Relationship between reward-related brain activity and opportunities to sit.

The present study tested whether energy-minimizing behaviors evoke reward-related brain activity that promotes the repetition of these behaviors via reinforcement learning processes. Fifty-eight healthy young adults in a standing position performed a task where they could earn a reward either by sitting down or squatting while undergoing electroencephalographic (EEG) recording. Reward-prediction errors were quantified as the amplitude of the EEG-derived reward positivity. Results showed that reward positivity was larger on reward versus no reward trials, confirming the validity of our paradigm to measure evoked reward-related brain activity. However, results showed no evidence that sitting (versus standing and squatting) trials led to larger reward positivity. Moreover, we found no evidence suggesting that this effect was moderated by typical physical activity, physical activity on the day of the study, or energy expenditure during the experiment. However, at the behavioral level, results showed that the probability of choosing the stimulus more likely to lead to sitting than standing increased as the number of trials increased. In addition, results revealed that the probability of changing the selected stimulus was higher when the previous trial was a stand trial relative to a sit trial. In sum, neural results showed no evidence supporting the theory that opportunities to minimize energy expenditure are rewarding. However, behavioral findings suggested participants tend to choose the less effortful behavioral alternative and were therefore consistent with the theory of effort minimization (TEMPA).

The effect of d-cycloserine on brain processing of breathlessness over pulmonary rehabilitation: an experimental medicine study.

Research question: Pulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial N-methyl-d-aspartate (NMDA)-receptor agonist d-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials. Methods: 72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ClinicalTrials.gov identifier: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250 mg d-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between d-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions. An exploratory analysis determined the interaction with breathlessness anxiety. Results: No difference between d-cycloserine and placebo groups was observed across the primary or secondary outcome measures. d-cycloserine was shown instead to interact with changes in breathlessness anxiety to dampen reactivity to breathlessness cues. Questionnaire and measures of respiratory function showed no group difference. This is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Conclusion: Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of d-cycloserine would not be worthwhile.

Contextual variation in cognitive performance of older adults: Demonstration of an age-of-examiner effect.

Objective: Consistent with research on stereotype threat, when examiners' characteristics make a stereotype of the participant group salient, it can hamper participants' performance. We hypothesized that younger examiners represent a subtle element activating age stereotypes, leading older people to perform worse as examiners' age decreases. Method: We analyzed data from the Survey of Health, Ageing, and Retirement in Europe (SHARE; NParticipants = 32768) and Vivre-Leben-Vivere studies (VLV, Nparticipants = 960), wherein older people were tested at home by examiners of different ages on eight cognitive tasks. Results: Our results indicate that participants' performance on five tasks was positively linked to examiners' age, showing that the older the examiner, the better the participants' performance. Conclusions: These findings could have implications for the current assessment of memory performance among older adults.

Does attentional suppression occur at the level of perception or decision-making? Evidence from Gaspelin et al.'s (2015) probe letter task.

Visual attention is often inadvertently captured by salient stimuli. It was suggested that it is possible to prevent attentional capture in some search tasks by suppressing salient stimuli below baseline. Evidence for attentional suppression comes from a probe task that was interleaved with the main search task. In the probe task of Gaspelin et al. (Psychol Sci 26(11):1740-1750, 2015. https://doi.org/10.1177/0956797615597913 ), letters were shown on the stimuli of the search display and participants had to identify as many letters as possible. Performance was found to be worse for letters shown on the distractor compared to non-salient non-target stimuli, suggesting that distractor processing was suppressed below baseline. However, it is unclear whether suppression occurred at the level of perception or decision-making because participants may have reported letters on the distractor less frequently than letters on nontargets. This decision-level bias may have degraded performance for letters on distractor compared to nontarget stimuli without changing perception. After replicating the original findings, we conducted two experiments where we avoided report bias by cueing only a single letter for report. We found that the difference between distractor and nontarget stimuli was strongly reduced, suggesting that decision-level processes contribute to attentional suppression. In contrast, the difference between target and non-target stimuli was unchanged, suggesting that it reflected perceptual-level enhancement of the target stimuli.

Am I really seeing what's around me? An ERP study on social anxiety under speech induction, uncertainty and social feedback.

