Spatiotemporal dynamics of odor representations in the human brain revealed by EEG decoding.

How the human brain translates olfactory inputs into diverse perceptions, from pleasurable floral smells to sickening smells of decay, is one of the fundamental questions in olfaction. To examine how different aspects of olfactory perception emerge in space and time in the human brain, we performed time-resolved multivariate pattern analysis of scalp-recorded electroencephalogram responses to 10 perceptually diverse odors and associated the resulting decoding accuracies with perception and source activities. Mean decoding accuracies of odors exceeded the chance level 100 ms after odor onset and reached maxima at 350 ms. The result suggests that the neural representations of individual odors were maximally separated at 350 ms. Perceptual representations emerged following the decoding peak: unipolar unpleasantness (neutral to unpleasant) from 300 ms, and pleasantness (neutral to pleasant) and perceptual quality (applicability to verbal descriptors such as "fruity" or "flowery") from 500 ms after odor onset, with all these perceptual representations reaching their maxima after 600 ms. A source estimation showed that the areas representing the odor information, estimated based on the decoding accuracies, were localized in and around the primary and secondary olfactory areas at 100 to 350 ms after odor onset. Odor representations then expanded into larger areas associated with emotional, semantic, and memory processing, with the activities of these later areas being significantly associated with perception. These results suggest that initial odor information coded in the olfactory areas (<350 ms) evolves into their perceptual realizations (300 to >600 ms) through computations in widely distributed cortical regions, with different perceptual aspects having different spatiotemporal dynamics.

Semantic context-dependent neural representations of odors in the human piriform cortex revealed by 7T MRI.

Olfactory perception depends not only on olfactory inputs but also on semantic context. Although multi-voxel activity patterns of the piriform cortex, a part of the primary olfactory cortex, have been shown to represent odor perception, it remains unclear whether semantic contexts modulate odor representation in this region. Here, we investigated whether multi-voxel activity patterns in the piriform cortex change when semantic context modulates odor perception and, if so, whether the modulated areas communicate with brain regions involved in semantic and memory processing beyond the piriform cortex. We also explored regional differences within the piriform cortex, which are influenced by olfactory input and semantic context. We used 2 × 2 combinations of word labels and odorants that were perceived as congruent and measured piriform activity with a 1-mm isotropic resolution using 7T MRI. We found that identical odorants labeled with different words were perceived differently. This labeling effect was observed in multi-voxel activity patterns in the piriform cortex, as the searchlight decoding analysis distinguished identical odors with different labels for half of the examined stimulus pairs. Significant functional connectivity was observed between parts of the piriform cortex that were modulated by labels and regions associated with semantic and memory processing. While the piriform multi-voxel patterns evoked by different olfactory inputs were also distinguishable, the decoding accuracy was significant for only one stimulus pair, preventing definitive conclusions regarding the locational differences between areas influenced by word labels and olfactory inputs. These results suggest that multi-voxel patterns of piriform activity can be modulated by semantic context, possibly due to communication between the piriform cortex and the semantic and memory regions.

Individuals With Autism Spectrum Disorder Show Altered Event-Related Potentials in the Late Stages of Olfactory Processing.

Atypical sensory reactivities are pervasive among people with autism spectrum disorder (ASD). With respect to olfaction, most previous studies have used psychophysical or questionnaire-based methodologies; thus, the neural basis of olfactory processing in ASD remains unclear. This study aimed to determine the stages of olfactory processing that are altered in ASD. Fourteen young adults with high-functioning ASD (mean age, 21 years; 3 females) were compared with 19 age-matched typically developing (TD) controls (mean age, 21 years; 4 females). Olfactory event-related potentials (OERPs) for 2-phenylethyl alcohol-a rose-like odor-were measured with 64 scalp electrodes while participants performed a simple odor detection task. Significant group differences in OERPs were found in 3 time windows 542 ms after the stimulus onset. The cortical source activities in these time windows, estimated using standardized low-resolution brain electromagnetic tomography, were significantly higher in ASD than in TD in and around the posterior cingulate cortex, which is known to play a crucial role in modality-general cognitive processing. Supplemental Bayesian analysis provided substantial evidence for an alteration in the later stages of olfactory processing, whereas conclusive evidence was not provided for the earlier stages. These results suggest that olfactory processing in ASD is altered at least at the later, modality-general processing stage.

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.

Extrinsic information influences taste and flavor perception: a review from psychological and neuroimaging perspectives.

