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While hormonal contraceptives (HCs) like oral contraceptive pills (OCs) and intrauterine devices (IUDs) can reportedly influence mood, the evidence is mixed, and the mechanisms remain unclear. Emotion reactivity and regulation processes may be hormone-sensitive and underlie these mood changes. This study sought to investigate the role of the menstrual cycle and HC use in emotion regulation using ERP measures during an emotion regulation paradigm. Participants with a natural cycle (NC) were measured in the mid-follicular and mid-luteal phase (within-subject design, n = 26), and compared with OC (n = 36) and IUD (n = 25) users. The centroparietal late positive potential (LPP) reflected negative emotion reactivity and its modulation by cognitive reappraisal served as a marker for emotion regulation processing. NC participants had a lower LPP amplitude in the mid-luteal compared to the mid-follicular phase. Reactivity to negative emotional stimuli decreased over time in the mid-luteal phase, whereas the HC groups showed sustained LPP activation. Reappraisal led only to significant LPP changes in the mid-follicular phase, and not in the mid-luteal phase or HC groups. Our results showed a specific left frontal activity (FR-LPP) in the contrast that reflected emotion regulation processing. This activity was highest in the mid-follicular phase, and was significantly different from the OC users but not from the IUD group. Higher self-reported PMS symptoms were associated with stronger effects on the reduced mid-luteal LPP activity and with lower FR-LPP amplitude in the mid-follicular phase. No effect of OC phase (active pill use versus pill pause) was found. These findings add insights into the neurophysiological underpinnings of hormone-related mood changes and demonstrate the importance of considering hormonal status and PMS symptoms in emotion research., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest in this manuscript., (Copyright © 2024. Published by Elsevier Ltd.)

The balance between goal-directed and habitual control has been proposed to determine the flexibility of instrumental behaviour, in both humans and animals. This view is supported by neuroscientific studies that have implicated dissociable neural pathways in the ability to flexibly adjust behaviour when outcome values change. A previous Diffusion Tensor Imaging study provided preliminary evidence that flexible instrumental performance depends on the strength of parallel cortico-striatal white-matter pathways previously implicated in goal-directed and habitual control. Specifically, estimated white-matter strength between caudate and ventromedial prefrontal cortex correlated positively with behavioural flexibility, and posterior putamen-premotor cortex connectivity correlated negatively, in line with the notion that these pathways compete for control. However, the sample size of the original study was limited, and so far, there have been no attempts to replicate these findings. In the present study, we aimed to conceptually replicate these findings by testing a large sample of 205 young adults to relate cortico-striatal connectivity to performance on the slips-of-action task. In short, we found only positive neural correlates of goal-directed performance, including striatal connectivity (caudate and anterior putamen) with the dorsolateral prefrontal cortex. However, we failed to provide converging evidence for the existence of a neural habit system that puts limits on the capacity for flexible, goal-directed action. We discuss the implications of our findings for dual-process theories of instrumental action., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Medication adherence can be vital for one's health, especially in older adults. However, previous research has demonstrated that medication adherence is negatively affected by age-related cognitive decline. In the current study we investigated whether older adults are able to compensate for this decline by relying more on the formation of efficient, automatized routines. To this end, we directly compared daily (placebo) medication adherence in a healthy sample of 68 younger (18-29  years) and 63 older adults (65-86  years) over a period of 4  weeks. We show that despite an age-related decline in cognitive functions (i.e., poorer working memory, prospective memory, task switching, and goal-directed control), older adults adhered better to a daily pill intake routine than younger adults did and, in line with our hypothesis about increased routine formation, reported higher subjective automaticity of pill intake. Across age groups, automatization of pill intake was related to intake regularity and conscientiousness, but not to individual differences in habit tendency as measured in the lab nor to explicit strategic planning. Crucially, the age-related increase in pill intake adherence was mediated by experienced automatization as well as motivation. These findings demonstrate that intact habitual processes and high motivation aid older adults in successfully forming daily routines., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van de Vijver, Brinkhof and de Wit.)

