Dopamine restores cognitive motivation in Parkinson’s disease

McGuigan, Sara; Zhou, Shou-Han; Brosnan, Méadhbh B.; Thyagarajan, Dominic; Bellgrove, Mark A.; Chong, Trevor T.‐J.

doi:10.1093/brain/awy341

Cited by 78 publications

(74 citation statements)

References 71 publications

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“…Converging evidence from research on Parkinson's disease (13)(14)(15)(16)(17), showing dopaminedependent changes in cognitive motivation, provides an initial basis for this conjecture. 35 Moreover, catecholamine-enhancing psychostimulants alter cognitive effort-based choice in both rodents (10) and humans (18).…”

Section: Main Textmentioning

confidence: 98%

“…By blocking dopamine transporters, methylphenidate increases extracellular striatal dopamine tone (26) and can further amplify transient dopamine release (27). Sulpiride is a D2 receptor antagonist which, at low doses increases striatal dopamine release by 95 binding pre-synaptic auto-receptors in both rodents and humans (6,17,(28)(29)(30)(31). In humans, sulpiride can enhance reward prediction error signaling and reward learning (31).…”

Section: Figmentioning

confidence: 99%

“…In cortico-striatal loops governing action selection, dopamine has opponent effects on D1 and D2expressing medium spiny neurons, which are thought to modulate the relative sensitivity to the benefits versus the costs of actions (5). Given that similar mechanisms are thought to govern 30 cognitive action selection (6-8), we hypothesized that striatal dopamine could promote willingness to exert cognitive effort, boosting motivated cognitive control for attention, planning, and decision-making (9-12).Converging evidence from research on Parkinson's disease (13)(14)(15)(16)(17), showing dopaminedependent changes in cognitive motivation, provides an initial basis for this conjecture. 35 Moreover, catecholamine-enhancing psychostimulants alter cognitive effort-based choice in both rodents (10) and humans (18).…”

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confidence: 99%

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Dopamine Promotes Cognitive Effort by Biasing the Benefits Versus Costs of Cognitive Work

Westbrook

Bosch

Määttä

et al. 2019

Preprint

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Stimulants like methylphenidate are increasingly used for cognitive enhancement, but precise mechanisms are unknown. Here we show that methylphenidate boosts willingness to expend cognitive effort by altering the benefit-to-cost ratio of cognitive work. Willingness to 15 expend effort was greater for participants with higher striatal dopamine synthesis capacity, while methylphenidate and sulpiride -a selective D2 receptor agent -increased cognitive motivation more for participants with lower synthesis capacity. A sequential sampling model informed by momentary gaze revealed that decisions to expend effort are related to amplification of benefitversus-cost information attended early in the decision process, while the effect of benefits is 20 strengthened with higher synthesis capacity and by methylphenidate. These findings demonstrate that methylphenidate boosts the perceived benefits-versus-costs of cognitive effort by modulating striatal dopamine signaling. Main Text:Cognitive control is subjectively effortful, causing people to avoid demanding tasks (1) 25 and to discount goals (2, 3), but incentives can offset these costs (2). Striatal dopamine invigorates physical action by mediating the tradeoff between physical costs and benefits (4). In cortico-striatal loops governing action selection, dopamine has opponent effects on D1 and D2expressing medium spiny neurons, which are thought to modulate the relative sensitivity to the benefits versus the costs of actions (5). Given that similar mechanisms are thought to govern 30 cognitive action selection (6-8), we hypothesized that striatal dopamine could promote willingness to exert cognitive effort, boosting motivated cognitive control for attention, planning, and decision-making (9-12).Converging evidence from research on Parkinson's disease (13)(14)(15)(16)(17), showing dopaminedependent changes in cognitive motivation, provides an initial basis for this conjecture. 35 Moreover, catecholamine-enhancing psychostimulants alter cognitive effort-based choice in both rodents (10) and humans (18). This raises the question of whether commonly used "smart drugs" act by enhancing the willingness rather than ability to exert cognitive control. Indeed, the dominant interpretation of stimulant effects is that they improve cognitive processing, via direct effects on cortical areas,

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Section: Main Textmentioning

confidence: 98%

Section: Figmentioning

confidence: 99%

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confidence: 99%

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Dopamine Promotes Cognitive Effort by Biasing the Benefits Versus Costs of Cognitive Work

Westbrook

Bosch

Määttä

et al. 2019

Preprint

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“…Such cognitive effects of catecholaminergic drugs have been most commonly attributed to a modulation of the ability to implement cognitive control, often associated with the prefrontal cortex [1]. However, recent progress suggests that cognitive control might also be altered by changing motivation, that is the willingness to engage with a cognitive task, rather than ability alone [17,18]. Specifically, we have posited that the cognitive enhancing effects of drugs like methylphenidate, which act by blocking the dopamine and noradrenaline transporters, reflect changes in cost/benefit-based decision making about cognitive control, elicited by striatal dopamine [19,20].…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, we have posited that the cognitive enhancing effects of drugs like methylphenidate, which act by blocking the dopamine and noradrenaline transporters, reflect changes in cost/benefit-based decision making about cognitive control, elicited by striatal dopamine [19,20]. While prior evidence, for example from medication withdrawal studies in Parkinson's disease, generally concurred with this hypothesis [18,[21][22][23] (but see [24]), there was, until recently, no direct evidence for a specific role for dopamine in the striatum. To definitively test this role for striatal dopamine in cognitive motivation, we set up two separate cognitive effort discounting experiments in the context of a large pharmacological PET study with 100 healthy volunteers.…”

Section: Introductionmentioning

confidence: 99%

Methylphenidate boosts choices of mental labor over leisure depending on baseline striatal dopamine

Hofmans

Papadopetraki²,

Bosch

et al. 2019

Preprint

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The cognitive enhancing effects of methylphenidate are well established, but the mechanisms remain unclear. We recently demonstrated that methylphenidate boosts cognitive motivation by enhancing the weight on the benefits of a cognitive task in a manner that depended on striatal dopamine. Here we considered the complementary hypothesis that methylphenidate might also act by changing the weight on the opportunity cost of a cognitive task. To this end, fifty healthy participants (25 women) completed a novel cognitive effort discounting task that was sensitive to opportunity cost, and required choices between task and leisure. They were tested on methylphenidate, sulpiride or placebo and also underwent an [18F]DOPA PET scan to quantify baseline dopamine synthesis capacity. Methylphenidate boosted choices of cognitive effort over leisure across the group, and this effect was greatest in participants with more striatal dopamine at baseline. The effects of sulpiride did not reach significance. This study strengthens the motivational account of methylphenidate’s effects on cognition and suggests that methylphenidate reduces the cost of mental labor by increasing striatal dopamine.

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Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor–Positive Allosteric Modulator, in Patients With Parkinson Disease

Wilbraham

Biglan

Svensson

et al. 2021

Clinical Pharm in Drug Dev

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Mevidalen (LY3154207) is a positive allosteric modulator of the dopamine D1 receptor that enhances the affinity of dopamine for the D1 receptor. The safety, tolerability, motor effects, and pharmacokinetics of mevidalen were studied in patients with Parkinson disease. Mevidalen or placebo was given once daily for 14 days to 2 cohorts of patients (cohort 1, 75 mg; cohort 2, titration from 15 to 75 mg). For both cohorts, the median time to maximum concentration for mevidalen plasma concentration was about 2 hours, the apparent steady-state clearance was 20-25 L/h, and mevidalen plasma concentrations were similar between the 1st and 14th administration in cohort 1, indicating minimal accumulation upon repeated dosing. Mevidalen was well tolerated, and most treatment-emergent adverse events were mild. Blood pressure and pulse rate increased when taking mevidalen, but there was considerable overlap with patients taking placebo, and vital signs normalized with repeated dosing. In the Movement Disorder Society-United Parkinson's Disease Rating Scale, all patients taking mevidalen showed a better motor examination sub-score on day 6 compared to only some patients in the placebo group. These data support examining mevidalen for symptomatic treatment of patients with Parkinson disease and Lewy body dementia.

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Dopamine restores cognitive motivation in Parkinson’s disease

Cited by 78 publications

References 71 publications

Dopamine Promotes Cognitive Effort by Biasing the Benefits Versus Costs of Cognitive Work

Dopamine Promotes Cognitive Effort by Biasing the Benefits Versus Costs of Cognitive Work

Methylphenidate boosts choices of mental labor over leisure depending on baseline striatal dopamine

Safety, Tolerability, and Pharmacokinetics of Mevidalen (LY3154207), a Centrally Acting Dopamine D1 Receptor–Positive Allosteric Modulator, in Patients With Parkinson Disease

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