The perception of taste and flavor can be greatly biased by extrinsic cues, or the information about a food that comes from outside of the food itself, such as package designs, brands, prices, and so on. In order to understand taste/flavor experiences in a broader context, it is necessary to consider factors other than the food/tastants themselves. This review aims to summarize some of the relevant findings from psychological and neuroimaging studies, focusing on depicting how extrinsic cues exert their effect on taste and flavor. Currently, the most frequently considered psychological mediator for the effects of extrinsic cues is expectation. Depending on the gap between expectation and taste/flavor experience, four major models predict outcomes of expectation effects: (1) assimilation, (2) generalized-negativity, (3) contrast, and (4) assimilation-contrast. Among them, the most influential is the assimilation model proposing that taste/flavor experiences are modified toward what one expects. Thus far, all the neuroimaging studies examining the influence of extrinsic cues have dealt with assimilation effects. They suggest that when extrinsic cues influence taste/flavor perception, cortical representations of taste/flavor are also modulated. Collectively neuroimaging findings partly answer questions arising from psychological aspects: the influence of extrinsic cues is not due to superficial response bias but to truly changed perception. These findings, albeit limited to assimilation effects, suggest that combined understanding from both psychological and neuroimaging studies would help deepen our understanding of the taste experience.

Discovery of novel 2-(alkylmorpholin-4-yl)-6-(3-fluoropyridin-4-yl)-pyrimidin-4(3H)-ones as orally-active GSK-3ß inhibitors for Alzheimer's disease.

We herein describe the results of further evolution of GSK-3ß inhibitors for Alzheimer's disease from our promising compounds with in vivo tau phosphorylation inhibitory activity by oral administration. Introduction of a low alkyl group instead of the phenyl group at the 3-position of the morpholine moiety aiming to improve pharmacokinetic profiles resulted in potent low molecular weight GSK-3ß inhibitors with good in vitro pharmacokinetic profiles, which also showed in vivo tau phosphorylation inhibitory activity by oral administration. Effect of the stereochemistry of the alkyl moiety is also discussed using docking models.

A cross sectional study on fertility knowledge in Japan, measured with the Japanese version of Cardiff Fertility Knowledge Scale (CFKS-J).

BACKGROUND: A recent survey of 79 countries showed that fertility knowledge was lower in Japan than in any other developed country. Given the fertility decline in Japan and the importance of fertility knowledge, we conducted an online survey to examine fertility knowledge and the related factors for effective public education. METHODS: We studied people aged 18-59 years old, n = 4,328 (the "General" group), and also people who had been trying to conceive for at least six months, 18-50 years old, n = 618 (the "Triers" group). Fertility knowledge was assessed using the Japanese version of the 13-item Cardiff Fertility Knowledge Scale (CFKS-J). All participants provided socio-demographic and fertility information. Participants also completed a 14-item health literacy scale and an 11-item health numeracy scale. We asked participants who were aware of age-related decline in fertility when and where they first acquired that knowledge. RESULTS: The average percentages of CFKS-J items answered correctly were 53.1% in the Triers group and 44.4% in the General group (p < 0.001). Multivariate linear regression models showed in the Triers group greater fertility knowledge was associated with greater health literacy and prior medical consultation regarding their fertility. In the General group greater fertility knowledge was associated with being female, younger, university educated, currently trying to conceive, non-smoking, having higher household income, having higher health literacy and having higher health numeracy. Of those who were aware of the age-related decline in fertility, around 3% first learned the fact "at school", and around 65% first learned it "through mass media" or "via the Internet". More than 30% of the respondents first learned it "less than 5 years before" the survey. CONCLUSIONS: Although fertility knowledge had improved since a previous study, possibly due to recent media coverage of age-related infertility, it was still low. Educational interventions, both in schools and in the community, may be needed to increase fertility knowledge in the general population because most people obtain fertility knowledge from mass media, which has been shown to often present distorted and inaccurate fertility information.

Correlation between LIFG and autonomic activation during stressful tasks: a functional near-infrared spectroscopy (fNIRS) study.

