The effects of an 8-week mindful eating intervention on anticipatory reward responses in striatum and midbrain.

Introduction: Accumulating evidence suggests that increased neural responses during the anticipation of high-calorie food play an important role in the tendency to overeat. A promising method for counteracting enhanced food anticipation in overeating might be mindfulness-based interventions (MBIs). However, the neural mechanisms by which MBIs can affect food reward anticipation are unclear. In this randomized, actively controlled study, the primary objective was to investigate the effect of an 8-week mindful eating intervention on reward anticipation. We hypothesized that mindful eating would decrease striatal reward anticipation responses. Additionally, responses in the midbrain-from which the reward pathways originate-were explored. Methods: Using functional magnetic resonance imaging (fMRI), we tested 58 healthy participants with a wide body mass index range (BMI: 19-35 kg/m2), motivated to change their eating behavior. During scanning they performed an incentive delay task, measuring neural reward anticipation responses to caloric and monetary cues before and after 8 weeks of mindful eating or educational cooking (active control). Results: Compared with the educational cooking intervention, mindful eating affected neural reward anticipation responses, with reduced caloric relative to monetary reward responses. This effect was, however, not seen in the striatum, but only in the midbrain. The secondary objective was to assess temporary and long-lasting (1 year follow-up) intervention effects on self-reported eating behavior and anthropometric measures [BMI, waist circumference, waist-to-hip-ratio (WHR)]. We did not observe effects of the mindful eating intervention on eating behavior. Instead, the control intervention showed temporary beneficial effects on BMI, waist circumference, and diet quality, but not on WHR or self-reported eating behavior, as well as long-lasting increases in knowledge about healthy eating. Discussion: These results suggest that an 8-week mindful eating intervention may have decreased the relative salience of food cues by affecting midbrain but not striatal reward responses, without necessarily affecting regular eating behavior. However, these exploratory results should be verified in confirmatory research.The primary and secondary objectives of the study were registered in the Dutch Trial Register (NTR): NL4923 (NTR5025).

Cognitive Control and Weight Loss After Bariatric Surgery: the BARICO Study.

BACKGROUND AND OBJECTIVES: Bariatric surgery (BS) is an effective treatment for obesity. However, some individuals experience insufficient weight loss after surgery. Therefore, we investigated whether cognitive control affects weight loss after Roux-en-Y gastric bypass (RYGB). METHODS: Within this exploratory observational study, part of the BARICO study (BAriatric surgery Rijnstate and Radboudumc neuroImaging and Cognition in Obesity), participants aged between 35 and 55 years eligible for RYGB were included. Before and after BS, body weight, (delta) BMI and percentage total body weight loss (%TBWL) were determined. Additionally, at baseline, Stroop task-performance, -activation and -connectivity were assessed by a color-word paradigm task during functional neuroimaging to determine the ability of participants to inhibit cognitive interference. RESULTS: Seventy-six participants were included, of whom 14 were excluded from fMRI analysis, leaving 62 participants. Participants were aged 45.0 ± 5.9 years with a mean pre-surgery BMI of 40.2 ± 3.3 kg/m2, and 86% were women. Mean decrease in BMI was 13.8 ± 2.5 kg/m2, and mean %TBWL was 34.9 ± 6.3% 1 year after BS. Stroop task performance did not correlate with (delta) BMI and %TBWL. The inferior parietal/middle occipital gyrus, inferior frontal gyrus, and supplementary motor cortex were involved in cognitive interference, although activity in these regions did not predict weight loss after surgery. Lastly, generalized psychophysiological interaction did not provide evidence for (delta) BMI- and %TBWL-dependent connectivity modulation. DISCUSSION: Cognitive control did not predict weight loss after surgery. Future studies should focus on longer follow-up periods to understand the relation between cognitive control and weight loss. TRIAL REGISTRATION: NL7090 ( https://www.clinicaltrialregister.nl/nl/trial/28949 ).

A systematic review exploring the association between the human gut microbiota and brain connectivity in health and disease.