Despite good intentions, people often fail to cross the "intention-behavior gap," especially when goal achievement requires repeated action. To bridge this gap, the formation of automatized routines may be crucial. However, people may differ in the tendency to switch from goal-directed toward habitual control. To shed light on why some people succeed in forming routines while others struggle, the present study related the automatization of a novel, daily routine to individual differences in white-matter connectivity in corticostriatal networks that have been implicated in goal-directed and habitual control. Seventy-seven participants underwent diffusion-weighted imaging and formed the daily routine of taking a (placebo) pill for 3 weeks. Pill intake was measured by electronic pill boxes, and participants filled out a daily online questionnaire on the subjective automaticity of this behavior. Automatization of pill intake was negatively related to striatal (mainly caudate) connectivity with frontal goal-directed and cognitive control regions, namely, ventromedial pFC and anterior cingulate gyrus. Furthermore, daily pill intake was positively related to individual differences in striatal (mainly caudate) connectivity with cognitive control regions, including dorsolateral and anterior pFC. Therefore, strong control networks may be relevant for implementing a new routine but may not benefit its automatization. We also show that habit tendency (assessed with an outcome-devaluation task), conscientiousness, and daily life regularity were positively related to routine automatization. This translational study moves the field of habit research forward by relating self-reported routine automatization to individual differences in performance on an experimental habit measure and to brain connectivity., (© 2023 Massachusetts Institute of Technology.)

The impact of the COVID-19 pandemic on mental health, well-being, and behavior is likely influenced by individual characteristics that determine one's capacity for resilience. In this exploratory study, we examined whether individual differences in working memory (WM) capacity and habit propensity (HP), measured before the outbreak, could predict variation in subsequent psychological coping efficacy (as operationalized by measures of depression, mental well-being, perceived stress, and loneliness) and behavioral adjustment (by evaluating compliance and self-reported automaticity of four COVID-19 guidelines) among Dutch older adults ( n  = 36) during the pandemic (measured April 25 to May 6, 2020). While we found elevated levels of depression and emotional loneliness, overall mental well-being, and perceived stress were not affected by the pandemic. Contrary to our expectations, we found no robust evidence for a protective role of WM in predicting these outcomes, although our findings hint at a positive relationship with perceived change in mental well-being. Interestingly, WM and HP were found to affect the self-reported automaticity levels of adherence to behavioral COVID-19 guidelines (i.e., washing hands, physical distancing), where a strong HP appeared beneficial when deliberate resources were less available (e.g., low WM capacity). These novel and preliminary findings offer new potential avenues for investigating individual differences in resilience in times of major life events or challenges., Supplementary Information: The online version contains supplementary material available at 10.1007/s10804-022-09404-9., Competing Interests: Conflict of interestThe authors report no conflict of interest., (© The Author(s) 2022.)

Background and Objective: Enthusiasm for the use of outcomes-based managed entry agreements (OBMEAs) to manage uncertainties apparent at the time of appraisal/pricing and reimbursement of new medicines has waned over the past decade, as challenges in establishment, implementation and re-appraisal have been identified. With the recent advent of innovative treatments for rare diseases that have uncertainties in the clinical evidence base, but which could meet a high unmet need, there has been renewed interest in the potential of OBMEAs. The objective of this research was to review the implementation of OBMEAs for two case studies across countries in the European Union, Australia and Canada, to identify good practices that could inform development of tools to support implementation of OBMEAs., Methods: To investigate how OBMEAs are being implemented with rare disease treatments, we collected information from health technology assessment/payer experts in countries that had implemented OBMEAs for either nusinersen in spinal muscular atrophy or tisagenlecleucel in two cancer indications. Operational characteristics of the OBMEAs that were publicly available were documented. Then, the experts discussed issues in implementing these OBMEAs and specific approaches taken to overcome challenges., Results: The OBMEAs identified were based on individual outcomes to ensure appropriate use, manage continuation of treatment and in two cases linked to payment schedules, or they were population based, coverage with evidence development. For nusinersen, population-based OBMEAs are documented in Belgium, England and the Netherlands and individual-based schemes in Bulgaria, Ireland, Italy and Lithuania. For tisagenlecleucel, there were population-based schemes in Australia, Belgium, England and France and individual-based schemes in Italy and Spain. Comparison of the OBMEA constructs showed some clear published frameworks and clarity of the uncertainties to be addressed that were similar across countries. Agreements were generally made between the marketing authorisation holder and the payer with involvement of expert physicians. Only England and the Netherlands involved patients. Italy used its long-established, national, web-based, treatment-specific data collection system linked to reimbursement and Spain has just developed such a national treatment registry system. Other countries relied on a variety of data collection systems (including clinical registries) and administrative data. Durations of agreements varied for these treatments as did processes for interim reporting. The processes to ensure data quality, completeness and sufficiency for re-analysis after coverage with evidence development were not always clear, neither were analysis plans., Conclusions: These case studies have shown that important information about the constructs of OBMEAs for rare disease treatments are publicly available, and for some jurisdictions, interim reports of progress. Outcomes-based managed entry agreements can play an important role not only in reimbursement, but also in treatment optimisation. However, they are complex to implement and should be the exception and not the rule. More recent OBMEAs have developed document covenants among stakeholders or electronic systems to provide assurances about data sufficiency. For coverage with evidence development, there is an opportunity for greater collaboration among jurisdictions to share processes, develop common data collection agreements, and share interim and final reports. The establishment of an international public portal to host such reports would be particularly valuable for rare disease treatments., (© 2021. The Author(s).)

