Dopamine D2 Receptor Modulates Exercise Related Effect on Cortical Excitation/Inhibition and Motor Skill Acquisition.

Exercise is known to benefit motor skill learning in health and neurological disease. Evidence from brain stimulation, genotyping, and Parkinson's disease studies converge to suggest that the dopamine D2 receptor, and shifts in the cortical excitation and inhibition (E:I) balance, are prime candidates for the drivers of exercise-enhanced motor learning. However, causal evidence using experimental pharmacological challenge is lacking. We hypothesized that the modulatory effect of the dopamine D2 receptor on exercise-induced changes in the E:I balance would determine the magnitude of motor skill acquisition. To test this, we measured exercise-induced changes in excitation and inhibition using paired-pulse transcranial magnetic stimulation (TMS) in 22 healthy female and male humans, and then had participants learn a novel motor skill-the sequential visual isometric pinch task (SVIPT). We examined the effect of D2 receptor blockade (800 mg sulpiride) on these measures within a randomized, double-blind, placebo-controlled design. Our key result was that motor skill acquisition was driven by an interaction between the D2 receptor and E:I balance. Specifically, poorer skill learning was related to an attenuated shift in the E:I balance in the sulpiride condition, whereas this interaction was not evident in placebo. Our results demonstrate that exercise-primed motor skill acquisition is causally influenced by D2 receptor activity on motor cortical circuits.

The effect of Huntington's disease on cognitive and physical motivation.

Apathy is one of the most common neuropsychiatric features of Huntington's disease. A hallmark of apathy is diminished goal-directed behaviour, which is characterized by a lower motivation to engage in cognitively or physically effortful actions. However, it remains unclear whether this reduction in goal-directed behaviour is driven primarily by a motivational deficit and/or is secondary to the progressive cognitive and physical deficits that accompany more advanced disease. We addressed this question by testing 17 individuals with manifest Huntington's disease and 22 age-matched controls on an effort-based decision-making paradigm. Participants were first trained on separate cognitively and physically effortful tasks and provided explicit feedback about their performance. Next, they chose on separate trials how much effort they were willing to exert in each domain in return for varying reward. At the conclusion of the experiment, participants were asked to rate their subjective perception of task load. In the cognitive task, the Huntington's disease group were more averse to cognitive effort than controls. Although the Huntington's disease group were more impaired than controls on the task itself, their greater aversion to cognitive effort persisted even after controlling for task performance. This suggests that the lower levels of cognitive motivation in the Huntington's disease group relative to controls was most likely driven by a primary motivational deficit. In contrast, both groups expressed a similar preference for physical effort. Importantly, the similar levels of physical motivation across both groups occurred even though participants with Huntington's disease performed objectively worse than controls on the physical effort task, and were aware of their performance through explicit feedback on each trial. This indicates that the seemingly preserved level of physical motivation in Huntington's disease was driven by a willingness to engage in physically effortful actions despite a reduced capacity to do so. Finally, the Huntington's disease group provided higher ratings of subjective task demand than controls for the cognitive (but not physical) effort task and when assessing the mental (but not the physical) load of each task. Together, these results revealed a dissociation in cognitive and physical motivation deficits between Huntington's disease and controls, which were accompanied by differences in how effort was subjectively perceived by the two groups. This highlights that motivation is the final manifestation of a complex set of mechanisms involved in effort processing, which are separable across different domains of behaviour. These findings have important clinical implications for the day-to-day management of apathy in Huntington's disease.

Amphetamines Improve the Motivation to Invest Effort in Attention-Deficit/Hyperactivity Disorder.

