Social Activities and Risk of Dementia in Community-Dwelling Older People: Gender-Specific Findings From a Prospective Cohort Study.

OBJECTIVES: This study examines the gender-specific associations between a wide range of social activities and dementia risk. METHODS: A prospective cohort study was conducted involving community-dwelling older Australians (≥70 years) without significant cognitive impairment at enrolment. During the first year of enrolment, we assessed 25 self-reported social activities covering various aspects, including support from relatives and friends, community participation, social interactions with surroundings, and loneliness. Dementia diagnosis followed DSM-IV criteria, adjudicated by an international expert panel. To estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between social activities and dementia, we performed Cox proportional hazards models, adjusting for age, educational attainment, baseline global cognition, and depressive symptoms. RESULTS: Among 9,936 participants who completed all social activity questionnaires (median [IQR] age: 73.4 [71.6-77.1] years; 47.4% men), dementia was diagnosed in 3.8% of men (n = 181/4,705) and 2.6% of women (n = 138/5,231) over a median 6.4 years (IQR: 5.3-7.6, range: 0.2-10.1) follow-up. Gender-specific relationships emerged: caregiving for a person with illness/disability in women (HR: 0.65, 95% CI: 0.42-0.99), and having ≥9 relatives feeling close to call for help in men (HR: 0.56, 95% CI: 0.33-0.96; reference <9 relatives) were associated with reduced dementia risk. Unexpectedly, in women, having ≥5 friends with whom they felt comfortable discussing private matters were associated with a greater dementia risk (HR: 1.69, 95% CI: 1.10-2.59; reference ≤2 friends). Imputed models further identified that babysitting/childminding was associated with lower dementia risk in men (HR: 0.75, 95% CI: 0.56-0.99). No other social activities showed significant associations with dementia. DISCUSSION: This study provides evidence of social activities influencing dementia risk. Further investigations are required to uncover the mechanisms driving these observed relationships.

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 hypothesised 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 randomised, 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.Significance statement Exercise is known to benefit the ability to acquire new motor skills, but the neural mechanisms driving this phenomenon are not well understood. We tested whether the effects of exercise on cortical neurophysiology and motor skill learning was due to dopaminergic neuromodulation. We obtained measures of cortical excitation and inhibition before and after high-intensity cardiorespiratory exercise, and then had participants learn a novel motor skill. We provide causal evidence that motor skill acquisition is driven by an interaction between the dopamine D2 receptor and exercise-induced shifts in the cortical excitation:inhibition balance. Such findings have implications for prescribing exercise to improve motor learning in disorders of dopamine dysfunction, such as Parkinson's disease.

Association of plasma high-density lipoprotein cholesterol level with risk of incident dementia: a cohort study of healthy older adults.

Background: Recent studies have reported associations between high plasma high-density lipoprotein cholesterol (HDL-C) levels and risk of all-cause mortality, age-related macular degeneration, sepsis and fractures, but associations with dementia risk remain unclear. To determine whether high plasma HDL-C levels are associated with increased incident dementia risk in initially-healthy older people. Methods: We conducted a post-hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial; a double-blind, randomized, placebo-controlled trial of daily low-dose aspirin in healthy older people. ASPREE recruited 16,703 participants aged ≥70 years (from Australia) and 2411 participants aged ≥65 years (from the US) between 2010 and 2014. Participants had no diagnosed cardiovascular disease, dementia, physical disability, or life-threatening illness at enrolment and were cognitively healthy (3MS score ≥78). All-cause dementia was a primary trial endpoint, and determined by DSM-IV criteria. Cox regression was used to examine hazard ratios between HDL-C categories <40 mg/dL, 40-60 mg/dL (reference category), 60-80 mg/dL, and >80 mg/dL and dementia. Restricted cubic spline curves were used to determine nonlinear associations. Data analysis was performed from October 2022 to January 2023. Findings: Of the 18,668 participants, 850 (4.6%) cases of incident dementia were recorded over 6.3 (SD 1.8) years. Participants with high HDL-C (>80 mg/dL) had a 27% higher risk of dementia (HR 1.27, 95% CI 1.03, 1.58). Age stratified analyses demonstrated that the risk of incident dementia was higher in participants ≥75 years compared to participants <75 years (HR 1.42, 95% CI 1.10, 1.83 vs HR 1.02, 95% CI 0.68, 1.51). Associations remained significant after adjusting for covariates including age, sex, country of enrolment, daily exercise, education, alcohol consumption, weight change over time, non-HDL-C, HDL-C-PRS, and APOE genotype. Interpretation: In a population of initially-healthy older adults aged ≥75 years, high HDL-C levels were associated with increased risk of all-cause dementia. Funding: National Institutes of Health, USA; National Health and Medical Research Council Australia; Monash University (Melbourne, VIC, Australia); and the Victorian Cancer Agency (Australia).

