Continuous Theta Burst Stimulation to the left anterior medial prefrontal cortex influences metacognitive efficiency.

The contribution of the prefrontal areas to visual awareness is critical for the Global Neuronal Workspace Theory and higher-order theories of consciousness. The goal of the present study was to test the potential engagement of the anterior medial prefrontal cortex (aMPFC) in visual awareness judgements. We aimed to temporarily influence the neuronal dynamics of the left aMPFC via neuroplasticity-like mechanisms. We used different Theta Burst Stimulation (TBS) protocols in combination with a visual identification task and visual awareness ratings. Either continuous TBS (cTBS), intermittent TBS (iTBS), or sham TBS was applied prior to the experimental paradigm in a within-participant design. Compared with sham TBS, we observed an increase in participants' ability to judge their perception adequately (metacognitive efficiency) following cTBS but not iTBS. The effect was accompanied by lower visual awareness ratings in incorrect responses. No significant differences in the identification task performance were observed. We interpret these results as evidence of the involvement of PFC in the brain network that underlies metacognition. Further, we discuss whether the results of TMS studies on perceptual metacognition can be taken as evidence for PFC involvement in awareness itself.

Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses.

Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.

Task requirements affect the neural correlates of consciousness.

In the search for the neural correlates of consciousness, it is often assumed that there is a stable set within the relevant sensory modality. Within the visual modality, the debate has centred upon whether frontal or occipital activations are the best predictors of perceptual awareness. Although not accepted by all as definitive evidence, no-report and decoding studies have indicated that occipital activity is the most consistently correlated with perceptual awareness whereas frontal activity might be closely related to aspects of cognition typically related to reports. However, perception is rarely just passive perception of something, but more or less always perception for something. That is, the task at hand for the perceiver may influence what is being perceived. This suggests an alternative view: that consciousness is not one specific 'function' that can be localized consistently to one area or event-related component and that the specific attributes of the neural correlates of consciousness depend on the task at hand. To investigate whether and how tasks may influence the neural correlates of consciousness, we here contrasted two tasks, a perceptual task and a conceptual task, using identical stimuli in both tasks. Using magnetoencephalography, we found that the perceptual task recruited more occipital resources than the conceptual task. Furthermore, we found that between the two conditions, the amount of frontal resources recruited differed between different gradations of perceptual awareness partly in an unexpected manner. These findings support a view of task affecting the neural correlates of consciousness.

Spatiotemporal dynamics of brightness coding in human visual cortex revealed by the temporal context effect.

Human visual perception is modulated by both temporal and spatial contexts. One type of modulation is apparent in the temporal context effect (TCE): In the presence of a constant luminance patch (a long flash), the perceived brightness of a short flash increases monotonically with onset asynchrony. The aim of the current study was to delineate the neural correlates of this illusory effect, particularly focusing on its dynamic neural representation among visual cortical areas. We reconstructed sources of magnetoencephalographic (MEG) data recorded from observers (6 male and 9 female human adults) experiencing the TCE. Together with retinotopic mapping, signals from different occipital lobe areas were extracted to investigate whether different visual areas have differential representation of the onset vs. offset synchronized short flashes. From the data, TCE related responses were observed in LO and V4 in the time window of 200-250 m s, while neuronal responses to physical luminances were observed in the early time window at around 100 m s across early visual cortex, such as V1 and V2, also in V4 and VO. Based on these findings, we suggest that two distinct processes might be involved in brightness coding: one bottom-up process which is stimulus energy driven and responds fast, and another process which may be broadly characterized as top-down or lateral, is context driven, and responds slower. For both processes, we found that V4 might play a critical role in dynamically integrating luminances into brightness perception, a finding that is consistent with the view of V4 as a bottom-up and top-down integration complex.

Comparing theories of consciousness: Object position, not probe modality, reliably influences experience and accuracy in object recognition tasks.

