Investigating cognitive effort and its role in control over Pavlovian bias

Effort is a key determinant of cognitive performance, particularly for processes involving cognitive control – without it, performance may be slow, inaccurate or biased. Related to this, decreased ability to exert effort has been implicated in the symptoms of conditions including depression and anxiety. In this thesis I investigate the role of effort in the specific case of control over Pavlovian biases. In the first two experimental chapters I examine whether Pavlovian biases are in principle modifiable, a necessary precondition for demonstrating that they are also controllable. Following a simple programme of behavioural training, participants showed reduced influence of Pavlovian biases on behaviour, a result which is consistent with increased cognitive control. In the third experimental chapter, I present a new task for measuring cognitive effort sensitivity, suitable in particular for individual differences research. Subsequently, in the final experimental chapter, I use this task to test directly the hypothesis that the strength of Pavlovian bias is influenced by effortful cognitive control. I present initial evidence that indeed willingness to exert effort and the strength of Pavlovian biases seem to be negatively correlated, while effort also seems to be negatively associated with both depression and anxiety symptoms. Finally, in a standalone theoretical chapter, I discuss the rationale for effort costs, which currently are not well understood; I introduce and extend two existing ideas from outside of neuroscience which I think may be informative in this regard. Overall this thesis extends our understanding of the link between effort and control, suggesting in particular that the expression of Pavlovian biases can be framed in terms of effort-based decision-making. Additionally, by introducing fresh ideas about the basis of cognitive effort costs, it is hoped that this thesis will provide stronger foundations on which experimental research on cognitive effort can be built in the future

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Measuring cognitive effort without difficulty

An important finding in the cognitive effort literature has been that sensitivity to the costs of effort varies between individuals, suggesting that some people find effort more aversive than others. It has been suggested this may explain individual differences in other aspects of cognition; in particular that greater effort sensitivity may underlie some of the symptoms of conditions such as depression and schizophrenia. In this paper we highlight a major problem with existing measures of cognitive effort that hampers this line of research, specifically the confounding of effort and difficulty. This means that behaviour thought to reveal effort costs could equally be explained by cognitive capacity, which influences the frequency of success and thereby the chance of obtaining reward. To address this shortcoming we introduce a new test, the Number Switching Task (NST), specially designed such that difficulty will be unaffected by the effort manipulation and can easily be standardised across participants. In a large, online sample we show that these criteria are met successfully and reproduce classic effort discounting results with the NST. We also demonstrate the use of computational modelling with this task, producing behavioural parameters which can then be associated with other measures, and report a preliminary association with the Need for Cognition scale

Training successfully reduces the strength of Pavlovian biases

Pavlovian biases are fixed patterns of responses that include approaching stimuli associated with reward and avoiding those associated with punishment. These prepotent behavioural responses can sometimes conflict with those produced by other behavioural action selection systems, giving rise to suboptimal behaviour. This is particularly important in the context of affective disorders like anxiety and depression, in which Pavlovian biases are enhanced (Mkrtchian et al., 2017; Nord et al., 2018), and are thought to contribute to the induction and maintenance of symptoms (Dayan & Huys, 2008). In this study we investigated whether participants could be trained to exert more control over these biases. This would present a potential new opportunity for treating anxiety and depression. In addition, it would be the first direct, behavioural demonstration that Pavlovian biases are modifiable. We conducted a double-blind, sham-controlled study (N=800) and found that the active training intervention was indeed effective: after selectively practicing the conflict trials of the Orthogonal Go/No-Go task (Guitart-Masip et al., 2011), which require high control, participants were more accurate and showed less influence of Pavlovian biases (especially avoidance bias) when tested on the full task. We discuss what this means for understanding Pavlovian biases, and suggest that future studies should now be aimed at facilitating transfer of these effects to other aspects of anxiety and depression symptoms

Traumatic brain injury : integrated approaches to improve prevention, clinical care, and research

Rahul Raj on työryhmän InTBIR Participants Investigators jäsen.Peer reviewe