3-generation family medical histories of mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions associated with autism.

Background: Family histories of different mental and non-mental conditions have often been associated with autism spectrum disorder (ASD) but the restricted scope of conditions and family members that have been investigated limits etiologic understanding. We aimed to perform a comprehensive assessment of ASD associations with 3-generation family histories of 90 mental, neurologic, cardiometabolic, birth defect, asthma, allergy, and autoimmune conditions. The assessment comprised separate estimates of association with ASD overall; separate estimates by sex and intellectual disability (ID) status; as well as separate estimates of the co-occurrence of each of the 90 disorders in autistic persons. Additionally, we aimed to provide interactive catalogues of results to facilitate results visualization and further hypothesis-generation. Methods: We conducted a population-based, registry cohort study comprised of all live births in Denmark, 1980-2012, of Denmark-born parents, and with birth registry information (1,697,231 births), and their 3-generation family member types (20 types). All cohort members were followed from birth through April 10, 2017 for an ASD diagnosis. All participants (cohort members and each family member) were followed from birth through April 10, 2017 for each of 90 diagnoses, emigration or death. Adjusted hazard ratios (aHR) were estimated for ASD overall; by sex; or accounting for ID via separate Cox regression models for each diagnosis-family member type combination, adjusting for birth year, sex, birth weight, gestational age, parental ages at birth, and number of family member types of index person. aHRs were also calculated for sex-specific co-occurrence of each disorder, for ASD overall and considering ID. A catalogue of all results is displayed via interactive heat maps here: https://ncrr-au.shinyapps.io/asd-riskatlas/ and interactive graphic summaries of results are here: https://public.tableau.com/views/ASDPlots_16918786403110/e-Figure5. Results: Increased aHRs for ASD (26,840 cases; 1.6% of births) were observed for almost all individual mental disorder-family member type combinations yet for fewer non-mental disorder-family member type combinations. aHRs declined with diminishing degree of relatedness between the index person and family member for some disorders, especially mental disorders. Variation in aHR magnitude by family member sex (e.g., higher maternal than paternal aHRs) or side of the family (e.g., higher maternal versus paternal half sibling aHRs) was more evident among non-mental than mental disorders. Co-occurring ID in the family member or the index person impacted aHR variation. Conclusion: Our approach revealed considerable breadth and variation in magnitude of familial health history associations with ASD by type of condition, sex of the affected family member, side of the family, sex of the index person, and ID status which is indicative of diverse genetic, familial, and non-genetic ASD etiologic pathways. More careful attention to identifying sources of autism likelihood encompassed in family medical history, in addition to genetics, may accelerate understanding of factors underlying neurodiversity.

A construct-first approach to consciousness science.

We propose a new approach to consciousness science that instead of comparing complex theoretical positions deconstructs existing theories, takes their central assumptions while disregarding their auxiliary hypotheses, and focuses its investigations on the main constructs that these central assumptions rely on (like global workspace, recurrent processing, metarepresentation). Studying how these main constructs are anchored in lower-level constructs characterizing underlying neural processing will not just offer an alternative to theory comparisons but will also take us one step closer to empirical resolutions. Moreover, exploring the compatibility and possible combinations of the lower-level constructs will allow for new theoretical syntheses. This construct-first approach will improve our ability to understand the commitments of existing theories and pave the way for moving beyond them.

Does report modality modulate psychophysical sensitivity? The jury remains out.

Scientific studies of perception use motoric reports as the principal means of communicating subjective experience. In such experiments, a widely held and implicit assumption is that the motor action conveys but does not tamper with perceptual experience. We tested nine observers on a luminance detection task in a cross-over repeated measures design. In separate conditions, observers reported their detection via movements of either their hands or eyes. We found only anecdotal evidence for any modality-dependent effect on psychophysical sensitivity. We also reanalyzed an existing dataset from which deployed a similar detection paradigm involving hand and eye reports. In the four paradigm variants tested, we again only found anecdotal evidence for the effect of report modality on psychophysical sensitivity. Both studies reported here provide only anecdotal evidence; thus, whether we can replicate report-dependent perceptual effects still needs to be resolved. We argue why this remains an important question for consciousness research and why it deserves more rigorous and high-powered replication attempts.

