Dopamine and Cognition

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

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.

Study Overview

• Status: Completed
• Conditions: 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: Drug: Sulpiride 400 MG; Drug: Placebo

Detailed Description

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
• Enrollment (Actual): 47
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands
      • Donders Centre for Cognition, Radboud University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diastolic blood pressure	Unit of measurement: mmHG	Measured at baseline on intervention day 1 (before pharmacological intervention took place)
Diastolic blood pressure	Unit of measurement: mmHG	Measured at baseline on intervention day 2 (before pharmacological intervention took place)
Diastolic blood pressure	Unit of measurement: mmHG	Measured 90 min post drug/placebo intake on intervention day 1
Diastolic blood pressure	Unit of measurement: mmHG	Measured 90 min post drug/placebo intake on intervention day 2
Diastolic blood pressure	Unit of measurement: mmHG	Measured 300 min post drug/placebo intake on intervention day 1
Diastolic blood pressure	Unit of measurement: mmHG	Measured 300 min post drug/placebo intake on intervention day 2
Systolic blood pressure	Unit of measurement: mmHG	Measured at baseline on intervention day 1 (before pharmacological intervention took place)
Systolic blood pressure	Unit of measurement: mmHG	Measured at baseline on intervention day 2 (before pharmacological intervention took place)
Systolic blood pressure	Unit of measurement: mmHG	Measured 90 min post drug/placebo intake on intervention day 1
Systolic blood pressure	Unit of measurement: mmHG	Measured 90 min post drug/placebo intake on intervention day 2
Systolic blood pressure	Unit of measurement: mmHG	Measured 300 min post drug/placebo intake on intervention day 1
Systolic blood pressure	Unit of measurement: mmHG	Measured 300 min post drug/placebo intake on intervention day 2
Heart rate	Unit of measurement: beats per minute (bpm)	Measured at baseline on intervention day 1 (before pharmacological intervention took place)
Heart rate	Unit of measurement: beats per minute (bpm)	Measured at baseline on intervention day 2 (before pharmacological intervention took place)
Heart rate	Unit of measurement: beats per minute (bpm)	Measured 90 min post drug/placebo intake on intervention day 1
Heart rate	Unit of measurement: beats per minute (bpm)	Measured 90 min post drug/placebo intake on intervention day 2
Heart rate	Unit of measurement: beats per minute (bpm)	Measured 300 min post drug/placebo intake on intervention day 1
Heart rate	Unit of measurement: beats per minute (bpm)	Measured 300 min post drug/placebo intake on intervention day 2
Body temperature	Measured in degree Celsius by an in-ear thermometer	Measured at baseline on intervention day 1 (before pharmacological intervention took place)
Body temperature	Measured in degree Celsius by an in-ear thermometer	Measured at baseline on intervention day 2 (before pharmacological intervention took place)
Body temperature	Measured in degree Celsius by an in-ear thermometer	Measured 90 min post drug/placebo intake on intervention day 1
Body temperature	Measured in degree Celsius by an in-ear thermometer	Measured 90 min post drug/placebo intake on intervention day 2
Body temperature	Measured in degree Celsius by an in-ear thermometer	Measured 300 min post drug/placebo intake on intervention day 1
Body temperature	Measured in degree Celsius by an in-ear thermometer	Measured 300 min post drug/placebo intake on intervention day 2
Respiration movements	Voltage change over time measured by a respiration belt around participants' abdomen during MRI scanning	Measured during the MRI scan (115 min post drug/placebo) on intervention day 1. The pharmacological intervention sessions take place at least 14 days apart)
Respiration movements	Voltage change over time measured by a respiration belt around participants' abdomen during MRI scanning	Measured during the MRI scan (115 min post drug/placebo) on intervention day 2. The pharmacological intervention sessions take place at least 14 days apart)
Visual Analogue Scale (VAS)	Measured with 16 mood rating items measured on a continuous scale from 1 to 10 by self-report	Measured at baseline on intervention day 1 (before pharmacological intervention took place)
Visual Analogue Scale (VAS)	Measured with 16 mood rating items measured on a continuous scale from 1 to 10 by self-report	Measured at baseline on intervention day 2 (before pharmacological intervention took place)
Visual Analogue Scale (VAS)	Measured with 16 mood rating items measured on a continuous scale from 1 to 10 by self-report	Measured 90 min post drug/placebo intake on intervention day 1
Visual Analogue Scale (VAS)	Measured with 16 mood rating items measured on a continuous scale from 1 to 10 by self-report	Measured 90 min post drug/placebo intake on intervention day 2
Visual Analogue Scale (VAS)	Measured with 16 mood rating items measured on a continuous scale from 1 to 10 by self-report	Measured 300 min post drug/placebo intake on intervention day 1
Visual Analogue Scale (VAS)	Measured with 16 mood rating items measured on a continuous scale from 1 to 10 by self-report	Measured 300 min post drug/placebo intake on intervention day 2
Positive and Negative Affect Scale (PANAS)	Measured with 20 statements regarding feelings and emotions measured on a 5-point Likert scale by self-report	Measured at baseline on intervention day 1 (before pharmacological intervention took place)
Positive and Negative Affect Scale (PANAS)	Measured with 20 statements regarding feelings and emotions measured on a 5-point Likert scale by self-report	Measured at baseline on intervention day 2 (before pharmacological intervention took place)
Positive and Negative Affect Scale (PANAS)	Measured with 20 statements regarding feelings and emotions measured on a 5-point Likert scale by self-report	Measured 90 min post drug/placebo intake on intervention day 1
Positive and Negative Affect Scale (PANAS)	Measured with 20 statements regarding feelings and emotions measured on a 5-point Likert scale by self-report	Measured 90 min post drug/placebo intake on intervention day 2
Positive and Negative Affect Scale (PANAS)	Measured with 20 statements regarding feelings and emotions measured on a 5-point Likert scale by self-report	Measured 300 min post drug/placebo intake on intervention day 1
Positive and Negative Affect Scale (PANAS)	Measured with 20 statements regarding feelings and emotions measured on a 5-point Likert scale by self-report	Measured 300 min post drug/placebo intake on intervention day 2
Menstrual cycle stage (for female participants)	Day of onset of last menstrual bleeding measured by self-report	Measured within the first 10 min of the intervention day 1 (i.e., 10 min pre drug/placebo)
Menstrual cycle stage (for female participants)	Day of onset of last menstrual bleeding measured by self-report	Measured within the first 10 min of the intervention day 2 (i.e., 10 min pre drug/placebo)