Prevailing frameworks propose that a key feature of attention-deficit/hyperactivity disorder (ADHD) is lower motivation. An important component of motivation is the willingness to engage in cognitively or physically effortful behavior. However, the degree to which effort sensitivity is impaired in ADHD has rarely been tested, and the efficacy of stimulant medication in ameliorating any such impairments is unclear. Here, we tested 20 individuals with ADHD (11 males, 9 females) who were managed with amphetamine-based medication (dexamfetamine, lisdexamfetamine), and 24 controls (8 males, 16 females). Individuals with ADHD were tested over two counterbalanced sessions, ON and OFF their usual amphetamine-based medication. In each session, participants performed an effort-based decision-making task, in which they were required to choose how much cognitive or physical effort they were willing to engage in return for reward. Our results revealed three main findings. First, individuals with ADHD had lower motivation relative to controls to invest effort in both the cognitive and physical domains. Second, amphetamine increased motivation uniformly across both domains. Finally, the net effect of amphetamine treatment was to mostly restore motivation across both domains of effort relative to healthy controls. These data provide clear evidence for a heightened sensitivity to both cognitive and physical effort in ADHD, and reveal the efficacy of amphetamine-based drugs in restoring effort sensitivity to levels similar to controls. These findings confirm the existence of reduced motivational drive in ADHD, and more broadly provide direct causal evidence for a domain-general role of catecholamines in motivating effortful behavior.SIGNIFICANCE STATEMENT A core feature of attention-deficit/hyperactivity disorder (ADHD) is thought to be a heightened aversion to effort. Surprisingly, however, the degree to which effort sensitivity is impaired in ADHD has rarely been tested. More broadly, the relative efficacy of catecholamines in motivating the investment of cognitive and physical effort is unclear. We tested 20 individuals with ADHD ON and OFF amphetamines, and compared their behavior on an effort-based decision-making task to 24 controls. When tested OFF medication, the ADHD group was less cognitively and physically motivated than controls. However, amphetamines led to a comparable increase in motivation across both domains. This demonstrates the efficacy of catecholamines in facilitating domain-general effort, and highlights the broader potential of such drugs to treat disorders of motivation.

Exercise-induced cortical disinhibition mediates the relationship between fitness and memory in older adults.

Regular exercise benefits learning and memory in older adults, but the neural mechanisms mediating these effects remain unclear. Evidence in young adults indicates that acute exercise creates a favourable environment for synaptic plasticity by enhancing cortical disinhibition. As such, we investigated whether plasticity-related disinhibition mediated the relationship between cardiorespiratory fitness and memory function in healthy older adults (n = 16, mean age = 66.06). Participants completed a graded maximal exercise test and assessments of visual and verbal memory, followed by two counterbalanced sessions involving 20 min of either high-intensity interval training exercise or rest. Disinhibition was measured following intermittent theta burst stimulation via paired-pulse transcranial magnetic stimulation. In line with our hypotheses, we observed a positive correlation between cardiorespiratory fitness and verbal memory, which was mediated by plasticity-related cortical disinhibition. Our novel finding implicates cortical disinhibition as a mechanism through which the effects of acute bouts of exercise may translate to improved memory in older adults. This finding extends current understanding of the physiological mechanisms underlying the positive influence of cardiorespiratory fitness for memory function in older adults, and further highlights the importance of promoting exercise engagement to maintain cognitive health in later life. KEY POINTS: There are well established benefits of regular exercise for memory function in older adults, but the mechanisms are unclear. Cortical disinhibition is important for laying down new memories, and is enhanced following acute exercise in young adults, suggesting it is a potential mechanism underlying these benefits in ageing. Older adults completed a fitness test and assessments of memory, followed by two sessions involving either 20 min of exercise or rest. Disinhibition was measured following intermittent theta burst stimulation via paired-pulse transcranial magnetic stimulation. Cardiorespiratory fitness was positively associated with memory performance. Higher fitness was associated with enhanced cortical disinhibition following acute exercise. Cortical disinhibition completely mediated the relationship between fitness and memory. This novel finding provides a mechanistic account for the positive influence of cardiorespiratory fitness on memory in later life, and emphasises the importance of regular exercise for cognitive health in older populations.

Cardiovascular Disease Risk Scores and Incident Dementia and Cognitive Decline in Older Men and Women.

