Danae Papadopetraki

BACKGROUND Basal ganglia (BG) dysfunction is the hallmark of several neurological and neuropsychiatric disorders. BG dysfunction impairs cost-benefit decision-making, a brain computational process of trading off between reward and costs, and may underlie clinical observations of neuropsychiatric symptoms such as amotivation, impulsivity, and risk-taking. There is an unmet need for a remote digital monitoring tool for cost-benefit decision-making that can be administered repeatedly by a patient at home to provide a longitudinal proxy of basal ganglia functioning to inform clinical practice and drug development efforts. OBJECTIVE This report describes a data-driven and iterative prototyping effort of a smartphone-based, cost-benefit, decision-making test battery developed to measure basal ganglia functioning in three cost domains: effort, delay, and risk. Via an iterative process consisting of multiple rounds of data collection with online community-based samples, we aimed to establish feasibility, proof-of-concept, test-retest reliability over up to 4.5 months, and convergent validity with relevant clinical symptoms, namely apathy and impulsivity. METHODS We converted a lab-based, decision-making test battery to a URL-based test administered on private smartphones. An online pool of n = 879 volunteers aged 40-80 years participated. Using a data-driven approach, we iteratively (6 rounds) refined and shortened the test to a prototype with a target participant burden of less than 5 minutes while preserving its psychometric properties. Proof of concept, test-retest reliability (intraclass correlation coefficients (ICCs)), and convergent validity with the Starkstein Apathy Scale (SAS) and Barrat Impulsiveness Scale (BIS-11) were established for the final version. RESULTS Consistent monotonic effects of cost levels in all cost domains were observed, demonstrating proof of concept. Measures of motivation, impulsivity, and risk-taking showed good to excellent test-retest reliability (ICCs 0.69 – 0.97). Metrics of impulsivity showed convergent validity with its clinical anchor, BIS-11 (t = -2.83, p = 0.005)), and the metric of motivation showed convergent validity with SAS (t = -2.29, p = 0.022). CONCLUSIONS This accessible, short, scalable, and replicable digital smartphone-based decision-making test battery may represent an efficient and robust means to estimate cost-benefit decision-making associated with basal ganglia functioning and its changes over time. CLINICALTRIAL This is not a RCT

Objective: Parkinson's disease (PD) resting tremor is thought to be initiated in the basal ganglia and amplified in the cerebello‐thalamo‐cortical circuit. Because stress worsens tremor, the noradrenergic system may play a role in amplifying tremor. We tested if and how propranolol, a non‐selective beta‐adrenergic receptor antagonist, reduces PD tremor and whether or not this effect is specific to stressful conditions.Methods: In a cross‐over, double‐blind intervention study, participants with PD resting tremor received propranolol (40 mg, single dose) or placebo (counter‐balanced) on 2 different days. During both days, we assessed tremor severity (with accelerometry) and tremor‐related brain activity (with functional magnetic resonance imaging), as well as heart rate and pupil diameter, while subjects performed a stressful cognitive load task that has been linked to the noradrenergic system. We tested for effects of drug (propranolol vs placebo) and stress (cognitive load vs rest) on tremor power and tremor‐related brain activity.Results: We included 27 PD patients with prominent resting tremor. Tremor power significantly increased during cognitive load versus rest (F[1,19] = 13.8; p = 0.001; = 0.42) and decreased by propranolol versus placebo (F[1,19] = 6.4; p = 0.02; = 0.25), but there was no interaction. We observed task‐related brain activity in a stress‐sensitive cognitive control network and tremor power‐related activity in the cerebello‐thalamo‐cortical circuit. Propranolol significantly reduced tremor‐related activity in the motor cortex compared to placebo (F[1,21] = 5.3; p = 0.03; = 0.20), irrespective of cognitive load.Interpretation: Our findings indicate that propranolol has a general, context‐independent, tremor‐reducing effect that may be implemented at the level of the primary motor cortex. ANN NEUROL 2025;97:741–752

Objective: Parkinson’s disease (PD) resting tremor is thought to be initiated in the basal ganglia and amplified in the cerebello-thalamo-cortical circuit. Since stress worsens tremor, the noradrenergic system may play a role in amplifying tremor. We tested if and how propranolol, a non-selective beta-adrenergic receptor antagonist, reduces PD tremor, and whether or not this effect is specific to stressful conditions. Methods: In a cross-over, double-blind intervention study, participants with PD resting tremor received propranolol (40mg, single dose) or placebo (counter-balanced) on two different days. During both days, we assessed tremor severity (with accelerometry) and tremor-related brain activity (with functional Magnetic Resonance Imaging; fMRI), as well as heart rate and pupil diameter, while subjects performed a stressful cognitive load task that has been linked to the noradrenergic system. We tested for effects of drug (propranolol vs. placebo) and stress (cognitive load vs. rest) on tremor power and tremor-related brain activity. Results: We included 27 PD patients with clear resting tremor. Tremor power significantly increased during cognitive load vs. rest ( F (1,19)=13.8; p =.001; η _p ² =0.42) and decreased by propranolol vs. placebo ( F (1,19)=6.4; p =.02; η _p ² =0.25), but there was no interaction. We observed task-related brain activity in a stress-sensitive cognitive control network, and tremor power-related activity in the cerebello-thalamo-cortical circuit. Propranolol significantly reduced tremor-related activity in the motor cortex compared to placebo ( F (1,21)=5.3; p =.03; η _p ² =0.20), irrespective of cognitive load. Interpretation: Our findings indicate that the noradrenergic system has a general, context-independent role in amplifying PD tremor at the level of the primary motor cortex.

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.

Interaction between Pavlovian and instrumental control systems is key for adaptive motivated behavior, but also plays an important role in various neuropsychiatric disorders, including depression, addiction, and anxiety. Here, we employed the flouorodopa positron emission tomography ([¹⁸F]-DOPA PET) in healthy participants (N = 100) to assess whether dopamine synthesis capacity (K_i), specifically in the ventral striatum, accounts for individual variation in Pavlovian-to-instrumental transfer (PIT). Surprisingly, this was not the case. Rather, the relationship of ventral striatal Ki with PIT depended on working memory (WM) capacity. Ventral striatal dopamine boosted the effects of Pavlovian cues on instrumental responding to a greater degree in participants with higher WM capacity. Caution is warranted to interpret this post hoc four-way interaction given the modest sample size. Nonetheless, these results chime with prior findings demonstrating that dopaminergic drugs boost Pavlovian biases to a greater degree in participants with greater WM capacity and highlight the importance of interactions between striatal dopamine and WM capacity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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.

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.

Responsible use of psychostimulants: Psychostimulants have a place in the therapy of attentional disorders. However, they are also widely used off-label to enhance cognitive performance, and their mechanisms of action remain elusive. Westbrook et al. studied the effects of these drugs and concurrently measured striatal dopamine synthesis capacity in young, healthy participants (see the Perspective by Janes). They administered a placebo, methylphenidate (a dopamine and noradrenaline reuptake blocker), and sulpiride (a selective D2 receptor antagonist) while participants made explicit cost-benefit decisions about whether to engage in cognitive effort. Higher dopamine synthesis capacity in the caudate nucleus was associated with greater willingness to allocate cognitive effort. In addition, methylphenidate and sulpiride increased subjective values and motivation to work specifically for people with low dopamine synthesis capacity. Cognition-enhancing drugs may thus act at the motivational level rather than directly boosting cognition per se. Science , this issue p. 1362 ; see also p. 1300

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 [ ¹⁸ F]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.