Win-loss parameters for right-censored event data, with application to recurrent events.

The win ratio has become a popular method for comparing multiple event data between two groups in clinical cohort studies. The win ratio compares the event data in prioritized order, where the first prioritized event is death and a typical example for the second prioritized event is hospitalization. Literature is sparse on inference for win and loss parameters, including the win ratio, for censored event data. Inference for two prioritized censored event times has been developed for independent right-censoring. Many clinical studies include recurrent event data such as hospitalizations. In this article, we suggest inference for win-loss parameters for death and a recurrent event outcome under independent right-censoring. The small sample properties of the proposed method are studied in a simulation study showing that the variance formula is accurate even for small samples. The method is applied on a data set from a randomized clinical trial.

Regression models for censored time-to-event data using infinitesimal jack-knife pseudo-observations, with applications to left-truncation.

Jack-knife pseudo-observations have in recent decades gained popularity in regression analysis for various aspects of time-to-event data. A limitation of the jack-knife pseudo-observations is that their computation is time consuming, as the base estimate needs to be recalculated when leaving out each observation. We show that jack-knife pseudo-observations can be closely approximated using the idea of the infinitesimal jack-knife residuals. The infinitesimal jack-knife pseudo-observations are much faster to compute than jack-knife pseudo-observations. A key assumption of the unbiasedness of the jack-knife pseudo-observation approach is on the influence function of the base estimate. We reiterate why the condition on the influence function is needed for unbiased inference and show that the condition is not satisfied for the Kaplan-Meier base estimate in a left-truncated cohort. We present a modification of the infinitesimal jack-knife pseudo-observations that provide unbiased estimates in a left-truncated cohort. The computational speed and medium and large sample properties of the jack-knife pseudo-observations and infinitesimal jack-knife pseudo-observation are compared and we present an application of the modified infinitesimal jack-knife pseudo-observations in a left-truncated cohort of Danish patients with diabetes.

Worlds apart? Testing the cultural distance hypothesis in music perception of Chinese and Western listeners.

According to the cultural distance hypothesis (CDH), individuals learn culture-specific statistical structures in music as internal stylistic models and use these models in predictive processing of music, with musical structures closer to their home culture being easier to predict. This cultural distance effect may be affected by domain-specific (musical ability) and domain-general individual characteristics (openness, implicit cultural bias). To test the CDH and its modulation by individual characteristics, we recruited Chinese and Western adults to categorize stylistically ambiguous and unambiguous Chinese and Western melodies by cultural origin. Categorization performance was better for unambiguous (low CD) than ambiguous melodies (high CD), and for in-culture melodies regardless of ambiguity for both groups, providing evidence for CDH. Musical ability, but not other traits, correlated positively with melody categorization, suggesting that musical ability refines internal stylistic models. Therefore, both cultures show musical enculturation in their home culture with a modulatory effect of individual musical ability.

Bivariate pseudo-observations for recurrent event analysis with terminal events.

The analysis of recurrent events in the presence of terminal events requires special attention. Several approaches have been suggested for such analyses either using intensity models or marginal models. When analysing treatment effects on recurrent events in controlled trials, special attention should be paid to competing deaths and their impact on interpretation. This paper proposes a method that formulates a marginal model for recurrent events and terminal events simultaneously. Estimation is based on pseudo-observations for both the expected number of events and survival probabilities. Various relevant hypothesis tests in the framework are explored. Theoretical derivations and simulation studies are conducted to investigate the behaviour of the method. The method is applied to two real data examples. The bivariate marginal pseudo-observation model carries the strength of a two-dimensional modelling procedure and performs well in comparison with available models. Finally, an extension to a three-dimensional model, which decomposes the terminal event per death cause, is proposed and exemplified.

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.

Doubting the double-blind: Introducing a questionnaire for awareness of experimental purposes in neurofeedback studies.