People often claim seeing images completely despite performing poorly. This highlights an issue with conscious representations. We introduce an experimental manipulation aiming to disentangle two prevalent positions: Rich views posit that people virtually represent the external world with unlimited capacity; Sparse views state that representations are reconstructed from expectations and information. In two experiments using the object recognition task, we tested two probe types: Images, which should aid reconstruction more, and Words, which should aid it less. From a sparse view, one should expect that Images lead to greater accuracy and reported experience. We found no reliable differences in accuracy and reported experience across probe types; however, we observed that the object positions influenced both accuracy and reported experience, which is surprising from a Rich view as it seemingly requires assumptions of different access across the visual field. Both theoretical positions thus currently need further development to explain our results.

Human Occipital and Parietal GABA Selectively Influence Visual Perception of Orientation and Size.

GABA is the primary inhibitory neurotransmitter in human brain. The level of GABA varies substantially across individuals, and this variability is associated with interindividual differences in visual perception. However, it remains unclear whether the association between GABA level and visual perception reflects a general influence of visual inhibition or whether the GABA levels of different cortical regions selectively influence perception of different visual features. To address this, we studied how the GABA levels of parietal and occipital cortices related to interindividual differences in size, orientation, and brightness perception. We used visual contextual illusion as a perceptual assay since the illusion dissociates perceptual content from stimulus content and the magnitude of the illusion reflects the effect of visual inhibition. Across individuals, we observed selective correlations between the level of GABA and the magnitude of contextual illusion. Specifically, parietal GABA level correlated with size illusion magnitude but not with orientation or brightness illusion magnitude; in contrast, occipital GABA level correlated with orientation illusion magnitude but not with size or brightness illusion magnitude. Our findings reveal a region- and feature-dependent influence of GABA level on human visual perception. Parietal and occipital cortices contain, respectively, topographic maps of size and orientation preference in which neural responses to stimulus sizes and stimulus orientations are modulated by intraregional lateral connections. We propose that these lateral connections may underlie the selective influence of GABA on visual perception.SIGNIFICANCE STATEMENT GABA, the primary inhibitory neurotransmitter in human visual system, varies substantially across individuals. This interindividual variability in GABA level is linked to interindividual differences in many aspects of visual perception. However, the widespread influence of GABA raises the question of whether interindividual variability in GABA reflects an overall variability in visual inhibition and has a general influence on visual perception or whether the GABA levels of different cortical regions have selective influence on perception of different visual features. Here we report a region- and feature-dependent influence of GABA level on human visual perception. Our findings suggest that GABA level of a cortical region selectively influences perception of visual features that are topographically mapped in this region through intraregional lateral connections.

Occipital MEG Activity in the Early Time Range (<300 ms) Predicts Graded Changes in Perceptual Consciousness.

Two electrophysiological components have been extensively investigated as candidate neural correlates of perceptual consciousness: An early, occipitally realized component occurring 130-320 ms after stimulus onset and a late, frontally realized component occurring 320-510 ms after stimulus onset. Recent studies have suggested that the late component may not be uniquely related to perceptual consciousness, but also to sensory expectations, task associations, and selective attention. We conducted a magnetoencephalographic study; using multivariate analysis, we compared classification accuracies when decoding perceptual consciousness from the 2 components using sources from occipital and frontal lobes. We found that occipital sources during the early time range were significantly more accurate in decoding perceptual consciousness than frontal sources during both the early and late time ranges. These results are the first of its kind where the predictive values of the 2 components are quantitatively compared, and they provide further evidence for the primary importance of occipital sources in realizing perceptual consciousness. The results have important consequences for current theories of perceptual consciousness, especially theories emphasizing the role of frontal sources.

Discriminating between first- and second-order cognition in first-episode paranoid schizophrenia.

