Toward noninvasive brain stimulation 2.0 in Alzheimer's disease

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.

Keywords: Alzheimer’s disease; Noninvasive brain stimulation; Precision medicine; Transcranial electrical stimulation; Transcranial magnetic stimulation.

Conflict of interest statement

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 fees from Servier, Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics.

HH is inventor of the following patents and has received no royalties:

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AV declares no competing financial interests related to the present article; his contribution to this article reflects only and exclusively his own academic expertise on the matter. This work was initiated during his previous position at Sorbonne University, Paris, France. AV was an employee of Eisai Inc. (November 2019 - June 2021). AV does not receive any fees or honoraria since November 2019. Before November 2019 he had he received lecture honoraria from Roche, MagQu LLC, and Servier.

MAN reports personal fees from Neuroelectrics, outside the submitted work.

YS reports personal fees from Eisai, personal fees from Lilly, personal fees from Arcadia, outside the submitted work.

BB declares no conflict of interest.

SFC declares no conflict of interest.

MC was supported by the Italian Ministry of Health (Ricerca Corrente).

GR reports personal fees and other from Neuroelectrics, outside the submitted work; In addition, Dr. Ruffini has a patent WO2015059545A1 issued to Neuroelectrics, and a patent PCT/US19/17977 pending to Neuroelectrics.

GEF reports grants from National Institutes of Health, from null, during the conduct of the study.

PMR declares no conflict of interest.

BD declares no conflict of interest.

AA reports other from NeuroCare GmbH, personal fees from Savir GmbH, grants from State of Lower Saxony, Germany, outside the submitted work.

CB declares no conflict of interest.

JPL declares no conflict of interest.

BD reports personal fees from Acadia, personal fees from Alector, personal fees from Arkuda, personal fees from Axovant, personal fees from Biogen, personal fees from Eisai, personal fees from Life Molecular Sciences, personal fees from Lilly, personal fees from Merck, personal fees from Novartis, personal fees from Wave LifeSciences, personal fees from Elsevier, personal fees from Oxford University Press, personal fees from Cambridge University Press, grants from NIH, grants from Alzheimer’s Drug Discover Foundation, outside the submitted work.

GD declares no conflict of interest.

UZ reports grants from European Research Council (ERC), grants from German Research Foundation (DFG), grants from German Ministry of Education and Research (BMBF), grants from Janssen Pharmaceuticals NV, grants from Takeda Pharmaceutical Company Ltd, personal fees from Bayer Vital GmbH, personal fees from Pfizer GmbH, personal fees from CorTec GmbH, outside the submitted work.

APL reports grants from DARPA, National Science Foundation, and National Institutes of Health, during the conduct of the study; personal fees from Neuroelectrics, Starlab, Magstim, Cognito, and MedRhythms for work as medical and scientific advisor. In addition, Dr. Pascual-Leone is co-founder of Linus Health and Ti Solutions AG; has several issued and pending patents on use of noninvasive brain stimulation in combination with EEG and MRI issued.

ES reports grants from DARPA, Alzheimer Drug Discovery Foundation, and National Institutes of Health, personal fees from Neurocare outside the submitted work; ES reports issued and pending patents on noninvasive brain stimulation applications in neurological diseases.

Copyright © 2022 Elsevier B.V. All rights reserved.

Figures

Fig. 1.

Past and Present NiBS Applications in AD. Traditional stimulation targets in AD therapeutic studies have been mostly represented by superficial cortical regions whose dysfunctions are responsible for early cognitive symptoms (language, memory, orientation deficits) that generally bring the individual under clinical attention. The most common stimulation sites in TMS (a) and tES (b) multi-session, sham-controlled studies of the past 10 years are presented in form of pie charts as well as on brain surfaces. The size of the dots is proportional to the number of studies targeting each region. Most TMS studies have administered high-frequency stimulation protocols (patterned 5–20 Hz stimulation), whereas few tES studies have compared the effects of anodal and cathodal stimulation targeting the same area. Overall, few studies used neuronavigated MRI-based stimulation protocols and no studies have leveraged functional magnetic resonance imaging (fMRI) or positron emission tomography (PET) to guide target selection. (c) Details on the parameters of stimulation and overall number of sessions across studies are also reported for TMS and tES.

