Causal role of lateral prefrontal cortex in mental effort and fatigue

Dorsolateral prefrontal cortex (DLPFC) is well‐known for its role in exerting mental work, however the contribution of DLPFC for deciding whether or not to engage in effort remains unknown. Here, we assessed the causal role of DLPFC in effort‐based decision making. We disrupted functioning of DLPFC with noninvasive brain stimulation before participants repeatedly decided whether to exert mental effort in a working memory task. We found the same DLPFC subregion involved in mental effort exertion to influence also effort‐based decisions: First, it enhanced effort discounting, suggesting that DLPFC may signal the capacity to successfully deal with effort demands. Second, a novel computational model integrating the costs of enduring effort into the effort‐based decision process revealed that DLPFC disruption reduced fatigue after accumulated effort exertion, linking DLPFC activation with fatigue. Together, our findings indicate that in effort‐based decisions DLPFC represents the capacity to exert mental effort and the updating of this information with enduring time‐on‐task, informing theoretical accounts on the role of DLPFC in the motivation to exert mental effort and the fatigue arising from it

Brain stimulation over dorsomedial prefrontal cortex modulates effort-based decision making

Deciding whether to engage in strenuous mental activities requires trading-off the potential benefits against the costs of mental effort, but it is unknown which brain rhythms are causally involved in such cost-benefit calculations. We show that brain stimulation targeting midfrontal theta oscillations increases the engagement in goal-directed mental effort. Participants received transcranial alternating current stimulation over dorsomedial prefrontal cortex while deciding whether they are willing to perform a demanding working memory task for monetary rewards. Midfrontal theta tACS increased the willingness to exert mental effort for rewards while leaving working memory performance unchanged. Computational modelling using a hierarchical Bayesian drift diffusion model suggests that theta tACS shifts the starting bias before evidence accumulation towards high reward-high effort options without affecting the velocity of the evidence accumulation process. Our findings suggest that the motivation to engage in goal-directed mental effort can be increased via midfrontal tACS

Antibodies against viral nucleo-, phospho-, and X protein contribute to serological diagnosis of fatal Borna disease virus 1 infections

Borna disease virus 1 (BoDV-1) causes rare but often fatal encephalitis in humans. Late diagnosis prohibits an experimental therapeutic approach. Here, we report a recent case of fatal BoDV-1 infection diagnosed on day 12 after hospitalization by detection of BoDV-1 RNA in the cerebrospinal fluid. In a retrospective analysis, we detect BoDV-1 RNA 1 day after hospital admission when the cell count in the cerebrospinal fluid is still normal. We develop a new ELISA using recombinant BoDV-1 nucleoprotein, phosphoprotein, and accessory protein X to detect seroconversion on day 12. Antibody responses are also shown in seven previously confirmed cases. The individual BoDV-1 antibody profiles show variability, but the usage of three different BoDV-1 antigens results in a more sensitive diagnostic tool. Our findings demonstrate that early detection of BoDV-1 RNA in cerebrospinal fluid and the presence of antibodies against at least two different viral antigens contribute to BoDV-1 diagnosis. Physicians in endemic regions should consider BoDV-1 infection in cases of unclear encephalopathy and initiate appropriate diagnostics at an early stage

Cellular delivery of small interfering RNA by a non-covalently attached cell-penetrating peptide: quantitative analysis of uptake and biological effect

Cell-penetrating peptides (CPPs) have evolved as promising new tools to deliver nucleic acids into cells. So far, the majority of these delivery systems require a covalent linkage between carrier and cargo. To exploit the higher flexibility of a non-covalent strategy, we focused on the characterisation of a novel carrier peptide termed MPGα, which spontaneously forms complexes with nucleic acids. Using a luciferase-targeted small interfering RNA (siRNA) as cargo, we optimised the conditions for MPGα-mediated transfection of mammalian cells. In this system, reporter gene activity could be inhibited up to 90% with an IC(50) value in the sub-nanomolar range. As a key issue, we addressed the cellular uptake mechanism of MPGα/siRNA complexes applying various approaches. First, transfection of HeLa cells with MPGα/siRNA complexes in the presence of several inhibitors of endocytosis showed a significant reduction of the RNA interference (RNAi) effect. Second, confocal laser microscopy revealed a punctual intracellular pattern rather than a diffuse distribution of fluorescently labelled RNA-cargo. These data provide strong evidence of an endocytotic pathway contributing significantly to the uptake of MPGα/siRNA complexes. Finally, we quantified the intracellular number of siRNA molecules after MPGα-mediated transfection. The amount of siRNA required to induce half maximal RNAi was 10 000 molecules per cell. Together, the combination of methods provided allows for a detailed side by side quantitative analysis of cargo internalisation and related biological effects. Thus, the overall efficiency of a given delivery technique as well as the mechanism of uptake can be assessed

Motivation for the greater good: neural mechanisms of overcoming costs

To obtain greater goods decision makers often have to incur and endure costs. Here we review mechanisms that enhance the willingness to accept and overcome costs in individual and social settings. General, cost-invariant mechanisms involve controlling and reducing reward-related impulsivity, abstracting from personal and situational circumstances, changing the availability of options in the choice set, and reinterpreting aspects of the choice alternatives. These mechanisms are based on fronto-striatal and fronto-parietal networks for valuation and goal-setting. More specific, cost-variant mechanisms include effort endurance, imagining future events, tolerating risk, and empathy. These mechanisms rely on cost-specific brain mechanisms, as well as interactions with the valuation network in accordance with cost-variant changes in the valuation of the costly choice alternatives. We identify knowledge gaps, which are exacerbated by studies typically focusing only on one cost type. Moreover, many of the identified mechanisms of enduring costs provide largely untrodden paths for interventions to increase cost endurance in clinical and non-clinical domains

Know your weaknesses: Sophisticated impulsiveness motivates voluntary self-restrictions

Restricting one's access to temptations (precommitment) facilitates the achievement of long-term goals. The sophisticated impulsiveness model of precommitment posits that impulsive agents who are aware that they are impulsive should show the strongest preference for precommitment. Empirically however, two central predictions of this theoretical notion remained untested: whether impulsiveness causally drives the demand for precommitment and whether the willingness to precommit depends on metacognitive awareness of one's impulsiveness. Here, we tested these predictions in three independent experiments. Participants performed a delay discounting task in which they could precommit to larger-later rewards. The results of Experiment 1 provide causal evidence that reducing impulse control capacities increases precommitment demand. Moreover, Experiments 2 and 3 support the hypothesis that metacognitive awareness of one's impulsiveness moderates the relationship between impulsiveness and precommitment. Together, our data put the sophisticated impulsiveness model of precommitment on strong empirical foundations