Pramipexole Enhances Reward Learning by Preserving Value Estimates

Background: Dopamine D2-like receptor agonists show promise as treatments for depression. They are thought to act by altering how individuals learn from rewarding experiences. However, the nature of these reward learning alterations, and the mechanisms by which they are produced is not clear. Reinforcement learning accounts describe three distinct processes that may produce similar changes in reward learning behaviour; increased reward sensitivity, increased inverse decision temperature and decreased value decay. As these processes produce equivalent effects on behaviour, arbitrating between them requires measurement of how expectations and prediction errors are altered. In the present study, we characterised the behavioural effects of a sustained 2-week course of the D2/3/4 receptor agonist pramipexole on reward learning and used fMRI measures of expectation and prediction error to assess which of these three mechanistic processes were responsible for the behavioural effects. Methods: 40 healthy volunteers (Age: 18-43, 50% female) were randomly allocated to receive either two weeks of pramipexole (titrated to 1mg/day) or placebo in a double-blind, between subject design. Participants completed a probabilistic instrumental learning task, in which stimuli were associated with either rewards or losses, before the pharmacological intervention and twice between days 12-15 of the intervention (once with and once without fMRI). Both asymptotic choice accuracy, and a reinforcement learning model, were used to assess reward learning. Results: Behaviourally, pramipexole specifically increased choice accuracy in the reward condition, with no effect in the loss condition. Pramipexole increased the BOLD response in the orbital frontal cortex during the expectation of win trials but decreased the BOLD response to reward prediction errors in the ventromedial prefrontal cortex. This pattern of results indicates that pramipexole enhances choice accuracy by reducing the decay of estimated values during reward learning. Conclusions: The D2-like receptor agonist pramipexole enhances reward learning by preserving learned values. This is a plausible candidate mechanism for pramipexoles observed anti-depressant effect.

Behavioural Challenges Associated With Risk-Adapted Cancer Screening

Cancer screening programmes have a major role in reducing cancer incidence and mortality. Traditional internationally-adopted protocols have been to invite all ‘eligible individuals’ for the same test at the same frequency. However, as highlighted in Cancer Research UK’s 2020 strategic vision, there are opportunities to increase effectiveness and cost-effectiveness, and reduce harms of screening programmes, by making recommendations on the basis of personalised estimates of risk. In some respects, this extends current approaches of providing more intensive levels of care outside screening programmes to individuals at very high risk due to their family history or underlying conditions. However, risk-adapted colorectal cancer screening raises a wide range of questions, not only about how best to change existing programmes but also about the psychological and behavioural effects that these changes might have. Previous studies in other settings provide some important information but remain to be tested and explored further in the context of colorectal screening. Conducting behavioural science research in parallel to clinical research will ensure that risk-adapted screening is understood and accepted by the population that it aims to serve.

Behavioural effects of task-relevant neuromodulation by rTMS on giving-up

Recent studies suggest that online repetitive transcranial magnetic stimulation (rTMS) can induce local entrainment of ongoing endogenous oscillatory activity during a task. This effect may impact cognitive performance, depending on the function of the oscillation. In this study, we aimed to investigate the effects of stimulation frequency and target location that are relevant to the cognitive processes of giving-up. We first investigated the correlations between the EEG oscillations and cognitive giving-up processes during problem-solving tasks (Experiment 1). We then conducted online rTMS to examine the frequency-dependent stimulation effects of rTMS on the performance of problem-solving tasks and ongoing oscillations (Experiment 2). The results of Experiment 1 suggested that the frontal theta rhythm is associated with the giving-up processes and that the frontal alpha rhythm is associated with problem-solving behaviour. Accordingly, we hypothesised that rTMS at the theta frequency would induce ongoing theta activity and accelerate the giving-up behaviour, while rTMS at the alpha frequency would induce ongoing alpha activity and slow down the giving-up behaviour in Experiment 2. The results showed that theta-frequency rTMS application induced an increase in theta amplitudes and shortened the giving-up response. Alpha-frequency rTMS application induced an increase in alpha amplitudes, but did not change giving-up responses. Considering the close resemblance between giving-up behaviour and rumination in depression, neuromodulation of cognitive giving-up processes may lead to a new intervention to treat depression by rTMS. Furthermore, this study strengthens the hypothesis that modulating task-relevant oscillations by rTMS could induce behavioural changes related to cognitive performance.

COVID-19 vaccination, risk-compensatory behaviours, and social contacts in four countries in the UK

The physiological effects of vaccination against SARS-CoV-2 (COVID-19) are well documented, yet the behavioural effects are largely unknown. Risk compensation suggests that gains in personal safety, as a result of vaccination, are offset by increases in risky behaviour, such as socialising, commuting and working outside the home. This is potentially problematic because transmission of SARS-CoV-2 is driven by contacts, which could be amplified by vaccine-related risk compensation behaviours. Here, we show that social behaviours were overall unrelated to personal vaccination, but - adjusting for variation in mitigation policies - were responsive to the level of vaccination in the wider population: individuals in the UK were risk compensating when rates of vaccination were rising. This effect was observed across four nations of the UK, each of which varied policies autonomously.

