Rumana Chowdhury

Dopamine restores reward prediction errors in old age

Senescence affects the ability to utilize information about the likelihood of rewards for optimal decision-making. Using functional magnetic resonance imaging in humans, we found that healthy older adults had an abnormal signature of expected value, resulting in an incomplete reward prediction error (RPE) signal in the nucleus accumbens, a brain region that receives rich input projections from substantia nigra/ventral tegmental area (SN/VTA) dopaminergic neurons. Structural connectivity between SN/VTA and striatum, measured by diffusion tensor imaging, was tightly coupled to inter-individual differences in the expression of this expected reward value signal. The dopamine precursor levodopa (L-DOPA) increased the task-based learning rate and task performance in some older adults to the level of young adults. This drug effect was linked to restoration of a canonical neural RPE. Our results identify a neurochemical signature underlying abnormal reward processing in older adults and indicate that this can be modulated by L-DOPA.

Dopamine Modulates Episodic Memory Persistence in Old Age

Activation of the hippocampus is required to encode memories for new events (or episodes). Observations from animal studies suggest that, for these memories to persist beyond 4–6 h, a release of dopamine generated by strong hippocampal activation is needed. This predicts that dopaminergic enhancement should improve human episodic memory persistence also for events encoded with weak hippocampal activation. Here, using pharmacological functional MRI (fMRI) in an elderly population in which there is a loss of dopamine neurons as part of normal aging, we show this very effect. The dopamine precursor levodopa led to a dose-dependent (inverted U-shape) persistent episodic memory benefit for images of scenes when tested after 6 h, independent of whether encoding-related hippocampal fMRI activity was weak or strong (U-shaped dose–response relationship). This lasting improvement even for weakly encoded events supports a role for dopamine in human episodic memory consolidation, albeit operating within a narrow dose range.

How Dopamine Enhances an Optimism Bias in Humans

Summary When predicting financial profits [1], relationship outcomes [2], longevity [3], or professional success [4], people habitually underestimate the likelihood of future negative events (for review see [5]). This well-known bias, termed unrealistic optimism [6], is observed across age [7], culture [8], and species [9] and has a significant societal impact on domains ranging from financial markets to health and well being. However, it is unknown how neuromodulatory systems impact on the generation of optimistically biased beliefs. This question assumes great importance in light of evidence that common neuropsychiatric disorders, such as depression, are characterized by pessimism [10, 11]. Here, we show that administration of a drug that enhances dopaminergic function (dihydroxy-L-phenylalanine; L-DOPA) increases an optimism bias. This effect is due to L-DOPA impairing the ability to update belief in response to undesirable information about the future. These findings provide the first evidence that the neuromodulator dopamine impacts on belief formation by reducing negative expectations regarding the future.

Dopamine Modulates Reward-Related Vigor

Subjects routinely control the vigor with which they emit motoric responses. However, the bulk of formal treatments of decision-making ignores this dimension of choice. A recent theoretical study suggested that action vigor should be influenced by experienced average reward rate and that this rate is encoded by tonic dopamine in the brain. We previously examined how average reward rate modulates vigor as exemplified by response times and found a measure of agreement with the first suggestion. In the current study, we examined the second suggestion, namely the potential influence of dopamine signaling on vigor. Ninety healthy subjects participated in a double-blind experiment in which they received one of the following: placebo, L-DOPA (which increases dopamine levels in the brain), or citalopram (which has a selective, if complex, effect on serotonin levels). Subjects performed multiple trials of a rewarded odd-ball discrimination task in which we varied the potential reward over time in order to exercise the putative link between vigor and average reward rate. Replicating our previous findings, we found that a significant fraction of the variance in subjects’ responses could be explained by our experimentally manipulated changes in average reward rate. Crucially, this relationship was significantly stronger under L-Dopa than under Placebo, suggesting that the impact of average reward levels on action vigor is indeed subject to a dopaminergic influence.

Action controls dopaminergic enhancement of reward representations

Dopamine is widely observed to signal anticipation of future rewards and thus thought to be a key contributor to affectively charged decision making. However, the experiments supporting this view have not dissociated rewards from the actions that lead to, or are occasioned by, them. Here, we manipulated dopamine pharmacologically and examined the effect on a task that explicitly dissociates action and reward value. We show that dopamine enhanced the neural representation of rewarding actions, without significantly affecting the representation of reward value as such. Thus, increasing dopamine levels with levodopa selectively boosted striatal and substantia nigra/ventral tegmental representations associated with actions leading to reward, but not with actions leading to the avoidance of punishment. These findings highlight a key role for dopamine in the generation of appetitively motivated actions.