It remains unclear whether language tasks in one's first (L1) or second (L2) language can cause stress responses and whether frontal, autonomic and behavioral responses to stressful tasks are correlated. In this study, we studied 22 Chinese subjects whose L2 was English and measured the cerebral blood oxygenation in their frontal lobe by using functional near-infrared spectroscopy (fNIRS) as participants engaged in a mental arithmetic task (MAT) and verbal fluency tasks (VFTs) in L1 (Chinese) and L2 (English). To examine the activated cortical areas, we estimated the channel location based on Montreal Neurological Institute (MNI) standard brain space by using a probabilistic estimation method. We evaluated heart rate (HR) changes to analyze autonomic nervous system (ANS) functioning. We found that the MAT and VFTs induced greater increases in HR than did the control (Ctrl) task. Furthermore, subjects developed greater increases in HR in the MAT and VFTL2 than they did in the VFTL1. Compared with the Ctrl task, the MAT and both VFTL1 and VFTL2 produced robust and widespread bilateral activation of the frontal cortex. Interestingly, partial correlation analysis indicated that the activity in the left inferior frontal gyrus (LIFG) [Brodmann's area (BA) 47] was consistently correlated with the increases in HR across the three tasks (MAT, VFTL2, and VFTL1), after controlling for the performance data. The present results suggested that a VFT in L2 may be more stressful than in L1. The LIFG may affect the activation of the sympathetic system induced by stressful tasks, including MATs and VFTs.

Reading comprehension of health checkup reports and health literacy in Japanese people.

OBJECTIVES: To determine the reading comprehension of health checkup reports in the context of health literacy (HL) in Japanese people. METHODS: A web-based survey was conducted among 424 Japanese adults aged 35-59 years. Participants were asked to read specifically designed health checkup reports and then answer a series of questions to examine whether they accomplished the fundamental purposes of health checkup reports (recognition of the problems, recognition of the risk of illness, recognition of the need for preventive action, and motivation for preventive action). HL was simultaneously measured using the 14-item health literacy scale (HLS-14), the 11-item Lipkus scale (Lipkus-J), and the Newest Vital Sign (NVS-J). RESULTS: About 70 % of the study subjects misread the normal/abnormal classification for at least one items. Those with lower HLS-14 scores were significantly less likely to recognize the problems, the risk of illness, and the need for preventive action for the examinee, and also less likely to express their willingness to take preventive action in compliance with the doctor's advice after having received the health checkup report. Compared with the HLS-14 scores, the Lipkus-J and NVS-J scores showed hardly any association with the reading comprehension of health checkup reports. CONCLUSION: All examinees do not always have an adequate level of HL. HL may be the major determinant of reading comprehension of health checkup reports. For more effective health checkups, health promotion service providers should become aware of the existence of examinees with inadequate HL and address the problem of misreading health checkup results.

Superiority of experts over novices in trueness and precision of concentration estimation of sodium chloride solutions.

Several studies have reported that experts outperform novices in specific domains. However, the superiority of experts in accuracy, taking both trueness and precision into consideration, has not yet been explored. Here, we examined differences between expert and novice performances by evaluating the accuracy of their estimations of physical concentrations of sodium chloride in solutions while employing a visual analog scale. In Experiment 1, 14 experts and 13 novices tasted 6 concentrations of the solutions until they had learned their intensities. Subsequently, they repeatedly rated the concentration of 3 other solutions in random order. Although we did not find a difference between the performances of the 2 groups in trueness (difference between rating and correct concentration), the precision (consistency of ratings for each participant) of experts was higher than that of novices. In Experiment 2, 13 experts who had participated in Experiment 1 and 10 experts and 12 novices who had not participated in Experiment 1 rated the salt concentration in sodium chloride/sucrose mixtures in the same way as in Experiment 1. Both trueness and precision of performance were higher in both expert groups than in the novice group. By introducing precision and trueness parameters, we succeeded in quantifying the estimations of experts and novices in rating the concentration of solutions, revealing experts' superiority even for a task they had not been trained for.

Health numeracy in Japan: measures of basic numeracy account for framing bias in a highly numerate population.

