Brain and neuroscience advances最新文献

Negative urgency describes the tendency for rash and impulsive behaviour during negative emotional states and has been linked to a number of psychiatric disorders. However, there has been limited research on negative urgency as an explanatory mechanism for impulsivity in experimental animals. Such research has important implications for elucidating the neurobiology of negative urgency and thereby the development of future therapeutic interventions. In this study, we investigated the effects of negative urgency using a partial reinforcement schedule to increase the frequency of non-rewarded (i.e. frustrative) trials in the five-choice serial reaction time task, a widely used task to assess visual attention and impulsivity. Using a Markov chain model to analyse trial-by-trial outcomes we found that premature (i.e. impulsive) responses in the five-choice serial reaction time task were more likely to occur after a non-rewarded trial, and mostly after a previous premature trial. However, contrary to the frustration hypothesis of negative urgency, increasing the probability of reinforcement (p(R)) from p(R) = 0.5 to p(R) = 1 increased the number of premature responses in each session. Micro and macro levels of analyses revealed that impulsivity in the five-choice serial reaction time task is governed by at least two processes, one dependent on the overall level of reinforcement hypothesised to determine the state of behavioural activation, the second dependent on trial-by-trial outcomes consistent with negative urgency effects. These processes may depend on distinct neurobiological mechanisms and have relevance for neuropsychiatric disorders that implicate impulsive behaviours dependent on positive and negative affective states.

Synapse loss is associated with cognitive decline in Alzheimer's disease, and owing to their plastic nature, synapses are an ideal target for therapeutic intervention. Oligomeric amyloid beta around amyloid plaques is known to contribute to synapse loss in mouse models and is associated with synapse loss in human Alzheimer's disease brain tissue, but the mechanisms leading from Aβ to synapse loss remain unclear. Recent data suggest that the fast-activating and -inactivating voltage-gated potassium channel subtype 3.4 (Kv3.4) may play a role in Aβ-mediated neurotoxicity. Here, we tested whether this channel could also be involved in Aβ synaptotoxicity. Using adeno-associated virus and clustered regularly interspaced short palindromic repeats technology, we reduced Kv3.4 expression in neurons of the somatosensory cortex of APP/PS1 mice. These mice express human familial Alzheimer's disease-associated mutations in amyloid precursor protein and presenilin-1 and develop amyloid plaques and plaque-associated synapse loss similar to that observed in Alzheimer's disease brain. We observe that reducing Kv3.4 levels ameliorates dendritic spine loss and changes spine morphology compared to control virus. In support of translational relevance, Kv3.4 protein was observed in human Alzheimer's disease and control brain and is associated with synapses in human induced pluripotent stem cell-derived cortical neurons. We also noted morphological changes in induced pluripotent stem cell neurones challenged with human Alzheimer's disease-derived brain homogenate containing Aβ but, in this in vitro model, total mRNA levels of Kv3.4 were found to be reduced, perhaps as an early compensatory mechanism for Aβ-induced damage. Overall, our results suggest that approaches to reduce Kv3.4 expression and/or function in the Alzheimer's disease brain could be protective against Aβ-induced synaptic alterations.

The ability of the N-methyl-D-aspartate receptor antagonist ketamine to induce a rapid and sustained antidepressant effect has led to a surge in pre-clinical studies investigating underlying mechanisms and seeking novel treatments. Animal models are key to this research as they can provide a behavioural readout linking underlying mechanisms to clinical benefits. However, quantifying depression-related behaviours in rodents represents a major challenge with the validity of traditional methods such as models of behavioural despair (forced swim test and tail suspension test) a topic of debate. While there is good evidence to support the value of using these behavioural readouts to study the effects of stress, these approaches have largely failed to detect reliable phenotypic effects in other disease models. In this systematic review, we identified publications which had tested N-methyl-D-aspartate receptor antagonists in normal animals using either the forced swim test or tail suspension test. We compared findings for different doses and time points and also drugs with different clinical profiles to investigate how well the outcomes in the rodent model predicted their effects in the clinic. Despite clear evidence that N-methyl-D-aspartate receptor antagonists reduce immobility time and hence exhibit an antidepressant profile in these tasks, we found similar effects with both clinically effective drugs as well as those which have failed to show efficacy in clinical trials. These findings suggest that behavioural despair tests in normal animals do not provide a good method to predict clinical efficacy of N-methyl-D-aspartate receptor antagonists.

This study investigated neuroanatomic, genetic, cognitive, sociodemographic and emotional underpinnings of the Negative Urgency subscale of the Urgency, Premeditation, Perseverance, Sensation-Seeking and Positive Urgency Impulsive Behavior Scale in a healthy developmental sample. The goal of the investigation is to contribute to the harmonisation of behavioural, brain and neurogenetic aspects of behavioural self-control. Three domains - (1) Demographic, developmental, psychiatric and cognitive ability; (2) Regional brain volumes (neurobiological); and (3) Genetic variability (single nucleotide polymorphisms) - were examined, and models with relevant predictor variables were selected. Least absolute shrinkage and selection operator and best subset regressions were used to identify sparse models predicting negative urgency scores, which revealed that variables related to emotional regulation and right cingulate volume, as well as single nucleotide polymorphisms in CADM2 and SLC6A4, were associated with negative urgency. Our results contribute to the construct and criterion validity of negative urgency and support the hypothesis that negative urgency is a result of a complex array of influences across domains whose integration furthers developmental psychopathology research.