Cognitive models of social anxiety propose that socially anxious individuals engage in excessive self-focusing attention when entering a social situation. In the present study, speech anxiety was induced to socially anxious and control participants. Event-related potentials were recorded while participants performed a perceptual judgement task using distinct or ambiguous stimuli, before and after social feedback. Disputed feedback led to more revisions and decreased levels of confidence, especially among socially anxious individuals. Prior feedback, greater occipital P1 amplitudes in both groups for ambiguous probes indicated heightened sensory facilitation to ambiguous information, and greater anterior N1 amplitudes for ambiguous stimuli in highly anxious participants suggested anticipation of negative feedback in this group. Post-feedback, P1, N1 and LPP amplitudes were reduced overall among socially anxious individuals indicating a reduction in sensory facilitation of visual information. These results suggest excessive self-focusing among socially anxious individuals, possibly linked to anticipation of an anxiety-provoking social situation.

Multi-view confocal microscopy enables multiple organ and whole organism live-imaging.

Understanding how development is coordinated in multiple tissues and gives rise to fully functional organs or whole organisms necessitates microscopy tools. Over the last decade numerous advances have been made in live-imaging, enabling high resolution imaging of whole organisms at cellular resolution. Yet, these advances mainly rely on mounting the specimen in agarose or aqueous solutions, precluding imaging of organisms whose oxygen uptake depends on ventilation. Here, we implemented a multi-view multi-scale microscopy strategy based on confocal spinning disk microscopy, called Multi-View confocal microScopy (MuViScopy). MuViScopy enables live-imaging of multiple organs with cellular resolution using sample rotation and confocal imaging without the need of sample embedding. We illustrate the capacity of MuViScopy by live-imaging Drosophila melanogaster pupal development throughout metamorphosis, highlighting how internal organs are formed and multiple organ development is coordinated. We foresee that MuViScopy will open the path to better understand developmental processes at the whole organism scale in living systems that require gas exchange by ventilation.

The cluster depth tests: Toward point-wise strong control of the family-wise error rate in massively univariate tests with application to M/EEG.

The cluster mass test has been widely used for massively univariate tests in M/EEG, fMRI and, recently, pupillometry analysis. It is a powerful method for detecting effects while controlling weakly the family-wise error rate (FWER), although its correct interpretation can only be performed at the cluster level without any point-wise conclusion. It implies that the discoveries of a cluster mass test cannot be precisely localized in time or in space. We propose a new multiple comparisons procedure, the cluster depth tests, that both controls the FWER while allowing an interpretation at the time point level. We show the conditions for a strong control of the FWER, and a simulation study shows that the cluster depth tests achieve large power and guarantee the FWER even in the presence of physiologically plausible effects. By having an interpretation at the time point/voxel level, the cluster depth tests make it possible to take full advantage of the high temporal resolution of EEG recording and give a precise timing of the start and end of the significant effects.

Cnr2 Is Important for Ribbon Synapse Maturation and Function in Hair Cells and Photoreceptors.

The role of the cannabinoid receptor 2 (CNR2) is still poorly described in sensory epithelia. We found strong cnr2 expression in hair cells (HCs) of the inner ear and the lateral line (LL), a superficial sensory structure in fish. Next, we demonstrated that sensory synapses in HCs were severely perturbed in larvae lacking cnr2. Appearance and distribution of presynaptic ribbons and calcium channels (Cav1.3) were profoundly altered in mutant animals. Clustering of membrane-associated guanylate kinase (MAGUK) in post-synaptic densities (PSDs) was also heavily affected, suggesting a role for cnr2 for maintaining the sensory synapse. Furthermore, vesicular trafficking in HCs was strongly perturbed suggesting a retrograde action of the endocannabinoid system (ECs) via cnr2 that was modulating HC mechanotransduction. We found similar perturbations in retinal ribbon synapses. Finally, we showed that larval swimming behaviors after sound and light stimulations were significantly different in mutant animals. Thus, we propose that cnr2 is critical for the processing of sensory information in the developing larva.

Imaging the response to DNA damage in heterochromatin domains reveals core principles of heterochromatin maintenance.