INTRODUCTION: Risk factors for cardiovascular disease (CVD) also increase the risk of dementia. However, whether commonly used CVD risk scores are associated with dementia risk in older adults who do not have a history of CVD, and potential gender differences in this association, remains unclear. The aim of this study was to determine whether CVD risk scores are prospectively associated with cognitive decline and dementia in initially healthy older men and women. METHODS: A total of19,114 participants from a prospective cohort of individuals aged 65+ years without known CVD or dementia were recruited. The atherosclerotic cardiovascular disease risk score (ASCVDRS), Systematic Coronary Risk Evaluation 2-Older Persons (SCORE2-OP), and the Framingham risk score (FRS) were calculated at baseline. Risk of dementia (according to DSM-IV criteria) and cognitive decline (defined as a >1.5 standard deviation decline in global cognition, episodic memory, psychomotor speed, or verbal fluency from the previous year) were assessed using hazard ratio. RESULTS: Over a median follow-up of 6.4 years, 850 individuals developed dementia and 4,352 cognitive decline. Men and women in the highest ASCVDRS tertile had a 41% (95% CI 1.08, 1.85) and 45% (1.11, 1.89) increased risk of dementia compared to the lowest tertile, respectively. Likewise, men and women in the highest SCORE2-OP tertile had a 64% (1.24, 2.16) and 60% (1.22, 2.11) increased risk of dementia compared to the lowest tertile, respectively. Findings were similar, but the risk was slightly lesser when examining risk of cognitive decline for both ASCVDRS and SCORE2-OP. However, FRS was only associated with the risk of cognitive decline among women (highest vs. lowest tertiles: 1.13 [1.01-1.26]). CONCLUSION: These findings suggest the utility of the ASCVDRS and SCORE2-OP in clinical practice, to not only assess future risk of CVD, but also as potential early indicators of cognitive impairment, even in relatively healthy older men and women.

Model-based and model-free mechanisms in methamphetamine use disorder.

People with methamphetamine use disorder (MUD) struggle to shift their behaviour from methamphetamine-orientated habits to goal-oriented choices. The model-based/model-free framework is well suited to understand this difficulty by unpacking the computational mechanisms that support experienced-based (model-free) and goal-directed (model-based) choices. We aimed to examine whether 1) participants with MUD differed from controls on behavioural proxies and/or computational mechanisms of model-based/model-free choices; 2) model-based/model-free decision-making correlated with MUD symptoms; and 3) model-based/model-free deficits improved over six weeks in the group with MUD. Participants with MUD and controls with similar age, IQ and socioeconomic status completed the Two-Step Task at treatment commencement (MUD n = 30, Controls n = 31) and six weeks later (MUD n = 23, Controls n = 26). We examined behavioural proxies of model-based/model-free decisions using mixed logistic regression, and their underlying mechanisms using computational modelling. At a behavioural level, participants with MUD were more likely to switch their choices following rewarded actions, although this pattern improved at follow up. At a computational level, groups were similar in their use of model-based mechanisms, but participants with MUD were less likely to apply model-free mechanisms and less likely to repeat rewarded actions. We did not find evidence that individual differences in model-based or model-free parameters were associated with greater severity of methamphetamine dependence, nor did we find that group differences in computational parameters changed between baseline and follow-up assessment. Decision-making challenges in people with MUD are likely related to difficulties in pursuing choices previously associated with positive outcomes.

Gender-specific analysis of social connection patterns and risk of dementia in community-dwelling older people.

INTRODUCTION: Poor social connection is considered a risk factor for dementia. Since socializing behaviors may cluster together or act compensatorily, we aimed to investigate social connection patterns and their association with dementia, for men and women separately. METHODS: A total of 12,896 community-dwelling older adults (mean ± SD age: 75.2 ± 4.3 years, 54% women) without major cognitive impairment were included. Latent class analysis was conducted using 24 baseline social connection indicators. Cox proportional hazards regression was used to estimate the association between latent classes and incident dementia over 12 (median: 8.4) years follow-up. RESULTS: Three distinct classes were identified in both genders: strong social connections with an intermediate friend-relative network (Class 1: men, 43.8%; women, 37.9%), weak social connections (Class 2: men, 29.6%; women, 27.4%), and strong social connections with a larger friend-relative network (Class 3: men, 26.6%; women, 34.7%). Compared to Class 1, men in Class 2 (HR: 1.38, 95% CI: 1.08-1.77) and women in Class 3 (HR: 1.27, 95% CI: 1.01-1.60) had an increased risk of dementia. DISCUSSION: Dementia risk varies with different social connection patterns among older men and women. HIGHLIGHTS: Three distinct social connection patterns were identified based on 24 indicators. These patterns were related to dementia risk differently in men and women. In men, a weak social connection pattern was associated with a higher dementia risk. In women, a strong social connection with a relatively larger friend-relative network was associated with a greater dementia risk.

Effort Reinforces Learning.