A body of pre-clinical evidence shows how the gut microbiota influence brain functioning, including brain connectivity. Linking measures of brain connectivity to the gut microbiota can provide important mechanistic insights into the bi-directional gut-brain communication. In this systematic review, we therefore synthesized the available literature assessing this association, evaluating the degree of consistency in microbiota-connectivity associations. Following the PRISMA guidelines, a PubMed search was conducted, including studies published up to September 1, 2022. We identified 16 studies that met the inclusion criteria. Several bacterial genera, including Prevotella, Bacteroides, Ruminococcus, Blautia, and Collinsella were most frequently reported in association with brain connectivity. Additionally, connectivity of the salience (specifically the insula and anterior cingulate cortex), default mode, and frontoparietal networks were most frequently associated with the gut microbiota, both in terms of microbial diversity and composition. There was no discernible pattern in the association between microbiota and brain connectivity. Altogether, based on our synthesis, there is evidence for an association between the gut microbiota and brain connectivity. However, many findings were poorly replicated across studies, and the specificity of the association is yet unclear. The current studies show substantial inter-study heterogeneity in methodology and reporting, limiting the robustness and reproducibility of the findings and emphasizing the need to harmonize methodological approaches. To enhance comparability and replicability, future research should focus on further standardizing processing pipelines and employing data-driven multivariate analysis strategies.

Development of Spatial Orientation in Two-to-Three-Year-Old Children in Relation to Lifestyle Factors.

Various lifestyle factors, including diet, physical activity, and sleep, have been studied in the context of children's health. However, how these lifestyle factors contribute to the development of cognitive abilities, including spatial cognition, remains vastly understudied. One landmark in spatial cognitive development occurs between 2.5 and 3 years of age. For spatial orientation at that age, children learn to use allocentric reference frames (using spatial relations between objects as the primary reference frame) in addition to, the already acquired, egocentric reference frames (using one's own body as the primary reference frame). In the current virtual reality study in a sample of 30-36-month-old toddlers (N = 57), we first demonstrated a marginally significant developmental shift in spatial orientation. Specifically, task performance with allocentric performance increased relative to egocentric performance (ηp2 = 0.06). Next, we explored a variety of lifestyle factors, including diet, in relation to task performance, to explain individual differences. Screen time and gestational weight gain of the mother were negatively associated with spatial task performance. The findings presented here can be used to guide future confirmatory studies about the role of lifestyle factors in the development of spatial cognition.

Correction: Protocol of the Healthy Brain Study: An accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context.

[This corrects the article DOI: 10.1371/journal.pone.0260952.].

Protocol of the Healthy Brain Study: An accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context.

The endeavor to understand the human brain has seen more progress in the last few decades than in the previous two millennia. Still, our understanding of how the human brain relates to behavior in the real world and how this link is modulated by biological, social, and environmental factors is limited. To address this, we designed the Healthy Brain Study (HBS), an interdisciplinary, longitudinal, cohort study based on multidimensional, dynamic assessments in both the laboratory and the real world. Here, we describe the rationale and design of the currently ongoing HBS. The HBS is examining a population-based sample of 1,000 healthy participants (age 30-39) who are thoroughly studied across an entire year. Data are collected through cognitive, affective, behavioral, and physiological testing, neuroimaging, bio-sampling, questionnaires, ecological momentary assessment, and real-world assessments using wearable devices. These data will become an accessible resource for the scientific community enabling the next step in understanding the human brain and how it dynamically and individually operates in its bio-social context. An access procedure to the collected data and bio-samples is in place and published on https://www.healthybrainstudy.nl/en/data-and-methods/access. Trail registration: https://www.trialregister.nl/trial/7955.

Correlation between brain function and ADHD symptom changes in children with ADHD following a few-foods diet: an open-label intervention trial.

Research into the effect of nutrition on attention-deficit hyperactivity disorder (ADHD) in children has shown that the few-foods diet (FFD) substantially decreases ADHD symptoms in 60% of children. However, the underlying mechanism is unknown. In this open-label nutritional intervention study we investigated whether behavioural changes after following an FFD are associated with changes in brain function during inhibitory control in 79 boys with ADHD, aged 8-10 years. Parents completed the ADHD Rating Scale before (t1) and after the FFD (t2). Functional magnetic resonance imaging (fMRI) scans were acquired during a stop-signal task at t1 and t2, and initial subject-level analyses were done blinded for ARS scores. Fifty (63%) participants were diet responders, showing a decrease of ADHD symptoms of at least 40%. Fifty-three children had fMRI scans of sufficient quality for further analysis. Region-of-interest analyses demonstrated that brain activation in regions implicated in the stop-signal task was not associated with ADHD symptom change. However, whole-brain analyses revealed a correlation between ADHD symptom decrease and increased precuneus activation (pFWE(cluster) = 0.015 for StopSuccess > Go trials and pFWE(cluster) < 0.001 for StopSuccess > StopFail trials). These results provide evidence for a neurocognitive mechanism underlying the efficacy of a few-foods diet in children with ADHD.

