Rationale
The ability to monitor the consequences of our actions for others is imperative for flexible and adaptive behavior, and allows us to act in a (pro)social manner. Yet, little is known about ...the neurochemical mechanisms underlying alterations in (pro)social performance monitoring.
Objective
The aim of this functional magnetic resonance imaging (fMRI) study was to improve our understanding of the role of dopamine and oxytocin and their potential overlap in the neural mechanisms underlying performance monitoring for own versus others’ outcomes.
Method
Using a double-blind placebo-controlled cross-over design, 30 healthy male volunteers were administered oxytocin (24 international units), the dopamine precursor L-DOPA (100 mg + 25 mg carbidopa), or placebo in three sessions. Participants performed a computerized cannon shooting game in two recipient conditions where mistakes resulted in negative monetary consequences for (1) oneself or (2) an anonymous other participant.
Results
Results indicated reduced error-correct differentiation in the ventral striatum after L-DOPA compared to placebo, independent of recipient. Hence, pharmacological manipulation of dopamine via L-DOPA modulated performance-monitoring activity in a brain region associated with reward prediction and processing in a domain-general manner. In contrast, oxytocin modulated the BOLD response in a recipient-specific manner, such that it specifically enhanced activity for errors that affected the other in the pregenual anterior cingulate cortex (pgACC), a region previously implicated in the processing of social rewards and prediction errors. Behaviorally, we also found reduced target sizes—indicative of better performance—after oxytocin, regardless of recipient. Moreover, after oxytocin lower target sizes specifically predicted higher pgACC activity when performing for others.
Conclusions
These different behavioral and neural patterns after oxytocin compared to L-DOPA administration highlight a divergent role of each neurochemical in modulating the neural mechanisms underlying social performance monitoring.
Abstract
The CRISPR system is widely used in genome editing for biomedical research. Here, using either dual paired Cas9D10A nickases or paired Cas9 nuclease we characterize unintended larger ...deletions at on-target sites that frequently evade common genotyping practices. We found that unintended larger deletions are prevalent at multiple distinct loci on different chromosomes, in cultured cells and mouse embryos alike. We observed a high frequency of microhomologies at larger deletion breakpoint junctions, suggesting the involvement of microhomology-mediated end joining in their generation. In populations of edited cells, the distribution of larger deletion sizes is dependent on proximity to sgRNAs and cannot be predicted by microhomology sequences alone.
Oxytocin attenuates responses to stress and threat (e.g., by fostering social approach in animals), but direct investigations of whether the hormone also facilitates approach-related social behaviors ...in humans are lacking. To assess approach-avoidance tendencies, we had participants respond to images of happy and angry faces with direct or averted gaze by either pulling a joystick toward themselves (approach) or pushing it away from themselves (avoidance). When given a placebo, participants' action tendencies were typical, with happy faces eliciting approach responses and angry faces eliciting avoidance responses. However, 24 IU of oxytocin moderated these tendencies, with the inclination to approach angry faces with direct gaze being negatively related to social anxiety. The results demonstrate that oxytocin facilitates approach in humans in response to social threat, which verifies its anxiolytic potential. Moreover, they underscore the moderating role of dispositional factors reported in endocrine research and their therapeutic implications.
Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides' functions are not fully understood and ...seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1-40 and Aβ1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1-42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.