It remains unclear whether the negative reinforcement pathway to problematic drinking exists, and if so, for whom. One idea that has received some support recently is that people who tend to act impulsively in response to negative emotions (i.e. people high in negative urgency) may specifically respond to negative affect with increased alcohol consumption. We tested this idea in a preregistered secondary data analysis of two ecological momentary assessment studies using college samples. Participants (N = 226) reported on their current affective state multiple times per day and also the following morning reported alcohol use of the previous night. We assessed urgency both at baseline and during the momentary affect assessments. Results from our Bayesian model comparison procedure, which penalises increasing model complexity, indicate that no combination of the variables of interest (negative affect, urgency, and the respective interactions) outperformed a baseline model that included two known demographic predictors of alcohol use. A non-preregistered exploratory analysis provided some evidence for the effect of daily positive affect, positive urgency, as well as their interaction on subsequent alcohol use. Taken together, our results suggest that college students' drinking may be better described by a positive rather than negative reinforcement cycle.

Impulsive urgency describes the tendency to act rashly when experiencing extreme emotions. This Australian study aimed to investigate the predictive utility of impulsivity, including impulsive urgency (positive and negative), across a range of problem behaviours. Data from two community samples, one retrospective (n = 281) and one current (n = 604), were analysed using hierarchical regression to determine which facets of impulsivity, as assessed with a comprehensive scale (i.e. negative urgency, positive urgency, lack or premeditation, lack of perseverance, and sensation seeking), best predicted a series of problem behaviours (i.e. problem gambling, disorderly alcohol use, online gambling disorder, obsessive-compulsive disorder behaviours, and social media addiction). The impulsive urgency facets were shown to be significant predictors across the behaviours examined. More specifically, negative urgency was the strongest predictor of disorderly alcohol use, obsessive-compulsive disorder behaviours, and social media addiction. Positive urgency was associated with problem gambling and online gambling disorder behaviours. These findings suggest that impulsive urgency is a key contributing factor in many behavioural problems and that the valence of the urgency is an important consideration when addressing a broad range of psychopathologies.

Attention involves both an ability to selectively focus on relevant information and simultaneously ignore irrelevant information (i.e. inhibitory control). Many factors impact inhibitory control such as individual differences, relative timing of stimuli presentation, distractor characteristics, and participant age. Previous research with young adults responding to an attention-demanding rapid serial visual presentations of pictures superimposed with task-irrelevant words evaluated the extent to which unattended information may be subject to inhibitory control. Surprise recognition tests following the rapid serial visual presentation task showed that recognition for unattended words presented with non-targets (i.e. non-aligned or 'NA' words) during the rapid serial visual presentation task were recognised at chance levels. However, when the unattended words were infrequently paired with the attended picture targets (i.e. target-aligned or 'TA' words), recognition rates were significantly below chance and significantly lower compared to NA words, suggesting selective inhibitory control for the previously unattended TA words. The current study adapted this paradigm to compare healthy younger and older adults' ability to engage in inhibitory control. In line with previous research, younger adults demonstrated selective inhibition with recognition rates for TA words significantly lower than NA words and chance, while NA words were recognised at chance levels. However, older adults showed no difference in recognition rates between word types (TA versus NA). Rather all items were recognised at rates significantly below chance suggesting inhibited recognition for all unattended words, regardless of when they were presented during the primary task. Finally, older adults recognised significantly fewer NA words compared to young adults. These findings suggest that older adults may experience a decline in their ability to selectively inhibit the processing of irrelevant information, while maintaining the capacity to exercise global inhibition over unattended lexical information.

Cannabis has been shown to cause structural and functional neurocognitive changes in heavy users. Cannabis use initiation aligns with brain development trajectories; therefore, it is imperative that the potential neurological implications of cannabis use are understood. Males and females reach neurodevelopmental milestones at different rates making it necessary to consider biological sex in all cannabis and brain-based research. Through use of a systamatic review in accordance with PRISMA guidelines, we aimed to understand the interaction between biological sex and cannabis use on brain-based markers. In total, 18 articles containing a sex-based analysis of cannabis users were identified. While the majority of studies (n = 11) reported no sex by cannabis use interactions on brain-based markers, those that reported findings (n = 8) suggest females may be more susceptible to cannabis' neurotoxic effects. Unfortunately, a large portion of the literature was excluded due to no sex-based analysis. In addition, studies that reported no sex differences often contained a reduced number of females which may result in some studies being underpowered for sex-based analyses, making it difficult to draw firm conclusions. Suggestions to improve cannabis and sex-based reseach are proposed.