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

Not Applicable

Recruiting

• Conditions: Parkinson Disease; Mild Cognitive Impairment
• Interventions: Device: High-frequency (10Hz) rTMS; Device: Anodal tDCS

• Registration Number: NCT06399731
• Lead Sponsor: Amsterdam UMC

Brief Summary

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.

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 Timeline

• Study First Submitted: 2024-05-01
• Study First Submitted QC: 2024-05-03
• Study First Posted: 2024-05-06
• Study Start: 2024-05-31
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-12
• Last Update Posted: 2024-07-16
• Primary Completion: 2025-12-01
• Study Completion: 2026-05-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 20

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Intervention arm 1: rTMS followed by tDCS	High-frequency (10Hz) rTMS	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.
Intervention arm 2: tDCS followed by rTMS	High-frequency (10Hz) 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.
Intervention arm 1: rTMS followed by tDCS	Anodal 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.
Intervention arm 2: tDCS followed by rTMS	Anodal tDCS	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Amsterdam UMC; 🇳🇱 Amsterdam, Noord-Holland, Netherlands