Humans routinely learn the value of actions by updating their expectations based on past outcomes - a process driven by reward prediction errors (RPEs). Importantly, however, implementing a course of action also requires the investment of effort. Recent work has revealed a close link between the neural signals involved in effort exertion and those underpinning reward-based learning, but the behavioral relationship between these two functions remains unclear. Across two experiments, we tested healthy male and female human participants (N = 140) on a reinforcement learning task in which they registered their responses by applying physical force to a pair of hand-held dynamometers. We examined the effect of effort on learning by systematically manipulating the amount of force required to register a response during the task. Our key finding, replicated across both experiments, was that greater effort increased learning rates following positive outcomes and decreased them following negative outcomes, which corresponded to a differential effect of effort in boosting positive RPEs and blunting negative RPEs. Interestingly, this effect was most pronounced in individuals who were more averse to effort in the first place, raising the possibility that the investment of effort may have an adaptive effect on learning in those less motivated to exert it. By integrating principles of reinforcement learning with neuroeconomic approaches to value-based decision-making, we show that the very act of investing effort modulates one's capacity to learn, and demonstrate how these functions may operate within a common computational framework.SIGNIFICANCE STATEMENT Recent work suggests that learning and effort may share common neurophysiological substrates. This raises the possibility that the very act of investing effort influences learning. Here, we tested whether effort modulates teaching signals in a reinforcement learning paradigm. Our results showed that effort resulted in more efficient learning from positive outcomes and less efficient learning from negative outcomes. Interestingly, this effect varied across individuals, and was more pronounced in those who were more averse to investing effort in the first place. These data highlight the importance of motivational factors in a common framework of reward-based learning, which integrates the computational principles of reinforcement learning with those of value-based decision-making.

Ageing attenuates exercise-enhanced motor cortical plasticity.

Cardiorespiratory exercise is known to modulate motor cortical plasticity in young adults, but the influence of ageing on this relationship is unknown. Here, we compared the effects of a single session of cardiorespiratory exercise on motor cortical plasticity in young and older adults. We acquired measures of cortical excitatory and inhibitory activity of the primary motor cortex using transcranial magnetic stimulation (TMS) from 20 young (mean ± SD = 25.30 ± 4.00 years, 14 females) and 20 older (mean ± SD = 64.10 ± 6.50 years, 11 females) healthy adults. Single- and paired-pulse TMS measurements were collected before and after a 20 min bout of high-intensity interval cycling exercise or an equivalent period of rest, and again after intermittent theta burst stimulation (iTBS). In both young (P = 0.027, Cohen's d = 0.87) and older adults (P = 0.006, Cohen's d = 0.85), there was an increase in glutamatergic excitation and a reduction in GABAergic inhibition from pre- to postexercise. However, in contrast to younger adults, older adults showed an attenuated plasticity response to iTBS following exercise (P = 0.011, Cohen's d = 0.85). These results demonstrate an age-dependent decline in cortical plasticity and indicate that a preceding bout of high-intensity interval exercise might be less effective for enhancing primary motor cortex plasticity in older adults. Our findings align with the hypothesis that the capacity for cortical plasticity is altered in older age. KEY POINTS: Exercise enhances motor cortical plasticity in young adults, but how ageing influences this effect is unknown. Here, we compared primary motor cortical plasticity responses in young and older adults before and after a bout of high-intensity interval exercise and again after a plasticity-inducing protocol, intermittent theta burst stimulation. In both young and older adults, exercise led to an increase in glutamatergic excitation and a reduction in GABAergic inhibition. Our key result was that older adults showed an attenuated plasticity response to theta burst stimulation following exercise, relative to younger adults. Our findings demonstrate an age-dependent decline in exercise-enhanced cortical plasticity and indicate that a preceding bout of high-intensity interval exercise might be less effective for enhancing primary motor cortex plasticity in older adults.

When knowledge hurts: humans are willing to receive pain for obtaining non-instrumental information.

Humans and other animals value information that reduces uncertainty or leads to pleasurable anticipation, even if it cannot be used to gain tangible rewards or change outcomes. In exchange, they are willing to incur significant costs, sacrifice rewards or invest effort. We investigated whether human participants were also willing to endure pain-a highly salient and aversive cost-to obtain such information. Forty participants performed a computer-based task. On each trial, they observed a coin flip, with each side associated with different monetary rewards of varying magnitude. Participants could choose to endure a painful stimulus (low, moderate or high pain) to learn the outcome of the coin flip immediately. Importantly, regardless of their choice, winnings were always earned, rendering this information non-instrumental. Results showed that agents were willing to endure pain in exchange for information, with a lower likelihood of doing so as pain levels increased. Both higher average rewards and a larger variance between the two possible rewards independently increased the willingness to accept pain. Our results show that the intrinsic value of escaping uncertainty through non-instrumental information is sufficient to offset pain experiences, suggesting a shared mechanism through which these can be directly compared.