BACKGROUND: Health numeracy is an important factor in how well people make decisions based on medical risk information. However, in many countries, including Japan, numeracy studies have been limited. METHODS: To fill this gap, we evaluated health numeracy levels in a sample of Japanese adults by translating two well-known scales that objectively measure basic understanding of math and probability: the 3-item numeracy scale developed by Schwartz and colleagues (the Schwartz scale) and its expanded version, the 11-item numeracy scale developed by Lipkus and colleagues (the Lipkus scale). RESULTS: Participants' performances (n = 300) on the scales were much higher than in original studies conducted in the United States (80% average item-wise correct response rate for Schwartz-J, and 87% for Lipkus-J). This high performance resulted in a ceiling effect on the distributions of both scores, which made it difficult to apply parametric statistical analysis, and limited the interpretation of statistical results. Nevertheless, the data provided some evidence for the reliability and validity of these scales: The reliability of the Japanese versions (Schwartz-J and Lipkus-J) was comparable to the original in terms of their internal consistency (Cronbach's α = 0.53 for Schwartz-J and 0.72 for Lipkus-J). Convergent validity was suggested by positive correlations with an existing Japanese health literacy measure (the Test for Ability to Interpret Medical Information developed by Takahashi and colleagues) that contains some items relevant to numeracy. Furthermore, as shown in the previous studies, health numeracy was still associated with framing bias with individuals whose Lipkus-J performance was below the median being significantly influenced by how probability was framed when they rated surgical risks. A significant association was also found using Schwartz-J, which consisted of only three items. CONCLUSIONS: Despite relatively high levels of health numeracy according to these scales, numeracy measures are still important determinants underlying susceptibility to framing bias. This suggests that it is important in Japan to identify individuals with low numeracy skills so that risk information can be presented in a way that enables them to correctly understand it. Further investigation is required on effective numeracy measures for such an intervention in Japan.

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.

Process-specific prefrontal contributions to episodic encoding and retrieval of tastes: a functional NIRS study.

The neural basis of memory subprocesses, encoding and retrieval, have been extensively examined in functional neuroimaging studies. However, the cortical substrates of taste memory, which form an important part of our episodic memory, have rarely been explored in humans. Previously, we have used functional near-infrared spectroscopy (fNIRS) and found activation of the lateral prefrontal cortex (LPFC) related to taste encoding. The method used in the current study allowed brain monitoring while participants tasted liquid taste-stimuli in upright positions. Here, using the same system, we examined the LPFC activity of 28 healthy volunteers during both the encoding and the retrieval of taste memory. The contrast between the retrieval and eyes-closed-resting conditions revealed activation in the bilateral LPFC. This activation was significantly larger than that for encoding in the bilateral frontopolar and right dorso-LPFC regions, particularly in the right hemisphere (N=28, P<0.05, FDR corrected), exhibiting right hemispheric dominance. Our findings are in line with the hemispheric encoding/retrieval asymmetry (HERA) model, which proposes a process-specific prefrontal contribution to memory function.

Virtual screening and further development of novel ALK inhibitors.

Anaplastic lymphoma kinase (ALK) has been in the spotlight in recent years as a promising new target for therapy of non-small-cell lung cancer (NSCLC). Since the identification of the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene in some NSCLC patients was reported in 2007, various research groups have been seeking ALK inhibitors. Above all, crizotinib (PF-02341066) has been under clinical trial, and its therapeutic efficacy of inhibiting ALK in NSCLC has been reported. Among anticancer drugs, drug resistance appears frequently necessitating various kinds of inhibitors. We identified novel ALK inhibitors by virtual screening from the public chemical library collected by the Chemical Biology Research Initiative (CBRI) at the University of Tokyo, and inhibitors that are more potent were developed.

Identification of novel ASK1 inhibitors using virtual screening.

Apoptosis signal-regulating kinase 1 (ASK1, also called MAP3K5) is a mitogen-activated protein kinase kinase kinase (MAP3K) that plays important roles in stress-induced cell death and inflammation, and is expected as a new therapeutic target for cancer, cardiovascular diseases, and neurodegenerative diseases. We identified novel ASK1 inhibitors by virtual screening from the public chemical library collected by Chemical Biology Research Initiative (CBRI) at the University of Tokyo.

Lin4Neuro: a customized Linux distribution ready for neuroimaging analysis.

BACKGROUND: A variety of neuroimaging software packages have been released from various laboratories worldwide, and many researchers use these packages in combination. Though most of these software packages are freely available, some people find them difficult to install and configure because they are mostly based on UNIX-like operating systems. We developed a live USB-bootable Linux package named "Lin4Neuro." This system includes popular neuroimaging analysis tools. The user interface is customized so that even Windows users can use it intuitively. RESULTS: The boot time of this system was only around 40 seconds. We performed a benchmark test of inhomogeneity correction on 10 subjects of three-dimensional T1-weighted MRI scans. The processing speed of USB-booted Lin4Neuro was as fast as that of the package installed on the hard disk drive. We also installed Lin4Neuro on a virtualization software package that emulates the Linux environment on a Windows-based operation system. Although the processing speed was slower than that under other conditions, it remained comparable. CONCLUSIONS: With Lin4Neuro in one's hand, one can access neuroimaging software packages easily, and immediately focus on analyzing data. Lin4Neuro can be a good primer for beginners of neuroimaging analysis or students who are interested in neuroimaging analysis. It also provides a practical means of sharing analysis environments across sites.

Acute moderate exercise elicits increased dorsolateral prefrontal activation and improves cognitive performance with Stroop test.

A growing number of human studies have reported the beneficial influences of acute as well as chronic exercise on cognitive functions. However, neuroimaging investigations into the neural substrates of the effects of acute exercise have yet to be performed. Using multichannel functional near-infrared spectroscopy (fNIRS), we sought cortical activation related to changes in the Stroop interference test, elicited by an acute bout of moderate exercise, in healthy volunteers (N=20). The compactness and portability of fNIRS allowed on-site cortical examination in a laboratory with a cycle ergometer, enabling strict control of the exercise intensity of each subject by assessing their peak oxygen intake (VO2peak). We defined moderate exercise intensity as 50% of a subject's peak oxygen uptake (50%VO2peak). An acute bout of moderate exercise caused significant improvement of cognitive performance reflecting Stroop interference as measured by reaction time. Consistent with previous functional neuroimaging studies, we detected brain activation due to Stroop interference (incongruent minus neutral) in the lateral prefrontal cortices in both hemispheres. This Stroop-interference-related activation was significantly enhanced in the left dorsolateral prefrontal cortex due to the acute bout of moderate exercise. The enhanced activation significantly coincided with the improved cognitive performance. This suggests that the left dorsolateral prefrontal cortex is likely the neural substrate for the improved Stroop performance elicited by an acute bout of moderate exercise. fNIRS, which allows physiological monitoring and functional neuroimaging to be combined, proved to be an effective tool for examining the cognitive effects of exercise.

Structure-activity relationship of novel DAPK inhibitors identified by structure-based virtual screening.

Death-associated protein kinase (DAPK) is a serine/threonine protein kinase implicated in diverse programmed cell death pathways. DAPK is a promising target protein for the treatment of ischemic diseases. We identified novel potent and selective DAPK inhibitors efficiently by structure-based virtual screening, then further developed the hit compounds. In this paper, we describe the development of the hit compounds and the structure-activity relationship studies of the DAPK inhibitors in detail, including calculation of the solvated interaction energy (SIE), and verification of selectivity using a kinase panel.

Interactive effects of carbon footprint information and its accessibility on value and subjective qualities of food products.

We aimed to explore the interactive effects of the accessibility of information and the degree of carbon footprint score on consumers' value judgments of food products. Participants (n=151, undergraduate students in Japan) rated their maximum willingness to pay (WTP) for four food products varying in information accessibility (active-search or read-only conditions) and in carbon footprint values (low, middle, high, or non-display) provided. We also assessed further effects of information accessibly and carbon footprint value on other product attributes utilizing the subjective estimation of taste, quality, healthiness, and environmental friendliness. Results of the experiment demonstrated an interactive effect of information accessibility and the degree of carbon emission on consumer valuation of carbon footprint-labeled food. The carbon footprint value had a stronger impact on participants' WTP in the active-search condition than in the read-only condition. Similar to WTP, the results of the subjective ratings for product qualities also exhibited an interactive effect of the two factors on the rating of environmental friendliness for products. These results imply that the perceived environmental friendliness inferable from a carbon footprint label contributes to creating value for a food product.

Mapping of optical pathlength of human adult head at multi-wavelengths in near infrared spectroscopy.

Measurement of multichannel continuous-wave near-infrared spectroscopy (CW-NIRS) is dependent on the modified Beer-Lambert law, which includes optical pathlength (PL) as an essential parameter. PLs are known to differ across different head regions and different individuals, but the distribution of PLs for the whole head has not been evaluated so far. Thus, using time-resolved near-infrared spectroscopy (TR-NIRS), we measured the optical characteristics including PL, scattering coefficients (mu'(s)), and absorption coefficients (mu(a)) at three wavelengths (760, 800, 830 nm). Then, we constructed maps of these parameters on the subjects' head surface. While the PLs in nearby channels are similar, they differ depending on the regions of the head. The PLs in the region above the Sylvian fissure tended to be shorter than those in the other regions at all of the wavelengths. The difference in the distribution of PLs may be attributed to differences in tissue absorption and scattering properties. The current study suggests the importance of considering PL differences in interpreting functional data obtained by CW-NIRS.