Psychological Effects of Levodopa in Parkinson's Disease

Unravelling the Impact of Levodopa on Dysfunctional Brain Networks in Parkinson's Disease With Neuropsychiatric Fluctuations

The investigators aim is to study neuropsychiatric symptoms and underlying abnormalities in resting-state fMRI in patients with Parkinson's disease (PD) suffering from neuropsychiatric fluctuations, to enhance the understanding of the pathophysiological mechanisms underlying neuropsychiatric symptoms.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease
• Intervention / Treatment: Other: Dopaminergic OFF-drug state; Other: Dopaminergic ON-drug state

Detailed Description

Parkinson's disease (PD) is primarily classified and known as a movement disorder characterized by tremor, bradykinesia and rigidity. However, clinical examination and research have shown that PD extensively affects other systems as well, giving rise to non-motor symptoms (NMS) such as anxiety, sleep disorders, apathy, depression, cognitive impairment, and hallucinations. These non-motor fluctuations (NMF) represent a main source of disability in PD and among those, neuropsychiatric fluctuations are the most frequent. During the dopaminergic OFF-drug state anxiety, apathy, and depression are common, whereas during the dopaminergic ON-drug state euphoria, well-being, impulse control disorders (ICD) and other behavioral addictions, mania, and psychosis might occur.

Despite the severe consequences associated with dopaminergic modulation, the understanding of the pathophysiological mechanisms of neuropsychiatric symptoms is still limited and better detection and more effective treatments are needed. Fluctuating PD is a very powerful model allowing to study opposite psychiatric states intra-individually in both levodopa dopaminergic ON- and OFF-drug state, allowing to abstract many interpersonal variables.

Neurotechnology and advanced neuroimaging techniques can improve the understanding of the neural basis and brain mechanisms of specific neuropsychiatric symptoms in PD. In particular, dynamic functional connectivity (FC) analysis characterizes functional abnormalities from resting state (rs)-fMRI not only in terms of brain activations, but also of whole-brain functional networks and the transitions between maps of activations. The temporal evolution of these networks, assessed with dynamic FC approaches, has recently shown to be relevant in several clinical contexts.

Therefore, the investigators long-term goal is to identify specific resting-state signatures/biomarkers for the individual neuropsychiatric PD symptoms related to disease in dopaminergic OFF-drug state (depression, anxiety, apathy, fatigue, shame, bradyphrenia) and to dopaminergic treatment in dopaminergic ON-drug state (mania, impulse control disorders, hallucinations, psychosis, creative thinking), which might be used in the future as a proxy for the measurement of neuropsychiatric symptoms/fluctuations and thus to assess the effectiveness of specific therapies.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Paul Krack, Prof.; Phone Number: +41 031 632 21 68; Email: paul.krack@insel.ch
• Study Contact Backup: Name: Marie Elise Maradan; Phone Number: +41 031 632 63 62; Email: marie.maradan@insel.ch

Study Locations

• Switzerland
  • Bern, Switzerland, 3010
    • Recruiting
    • University Hospital Inselspital, Berne
    • Contact: Paul Krack, Prof.; Phone Number: +41 031 632 21 68; Email: paul.krack@insel.ch
    • Contact: Marie Elise Maradan; Phone Number: +41 031 632 63 62; Email: marie.maradan@insel.ch
  • Geneva, Switzerland, 1202
    • Active, not recruiting
    • EPFL Campus Biotech
  • Geneva, Switzerland, 1202
    • Active, not recruiting
    • EPFL Institute of Bioengineering
  • Geneva, Switzerland, 1205
    • Recruiting
    • University Hospital Geneva (HUG)
    • Contact: Vanessa Fleury, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults above 18 years old
• Male or female
• Diagnosed with Parkinson's disease
• Able to understand instructions, neuropsychological tests and provide written informed consent
• Able to understand the locally used language of the experimental site and speak fluently
• Presence of neuropsychiatric fluctuations, defined as the sum ≥ 3 of items included in the Ardouin Scale of Behaviour in Parkinson's Disease (ASBPD) part 2

Exclusion Criteria:

