Action planning with two-handed tools

In tool use, the intended external goals have to be transformed into bodily movements by taking into account the target-to-movement mapping implemented by the tool. In bimanual tool use, this mapping may depend on the part of the tool that is operated and the effector used (e.g. the left and right hand at the handle bar moving in opposite directions in order to generate the same bicycle movement). In our study, we investigated whether participants represent the behaviour of the tool or only the effector-specific mapping when using two-handed tools. In three experiments, participants touched target locations with a two-jointed lever, using either the left or the right hand. In one condition, the joint of the lever was constant and switching between hands was associated with switching the target-to-movement-mapping, whereas in another condition, switching between hands was associated with switching the joint, but the target-to-movement-mapping remained constant. Results indicate pronounced costs of switching hands in the condition with constant joint, whereas they were smaller with constant target-to-movement mapping. These results suggest that participants have tool-independent representations of the effector-specific mappings

Studying Brugada syndrome with an SCN1B variants in human-induced pluripotent stem cell-derived cardiomyocytes

BACKGROUND: Among rare channelopathies BrS patients are at high risk of sudden cardiac death (SCD). SCN5A mutations are found in a quarter of patients. Other rare gene mutations including SCN1B have been implicated to BrS. Studying the human cellular phenotype of BrS associated with rare gene mutation remains lacking. OBJECTIVES: We sought to study the cellular phenotype of BrS with the SCN1B gene variants using human-induced pluripotent stem cell (hiPSCs)–derived cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS: A BrS patient suffering from recurrent syncope harboring a two variants (c.629T > C and c.637C > A) in SCN1B, which encodes the function-modifying sodium channel beta1 subunit, and three independent healthy subjects were recruited and their skin biopsies were used to generate hiPSCs, which were differentiated into cardiomyocytes (hiPSC-CMs) for studying the cellular electrophysiology. A significantly reduced peak and late sodium channel current (I(Na)) and a shift of activation curve to more positive potential as well as a shift of inactivation curve to more negative potential were detected in hiPSC-CMs of the BrS patient, indicating that the SCN1B variants impact the function of sodium channels in cardiomyocytes. The reduced I(Na) led to a reduction of amplitude (APA) and upstroke velocity (V(max)) of action potentials. Ajmaline, a sodium channel blocker, showed a stronger effect on APA and Vmax in BrS cells as compared to cells from healthy donors. Furthermore, carbachol was able to increase arrhythmia events and the beating frequency in BrS. CONCLUSION: Our hiPSC-CMs from a BrS-patient with two variants in SCN1B recapitulated some key phenotypic features of BrS and can provide a platform for studies on BrS with SCN1B variants

The role of response modalities in cognitive task representations

The execution of a task necessitates the use of a specific response modality. We examined the role of different response modalities by using a task-switching paradigm. In Experiment 1, subjects switched between two numerical judgments, whereas response modality (vocal vs. manual vs. foot responses) was manipulated between groups. We found judgment-shift costs in each group, that is irrespective of the response modality. In Experiment 2, subjects switched between response modalities (vocal vs. manual, vocal vs. foot, or manual vs. foot). We observed response-modality shift costs that were comparable in all groups. In sum, the experiments suggest that the response modality (combination) does not affect switching per se. Yet, modality-shift costs occur when subjects switch between response modalities. Thus, we suppose that modality-shift costs are not due to a purely motor-related mechanisms but rather emerge from a general switching process. Consequently, the response modality has to be considered as a cognitive component in models of task switching

No-go trials can modulate switch cost by interfering with effects of task preparation

It has recently been shown that the cost associated with switching tasks is eliminated following ‘no-go’ trials, in which response selection is not completed, suggesting that the switch cost depends on response selection. However, no-go trials may also affect switch costs by interfering with the effects of task preparation that precede response selection. To test this hypothesis we evaluated switch costs following standard go trials with those following two types of non-response trials: no-go trials, for which a stimulus is presented that indicates no response should be made (Experiment 1); and cue-only trials in which no stimulus is presented following the task cue (Experiment 2). We hypothesized that eliminating no-go stimuli would reveal effects of task preparation on the switch cost in cue-only trials. We found no switch cost following no-go trials (Experiment 1), but a reliable switch cost in cue-only trials (i.e., when no-go stimuli were removed; Experiment 2). We conclude that no-go trials can modulate the switch cost, independent of their effect on response selection, by interfering with task preparation, and that the effects of task preparation on switch cost are more directly assessed by cue-only trials

Modulating proactive cognitive control by reward:Differential anticipatory effects of performance contingent and non-contingent rewards

The present study investigated the influences of two different forms of reward presentation in modulating cognitive control. In three experiments, participants performed a flanker task for which one-third of trials were precued for a chance of obtaining a reward (reward trials). In Experiment 1, a reward was provided if participants made the correct response on reward trials, but a penalty was given if they made an incorrect response on these trials. The anticipation of this performance-contingent reward increased response speed and reduced the flanker effect, but had little influence on the sequential modulation of the flanker effect after incompatible trials. In Experiment 2, participants obtained a reward randomly on two-thirds of the precued reward trials and were given a penalty on the remaining one-third, regardless of their performance. The anticipation of this non-contingent reward had little influence on the overall response speed or flanker effect, but reduced the sequential modulation of the flanker effect after incompatible trials. Experiment 3 also used performance non-contingent rewards, but participants were randomly penalized more often than they were rewarded; non-contingent penalty had little influence on the sequential modulation of the flanker effect. None of the three experiments showed a reliable influence of the actual acquisition of rewards on task performance. These results indicate anticipatory effects of performance-contingent and non-contingent rewards on cognitive control with little evidence of aftereffects

A preclinical study on brugada syndrome with a CACNB2 variant using human cardiomyocytes from induced pluripotent stem cells

AIMS: Some gene variants in the sodium channels, as well as calcium channels, have been associated with Brugada syndrome (BrS). However, the investigation of the human cellular phenotype and the use of drugs for BrS in presence of variant in the calcium channel subunit is still lacking. OBJECTIVES: The objective of this study was to establish a cellular model of BrS in the presence of a CACNB2 variant of uncertain significance (c.425C > T/p.S142F) using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and test drug effects using this model. METHODS AND RESULTS: This study recruited cells from a patient with Brugada syndrome (BrS) and recurrent ventricular fibrillation carrying a missense variant in CACNB2 as well as from three healthy independent persons. These cells (hiPSC-CMs) generated from skin biopsies of healthy persons and the BrS patient (BrS-hiPSC-CMs) as well as CRISPR/Cas9 corrected cells (isogenic control, site-variant corrected) were used for this study. The hiPSC-CMs from the BrS patient showed a significantly reduced L-type calcium channel current (I(Ca-L)) compared with the healthy control hiPSC-CMs. The inactivation curve was shifted to a more positive potential and the recovery from inactivation was accelerated. The protein expression of CACNB2 of the hiPSC-CMs from the BrS-patient was significantly decreased compared with healthy hiPSC-CMs. Moreover, the correction of the CACNB2 site-variant rescued the changes seen in the hiPSC-CMs of the BrS patient to the normal state. These data indicate that the CACNB2 gene variant led to loss-of-function of L-type calcium channels in hiPSC-CMs from the BrS patient. Strikingly, arrhythmia events were more frequently detected in BrS-hiPSC-CMs. Bisoprolol (beta-blockers) at low concentration and quinidine decreased arrhythmic events. CONCLUSIONS: The CACNB2 variant (c.425C > T/p.S142F) causes a loss-of-function of L-type calcium channels and is pathogenic for this type of BrS. Bisoprolol and quinidine may be effective for treating BrS with this variant