eIF2α phosphorylation evokes dystonia-like movements with D2-receptor and cholinergic origin and abnormal neuronal connectivity.

Dystonia is the 3rd most common movement disorder. Dystonia is acquired through either injury or genetic mutations, with poorly understood molecular and cellular mechanisms. Eukaryotic initiation factor alpha (eIF2α) controls cell state including neuronal plasticity via protein translation control and expression of ATF4. Dysregulated eIF2α phosphorylation (eIF2α-P) occurs in dystonia patients and models including DYT1, but the consequences are unknown. We increased/decreased eIF2α-P and tested motor control and neuronal properties in a Drosophila model. Bidirectionally altering eIF2α-P produced dystonia-like abnormal posturing and dyskinetic movements in flies. These movements were also observed with expression of the DYT1 risk allele. We identified cholinergic and D2-receptor neuroanatomical origins of these dyskinetic movements caused by genetic manipulations to dystonia molecular candidates eIF2α-P, ATF4, or DYT1, with evidence for decreased cholinergic release. In vivo, increased and decreased eIF2α-P increase synaptic connectivity at the NMJ with increased terminal size and bouton synaptic release sites. Long-term treatment of elevated eIF2α-P with ISRIB restored adult longevity, but not performance in a motor assay. Disrupted eIF2α-P signaling may alter neuronal connectivity, change synaptic release, and drive motor circuit changes in dystonia.

Transfer of learning: Analysis of dose-response functions from a large-scale, online, cognitive training dataset.

Fundamental to the efficacy of cognitive training (CT) is its dose. Here we used the power and breadth afforded by a large dataset to measure precisely dose-response (D-R) functions for CT and to examine the generality of their magnitude and form. The present observational study involved 107,000 users of Lumosity, a commercial program comprising computer games designed to provide CT over the internet. In addition to training with Lumosity games, these users took an online battery of cognitive assessments (NeuroCognitive Performance Test, NCPT) on two or more occasions separated by at least 10 weeks. Changes in performance on the NCPT between the first and second assessments were examined as a function of the amount of intervening gameplay. The resulting D-R functions were obtained both for overall performance on the NCPT and performance on its eight subtests. Also examined were differences between D-R functions from demographic groups defined by age, gender, and education. Monotonically increasing D-R functions, well fit by an exponential approach to an asymptote, were found consistently for overall performance on the NCPT, performance on seven of the eight subtests, and at each level of age, education, and gender. By examining how individual parameters of the D-R functions varied across subtests and groups, it was possible to measure separately changes in the effects on NCPT performance of 1) transfer from CT and 2) direct practice due to repeated testing. The impact of both transfer and direct practice varied across subtests. In contrast, while the effects of direct practice diminished with age, those of transfer remained constant. Besides its implications for CT by older adults, this latter finding suggests that direct practice and transfer do not involve identical learning processes, with transfer being limited to learning processes that remain constant across the adult lifespan.

Modelling human behaviour in cognitive tasks with latent dynamical systems.

Response time data collected from cognitive tasks are a cornerstone of psychology and neuroscience research, yet existing models of these data either make strong assumptions about the data-generating process or are limited to modelling single trials. We introduce task-DyVA, a deep learning framework in which expressive dynamical systems are trained to reproduce sequences of response times observed in data from individual human subjects. Models fitted to a large task-switching dataset captured subject-specific behavioural differences with high temporal precision, including task-switching costs. Through perturbation experiments and analyses of the models' latent dynamics, we find support for a rational account of switch costs in terms of a stability-flexibility trade-off. Thus, our framework can be used to discover interpretable cognitive theories that explain how the brain dynamically gives rise to behaviour.

A massive dataset of the NeuroCognitive Performance Test, a web-based cognitive assessment.

We present a dataset of approximately 5.5 million subtest scores from over 750,000 adults who completed the NeuroCognitive Performance Test (NCPT; Lumos Labs, Inc.), a validated, self-administered cognitive test accessed via web browser. The dataset includes assessment scores from eight test batteries consisting of 5-11 subtests that collectively span several cognitive domains including working memory, visual attention, and abstract reasoning. In addition to the raw scores and normative data from each subtest, the dataset includes basic demographic information from each participant (age, gender, and educational background). The scale and diversity of the dataset provides an unprecedented opportunity for researchers to investigate population-level variability in cognitive abilities and their relation to demographic factors. To facilitate reuse of this dataset by other researchers, we provide a Python module that supports several common preprocessing steps.

[Rationalism and mystification. On the formal pathetic of being against]. / Rationalismus und Mystifikation: Zur formalen Pathetik des Dagegenseins.

The article presents the results of the interpretation of qualitative interviews with coronavirus critics. It focuses on the forms of social criticism manifested in the interviews. The analysis (1) shows that the critique is based on a rationalistic ideal of crisis resolution. The fact that the coronavirus crisis, from this point of view, is not dealt with rationally is seen as an indication that there is something fundamentally wrong with it. It is this problem that the conspirituality of the critics reacts to: a combination of conspiracy theory and esoteric ideas whose unity is based on the interest in the mysterious. The analysis (2) allows to determine the specific style of the critique of counter-measures as formal pathetics: Substantially, it remains relatively empty, while rhetorically it is emphasized all the more emphatically. The rhetorical means are the most drastic comparisons possible, the romanticism of the heroic resistance and the claim to be committed to the well-being of children. Finally, (3) we put forward a socio-theoretical embedding of the critique of counter-measures, which assumes with Eisenstadt that modern society is characterized by an erosion of the foundations of all certainty. This leads to a fundamental credibility problem, manifesting itself in the loss of confidence in central social institutions (politics, science, medicine, media). The criticism of counter-measures expresses that in an ideal-typical way.

Separable Influences of Reward on Visual Processing and Choice.

Primate vision is characterized by constant, sequential processing and selection of visual targets to fixate. Although expected reward is known to influence both processing and selection of visual targets, similarities and differences between these effects remain unclear mainly because they have been measured in separate tasks. Using a novel paradigm, we simultaneously measured the effects of reward outcomes and expected reward on target selection and sensitivity to visual motion in monkeys. Monkeys freely chose between two visual targets and received a juice reward with varying probability for eye movements made to either of them. Targets were stationary apertures of drifting gratings, causing the end points of eye movements to these targets to be systematically biased in the direction of motion. We used this motion-induced bias as a measure of sensitivity to visual motion on each trial. We then performed different analyses to explore effects of objective and subjective reward values on choice and sensitivity to visual motion to find similarities and differences between reward effects on these two processes. Specifically, we used different reinforcement learning models to fit choice behavior and estimate subjective reward values based on the integration of reward outcomes over multiple trials. Moreover, to compare the effects of subjective reward value on choice and sensitivity to motion directly, we considered correlations between each of these variables and integrated reward outcomes on a wide range of timescales. We found that, in addition to choice, sensitivity to visual motion was also influenced by subjective reward value, although the motion was irrelevant for receiving reward. Unlike choice, however, sensitivity to visual motion was not affected by objective measures of reward value. Moreover, choice was determined by the difference in subjective reward values of the two options, whereas sensitivity to motion was influenced by the sum of values. Finally, models that best predicted visual processing and choice used sets of estimated reward values based on different types of reward integration and timescales. Together, our results demonstrate separable influences of reward on visual processing and choice, and point to the presence of multiple brain circuits for the integration of reward outcomes.

Outcomes in CME/CPD - Special Collection: How to make the "pyramid" a perpetuum mobile.

Continuing medical education (CME) should not be an end in itself, but as expressed in Moore's pyramid, help to improve both individual patient and ultimately community, health. However, there are numerous barriers to translation of physician competence into improvements in community health. To enhance the effect CME may achieve in improving community health the authors suggest a kick-off/keep-on continuum of medical competence, and integration of aspects of public health at all levels from planning to delivery and outcomes measurement in CME.

Inferring latent learning factors in large-scale cognitive training data.

The flexibility to learn diverse tasks is a hallmark of human cognition. To improve our understanding of individual differences and dynamics of learning across tasks, we analyse the latent structure of learning trajectories from 36,297 individuals as they learned 51 different tasks on the Lumosity online cognitive training platform. Through a data-driven modelling approach using probabilistic dimensionality reduction, we investigate covariation across learning trajectories with few assumptions about learning curve form or relationships between tasks. Modelling results show substantial covariation across tasks, such that an entirely unobserved learning trajectory can be predicted by observing trajectories on other tasks. The latent learning factors from the model include a general ability factor that is expressed mostly at later stages of practice and additional task-specific factors that carry information capable of accounting for manually defined task features and task domains such as attention, spatial processing, language and math.