Performance-based managed entry agreements (PB-MEAs) might allow patient access to new medicines, but practical hurdles make competent authorities for pricing and reimbursement (CAPR) reluctant to implement PB-MEAs. We explored if the feasibility of PB-MEAs might improve by better aligning regulatory postauthorization requirements with the data generation of PB-MEAs and by active collaboration and data sharing. Reviewers from seven CAPRs provided structured assessments of the information available at the European Medicines Agency (EMA) Web site on regulatory postauthorization requirements for fifteen recently authorized products. The reviewers judged to what extent regulatory postauthorization studies could help implement PB-MEAs by addressing uncertainty gaps. Study domains assessed were: patient population, intervention, comparators, outcomes, time horizon, anticipated data quality, and anticipated robustness of analysis. Reviewers shared general comments about PB-MEAs for each product and on cooperation with other CAPRs. Reviewers rated regulatory postauthorization requirements at least partly helpful for most products and across domains except the comparator domain. One quarter of responses indicated that public information provided by the EMA was insufficient to support the implementation of PB-MEAs. Few PB-MEAs were in place for these products, but the potential for implementation of PB-MEAs or collaboration across CAPRs was seen as more favorable. Responses helped delineate a set of conditions where PB-MEAs may help reduce uncertainty. In conclusion, PB-MEAs are not a preferred option for CAPRs, but we identified conditions where PB-MEAs might be worth considering. The complexities of implementing PB-MEAs remain a hurdle, but collaboration across silos and more transparency on postauthorization studies could help overcome some barriers.

In young adults, individual differences in working memory (WM) contribute to reinforcement learning (RL). Age-related RL changes, however, are mostly attributed to decreased reward prediction-error (RPE) signaling. Here, we investigated the contribution of WM to RL in young (18-35) and older (≥65) adults. Because WM supports maintenance across a limited timescale, we only expected a relation between RL and WM with short delays between stimulus repetitions. Our results demonstrated better learning with short than long delays. A week later, however, long-delay associations were remembered better. Computational modeling corroborated that during learning, WM was more engaged by young adults in the short-delay condition than in any other age-condition combination. Crucially, both model-derived and neuropsychological assessments of WM predicted short-delay learning in older adults, who further benefitted from using self-conceived learning strategies. Thus, depending on the timescale of learning, age-related RL changes may not only reflect decreased RPE signaling but also WM decline.