Collaborators and Investigators

• Sponsor: Donders Centre for Cognitive Neuroimaging
• Collaborators: Dr. Hanneke den Ouden, Donders Centre for Cognition, Radboud University; Dr. Rebecca Calcott, Donders Centre for Cognitive Neuroimaging, Radboud University; Prof. Dr. Robbert-Jan Verkes, Radboud University Medical Centre Department of Psychiatry; Floortje Spronkers, Donders Centre for Cognition, Radboud University; Funding: NWO + KNAW

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2021
• Primary Completion (Actual): July 12, 2022
• Study Completion (Actual): July 12, 2022

Study Registration Dates

• First Submitted: March 21, 2023
• First Submitted That Met QC Criteria: May 22, 2023
• First Posted (Actual): June 1, 2023

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 19, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Dopamine Agents; Dopamine Antagonists; Antidepressive Agents, Second-Generation; Sulpiride
• Other Study ID Numbers: 3017048.09

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Following publication, raw and processed data will be archived for scientific integrity. The data use agreement gives access to the data, provided that certain conditions set by the local institutional guidelines as well as (inter)national (EU) law are met.

Data sharing will be done using the Donders Institute research data repository (http://data.donders.ru.nl) in accordance to institutional and EU guidelines.

• IPD Sharing Time Frame: After publication
• IPD Sharing Access Criteria: As described on the website of the Donders Repository, shared data can be accessed via a persistent identifier. This identifier can be obtained directly from the authors or via a link in the publication. Also see: https://data.donders.ru.nl/doc/help/user-manual/access-shared-data/request-access.html?4
• IPD Sharing Supporting Information Type: ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No