INTRODUCTION: An impairment of visually perceiving backward masked stimuli is commonly observed in patients with schizophrenia, yet it is unclear whether this impairment is the result of a deficiency in first or higher order processing and for which subtypes of schizophrenia it is present. METHODS: Here, we compare identification (first order) and metacognitive (higher order) performance in a visual masking paradigm between a highly homogenous group of young first-episode patients diagnosed with paranoid schizophrenia (N = 11) to that of carefully matched healthy controls (N = 13). RESULTS: We find no difference across groups in first-order performance, but find a difference in metacognitive performance, particularly for stimuli with relatively high visibility. CONCLUSIONS: These results indicate that the masking deficit is present in first-episode patients with paranoid schizophrenia, but that it is primarily an impairment of metacognition.

Making sense: Dopamine activates conscious self-monitoring through medial prefrontal cortex.

When experiences become meaningful to the self, they are linked to synchronous activity in a paralimbic network of self-awareness and dopaminergic activity. This network includes medial prefrontal and medial parietal/posterior cingulate cortices, where transcranial magnetic stimulation may transiently impair self-awareness. Conversely, we hypothesize that dopaminergic stimulation may improve self-awareness and metacognition (i.e., the ability of the brain to consciously monitor its own cognitive processes). Here, we demonstrate improved noetic (conscious) metacognition by oral administration of 100 mg dopamine in minimal self-awareness. In a separate experiment with extended self-awareness dopamine improved the retrieval accuracy of memories of self-judgment (autonoetic, i.e., explicitly self-conscious) metacognition. Concomitantly, magnetoencephalography (MEG) showed increased amplitudes of oscillations (power) preferentially in the medial prefrontal cortex. Given that electromagnetic activity in this region is instrumental in self-awareness, this explains the specific effect of dopamine on explicit self-awareness and autonoetic metacognition.

Magnetoencephalographic activity related to conscious perception is stable within individuals across years but not between individuals.

Studies indicate that conscious perception is related to changes in neural activity within a time window that varies between 130 and 320 msec after stimulus presentation, yet it is not known whether such neural correlates of conscious perception are stable across time. Here, we examined the generalization across time within individuals and across different individuals. We trained classification algorithms to decode conscious perception from neural activity recorded during binocular rivalry using magnetoencephalography (MEG). The classifiers were then used to predict the perception of the same participants during different recording sessions either days or years later as well as between different participants. No drop in decoding accuracy was observed when decoding across years compared with days, whereas a large drop in decoding accuracy was found for between-participant decoding. Furthermore, underlying percept-specific MEG signals remained stable in terms of latency, amplitude, and sources within participants across years, whereas differences were found in all of these domains between individuals. Our findings demonstrate that the neural correlates of conscious perception are stable across years for adults, but differ across individuals. Moreover, the study validates decoding based on MEG data as a method for further studies of correlations between individual differences in perceptual contents and between-participant decoding accuracies.

Distinct MEG correlates of conscious experience, perceptual reversals and stabilization during binocular rivalry.

During binocular rivalry, visual perception alternates spontaneously between two different monocular images. Such perceptual reversals are slowed or halted if stimuli are presented intermittently with inter-stimulus intervals larger than ~400 ms--a phenomenon called stabilization. Often, the neural correlates of reversal and stabilization are studied separately, and both phenomena in turn are studied separately from the neural correlates of conscious perception. To distinguish the neural correlates of perceptual content, stabilization and reversal, we recorded MEG signals associated with each in the same group of healthy humans observing repeated trials of intermittent presentation of a dichoptic stimulus. Perceptual content correlated mainly with modulation of stimulus-specific activity in occipital/temporal areas 150-270 ms after stimulus onset, possibly reflecting inhibition of the neural populations representing the suppressed image. Stability of perception reflected a gradual build-up of this modulation across at least 10 trials and was also, to some extent, associated with parietal activity 40-90 ms and 220-270 ms after stimulus onset. Perceptual reversals, in contrast, were associated with parietal (150-270 ms) and temporal (150-210 ms) activity on the trial before the reversal and a gradual change in perception-specific activity in occipital (150-270 ms) and temporal (220-420 ms) areas across at least 10 trials leading up to a reversal. Mechanistically, these findings suggest that stability of perception during rivalry is maintained by modulation of activity related to the two monocular images, and gradual adaptation of neuronal populations leads to instability that is eventually resolved by signals from parietal and late sensory cortices.

