Ruben van Den Bosch

Obesity is associated with low-grade inflammation, which – our prior work shows – causally and reversibly increases effort aversion and related brain responses during food-related decision-making. However, how these laboratory findings translate to daily-life (food) motivation remains unclear. This study investigated low-grade inflammation in more ecologically valid measures of (food-related) motivation in obesity. We conducted a cross-sectional study (N=145 women, BMI>27 kg/m2, 18-59 yrs) and a 12-week randomized controlled trial (N=57 women, BMI>30 kg/m2, 18-59 years, C-reactive protein (CPR)>3 mg/l) testing the anti-inflammatory drug colchicine versus placebo. We measured effort-related food intake using a bogus taste test, daily-life motivation using ecological momentary assessment (EMA), and dietary intake using a food frequency questionnaire (FFǪ). INFLA-score (CRP, white blood cell count, neutrophil-to-lymphocyte ratio, platelets) related to lower intake of high-effort food items on the taste test (β –0.26 SD, p=0.011), lower engagement in high-effort activities (OR 0.72, p<0.001), and negatively moderated the association between anticipation and activity completion in EMA (OR 0.89, p=0.032). On the FFǪ, INFLA-score related to lower intake of legumes and fruits and more intake of processed meat (all p<0.05). Colchicine decreased overall caloric intake (β –341 kcal, p=0.018). A decrease in inflammation related to healthier dietary choices (Spearman ρ=0.37, p=0.013). Colchicine did not affect effort-related food intake on the taste test or EMA. These findings indicate that that obesity-related inflammation is associated with increased effort-related food intake and motivation in daily life, and that reducing inflammation decreases (unhealthy) food intake. Such effects may partly underlie the challenges of achieving and maintaining weight loss.

The psychostimulant methylphenidate may exert its effects on cognition and associated brain signals via action on the dopamine or noradrenaline transporter (DAT/NET). A recently developed and increasingly popular dual-regression approach (REACT; Dipasquale et al. (2019)) hones in on the molecular mechanisms underlying (drug-induced) changes in fMRI signal by enriching the analysis with information about the spatial distribution of molecular targets of interest. This method has great potential, but hitherto lacked validation of its molecular specificity and functional relevance. Here, we leverage a unique pharmaco-fMRI dataset with established dopamine-dependent methylphenidate effects on neural reward prediction error signaling, one of the key functional signatures of dopamine. Using REACT we found that methylphenidate significantly modulated both DAT and NET-related functional connectivity networks, but only the effect on the DAT network varied with interindividual differences in striatal dopamine synthesis capacity, as measured with [18F]FDOPA PET imaging. Furthermore, methylphenidate affected DAT-related connectivity in the prefrontal cortex in the same location where it affected neural reward prediction error signaling. Together, these findings firmly establish the validity of REACT as a tool for isolating the role of dopamine from that of noradrenaline in methylphenidate’s effects on brain function.

Inflammation relates to decreased effortful behaviour and altered effort-related responses in brain regions, such as the dorsomedial prefrontal cortex (dmPFC). Inflammation is prevalent in obesity, but its effects on effortful versus more convenient food choices are unknown. We investigated the role of low-grade inflammation in effortful food choice using functional MRI in a cross-sectional study (n=150 women, BMI>27 kg/m ² ) and a 12-week randomized controlled trial (n=59 women, BMI>30 kg/m ² , CRP>3 mg/L; colchicine 0.5 mg/d vs. placebo). Inflammation was related to less high-effort choices (OR=0.27, p=0.004) and higher effort-related dmPFC signal (β=0.23, p=0.025, R _partial ² =0.039), and mediated the association between BMI and dmPFC signal. Colchicine decreased systemic inflammation (i.e. INFLA-score) as expected (β=-0.10 SD, ppartial ² =0.030), increased high-effort choices (OR=1.32, p=0.044), and marginally decreased effort-related dmPFC signal (β=-0.13, p=0.053, R _partial ² =0.037). These findings show a causal role for inflammation in choosing convenience foods in obesity via increased effort aversion and associated dmPFC processing.