High-intensity acute exercise impacts motor learning in healthy older adults.

Healthy aging is associated with changes in motor sequence learning, with some studies indicating decline in motor skill learning in older age. Acute cardiorespiratory exercise has emerged as a potential intervention to improve motor learning, however research in healthy older adults is limited. The current study investigated the impact of high-intensity interval exercise (HIIT) on a subsequent sequential motor learning task. Twenty-four older adults (aged 55-75 years) completed either 20-minutes of cycling, or an equivalent period of active rest before practicing a sequential force grip task. Skill learning was assessed during acquisition and at a 6-hour retention test. In contrast to expectation, exercise was associated with reduced accuracy during skill acquisition compared to rest, particularly for the oldest participants. However, improvements in motor skill were retained in the exercise condition, while a reduction in skill was observed following rest. Our findings indicate that high-intensity exercise conducted immediately prior to learning a novel motor skill may have a negative impact on motor performance during learning in older adults. We also demonstrated that exercise may facilitate early offline consolidation of a motor skill within this population, which has implications for motor rehabilitation.

Associations of body habitus and its changes with incident dementia in older adults.

BACKGROUND: This study examined the associations of body mass index (BMI) and waist circumference (WC), as well as their short- and long-term changes over time, with incident dementia in older individuals. METHODS: Data came from 18,837 community-dwelling individuals aged 65+ years from Australia and the United States, who were relatively healthy without major cognitive impairment at enrolment. Anthropometric measures were prospectively assessed at baseline, as well as change and variability from baseline to year two (three time-points). In a subgroup (n = 11,176), self-reported weight at age 18 and 70+ years was investigated. Dementia cases satisfied DSM-IV criteria. Cox regression was used to examine the associations between anthropometric measures and incident risk of dementia. RESULTS: Compared to normal weight, an overweight (HR: 0.67, 95%CI: 0.57-0.79, p < 0.001) or obese BMI (HR: 0.73, 95%CI: 0.60-0.89, p = 0.002), or a larger WC (elevated, HR: 0.71, 95%CI: 0.58-0.86, p < 0.001; highly elevated, HR: 0.65, 95%CI: 0.55-0.78, p < 0.001; relative to low) at baseline was associated with lower dementia risk. In contrast, substantial increases in BMI (>5%) over 2 years after baseline were associated with higher dementia risk (HR: 1.49, 95% CI: 1.17-1.91, p = 0.001). Increased dementia risk was also seen with an underweight BMI at baseline and a 2-year BMI decrease (>5%), but these associations appeared only in the first 4 years of follow-up. Compared to normal weight at both age 18 and 70+ years, being obese at both times was associated with increased dementia risk (HR: 2.27, 95%CI: 1.22-4.24, p = 0.01), while obesity only at age 70+ years was associated with decreased risk (HR: 0.70, 95%CI: 0.51-0.95, p = 0.02). CONCLUSIONS: Our findings suggest that long-term obesity and weight gain in later life may be risk factors for dementia. Being underweight or having substantial weight loss in old age may be early markers of pre-clinical dementia.

