Patients with Parkinson’s disease (PD) often develop cognitive impairments and executive dysfunction in addition to the most common motor symptoms such as bradykinesia, tremor, rigidity, and impairments of postural reflexes (Dubois and Pillon, 1996; Dirnberger and Jahanshahi, 2013). While previous research suggests that dopaminergic medication (Armstrong and Okun, 2020) and subthalamic nucleus deep brain stimulation (STN-DBS) effectively control the motor symptoms of the disease (Deuschl et al., 2006; Fasano et al., 2012; Weaver et al., 2012), there is evidence for impaired executive functions with dopaminergic medication (Cools, 2001) and STN-DBS in patients with PD (Fasano et al., 2010). One of the most widely explored behavioral changes related to dopaminergic medication or STN-DBS is impulsive behavior, which even though a unitary phenomenon, can be distinguished into multiple domains depending on the context of testing. Cognitive impulsivity, also referred to as an impulsive choice (Dalley Jeffrey et al., 2011), is described as a tendency to make rash decisions without effective evaluation of alternative choices (Cáceres and San, 2017) and can be expressed as impaired decision-making (Antonelli et al., 2011). Reflection impulsivity refers to reacting quickly without pausing for reflection (Jahanshahi, 2013). Motor impulsivity, on the other hand, refers to the impaired inhibition of a previously learned response and can be reactive or proactive (Antonelli et al., 2011). Reactive motor impulsivity refers to the inability to stop a response when a specific stop-signal is indicated (Antonelli et al., 2011). Proactive motor impulsivity is more goal-directed and relates to self-control. It involves, methods cautious responding to meet goals and objectives (Jahanshahi, 2013).

Dopaminergic medications have been associated with changes in all areas of impulsivity in PD: motor (Servan-Schreiber, 1996; Cohen et al., 1999; Nombela et al., 2014; Canário et al., 2019), reflection (Huq et al., 1988; Djamshidian et al., 2013), and cognitive (Antonelli et al., 2014; Canário et al., 2019) impulsivity. With STN-DBS in PD, there is evidence that DBS can increase impulsive responding in conditions of high decision conflict (Georgiev et al., 2016), while dopaminergic medication had no effect on this form of impulsivity (Frank et al., 2007). Another study examining the processing of rewards found that STN-DBS increased risky choices but did not worsen the evaluation of delayed rewards (Evens et al., 2015). Furthermore, it appears that, compared to healthy controls, STN-DBS in PD may increase reactive but not proactive impulsivity (Obeso et al., 2013). There is also evidence that dopamine agonists, rather than STN-DBS, increase reflection impulsivity (Djamshidian et al., 2013). Therefore, the results of the studies examining the effect of dopaminergic medication and STN-DBS on the different facets of impulsivity are inconsistent. To the best of our knowledge, to date, no study has tested the effect of both dopaminergic medication and STN-DBS within the same patient group on all three major impulsivity domains. Therefore, we set out to test the effect of STN-DBS and dopaminergic medication on motor, reflection, and cognitive impulsivity in PD patients treated with STN-DBS.

The demographic data and clinical characteristics of the participants are summarised in Table 1. The DBS parameter settings are presented in Table 2. In total, 20 PD patients treated with STN-DBS were included in the study. No patient took extended-release levodopa. Eighteen patients (90%) were taking extended-release dopaminergic agonists in the form of a once-daily morning dose, with a median withdrawal time of 20 h (range 19–24 h). The overnight withdrawal (at least 12 h) was applied for the immediate-release levodopa preparations. Seventeen patients (85%) had BDI-II scores between 0 and 13, indicating no or minimal depression, and three patients (85%) had BDI-II scores between 14 and 19, indicating mild depression. There were no patients with moderate or severe depression. Five patients (25%) reported SAS scores ≥14, indicating apathy, while the rest of the patients had scores lower than 14. Only three patients (15%) had total BIS-11 scores ≥72, indicating impulsiveness; the rest of the patients had total BIS-11 scores lower than 72. No patient had scored above the established cut-offs for gambling, sex, buying and eating. In total, 25% of the patients scored ≥10 on the combined measure (gambling+sex+buying+eating), and 35% had a score ≥ 7 for hobbyism and punding. The overall MDS-UPDRS III score ON medication/ON stimulation was the lowest, while it was the highest OFF/medication OFF stimulation (F(3, 57) = 90.29, p < 0.001).