Double-blinding subjects to the experiment's purpose is an important standard in neurofeedback studies. However, it is difficult to provide evidence that humans are entirely unaware of certain information. This study used insights from consciousness studies and neurophenomenology to develop a contingency awareness questionnaire for neurofeedback. We assessed whether participants had an awareness of experimental purposes to manipulate their attention and multisensory perception. A subset of subjects (5 out of 20) gained a degree of awareness of experimental purposes as evidenced by their correct guess about the purposes of the experiment to affect their attention and multisensory perceptions specific to their double-blinded group assignment. The results warrant replication before they are applied to clinical neurofeedback studies, given the considerable time taken to perform the questionnaire (∼25 min). We discuss the strengths and limitations of our contingency awareness questionnaire and the growing appeal of the double-blinded standard in clinical neurofeedback studies.

Can neurofeedback provide evidence of direct brain-behavior causality?

Neurofeedback is a procedure that measures brain activity in real-time and presents it as feedback to an individual, thus allowing them to self-regulate brain activity with effects on cognitive processes inferred from behavior. One common argument is that neurofeedback studies can reveal how the measured brain activity causes a particular cognitive process. The causal claim is often made regarding the measured brain activity being manipulated as an independent variable, similar to brain stimulation studies. However, this causal inference is vulnerable to the argument that other upstream brain activities change concurrently and cause changes in the brain activity from which feedback is derived. In this paper, we outline the inference that neurofeedback may causally affect cognition by indirect means. We further argue that researchers should remain open to the idea that the trained brain activity could be part of a "causal network" that collectively affects cognition rather than being necessarily causally primary. This particular inference may provide a better translation of evidence from neurofeedback studies to the rest of neuroscience. We argue that the recent advent of multivariate pattern analysis, when combined with implicit neurofeedback, currently comprises the strongest case for causality. Our perspective is that although the burden of inferring direct causality is difficult, it may be triangulated using a collection of various methods in neuroscience. Finally, we argue that the neurofeedback methodology provides unique advantages compared to other methods for revealing changes in the brain and cognitive processes but that researchers should remain mindful of indirect causal effects.

A window of subliminal perception.

Under labels such as unconscious processing and subliminal perception, identification of stimuli falling below the subjective threshold (whether truly unconscious or not) has been found remarkably accurate in some experiments while completely at chance in others. Here, we first identify that an apparent window of subliminal perception arises in humans under specific stimulus conditions using different experimental paradigms and analysis methods. We then show that the standard signal detection theory (SDT) model is unable to account for this window and extend it until it is. We finally compare a range of models on empirical data. The models performing best are notable for their absence of hierarchical levels, indicating that the window could be a base property of any phenomenally conscious system. The models explain previously incompatible findings in the literature, and they allow for estimations of peaks in subthreshold perception across the spectrum of stimulus saliency, which may be used in further studies of subliminal perception.

Neurofeedback Modulation of the Sound-induced Flash Illusion Using Parietal Cortex Alpha Oscillations Reveals Dependency on Prior Multisensory Congruency.

Spontaneous neural oscillations are key predictors of perceptual decisions to bind multisensory signals into a unified percept. Research links decreased alpha power in the posterior cortices to attention and audiovisual binding in the sound-induced flash illusion (SIFI) paradigm. This suggests that controlling alpha oscillations would be a way of controlling audiovisual binding. In the present feasibility study we used MEG-neurofeedback to train one group of subjects to increase left/right and another to increase right/left alpha power ratios in the parietal cortex. We tested for changes in audiovisual binding in a SIFI paradigm where flashes appeared in both hemifields. Results showed that the neurofeedback induced a significant asymmetry in alpha power for the left/right group, not seen for the right/left group. Corresponding asymmetry changes in audiovisual binding in illusion trials (with 2, 3, and 4 beeps paired with 1 flash) were not apparent. Exploratory analyses showed that neurofeedback training effects were present for illusion trials with the lowest numeric disparity (i.e., 2 beeps and 1 flash trials) only if the previous trial had high congruency (2 beeps and 2 flashes). Our data suggest that the relation between parietal alpha power (an index of attention) and its effect on audiovisual binding is dependent on the learned causal structure in the previous stimulus. The present results suggests that low alpha power biases observers towards audiovisual binding when they have learned that audiovisual signals originate from a common origin, consistent with a Bayesian causal inference account of multisensory perception.