Long-term reproducibility of GABA magnetic resonance spectroscopy.

Recent findings suggest that cortical gamma aminobutyric acid (GABA) levels may provide a surrogate marker for a number of psychiatric and neurological conditions, as well as behavioural traits. However, the natural variability of GABA levels in the human brain over long periods of time (>8 days) has not yet been studied. The purpose of this work was to investigate the long-term variability of GABA concentrations in the human occipital cortex. Nineteen healthy male participants were recruited and underwent two sessions of magnetic resonance spectroscopy (MRS) to determine occipital GABA levels with an average between-session interval of 7 months. We assessed between-session variability, as well as the correlation between session 1 and session 2 GABA measurements. The mean coefficient of variation between sessions was 4.3% (bootstrap 95% confidence interval: 2.5, 6.4), which is comparable to reported GABA variability measurements over much shorter time intervals (<8 days). A significant positive correlation was observed between session 1 and session 2 GABA measurements (r=0.53, p=0.014), and the intra-class correlation coefficient was calculated to be 0.52 which was also statistically significant (p=0.012). These findings establish experimentally that GABA concentrations in the occipital cortex, as measured by MRS, are relatively stable over periods as long as 7 months. The findings have significant implications for the internal validity of longitudinal studies of GABA levels in the human brain, and they lend foundational support to studies relating GABA levels to behavioural traits in healthy individuals.

Occipital GABA correlates with cognitive failures in daily life.

The brain has limited capacity, and so selective attention enhances relevant incoming information while suppressing irrelevant information. This process is not always successful, and the frequency of such cognitive failures varies to a large extent between individuals. Here we hypothesised that individual differences in cognitive failures might be reflected in inhibitory processing in the sensory cortex. To test this hypothesis, we measured GABA in human visual cortex using MR spectroscopy and found a negative correlation between occipital GABA (GABA+/Cr ratio) and cognitive failures as measured by an established cognitive failures questionnaire (CFQ). For a second site in parietal cortex, no correlation between CFQ score and GABA+/Cr ratio was found, thus establishing the regional specificity of the link between occipital GABA and cognitive failures. We further found that grey matter volume in the left superior parietal lobule (SPL) correlated with cognitive failures independently from the impact of occipital GABA and together, occipital GABA and SPL grey matter volume statistically explained around 50% of the individual variability in daily cognitive failures. We speculate that the amount of GABA in sensory areas may reflect the potential capacity to selectively suppress irrelevant information already at the sensory level, or alternatively that GABA influences the specificity of neural representations in visual cortex thus improving the effectiveness of successful attentional modulation.

Continuous theta-burst stimulation demonstrates a causal role of premotor homunculus in action understanding.

Although it is well established that regions of premotor cortex (PMC) are active during action observation, it remains controversial whether they play a causal role in action understanding. In the experiment reported here, we used off-line continuous theta-burst stimulation (cTBS) to investigate this question. Participants received cTBS over the hand and lip areas of left PMC, in separate sessions, before completing a pantomime-recognition task in which half of the trials contained pantomimed hand actions, and half contained pantomimed mouth actions. The results reveal a double dissociation: Participants were less accurate in recognizing pantomimed hand actions after receiving cTBS over the hand area than over the lip area and less accurate in recognizing pantomimed mouth actions after receiving cTBS over the lip area than over the hand area. This finding constrains theories of action understanding by showing that somatotopically organized regions of PMC contribute causally to action understanding and, thus, that the mechanisms underpinning action understanding and action performance overlap.

Test-retest reliability and validity of the Importance of Olfaction Questionnaire in Denmark.

