Non-invasive Brain Stimulation for the Treatment of Mild Cognitive Impairment in Parkinson's Disease (NESCIO-PD)

NEuroStimulation for the Treatment of Mild Cognitive Impairment in Parkinson's Disease: an Acceptability Cross-over Study

This cross-over pilot study aims to study the acceptability of two methods of non-invasive brain stimulation for the treatment of Parkinson's disease mild cognitive impairment (PD-MCI) - repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) targeted at the left dorsolateral prefrontal cortex (DLPFC). Twenty participants will undergo both interventions in a cross-over design. They sequentially undergo four consecutive phases (4 weeks each), 1) no-intervention baseline, 2) rTMS ór tDCS, 3) no-intervention, 4) second intervention. The primary outcome measure will be acceptability of the interventions, and secondary outcomes include feasibility, cognitive function, neuropsychiatric symptoms, motor function. We will use MRI to explore personalized targeting.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease; Mild Cognitive Impairment
• Intervention / Treatment: Device: High-frequency (10Hz) rTMS; Device: Anodal tDCS

Detailed Description

RATIONALE: Mild cognitive impairment (MCI) is a highly prevalent non-motor characteristic affecting about 40% of individuals with Parkinson's disease (PD). PD-MCI negatively impacts daily life functioning and quality of life and is associated with presence of other neuropsychiatric symptoms. Importantly, it constitutes a risk factor for later development of PD-related dementia.

Despite many endeavours to pharmacologically improve PD-MCI, there is currently no effective treatment. Optimization of dopaminergic therapy in early PD can relieve cognitive deficits, improving cognitive inflexibility and bradyphrenia, but also exacerbating other cognitive domains. Additionally, other non-pharmacological treatment options such as cognitive training have shown moderate effect sizes, but with limited transfer to daily functioning.

Non-invasive brain stimulation (NIBS) through repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) has promise in treating PD-MCI. NIBS, particularly institute-based rTMS, is, however, intensive and complex in use, specifically for individuals with motor and cognitive difficulties, which might limit its potential for clinical use.

OBJECTIVE: To study the acceptability and feasibility of rTMS and tDCS for the treatment of individuals with PD-MCI.

STUDY DESIGN: A cross-over design with three conditions: a baseline condition, rTMS, and tDCS. The study consists of 1) two four-week intervention periods, with rTMS treatment three times a week (total session duration ~40 mins, treatment duration = 20 mins) and tDCS treatment five times a week (total session duration ~30 mins, treatment duration = 20 mins. For the rTMS intervention, stimulation will be performed at the Amsterdam UMC, location VUmc (and thus includes travel time); 2) one 120-minute assessment (baseline) that includes neuropsychological and motor assessment, and MR imaging, and four 60-minute assessments that only includes neuropsychological assessment.

STUDY POPULATION: We will enroll twenty individuals with PD-MCI, according to level I criteria by the Movement Disorders Society: Montreal Cognitive Assessment score range [21-25], performance 1-2 SD below appropriate norms on at least 2 neuropsychological tests, or recent (< 6 months) classification of PD-MCI on neuropsychological assessment elsewhere.

INTERVENTION: Participants will undergo four consecutive phases in this intervention study: 1) a no-intervention baseline phase, 2) 12 sessions of 20-minute institute-based repetitive transcranial magnetic stimulation (rTMS) (10 Hz) or 20 sessions of 20-minute at-home anodal high-definition transcranial direct current stimulation (tDCS) targeting the left dorsolateral prefrontal cortex (DLPFC), 3) a second no-intervention baseline phase, 4) the second alternative NIBS intervention. All phases have a duration of 4 weeks and the order of the NIBS interventions is counterbalanced.