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.

Late-Life Metabolic Dysfunction-Associated Steatotic Liver Disease and its Association With Physical Disability and Dementia.

BACKGROUND: The burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is growing rapidly, including among older adults. The number of older adults is also rising with concomitantly increasing rates of age-related physical and cognitive dysfunction. However, data on whether MASLD affects physical and cognitive function in older adults is limited. As such, we aimed to identify whether prevalent MASLD influences the risk of incident physical disability or dementia in initially healthy older adults. METHODS: A post-hoc analysis of participants from the ASPREE-XT cohort study, which recruited community-dwelling older adults without a history of cardiovascular disease, dementia, or independence-limiting functional impairment. The Fatty Liver Index (to identify MASLD) was calculated in those with complete data. Cox proportional-hazards models were used to investigate the outcomes of dementia and persistent physical disability in participants with MASLD vs those without. RESULTS: Of the 9 097 individuals included (mean age 75.1 ±â€…4.2 years; 45.0% men), 341 (3.7%) developed persistent physical disability and 370 (4.1%) developed dementia over a median follow-up of 6.4 years (IQR 5.3-7.5 years). When adjusting for known contributors including age, gender, education, comorbidity, and functional measures, MASLD was associated with an increased risk of persistent physical disability (HR 1.41 [95% CI: 1.07-1.87]) and reduced risk of incident dementia (HR 0.63 [95% CI: 0.48-0.83]). CONCLUSIONS: Prevalent MASLD is associated with reduced rates of incident dementia but increased risk of persistent physical disability in initially relatively healthy older adults. Understanding the mechanisms underlying these divergent results to allow appropriate risk stratification and counseling is important.

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

Apathy is one of the most common neuropsychiatric features of Huntington's disease (HD). A hallmark of apathy is diminished goal-directed behaviour, which is characterised 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 HD 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 HD group were more averse to cognitive effort than controls. Although the HD 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 HD 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 HD 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 HD was driven by a willingness to engage in physically effortful actions despite a reduced capacity to do so. Finally, the HD 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 HD 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 HD.

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.

STAREE-Mind Imaging Study: a randomised placebo-controlled trial of atorvastatin for prevention of cerebrovascular decline and neurodegeneration in older individuals.

Introduction: Cerebrovascular disease and neurodegeneration are causes of cognitive decline and dementia, for which primary prevention options are currently lacking. Statins are well-tolerated and widely available medications that potentially have neuroprotective effects. The STAREE-Mind Imaging Study is a randomised, double-blind, placebo-controlled clinical trial that will investigate the impact of atorvastatin on markers of neurovascular health and brain atrophy in a healthy, older population using MRI. This is a nested substudy of the 'Statins for Reducing Events in the Elderly' (STAREE) primary prevention trial. Methods: Participants aged 70 years or older (n=340) will be randomised to atorvastatin or placebo. Comprehensive brain MRI assessment will be undertaken at baseline and up to 4 years follow-up, including structural, diffusion, perfusion and susceptibility imaging. The primary outcome measures will be change in brain free water fraction (a composite marker of vascular leakage, neuroinflammation and neurodegeneration) and white matter hyperintensity volume (small vessel disease). Secondary outcomes will include change in perivascular space volume (glymphatic drainage), cortical thickness, hippocampal volume, microbleeds and lacunae, prefrontal cerebral perfusion and white matter microstructure. Ethics and dissemination: Academic publications from this work will address the current uncertainty regarding the impact of statins on brain structure and vascular integrity. This study will inform the utility of repurposing these well-tolerated, inexpensive and widely available drugs for primary prevention of neurological outcomes in older individuals. Ethics approval was given by Monash University Human Research Ethics Committee, Protocol 12206. Trial registration number: ClinicalTrials.gov Identifier: NCT05586750.

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.

Normative Data for Single-Letter Controlled Oral Word Association Test in Older White Australians and Americans, African-Americans, and Hispanic/Latinos.