The psychostimulant methylphenidate may exert its effects on cognition and associated brain signals via action on the dopamine or noradrenaline transporter (DAT/NET). A recently developed and increasingly popular dual-regression approach (REACT; Dipasquale et al. (2019)) attempts to hone in on the molecular mechanisms underlying (drug-induced) changes in fMRI signal by enriching the analysis with information about the spatial distribution of molecular targets of interest. This method has great potential, but hitherto lacked validation of its molecular specificity and functional relevance. Here we leverage a unique pharmaco-fMRI dataset with established dopamine-dependent methylphenidate effects on neural reward prediction error (RPE) signaling, the canonical functional signature of dopamine. Using REACT we found that methylphenidate significantly modulated both DAT and NET-related functional connectivity networks, but only the effect on the DAT network varied with interindividual differences in striatal dopamine synthesis capacity, as measured with [ ¹⁸ F]FDOPA PET. Furthermore, methylphenidate affected DAT-related connectivity in the prefrontal cortex in the same location where it affected neural RPE signaling. Together, these findings firmly establish the validity of REACT as a tool for isolating the role of dopamine from that of noradrenaline in methylphenidate’s effects on brain function.

Associations can be learned incrementally, via reinforcement learning (RL), or stored instantly in working memory (WM). While WM is fast, it is also capacity-limited and effortful. Striatal dopamine may promote RL plasticity, and WM, by facilitating updating and effort exertion. Yet, prior studies have failed to distinguish between dopamine's effects on RL versus WM. N = 100 participants completed a paradigm isolating these systems in a double-blind study measuring dopamine synthesis with [18F]-FDOPA imaging and manipulating dopamine with methylphenidate and sulpiride. Learning is enhanced among high synthesis capacity individuals and by methylphenidate, but impaired by sulpiride. Methylphenidate also blunts effort cost learning. Computational modeling reveals that individuals with high dopamine synthesis rely more on WM, while methylphenidate boosts their RL rates. The D2 antagonist sulpiride reduces accuracy due to diminished WM involvement and faster WM decay. We conclude that dopamine enhances both slow RL, and fast WM, by promoting plasticity and reducing effort sensitivity. These results also highlight the need to control for dopamine's effects on WM when testing its effects on RL.

Catecholamine-enhancing psychostimulants, such as methylphenidate have long been argued to undermine creative thinking. However, prior evidence for this is weak or contradictory, stemming from studies with small sample sizes that do not consider the well-established large variability in psychostimulant effects across different individuals and task demands. We aimed to definitively establish the link between psychostimulants and creative thinking by measuring effects of methylphenidate in 90 healthy participants on distinct creative tasks that measure convergent and divergent thinking, as a function of individuals’ baseline dopamine synthesis capacity, indexed with ¹⁸F-FDOPA PET imaging. In a double-blind, within-subject design, participants were administered methylphenidate, placebo or selective D2 receptor antagonist sulpiride. The results showed that striatal dopamine synthesis capacity and/or methylphenidate administration did not affect divergent and convergent thinking. However, exploratory analysis demonstrated a baseline dopamine-dependent effect of methylphenidate on a measure of response divergence, a creativity measure that measures response variability. Response divergence was reduced by methylphenidate in participants with low dopamine synthesis capacity but enhanced in those with high dopamine synthesis capacity. No evidence of any effect of sulpiride was found. These results show that methylphenidate can undermine certain forms of divergent creativity but only in individuals with low baseline dopamine levels.

