Fronto-striatal structures related with model-based control as an endophenotype for obsessive–compulsive disorder

Recent theories suggest a shift from model-based goal-directed to model-free habitual decision-making in obsessive-compulsive disorder (OCD). However, it is yet unclear, whether this shift in the decision process is heritable. We investigated 32 patients with OCD, 27 unaffected siblings (SIBs) and 31 healthy controls (HCs) using the two-step task. We computed behavioral and reaction time analyses and fitted a computational model to assess the balance between model-based and model-free control. 80 subjects also underwent structural imaging. We observed a significant ordered effect for the shift towards model-free control in the direction OCD>SIB>HC in our computational parameter of interest. However less directed analyses revealed no shift towards model-free control in OCDs. Nonetheless, we found evidence for reduced model-based control in OCDs compared to HCs and SIBs via 2nd stage reaction time analyses. In this measure SIBs also showed higher levels of model-based control than HCs. Across all subjects these effects were associated with the surface area of the left medial/right dorsolateral prefrontal cortex. Moreover, correlations between bilateral putamen/right caudate volumes and these effects varied as a function of group: they were negative in SIBs and OCDs, but positive in HCs. Associations between fronto-striatal regions and model-based reaction time effects point to a potential endophenotype for OCD

Arbitration between model-free and model-based control is not affected by transient changes in tonic serotonin levels

Background: Serotonin has been suggested to modulate decision-making by influencing the arbitration between model-based and model-free control. Disruptions in these control mechanisms are involved in mental disorders such as drug dependence or obsessive-compulsive disorder. While previous reports indicate that lower brain serotonin levels reduce model-based control, it remains unknown whether increases in serotonergic availability might thus increase model-based control. Moreover, the mediating neural mechanisms have not been studied yet. Aim: The first aim of this study was to investigate whether increased/decreased tonic serotonin levels affect the arbitration between model-free and model-based control. Second, we aimed to identify the underlying neural processes. Methods: We employed a sequential two-stage Markov decision-task and measured brain responses during functional magnetic resonance imaging in 98 participants in a randomized, double-blind cross-over within-subject design. To investigate the influence of serotonin on the balance between model-free and model-based control, we used a tryptophan intervention with three intervention levels (loading, balanced, depletion). We hypothesized that model-based behaviour would increase with higher serotonin levels. Results: We found evidence that neither model-free nor model-based control were affected by changes in tonic serotonin levels. Furthermore, our tryptophan intervention did not elicit relevant changes in Blood-Oxygenation-Level Dependent activity

The neurochemical substrates of habitual and goal-directed control

Abstract: Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [18F]FDOPA, [11C]MADAM and [11C]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [11C]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations

The neurochemical substrates of habitual and goal-directed control

Abstract: Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [18F]FDOPA, [11C]MADAM and [11C]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [11C]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations

Dopaminergic and noradrenergic modulation of stress-induced alterations in brain activation associated with goal-directed behaviour

BACKGROUND: Acute stress is thought to reduce goal-directed behaviour, an effect purportedly associated with stress-induced release of catecholamines. In contrast, experimentally increased systemic catecholamine levels have been shown to increase goal-directed behaviour. Whether experimentally increased catecholamine function can modulate stress-induced reductions in goal-directed behaviour and its neural substrates, is currently unknown. AIM: To assess whether and how experimentally induced increases in dopamine and noradrenaline contribute to the acute stress effects on goal-directed behaviour and associated brain activation. METHODS: One hundred participants underwent a stress induction protocol (Maastricht acute stress test; MAST) or a control procedure and received methylphenidate (MPH) (40 mg, oral) or placebo according to a 2 × 2 between-subjects design. In a well-established instrumental learning paradigm, participants learnt stimulus–response–outcome associations, after which rewards were selectively devalued. Participants’ brain activation and associated goal-directed behaviour were assessed in a magnetic resonance imaging scanner at peak cortisol/MPH concentrations. RESULTS: The MAST and MPH increased physiological measures of stress (salivary cortisol and blood pressure), but only MAST increased subjective measures of stress. MPH modulated stress effects on activation of brain areas associated with goal-directed behaviour, including insula, putamen, amygdala, medial prefrontal cortex, frontal pole and orbitofrontal cortex. However, MPH did not modulate the tendency of stress to induce a reduction in goal-directed behaviour. CONCLUSION: Our neuroimaging data suggest that MPH-induced increases in dopamine and noradrenaline reverse stress-induced changes in key brain regions associated with goal-directed behaviour, while behavioural effects were absent. These effects may be relevant for preventing stress-induced maladaptive behaviour like in addiction or binge eating disorder

Assessing the influence of dopamine and mindfulness on the formation of routines in visual search