Reinforcement learning (RL) in humans is subserved by a network of striatal and frontal brain areas. The electrophysiological signatures of feedback evaluation are increasingly well understood, but how those signatures relate to the use of feedback to guide subsequent behavioral adjustment remains unclear. One mechanism for post-feedback behavioral optimization is the modulation of sensory processing. We used source-reconstructed MEG to test whether feedback affects the interactions between sources of oscillatory activity in the learning network and task-relevant stimulus-processing areas. Participants performed a probabilistic RL task in which they learned associations between colored faces and response buttons using trial-and-error feedback. Delta-band (2-4 Hz) and theta-band (4-8 Hz) power in multiple frontal regions were sensitive to feedback valence. Low and high beta-band power (12-20 and 20-30 Hz) in occipital, parietal, and temporal regions differentiated between color and face information. Consistent with our hypothesis, single-trial power-power correlations between frontal and posterior-sensory areas were modulated by the interaction between feedback valence and the relevant stimulus characteristic (color versus identity). These results suggest that long-range oscillatory coupling supports post-feedback updating of stimulus processing., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The mere perception of high-calorie food items can trigger strong action tendencies towards these foods. Go/no-go training has successfully been applied to reduce such action tendencies. This study investigated the electrophysiological mechanisms that may underlie the beneficial effects of go/no-go training on food consumption. EEG was measured while 19 participants passively observed pictures of food and non-food items, both before and after the go/no-go training. During training, 50% of the food and non-food items were consistently paired with a go/no-go response. After training, food items that had been associated with a response induced larger mu desynchronization at electrodes over sensorimotor regions, whereas food items that had been associated with withholding from responding induced larger increases in theta power at frontal midline electrodes. These findings suggest that the exerted cognitive control during go/no-go training with attractive food stimuli may become associated with these stimuli and signal the required level of control during subsequent encounters., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Reinforcement learning (RL) is supported by a network of striatal and frontal cortical structures that are connected through white-matter fiber bundles. With age, the integrity of these white-matter connections declines. The role of structural frontostriatal connectivity in individual and age-related differences in RL is unclear, although local white-matter density and diffusivity have been linked to individual differences in RL. Here we show that frontostriatal tract counts in young human adults (aged 18-28), as assessed noninvasively with diffusion-weighted magnetic resonance imaging and probabilistic tractography, positively predicted individual differences in RL when learning was difficult (70% valid feedback). In older adults (aged 63-87), in contrast, learning under both easy (90% valid feedback) and difficult conditions was predicted by tract counts in the same frontostriatal network. Furthermore, network-level analyses showed a double dissociation between the task-relevant networks in young and older adults, suggesting that older adults relied on different frontostriatal networks than young adults to obtain the same task performance. These results highlight the importance of successful information integration across striatal and frontal regions during RL, especially with variable outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Feedback-based learning declines with age. Because older adults are generally biased toward positive information ("positivity effect"), learning from positive feedback may be less impaired than learning from negative outcomes. The literature documents mixed results, due possibly to variability between studies in task design. In the current series of studies, we investigated the influence of feedback valence on reinforcement learning in young and older adults. We used nonprobabilistic learning tasks, to more systematically study the effects of feedback magnitude, learning of stimulus-response (S-R) versus stimulus-outcome (S-O) associations, and working-memory capacity. In most experiments, older adults benefitted more from positive than negative feedback, but only with large feedback magnitudes. Positivity effects were pronounced for S-O learning, whereas S-R learning correlated with working-memory capacity in both age groups. These results underline the context dependence of positivity effects in learning and suggest that older adults focus on high gains when these are informative for behavior.

Aging induces a decline in the ties that bind anatomical networks centered on the prefrontal cortex, which are critical for reinforcement learning and decision making. At the neurophysiological level, the prefrontal cortex may engage electrophysiological oscillatory synchronization to coordinate other brain systems during learning. We recorded scalp EEG from 21 older (mean age 69 years) and 20 young (mean age 22 years) healthy human adults while they learned stimulus-response mappings by trial-and-error using feedback. In young adults, theta-band (4-8 Hz) oscillatory power over medial frontal and anterior frontal cortex predicted learning after errors. Older adults demonstrated a decrease in the theta-band learning-predictive signals over medial frontal but not anterior frontal cortex. This age-related decrease in task-relevant medial frontal theta power may be related to the more general decrease in medial frontal theta power that we observed during rest. These results demonstrate a shift in cortical networks that support reinforcement learning in older adults, and shed new light on the changes in neurophysiological (oscillatory) mechanisms with neurocognitive aging., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Why are some individuals more susceptible to the formation of inflexible habits than others? In the present study, we used diffusion tensor imaging to demonstrate that brain connectivity predicts individual differences in relative goal-directed and habitual behavioral control in humans. Specifically, vulnerability to habitual "slips of action" toward no-longer-rewarding outcomes was predicted by estimated white matter tract strength in the premotor cortex seeded from the posterior putamen (as well as by gray matter density in the posterior putamen as determined with voxel-based morphometry). In contrast, flexible goal-directed action was predicted by estimated tract strength in the ventromedial prefrontal cortex seeded from the caudate. These findings suggest that integrity of dissociable corticostriatal pathways underlies individual differences in action control in the healthy population, which may ultimately mediate vulnerability to impulse control disorders.

