Dopamine Effect on Inhibitory Control (DEI)

The effect of Levodopa medication on inhibitory control in Parkinson's patients is extremely debated despite the fact that this has potential clinical and therapeutic implications. A key confounding factor of many previous studies is that they did not take the disease duration in consideration. In fact, in moderate-to-advanced stages of Parkinson dopaminergic drugs could not produce a clear effect because too few dopaminergic cells for the drugs to operate on survived. Hence, in this study, we will compare the performance in the stop signal task in early-stage versus moderate-to-advanced stages Parkinson's patients both in ON and in OFF medication. In addition, to have a baseline measure of inhibitory control we will compare patient's performances with that of age-matched subjects.

The ability to stop a pending action is fundamental for survival in a natural environment where events cannot be fully predicted. Sudden events, such as the appearance of a physical obstacle, often require a quick change of the planned motor strategy and the first step toward this goal is to suppress the pre-programmed actions. Thus voluntary inhibition plays a crucial role in cognitive control and behavioral flexibility (1, 2). It has been shown that Parkinson's patients suffer from a specific deficit in this functions (3, 4, 5). However, it is extremely debated whether and how Levodopa medication (levodopa, dopamine agonists, anticholinergic drugs, or a combination of levodopa and an anticholinergic drug) affects response inhibition. A number of studies measuring inhibitory control via the stop signal task in Parkinson's patients seem to indicate that dopaminergic medications do not influence this executive function (5, 6, 7). However, a recent study (8) found that Levodopa medication does not affect specifically inhibitory control or movement readiness, but the balance between them. In fact, Parkinson's patients in the OFF medication state were able to maintain response latencies in the same range as healthy controls, but they showed a significant reduction in the ability to stop reactions abruptly. In contrast, patients' performance shifted significantly when taking dopaminergic medications. They move slower but stopping improved relative to the off dopamine state. This pattern suggests a role for dopamine in modulating the tradeoff between the two action control processes. In addition, studies of other specific populations and healthy adults suggest that dopaminergic medications deserve reconsideration in response inhibition. For instance, positron emission (PET) studies have found that higher levels of striatal D1 and D2/D3 receptor availability predict better performance on the stop signal task (9, 10) and that response inhibition performance evokes dopamine release in prefrontal, parietal, and temporal cortex in healthy adults (11). Even more importantly, a few recent studies provided evidence that early-stage Parkinson's patients with response inhibition impairment seem to benefit from dopaminergic treatment (12,13). Therefore, a plausible hypothesis is that the absence of a clear effect of dopaminergic medications could be ascribed to the fact that in most previous studies included Parkinson's patients in the moderate-to-advanced stages. In those patients, the diminished efficacy of dopaminergic drugs could be a consequence that too few dopaminergic cells for the drugs to operate on survived (14). Hence, the aim of the present work is to re-assess the impact of dopaminergic medications on inhibitory control on Parkinson's patients using a reaching version of the stop signal task (e.g. 4, 15, 16, 17, 18) taking the disease duration in consideration. To this aim, the investigators will compare the performance in the stop signal task in early-stage versus moderate-to-advanced stages Parkinson's patients both in ON and in OFF medication. Finally, to have a baseline measure of inhibitory control the investigators will compare patients' performances with those of age-matched subjects.

Levodopa medication, stop signal task, inhibitory control, Parkinson's Disease, stop signal reaction time, proactive inhibition

Both groups of patients will perform the stop-signal task and the go-only task under two conditions: a) ON Levodopa medication state calculated after the first-morning dose which normally allowed the patient to attain the best control of symptoms (4) b) OFF Levodopa medication state. i.e patients did not take medications overnight prior to the study (19). Experimental conditions will be counterbalanced across patients and administered in two different experimental sessions occurring on different days. Healthy controls will perform the stop signal task and the go-only task in the same day. The order of administration will be counterbalanced.