Perceptions of Brain Training: Public Expectations of Cognitive Benefits From Popular Activities.

Many popular activities are thought by the general public to improve cognitive function. Such expectations can influence how often people engage in these activities, as well as the scientific evaluation of their putative cognitive benefits, e.g., via placebo effects. Here, we gathered survey data about the public's perceptions of nine different activities commonly thought to be cognitively stimulating, including "brain-training" games. Information was collected about the degree to which participants thought each activity was beneficial for improving cognitive function and how often they engaged in each activity. The patterns of correlation between ratings reveal details about the perception of cognitive benefits and its relation to engagement. They suggest that participants varied with respect to an overarching perception of the entire set of activities, which were perceived also as divided into three clusters. Frequency of engagement and perceived cognitive benefits were positively correlated across participants for each activity considered individually. But, when the activities were compared, the magnitude of their perceived benefits was not a good predictor of their frequency of engagement (and vice versa). Though small, there were systematic demographic differences. Women were more optimistic than men about cognitive benefits. Individual participants differed in the range of their ratings of benefit across activities, and these ranges were greater for younger than older participants, suggesting that perceptions of benefit are more differentiated among the young. Besides contributing to a better understanding of public expectations of cognitive benefits, the findings of this study are relevant to the critical evaluation of such benefits. Our survey can be viewed as providing an interface between expectations held by the general public and the design of studies examining the efficacy of cognitive training. The type of information it provides could be used in the selection of activities performed by an active control group, so that control activities match the treatment intervention as closely as possible with respect to such expectations.

Computerized Cognitive Training by Healthy Older and Younger Adults: Age Comparisons of Overall Efficacy and Selective Effects on Cognition.

Among the non-pharmacological methods under development for maintaining cognitive function across the lifespan is computerized cognitive training (CCT). There has been considerable interest in using CCT to slow or remediate age-related cognitive decline, both normal and pathological. Toward these ends, it would be useful to know how the effects of CCT on cognitive function vary over the course of normal cognitive aging. Are there changes in either 1) the overall efficacy of CCT or 2) which cognitive faculties are affected? To address these two questions, we reanalyzed results from a large online study by Hardy et al. (1) of 4,715 adults between 18 and 80 that examined effects of CCT on both a neuropsychological test battery and self-reported ratings of cognition and affect in daily living. Combined across all participants, Hardy et al. found greater improvement on both types of assessment following 10 weeks of CCT with the commercial program Lumosity, as compared to practice with a control activity involving computerized crossword puzzles. The present study compared the size of these effects on the older (50-80) and younger (18-49) participants. To address the question of overall efficacy, we examined CCT effects (treatment minus control) on overall performance of the test battery and mean rating. No significant difference on either measure was found between the two age cohorts. To address the question of whether the same magnitude of overall effects on both age cohorts was due to equivalent effects on the same set of underlying cognitive functions, we examined the patterns of CCT effects across individual subtests and rated items. These patterns did not differ significantly between the two age cohorts. Our findings suggest that benefits from CCT can occur to a similar degree and in a similar way across an extended part of the adult lifespan. Moreover, the overall effects of CCT delivered over the internet were of the same small to medium size as those typically found in the lab or clinic. Besides improving access and reducing the cost of CCT for older adults, delivery over the internet makes long-term training more practicable, which could potentially yield larger benefits.

Independent Continuing Medical Education (CME)/Continuing Professional Development (CPD) Must Deliver Unbiased Information.

Physicians commit themselves always to act in the best interests of their patients, and this includes their approach to continuing medical education (CME) as well as continuing professional development (CPD). For many years professional codes, and in some countries also the civil law, have defined that CME/CPD must be independent of commercial interests. Over the last few decades, numerous bodies have introduced CME/CPD accreditation to ensure that the planning and conduct of CME/CPD follows a set of defined standards, with independence of commercial interests as one of the leading principles. Recently industry has proposed that it be accepted by accrediting bodies as a direct provider of accredited CME-CPD. Such a move would not only open the door to the introduction of an inevitable bias in CME/CPD but would jeopardise the professional standing of physicians. Accreditation of CME/CPD currently serves several different purposes, but its credibility depends on whether it can retain its ability to differentiate independent CME/CPD from the provision of commercially framed information.

Solar autocalibrating XUV-IR spectrometer system (SOLACER) for the measurement of solar spectral irradiance.

