The effects of repetitive transcranial magnetic stimulation in older adults with mild cognitive impairment: a protocol for a randomized, controlled three-arm trial

Joy L Taylor, Benjamin C Hambro, Nicole D Strossman, Priyanka Bhatt, Beatriz Hernandez, J Wesson Ashford, Jauhtai Joseph Cheng, Michael Iv, Maheen M Adamson, Laura C Lazzeroni, Margaret Windy McNerney, Joy L Taylor, Benjamin C Hambro, Nicole D Strossman, Priyanka Bhatt, Beatriz Hernandez, J Wesson Ashford, Jauhtai Joseph Cheng, Michael Iv, Maheen M Adamson, Laura C Lazzeroni, Margaret Windy McNerney

Abstract

Background: Mild Cognitive Impairment (MCI) carries a high risk of progression to Alzheimer's disease (AD) dementia. Previous clinical trials testing whether cholinesterase inhibitors can slow the rate of progression from MCI to AD dementia have yielded disappointing results. However, recent studies of the effects of repetitive transcranial magnetic stimulation (rTMS) in AD have demonstrated improvements in cognitive function. Because few rTMS trials have been conducted in MCI, we designed a trial to test the short-term efficacy of rTMS in MCI. Yet, in both MCI and AD, we know little about what site of stimulation would be ideal for improving cognitive function. Therefore, two cortical sites will be investigated in this trial: (1) the dorsolateral prefrontal cortex (DLPFC), which has been well studied for treatment of major depressive disorder; and (2) the lateral parietal cortex (LPC), a novel site with connectivity to AD-relevant limbic regions.

Methods/design: In this single-site trial, we plan to enroll 99 participants with single or multi-domain amnestic MCI. We will randomize participants to one of three groups: (1) Active DLPFC rTMS; (2) Active LPC rTMS; and (3) Sham rTMS (evenly split between DLPFC and LPC locations). After completing 20 bilateral rTMS treatment sessions, participants will be followed for 6 months to test short-term efficacy and track durability of effects. The primary efficacy measure is the California Verbal Learning Test-II (CVLT-II), assessed 1 week after intervention. Secondary analyses will examine effects of rTMS on other cognitive measures, symptoms of depression, and brain function with respect to the site of stimulation. Finally, selected biomarkers will be analyzed to explore predictors of response and mechanisms of action.

Discussion: The primary aim of this trial is to test the short-term efficacy of rTMS in MCI. Additionally, the project will provide information on the durability of cognitive effects and potentially distinct effects of stimulating DLPFC versus LPC regions. Future efforts would be directed toward better understanding therapeutic mechanisms and optimizing rTMS for treatment of MCI. Ultimately, if rTMS can be utilized to slow the rate of progression to AD dementia, this will be a significant advancement in the field.

Trial registration: Clinical Trials NCT03331796. Registered 6 November 2017, https://ichgcp.net/clinical-trials-registry/NCT03331796. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A.

Protocol version: This report is based on version 1, approved by the DSMB on 30 November, 2017 and amended on 14 August, 2018 and 19 September, 2019.

Keywords: Aging; Alzheimer disease; Mild cognitive impairment; Neuroimaging; Parietal cortex; Prefrontal cortex; Transcranial magnetic stimulation.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
A summary of the study design and participant flow through the study

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