Review
Toward noninvasive brain stimulation 2.0 in Alzheimer’s disease

https://doi.org/10.1016/j.arr.2021.101555Get rights and content

Highlights

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    The use of Noninvasive Brain Stimulation in Alzheimer’s Disease is promising.

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    The rising of precision-medicine strives towards the personalization of protocols.

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    We review and discuss the most innovative solutions to tailor stimulation interventions.

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    Multidisciplinary approaches might be the key to increase the efficacy of protocols.

Abstract

Noninvasive brain stimulation techniques (NiBS) have gathered substantial interest in the study of dementia, considered their possible role in help defining diagnostic biomarkers of altered neural activity for early disease detection and monitoring of its pathophysiological course, as well as for their therapeutic potential of boosting residual cognitive functions. Nevertheless, current approaches suffer from some limitations. In this study, we review and discuss experimental NiBS applications that might help improve the efficacy of future NiBS uses in Alzheimer’s Disease (AD), including perturbation-based biomarkers for early diagnosis and disease tracking, solutions to enhance synchronization of oscillatory electroencephalographic activity across brain networks, enhancement of sleep-related memory consolidation, image-guided stimulation for connectome control, protocols targeting interneuron pathology and protein clearance, and finally hybrid-brain models for in-silico modeling of AD pathology and personalized target selection. The present work aims to stress the importance of multidisciplinary, translational, model-driven interventions for precision medicine approaches in AD.

Section snippets

Precision medicine in Alzheimer’s disease

In high- and middle-income countries, life expectancy has increased, with the older age population outnumbering previous census reports. As people age, however, the incidence of neurodegenerative diseases also rises, with 6.2 million people being affected by Alzheimer’s Disease (AD) in the United States alone in 2021, an estimate expected to increase in the forthcoming years (Alzheimer’s Association, 2021). The biggest challenges in AD are represented by its complex, multifactorial nature,

Noninvasive brain stimulation approaches in Alzheimer’s disease: towards precision medicine

NiBS can be useful in understanding brain network pathophysiology, expanding on traditional recording techniques of spontaneous or evoked electroencephalographic or magnetoencephalographic activity. Indeed, NiBS offers the opportunity to directly interact with brain functioning in a noninvasive, safe and painless way, with a good time resolution and relatively high spatial precision.

In the clinical domain, TMS is the most widely used technique of noninvasive modulation of state and activities

A translational framework and roadmap for NiBS in AD

Early in the pathophysiological course of AD, changes of the excitation/inhibition balance due to altered interneuronal responses and synaptic transmission occur that can be detected through TMS-derived measures of cortical excitability. The use of combined TMS-EEG might help to expand the detection of cortical alterations beyond the motor cortex and possibly stimulate residual plasticity mechanisms (Fig. 4a–c, 1st row). Pathological shifts in brain oscillations -namely of the networks

Conclusions

Conceptually new NiBS approaches are now under the lens of ongoing trials, aiming at system-scaled interventions capable of integrating the multi-level biological and neurophysiological complexity of AD. Such innovative therapeutic approaches are supported by high spatiotemporal resolution, adaptive tuning based on ongoing plastic changes, and individualized protocols. Our view on present and future NiBS opportunities in AD aims to primarily stress the importance of multidisciplinary,

CRediT authorship contribution statement

Arianna Menardi: Conceptualization, Writing – original draft. Simone Rossi: Writing – review & editing. Giacomo Koch: Writing – review & editing. Harald Hampel: Writing – review & editing. Andrea Vergallo: Writing – review & editing. Michael A. Nitsche: Writing – review & editing. Yaakov Stern: Writing – review & editing. Barbara Borroni: Writing – review & editing. Stefano F. Cappa: Writing – review & editing. Maria Cotelli: Writing – review & editing. Giulio Ruffini: Writing – review &

Declaration of interest

AM declares no conflict of interest.

SR declares no conflict of interest.

GK declares no conflict of interest.

HH is an employee of Eisai Inc. He declares no competing financial interests related to the present article and his contribution to this article reflects entirely and only his own academic expertise on the matter. HH serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia and does not receive any fees or honoraria since May 2019; before May 2019 he had received lecture

Acknowledgements

We would like to acknowledge support from the NIH in the USA, specifically the National Institue of Aging (NIA) via the grant R01 AG060981-01 awarded to the senior author Emiliano Santarnecchi.

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