Fig. 2.

NiBS Precision Medicine Approaches. Novel therapeutic opportunities cover a range of approaches for targeting AD pathological hallmarks. (a) tACS mechanisms of action for the synchronization of oscillatory activity across distant cortical sites, which could be applied to re-tune aberrant cross-frequency ratios (e. g., decrease alpha/beta over theta/delta ratio), as well as to promote oscillatory frequencies with a possible role in the reduction of proteinopathy and neuroinflammation (e.g. gamma band). Adaptive protocols could make use of the incoming information regarding the occurring neural changes for the continuous fine-tuning of stimulation parameters. This can be achieved online during continuous EEG monitoring (as for closed-loop protocols), or offline via repeated neuroimaging data collection, necessary to monitor changes in brain properties (e.g., connectivity, perfusion) and thus adjust stimulation protocols. (b) The cortical response to a TMS pulse can be used as a biomarker for the identification of abnormal (e.g., increased or decreased) brain functions when compared to age-matched populations. Furthermore, TMS-EEG can be a direct marker of stimulation spreading, probing major communications pathways in the brain and further highlighting possible aberrant trajectories or compensatory recruitment. (c) Brain network graphs can be used to guide NiBS via network control theory principles. The study of individual topological properties of nodes and the patterns of information flow can be informative for the identification of the most suitable cortical targets to correct deviant pathological trajectories affecting brain networks (e.g., the DMN) and secondarily affect deep structures not directly targetable (e.g., the hippocampi). Furthermore, the control of brain states might favor the transition between them, for example promoting the switch to a particular cognitive state, or even promoting resilience states toward higher network robustness to external perturbations.

Fig. 3.

Therapeutic Targets and Personalized Montages. (a) Numerous targets of interest exist that might guide future interventions. NiBS might be used to boost diminished activity in affected networks (e.g., DMN) or to decrease the hyperactivity in others (e.g., SN), favoring a return to inter-network balancing similar to healthy controls. Excitatory protocols might also be employed to increase the metabolism in affected areas or to sustain the metabolism in preserved areas. The notion on the spreading routes of the pathology might indeed encourage preventive interventions, whereby excitatory protocols might help sustaining neural functions in regions yet-to-be affected. Similarly, atrophic regions might still represent a NiBS target for sustenance of spared neural mechanisms, as well as a prevention for future atrophy. Finally, tACS might be employed for the targeting of neuroinflammation and proteinopathies, with important implications in the quest for amyloid-β plaques reduction and PV+ interneurons targeting. (b) The heterogeneity of AD pathology further requires targeting to be achieved through highly personalized montages that consider individual brain morphology and tissue characteristics (atrophy, CSF, etc.). (c) Highly personalized solutions can be achieved based for instance on amyloid deposition. (d) An even greater level of personalization could be achieved through the implementation of hybrid models, which further allow optimization towards targeting of specific neuronal populations, such as PV+ inhibitory interneurons and pyramidal neurons.

Fig. 4.

Pathophysiological Framework and Opportunities. Known pathophysiological alterations characterizing the AD course are briefly summarized (a) together with their main neural correlates (b). Proposed NiBS biomarkers and interventions associated with each of the pathophysiological alterations are suggested (c) ranging from the use of combined TMS-EEG as a biomarker of disease stage and progression, to frequency-specific tACS to restore altered intrinsic brain rhythms and abnormal protein accumulation, up to the study of brain networks dynamics and their modulation. In an ideal interventional timeline, NiBS biomarkers assessed at baseline could guide the tuning of the protocol based on the individual profile, including daily habits, to opt between different interventional plans (priming, synergistically combined with other training/activities, or as consolidation between cycles of activities). For the same reason, clinical outcomes should be directed toward the impact that NiBS interventions might have on the daily life of the individual, aiming toward improved cognition, mood, self-independence and overall greater resilience to the pathology, to guarantee a return/maintenance of a high life quality (d).