While measures to detect psychophysical olfactory ability are a crucial part of clinicians' assessment of potential olfactory loss, it gives no indication of how olfaction is experienced by the patient and these different aspects often deviate substantially. To ensure quality and reproducibility of subjectively reported olfactory experience and significance, the Importance of Olfaction Questionnaire (IO-Q) was introduced around a decade ago, and while initial validations have produced promising results, important aspects remain nearly unexamined. For example, the test-retest reliability has rarely been examined and the difference of online versus pen-and-paper administration remains unexplored. Here, we translated IO-Q to Danish and examined its validity, test-retest reliability and mode of administration. A cohort of 179 younger, Danish participants with a high level of English proficiency took the test twice with varying time in-between. The first test was taken digitally and in English, while the second was taken using pen-and-paper and in Danish. The distribution of scores and the relationship between the IO-Q and subscale scores were nearly identical between tests, indicating little to no influence of language/test modality in the sampled population. The internal consistency was comparable to previously published results. Likewise, an acceptable test-retest reliability was observed for the full IO-Q and slightly lower for subscales. No significant effect of time was found across several weeks. In conclusion, the IO-Q performed satisfactorily in all examinations and could therefore serve as a valuable clinical measure of subjective olfactory experience, and its Danish translation shows highly similar characteristics to the original, English version.

Early visual responses predict conscious face perception within and between subjects during binocular rivalry.

Previous studies indicate that conscious face perception may be related to neural activity in a large time window around 170-800 msec after stimulus presentation, yet in the majority of these studies changes in conscious experience are confounded with changes in physical stimulation. Using multivariate classification on MEG data recorded when participants reported changes in conscious perception evoked by binocular rivalry between a face and a grating, we showed that only MEG signals in the 120-320 msec time range, peaking at the M170 around 180 msec and the P2m at around 260 msec, reliably predicted conscious experience. Conscious perception could not only be decoded significantly better than chance from the sensors that showed the largest average difference, as previous studies suggest, but also from patterns of activity across groups of occipital sensors that individually were unable to predict perception better than chance. In addition, source space analyses showed that sources in the early and late visual system predicted conscious perception more accurately than frontal and parietal sites, although conscious perception could also be decoded there. Finally, the patterns of neural activity associated with conscious face perception generalized from one participant to another around the times of maximum prediction accuracy. Our work thus demonstrates that the neural correlates of particular conscious contents (here, faces) are highly consistent in time and space within individuals and that these correlates are shared to some extent between individuals.

Measuring and testing awareness of emotional face expressions.

Comparison of behavioural measures of consciousness has attracted much attention recently. In a recent article, Szczepanowski et al. conclude that confidence ratings (CR) predict accuracy better than both the perceptual awareness scale (PAS) and post-decision wagering (PDW) when using stimuli with emotional content (fearful vs. neutral faces). Although we find the study interesting, we disagree with the conclusion that CR is superior to PAS because of two methodological issues. First, the conclusion is not based on a formal test. We performed this test and found no evidence that CR predicted accuracy better than PAS (p=.4). Second, Szczepanowski et al. used the present version of PAS in a manner somewhat different from how it was originally intended, and the participants may not have been adequately instructed. We end our commentary with a set of recommendations for future studies using PAS.

Shared parenting and father involvement after divorce in Denmark.

The Scandinavian countries make interesting samples for the study of shared parenting as they are characterized by some of the highest levels of father involvement and gender equality globally. Despite numerous studies, data from Denmark is noticeably absent in the international debate, partly due to a researcher preference for publishing in Danish. Here, I present an overview of the increase in father involvement in Denmark since the 1960s and on the increase in shared parenting across recent decades. I further examine Danish law, ministerial guidelines and guidelines from major Danish public and private institutions/organizations involved in deciding or advising on parenting practices post-divorce. I relate these to international research findings as well as to findings from Danish research. Overall, I find that Danish guidelines/practice have several reservations against shared parenting and substantial father involvement, which are not considered warranted by a substantial number of scientists and which are not supported by the majority of the available evidence. It thus appears that societal transition toward increased shared parenting has happened on a largely voluntary basis in spite of official law/practice. Updated law and/or ministerial guidelines are likely necessary if politicians desire that children experience the same high degree of father involvement post-divorce that they experience in society in general.