The emerging field of non-invasive brain stimulation in Alzheimer's disease

Abstract

Treating cognitive impairment is a holy grail of modern clinical neuroscience. In the past few years, non-invasive brain stimulation is increasingly emerging as a therapeutic approach to ameliorate performance in patients with cognitive impairment and as an augmentation approach in persons whose cognitive performance is within normal limits. In patients with Alzheimer's disease, better understanding of brain connectivity and function has allowed for the development of different non-invasive brain stimulation protocols. Recent studies have shown that transcranial stimulation methods enhancing brain plasticity with several modalities have beneficial effects on cognitive functions. Amelioration has been shown in preclinical studies on behaviour of transgenic mouse models for Alzheimer's pathology and in clinical studies with variable severity of cognitive impairment. While the field is still grappling with issues related to the standardization of target population, frequency, intensity, treatment duration and stimulated region, positive outcomes have been reported on cognitive functions and on markers of brain pathology. Here we review the most encouraging protocols based on repetitive transcranial magnetic stimulation, transcranial direct current stimulation, transcranial alternating current stimulation, visual-auditory stimulation, photobiomodulation and transcranial focused ultrasound, which have demonstrated efficacy to enhance cognitive functions or slow cognitive decline in patients with Alzheimer's disease. Beneficial non-invasive brain stimulation effects on cognitive functions are associated with the modulation of specific brain networks. The most promising results have been obtained targeting key hubs of higher-level cognitive networks, such as the frontal-parietal network and the default mode network. The personalization of stimulation parameters according to individual brain features sheds new light on optimizing non-invasive brain stimulation protocols for future applications.

Keywords: Alzheimer’s disease; photobiomodulation; transcranial alternating current stimulation; transcranial direct current stimulation; transcranial focused ultrasound; transcranial magnetic stimulation.

Figure 1

Effect of non-invasive brain stimulation on cognition in persons at high risk of Alzheimer’s disease dementia or with Alzheimer’s disease dementia. The image summarizes the degree of evidence that non-invasive brain stimulation (NIBS) techniques can improve cognitive functions in individuals at high risk of dementia or with Alzheimer’s disease (AD) dementia. NIBS techniques based on magnetic or electrical stimulation (e.g. rTMS, tDCS, 40 Hz tACS) commonly target the dorsolateral prefrontal cortex (DLPFC), the precuneus (Prec), or the temporoparietal cortex (TPC), while NIBS techniques based on sensory or electrical stimulation (e.g. auditory/visual, tACS) can target specific rhythms (e.g. 40 Hz). NIBS protocols variably affect cognitive functions and these effects are associated with the modulation of specific brain networks. Arrow size denotes the degree of evidence for each NIBS technique (thicker = higher). Functional brain networks are shown in blue and axonal connections with red/green-blue colour coding. Network hubs and axons were derived from resting state functional MRI and diffusion weighted images of a volunteer scanned on 7 T MRI. rTMS = repetitive transcranial magnetic stimulation; tDCS = transcranial direct current stimulation; 40 Hz tACS = transcranial alternate current stimulation in the gamma frequency; 40 Hz sensory = visual and/or auditory sensory stimulation in the gamma frequency; L = left; R = right.