Dopamine and Cognition

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Dopaminergic Mechanisms of Gating Working Memory, Learning and Motivation: a Pharmaco-fMRI Study

Conditions
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Sulpiride's Effect on Striatal BOLD Signal During Working Memory Gating, Interaction of Sulpiride, Average Reward Rate and Evidence Accumulation, Interaction of Sulpiride, Average Reward Rate and Cognitive Effort

Intervention / Treatment
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* Drug: Sulpiride 400 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers between 18 and 45 years of age Predominant right-handedness Exclusion Criteria: Presence of prolactin-dependent tumors (e.g., pituitary prolactinoma or breast cancer) (History of) autonomic failure (e.g., vasovagal reflex syncope). (History of) clinically significant hepatic, cardiac, obstructive respiratory, renal, cerebrovascular, cardiovascular, metabolic, ocular or pulmonary disease/disorders (History of) epilepsy in adulthood (i.e. no insult after 18 years of age, no current medication for epilepsy and no insult in the last five years) Diagnosis (or history of) endocrine treatment Diagnosis (or history of) neuroendocrine treatment (e.g., phechromocytoma, hyperthyroidism, Cushing's syndrome) (History of) melanoma Hypersensitivity to sulpiride One first degree or two or more second degree family members with a history of sudden death or ventricular arrhythmia Abnormal QT interval (assessed via ECG) Uncontrolled hypertension, defined as diastolic blood pressure at rest > 95 mmHg or systolic blood pressure at rest > 180 mmHg Hypotension, defined as diastolic blood pressure < 50 mm Hg or systolic < 95 mm Hg or resting pulse rate < 45 beats/min Diabetes History of prescribed medication within the last month prior to the start of the study. History of 'over the counter' medication within the last two months (with exception of occasional use of paracetamol, acetylsalicylic acid, and ibuprofen). Possible pregnancy or breastfeeding No appropriate contraception Undiagnosed skin lesions Lactose intolerance Glaucoma or increased risk for glaucoma Possible pregnancy or breastfeeding Metal objects in or around the body (braces, pacemaker, metal fragments, hearing devices) Claustrophobia Diagnosis (or history of) psychiatric treatment (e.g., severe depression, anorexia nervosa, severe mood disorders, mania, schizophrenia or borderline personality disorder) Diagnosis (or history of) neurological treatment (History of) drug dependence (opiate, LSD, (meth)amphetamine, cocaine, solvents, or barbiturate) or alcohol dependence Suicidality Use of MAO inhibitor, anaesthetic, antidepressant or antipsychotic drugs within the week prior to the start of the study. Average use of psychotropic medication or recreational drugs weekly or more. Cannabis use within 2 weeks prior to the start of the study, and periods of more than 3 months using weekly or more in the last 6 months Use of psychotropic medication, or of recreational drugs over a period of 72 hours prior to the test sessions, and use of alcohol within the last 24 hours before each measurement. Average use of more than 3 alcohol beverages daily. Average use of psychotropic medication or recreational drugs weekly or more. Habitual smoking, i.e., more than a pack of cigarettes per week and/or a self-reported inability or unease to cease smoking for 24 hours to testing. Regular use of corticosteroids. Abnormal hearing or (uncorrected) vision. First degree family member with schizophrenia or bipolar disorder Irregular sleep/wake rhythm (e.g., regular nightshifts or cross timezone travel). Left handedness (because lateralisations of brain activation may differ from right-handed people).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a within-subjects (i.e., crossover), double-blind, randomized placebo-controlled study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sulpiride<br>All study participants receive both placebo and the active medication (sulpiride 400mg), in a within-subjects , double-blind, randomized design. | Drug: Sulpiride 400 MG<br>* 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.<br>* Other names: Dogmatil;|
| Placebo Comparator: Placebo<br>All study participants receive both placebo and the active medication (sulpiride 400mg), in a within-subjects , double-blind, randomized design. | Drug: Placebo<br>* All participants will receive placebo during one of the sessions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 | 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 | 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. | 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. | 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. | 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. | Measured at intervention day 2, 215 min after the pharmacological intervention took place. Measurements are compared regarding intervention type (drug versus placebo). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Eye-blink rate | Number of spontaneous eye blinks per minute, as a clinically relevant biomarker of striatal dopamine function | Measured at baseline during intake session | 
| Operation Span test | Number of letters remembered while performing math problems, as a parameter for working memory capacity | 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 | 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 | 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 | 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 | 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) | Baseline measure via online questionnaire in between first and second intervention session (these take place at least 14 days apart) | 
| Behavioural Inhibition Scale/Behavioural Activation Scale | Average score as indicator of behavioural activation and inhibition | 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 | 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 | 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 | Baseline measure via online questionnaire in between first and second intervention session (these take place at least 14 days apart) |