Learning from errors or negative feedback is crucial for adaptive behavior. FMRI studies have demonstrated enhanced anterior cingulate cortex activity for errors that were later corrected versus ...repeated errors even when a substantial delay between the error and the opportunity to correct was introduced. We aimed at identifying the electrophysiological correlates of these processes by investigating the feedback‐related negativity (FRN) and stimulus‐locked P3. Participants had to learn and recall the location of 2‐digit targets over consecutive rounds. Feedback was provided in two steps, first a color change indicated a correct or incorrect response (feedback phase) followed by presentation of the correct digit information (re‐encoding phase). Behaviorally, participants improved performance from the first to the third round. FRN amplitudes time‐locked to feedback were enhanced for corrected compared to repeated errors. The P3 in response to re‐encoding did not differ between the two error types. The finding that FRN amplitudes positively predicted memory performance is consistent with the idea that the FRN reflects prediction errors and the need for enhanced cognitive control. Interestingly, this happens early during feedback processing and not at a later time point when re‐encoding of correct information takes place. The prediction error signal reflected in the FRN is usually elicited by performance errors, but may thus also play a role in preparing/optimizing the system for memory formation. This supports the existence of a close link between action control and memory processes even when there is a substantial delay between error feedback and the opportunity to correct the error.
Using EEG and a visual associative learning paradigm, we disentangled processing of initial negative feedback and later re‐encoding of correct information. The results showed that the amplitude of the feedback‐related negativity (FRN), but not the P3, positively predicted memory performance. This was specific for feedback processing and not at the later time point of re‐encoding. These findings support the idea that the FRN reflects prediction errors and the need for enhanced cognitive control.
•Both l-DOPA and OT modulated prediction error (PE) signals regardless of recipient.•Both drugs blunted PEs in ventral striatum and led to negative PEs in other regions.•OT also led to opposing ...neural signaling of self-benefitting and prosocial PEs.•Prosocial PEs in these regions related positively to learning rates after OT.•No effect of either drug on self-benefitting and prosocial learning rates.
Humans learn through reinforcement, particularly when outcomes are unexpected. Recent research suggests similar mechanisms drive how we learn to benefit other people, that is, how we learn to be prosocial. Yet the neurochemical mechanisms underlying such prosocial computations remain poorly understood. Here, we investigated whether pharmacological manipulation of oxytocin and dopamine influence the neurocomputational mechanisms underlying self-benefitting and prosocial reinforcement learning. Using a double-blind placebo-controlled cross-over design, we administered intranasal oxytocin (24 IU), dopamine precursor l-DOPA (100 mg + 25 mg carbidopa), or placebo over three sessions. Participants performed a probabilistic reinforcement learning task with potential rewards for themselves, another participant, or no one, during functional magnetic resonance imaging. Computational models of reinforcement learning were used to calculate prediction errors (PEs) and learning rates. Participants behavior was best explained by a model with different learning rates for each recipient, but these were unaffected by either drug. On the neural level, however, both drugs blunted PE signaling in the ventral striatum and led to negative signaling of PEs in the anterior mid-cingulate cortex, dorsolateral prefrontal cortex, inferior parietal gyrus, and precentral gyrus, compared to placebo, and regardless of recipient. Oxytocin (versus placebo) administration was additionally associated with opposing tracking of self-benefitting versus prosocial PEs in dorsal anterior cingulate cortex, insula and superior temporal gyrus. These findings suggest that both l-DOPA and oxytocin induce a context-independent shift from positive towards negative tracking of PEs during learning. Moreover, oxytocin may have opposing effects on PE signaling when learning to benefit oneself versus another.
Our mistakes often have negative consequences for ourselves, but may also harm the people around us. Continuous monitoring of our performance is therefore crucial for both our own and others’ ...well-being. Here, we investigated how modulations in responsibility for other’s harm affects electrophysiological correlates of performance-monitoring, viz. the error-related negativity (ERN) and error positivity (Pe). Healthy participants (N = 27) performed a novel social performance-monitoring paradigm in two responsibility contexts. Mistakes made in the harmful context resulted in a negative consequence for a co-actor, i.e., hearing a loud aversive sound, while errors in the non-harmful context were followed by a soft non-aversive sound. Although participants themselves did not receive auditory feedback in either context, they did experience harmful mistakes as more distressing and reported higher effort to perform well in the harmful context. ERN amplitudes were enhanced for harmful compared to non-harmful mistakes. Pe amplitudes were unaffected. The present study shows that performing in a potentially harmful social context amplifies early automatic performance-monitoring processes and increases the impact of the resulting harmful mistakes. These outcomes not only further our theoretical knowledge of social performance monitoring, but also demonstrate a novel and useful paradigm to investigate aberrant responsibility attitudes in various clinical populations.
