Neuroprotection and Non-Invasive Brain Stimulation: Facts or Fiction?

Abstract

Non-Invasive Brain Stimulation (NIBS) techniques, such as transcranial Direct Current Stimulation (tDCS) and repetitive Magnetic Transcranial Stimulation (rTMS), are well-known non-pharmacological approaches to improve both motor and non-motor symptoms in patients with neurodegenerative disorders. Their use is of particular interest especially for the treatment of cognitive impairment in Alzheimer's Disease (AD), as well as axial disturbances in Parkinson's (PD), where conventional pharmacological therapies show very mild and short-lasting effects. However, their ability to interfere with disease progression over time is not well understood; recent evidence suggests that NIBS may have a neuroprotective effect, thus slowing disease progression and modulating the aggregation state of pathological proteins. In this narrative review, we gather current knowledge about neuroprotection and NIBS in neurodegenerative diseases (i.e., PD and AD), just mentioning the few results related to stroke. As further matter of debate, we discuss similarities and differences with Deep Brain Stimulation (DBS)-induced neuroprotective effects, and highlight possible future directions for ongoing clinical studies.

Keywords: Alzheimer’s Disease; Parkinson’s Disease; deep brain stimulation; neurodegenerative disorders; neuroprotection; non-invasive brain stimulation; pathological proteins; rTMS; tDCS.

Figure 1

Schematic overview of neuroprotective effects of tDCS in animal models of Parkinson’s disease. SOD = superoxide dismutase; GSH-Px = glutathione peroxidase; BDNF = brain-derived neurotrophic factor; MDA = malonaldehyde; DA = dopamine; TH = tyrosine hydroxylase. Feng et al., 2020 [44]; Lee et al., 2019 [17]; Li et al., 2015 [19]; Lee et al., 2018 [45].

Figure 2

Schematic overview of neuroprotective effects of NIBS in Alzheimer’s disease. tDCS = transcranial direct current stimulation; tACS = transcranial alternating current stimulation; rTMS = repetitive transcranial magnetic stimulation; BDNF = brain-derived neurotrophic factor; TrkB = Tropomyosin receptor kinase B; NGF = Nerve growth factor; NO = nitric oxide; OxS = oxidative stress. Choung et al., 2021 [70]; Velioglu et al., 2021 [71]; Tan et al., 2013 [73]; Chen et al., 2020 [74]; Marceglia et al., 2016 [83]; Luo et al., 2022 [88]; Khedr et al., 2019 [90].

Figure 3

Schematic overview of comparisons in neuroprotective effects between NIBS and DBS. tDCS = transcranial direct current stimulation; DA = dopamine; SOD = superoxide dismutase; GSH-PX = glutathione peroxidase; TH = tyrosine hydroxylase; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MDA = malonaldehyde; LF-rTMS = low frequency repetitive transcranial magnetic stimulation; BDNF = Brain-Derived Neurotrophic Factor; NGF = nerve growth factor; NO = nitric oxide; Aβ = amyloid-β peptide; BBB = blood brain barrier; HF-rTMS = high frequency repetitive transcranial magnetic stimulation; TrkB = Tropomyosin receptor kinase B; SNpc = substantia nigra pars compacta; PAG = periaqueductal grey matter; Akt = Protein kinase B; STN = subthalamic nucleus. Feng et al., 2020 [44]; Lee et al., 2019 [17]; Li et al., 2015 [19]; Lee et al., 2018 [45]; Tan et al., 2013 [73]; Marceglia et al., 2016 [83]; Khedr et al., 2019 [90]; Luo et al., 2022 [88]; Chen et al., 2020 [74]; Choung et al., 2021 [70]; