related to emotional instability (i.e., depression and hypomanic personality traits). Finally, we investigated the applicability and feasibility of our whole-brain model in a therapeutic setting by conducting in silico excitatory stimulations to parsimoniously mimic clinical neuro-stimulation paradigms in ADHD. We tested the effect of stimulating any individual brain region on the key network measures derived from the simulated brain network and its contribution in rectifying the brain dynamics to that of the healthy brain, separately for each ADHD subgroup. This showed that this was indeed possible for both subgroups. However, the current effect sizes were small suggesting that the stimulation protocol needs to be tailored at the individual level. These findings demonstrate the potential of this new modelling framework to unveil hidden neurophysiological profiles and establish tailored clinical interventions.

Parkinson's Disease Affects Functional Connectivity within the Olfactory-Trigeminal Network.

BACKGROUND: Olfactory dysfunction (OD) is a frequent symptom of Parkinson's disease (PD) that appears years prior to diagnosis. Previous studies suggest that PD-related OD is different from non-parkinsonian forms of olfactory dysfunction (NPOD) as PD patients maintain trigeminal sensitivity as opposed to patients with NPOD who typically exhibit reduced trigeminal sensitivity. We hypothesize the presence of a specific alteration of functional connectivity between trigeminal and olfactory processing areas in PD. OBJECTIVE: We aimed to assess potential differences in functional connectivity within the chemosensory network in 15 PD patients and compared them to 15 NPOD patients, and to 15 controls. METHODS: Functional MRI scanning session included resting-state and task-related scans where participants carried out an olfactory and a trigeminal task. We compared functional connectivity, using a seed-based correlation approach, and brain network modularity of the chemosensory network. RESULTS: PD patients had impaired functional connectivity within the chemosensory network while no such changes were observed for NPOD patients. No group differences we found in modularity of the identified networks. Both patient groups exhibited impaired connectivity when executing an olfactory task, while network modularity was significantly weaker for PD patients than both other groups. When performing a trigeminal task, no changes were found for PD patients, but NPOD patients exhibited impaired connectivity. Conversely, PD patients exhibited a significantly higher network modularity than both other groups. CONCLUSION: In summary, the specific pattern of functional connectivity and chemosensory network recruitment in PD-related OD may explain distinct behavioral chemosensory features in PD when compared to NPOD patients and healthy controls.

Relationship between odor intensity estimates and COVID-19 prevalence prediction in a Swedish population.

In response to the COVID-19 pandemic, countries have implemented various strategies to reduce and slow the spread of the disease in the general population. For countries that have implemented restrictions on its population in a step-wise manner, monitoring of COVID-19 prevalence is of importance to guide decision on when to impose new, or when to abolish old, restrictions. We are here determining whether measures of odor intensity in a large sample can serve as one such measure. Online measures of how intense common household odors are perceived and symptoms of COVID-19 were collected from 2440 Swedes. Average odor intensity ratings were then compared to predicted COVID-19 population prevalence over time in the Swedish population and were found to closely track each other (r=-0.83). Moreover, we found that there was a large difference in rated intensity between individuals with and without COVID-19 symptoms and number of symptoms was related to odor intensity ratings. Finally, we found that individuals progressing from reporting no symptoms to subsequently reporting COVID-19 symptoms demonstrated a large drop in olfactory performance. These data suggest that measures of odor intensity, if obtained in a large and representative sample, can be used as an indicator of COVID-19 disease in the general population. Importantly, this simple measure could easily be implemented in countries without widespread access to COVID-19 testing or implemented as a fast early response before wide-spread testing can be facilitated.

Non-invasive recording from the human olfactory bulb.

Current non-invasive neuroimaging methods can assess neural activity in all areas of the human brain but the olfactory bulb (OB). The OB has been suggested to fulfill a role comparable to that of V1 and the thalamus in the visual system and have been closely linked to a wide range of olfactory tasks and neuropathologies. Here we present a method for non-invasive recording of signals from the human OB with millisecond precision. We demonstrate that signals obtained via recordings from EEG electrodes at the nasal bridge represent responses from the human olfactory bulb - recordings we term Electrobulbogram (EBG). The EBG will aid future olfactory-related translational work but can also potentially be implemented as an everyday clinical tool to detect pathology-related changes in human central olfactory processing in neurodegenerative diseases. In conclusion, the EBG is localized to the OB, is reliable, and follows response patterns demonstrated in non-human animal models.

Dynamic synergetic configurations of resting-state networks in ADHD.

Attention deficit hyperactivity disorder (ADHD) is characterized by high distractibility and impaired executive functions. Notably, there is mounting evidence suggesting that ADHD could be regarded as a default mode network (DMN) disorder. In particular, failure in regulating the dynamics of activity and interactions of the DMN and cognitive control networks have been hypothesized as the main source of task interference causing attentional problems. On the other hand, previous studies indicated pronounced fluctuations in the strength of functional connections over time, particularly for the inter-network connections between the DMN and fronto-parietal control networks. Hence, characterization of connectivity disturbances in ADHD requires a thorough assessment of time-varying functional connectivity (FC). In this study, we proposed a dynamical systems perspective to assess how the DMN over time recruits different configurations of network segregation and integration. Specifically, we were interested in configurations for which both intra- and inter-network connections are retained, as opposed to commonly used methods which assess network segregation as a single measure. From resting-state fMRI data, we extracted three different stable configurations of FC patterns for the DMN, namely synergies. We provided evidence supporting our hypothesis that ADHD differs compared to controls, both in terms of recruitment rate and topology of specific synergies between resting-state networks. In addition, we found a relationship between synergetic cooperation patterns of the DMN with cognitive control networks and a behavioral measure which is sensitive to ADHD-related symptoms, namely the Stroop color-word task.

Reduction of physiological stress by urban green space in a multisensory virtual experiment.

Although stress is an increasing global health problem in cities, urban green spaces can provide health benefits. There is, however, a lack of understanding of the link between physiological mechanisms and qualities of urban green spaces. Here, we compare the effects of visual stimuli (360 degree virtual photos of an urban environment, forest, and park) to the effects of congruent olfactory stimuli (nature and city odours) and auditory stimuli (bird songs and noise) on physiological stress recovery. Participants (N = 154) were pseudo-randomised into participating in one of the three environments and subsequently exposed to stress (operationalised by skin conductance levels). The park and forest, but not the urban area, provided significant stress reduction. High pleasantness ratings of the environment were linked to low physiological stress responses for olfactory and to some extent for auditory, but not for visual stimuli. This result indicates that olfactory stimuli may be better at facilitating stress reduction than visual stimuli. Currently, urban planners prioritise visual stimuli when planning open green spaces, but urban planners should also consider multisensory qualities.