Background: The Controlled Oral Word Association Test (COWAT) is a commonly used measure of verbal fluency. While a normal decline in verbal fluency occurs in late adulthood, significant impairments may indicate brain injury or diseases such as Alzheimer's disease. Normative data is essential to identify when test performance falls below expected levels based on age, gender, and education level. Objective: This study aimed to establish normative performance data on single-letter COWAT for older community-dwelling adults. Methods: Over 19,000 healthy men and women, without a diagnosis of dementia or a Modified Mini-Mental State Examination score below 77/100, were recruited for the ASPREE trial. Neuropsychological assessments, including the COWAT with letter F, were administered at study entry. Results: Median participant age was 75 years (range 65-98), with 56.5% being women. The majority of participants had 9-11 years of education in Australia and over 12 years in the U.S. The COWAT performance varied across ethno-racial groups and normative data were thus presented separately for 16,335 white Australians, 1,084 white Americans, 896 African-Americans, and 316 Hispanic/Latinos. Women generally outperformed men in the COWAT, except for Hispanic/Latinos. Higher education levels consistently correlated with better COWAT performance across all groups, while the negative association with age was weaker. Conclusions: This study provides comprehensive normative data for the COWAT stratified by ethno-racial groups in Australia and the U.S., considering age, gender, and education level. These norms can serve as reference standards for screening cognitive impairments in older adults in both clinical and research settings.

Exploring the Potential Association Between Self-Reported Psychological Stress and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease in Midlife: A Cross-Sectional Study.

Psychological stress is associated with dementia risk. However, the underlying mechanisms are unclear. This cross-sectional study examined the association between self-reported psychological stress and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease and neurodegeneration in 73 cognitively unimpaired middle-aged adults from the Healthy Brain Project (mean age = 58±7 years). Linear regression analyses did not reveal any significant associations of psychological stress with CSF amyloid-ß42, phosphorylated tau-181, total tau, or neurofilament light chain. Cohen's f2 effect sizes were small in magnitude (f2≤0.08). Further research is needed to replicate our findings, particularly given that the sample reported on average low levels of stress.

Association Between Triglycerides and Risk of Dementia in Community-Dwelling Older Adults: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: It has been suggested that higher triglyceride levels were associated with a lower risk of Alzheimer disease. This study aimed to examine the association of triglycerides with dementia and cognition change in community-dwelling older adults. METHODS: This prospective longitudinal study used data from the Aspirin in Reducing Events in the Elderly (ASPREE) randomized trial of adults aged 65 years or older without dementia or previous cardiovascular events at enrollment. The main outcome was incident dementia. Other outcomes included changes in composite cognition and domain-specific cognition (global cognition, memory, language and executive function, and psychomotor speed). The association between baseline triglycerides and dementia risk was estimated using Cox proportional hazard models adjusting for relevant risk factors. Linear mixed models were used to investigate cognitive change. The analysis was repeated in a subcohort of participants with available APOE-ε4 genetic data with additional adjustment for APOE-ε4 carrier status and an external cohort (UK Biobank) with similar selection criteria applied. RESULTS: This study included 18,294 ASPREE participants and 68,200 UK Biobank participants (mean age: 75.1 and 66.9 years; female: 56.3% and 52.7%; median [interquartile range] triglyceride: 106 [80-142] mg/dL and 139 [101-193] mg/dL), with dementia recorded in 823 and 2,778 individuals over a median follow-up of 6.4 and 12.5 years, respectively. Higher triglyceride levels were associated with lower dementia risk in the entire ASPREE cohort (hazard ratio [HR] with doubling of triglyceride: 0.82, 95% CI 0.72-0.94). Findings were similar in the subcohort of participants with APOE-ε4 genetic data (n = 13,976) and in the UK Biobank cohort (HR was 0.82 and 0.83, respectively, all p ≤ 0.01). Higher triglycerides were also associated with slower decline in composite cognition and memory over time (p ≤ 0.05). DISCUSSION: Older adults with higher triglyceride levels within the normal to high-normal range had a lower dementia risk and slower cognitive decline over time compared with individuals with lower triglyceride levels. Higher triglyceride levels may be reflective of better overall health and/or lifestyle behaviors that would protect against dementia development. Future studies are warranted to investigate whether specific components within the total circulating pool of plasma triglycerides may promote better cognitive function, with the hope of informing the development of new preventive strategies.