Given experience in cluttered but stable visual environments, our eye‐movements form stereotyped routines that sample task‐relevant locations, while not mixing‐up routines between similar task‐settings. Both dopamine signaling and mindfulness have been posited as factors that influence the formation of such routines, yet quantification of their impact remains to be tested in healthy humans. Over two sessions, participants searched through grids of doors to find hidden targets, using a gaze‐contingent display. Within each session, door scenes appeared in either one of two colors, with each color signaling a differing set of likely target locations. We derived measures for how well target locations were learned (target‐accuracy), how routine were sets of eye‐movements (stereotypy), and the extent of interference between the two scenes (setting‐accuracy). Participants completed two sessions, where they were administered either levodopa (dopamine precursor) or placebo (vitamin C), under double‐blind counterbalanced conditions. Dopamine and trait mindfulness (assessed by questionnaire) interacted to influence both target‐accuracy and stereotypy. Increasing dopamine improved accuracy and reduced stereotypy for high mindfulness scorers, but induced the opposite pattern for low mindfulness scorers. Dopamine also disrupted setting‐accuracy invariant to mindfulness. Our findings show that mindfulness modulates the impact of dopamine on the target‐accuracy and stereotypy of eye‐movement routines, whereas increasing dopamine promotes interference between task‐settings, regardless of mindfulness. These findings provide a link between non‐human and human models regarding the influence of dopamine on the formation of task‐relevant eye‐movement routines and provide novel insights into behavior‐trait factors that modulate the use of experience when building adaptive repertoires

Differential prioritization of intramaze cue and boundary information during spatial navigation across the human lifespan

Spatial learning can be based on intramaze cues and environmental boundaries. These processes are predominantly subserved by striatal- and hippocampal-dependent circuitries, respectively. Maturation and aging processes in these brain regions may affect lifespan differences in their contributions to spatial learning. We independently manipulated an intramaze cue or the environment’s boundary in a navigation task in 27 younger children (6–8 years), 30 older children (10–13 years), 29 adolescents (15–17 years), 29 younger adults (20–35 years) and 26 older adults (65–80 years) to investigate lifespan age differences in the relative prioritization of either information. Whereas learning based on an intramaze cue showed earlier maturation during the progression from younger to later childhood and remained relatively stable across adulthood, maturation of boundary-based learning was more protracted towards peri-adolescence and showed strong aging-related decline. Furthermore, individual differences in prioritizing intramaze cue- over computationally more demanding boundary-based learning was positively associated with cognitive processing fluctuations and this association was partially mediated by spatial working memory capacity during adult, but not during child development. This evidence reveals different age gradients of two modes of spatial learning across the lifespan, which seem further influenced by individual differences in cognitive processing fluctuations and working memory, particularly during aging

Evidence for dopaminergic involvement in endogenous modulation of pain relief

Relief of ongoing pain is a potent motivator of behavior, directing actions to escape from or reduce potentially harmful stimuli. Whereas endogenous modulation of pain events is well characterized, relatively little is known about the modulation of pain relief and its corresponding neurochemical basis. Here, we studied pain modulation during a probabilistic relief-seeking task (a ‘wheel of fortune’ gambling task), in which people actively or passively received reduction of a tonic thermal pain stimulus. We found that relief perception was enhanced by active decisions and unpredictability, and greater in high novelty-seeking trait individuals, consistent with a model in which relief is tuned by its informational content. We then probed the roles of dopaminergic and opioidergic signaling, both of which are implicated in relief processing, by embedding the task in a double-blinded cross-over design with administration of the dopamine precursor levodopa and the opioid receptor antagonist naltrexone. We found that levodopa enhanced each of these information-specific aspects of relief modulation but no significant effects of the opioidergic manipulation. These results show that dopaminergic signaling has a key role in modulating the perception of pain relief to optimize motivation and behavior

Psychobiological mechanisms of endogenous pain modulation by pain relief as reward

Pain is much more than a sensory experience. Pain has strong emotional and motivational components that fulfill crucial functions for survival and well-being, because they drive behavior to avoid and escape from pain. This motivation is also reflected in the opposite and rewarding nature of the pleasure of pain relief. Both endogenous modulation of the perception of pain and pain relief are thought to promote the motivational drive and with that behavior that serves homeostatic needs. In contrast to pain and despite this crucial role of pain relief as reward, the psychobiological mechanisms underlying pain relief perception as well as related learning remain poorly understood. The aim of this dissertation was to deepen our understanding of psychological and neurobiological mechanisms of pain relief in healthy humans and possible alterations of these mechanisms in patients suffering from chronic pain. In a first experimental study, the role of the neurotransmitters dopamine and endogenous opioids in pain modulation and reinforcement learning were investigated using a probabilistic relief seeking task in healthy volunteers. The results showed that the informational value of pain and pain relief was endogenously enhanced in states of active decision making compared to passive states. This endogenous pain modulation scaled with perceived uncertainty of expected outcomes. Dopamine increased endogenous pain and pain relief modulation, while no evidence for the involvement of endogenous opioids was found. Successful reinforcement learning as found in the placebo condition was impaired by dopamine and endogenous opioids. The same probabilistic relief seeking task was used in a second study to investigate neural correlates of learning driven by pain and pain relief using functional magnetic resonance imaging in patients with chronic pain and healthy controls. This study replicated the effects of endogenous pain modulation by its informational value, while no alterations in patients with chronic pain were found compared to healthy controls. This result suggests that motivationally driven enhancement of pain relief perception is a robust phenomenon that appears to be spared by maladaptive changes during pain chronification. However, compared to healthy controls patients with fibromyalgia showed a stronger bias towards relief related cues during learning, but a weaker association of activation in the pregenual anterior cingulate cortex with relief prediction errors. These findings suggest that although the informational content of pain relief seems to be preserved in patients with chronic pain, subtle differences in the underlying mechanisms may reflect altered reward processing in chronic pain, which have been discussed before. In sum, the results highlight the important role of motivation and prospective control of behavior for endogenous modulation of pain and pain relief and provide insights in underlying psychobiological mechanisms in healthy states and in chronic pain