The Effect of Ropinirole on Functional Connectivity and Metacognition in Healthy Subjects

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universita' Degli Studi Di Modena E Reggio Emilia

Participant type

Healthy volunteers

Age range

18-64 years

Gender

Male

Therapeutic area

Phenomena and Processes [G] - Biological Phenomena [G16], Psychiatry and Psychology [F] - Behavior and Behavior Mechanisms [F01], Psychiatry and Psychology [F] - Behavioral Disciplines and Activities [F04], Phenomena and Processes [G] - Mathematical Concepts [G17]

Decision date (initial)

2025-12-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

University of Modena and Reggio Emilia

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others

The primary objective is to determine whether a single oral dose of the dopamine agonist ropinirole modulates metacognitive performance in healthy adults. Metacognition refers to the ability to reflect on and accurately judge one’s own cognitive performance. By studying metacognition in healthy volunteers, we can probe how neuromodulation might enhance or impair self-monitoring abilities, providing insight relevant to disorders characterized by anosognosia or unawareness of neurological disturbances.
Pharmacological studies in healthy people have only recently begun to demonstrate that metacognitive ability is indeed susceptible to drug manipulation. Notably, Hauser et al. (2017) provided the first evidence that a drug can selectively improve metacognitive performance: in a placebo-controlled trial, blocking noradrenergic β-receptors with propranolol significantly increased subjects’ metacognitive accuracy (measured as type-II ROC area) without improving basic task performance. We aim to extend this line of research by testing a dopaminergic agent’s impact on metacognitive abilities. In particular, we hypothesize that increasing dopaminergic tone will transiently alter an individual’s insight into their performance by inducing overconfidence. This hypothesis is supported by preliminary evidence that inducing a transient hyper-dopaminergic state in healthy people can change both brain network dynamics and one’s capacity to judge personal errors.
Through a controlled pharmacological challenge, our study will assess whether a single oral dose of the dopamine-agonist ropinirole can measurably improve or impair metacognitive performance on cognitive tasks requiring self-evaluation of accuracy.
More precisely, we will use metacognitive measures from experimental psychology (Fleming & Lau, 2014; Ernst et al, 2017) to test the hypothesis that, relative to placebo, a single dose of ropinirole given to healthy volunteers transiently increases metacognitive bias (i.e., the difference between confidence rating and actual performance) and decreases metacognitive relative accuracy (measured as metacognitive efficiency, i.e., the ratio between performance and metacognitive performance, and Goodman–Kruskal Gamma correlation, i.e., the ability to identify with higher confidence correct answers and with lower confidence errors), without affecting the level of the actual cognitive performance.
In other words, the primary objective is to test if a single dose of ropinirole makes the subject over-confident about their cognitive performance and decreases how well that participant’s confidence in their answers discriminates correct responses from incorrect ones and predicts whether those answers are correct on a trial-by-trial basis.
Demonstrating drug-induced changes in metacognition will contribute to clarify the neurotransmitter systems involved in self-awareness and point toward novel pro-metacognitive interventions for patients with anosognosia or impaired insight.