MAIN STUDY PARAMETERS: The primary outcome measure will be acceptability of the interventions, and secondary outcomes include feasibility, cognitive function, neuropsychiatric symptoms, motor function. We will use MRI to explore personalized targeting.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Tim D van Balkom, PhD; Phone Number: +31204441162; Email: t.vanbalkom@amsterdamumc.nl
• Study Contact Backup: Name: Chris Vriend, PhD; Phone Number: +31204441162; Email: c.vriend@amsterdamumc.nl

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands
      • Recruiting
      • Amsterdam UMC
      • Contact: Tim D van Balkom, PhD; Phone Number: +31625694901; Email: t.vanbalkom@amsterdamumc.nl
      • Contact: Chris Vriend, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Clinical diagnosis of Parkinson's disease, diagnosed by a neurologist;
• Mild to moderate disease stage (Hoehn & Yahr disease stage < 4);

• Movement Disorders Society level I criteria for PD-MCI (Litvan et al., 2012):

  • Montreal Cognitive Assessment score range [21-25] (Dalrymple-Alford et al., 2010), or
  • performance 1-2 SD below appropriate norms on at least 2 neuropsychological tests, or
  • classification of PD-MCI based on recent (< 6 months previous to participation) neuropsychological assessment taken elsewhere (report will be requested);- In case of (dopaminergic) medication use, participants are on stable medication for at least one month before participation and expect to remain on stable medication during the study

Exclusion Criteria:

• Indication for dementia based on the SAGE (cut-off ≤ 14; Scharre et al., 2010);
• Severe depressive disorder (Beck Depression Inventory - Ib score > 18);
• Psychotic disorder (except for benign hallucinations with insight), screened with the Scale for Assessment of Positive Symptoms for Parkinson's disease;
• Indication of alcohol or drug abuse;

• Contra-indication for rTMS according to Magstim Rapid2 Manual; rTMS should not be:

  • used on or in the vicinity of patients or users with cardiac demand pacemakers, implanted medication pumps, cochlear devices, implanted defibrillators and/or implanted neurostimulators
  • used on or in the vicinity of patients with implanted metal objects• used on patients where the skin in the area to be contacted is broken
  • used on those with large ischaemic scars
  • used on pregnant women
  • used on infants under the age of 2 years
  • used on epileptic individuals
  • used on those with a family history of convulsions
  • used on individuals with brain lesions that could affect seizure threshold
  • used on individuals suffering from multiple sclerosis
  • used on individuals taking tricyclic antidepressants, neuroleptic agents or any other drug that could lower seizure threshold,
  • used on individuals suffering from sleep deprivation during rTMS procedures
  • used on individuals with a heavy consumption of alcohol or those using epileptogenic drugs
  • used on individuals with severe heart disease or with increased intracranial pressure be used on those who have uncontrolled migraines

• Contra-indication for tDCS according to Neuroelectrics Starstim Manual; tDCS should not be used in case of:

  • Patients with a history of seizures;
  • Patients with unexplained episodes of loss of consciousness, since such condition could be related with brain alterations or epilepsy;
  • Patients with unstable or non-controlled neuropsychiatric illness;
  • Patients having implanted brain medical devices;
  • Patients with implanted pacemakers;
  • Patients having any electrically, magnetically or mechanically activated implant;
  • Patients having cardiac, neural or medication implants;
  • Patients having vascular clips or any other electrically sensitive support system in the brain;
  • Patients with serious brain injury;
  • Patients showing damage of skin at sites of stimulation (the device can only be used in healthy skin without wounds, otherwise the resistance to current can be altered);
  • Patients suffering from skin problems, such as dermatitis, psoriasis or eczema;
  • Patients suffering from severe or frequent headaches;
  • Patients with any serious life-threatening disease such as congestive heart failure, pulmonary obstructive chronic disease or active neoplasia;
  • Pregnant women (women of childbearing age should undertake a pregnancy test to confirm eligibility before treatment).