Computational mechanisms underpinning greater exploratory behaviour in excess weight relative to healthy weight adolescents.

Obesity in adolescence is associated with cognitive changes that lead to difficulties in shifting unhealthy habits in favour of alternative healthy behaviours, similar to addictive behaviours. An outstanding question is whether this shift in goal-directed behaviour is driven by over-exploitation or over-exploration of rewarding outcomes. Here, we addressed this question by comparing explore/exploit behaviour on the Iowa Gambling Task in 43 adolescents with excess weight against 38 adolescents with healthy weight. We computationally modelled both exploitation behaviour (e.g., reinforcement sensitivity and inverse decay parameters), and explorative behaviour (e.g., maximum directed exploration value). We found that overall, adolescents with excess weight displayed more behavioural exploration than their healthy-weight counterparts - specifically, demonstrating greater overall switching behaviour. Computational models revealed that this behaviour was driven by a higher maximum directed exploration value in the excess-weight group (U = 520.00, p = .005, BF10 = 5.11). Importantly, however, we found substantial evidence that groups did not differ in reinforcement sensitivity (U = 867.00, p = .641, BF10 = 0.30). Overall, our study demonstrates a preference for exploratory behaviour in adolescents with excess weight, independent of sensitivity to reward. This pattern could potentially underpin an intrinsic desire to explore energy-dense unhealthy foods - an as-yet untapped mechanism that could be targeted in future treatments of obesity in adolescents.

Validation of newly derived polygenic risk scores for dementia in a prospective study of older individuals.

INTRODUCTION: Recent genome-wide association studies identified new dementia-associated variants. We assessed the performance of updated polygenic risk scores (PRSs) using these variants in an independent cohort. METHODS: We used Cox models and area under the curve (AUC) to validate new PRSs (PRS-83SNP, PRS-SBayesR, and PRS-CS) compared with an older PRS-23SNP in 12,031 initially-healthy participants ≥70 years of age. Dementia was rigorously adjudicated according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. RESULTS: PRS-83SNP, PRS-SBayesR, and PRS-CS were associated with incident dementia, with fully adjusted (including apolipoprotein E [APOE] ε4) hazard ratios per standard deviation (SD) of 1.35 (1.23-1.47), 1.37 (1.25-1.50), and 1.42 (1.30-1.56), respectively. The AUC of a model containing conventional/non-genetic factors and APOE was 74.7%. This was improved to 75.7% (p = 0.007), 76% (p = 0.004), and 76.1% (p = 0.003) with addition of PRS-83SNP, PRS-SBayesR, and PRS-CS, respectively. The PRS-23SNP did not improve AUC (74.7%, p = 0.95). CONCLUSION: New PRSs for dementia significantly improve risk-prediction performance, but still account for less risk than APOE genotype overall.

Neural underpinnings of food choice and consumption in obesity.

BACKGROUND/OBJECTIVES: Obesity is associated with unhealthy food choices. Food selection is driven by the subjective valuation of available options, and the perceived and actual rewards accompanying consumption. These cognitive operations are mediated by brain regions including the ventromedial prefrontal cortex (vmPFC), dorsal anterior cingulate cortex (dACC), and ventral striatum (vStr). This study investigated the relationship between body mass index (BMI) and functional activations in the vmPFC, dACC, and vStr during food selection and consumption. SUBJECTS/METHODS: After overnight fasting, 26 individuals (BMI: 18-40 kg/m2) performed a food choice task while being scanned with functional magnetic resonance imaging (fMRI). Each trial involved selecting one beverage from a pair of presented options, followed by delivery of a 3 mL aliquot of the selected option using an MR-compatible gustometer. We also tracked subjective preference for each beverage throughout the experiment. RESULTS: During food choice, individuals with greater BMI had less activation in the dorsolateral prefrontal cortex when selecting a high-value option and less vmPFC activation upon its consumption. Independent of BMI, during food choice the dACC and anterior insula elicited higher activation when a less preferred beverage was selected. Activation of the dACC and a broader frontoparietal network was also observed when deciding between options more similar in value. During consumption, receipt of a more preferred beverage was associated with greater vmPFC response, and attenuation of the dACC. CONCLUSIONS: An individual's preference for a food option modulates the brain activity associated with choosing and consuming it. The relationship between food preference and underlying brain activity is altered in obesity, with reduced engagement of cognition-related regions when presented with a highly valued option, but a blunted response in reward-related regions upon consumption.