Our study examined the effects of dopaminergic medication and STN-DBS on motor, reflection, and cognitive impulsivity domains in PD patients. The main finding of the study was that the combination of dopaminergic medication and STN-DBS had a significant effect on motor impulsivity, increasing both proactive and reactive motor impulsivity subdomains, but had no effect on reflection and cognitive impulsivity domains.

To date, studies have focussed on assessing the effect of dopaminergic medication and STN-DBS alone, showing that either dopaminergic medication (Antonelli et al., 2014; Canário et al., 2019) or STN-DBS (Mirabella et al., 2012; Georgiev et al., 2016) can increase motor impulsivity. Our results are therefore the first to demonstrate that the combination of STN-DBS and dopaminergic medication causes motor impulsivity in STN-DBS-operated PD patients. In addition, the results of our study indicate that both proactive and reactive inhibitory control are impaired in patients ON stimulation and ON medication. While proactive inhibition (BX trials) refers to the ability to prepare for inhibition, involving recruiting the stopping network before inhibition occurs, reactive inhibition (AY trials) does not involve preparation but rather the reactive cessation of a response that has already been initiated (Esteban-Peñalba et al., 2021). Indeed, STN-DBS has previously been shown to be associated with the modulation of networks associated with both proactive and reactive inhibition (Ballanger et al., 2009). These networks include the pre-supplementary motor area, the dorsal and ventral premotor cortex, the dorsal anterior cingulate cortex, the primary motor cortex, and the inferior frontal cortex. Similarly, dopaminergic medication has been shown to impair both proactive and reactive inhibition in PD (Mirabella et al., 2024), although the results of other studies suggest selective dopaminergic medication-dependent impairment of reactive inhibition, and preservation of proactive inhibition (Canário et al., 2019), or conversely an impairment of proactive inhibition and preservation of reactive inhibition (Kricheldorff et al., 2023).

We found no effects of dopaminergic medication and STN-DBS on cognitive and reflection impulsivity. Our results are consistent with data from studies showing no differences in cognitive impulsivity between PD patients and healthy controls (Antonelli et al., 2011), suggesting normal performance of PD patients on cognitive impulsivity tasks. However, some studies have found differences in different subgroups of PD patients. In contrast to patients with PD without impulse control disorders, patients with PD with impulse control disorders show impaired cognitive impulsivity (Rossi et al., 2010). In our study, the rate of impulse control disorders among patients was low, which could explain the relatively stable level of cognitive impulsivity on which dopaminergic medication and STN-DBS had no effect. In PD patients with impulse control disorders, activation of cortical and subcortical areas that play a role in the performance of cognitive impulsivity tasks, such as the ventromedial prefrontal cortex and amygdala-ventral striatum system, has been observed (Rossi et al., 2010). In addition, dopaminergic medication, particularly dopamine agonists, may promote cognitive impulsivity in PD. STN-DBS may also be involved in cognitive impulsivity, in terms of its role in conflictual decision-making, although the evidence for the involvement of STN-DBS in motor impulsivity is much stronger.

Reflection impulsivity, sometimes considered a subtype of cognitive impulsivity, is the least studied form of impulsivity in PD. Similar to cognitive impulsivity, the results on reflection impulsivity tasks may depend on the presence of impulse control disorders (Hlavatá et al., 2019), which could explain our results as the rate of impulse control disorders in our patients was small. However, another study found an effect of dopaminergic medication, particularly dopamine agonists, on reflection impulsivity tested with the beads task even in patients without impulse control disorders (Djamshidian et al., 2013). In this study, patients taking dopamine agonists gathered significantly less information and made more irrational decisions, independent of STN-DBS, suggesting that reflection impulsivity may not be directly dependent on STN activity. Nevertheless, similar to our study, some studies have found no impairment of reflection impulsivity in PD (Czernecki et al., 2002; Euteneuer et al., 2009).

Impulsivity is a complex concept that encompasses various processes and subdomains, including motor, cognitive, and reflection impulsivity. Compared to cognitive and reflection impulsivity, motor impulsivity seems to be better characterised and defined. The STN-DBS may be involved in cognitive and reflection impulsivity in relation to its role in limbic circuity and its role in high-conflict decision-making processes (Antonelli et al., 2011; Jahanshahi, 2013; Jahanshahi et al., 2015). However, the role of STN-DBS in motor impulsivity is much more obvious, although there are still open questions, such as which factors influence STN activity and response threshold adaptation (Jahanshahi et al., 2015). The predominant involvement of the STN in motor impulsivity may partly explain our results showing a clear effect of STN-DBS (and dopaminergic medication) on motor but not on cognitive and reflection impulsivity. Furthermore, the variability of results across studies could be due to the fact that different studies used different paradigms to explain the same or a similar phenomenon (e.g., Go-No-Go and Stop-signal task to explain motor impulsivity) (Jahanshahi, 2013; Jahanshahi et al., 2015). In addition, the study populations also differ significantly in terms of the degree of impulsivity of the study population, which could influence cognitive and reflection impulsivity, especially in impulse control disorders. In our study, a small proportion of patients were categorised as impulsive based on either the BIS-11 or the QUIP-RS, which could explain the fact that dopaminergic medication and STN-DBS did not affect these subdomains of impulsivity.

The main limitations of our study were the relatively small sample size and the fact that we did not include healthy controls. However, the PD patients in our study were tested under four different conditions to investigate the effect of dopaminergic medication and STN-DBS on three different types of impulsivity. By comparing different treatment conditions, including both DBS and dopaminergic medication, in the same patients, we were able to reduce potential differences between patients. In addition, the main objective of the study was to test the effect of dopaminergic medication and STN-DBS on different domains of impulsivity in PD. Our study focussed on short-term changes in treatment conditions. However, we used the common real-world definition of nocturnal drug withdrawal to define the OFF state in PD. In addition, we wanted to test the acute effect of stimulation manipulations on impulsivity. Although a 40-min stimulation withdrawal may seem short, there was a clear difference in motor state with stimulation OFF versus simulation ON, both with dopaminergic medication ON and OFF. In addition, a relatively short period of stimulation withdrawal has been used to date in many studies (Pillon et al., 2000; Plessow et al., 2014; Brandt et al., 2015; Castrioto et al., 2015). PD patients included in our study did not have dementia. This fact allowed for greater power to detect differences between conditions. However, future studies would benefit from including patients with different stages and severity of cognitive impairment that could allow for the evaluation a possible relationship between impulsivity and cognitive impairment or impairment of individual cognitive domains. We found an effect of stimulation and medication on motor impulsivity but not on cognitive and reflection impulsivity. Future studies might benefit from using more than one task for different types of impulsivity, although this could significantly increase the duration of experiments to ensure that the lack of effect is truly due to the lack of effect of medication and/or stimulation on specific domains of impulsivity rather than the inability to detect the effect due to task-related characteristics.

In summary, our study found that the combination of dopaminergic medication and STN-DBS leads to increased motor impulsivity but does not affect cognitive and reflection impulsivity in PD patients. This finding could have clinical implications by highlighting the potential worsening of impulsivity when combining dopaminergic medication and STN-DBS. Future research examining the effects of dopaminergic medication and STN-DBS is needed to replicate our findings and to focus on long-term differences in different domains of impulsivity.

The datasets presented in this article are not readily available because the data that support the findings of this study are available from the corresponding author, DG, upon reasonable request. Requests to access the datasets should be directed to dejan.georgiev@kclj.si.

The studies involving humans were approved by Medical Ethical Committee of the Republic of Slovenia. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants' legal guardians/next of kin.

MH: Data curation, Investigation, Visualization, Writing – original draft, Writing – review & editing. SV: Validation, Writing – review & editing. RB: Validation, Writing – review & editing. MB: Writing – review & editing. MJ: Validation, Writing – review & editing. MT: Validation, Writing – review & editing. DG: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Supervision, Validation, Visualization, Writing – review & editing.