Sex Differences and the Role of Gaming Experience in Spatial Cognition Performance in Primary School Children: An Exploratory Study.

Sex differences are repeatedly observed in spatial cognition tasks. However, the role of environmental factors such as gaming experience remains unclear. In this exploratory study, navigation and object-relocation were combined in a naturalistic virtual reality-based spatial task. The sample consisted of n = 53 Dutch children aged 9-11 years. Overall, girls (n = 24) and boys (n = 29) performed equally accurately, although there was an increase in accuracy with age for boys (ηp2 = 0.09). Boys navigated faster than girls (ηp2 = 0.29), and this difference increased with age (ηp2 = 0.07). More gaming experience in boys versus girls (Cohen's d = 0.88) did not explain any result observed. We encourage future confirmatory studies to use the paradigm presented here to investigate the current results in a larger sample. These findings could be beneficial for optimizing spatial cognition training interventions.

Correction: Szopinska-Tokov et al. Investigating the Gut Microbiota Composition of Individuals with Attention-Deficit/Hyperactivity Disorder and Association with Symptoms. Microorganisms 2020, 8, 406.

The authors wish to make the following correction to this paper [...].

Probiotics-induced changes in gut microbial composition and its effects on cognitive performance after stress: exploratory analyses.

Stress negatively affects cognitive performance. Probiotics remediate somatic and behavioral stress responses, hypothetically by acting on the gut microbiota. Here, in exploratory analyses, we assessed gut microbial alterations after 28-days supplementation of multi-strain probiotics (EcologicBarrier consisting of Lactobacilli, Lactococci, and Bifidobacteria in healthy, female subjects (probiotics group n = 27, placebo group n = 29). In an identical pre-session and post-session, subjects performed a working memory task before and after an acute stress intervention. Global gut microbial beta diversity changed over time, but we were not able to detect differences between intervention groups. At the taxonomic level, Time by Intervention interactions were not significant after multiple comparison correction; the relative abundance of eight genera in the probiotics group was higher (uncorrected) relative to the placebo group: Butyricimonas, Parabacteroides, Alistipes, Christensenellaceae_R-7_group, Family_XIII_AD3011_group, Ruminococcaceae_UCG-003, Ruminococcaceae_UCG-005, and Ruminococcaceae_UCG-010. In a second analysis step, association analyses were done only within this selection of microbial genera, revealing the probiotics-induced change in genus Ruminococcaceae_UCG-003 was significantly associated with probiotics' effect on stress-induced working memory changes (rspearman(27) = 0.565; pFDR = 0.014) in the probiotics group only and independent of potential confounders (i.e., age, BMI, and baseline dietary fiber intake). That is subjects with a higher increase in Ruminococcaceae_UCG-003 abundance after probiotics were also more protected from negative effects of stress on working memory after probiotic supplementation. The bacterial taxa showing an increase in relative abundance in the probiotics group are plant fiber degrading bacteria and produce short-chain fatty acids that are known for their beneficial effect on gut and brain health, e.g., maintaining intestinal-barrier and blood-brain-barrier integrity. This study shows that gut microbial alterations, modulated through probiotics use, are related to improved cognitive performance in acute stress circumstances.

Distraction decreases rIFG-putamen connectivity during goal-directed effort for food rewards.