Individual differences in striatal dopamine synthesis capacity have been associated with working memory capacity, trait impulsivity, and spontaneous eye-blink rate (sEBR), as measured with readily available and easily administered, ‘off-the-shelf’ tests. Such findings have raised the suggestion that individual variation in dopamine synthesis capacity, estimated with expensive and invasive brain positron emission tomography (PET) scans, can be approximated with simple, more pragmatic tests. However, direct evidence for the relationship between these simple trait measures and striatal dopamine synthesis capacity has been limited and inconclusive. We measured striatal dopamine synthesis capacity using [¹⁸F]-FDOPA PET in a large sample of healthy volunteers (N = 94) and assessed the correlation with simple, short tests of working memory capacity, trait impulsivity, and sEBR. We additionally explored the relationship with an index of subjective reward sensitivity. None of these trait measures correlated significantly with striatal dopamine synthesis capacity, nor did they have out-of-sample predictive power. Bayes factor analyses indicated the evidence was in favour of absence of correlations for all but subjective reward sensitivity. These results warrant caution for using these off-the-shelf trait measures as proxies of striatal dopamine synthesis capacity.

Psychostimulants such as methylphenidate are widely used for their cognitive enhancing effects, but there is large variability in the direction and extent of these effects. We tested the hypothesis that methylphenidate enhances or impairs reward/punishment-based reversal learning depending on baseline striatal dopamine levels and corticostriatal gating of reward/punishment-related representations in stimulus-specific sensory cortex. Young healthy adults (N = 100) were scanned with functional magnetic resonance imaging during a reward/punishment reversal learning task, after intake of methylphenidate or the selective D_2/3-receptor antagonist sulpiride. Striatal dopamine synthesis capacity was indexed with [¹⁸F]DOPA positron emission tomography. Methylphenidate improved and sulpiride decreased overall accuracy and response speed. Both drugs boosted reward versus punishment learning signals to a greater degree in participants with higher dopamine synthesis capacity. By contrast, striatal and stimulus-specific sensory surprise signals were boosted in participants with lower dopamine synthesis. These results unravel the mechanisms by which methylphenidate gates both attention and reward learning.

Individual differences in striatal dopamine synthesis capacity have been associated with working memory capacity, trait impulsivity and spontaneous eye-blink rate (sEBR), as measured with readily available and easily administered, ‘off-the-shelf’ tests. Such findings have raised the suggestion that individual variation in dopamine synthesis capacity, estimated with expensive and invasive brain positron emission tomography (PET) scans, can be approximated with simple, more pragmatic tests. However, direct evidence for the relationship between these simple trait measures and striatal dopamine synthesis capacity has been limited and inconclusive. We measured striatal dopamine synthesis capacity using [ ¹⁸ F]-FDOPA PET in a large sample of healthy volunteers (N=94) and assessed the correlation with simple, short tests of working memory capacity, trait impulsivity, and sEBR. We additionally explored the relationship with an index of subjective reward sensitivity. None of these trait measures correlated significantly with striatal dopamine synthesis capacity, nor did they have out-of-sample predictive power. Bayes Factor analyses indicated the evidence was in favour of absence of correlations for all but subjective reward sensitivity. These results warrant caution for using these off-the-shelf trait measures as proxies of striatal dopamine synthesis capacity.

Psychostimulants such as methylphenidate are widely used for their cognitive enhancing effects, but there is large variability in the direction and extent of these effects, and there are concerns about the potential for abuse. We tested the hypothesis that methylphenidate enhances or impairs reward/punishment-based reversal learning depending on baseline striatal dopamine levels and corticostriatal gating of reward/punishment-related representations in stimulus-specific sensory cortex. Young healthy adults were scanned with functional magnetic resonance imaging during a reward/punishment reversal learning task, after intake of methylphenidate or the selective D_2/3-receptor antagonist sulpiride. Striatal dopamine synthesis capacity was indexed with [¹⁸F]DOPA positron emission tomography. Reward versus punishment learning signals were boosted to a greater degree in participants with higher dopamine synthesis capacity. By contrast, striatal and stimulus-specific sensory surprise signals were boosted in participants with lower dopamine synthesis. These results unravel the mechanisms by which methylphenidate modulates reward and attention, impacting our understanding of how it can both enhance attention and mitigate reward-related compulsivity.