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Dopamine Effect on Inhibitory Control (DEI)

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ClinicalTrials.gov Identifier: NCT03665493
Recruitment Status : Not yet recruiting
First Posted : September 11, 2018
Last Update Posted : July 4, 2019
Sponsor:
Information provided by (Responsible Party):
Giovanni Mirabella, Neuromed IRCCS

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Idiopathic Parkinson's Disease Drug: PD patients H&Y=1.5-2 Medications ON Drug: PD patients H&Y=1.5-2 Medications OFF Behavioral: Healthy age-matched controls Drug: PD patients H&Y=3 Medications OFF Drug: PD patients H&Y=3 Medications ON Not Applicable

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Intervention Model Description:

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.

Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Dopamine Effect on Inhibitory Control
Estimated Study Start Date : September 2019
Estimated Primary Completion Date : February 2020
Estimated Study Completion Date : October 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: PD patients H&Y=1.5-2 Medications ON
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
Drug: PD patients H&Y=1.5-2 Medications ON
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.

Experimental: PD patients H&Y=3 Medications ON
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
Drug: PD patients H&Y=3 Medications ON
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.

Experimental: PD patients H&Y=1.5-2 Medications OFF
Same as above described
Drug: PD patients H&Y=1.5-2 Medications OFF
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

Experimental: PD patients H&Y=3 Medications OFF
Same as above described
Drug: PD patients H&Y=3 Medications OFF
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

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




Primary Outcome Measures :
  1. Changes of length of the Stop Signal Reaction Time [ Time Frame: Up to one year ]
    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).

  2. Changes of the length of Reaction Times and Movement Times [ Time Frame: Up to one year ]
    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)



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Ages Eligible for Study:   40 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Right-handedness (as assessed by the Edinburgh Handedness Inventory)
  2. Being in stable treatment with the administration of L-dopa and dopamine agonists (i.e. not having motor fluctuations and/or dyskinesia)
  3. Having a Hoehn & Yahr score between 1.5 and 3

Exclusion Criteria:

  1. Presence of severe sensory deficits
  2. Presence of overt signs of dementia (a. mini-mental state examination, MMSE must be ≥24; b. intelligence quotient ≥75).
  3. Comorbidity with other psychiatric disorders that might interfere with task execution (i.e. attentional disorders).
  4. Presence of severe tremor or rigidity of the right arm in the OFF medication state.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03665493


Contacts
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Contact: Giovanni Mirabella, Ph.D. 3282190201 giovanni.mirabella@uniroma1.it

Sponsors and Collaborators
Giovanni Mirabella

Publications of Results:

Other Publications:
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Responsible Party: Giovanni Mirabella, Principal Investigator, Neuromed IRCCS
ClinicalTrials.gov Identifier: NCT03665493     History of Changes
Other Study ID Numbers: GMirab_01
First Posted: September 11, 2018    Key Record Dates
Last Update Posted: July 4, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Giovanni Mirabella, Neuromed IRCCS:
Levodopa medication
stop signal task
inhibitory control
Parkinson's Disease
stop signal reaction time
proactive inhibition

Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Levodopa
Dopamine
Dopamine Agents
Dopamine Agonists
Antiparkinson Agents
Anti-Dyskinesia Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Cardiotonic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Protective Agents