Secondary objectives 1

1. The secondary, parallel objective is to determine whether a single oral dose of ropinirole modulates resting-state functional connectivity of the brain in healthy adults. Functional connectivity can be measured with functional magnetic resonance imaging (fMRI) sequences acquired within standard MRI protocols. Resting fMRI connectivity provides a window into the brain’s intrinsic network organization, and prior pharmacological challenge studies have shown that even a single dose of various psychoactive compounds can reconfigure these networks (Klaassent et al 2017; Müller et al 2020). These examples illustrate that phMRI (pharmacological MRI) can capture drug-induced reorganization of brain networks in vivo, and that different neurotransmitter systems (serotonergic, dopaminergic, etc.) have distinct signatures of connectivity change. Metacognition – the ability to reflect on and accurately judge one’s own cognitive performance – is known to rely on specific brain networks. In particular, self‐monitoring and awareness engage regions such as the orbitofrontal cortex, insula, and medial temporal lobe, which are key nodes of the brain’s default mode network (DMN) as well as of the brain’s salience network (SN). Impairments in these self-awareness and error-monitoring networks have been linked to clinical conditions; for example, Alzheimer’s disease patients with poor insight (anosognosia) exhibit abnormally decreased functional connectivity in the DMN and abnormally increased functional connectivity in the SN (Zamboni et al 2013; Tondelli et al 2004). Building on this knowledge, our study’s secondary objective is to identify connectivity alterations provoked by a single dose of the dopamine-agonist ropinirole in healthy individuals. Dopaminergic circuits are known to shape the functional coupling of fronto-striatal and limbic regions that underpin motivation and cognitive control. However, their influence on broad resting-state networks in the healthy human brain is not fully characterized. By administering a one-time dose of a dopaminergic agent and measuring resting-state fMRI, we will test whether increasing dopamine transmission leads to reconfiguration of large-scale networks (e.g. decreased connectivity in the default mode network or in its anti-correlation with salience network). This approach is directly inspired by our hypothesis (and prior pilot observations) that boosting dopamine will alter intrinsic connectivity patterns along with cognitive self-monitoring. Any detected shifts – such as modulation of connectivity in self-referential networks (DMN) or salience network (SN) – will not only support our primary cognitive findings but also reveal the neural network mechanisms through which dopamine influences introspective accuracy. Ultimately, by correlating the drug-induced changes in brain connectivity with changes in metacognitive performance, we hope to more clearly articulate the neurobiological underpinnings of metacognition. In summary, the study is designed to elucidate whether a dopamine-driven neurotransmitter challenge can simultaneously (1) alter the capacity for self-evaluation and (2) remodel resting brain networks, thereby shedding light on the brain–behaviour relationship between connectivity and metacognitive insight.

Conditions and MedDRA coding

Healthy volunteers (mechanistic study evaluating the effect of a single oral dose of ropinirole 1 mg on metacognition and resting‑state functional brain connectivity. Product has MA and has been shown to be safe in humans)

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Male
2. Cognitively healthy (Mini-Mental State Examination, MMSE=30)
3. Age 20-35
4. Able to understand and write in Italian
5. Years of Education > 13 years
6. Participants are required to ensure no alcohol or any psychotropic substance intake for all the duration of the study
7. Consent to refrain from driving until midnight in the day of the session
8. Required to fast 3 hours before drug/placebo administration
9. On no medical treatment
10. Nonsmoker

Exclusion criteria 7

1. Known allergy to ropinirole and to eccipients
2. Controindication to MRI (e.g. claustrophobia, metallic implants or foreign bodies, pacemaker)
3. History of neurological or psychiatric conditions at screening visit or from past history
4. Significant or severe medical conditions including pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, cardiovascular or oncologic disease, or any other condition that, in the opinion of the Investigator, could jeopardize the safety of the subject, ability to complete or comply with the study procedures or validity of the study results
5. Evidence of renal (creatinine clearance < 60 mL/min) or hepatic dysfunction (GOT/GPT > 31 U/L) on blood testing at screening or from past clinical history
6. History of substance abuse
7. On medical treatment at screening

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint will be the within-participant change in metacognitive efficiency (M-ratio; meta-d'/d') under ropinirole 1 mg versus placebo, estimated from confidence ratings on cognitive testing. It will be derived from trial-wise accuracy and confidence ratings on a modified version of the Rey Auditory-Verbal Learning Test, and computed using a signal-detection-theoretic framework, which separates metacognitive sensitivity from task performance

Secondary endpoints 1

1. Secondary endpoints will be pre-specified seed-to-seed connectivity measures from Resting-state fMRI (rs-fMRI) data specifically targeting the Default Mode Network (DMN) and Salience Network (SN).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universita' Degli Studi Di Modena E Reggio Emilia

Sponsor organisation

Universita' Degli Studi Di Modena E Reggio Emilia

Address

Via Universita 4

City

Modena

Postcode

41121

Country

Italy

Scientific contact point

Organisation

Universita' Degli Studi Di Modena E Reggio Emilia

Contact name

Giovanna Zamboni

Public contact point

Organisation

Universita' Degli Studi Di Modena E Reggio Emilia

Contact name

Giovanna Zamboni

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications