Optimistic and Pessimistic Dopamine Signals in the Human Brain: a Mapping and Modelling Study in Health and Parkinson's Disease

NCT07402928 | Recruiting

• 1 other identifier: H-24084004
• Study Type: observational
• Target: 140
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this observational study is to investigate whether the healthy human brain shows a diversity of optimistic and pessimistic reward signals and whether changes in this distribution in Parkinson's disease (PD) can provide mechanistic insights into the cause of symptoms. The main hypotheses it aims to test are:

1. 1.As shown in mice, a diversity of optimistic and pessimistic dopamine reward signals exists in the human ventral tegmental area (VTA) and the ventro-rostral basal ganglia circuit.
2. 2.Pessimistic neurons are more severely affected by neurodegeneration in PD.

Conditions

Healthy; Parkinson; Medication Administration

Keywords

dopamine; reinforcement learning; distributional reinforcement learning; reward prediction error; reward; fMRI; parkinson

Outcome Measures

Primary Outcomes (1)

• Topographic distribution of the degree of optimism or pessimism

  The main outcome measure is the topographic distribution of the degree of optimism or pessimism of each voxel's prediction error signal across the brains' cortical and sub-cortical grey matter. Investigators focus on the dopaminergic midbrain regions VTA/SNc and their main target region, the striatum. In sub-study 1, this distribution will be compared between people with Parkinson's disease and healthy controls. In sub-study 2, the change in distribution between the off- and the on-medication state in patients with PD will be compared to the test-retest change in distribution in control participants.

  Day 1 and Day 2

Secondary Outcomes (17)

• Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS)

  Day 1 and Day 2

• Major Depression Inventory (MDI)

  Day 1 and Day 2

• Montreal Cognitive Assessment (MoCA)

  PD patients: ON-medication (Day 1 or Day 2, counterbalanced). Healthy controls: Day 1.

• Apathy Scale (AS)

  Day 1 and Day 2

• Lille Apathy Rating Scale (LARS)

  Day 1 and Day 2

Study Arms (2)

Patients with Parkinson's Disease

Inclusion criteria: * At least 35 years of age. * Clinically established or probable PD according to the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's Disease * Akinetic-rigid type PD * Stable antiparkinsonian medicine for 4 weeks without major side effects such as dyskinesia or on-off periods. * Signed informed consent. Exclusion criteria: * Female participants of childbearing age must not be pregnant, and they must use contraception. * Breastfeeding. * History of other neurologic or psychiatric disease other than depression. * Claustrophobia, pacemakers, implanted electronic devices, metal in the body, or other contraindications for MR scans. * Patients receiving advanced PD treatment such as duodopa pump or apomorphine pen * Regular intake of antipsychotics and GABAergic medications (such as pregabalin and gabapentine). * Severe depression (MDI score \> 29). * Refuse to be informed about new health-related findings that might appear through participation.

Healthy controls

Inclusion criteria * At least 35 years of age. * Signed informed consent. Exclusion criteria * Female participants of childbearing age must not be pregnant, and they must use contraception. * Breastfeeding. * History of neurologic or psychiatric disease other than depression. * Claustrophobia, pacemakers, implanted electronic devices, metal in the body, or other contraindications for MR scans. * Regular intake of antipsychotics and GABAergic medications (such as pregabalin and gabapentine). * Severe depression (MDI score \> 29). * Refuse to be informed about new health-related information and accidental health-related findings that might appear through participation.

Eligibility Criteria

• Age: 35 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with PD and healthy volunteers, who are age- and sex-matched to the PD group.

You may qualify if:

• At least 35 years of age.
• Clinically established or probable PD according to the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's Disease
• Akinetic-rigid type PD
• Stable antiparkinsonian medicine for 4 weeks without major side effects such as dyskinesia or on-off periods.
• Signed informed consent.

You may not qualify if:

• Female participants of childbearing age must not be pregnant, and they must use contraception.
• Breastfeeding.
• History of other neurologic or psychiatric disease other than depression.
• Claustrophobia, pacemakers, implanted electronic devices, metal in the body, or other contraindications for MR scans.
• Patients receiving advanced PD treatment such as duodopa pump or apomorphine pen
• Regular intake of antipsychotics and GABAergic medications (such as pregabalin and gabapentine).
• Severe depression (MDI score \> 29).
• Refuse to be informed about new health-related findings that might appear through participation.
• HEALTHY CONTROLS:
• At least 35 years of age.
• Signed informed consent.
• Female participants of childbearing age must not be pregnant, and they must use contraception.
• Breastfeeding.
• History of neurologic or psychiatric disease other than depression.
• Claustrophobia, pacemakers, implanted electronic devices, metal in the body, or other contraindications for MR scans.