• Contra-indication for MR imaging:

  • metal in the body (pacemaker, port-a-cath, prosthesis, (cochlear) implant)
  • previous brain surgery
  • head trauma that resulted in unconsciousness for at least 1 hour
  • clips
  • (old metal containing) tattoo
  • irremovable piercings
  • irremovable metal braces
  • pregnancy
  • claustrophobia other problems lying still for 45 minutes
  • metal in the teeth
  • neurostimulator (including deep brain stimulation)
• Space-occupying lesion on MRI.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention arm 1: rTMS followed by tDCS; Participants in intervention arm 1 will undergo four phases in the following order: 1) a no-intervention baseline phase, 2) 12 sessions of 20-minute institute-based repetitive transcranial magnetic stimulation (rTMS) (10 Hz) targeting the left DLPFC, 3) a second no-intervention baseline phase, 4) 20 sessions of 20-minute at-home anodal high-definition transcranial direct current stimulation (tDCS) targeting the left DLPFC. All phases have a duration of 4 weeks.	Device: High-frequency (10Hz) rTMS; High-frequency (10 Hz) rTMS targeting the left DLPFC, based on fMRI-peak activation during performance of the Tower of London task, at 110% resting motor threshold intensity, corrected for scalp-cortex distance at the target location, for a total of 3000 pulses per session, using 30 trains of 10 seconds with 30-second inter-train intervals (total duration: 20 minutes), using neuronavigation to record the pulse location.; Device: Anodal tDCS; Anodal high-definition tDCS. The anode will be placed at the F3 EEG location, coordinates registered using neuronavigation on the first intervention session on-site, and cathodes at Fp1, Fz, C3 and F7, in a ring surrounding the anode, using π cm2 circular stimulation electrodes, stimulating the left DLPFC at 2 mA intensity for a duration of 20 minutes, 15 s ramp up and 15 s ramp down. After an initial on-site instructional tDCS session, the tDCS intervention will be delivered at home, in part remotely-supervised via MS Teams.
Experimental: Intervention arm 2: tDCS followed by rTMS; Participants in intervention arm 2 will undergo four phases in the following order: 1) a no-intervention baseline phase, 2) 20 sessions of 20-minute at-home anodal high-definition transcranial direct current stimulation (tDCS) targeting the left DLPFC, 3) a second no-intervention baseline phase, 4) 12 sessions of 20-minute institute-based repetitive transcranial magnetic stimulation (rTMS) (10 Hz) targeting the left DLPFC. All phases have a duration of 4 weeks.	Device: High-frequency (10Hz) rTMS; High-frequency (10 Hz) rTMS targeting the left DLPFC, based on fMRI-peak activation during performance of the Tower of London task, at 110% resting motor threshold intensity, corrected for scalp-cortex distance at the target location, for a total of 3000 pulses per session, using 30 trains of 10 seconds with 30-second inter-train intervals (total duration: 20 minutes), using neuronavigation to record the pulse location.; Device: Anodal tDCS; Anodal high-definition tDCS. The anode will be placed at the F3 EEG location, coordinates registered using neuronavigation on the first intervention session on-site, and cathodes at Fp1, Fz, C3 and F7, in a ring surrounding the anode, using π cm2 circular stimulation electrodes, stimulating the left DLPFC at 2 mA intensity for a duration of 20 minutes, 15 s ramp up and 15 s ramp down. After an initial on-site instructional tDCS session, the tDCS intervention will be delivered at home, in part remotely-supervised via MS Teams.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantative acceptability of the interventions (measured seperately)	Measured with Theoretical Framework of Acceptability questionnaire ("TFA-PD questionnaire") score, measuring seven domains of acceptability	Eight weeks and sixteen weeks (after first and second intervention)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Qualitative acceptability assessment of both interventions	Qualitative assessment from focus groups after study termination	After study termination (i.e., all participants finished)
Intervention compliance (feasibility)	Percent of missed intervention sessions	Eight weeks and sixteen weeks (during first and second intervention)
Intervention attrition (feasibility)	Count of dropped out participants	After study termination (i.e., all participants finished)