No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients.

We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (0.15 mg/kg). Patients were genotyped for the genetic variants (rs12208357, rs34059508, rs72552763 and rs34130495) in OCT1. Eighty-six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (-0.7-2.4), -5.9 (-11.8 to -0.03) and -1.1 (-2.5-0.4) h/L*10-6 , respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUCM3G/Dose )/(AUCmorphine/Dose ) and (AUCM6G/Dose )/(AUCmorphine/Dose ) ratio was reduced, -1.8 (-3.2 to -0.4) and -0.4 (-0.7 to -0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre-emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery.

The Perceptual Awareness Scale-recent controversies and debates.

Accurate insight into subjective experience is crucial for the science of consciousness. The Perceptual Awareness Scale (PAS) was created in 2004 as a method for obtaining precise introspective reports for participants in research projects, and since then, the scale has become increasingly popular. This does not mean, of course, that no critiques have been voiced. Here, we briefly recapitulate our main thoughts on the intended PAS usage and the findings of the first decade, and we update this with the latest empirical and theoretical developments. We focus specifically on findings with relevance to whether consciousness is gradual or all-or-none phenomenon, to what should be considered conscious/unconscious, and to whether PAS is preferable to alternative measures of awareness. We respond in detail to some recent, selected articles.

Investigating the validity of the Perceptual Awareness Scale - The effect of task-related difficulty on subjective rating.

The Perceptual Awareness Scale (PAS) is often used to probe conscious experience, but the assumptions behind the scale and its validity are rarely tested. Using a continuous colour estimation task to assess perceptual quality, we focus on how well PAS follows perceptual quality and how the presence of the estimation task affects PAS ratings. We varied the number and presentation time of stimuli in a simultaneous presentation and target position in a sequential presentation. In all experiments, PAS rating closely followed colour precision. However, it was affected by task-induced response bias, even when the possible task difficulty was judged, without performing the task itself. Still, this bias was only observed on the absolute rating level rather than the scale's ability to capture changes in perceptual quality. Reported studies shed light on factors influencing scales outside of the scale formulation and construction.

Comparing theories of consciousness: why it matters and how to do it.

The theoretical landscape of scientific studies of consciousness has flourished. Today, even multiple versions of the same theory are sometimes available. To advance the field, these theories should be directly compared to determine which are better at predicting and explaining empirical data. Systematic inquiries of this sort are seen in many subfields in cognitive psychology and neuroscience, e.g. in working memory. Nonetheless, when we surveyed publications on consciousness research, we found that most focused on a single theory. When 'comparisons' happened, they were often verbal and non-systematic. This fact in itself could be a contributing reason for the lack of convergence between theories in consciousness research. In this paper, we focus on how to compare theories of consciousness to ensure that the comparisons are meaningful, e.g. whether their predictions are parallel or contrasting. We evaluate how theories are typically compared in consciousness research and related subdisciplines in cognitive psychology and neuroscience, and we provide an example of our approach. We then examine the different reasons why direct comparisons between theories are rarely seen. One possible explanation is the unique nature of the consciousness phenomenon. We conclude that the field should embrace this uniqueness, and we set out the features that a theory of consciousness should account for.

Insect Consciousness.

The question of consciousness in other species, not least species very physically different from humans such as insects, is highly challenging for a number of reasons. One reason is that we do not have any available empirical method to answer the question. Another reason is that current theories of consciousness disagree about the relation between physical structure and consciousness, i.e., whether consciousness requires specific, say, neural structures or whether consciousness can be realized in different ways. This article sets out to analyze if and how there could be an empirical and/or a theoretical approach to the topic on the basis of current consciousness research in humans.