•Novel paradigm to study performance monitoring in different responsibility contexts.•Making mistakes that harm others is associated with enhanced ERN amplitudes.•Potentially harmful social contexts amplify early performance-monitoring processes.•Results consistent with idea that distress associated with errors scales with ERN.•Enables research in clinical populations with aberrant responsibility attitudes.
When Errors Are Rewarding de Bruijn, Ellen R. A; de Lange, Floris P; von Cramon, D. Yves ...
The Journal of neuroscience,
09/2009, Letnik:
29, Številka:
39
Journal Article
Recenzirano
Odprti dostop
For social beings like humans, detecting one's own and others' errors is essential for efficient goal-directed behavior. Although one's own errors are always negative events, errors from other ...persons may be negative or positive depending on the social context. We used neuroimaging to disentangle brain activations related to error and reward processing, by manipulating the social context (cooperation or competition). Activation in posterior medial frontal cortex (pMFC) was increased for all errors, independent of who made the error or the reward outcome. Conversely, activity in striatum was modulated by reward, independent of whether the action was erroneous or not. The results demonstrate a clear distinction between error and reward processing in the human brain. Importantly, the current study indicates that error detection in pMFC is independent of reward and generalizes beyond our own actions, highlighting its role in optimizing performance in both individual and joint action.
Abstract In depression, approach deficits often impair everyday social functioning, but empirical findings on performance-based measurements of approach–avoidance behavior remain conflicting. To ...investigate action tendencies in patients with depression, the current study used an explicit version of the Approach–Avoidance Task (AAT). In this task, participants responded to emotional faces by either pulling a joystick toward (approach) or pushing it away from themselves (avoid). Reaction times to happy and angry expressions with direct and averted gaze were assessed in 30 patients with major depressive disorder and 20 matched healthy controls. In contrast to healthy individuals, depressed patients did not show approach–avoidance tendencies, i.e., there was no dominant behavioral tendency and they reacted to happy and angry expressions likewise. These results indicate that behavioral adjustments to different emotional expressions, gaze directions or motivational demands were lacking in depression. Crucially, this distinguishes depressed patients not only from healthy individuals, but also from other clinical populations that demonstrate aberrant approach–avoidance tendencies, e.g., patients with social anxiety or psychopathy. As responding flexibly to different social signals is integral to social interactions, the absence of any social motivational tendencies seems maladaptive, but may also provide opportunities for modifying action tendencies in a therapeutic context.
Down syndrome is associated with genome-wide perturbation of gene expression, which may be mediated by epigenetic changes. We perform an epigenome-wide association study on neonatal bloodspots ...comparing 196 newborns with Down syndrome and 439 newborns without Down syndrome, adjusting for cell-type heterogeneity, which identifies 652 epigenome-wide significant CpGs (P < 7.67 × 10
) and 1,052 differentially methylated regions. Differential methylation at promoter/enhancer regions correlates with gene expression changes in Down syndrome versus non-Down syndrome fetal liver hematopoietic stem/progenitor cells (P < 0.0001). The top two differentially methylated regions overlap RUNX1 and FLI1, both important regulators of megakaryopoiesis and hematopoietic development, with significant hypermethylation at promoter regions of these two genes. Excluding Down syndrome newborns harboring preleukemic GATA1 mutations (N = 30), identified by targeted sequencing, has minimal impact on the epigenome-wide association study results. Down syndrome has profound, genome-wide effects on DNA methylation in hematopoietic cells in early life, which may contribute to the high frequency of hematological problems, including leukemia, in children with Down syndrome.
PDF