The accurate measurement of solar spectral irradiance (SSI) from space is challenging because it requires a system that can reliably exclude the impact of degradation on the instruments for the full duration of a long-term mission. The new Autocalibrating XUV-IR Spectrometer System (SOLACER) presented here meets this requirement. It is a compact and moderate-cost instrument that allows repeated onboard calibration of the spectrometers (SPs) providing SSI data of significantly increased accuracy. To this end, absolute radiometers and ionization chambers with proven long-term stability serve as primary irradiance detectors to determine the absolute SSI fluxes passing through a series of narrow- and medium-band filters with updated transmission. Consecutively cross-calibrated bolometers (BOSs) and highly sensitive photomultiplier tubes are used as secondary irradiance detectors. The new SOLACER instrument is designed to cover the spectral range from about 2-2800 nm with eight planar grating SPs. Adding total solar irradiance and BOS sensors adapted to observe the Earth's infrared emission and the reflected solar radiation, the global energy budget at the top of the atmosphere can be measured to provide data of higher absolute accuracy for climate modeling, too.

Enhanced Neural Processing by Covert Attention only during Microsaccades Directed toward the Attended Stimulus.

Attention can be "covertly" directed without eye movements; yet, even during fixation, there are continuous microsaccades (MSs). In areas V4 and IT of macaques, we found that firing rates and stimulus representations were enhanced by attention but only following a MS toward the attended stimulus. The onset of neural attentional modulations was tightly coupled to the MS onset. The results reveal a major link between the effects of covert attention on cortical visual processing and the overt movement of the eyes.

Pulvinar-Cortex Interactions in Vision and Attention.

The ventro-lateral pulvinar is reciprocally connected with the visual areas of the ventral stream that are important for object recognition. To understand the mechanisms of attentive stimulus processing in this pulvinar-cortex loop, we investigated the interactions between the pulvinar, area V4, and IT cortex in a spatial-attention task. Sensory processing and the influence of attention in the pulvinar appeared to reflect its cortical inputs. However, pulvinar deactivation led to a reduction of attentional effects on firing rates and gamma synchrony in V4, a reduction of sensory-evoked responses and overall gamma coherence within V4, and severe behavioral deficits in the affected portion of the visual field. Conversely, pulvinar deactivation caused an increase in low-frequency cortical oscillations, often associated with inattention or sleep. Thus, cortical interactions with the ventro-lateral pulvinar are necessary for normal attention and sensory processing and for maintaining the cortex in an active state.

Prefrontal contributions to visual selective attention.

The faculty of attention endows us with the capacity to process important sensory information selectively while disregarding information that is potentially distracting. Much of our understanding of the neural circuitry underlying this fundamental cognitive function comes from neurophysiological studies within the visual modality. Past evidence suggests that a principal function of the prefrontal cortex (PFC) is selective attention and that this function involves the modulation of sensory signals within posterior cortices. In this review, we discuss recent progress in identifying the specific prefrontal circuits controlling visual attention and its neural correlates within the primate visual system. In addition, we examine the persisting challenge of precisely defining how behavior should be affected when attentional function is lost.

The role of lateral tension in calcium-induced DPPS vesicle rupture.

We assess the role of lateral tension in rupturing anionic dipalmitoylphosphatidyserine (DPPS), neutral dipalmitoylphosphatidylcholine (DPPC), and mixed DPPS-DPPC vesicles. Binding of Ca(2+) is known to have a significant impact on the effective size of DPPS lipids and little effect on the size of DPPC lipids in bilayer structures. In the present work we utilized laser transmission spectroscopy (LTS) to assess the effect of Ca(2+)-induced stress on the stability of the DPPS and DPPC vesicles. The high sensitivity and resolution of LTS has permitted the determination of the size and shape of liposomes in solution. The results indicate a critical size after which DPPS single shell vesicles are no longer stable. Our measurements indicate Ca(2+) promotes bilayer fusion up to a maximum diameter of ca. 320 nm. These observations are consistent with a straightforward free-energy-based model of vesicle rupture involving lateral tension between lipids regulated by the binding of Ca(2+). Our results support a critical role of lateral interactions within lipid bilayers for controlling such processes as the formation of supported bilayer membranes and pore formation in vesicle fusion. Using this free energy model we are able to infer a lower bound for the area dilation modulus for DPPS (252 pN/nm) and demonstrate a substantial free energy increase associated with vesicle rupture.

