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| ID | Type | Description | Link |
|---|---|---|---|
| 10390052210003 | Other Grant/Funding Number | ZonMw | |
| NL84843.018.23 | Registry Identifier | ToetsingOnline |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Intervention arm 1: rTMS followed by tDCS | Experimental | 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 | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| High-frequency (10Hz) rTMS | Device | 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. |
| 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) |
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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):
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:
Contra-indication for tDCS according to Neuroelectrics Starstim Manual; tDCS should not be used in case of:
Contra-indication for MR imaging:
Space-occupying lesion on MRI.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Tim D van Balkom, PhD | Contact | +31204441162 | t.vanbalkom@amsterdamumc.nl | |
| Chris Vriend, PhD | Contact | +31204441162 | c.vriend@amsterdamumc.nl |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Amsterdam UMC | Recruiting | Amsterdam | North Holland | Netherlands |
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.
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.
A data sharing agreement or equivalent will be set up.
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| ID | Term |
|---|---|
| D010300 | Parkinson Disease |
| D060825 | Cognitive Dysfunction |
| ID | Term |
|---|---|
| D020734 | Parkinsonian Disorders |
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D050781 | Transcranial Magnetic Stimulation |
| D065908 | Transcranial Direct Current Stimulation |
| ID | Term |
|---|---|
| D055909 | Magnetic Field Therapy |
| D013812 | Therapeutics |
| D004599 | Electric Stimulation Therapy |
| D003295 | Convulsive Therapy |
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Four consecutive phases: 1) a no-intervention baseline phase, 2) rTMS or tDCS, 3) a second no-intervention baseline phase, 4) the second NIBS intervention. All phases have a duration of 4 weeks and the order of the NIBS interventions is counterbalanced.
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| Anodal tDCS | Device | 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. |
|
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 |
| Baseline |
| Age | Baseline |
| Sex | 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 |
| D009422 | Nervous System Diseases |
| D009069 | Movement Disorders |
| D000080874 | Synucleinopathies |
| D019636 | Neurodegenerative Diseases |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D013000 |
| Psychiatric Somatic Therapies |
| D004191 | Behavioral Disciplines and Activities |
| D004597 | Electroshock |
| D011580 | Psychological Techniques |