Cortical Grey Matter Mediates Increases in Model-Based Control and Learning from Positive Feedback from Adolescence to Adulthood.

Cognition and brain structure undergo significant maturation from adolescence into adulthood. Model-based (MB) control is known to increase across development, which is mediated by cognitive abilities. Here, we asked two questions unaddressed in previous developmental studies. First, what are the brain structural correlates of age-related increases in MB control? Second, how are age-related increases in MB control from adolescence to adulthood influenced by motivational context? A human developmental sample (n = 103; age, 12-50, male/female, 55:48) completed structural MRI and an established task to capture MB control. The task was modified with respect to outcome valence by including (1) reward and punishment blocks to manipulate the motivational context and (2) an additional choice test to assess learning from positive versus negative feedback. After replicating that an age-dependent increase in MB control is mediated by cognitive abilities, we demonstrate first-time evidence that gray matter density (GMD) in the parietal cortex mediates the increase of MB control with age. Although motivational context did not relate to age-related changes in MB control, learning from positive feedback improved with age. Meanwhile, negative feedback learning showed no age effects. We present a first report that an age-related increase in positive feedback learning was mediated by reduced GMD in the parietal, medial, and dorsolateral prefrontal cortex. Our findings indicate that brain maturation, putatively reflected in lower GMD, in distinct and partially overlapping brain regions could lead to a more efficient brain organization and might thus be a key developmental step toward age-related increases in planning and value-based choice.SIGNIFICANCE STATEMENT Changes in model-based decision-making are paralleled by extensive maturation in cognition and brain structure across development. Still, to date the neuroanatomical underpinnings of these changes remain unclear. Here, we demonstrate for the first time that parietal GMD mediates age-dependent increases in model-based control. Age-related increases in positive feedback learning were mediated by reduced GMD in the parietal, medial, and dorsolateral prefrontal cortex. A manipulation of motivational context did not have an impact on age-related changes in model-based control. These findings highlight that brain maturation in distinct and overlapping cortical regions constitutes a key developmental step toward improved value-based choices.

Cortical dopamine reduces the impact of motivational biases governing automated behaviour.

Motivations shape our behaviour: the promise of reward invigorates, while in the face of punishment, we hold back. Abnormalities of motivational processing are implicated in clinical disorders characterised by excessive habits and loss of top-down control, notably substance and behavioural addictions. Striatal and frontal dopamine have been hypothesised to play complementary roles in the respective generation and control of these motivational biases. However, while dopaminergic interventions have indeed been found to modulate motivational biases, these previous pharmacological studies used regionally non-selective pharmacological agents. Here, we tested the hypothesis that frontal dopamine controls the balance between Pavlovian, bias-driven automated responding and instrumentally learned action values. Specifically, we examined whether selective enhancement of cortical dopamine either (i) enables adaptive suppression of Pavlovian control when biases are maladaptive; or (ii) non-specifically modulates the degree of bias-driven automated responding. Healthy individuals (n = 35) received the catechol-o-methyltransferase (COMT) inhibitor tolcapone in a randomised, double-blind, placebo-controlled cross-over design, and completed a motivational Go NoGo task known to elicit motivational biases. In support of hypothesis (ii), tolcapone globally decreased motivational bias. Specifically, tolcapone improved performance on trials where the bias was unhelpful, but impaired performance in bias-congruent conditions. These results indicate a non-selective role for cortical dopamine in the regulation of motivational processes underpinning top-down control over automated behaviour. The findings have direct relevance to understanding neurobiological mechanisms underpinning addiction and obsessive-compulsive disorders, as well as highlighting a potential trans-diagnostic novel mechanism to address such symptoms.

A Translational Paradigm to Study the Effects of Uncontrollable Stress in Humans.

Theories on the aetiology of depression in humans are intimately linked to animal research on stressor controllability effects. However, explicit translations of established animal designs are lacking. In two consecutive studies, we developed a translational paradigm to study stressor controllability effects in humans. In the first study, we compared three groups of participants, one exposed to escapable stress, one yoked inescapable stress group, and a control group not exposed to stress. Although group differences indicated successful stress induction, the manipulation failed to differentiate groups according to controllability. In the second study, we employed an improved paradigm and contrasted only an escapable stress group to a yoked inescapable stress group. The final design successfully induced differential effects on self-reported perceived control, exhaustion, helplessness, and behavioural indices of adaptation to stress. The latter were examined in a new escape behaviour test which was modelled after the classic shuttle box animal paradigm. Contrary to the learned helplessness literature, exposure to uncontrollable stress led to more activity and exploration; however, these behaviours were ultimately not adaptive. We discuss the results and possible applications in light of the findings on learning and agency beliefs, inter-individual differences, and interventions aimed at improving resilience to stress-induced mental dysfunction.

Aberrant probabilistic reinforcement learning in first-degree relatives of individuals with bipolar disorder.

BACKGROUND: Motivational dysregulation represents a core vulnerability factor for bipolar disorder. Whether this also comprises aberrant learning of stimulus-reinforcer contingencies is less clear. METHODS: To answer this question, we compared healthy first-degree relatives of individuals with bipolar disorder (n = 42) known to convey an increased risk of developing a bipolar spectrum disorder and healthy individuals (n = 97). Further, we investigated the effects of the behavioral activation system (BAS) on reinforcement learning across the entire sample. All participants were assessed with a probabilistic learning task that distinguishes learning from positive and negative feedback. Main outcome measures included choice frequencies and learning rate parameters generated by computational reinforcement learning algorithms. RESULTS: First-degree relatives choose more rewarding stimuli more consistently and showed marginally reduced learning rates from unexpected negative feedback. Further, first-degree relatives had lower BAS scores than controls, which were negatively associated with learning rates from unexpected negative feedback. LIMITATIONS: However as probands also reported other mental disorders such as Attention-Deficit/Hyperactivity Disorder and substance abuse among their first-degree relatives, we cannot know, whether these findings are specific to the risk for bipolar disorder. CONCLUSION: The behavior of first-degree relatives of individuals with bipolar disorder, who also display increased BAS sensitivity, is less influenced by unexpected negative feedback. This reduced learning from unexpected negative feedback biases subsequent choices towards stimuli with higher probabilities for a reward. In sum, our results confirm the role of aberrant reinforcement learning in the pathophysiology of bipolar disorder.

