Objective: In this study, we aim to address the effects of dopaminergic treatment (DT) on the two domains of motor inhibition [1], i.e., reactive (the ability to react to a stop signal) and proactive inhibition (the ability to adapt the motor strategies according to the current context flexibly) according to the stage of Parkinson’s disease (PD).

Background: Inhibitory control plays a crucial role in decision-making, allowing behavioral flexibility in a continually changing world [2]. This executive function is severely impaired in PD [3-7]), dramatically impacting patients’ ability to implement goal-oriented adaptive strategies. Although it is well known that the midbrain’s dopamine neurons have a crucial role in decision making [8, 9], the effects of DT on inhibition during the different phases of the disease are still largely unclear.

Method: We recruited cognitively unimpaired PD patients under dopaminergic treatment in the early (H&Y 1/1.5, n=20), intermediate (H&Y 2, n=20), and moderate/advanced (H&Y 2.5/3, n=20) stages and 20 age-matched healthy controls. Each patient underwent a standardized motor and cognitive assessment and stop-signal task (SST). Covariance analyses adjusted for the effect of age, sex, and UPDRS3 evaluated the differences between the performance in the SST (in terms of reactive and proactive inhibition) in DT ON and OFF and each stage of the disease.

Results: We found that both reactive and proactive inhibition is progressively impaired along the disease. However, the DT negatively affects reactive inhibition in the early and proactive inhibition in the intermediate PD stage. By contrast, DT does not impact motor inhibition in moderate/advanced patients.

Conclusion: In PD’s early and intermediate stages, the DT negatively impacts reactive and proactive inhibition, respectively, despite improving motor symptoms. Such evidence supports the dopamine overdose hypothesis [10], which suggests that the administration of DT in the first stages of PD benefits dopamine-depleted dorsal striatal circuitries improving motor symptoms but overdose the more intact dopamine-dependent circuitries of the ventral striatum, impairing executive functions relying on it. Such findings suggest that the DT has to be titrated carefully to maximize patients’ quality of life in the first stages of PD.

References: 1. Mirabella G. (2021) Inhibitory control and impulsive responses in neurodevelopmental disorders. Dev Med Child Neurol. 63(5):520-526
2. Mirabella G (2014) Should I stay or should I go? Conceptual underpinnings of goal-directed actions. Front Syst Neurosci. 8:206
3. Mirabella G, Iaconelli S, Romanelli P, Modugno N, Lena F, Manfredi M, Cantore G (2012) Deep Brain Stimulation of Subthalamic Nuclei Affects Arm Response Inhibition in Parkinson’s Patients. Cereb Cortex 22:1124-323
4. Mancini C, Modugno N, Santilli M, Pavone L, Grillea G, Morace R and Mirabella G (2019) Unilateral Stimulation of Subthalamic Nucleus Does Not Affect Inhibitory Control. Front. Neurol. 9:1149
5. Mirabella G, Iaconelli S, Modugno N, Giannini G, Lena F, Cantore G (2013) Stimulation of subthalamic nuclei restores a near-normal planning strategy in Parkinson’s patients. PLoS One. 8(5):e62793
6. Di Caprio V, Modugno N, Mancini C, Olivola E, Mirabella G. (2020) Early-stage Parkinson’s patients show selective impairment in reactive but not proactive inhibition. Mov Disord. 35:409-418
7. Mirabella G, Fragola M; Giannini G, Modugno N; Lakens D (2017) Inhibitory control is not lateralized in Parkinson’s patients. Neuropsychologia. 102:177-189
8. Montague PR, Hyman SE, Cohen JD. (2004) Computational roles for dopamine in behavioural control. Nature. 431:760-7
9. Ryterska A, Jahanshahi M, Osman M. (2013) What are people with Parkinson’s disease really impaired on when it comes to making decisions? A meta-analysis of the evidence. Neurosci Biobehav Rev. 37(10 Pt 2):2836-46
10. Vaillancourt DE, Schonfeld D, Kwak Y, Bohnen NI, Seidler R. (2013) Dopamine overdose hypothesis: evidence and clinical implications. Mov Disord. 28:1920-9

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effects-of-dopaminergic-medication-on-reactive-and-proactive-inhibitory-control/