Rationale: To unravel the role of dopamine in gating of working memory, motivation and learning. Objective: The primary objective of this study is to isolate effects of blocking D2 receptor stimulation on gating of working memory, reinforcement learning and reward-based motivation, and their associated physiological changes (measured with fMRI and eye tracking). The secondary objective is to assess the degree to which the effects of D2 receptor action vary as a function of proxy measures of baseline dopamine levels. Study design: A double-blind placebo controlled within-subject design will be employed, in which young healthy participants are tested twice, once on placebo, and once on a low oral dose (400mg) of the D2 receptor antagonist sulpiride. This design and drug dose is commonly used in our lab without side effects (previously approved CMO protocols 2011/204, 2008/078 \& 2016/2646). Study population: Healthy human participants, 18 - 45 yr old. We will recruit 46 participants. Intervention: Participants will receive both 400 mg sulpiride and placebo, in separate sessions in a counterbalanced order. Main study parameters/endpoints: BOLD signal measured with fMRI, and behavioural performance on cognitive tasks. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Participants will attend 3 study sessions: A screening session and 2 pharmaco-fMRI sessions (sulpiride and placebo). Participants will complete a baseline battery of tasks and questionnaires, a structural MRI scan, as well as a battery of tasks both in and outside the scanner. On the day preceding each pharmaco-fMRI session, participants will have to adhere to some simple restrictions with respect to medication, alcohol and drug intake. On the day of testing participants will have to refrain from smoking and stimulant-containing drinks. Sulpiride can be administered safely without any relevant risk of serious adverse events and has been approved for clinical use in the Netherlands.
A more detailed description can be found in the approved research protocol as well as the pre-registrations. The links to the pre-registrations will be made available upon publication.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
TRIPLE
Enrollment
47
All participants will receive one single dose of 400mg sulpiride. None of the participants will receive repeated doses. In order for the fMRI data acquisition to coincide with the time-window of maximal drug effects represented by a combination of plasma kinetics and physiological effects we will administer the drug 90 minutes prior to fMRI data acquisition.
All participants will receive placebo during one of the sessions.
Donders Centre for Cognition, Radboud University
Nijmegen, Gelderland, Netherlands
Working memory gating task: Reaction time
Reaction time \[ms\] during selective vs. non-selective input- and output-gating to assess the ability (speed) to selectively input- and output-gate working memory representations at intervention (sulpiride) versus placebo.
Time frame: Measured at intervention day 1, 115 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Working memory gating task: Reaction time
Reaction time \[ms\] during selective vs. non-selective input- and output-gating to assess the ability (speed) to selectively input- and output-gate working memory representations at intervention (sulpiride) versus placebo.
Time frame: Measured at intervention day 2, 115 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Working memory gating task: Accuracy
Accuracy \[%\] during selective vs. non-selective input- and output-gating to assess the ability (correctness) to selectively input- and output-gate working memory representations at intervention (sulpiride) versus placebo.
Time frame: Measured at intervention day 1, 115 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Working memory gating task: Accuracy
Accuracy \[%\] during selective vs. non-selective input- and output-gating to assess the ability (correctness) to selectively input- and output-gate working memory representations at intervention (sulpiride) versus placebo.
Time frame: Measured at intervention day 2, 115 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Working memory gating task: BOLD-response
BOLD-response to selective vs. global cues, examined for both pre- and retro-cue conditions (i.e., input- and output-gating respectively) to assess the neural response to selective working memory gating at intervention (sulpiride) versus placebo.
Time frame: Measured at intervention day 1, 115 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Working memory gating task: BOLD-response
BOLD-response to selective vs. global cues, examined for both pre- and retro-cue conditions (i.e., input- and output-gating respectively) to assess the neural response to selective working memory gating at intervention (sulpiride) versus placebo.
Time frame: Measured at intervention day 2, 115 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Simon task: Accuracy
Accuracy \[%\] during high and low average reward rate congruent and incongruent trials to assess cognitive effort investment after intervention versus placebo.
Time frame: Measured at intervention day 1, 250 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Simon task: Accuracy
Accuracy \[%\] during high and low average reward rate congruent and incongruent trials to assess cognitive effort investment after intervention versus placebo.
Time frame: Measured at intervention day 2, 250 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Simon task: Reaction time
Reaction time \[ms\] during high and low average reward rate congruent and incongruent trials to assess cognitive effort investment after intervention versus placebo
Time frame: Measured at intervention day 1, 250 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Simon task: Reaction time
Reaction time \[ms\] during high and low average reward rate congruent and incongruent trials to assess cognitive effort investment after intervention versus placebo
Time frame: Measured at intervention day 2, 250 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Perceptual decision-making task: Accuracy
Accuracy \[%\] as a function of average reward rate to assess cognitive effort investment after intervention versus placebo.
Time frame: Measured at intervention day 1, 215 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Perceptual decision-making task: Accuracy
Accuracy \[%\] as a function of average reward rate to assess cognitive effort investment after intervention versus placebo.
Time frame: Measured at intervention day 2, 215 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Perceptual decision-making task: Reaction time
Reaction time \[ms\] as a function of average reward rate to assess cognitive effort investment after intervention versus placebo.
Time frame: Measured at intervention day 1, 215 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Perceptual decision-making task: Reaction time
Reaction time \[ms\] as a function of average reward rate to assess cognitive effort investment after intervention versus placebo.
Time frame: Measured at intervention day 2, 215 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo).
Eye-blink rate
Number of spontaneous eye blinks per minute, as a clinically relevant biomarker of striatal dopamine function
Time frame: Measured at baseline during intake session
Operation Span test
Number of letters remembered while performing math problems, as a parameter for working memory capacity
Time frame: Measured at baseline during intake session
Digit Span test
Accuracy score \[nr of correct responses\] on forward span and backward span, as a parameter for working memory capacity
Time frame: Measured at baseline during intake session
Digit Span test
Accuracy score \[nr of correct responses\] on forward span and backward span, as a parameter for working memory capacity
Time frame: Measured during intervention day 1 (sessions at least 14 days apart), 290 min after the pharmacological intervention took place
Digit Span test
Accuracy score \[nr of correct responses\] on forward span and backward span, as a parameter for working memory capacity
Time frame: Measured during intervention day 2 (sessions at least 14 days apart), 290 min after the pharmacological intervention took place
Beck Depression Inventory
Average score as indicator of depressive symptoms
Time frame: Baseline measure via online questionnaire in between first and second intervention session (these take place at least 14 days apart)
Barratt Impulsiveness Scale
Average score as indicator of impulsivity (personality trait)
Time frame: Baseline measure via online questionnaire in between first and second intervention session (these take place at least 14 days apart)
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Behavioural Inhibition Scale/Behavioural Activation Scale
Average score as indicator of behavioural activation and inhibition
Time frame: Baseline measure via online questionnaire in between first and second intervention session (these take place at least 14 days apart)
State and Trait Anxiety Inventory
Average score as indicator of state and trait anxiety
Time frame: Baseline measure via online questionnaire in between first and second intervention session (these take place at least 14 days apart)
Utrechtse Burnout Schaal/Maslach Burnout Inventory
Average score as indicator of burn out
Time frame: Baseline measure via online questionnaire in between first and second intervention session (these take place at least 14 days apart)
Covid-19 Stress Scales
Average score as indicator of COVID-related stress and anxiety
Time frame: Baseline measure via online questionnaire in between first and second intervention session (these take place at least 14 days apart)