Association of Self-Reported Psychological Stress with Cognitive Decline: A Systematic Review.

Psychological stress is a potential modifiable risk factor for cognitive decline. However, the extent to which self-reported psychological stress is differentially associated with decline in specific cognitive domains remains unclear. Differences may be due to heterogeneity in the aspects of psychological stress investigated, for example, neuroticism (which is linked to vulnerability to stress), perceived stress, or exposure to stressful life events. This review aims to establish the associations between these aspects of self-reported psychological stress and cognitive decline. PsychINFO, Embase and MEDLINE were searched from database inception to September 2021. Studies were included if they were observational, prospective, and if they investigated the association between self-reported psychological stress and cognitive decline in adults with a minimum mean age of 40 years at baseline. Thirty studies satisfied the inclusion criteria, with most examining neuroticism (n = 17) as a predictor of cognitive decline. Fewer examined perceived stress (n = 7) or stressful life events (n = 6). There was evidence of an association between neuroticism and cognitive decline, particularly in the domain of memory. Similarly, across studies, perceived stress was also associated with memory decline. Research investigating the relationship between stressful life events and cognitive decline had fewer outcomes to interpret. Overall, the findings highlight that memory may be particularly susceptible to high levels of neuroticism and perceived stress. We identified a lack of research into some cognitive domains, such as executive function, which should be addressed by future studies.

Computational models of exploration and exploitation characterise onset and efficacy of treatment in methamphetamine use disorder.

People with Methamphetamine Use Disorder (PwMUD) spend substantial time and resources on substance use, which hinders their ability to explore alternate reinforcers. Gold-standard behavioural treatments attempt to remedy this by encouraging action towards non-drug reinforcers, but substance use often persists. We aimed to unravel the mechanistic drivers of this behaviour by applying a computational model of explore/exploit behaviour to decision-making data (Iowa Gambling Task) from 106 PwMUD and 48 controls. We then examined the longitudinal link between explore/exploit mechanisms and changes in methamphetamine use 6 weeks later. Exploitation parameters included reinforcement sensitivity and inverse decay (i.e., number of past outcomes used to guide choices). Exploration parameters included maximum directed exploration value (i.e., value of trying novel actions). The Timeline Follow Back measured changes in methamphetamine use. Compared to controls, PwMUD showed deficits in exploitative decision-making, characterised by reduced reinforcement sensitivity, U = 3065, p = 0.009, and less use of previous choice outcomes, U = 3062, p = 0.010. This was accompanied by a behavioural pattern of frequent shifting between choices, which appeared consistent with random exploration. Furthermore, PwMUD with greater reductions of methamphetamine use at 6 weeks had increased directed exploration (ß = 0.22, p = 0.045); greater use of past choice outcomes (ß = -0.39, p = 0.002) and greater choice consistency (ß = -0.39, p = 0.002). Therefore, limited computational exploitation and increased behavioural exploration characterise PwMUD's presentation to treatment, while increased directed exploration, use of past choice outcomes and choice consistency predict greater reductions of methamphetamine use.

Distractors Selectively Modulate Electrophysiological Markers of Perceptual Decisions.

Current models of perceptual decision-making assume that choices are made after evidence in favor of an alternative accumulates to a given threshold. This process has recently been revealed in human EEG recordings, but an unresolved issue is how these neural mechanisms are modulated by competing, yet task-irrelevant, stimuli. In this study, we tested 20 healthy participants on a motion direction discrimination task. Participants monitored two patches of random dot motion simultaneously presented on either side of fixation for periodic changes in an upward or downward motion, which could occur equiprobably in either patch. On a random 50% of trials, these periods of coherent vertical motion were accompanied by simultaneous task-irrelevant, horizontal motion in the contralateral patch. Our data showed that these distractors selectively increased the amplitude of early target selection responses over scalp sites contralateral to the distractor stimulus, without impacting on responses ipsilateral to the distractor. Importantly, this modulation mediated a decrement in the subsequent buildup rate of a neural signature of evidence accumulation and accounted for a slowing of RTs. These data offer new insights into the functional interactions between target selection and evidence accumulation signals, and their susceptibility to task-irrelevant distractors. More broadly, these data neurally inform future models of perceptual decision-making by highlighting the influence of early processing of competing stimuli on the accumulation of perceptual evidence.