Distracted eating can lead to increased food intake, but it is unclear how. We aimed to assess how distraction affects motivated, goal-directed responses for food reward after satiation. Thirty-eight healthy normal-weight participants (28F; 10M) performed a visual detection task varying in attentional load (high vs. low distraction) during fMRI. Simultaneously, they exerted effort for sweet and savory food rewards by repeated button presses. Two fMRI runs were separated by sensory-specific satiation (outcome devaluation) of one of the (sweet or savory) reward outcomes, to assess outcome-sensitive, goal-directed, responses (valued vs. devalued reward, post vs. pre satiation). We could not verify our primary hypothesis that more distraction leads to less activation in ventromedial prefrontal cortex (vmPFC) during goal-directed effort. Behaviorally, distraction also did not affect effort for food reward following satiation across subjects. For our secondary hypothesis, we assessed whether distraction affected other fronto-striatal regions during goal-directed effort. We did not obtain such effects at our whole-brain corrected threshold, but at an exploratory uncorrected threshold (p < 0.001), distraction decreased goal-directed responses (devalued vs. valued) in the right inferior frontal gyrus (rIFG). We continued with this rIFG region for the next secondary hypothesis; specifically, that distraction would reduce functional connectivity with the fronto-striatal regions found in the previous analyses. Indeed, distraction decreased functional connectivity between the rIFG and left putamen for valued versus devalued food rewards (pFWE(cluster) < 0.05). In an exploratory brain-behavior analysis, we showed that distraction-sensitive rIFG-responses correlated negatively (r = - 0.40; p = 0.014) with the effect of distraction on effort. Specifically, decreased distraction-related rIFG-responses were associated with increased effort for food reward after satiation. We discuss the absence of distraction effects on goal-directed responses in vmPFC and in behavior across participants. Moreover, based on our significant functional connectivity and brain-behavior results, we suggest that distraction might attenuate the ability to inhibit responses for food reward after satiation by affecting the rIFG and its connection to the putamen.

The cognitive effects of a promised bonus do not depend on dopamine synthesis capacity.

Reward motivation is known to enhance cognitive control. However, detrimental effects have also been observed, which have been attributed to overdosing of already high baseline dopamine levels by further dopamine increases elicited by reward cues. Aarts et al. (2014) indeed demonstrated, in 14 individuals, that reward effects depended on striatal dopamine synthesis capacity, measured with [18F]FMT-PET: promised reward improved Stroop control in low-dopamine individuals, while impairing it in high-dopamine individuals. Here, we aimed to assess this same effect in 44 new participants, who had previously undergone an [18F]DOPA-PET scan to quantify dopamine synthesis capacity. This sample performed the exact same rewarded Stroop paradigm as in the prior study. However, we did not find any correlation between reward effects on cognitive control and striatal dopamine synthesis capacity. Critical differences between the radiotracers [18F]DOPA and [18F]FMT are discussed, as the discrepancy between the current and our previous findings might reflect the use of the potentially less sensitive [18F]DOPA radiotracer in the current study.

What Should I Eat and Why? The Environmental, Genetic, and Behavioral Determinants of Food Choice: Summary from a Pennington Scientific Symposium.

This review details the proceedings of a Pennington Biomedical scientific symposium titled, "What Should I Eat and Why? The Environmental, Genetic, and Behavioral Determinants of Food Choice." The symposium was designed to review the literature about energy homeostasis, particularly related to food choice and feeding behaviors, from psychology to physiology. This review discusses the intrinsic determinants of food choice, including biological mechanisms (genetics), peripheral and central signals, brain correlates, and the potential role of the microbiome. This review also address the extrinsic determinants (environment) of food choice within our physical and social environments. Finally, this review reports the current treatment practices for the clinical management of eating-induced overweight and obesity. An improved understanding of these determinants will inform best practices for the clinical treatment and prevention of obesity. Strategies paired with systemic shifts in our public health policies and changes in our "obesogenic" environment will be most effective at attenuating the obesity epidemic.

Investigating the Gut Microbiota Composition of Individuals with Attention-Deficit/Hyperactivity Disorder and Association with Symptoms.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Given the growing evidence of gut microbiota being involved in psychiatric (including neurodevelopmental) disorders, we aimed to identify differences in gut microbiota composition between participants with ADHD and controls and to investigate the role of the microbiota in inattention and hyperactivity/impulsivity. Fecal samples were collected from 107 participants (NADHD = 42; Ncontrols = 50; NsubthreholdADHD = 15; range age: 13-29 years). The relative quantification of bacterial taxa was done using 16S ribosomal RNA gene amplicon sequencing. Beta-diversity revealed significant differences in bacterial composition between participants with ADHD and healthy controls, which was also significant for inattention, but showing a trend in case of hyperactivity/impulsivity only. Ten genera showed nominal differences (p < 0.05) between both groups, of which seven genera were tested for their association with ADHD symptom scores (adjusting for age, sex, body mass index, time delay between feces collection and symptoms assessment, medication use, and family relatedness). Our results show that variation of a genus from the Ruminococcaceae family (Ruminococcaceae_UCG_004) is associated (after multiple testing correction) with inattention symptoms and support the potential role of gut microbiota in ADHD pathophysiology.