Heterochromatin is a critical chromatin compartment, whose integrity governs genome stability and cell fate transitions. How heterochromatin features, including higher-order chromatin folding and histone modifications associated with transcriptional silencing, are maintained following a genotoxic stress challenge is unknown. Here, we establish a system for targeting UV damage to pericentric heterochromatin in mammalian cells and for tracking the heterochromatin response to UV in real time. We uncover profound heterochromatin compaction changes during repair, orchestrated by the UV damage sensor DDB2, which stimulates linker histone displacement from chromatin. Despite massive heterochromatin unfolding, heterochromatin-specific histone modifications and transcriptional silencing are maintained. We unveil a central role for the methyltransferase SETDB1 in the maintenance of heterochromatic histone marks after UV. SETDB1 coordinates histone methylation with new histone deposition in damaged heterochromatin, thus protecting cells from genome instability. Our data shed light on fundamental molecular mechanisms safeguarding higher-order chromatin integrity following DNA damage.

Shared and Anxiety-Specific Pediatric Psychopathology Dimensions Manifest Distributed Neural Correlates.

BACKGROUND: Imaging research has not yet delivered reliable psychiatric biomarkers. One challenge, particularly among youth, is high comorbidity. This challenge might be met through canonical correlation analysis designed to model mutual dependencies between symptom dimensions and neural measures. We mapped the multivariate associations that intrinsic functional connectivity manifests with pediatric symptoms of anxiety, irritability, and attention-deficit/hyperactivity disorder (ADHD) as common, impactful, co-occurring problems. We evaluate the replicability of such latent dimensions in an independent sample. METHODS: We obtained ratings of anxiety, irritability, and ADHD, and 10 minutes of resting-state functional magnetic resonance imaging data, from two independent cohorts. Both cohorts (discovery: n = 182; replication: n = 326) included treatment-seeking youth with anxiety disorders, with disruptive mood dysregulation disorder, with ADHD, or without psychopathology. Functional connectivity was modeled as partial correlations among 216 brain areas. Using canonical correlation analysis and independent component analysis jointly we sought maximally correlated, maximally interpretable latent dimensions of brain connectivity and clinical symptoms. RESULTS: We identified seven canonical variates in the discovery and five in the replication cohort. Of these canonical variates, three exhibited similarities across datasets: two variates consistently captured shared aspects of irritability, ADHD, and anxiety, while the third was specific to anxiety. Across cohorts, canonical variates did not relate to specific resting-state networks but comprised edges interconnecting established networks within and across both hemispheres. CONCLUSIONS: Findings revealed two replicable types of clinical variates, one related to multiple symptom dimensions and a second relatively specific to anxiety. Both types involved a multitude of broadly distributed, weak brain connections as opposed to strong connections encompassing known resting-state networks.

Fetal hemoglobin rescues ineffective erythropoiesis in sickle cell disease.

While ineffective erythropoiesis has long been recognized as a key contributor to anemia in thalassemia, its role in anemia of sickle cell disease (SCD) has not been critically explored. Using in vitro and in vivo derived human erythroblasts we assessed the extent of ineffective erythropoiesis in SCD. Modeling the bone marrow hypoxic environment, we found that hypoxia induces death of sickle erythroblasts starting at the polychromatic stage, positively selecting cells with high levels of fetal hemoglobin (HbF). Cell death was associated with cytoplasmic sequestration of heat shock protein 70 and was rescued by induction of HbF synthesis. Importantly, we document that in the bone marrow of SCD patients similar cell loss occurs during the final stages of terminal differentiation. Our study provides evidence for ineffective erythropoiesis in SCD and highlights an anti-apoptotic role for HbF during the terminal stages of erythroid differentiation. These findings imply that the beneficial effect on anemia of increased HbF levels is not only due to the increased life span of red cells but also a consequence of decreased ineffective erythropoiesis.

Self-defining memories after severe traumatic brain injury: A preliminary study.

Autobiographical memory plays a major role in the (re)construction of sense of identity, a recurrent issue after a traumatic brain injury (TBI). Although the recall of specific autobiographical events is frequently impaired in patients with TBI, little is known about how these changes affect their sense of self and identity. Thus, we examined self-defining memories (SDMs), that is, the most significant personal memories supporting one's sense of identity, in 16 patients with severe TBI and in matched controls. To this end, participants recalled three SDMs and rated their emotions in response to memory retrieval. In addition, characteristics of SDMs such as specificity, meaning-making, self-connections that reflect identity stability or identity change, content (theme, presence of tension, and redemption sequences) were analysed by independent raters. The main results showed that patients' SDMs were less specific and contained fewer redemption sequences than did those of controls but did not significantly differ in thematic content, presence of tension, meaning-making, self-connections that reflect identity stability or identity change and affective responses to memory retrieval. Furthermore, among the patients' memories that refer to the TBI-related event itself, only one contained an explicit meaning. Despite the lack of specificity in memories, patients with severe TBI were able to extract meaning from personal memories although they could struggle with integrating the TBI-related event into their sense of identity. These characteristics of SDMs may contribute to disturbances in sense of self and continuity in patients with severe TBI, as well as difficulties in personal or social adjustment. These results also open up relevant prospects for psychological interventions in identity-related issues in patients with TBI.

Permutation inference for canonical correlation analysis.

Canonical correlation analysis (CCA) has become a key tool for population neuroimaging, allowing investigation of associations between many imaging and non-imaging measurements. As age, sex and other variables are often a source of variability not of direct interest, previous work has used CCA on residuals from a model that removes these effects, then proceeded directly to permutation inference. We show that a simple permutation test, as typically used to identify significant modes of shared variation on such data adjusted for nuisance variables, produces inflated error rates. The reason is that residualisation introduces dependencies among the observations that violate the exchangeability assumption. Even in the absence of nuisance variables, however, a simple permutation test for CCA also leads to excess error rates for all canonical correlations other than the first. The reason is that a simple permutation scheme does not ignore the variability already explained by previous canonical variables. Here we propose solutions for both problems: in the case of nuisance variables, we show that transforming the residuals to a lower dimensional basis where exchangeability holds results in a valid permutation test; for more general cases, with or without nuisance variables, we propose estimating the canonical correlations in a stepwise manner, removing at each iteration the variance already explained, while dealing with different number of variables in both sides. We also discuss how to address the multiplicity of tests, proposing an admissible test that is not conservative, and provide a complete algorithm for permutation inference for CCA.

Attention shifting and subliminal cueing under high attentional load: an EEG study using emotional faces.

Emotional expressions and attentional processes interact such that emotion increases perceptual sensitivity in modality-specific brain areas leading to more efficient processing of the stimulus. In the current study, we asked the question of whether the emotional expressions can be processed subliminally when faces are attended but the emotional expression is irrelevant. We presented angry and neutral male and female faces supraliminally and subliminally to participants in an attention-shifting paradigm. Emotional expression was irrelevant to the task, but the gender of the face was predictive of the location of a subsequent target. Analysis of reaction times revealed that, in the supraliminal condition, targets appearing at validly cued locations produced quicker responses than targets at invalidly cued locations. Target-locked event-related potentials (ERPs) confirmed this result and showed that attention selection elicited higher responses at attended locations, as reflected by the N1 component. However, voluntary attention shifting was not triggered when the cue was not consciously perceived. No effects of emotion were observed following target presentation, suggesting that the high attentional load required by the experiment may have prevented the processing of emotion for undetectable faces, as demonstrated by the fact that, following cue onset, the N170 was modulated by emotion in supraliminal trials only. We therefore show that emotional expressions cannot be processed without awareness when faces are attended, but the emotional expression is irrelevant.

Dimerization and phosphorylation of Lutheran/basal cell adhesion molecule are critical for its function in cell migration on laminin.

