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

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

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease; Mild Cognitive Impairment; Cognitive Decline
• Intervention / Treatment: Device: intermittent theta burst stimulation

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2

Contacts and Locations

Study Locations

• Taiwan
  • New Taipei City, Taiwan
    • Shuang Ho Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Taipei Medical University Shuang Ho Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 5, 2020
• Primary Completion (Actual): January 31, 2022
• Study Completion (Actual): January 31, 2022

Study Registration Dates

• First Submitted: August 25, 2020
• First Submitted That Met QC Criteria: September 14, 2020
• First Posted (Actual): September 21, 2020

Study Record Updates

• Last Update Posted (Actual): October 26, 2022
• Last Update Submitted That Met QC Criteria: October 24, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Transcranial magnetic stimulation; non-invasive brain stimulation
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Alzheimer Disease; Cognitive Dysfunction
• Other Study ID Numbers: N202003022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No