Effects of distraction on taste-related neural processing: a cross-sectional fMRI study.

BACKGROUND: In the current obesogenic environment we often eat while electronic devices, such as smart phones, computers, or the television, distract us. Such "distracted eating" is associated with increased food intake and overweight. However, the underlying neurocognitive mechanisms of this phenomenon are unknown. OBJECTIVE: Our aim was to elucidate these mechanisms by investigating whether distraction attenuates processing in the primary and secondary taste cortices, located in the insula and orbitofrontal cortex (OFC), respectively. METHODS: Forty-one healthy, normal-weight participants received fixed amounts of higher- and lower-sweetness isocaloric chocolate milk while performing a high- or low-distracting detection task during fMRI in 2 test sessions. Subsequently, we measured ad libitum food intake. RESULTS: As expected, a primary taste cortex region in the right insula responded more to the sweeter drink (P < 0.001, uncorrected). Distraction did not affect this insular sweetness response across the group, but did weaken sweetness-related connectivity of this region to a secondary taste region in the right OFC (P-family-wise error, cluster, small-volume corrected = 0.020). Moreover, individual differences in distraction-related attenuation of taste activation in the insula predicted increased subsequent ad libitum food intake after distraction (r = 0.36). CONCLUSIONS: These results reveal a mechanism explaining how distraction during consumption attenuates neural taste processing. Moreover, our study shows that such distraction-induced decreases in neural taste processing contribute to individual differences in the susceptibility for overeating. Thus, being mindful about the taste of food during consumption could perhaps be part of successful prevention and treatment of overweight and obesity, which should be further tested in these target groups. This study was preregistered at the Open Science Framework as https://bit.ly/31RtDHZ.

Catecholaminergic modulation of the cost of cognitive control in healthy older adults.

Catecholamines have long been associated with cognitive control and value-based decision-making. More recently, we have shown that catecholamines also modulate value-based decision-making about whether or not to engage in cognitive control. Yet it is unclear whether catecholamines influence these decisions by altering the subjective value of control. Thus, we tested whether tyrosine, a catecholamine precursor altered the subjective value of performing a demanding working memory task among healthy older adults (60-75 years). Contrary to our prediction, tyrosine administration did not significantly increase the subjective value of conducting an N-back task for reward, as a main effect. Instead, in line with our previous study, exploratory analyses indicated that drug effects varied as a function of participants' trait impulsivity scores. Specifically, tyrosine increased the subjective value of conducting an N-back task in low impulsive participants, while reducing its value in more impulsive participants. One implication of these findings is that the over-the-counter tyrosine supplements may be accompanied by an undermining effect on the motivation to perform demanding cognitive tasks, at least in certain older adults. Taken together, these findings indicate that catecholamines can alter cognitive control by modulating motivation (rather than just the ability) to exert cognitive control.

Biomarker Research in ADHD: the Impact of Nutrition (BRAIN) - study protocol of an open-label trial to investigate the mechanisms underlying the effects of a few-foods diet on ADHD symptoms in children.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is the most common childhood behavioural disorder, causing significant impediment to a child's development. It is a complex disorder with numerous contributing (epi)genetic and environmental factors. Currently, treatment consists of behavioural and pharmacological therapy. However, ADHD medication is associated with several side effects, and concerns about long-term effects and efficacy exist. Therefore, there is considerable interest in the development of alternative treatment options. Double-blind research investigating the effects of a few-foods diet (FFD) has demonstrated a significant decrease in ADHD symptoms following an FFD. However, an FFD requires a considerable effort of both child and parents, limiting its applicability as a general ADHD treatment. To make FFD intervention less challenging or potentially obsolete, we need to understand how, and in which children, an FFD affects ADHD behaviour and, consequently, the child's well-being. We hypothesise that an FFD affects brain function, and that the nutritional impact on ADHD is effectuated by a complex interplay between the microbiota, gut and brain, that is, the microbiota-gut-brain axis. METHODS AND ANALYSIS: The Biomarker Research in ADHD: the Impact of Nutrition (BRAIN) study is an open-label trial with researchers blinded to changes in ADHD symptoms during sample processing and initial data analyses. ETHICS AND DISSEMINATION: The Medical Research and Ethics Committee of Wageningen University has approved this study (NL63851.081.17, application 17/24). Results will be disseminated through peer-reviewed journal publications, conference presentations, (social) media and the BRAIN study website. A summary of the findings will be provided to the participants. TRIAL REGISTRATION NUMBER: NCT03440346. STUDY DATES: Collection of primary outcome data started in March 2018 and will be ongoing until 100 children have participated in the study. Sample data analysis will start after all samples have been collected.