• Structural brain disease other than Parkinson's disease
• Substance abuse and/or dependence (other than DRT)
• Ongoing depression with suicidal ideation
• Severe tremors/dyskinesia/ interfering with MRI performance
• Participating in a pharmacological study
• Inability to provide informed consent (legal guardianship)
• MRI contraindications
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dopaminergic ON-drug state first, dopaminergic OFF-drug state second; The following examinations and assessments will be performed at visit 3 on regular treatment in dopaminergic ON-drug state and at visit 4 in dopaminergic OFF-drug state (overnight withdrawal of all antiparkinsonian drugs): MRI assessment,; Cognitive, neuropsychiatric and neurological assessment,; Robot-induced hallucinations through sensorimotor stimulation.	Other: Dopaminergic OFF-drug state; Dopaminergic OFF-drug state: Overnight withdrawal of dopaminergic antiparkinsonian drugs during visit 3 or 4. The sequence of drug conditions (dopaminergic OFF-drug/ON-drug state or ON-drug/OFF-drug state) will be randomized.; Other: Dopaminergic ON-drug state; Dopaminergic ON-drug state: Patient will be evaluated in his/her regular treatment in dopaminergic ON-drug state at visit 3 or 4. The sequence of drug conditions (dopaminergic OFF-drug/ON-drug state or ON-drug/OFF-drug state) will be randomized.
Experimental: Dopaminergic OFF-drug state first, dopaminergic ON-drug state second; The following examinations and assessments will be performed at visit 3 in dopaminergic OFF-drug state (overnight withdrawal of all antiparkinsonian drugs) and at visit 4 on regular treatment in dopaminergic ON-drug state: MRI assessment,; Cognitive, neuropsychiatric and neurological assessment,; Robot-induced hallucinations through sensorimotor stimulation.	Other: Dopaminergic OFF-drug state; Dopaminergic OFF-drug state: Overnight withdrawal of dopaminergic antiparkinsonian drugs during visit 3 or 4. The sequence of drug conditions (dopaminergic OFF-drug/ON-drug state or ON-drug/OFF-drug state) will be randomized.; Other: Dopaminergic ON-drug state; Dopaminergic ON-drug state: Patient will be evaluated in his/her regular treatment in dopaminergic ON-drug state at visit 3 or 4. The sequence of drug conditions (dopaminergic OFF-drug/ON-drug state or ON-drug/OFF-drug state) will be randomized.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of functional connectivity abnormalities with neuropsychiatric fluctuations	Score on the Neuropsychiatric Fluctuations Scale (NFS)	≤ 6 weeks
Correlation of functional connectivity abnormalities with shame	Score on the Shame Visual Analogic Scale	≤ 6 weeks
Correlation of functional connectivity abnormalities with hallucinations	Score on robot-induced presence hallucination (PH) ratings	≤ 6 weeks
Correlation of functional connectivity abnormalities with bradyphrenia	Score on the Bradyphrenia Scale	≤ 6 weeks
Correlation of functional connectivity abnormalities with creativity	Score on the Creative Thinking Scale	≤ 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The role of dopamine on hallucinations	Measurement of the influence of dopamine on hallucinations using the robot-induced presence hallucination (PH) ratings. Assessments will be performed under the two conditions (dopaminergic ON and OFF drug state) and compared. The higher the score, the more hallucinations are experienced by patients.	≤ 6 weeks
The role of dopamine on creativity	Measurement of the influence of dopamine on the Creative Thinking Scale. Assessments will be performed under the two conditions (dopaminergic ON and OFF drug state) and compared. The higher the score, the more creative the patients are.	≤ 6 weeks
The role of dopamine on shame	Measurement of the influence of dopamine on the Shame Visual Analogic Scale. Assessments will be performed under the two conditions (dopaminergic ON and OFF drug state) and compared. The higher the score, the more shame patients feel.	≤ 6 weeks
The role of dopamine on bradyphrenia	Measurement of the influence of dopamine on the bradyphrenia scale. Assessments will be performed under the two conditions (dopaminergic ON and OFF drug state) and compared. The higher the score, the more bradyphrenic the patients are.	≤ 6 weeks

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Collaborators: University Hospital, Geneva; Ecole Polytechnique Fédérale de Lausanne
• Investigators: Principal Investigator: Paul Krack, Prof., University Hospital Inselspital, Berne

Study record dates

Study Major Dates

• Study Start (Actual): November 10, 2021
• Primary Completion (Anticipated): September 30, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: September 28, 2021
• First Submitted That Met QC Criteria: November 2, 2021
• First Posted (Actual): November 12, 2021

Study Record Updates

• Last Update Posted (Actual): January 12, 2023
• Last Update Submitted That Met QC Criteria: January 11, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Hallucinations; Non-motor symptoms; Creativity; Embarrassment; Neuropsychiatric fluctuations; Shame; Bradyphrenia
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Protective Agents; Cardiotonic Agents; Dopamine Agents; Sympathomimetics; Dopamine; Dopamine Agonists
• Other Study ID Numbers: 2021-01608

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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