Tumor cell migration depends on the interactions of adhesion proteins with the extracellular matrix. Lutheran/basal cell adhesion molecule (Lu/BCAM) promotes tumor cell migration by binding to laminin α5 chain, a subunit of laminins 511 and 521. Lu/BCAM is a type I transmembrane protein with a cytoplasmic domain of 59 (Lu) or 19 (Lu(v13)) amino acids. Here, using an array of techniques, including site-directed mutagenesis, immunoblotting, FRET, and proximity-ligation assays, we show that both Lu and Lu(v13) form homodimers at the cell surface of epithelial cancer cells. We mapped two small-XXX-small motifs in the transmembrane domain as potential sites for monomers docking and identified three cysteines in the cytoplasmic domain as being critical for covalently stabilizing dimers. We further found that Lu dimerization and phosphorylation of its cytoplasmic domain were concomitantly needed to promote cell migration. We conclude that Lu is the critical isoform supporting tumor cell migration on laminin 521 and that the Lu:Lu(v13) ratio at the cell surface may control the balance between cellular firm adhesion and migration.

Interaction and threshold effects of appraisal on componential patterns of emotion: A study using cross-cultural semantic data.

Studies that investigated the relation between appraisal and emotion have largely focused on the linear effect of appraisal criteria on subjective feelings (e.g., the effect of appraised goal obstruction on anger). Emotional responding can be extended to include more than just feelings, however. Componential definitions of emotion also add motivation, physiology, and expression. Moreover, a linear model is not compatible with the idea held by many appraisal theorists that appraisal criteria interact to produce emotional responding. In the present study, we modeled adaptive nonlinear interaction effects of appraisal criteria on motivation, expression, and physiology simultaneously. We applied a combination of principal component analysis for data reduction and multivariate adaptive regression splines (MARS) for automatic interaction identification. Data were obtained from a large-scale cross-cultural study on emotion concepts conducted in 27 countries, which represented semantic profiles of component information in 24 common emotion words. Results of modeling indicated that (a) appraisal of relevance, familiarity, goal compatibility, coping potential, and suddenness showed main effects on component responses; (b) appraisals of agency and norm compatibility uniquely showed interaction effects on component responses; (c) interaction effects explained significant variance only in some component responses but not all; and (d) the emotion patterns simulated by the fitted MARS model could be clustered according to qualitative emotion categories. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Accounting for stimulus and participant effects in event-related potential analyses to increase the replicability of studies.

BACKGROUND: Event-related potentials (ERPs) are increasingly used in cognitive science. With their high temporal resolution, they offer a unique window into cognitive processes and their time course. In this paper, we focus on ERP experiments whose designs involve selecting participants and stimuli amongst many. Recently, Westfall et al. (2017) highlighted the drastic consequences of not considering stimuli as a random variable in fMRI studies with such designs. Most ERP studies in cognitive psychology suffer from the same drawback. NEW METHOD: We advocate the use of the Quasi-F or Mixed-effects models instead of the classical ANOVA/by-participant F1 statistic to analyze ERP datasets in which the dependent variable is reduced to one measure per trial (e.g., mean amplitude). We combine Quasi-F statistic and cluster mass tests to analyze datasets with multiple measures per trial. Doing so allows us to treat stimulus as a random variable while correcting for multiple comparisons. RESULTS: Simulations show that the use of Quasi-F statistics with cluster mass tests allows maintaining the family wise error rates close to the nominal alpha level of 0.05. COMPARISON WITH EXISTING METHODS: Simulations reveal that the classical ANOVA/F1 approach has an alarming FWER, demonstrating the superiority of models that treat both participant and stimulus as random variables, like the Quasi-F approach. CONCLUSIONS: Our simulations question the validity of studies in which stimulus is not treated as a random variable. Failure to change the current standards feeds the replicability crisis.

Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland.

Recent lineage tracing studies have revealed that mammary gland homeostasis relies on unipotent stem cells. However, whether and when lineage restriction occurs during embryonic mammary development, and which signals orchestrate cell fate specification, remain unknown. Using a combination of in vivo clonal analysis with whole mount immunofluorescence and mathematical modelling of clonal dynamics, we found that embryonic multipotent mammary cells become lineage-restricted surprisingly early in development, with evidence for unipotency as early as E12.5 and no statistically discernable bipotency after E15.5. To gain insights into the mechanisms governing the switch from multipotency to unipotency, we used gain-of-function Notch1 mice and demonstrated that Notch activation cell autonomously dictates luminal cell fate specification to both embryonic and basally committed mammary cells. These functional studies have important implications for understanding the signals underlying cell plasticity and serve to clarify how reactivation of embryonic programs in adult cells can lead to cancer.