The Effects of Intermittent Theta Burst Stimulation in MCI and Early AD

Study Overview
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Brief Summary
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Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that is increasingly used for a growing number of research and clinical applications.Typically, this transient magnetic field is focally applied with a figure-of-eight coil that is carefully placed on the surface of the scalp over a targeted stimulation site. Patterned repetitive TMS (rTMS), such as theta burst stimulation (TBS) can produce long-lasting effects on neural activity and behavior beyond the stimulation period (Chou et al., 2015a; Fitzgerald et al., 2006). In general, high frequency (> 5 Hz) rTMS and its newer version, intermittent theta burst stimulation (iTBS), facilitate cortical excitability, whereas low frequency (about 1 Hz) rTMS and continuous theta burst stimulation contribute to opposite effects (Pascual-Leone et al., 2000; Huang et al., 2005; Wassermann and Zimmermann, 2012).Careful manipulation of the parameters comprising these patterned rTMS pulse trains can induce neuroplastic changes that resemble either long-term potentiation (LTP) or depression (Chen et al., 1997; Pascual-Leone et al., 1994). Early studies targeting the motor cortex helped elucidate which rTMS parameters promote particular responses and their neurophysiological underpinnings (Klomjai et al., 2015). In recent years, rTMS has been closely investigated to evaluate its potential to modulate cognitive functions in Alzheimer'sdisease (AD) and mild cognitive impairment (MCI). As compared to conventional excitatory rTMS protocols, iTBS leads to comparable effects with similar number of pulses but considerable shorter duration and lower intensity of stimulation (Bakker et al., 2015; Rossi, Hallett, Rossini, Pascual-Leone, & Safety, 2009). Recent literature also suggest that TBS has lower rates of reported adverse event (AE) compared to rTMS (Najib & Horvath, 2014). Therefore, iTBS is assumed to modulate cognitive function in people with cognitive impairments.

Detailed Description
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Visit 1: Informed Consent, Brain MRI/Neuropsychological Battery Visit 2-11: (up to a week after visit 1) iTBS - or Sham-Treatment (10 sessions, 80% Resting Motor Threshold, 2s stimulation 8s inter-stimulus interval per train, 20 trains per block, 3 blocks per session with a 5-min break, 1 session per day) Visit 12: (1 day or same day after visit 11) Functional Brain MRI/Neuropsychological Battery Visit 13: (4 weeks after visit 11) Functional Brain MRI/Neuropsychological Battery

Official Title
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Cognitive Effects of Theta Burst Stimulation in Mild Cognitive Impairment and Alzheimer's Disease

Conditions
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Mild Cognitive Impairment, Alzheimer Disease, Cognitive Decline

Intervention / Treatment
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* Device: intermittent theta burst stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: normal visual acuity diagnosed with mild cognitive impairment or early dementia due to Alzheimer's disease (CDR = 0.5) by neurologists Exclusion Criteria: (family) history of seizure attacks in intensive care history of drug/alcohol dependence assistants or students of the PI major systemic diseases concerning cognitive decline (e.g., cardiopulmonary failure, liver/renal failure, poor controlled DM, traumatic brain injury, stroke, or other neurodegenerative diseases) claustrophobia metal implants taking medication lowering the threshold of seizure attacks fear of using TMS with specific allergens pregnant or breastfeeding women

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: active iTBS<br>The patient is treated with iTBS stimulation according to protocol with an active coil. | Device: intermittent theta burst stimulation<br>* active or Sham iTBS will be given to the AD/MCI patient<br>* Other names: Magstim rapid 2;|
| Sham Comparator: Sham iTBS<br>The patient is treated with Sham-iTBS stimulation according to protocol with an inactive coil. | Device: intermittent theta burst stimulation<br>* active or Sham iTBS will be given to the AD/MCI patient<br>* Other names: Magstim rapid 2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline in scores of any tests of the Neuropsychological Battery | WAIS-IV short-form, Word Sequence Learning Test, Benton Visual Retention Test, Color Trial Tests, 3-D Dimensional Constructional Test, Visual Confrontation Naming, Semantic Verbal Fluency Test, Stroop Color-Word Test | Baseline, immediate post-iTBS, follow-up (4 weeks post-iTBS) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain MRI | Change in white matter and brain activities at resting state at baseline compared to after iTBS stimulation | Baseline, immediate post-iTBS, follow-up (4 weeks post-iTBS) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcranial magnetic stimulation, non-invasive brain stimulation