With the growing rate of Alzheimer's disease (AD) and nominal medication effects comes the need for novel treatment approaches. Transcranial direct current stimulation (tDCS) is a method of non-invasive brain stimulation that uses weak electric currents to alter the excitability of the brain. Initial evidence suggests that tDCS may improve cognitive functioning in patients with mild cognitive impairment (MCI) and Alzheimer's dementia. As a result, tDCS holds promise for maximizing cognitive and functional abilities as well as delaying decline that demarcates transition to dementia; an impact that has significant personal and financial ramifications. Because very little is known about the most effective treatment conditions, the primary goal of this study is to define tDCS treatment parameters so that future studies can be performed more efficiently and with greater chances of success. High Definition (HD) tDCS will be used to enhance stimulation focality and avoid potential confounding effects of the traditional pad-based approach. In this study, patients with MCI will be randomized to receive five consecutive daily sessions of HD-tDCS at either sham, 1mA, 2mA, or 3mA. Stimulation will target the lateral temporal cortex; a neuroanatomical target affected early in the course of AD that is also part of the dysfunctional default mode network. The cognitive effects of HD-tDCS will be measured daily as well as after the 5 sessions. Network connectivity will be evaluated using resting-state functional magnetic resonance imaging (fMRI) (pre-treatment versus post-treatment).
Specific Aim 1 is to establish that HD-tDCS is well tolerated and that sham is an effective control condition. This will be the first study to systematically evaluate these factors using HD-tDCS and in patients with MCI.
Specific Aim 2 is to determine the multi-session impact of HD-tDCS electrical current intensity on network connectivity and cognitive measures. Human Connectome fMRI acquisition and graph theory analytic methods will be used to establish dose-response curves and obtain a deeper understanding of these effects at both local and network levels. Exploratory Specific Aim 3 will evaluate the impact of AD biomarkers on HD-tDCS response. This will be the first tDCS study to integrate the amyloid, tau, neurodegeneration (A/T/N) framework, specifically by using positron emission tomography (PET) ligands to measure beta-amyloid and neurofibrillary tau as well as MRI to quantify brain volume. This approach builds on decades of efforts to enhance early detection of AD pathology in vivo by translating this knowledge into a targeted treatment approach. This study immediately addresses field-relevant questions about dose-response (e.g., linear vs. non-linear effects) and mechanisms of action. The results will streamline participant selection in subsequent trials, thereby enhancing treatment outcome and reducing study costs through a precision medicine approach. Taken together, the results will guide the rational prescription of stimulation and serve as the foundation for a novel class of non-pharmacologic treatment.

Public Health Relevance

This study provides critical information about the effects of electrical brain stimulation in those with mild cognitive impairment. The findings will help determine ?how much? stimulation is needed to enhance cognitive abilities, how it affects brain functioning, and who is most likely to benefit. Ultimately, this information may guide treatment efforts for those at various stages of Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Mclinden, Kristina
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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