Cognitive variability in bipolar I disorder: A cluster-analytic approach informed by resting-state data.

BACKGROUND: While the presence of cognitive performance deficits in bipolar disorder I (BD-I) is well established, there is no consensus about which cognitive abilities are affected. Heterogeneous phenotypes displayed in BD-I further suggest the existence of subgroups among the disorder. The present study sought to identify different cognitive profiles among BD-I patients as well as potentially underlying neuronal network changes. METHODS: 54 euthymic BD-I patients underwent cognitive testing and resting state neuroimaging. Hierarchical cluster-analysis was performed on executive function scores of bipolar patients. The derived clusters were compared against 54 age-, gender- and IQ-matched healthy controls (HC) to facilitate the interpretation of results. Further, resting state network properties were compared to identify differences probably underlying cognitive profiles. RESULTS: A three-cluster solution emerged. Cluster 1 (n = 22) was characterized by deficits in cognitive flexibility and motor inhibition, cluster 2 (n = 12) displayed impulsive decision-making, while cluster 3 (n = 20) showed good visuospatial planning. Weaker connections in cluster 1 compared to cluster 2 were found between regions activated during tasks cluster 1 showed deficits on. Cluster 3 had a higher modularity than cluster 2, which correlated positively with problem solving performance and risk-taking in this cluster. CONCLUSION: Obtained clusters showed distinct cognitive profiles, characterized by deficits and strengths, most of which remained precluded in a general comparison. Weaker interregional connections and separated subnetworks might underly behavioral deficits and strengths, respectively. The findings help explain the phenotypic heterogeneity observed in BD-I. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.

Reward anticipation revisited- evidence from an fMRI study in euthymic bipolar I patients and healthy first-degree relatives.

BACKGROUND: Symptomatic phases in bipolar disorder (BD) are hypothesized to result from a hypersensitive behavioral activation system (BAS) being sensitive to potential rewards. However, studies on the neuronal underpinnings of reward anticipation in BD are scarce with contradictory findings and possibly confounded by effects of dopaminergic medication, necessitating further research on dysfunctional motivation in BD. Moreover, its role as vulnerability marker for BD is unclear. METHODS: Functional imaging was conducted in 16 euthymic BD-I patients free from dopaminergic medication and 19 healthy first-degree relatives using a monetary incentive delay task and compared to parallelized control groups. Further, reward proneness, using the BIS/BAS questionnaire, and its relationship to neural reward anticipation was investigated. RESULTS: BD-I patients displayed greater anterior cingulate cortex (ACC) activity during reward anticipation and higher BIS total scores compared to controls, with a positive relationship between the two measures. There were no neural or self-report group differences between relatives and controls. LIMITATIONS: Due to the experimental design, the role of the ACC during receipt of reward remains unknown, sample sizes were rather small, and patients were not naïve to dopaminergic drugs, making an exclusion of medication effects on findings impossible. CONCLUSIONS: Our findings give new insights on reward anticipation in BD. BD-I patients rated themselves as more risk avoidant and showed larger recruitment of the ACC rather than ventral striatum compared to controls during reward anticipation, possibly to down-regulate hyperactive limbic reward regions. This activation seems to be a consequence of rather than a vulnerability marker for the disorder.

Dysfunctional decision-making related to white matter alterations in bipolar I disorder.

OBJECTIVE: This study investigated how frontal white matter (WM) alterations in patients with bipolar I disorder (BD-I) are linked to motivational dysregulation, often reported in the form of risk-taking and impulsivity, and whether structure-function relations in patients might differ from healthy subjects (HC). METHOD: We acquired diffusion data from 24 euthymic BD-I patients and 24 controls, to evaluate WM integrity of selected frontal tracts. Risk-taking was assessed by the Cambridge Gambling Task and impulsivity by self-report with the Barratt-Impulsiveness Scale. RESULTS: BD-I patients displayed significantly lower integrity in the right cingulum compared to HC. They also showed more risk-taking behavior and reported increased trait-impulsivity. Risk-taking was negatively associated with WM integrity in the right cingulum. Impulsivity was not related to WM integrity in investigated tracts. Together with age and sex, FA in the cingulum explained 25% of variance in risk-taking scores in all study participants. The left inferior fronto-occipital fasciculus (IFOF) was specifically predictive of risk-taking behavior in BD-I patients, but not in HC. LIMITATIONS: The employed parameters did not allow us to specify the exact origin of WM changes, nor did the method allow the analysis of specific brain subregions. Also, sample size was moderate and the sample included patients with lifetime alcohol dependence/abuse, hence effects found need replication and have to be interpreted with caution. CONCLUSION: Our results further strengthen recent models linking structural changes in frontal networks to behavioral markers of BD-I. They extend recent findings by showing that risk-taking is also linked to the cingulum in BD-I and HC, while other prefrontal tracts (IFOF) are specifically implicated in risk-taking behavior in BD-I patients. Meanwhile, self-reported impulsivity was not associated with WM integrity of the tracts investigated in our study.