Usability of the tDCS device (feasibility)	System Usability Scale score	Eight weeks or sixteen weeks (after tDCS intervention)
Subjective cognitive function	PD-Cognitive Functional Rating Scale score	Four, eight, twelve and sixteen weeks
Subjective cognitive function	Cognitive Failures Questionnaire score	Four, eight, twelve and sixteen weeks
Global cognitive function	Montreal Cognitive Assessment score	Four, eight, twelve and sixteen weeks
Attention/mental processing speed	Trail Making Test A time	Four, eight, twelve and sixteen weeks
Executive function	Trail Making Test B time	Four, eight, twelve and sixteen weeks
Executive function/language	Letter Fluency score	Four, eight, twelve and sixteen weeks
Executive function	Tower of London Accuracy	Four, eight, twelve and sixteen weeks
Executive function	Tower of London Reaction Time	Four, eight, twelve and sixteen weeks
Episodic Memory	Rey Auditory Verbal Learning Test ("15 Woordentest") Direct Recall score	Four, eight, twelve and sixteen weeks
Episodic Memory	Rey Auditory Verbal Learning Test ("15 Woordentest") Delayed Recall score	Four, eight, twelve and sixteen weeks
Episodic Memory	Rey Auditory Verbal Learning Test ("15 Woordentest") Recognition score	Four, eight, twelve and sixteen weeks
Mental processing speed	Symbol Digit Modalities Test score	Four, eight, twelve and sixteen weeks
Verbal attention	Wechsler Adult Intelligence Scale IV-NL-Digit Span Forward	Four, eight, twelve and sixteen weeks
Working memory	Wechsler Adult Intelligence Scale IV-NL-Digit Span Backwards/Sorting	Four, eight, twelve and sixteen weeks
Depressive symptoms	Beck Depression Inventory-lb score	Four, eight, twelve and sixteen weeks
Anxiety symptoms	Parkinson Anxiety Scale score	Four, eight, twelve and sixteen weeks
Functional mobility	Timed Get-up and Go test score	Four, eight, twelve and sixteen weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age		Baseline
Sex		Baseline
Structural and functional connectivity	Measured with MPRAGE, resting-state fMRI, task-based fMRI, DWI	Baseline
Distance to optimal DLPFC stimulation target	Measured with optimal voxel coordinate based on task-based fMRI	Baseline
Education level	Years	Baseline
Education level	Verhage score	Baseline
Medication use	Levodopa equivalent daily dosage	Baseline, four, eight, twelve and sixteen weeks
Disease duration	Years	Baseline
Disease stage	Hoehn & Yahr stage	Baseline
Motor symptom severity	MDS-Unified PD Rating Scale Motor Assessment motor score	Baseline
Psychotic symptoms	Scale for the Assessment of Positive Symptoms for PD score	Baseline
General cognitive function	Self-Administered Gerocognitive Exam	Baseline
TMS adverse events	TMSens_Q adverse events questionnaire	During rTMS intervention (week 4-8, or week 12-16)
tDCS adverse events	Adapted tDCS adverse events questionnaire	During tDCS intervention (week 4-8, or week 12-16)
Visuospatial function	Benton Judgement of Line Orientation test score	Baseline
Substance abuse	CAGE Adapted to Include Drugs	Baseline
Intervention expectancy	Credibility-expectancy questionnaire	Four weeks, eight weeks

Collaborators and Investigators

• Sponsor: Amsterdam UMC

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: May 1, 2024
• First Submitted That Met QC Criteria: May 3, 2024
• First Posted (Actual): May 6, 2024

Study Record Updates

• Last Update Posted (Actual): July 16, 2024
• Last Update Submitted That Met QC Criteria: July 12, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Cognition Disorders; Parkinson Disease; Cognitive Dysfunction
• Other Study ID Numbers: 2023.0804; 10390052210003 (Other Grant/Funding Number: ZonMw); NL84843.018.23 (Registry Identifier: ToetsingOnline)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will commit to adhere to the findability, accessibility, interoperability and re-usability (FAIR) of the data collected during this study by publishing and sharing coded data and analysis code on online repositories to the limits of Dutch GDP regulations.
• IPD Sharing Time Frame: Anonymized data will be made available after full data collection has finished, when first data cleaning has been performed and the primary endpoint analyses have been performed.
• IPD Sharing Access Criteria: A data sharing agreement or equivalent will be set up.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; 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