Idiopathic Parkinson's patient's with Hoehn and Yahr score of 1.5- 2 i.e. in an early stage of the disease, under stable treatment with the administration of L-dopa and dopamine agonists. Patients will not present severe sensory deficits or any other neurological disease besides PD, as will be assessed by a standard neurological examination, and they will be all right-handed as will be assessed by the Edinburgh handedness inventory. Age range: 40-70

Parkinson's patient's with Hoehn and Yahr score of 3, i.e. in moderate-to-advanced stages of the disease under stable treatment with the administration of L-dopa and dopamine agonists. Patients will not present severe sensory deficits or any other neurological disease besides PD, as will be assessed by a standard neurological examination, and they will be all right-handed as will be assessed by the Edinburgh handedness inventory. Age range: 40-70

Healthy controls. Right-handed healthy subjects (it will be assessed by the Edinburgh handedness inventory) with normal or corrected-to-normal vision, without a history of neurological diseases. Age range: 40-70.

Parkinson's patients will be allowed to the first-morning dose of levodopa medicament (levodopa, dopamine agonists, anticholinergic drugs, or a combination of levodopa and an anticholinergic drug) which normally allowed the patient to attain the best control of symptoms one hour before being tested (19). Patients will perform both the stop-signal task and the go-only task. Experimental conditions will be counterbalanced across patients.

Parkinson's patients will not take medications overnight prior to the study (20). Patients will perform both the stop-signal task and the go-only task. Experimental conditions will be counterbalanced across patients. This intervention will be given on a different day with respect to the Medication ON intervention. The order of intervention will be counterbalanced across subjects

Healthy controls will perform the stop signal task and the go-only task in the same day. The order of administration will be counterbalanced.

Parkinson's patients will not take medications overnight prior to the study (20). Patients will perform both the stop-signal task and the go-only task. Experimental conditions will be counterbalanced across patients. This intervention will be given on a different day with respect to the Medication ON intervention. The order of intervention will be counterbalanced across subjects

Parkinson's patients will be allowed to the first-morning dose of levodopa medicament (levodopa, dopamine agonists, anticholinergic drugs, or a combination of levodopa and an anticholinergic drug) which normally allowed the patient to attain the best control of symptoms one hour before being tested (19). Patients will perform both the stop-signal task and the go-only task. Experimental conditions will be counterbalanced across patients.

Reactive inhibition refers to the ability of a subject to react to the stop instruction, and it is measured by the stop-signal reaction time (SSRT). This variable cannot be measured, but it can be estimated by using the race model (21, 4, 16, 17, 18, 22).

Proactive inhibition refers to the ability of subjects to shape their response strategy in anticipation of known task demands driven by endogenous signals. In the case of the countermanding task, the endogenous signal is represented by the awareness of the fact that sometimes an imperative stop-signal could have been presented. Proactive control could be assessed by measuring reaction times (i.e. the time to initiate a response, RTs) and movement times (i.e. the time to execute the motor response, MTs) of no-stop trials. Previous research has shown that when a movement is produced in the context of the countermanding task, that is when the subject executes a no-stop trial, its RT is lengthened (e.g. 4, 15, 16, 17, 18, 22) and its MT is shortened compared to situations in which the same movement has to be performed in the context of a simple RT-task (go-only trial; 4, 15, 17)

Inclusion Criteria: Right-handedness (as assessed by the Edinburgh Handedness Inventory) Being in stable treatment with the administration of L-dopa and dopamine agonists (i.e. not having motor fluctuations and/or dyskinesia) Having a Hoehn & Yahr score between 1.5 and 3 Exclusion Criteria: Presence of severe sensory deficits Presence of overt signs of dementia (a. mini-mental state examination, MMSE must be ≥24; b. intelligence quotient ≥75). Comorbidity with other psychiatric disorders that might interfere with task execution (i.e. attentional disorders). Presence of severe tremor or rigidity of the right arm in the OFF medication state.

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