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

Parkinson Disease Clinical Trial

— NESCIO-PD  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06399731
• Other study ID #: 2023.0804
• Secondary ID: 10390052210003NL
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 15, 2024
• Est. completion date: May 1, 2026

Study information

• Verified date: May 2024
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: Tim D van Balkom, PhD
• Phone: +31204441162
• Email: t.vanbalkom[@]amsterdamumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 20
• Est. completion date: May 1, 2026
• Est. primary completion date: December 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Mild Cognitive Impairment
• Parkinson Disease

Intervention

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.
• 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 p 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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Amsterdam UMC

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Structural and functional connectivity	Measured with MPRAGE, resting-state fMRI, task-based fMRI, DWI	Baseline
Other	Distance to optimal DLPFC stimulation target	Measured with optimal voxel coordinate based on task-based fMRI	Baseline
Other	Age		Baseline
Other	Sex		Baseline
Other	Education level	Years	Baseline
Other	Education level	Verhage score	Baseline
Other	Medication use	Levodopa equivalent daily dosage	Baseline, four, eight, twelve and sixteen weeks
Other	Disease duration	Years	Baseline
Other	Disease stage	Hoehn & Yahr stage	Baseline
Other	Motor symptom severity	MDS-Unified PD Rating Scale Motor Assessment motor score	Baseline
Other	Psychotic symptoms	Scale for the Assessment of Positive Symptoms for PD score	Baseline
Other	General cognitive function	Self-Administered Gerocognitive Exam	Baseline
Other	TMS adverse events	TMSens_Q adverse events questionnaire	During rTMS intervention (week 4-8, or week 12-16)
Other	tDCS adverse events	Adapted tDCS adverse events questionnaire	During tDCS intervention (week 4-8, or week 12-16)
Other	Visuospatial function	Benton Judgement of Line Orientation test score	Baseline
Other	Substance abuse	CAGE Adapted to Include Drugs	Baseline
Other	Intervention expectancy	Credibility-expectancy questionnaire	Four weeks, eight weeks
Primary	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	Qualitative acceptability assessment of both interventions	Qualitative assessment from focus groups after study termination	After study termination (i.e., all participants finished)
Secondary	Intervention compliance (feasibility)	Percent of missed intervention sessions	Eight weeks and sixteen weeks (during first and second intervention)
Secondary	Intervention attrition (feasibility)	Count of dropped out participants	After study termination (i.e., all participants finished)
Secondary	Usability of the tDCS device (feasibility)	System Usability Scale score	Eight weeks or sixteen weeks (after tDCS intervention)
Secondary	Subjective cognitive function	PD-Cognitive Functional Rating Scale score	Four, eight, twelve and sixteen weeks
Secondary	Subjective cognitive function	Cognitive Failures Questionnaire score	Four, eight, twelve and sixteen weeks
Secondary	Global cognitive function	Montreal Cognitive Assessment score	Four, eight, twelve and sixteen weeks
Secondary	Attention/mental processing speed	Trail Making Test A time	Four, eight, twelve and sixteen weeks
Secondary	Executive function	Trail Making Test B time	Four, eight, twelve and sixteen weeks
Secondary	Executive function/language	Letter Fluency score	Four, eight, twelve and sixteen weeks
Secondary	Executive function	Tower of London Accuracy	Four, eight, twelve and sixteen weeks
Secondary	Executive function	Tower of London Reaction Time	Four, eight, twelve and sixteen weeks
Secondary	Episodic Memory	Rey Auditory Verbal Learning Test ("15 Woordentest") Direct Recall score	Four, eight, twelve and sixteen weeks
Secondary	Episodic Memory	Rey Auditory Verbal Learning Test ("15 Woordentest") Delayed Recall score	Four, eight, twelve and sixteen weeks
Secondary	Episodic Memory	Rey Auditory Verbal Learning Test ("15 Woordentest") Recognition score	Four, eight, twelve and sixteen weeks
Secondary	Mental processing speed	Symbol Digit Modalities Test score	Four, eight, twelve and sixteen weeks
Secondary	Verbal attention	Wechsler Adult Intelligence Scale IV-NL-Digit Span Forward	Four, eight, twelve and sixteen weeks
Secondary	Working memory	Wechsler Adult Intelligence Scale IV-NL-Digit Span Backwards/Sorting	Four, eight, twelve and sixteen weeks
Secondary	Depressive symptoms	Beck Depression Inventory-lb score	Four, eight, twelve and sixteen weeks
Secondary	Anxiety symptoms	Parkinson Anxiety Scale score	Four, eight, twelve and sixteen weeks
Secondary	Functional mobility	Timed Get-up and Go test score	Four, eight, twelve and sixteen weeks