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.

Standardised images of novel objects created with generative adversarial networks.

An enduring question in cognitive science is how perceptually novel objects are processed. Addressing this issue has been limited by the absence of a standardised set of object-like stimuli that appear realistic, but cannot possibly have been previously encountered. To this end, we created a dataset, at the core of which are images of 400 perceptually novel objects. These stimuli were created using Generative Adversarial Networks that integrated features of everyday stimuli to produce a set of synthetic objects that appear entirely plausible, yet do not in fact exist. We curated an accompanying dataset of 400 familiar stimuli, which were matched in terms of size, contrast, luminance, and colourfulness. For each object, we quantified their key visual properties (edge density, entropy, symmetry, complexity, and spectral signatures). We also confirmed that adult observers (N = 390) perceive the novel objects to be less familiar, yet similarly engaging, relative to the familiar objects. This dataset serves as an open resource to facilitate future studies on visual perception.

Associations of Perceived Stress and Psychological Resilience With Cognition and a Modifiable Dementia Risk Score in Middle-Aged Adults.

OBJECTIVES: Psychological stress has been proposed as a risk factor for cognitive impairment and dementia. However, it remains unclear how an individual's stress-coping ability (i.e., psychological resilience) is related to cognition. This cross-sectional study investigated whether perceived stress and psychological resilience were associated with cognition and a modifiable dementia risk score in a large community-based sample of cognitively normal adults. The moderating effect of psychological resilience was also examined. METHODS: Participants (mean age = 57 ± 7 years) enrolled in the web-based Healthy Brain Project completed the Perceived Stress Scale and the Connor-Davidson Resilience Scale. Domains of attention and working memory were assessed using the Cogstate Brief Battery (n = 1,709), and associative memory was assessed using the Cambridge Neuropsychological Test Automated Battery (n = 1,522). Dementia risk was estimated for 1,913 participants using a modified version of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia dementia risk score, calculated using only readily modifiable dementia risk factors. RESULTS: In separate linear regression analyses adjusted for age, sex, education, and race, greater levels of perceived stress and lower levels of psychological resilience were associated with poorer performance across all cognitive domains, as well as a higher modifiable dementia risk score. Psychological resilience did not moderate the effect of perceived stress on cognition or the dementia risk score. DISCUSSION: Higher perceived stress and lower resilience were associated with poorer cognition and a greater burden of modifiable dementia risk factors. Intervention studies are required to determine if lowering stress and building resilience can mitigate cognitive deficits and reduce dementia risk.

Computational mechanisms underlying the dynamics of physical and cognitive fatigue.

The willingness to exert effort for reward is essential but comes at the cost of fatigue. Theories suggest fatigue increases after both physical and cognitive exertion, subsequently reducing the motivation to exert effort. Yet a mechanistic understanding of how this happens on a moment-to-moment basis, and whether mechanisms are common to both mental and physical effort, is lacking. In two studies, participants reported momentary (trial-by-trial) ratings of fatigue during an effort-based decision-making task requiring either physical (grip-force) or cognitive (mental arithmetic) effort. Using a novel computational model, we show that fatigue fluctuates from trial-to-trial as a function of exerted effort and predicts subsequent choices. This mechanism was shared across the domains. Selective to the cognitive domain, committing errors also induced momentary increases in feelings of fatigue. These findings provide insight into the computations underlying the influence of effortful exertion on fatigue and motivation, in both physical and cognitive domains.