Increasing age is associated with subtle but meaningful changes in decision-making. It is unknown, however, to what degree these psychological changes are reflective of age-related changes in decision quality. Here, we investigated the effect of age on latent cognitive processes associated with risky decision-making on the Balloon Analog Risk Task (BART). In the BART, participants repetitively inflate a balloon in order to increase potential reward. At any point, participants can decide to cash-out to harvest the reward, or they can continue, risking a balloon pop that erases all earnings. We found that among seniors, increasing age was associated with greater reward-related risk taking when the balloon has a higher probability of popping (i.e., a "high risk" condition). Cognitive modeling results from hierarchical Bayesian estimation suggested that performance differences were due to increased reward sensitivity in high risk conditions in seniors.

Reward-based decision-learning refers to the process of learning to select those actions that lead to rewards while avoiding actions that lead to punishments. This process, known to rely on dopaminergic activity in striatal brain regions, is compromised in Parkinson's disease (PD). We hypothesized that such decision-learning deficits are alleviated by induced positive affect, which is thought to incur transient boosts in midbrain and striatal dopaminergic activity. Computational measures of probabilistic reward-based decision-learning were determined for 51 patients diagnosed with PD. Previous work has shown these measures to rely on the nucleus caudatus (outcome evaluation during the early phases of learning) and the putamen (reward prediction during later phases of learning). We observed that induced positive affect facilitated learning, through its effects on reward prediction rather than outcome evaluation. Viewing a few minutes of comedy clips served to remedy dopamine-related problems associated with frontostriatal circuitry and, consequently, learning to predict which actions will yield reward.

Frontal oscillatory dynamics in the theta (4-8 Hz) and beta (20-30 Hz) frequency bands have been implicated in cognitive control processes. Here we investigated the changes in coordinated activity within and between frontal brain areas during feedback-based response learning. In a time estimation task, participants learned to press a button after specific, randomly selected time intervals (300-2000 msec) using the feedback after each button press (correct, too fast, too slow). Consistent with previous findings, theta-band activity over medial frontal scalp sites (presumably reflecting medial frontal cortex activity) was stronger after negative feedback, whereas beta-band activity was stronger after positive feedback. Theta-band power predicted learning only after negative feedback, and beta-band power predicted learning after positive and negative feedback. Furthermore, negative feedback increased theta-band intersite phase synchrony (a millisecond resolution measure of functional connectivity) among right lateral prefrontal, medial frontal, and sensorimotor sites. These results demonstrate the importance of frontal theta- and beta-band oscillations and intersite communication in the realization of reinforcement learning.

Ninety-six couples, consulting for primary (n = 73) or secondary (n = 23) infertility, and thought to be infertile due to a varicocele in the husband associated with sperm abnormalities, were subjected to a follow-up study. Of these, 57 were surgically corrected and 39 were not, depending only on the patient's choice. All women were intensively treated where necessary. All patients who were corrected were subjected to scrotal exploration in a search for epididymal anomalies. From our data we conclude that (1) on a statistical basis, comparing observed with expected pregnancy rates, varicocelectomy is useful in primary infertility and unnecessary in secondary infertility and (2) on an individual basis, patients with primary infertility and 'pure' varicoceles have a better prognosis than patients with concomitant epididymal dysfunction.