Dopamine and the motivation of cognitive control.

The major ascending neuromodulator dopamine has long been implicated in cognitive control. Effects of dopamine-related disorders and the treatment of the cognitive control deficits associated with these disorders are commonly attributed to modulation of the prefrontal cortex. However, many disorders that are accompanied by cognitive control deficits also implicate abnormal dopamine transmission in the striatum, which has been associated more readily with value-based learning, choice, and motivation. We put forward the hypothesis that effects of dopamine on cognitive control reflect, in part, indirect modulation of value-based learning and choice computations that alter the motivation to exert control. This hypothesis is grounded in accumulating evidence from work with experimental animals as well as neurochemical PET, pharmacologic fMRI, and computational modeling work with healthy volunteers and patients with addictive disorders, ADHD, and Parkinson's disease. Consistent with an "inverted-U"-shaped relationship between dopamine and value-based learning, this evidence suggests that dopaminergic drugs might paradoxically increase our drive away from cognitive control in individuals with high baseline levels of dopamine, perhaps by "overdosing" dopamine levels, and thus reducing the value of cognitive control. The hypothesis has implications for the many dopamine-related disorders, which are often accompanied by either apathy or problems with impulse control, and their pharmacotreatment with dopaminergic drugs. For example, the cognitive deficits that are commonly associated with prefrontal cortex dysfunctioning might instead reflect modulation of striatal dopamine and its role in the willingness rather than the ability to exert control.

Publisher Correction: Enhanced food-related responses in the ventral medial prefrontal cortex in narcolepsy type 1.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Study rationale and protocol of the BARICO study: a longitudinal, prospective, observational study to evaluate the effects of weight loss on brain function and structure after bariatric surgery.

INTRODUCTION: Weight loss after bariatric surgery (BS) is often associated with improved cognition and structural brain recovery. However, improved cognition after BS is not always exhibited by patients, in fact, in some cases there is even a decline in cognition. Long-term consequences of BS weight loss, in terms of obesity and related diseases, can be hard to determine due to studies having short follow-up periods and small sample sizes.The aim of the BARICO study (BAriatric surgery Rijnstate and Radboudumc neuroImaging and Cognition in Obesity) is to determine the long-term effect of weight loss after BS on brain function and structure, using sensitive neuropsychological tests and (functional) MRI ((f)MRI). Secondary study endpoints are associated with changes in metabolic and inflammation status of adipose tissue, liver and gut, in relation to brain structure and function. Also, the possible correlation between weight loss, gut microbiota composition change and neuropsychological outcomes will be investigated. METHODS AND ANALYSIS: Data from 150 Dutch BS patients (ages between 35 and 55, men and women) will be collected at various time points between 2 months before and up to 10 years after surgery. Neuropsychological tests, questionnaires, blood, faeces and tissue samples will be collected before, during and after surgery to measure changes in cognition, microbiota, metabolic activity and inflammation over time. A subgroup of 75 participants will undergo (f)MRI in relation to executive functioning (determined by the Stroop task), grey and white matter volumes and cerebral blood flow. Regression analyses will be used to explore associations between weight loss and outcome measures. ETHICS AND DISSEMINATION: This study has been approved by the medical review ethics committee CMO Region Arnhem and Nijmegen (NL63493.091.17). Research findings will be published in peer-reviewed journals and at conferences. TRIAL REGISTRATION NUMBER: NTR7288.