Sponsors & Collaborators

• Danish Research Centre for Magnetic Resonance: lead
• University Hospital Bispebjerg and Frederiksberg: collaborator

Study Sites (1)

Danish Research Centre for Magnetic Resonance (DRCMR), Hvidovre Hospital

Hvidovre, 2650, Denmark

RECRUITING

Related Publications (10)

• Surmeier DJ, Graves SM, Shen W. Dopaminergic modulation of striatal networks in health and Parkinson's disease. Curr Opin Neurobiol. 2014 Dec;29:109-17. doi: 10.1016/j.conb.2014.07.008. Epub 2014 Jul 22.

  PMID: 25058111 BACKGROUND

• Sulzer D. Multiple hit hypotheses for dopamine neuron loss in Parkinson's disease. Trends Neurosci. 2007 May;30(5):244-50. doi: 10.1016/j.tins.2007.03.009. Epub 2007 Apr 5.

  PMID: 17418429 BACKGROUND

• Bezprozvanny I. Calcium signaling and neurodegenerative diseases. Trends Mol Med. 2009 Mar;15(3):89-100. doi: 10.1016/j.molmed.2009.01.001. Epub 2009 Feb 21.

  PMID: 19230774 BACKGROUND

• GBD 2016 Parkinson's Disease Collaborators. Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018 Nov;17(11):939-953. doi: 10.1016/S1474-4422(18)30295-3. Epub 2018 Oct 1.

  PMID: 30287051 BACKGROUND

• Sierra M, Carnicella S, Strafella AP, Bichon A, Lhommee E, Castrioto A, Chabardes S, Thobois S, Krack P. Apathy and Impulse Control Disorders: Yin & Yang of Dopamine Dependent Behaviors. J Parkinsons Dis. 2015;5(3):625-36. doi: 10.3233/JPD-150535.

  PMID: 25870025 BACKGROUND

• Obeso JA, Marin C, Rodriguez-Oroz C, Blesa J, Benitez-Temino B, Mena-Segovia J, Rodriguez M, Olanow CW. The basal ganglia in Parkinson's disease: current concepts and unexplained observations. Ann Neurol. 2008 Dec;64 Suppl 2:S30-46. doi: 10.1002/ana.21481.

  PMID: 19127584 BACKGROUND

• Dabney W, Kurth-Nelson Z, Uchida N, Starkweather CK, Hassabis D, Munos R, Botvinick M. A distributional code for value in dopamine-based reinforcement learning. Nature. 2020 Jan;577(7792):671-675. doi: 10.1038/s41586-019-1924-6. Epub 2020 Jan 15.

  PMID: 31942076 BACKGROUND

• Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. Science. 1997 Mar 14;275(5306):1593-9. doi: 10.1126/science.275.5306.1593.

  PMID: 9054347 BACKGROUND

• Meder D, Herz DM, Rowe JB, Lehericy S, Siebner HR. The role of dopamine in the brain - lessons learned from Parkinson's disease. Neuroimage. 2019 Apr 15;190:79-93. doi: 10.1016/j.neuroimage.2018.11.021. Epub 2018 Nov 20.

  PMID: 30465864 BACKGROUND

• Stauffer WR. The biological and behavioral computations that influence dopamine responses. Curr Opin Neurobiol. 2018 Apr;49:123-131. doi: 10.1016/j.conb.2018.02.005. Epub 2018 Mar 2.

  PMID: 29505948 BACKGROUND

Study Officials

• David Meder, PhD

  Danish Research Centre for Magnetic Resonance (DRCMR), Hvidovre Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

David Meder, PhD

CONTACT

004529892696; davidm@drcmr.dk

Ditte H Frantzen, MSc

CONTACT

004542152404; dittehf@drcmr.dk

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 30, 2025
• First Posted: February 11, 2026
• Study Start: June 2, 2025
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027
• Last Updated: February 11, 2026

Record last verified: 2026-01

Locations

DK (1)