The role of dopamine D₂ receptor mechanisms in the development of MDMA sensitisation

<p>Rationale. ±3, 4-methelynedioxymethamphetamine (MDMA) is the primary psychoactive ingredient of the increasingly popular recreational street drug, ecstasy. As with other drugs of abuse, repeated intermitted exposure to MDMA can lead to an increase in the subsequent behavioural effects of the drug. This phenomenon, termed behavioural sensitisation, has been attributed to sensitisation of central DAergic mechanisms considered to underlie several aspects of addiction. Objectives. The purpose of the present research was to investigate the role of DA D₂ receptor mechanisms in the development of MDMA sensitisation and the acquisition of MDMA self-administration in rats. Methods. Rats received daily i.p. injections of the selective D₂ antagonist, eticlopride (0.0, 0.05, 0.3 mg/kg), prior to injections of MDMA (0.0, 10.0 mg/kg) for five days. Two days following the final pre-treatment session, the locomotor activating effects of MDMA (5 mg/kg, i.p.) were determined. Another group of rats were surgically implanted with i.v. jugular catheters before undergoing the same pre-treatment regimen. Two days following the final pre-treatment session, these rats were subsequently tested for acquisition of MDMA self-administration. The locomotor activating effects of MDMA (5 mg/kg i.p.) were determined two days following the last self-administration session. Results. Pre-treatment with MDMA enhanced the locomotor activating effects of MDMA and facilitated the acquisition of MDMA self-administration, as evidenced by an increased likelihood to meet an acquisition criterion. Co-administration of eticlopride during pre-treatment completely blocked the development of sensitisation to MDMA-produced hyperactivity but failed to significantly attenuate the facilitation of MDMA self-administration. Interestingly, pre-treatment with eticlopride alone also facilitated the acquisition of self-administration. MDMA self-administration failed to alter MDMA-produced locomotor hyperactivity. Conclusions. These findings suggest that repeated activation of DA D₂ receptors is required for the development of sensitisation to MDMA-produced hyperactivity but not for the development of sensitisation to MDMA-produced reinforcement. D₂ receptor mechanisms evidently play some role, however, because repeated exposure to eticlopride also facilitated MDMA self-administration. It is suggested that both sensitised DAergic mechanisms and desensitised 5-HTergic mechanisms contribute to the acquisition of MDMA self-administration.</p>

The role of dopamine D₂ receptor mechanisms in the development of MDMA sensitisation

<p>Rationale. ±3, 4-methelynedioxymethamphetamine (MDMA) is the primary psychoactive ingredient of the increasingly popular recreational street drug, ecstasy. As with other drugs of abuse, repeated intermitted exposure to MDMA can lead to an increase in the subsequent behavioural effects of the drug. This phenomenon, termed behavioural sensitisation, has been attributed to sensitisation of central DAergic mechanisms considered to underlie several aspects of addiction. Objectives. The purpose of the present research was to investigate the role of DA D₂ receptor mechanisms in the development of MDMA sensitisation and the acquisition of MDMA self-administration in rats. Methods. Rats received daily i.p. injections of the selective D₂ antagonist, eticlopride (0.0, 0.05, 0.3 mg/kg), prior to injections of MDMA (0.0, 10.0 mg/kg) for five days. Two days following the final pre-treatment session, the locomotor activating effects of MDMA (5 mg/kg, i.p.) were determined. Another group of rats were surgically implanted with i.v. jugular catheters before undergoing the same pre-treatment regimen. Two days following the final pre-treatment session, these rats were subsequently tested for acquisition of MDMA self-administration. The locomotor activating effects of MDMA (5 mg/kg i.p.) were determined two days following the last self-administration session. Results. Pre-treatment with MDMA enhanced the locomotor activating effects of MDMA and facilitated the acquisition of MDMA self-administration, as evidenced by an increased likelihood to meet an acquisition criterion. Co-administration of eticlopride during pre-treatment completely blocked the development of sensitisation to MDMA-produced hyperactivity but failed to significantly attenuate the facilitation of MDMA self-administration. Interestingly, pre-treatment with eticlopride alone also facilitated the acquisition of self-administration. MDMA self-administration failed to alter MDMA-produced locomotor hyperactivity. Conclusions. These findings suggest that repeated activation of DA D₂ receptors is required for the development of sensitisation to MDMA-produced hyperactivity but not for the development of sensitisation to MDMA-produced reinforcement. D₂ receptor mechanisms evidently play some role, however, because repeated exposure to eticlopride also facilitated MDMA self-administration. It is suggested that both sensitised DAergic mechanisms and desensitised 5-HTergic mechanisms contribute to the acquisition of MDMA self-administration.</p>

Causal evidence for the role of the sensory visual cortex in visual short-term memory maintenance

The role of the sensory visual cortex during visual short-term memory (VSTM) remains controversial. This controversy is possibly due to methodological issues in previous attempts to investigate the effects of transcranial magnetic stimulation (TMS) on VSTM. This study aims to use TMS, while covering previous methodological deficits. Young adults will be recruited to participate in two experiments using a VSTM orientation change-detection under TMS. Monocular vision will be ensured using red-blue goggles combined with red-blue stimuli. Double-pulse TMS will be delivered at different times (Experiment 1: 0ms, 200ms, or 1000ms; Experiment 2: 200ms, 1000ms) during a 2 s retention phase, on one side of the occipital hemisphere (right hemisphere for 50% of the participants). In experiment 2, a sham-TMS condition will be introduced. Behavioural effects in the ipsilateral occipital hemisphere to visual hemifield will indicate a causal involvement of the sensory visual cortex during a specific temporal point in VSTM.