Differential, but not opponent, effects of L-DOPA and citalopram on action learning with reward and punishment

RationaleDecision-making involves two fundamental axes of control namely valence, spanning reward and punishment, and action, spanning invigoration and inhibition. We recently exploited a go/no-go task whose contingencies explicitly decouple valence and action to show that these axes are inextricably coupled during learning. This results in a disadvantage in learning to go to avoid punishment and in learning to no-go to obtain a reward. The neuromodulators dopamine and serotonin are likely to play a role in these asymmetries: Dopamine signals anticipation of future rewards and is also involved in an invigoration of motor responses leading to reward, but it also arbitrates between different forms of control. Conversely, serotonin is implicated in motor inhibition and punishment processing.ObjectiveTo investigate the role of dopamine and serotonin in the interaction between action and valence during learning.MethodsWe combined computational modeling with pharmacological manipulation in 90 healthy human volunteers, using levodopa and citalopram to affect dopamine and serotonin, respectively.ResultsWe found that, after administration of levodopa, action learning was less affected by outcome valence when compared with the placebo and citalopram groups. This highlights in this context a predominant effect of levodopa in controlling the balance between different forms of control. Citalopram had distinct effects, increasing participants’ tendency to perform active responses independent of outcome valence, consistent with a role in decreasing motor inhibition.ConclusionsOur findings highlight the rich complexities of the roles played by dopamine and serotonin during instrumental learning.

Optimistic update bias increases in older age

Background Healthy older adults report greater well-being and life satisfaction than their younger counterparts. One potential explanation for this is enhanced optimism. We tested the influence of age on optimistic and pessimistic beliefs about the future and the associated structural neural correlates. Method Eighteen young and 18 healthy older adults performed a belief updating paradigm, measuring differences in updating beliefs for desirable and undesirable information about future negative events. These measures were related to regional brain volume, focusing on the anterior cingulate cortex (ACC) because this region is strongly linked to a positivity bias in older age. Results We demonstrate an age-related reduction in updating beliefs when older adults are faced with undesirable, but not desirable, information about negative events. This greater ‘update bias’ in older age persisted even after controlling for a variety of variables including subjective rating scales and poorer overall memory. A structural brain correlate of this greater ‘update bias’ was evident in greater grey matter volume in the dorsal ACC in older but not in young adults. Conclusions We show a greater update bias in healthy older age. The link between this bias and relative volume of the ACC suggests a shared mechanism with an age-related positivity bias. Older adults frequently have to make important decisions relating to personal, health and financial issues. Our findings have wider behavioural implications in these contexts because an enhanced optimistic update bias may skew such real-world decision making.

Parcellation of the human substantia nigra based on anatomical connectivity to the striatum

Substantia nigra/ventral tegmental area (SN/VTA) subregions, defined by dopaminergic projections to the striatum, are differentially affected by health (e.g. normal aging) and disease (e.g. Parkinsons disease). This may have an impact on reward processing which relies on dopaminergic regions and circuits. We acquired diffusion tensor imaging (DTI) with probabilistic tractography in 30 healthy older adults to determine whether subregions of the SN/VTA could be delineated based on anatomical connectivity to the striatum. We found that a dorsomedial region of the SN/VTA preferentially connected to the ventral striatum whereas a more ventrolateral region connected to the dorsal striatum. These SN/VTA subregions could be characterised by differences in quantitative structural imaging parameters, suggesting different underlying tissue properties. We also observed that these connectivity patterns differentially mapped onto reward dependence personality trait. We show that tractography can be used to parcellate the SN/VTA into anatomically plausible and behaviourally meaningful compartments, an approach that may help future studies to provide a more fine-grained synopsis of pathological changes in the dopaminergic midbrain and their functional impact.

Structural integrity of the substantia nigra and subthalamic nucleus predicts flexibility of instrumental learning in older-age individuals

Flexible instrumental learning is required to harness the appropriate behaviors to obtain rewards and to avoid punishments. The precise contribution of dopaminergic midbrain regions (substantia nigra/ventral tegmental area [SN/VTA]) to this form of behavioral adaptation remains unclear. Normal aging is associated with a variable loss of dopamine neurons in the SN/VTA. We therefore tested the relationship between flexible instrumental learning and midbrain structural integrity. We compared task performance on a probabilistic monetary go/no-go task, involving trial and error learning of: “go to win,” “no-go to win,” “go to avoid losing,” and “no-go to avoid losing” in 42 healthy older adults to previous behavioral data from 47 younger adults. Quantitative structural magnetization transfer images were obtained to index regional structural integrity. On average, both some younger and some older participants demonstrated a behavioral asymmetry whereby they were better at learning to act for reward (“go to win” > “no-go to win”), but better at learning not to act to avoid punishment (“no-go to avoid losing” > “go to avoid losing”). Older, but not younger, participants with greater structural integrity of the SN/VTA and the adjacent subthalamic nucleus could overcome this asymmetry. We show that interindividual variability among healthy older adults of the structural integrity within the SN/VTA and subthalamic nucleus relates to effective acquisition of competing instrumental responses.