Quantitative and rapid DNA detection by laser transmission spectroscopy.

Laser transmission spectroscopy (LTS) is a quantitative and rapid in vitro technique for measuring the size, shape, and number of nanoparticles in suspension. Here we report on the application of LTS as a novel detection method for species-specific DNA where the presence of one invasive species was differentiated from a closely related invasive sister species. The method employs carboxylated polystyrene nanoparticles functionalized with short DNA fragments that are complimentary to a specific target DNA sequence. In solution, the DNA strands containing targets bind to the tags resulting in a sizable increase in the nanoparticle diameter, which is rapidly and quantitatively measured using LTS. DNA strands that do not contain the target sequence do not bind and produce no size change of the carboxylated beads. The results show that LTS has the potential to become a quantitative and rapid DNA detection method suitable for many real-world applications.

Selective attention from voluntary control of neurons in prefrontal cortex.

Animals can learn to voluntarily control neuronal activity within various brain areas through operant conditioning, but the relevance of that control to cognitive functions is unknown. We found that rhesus monkeys can control the activity of neurons within the frontal eye field (FEF), an oculomotor area of the prefrontal cortex. However, operantly driven FEF activity was primarily associated with selective visual attention, and not oculomotor preparation. Attentional effects were untrained and were observed both behaviorally and neurophysiologically. Furthermore, selective attention correlated with voluntary, but not spontaneous, fluctuations in FEF activity. Our results reveal a specific association of voluntarily driven neuronal activity with "top-down" attention and suggest a basis for the use of neurofeedback training to treat disorders of attention.

The value of training in communication skills for continuing medical education.

OBJECTIVE: Question arises as to what extent communication skills are considered in continuing medical education (CME). METHODS: Analysis for CME-courses in communication skills in the area of the Chamber of Physicians North Rhine (ÄkNo), Germany. Supply Arm(A): CME events (n = 19,320) certified in 2007 were evaluated. Demand Arm(B): course participation of 850 family physicians in the period 2002-2007 was analyzed (n = 37,724). Tests were calculated to the level 0.05 using Mann-Whitney U-test. RESULTS: (A) 388 (2.0%) events were concerned with the topic communications. 59.3% involved active cooperation of the participants. 0.5% events devoted more than 50% of their duration to the topic communication. Proportions in the subjects of internal medicine, general medicine and pediatrics amounted to 0.2%. (B) 803 (2.1%) events with a focus on communication were identified. Women took part in significantly more events than men (p<0.002) and selected more interactive courses. CONCLUSION: Content on communication training was small. Increasing experience does not automatically improve communication skills but an extent of deliberate praxis seems to be necessary and must be sought and developed. PRACTICE IMPLICATIONS: Communication skills are still insufficiently provided in CME-courses and should be more directed to focus as treatment strategies and scientifically investigated for outcome improvements.

[Supply of and participation in CME activities in the area served the north rhine chamber of physicians in Germany]. / Angebot und Fortbildungsverhalten bei der Continuing Medical Education (CME) im Bereich der Ärztekammer Nordrhein.

INTRODUCTION: the study analyses the supply and the demand for Continuing Medical Education (CME) in the area served by the "Ärztekammer Nordrhein (ÄkNo)", which is one of the biggest regional Chambers of Physicians in Germany. Both the supply of all CME events certified by the ÄkNo in 2007 (n=18,932) and the participation of physicians in CME activities - using the example of family doctors (n=850), ophthalmologists (n=122) and orthopaedists (n=38) in the university towns of Cologne, Bonn and Aachen - was analysed for the period of 2002 to 2007 (n=44,760 events). METHODS: differences between groups were tested by the nonparametric Kruskal-Wallis method; adjustment for other factors was performed using Cochran-Mantel-Haenszel tests. The significance level was chosen to be 0.05. RESULTS: half of the accredited CME activities had been provided in the form of lectures accompanied by discussion. This didactic focus is reflected by the CME choices of the analysed physicians, although interactive, multimedia materials and case based formats have been demonstrated to be advantageous. Family physicians and ophthalmologists participated twice as often in CME events as orthopaedists (p<0.001). Across all the disciplines investigated, female physicians participated significantly more often in CME events than their male colleagues (p<0.03). CONCLUSION: our results show individual, group and gender specific differences in Continuing Medical Education which so far have not been adequately recognised and which warrants more research on CME.