Over the rainbow: Guidelines for meaningful use of colour maps in neurophysiology.

Visualization of complex data is commonplace in neurophysiology research. Here, we highlight specific perceptual issues related to the ongoing misuse of variations of the rainbow colour scheme, with a particular emphasis on time-frequency decompositions in electrophysiology as an illustrative example. We review the risks of biased interpretation of neurophysiological data in this context, and provide guidelines to improve the use of colour maps to visualise complex, multidimensional data in neurophysiology research.

A Cohort Study of Anticholinergic Medication Burden and Incident Dementia and Stroke in Older Adults.

BACKGROUND: Anticholinergic medications may increase risk of dementia and stroke, but prospective studies in healthy older people are lacking. OBJECTIVE: Compare risk of incident dementia and stroke by anticholinergic burden among initially healthy older people. DESIGN: Prospective cohort study. SETTING: Primary care (Australia and USA). PARTICIPANTS: 19,114 community-dwelling participants recruited for the ASPREE trial, aged 70+ years (65+ if US minorities) without major cardiovascular disease, dementia diagnosis, or Modified Mini-Mental State Examination score below 78/100. MEASUREMENTS: Baseline anticholinergic exposure was calculated using the Anticholinergic Cognitive Burden (ACB) score. Dementia was adjudicated using Diagnostic and Statistical Manual of Mental Disorders volume IV criteria, and stroke using the World Health Organization definition. RESULTS: At baseline, 15,000 participants (79%) had an ACB score of zero, 2930 (15%) a score of 1-2, and 1184 (6%) a score of ≥ 3 (indicating higher burden). After a median follow-up of 4.7 years and adjusting for baseline covariates, a baseline ACB score of ≥ 3 was associated with increased risk of ischemic stroke (adjusted HR 1.58, 95% CI 1.06, 2.35), or dementia (adjusted HR 1.36, 95% CI 1.01, 1.82), especially of mixed etiology (adjusted HR 1.53, 95% CI 1.06, 2.21). Results were similar for those exposed to moderate/highly anticholinergic medications. LIMITATIONS: Residual confounding and reverse causality are possible. Assessment of dose or duration was not possible. CONCLUSIONS: High anticholinergic burden in initially healthy older people was associated with increased risk of incident dementia and ischemic stroke. A vascular effect may underlie this association. These findings highlight the importance of minimizing anticholinergic exposure in healthy older people.

Are methamphetamine users compulsive? Faulty reinforcement learning, not inflexibility, underlies decision making in people with methamphetamine use disorder.

Methamphetamine use disorder involves continued use of the drug despite negative consequences. Such 'compulsivity' can be measured by reversal learning tasks, which involve participants learning action-outcome task contingencies (acquisition-contingency) and then updating their behaviour when the contingencies change (reversal). Using these paradigms, animal models suggest that people with methamphetamine use disorder (PwMUD) may struggle to avoid repeating actions that were previously rewarded but are now punished (inflexibility). However, difficulties in learning task contingencies (reinforcement learning) may offer an alternative explanation, with meaningful treatment implications. We aimed to disentangle inflexibility and reinforcement learning deficits in 35 PwMUD and 32 controls with similar sociodemographic characteristics, using novel trial-by-trial analyses on a probabilistic reversal learning task. Inflexibility was defined as (a) weaker reversal phase performance, compared with the acquisition-contingency phases, and (b) persistence with the same choice despite repeated punishments. Conversely, reinforcement learning deficits were defined as (a) poor performance across both acquisition-contingency and reversal phases and (b) inconsistent postfeedback behaviour (i.e., switching after reward). Compared with controls, PwMUD exhibited weaker learning (odds ratio [OR] = 0.69, 95% confidence interval [CI] [0.63-0.77], p < .001), though no greater accuracy reduction during reversal. Furthermore, PwMUD were more likely to switch responses after one reward/punishment (OR = 0.83, 95% CI [0.77-0.89], p < .001; OR = 0.82, 95% CI [0.72-0.93], p = .002) but just as likely to switch after repeated punishments (OR = 1.03, 95% CI [0.73-1.45], p = .853). These results indicate that PwMUD's reversal learning deficits are driven by weaker reinforcement learning, not inflexibility.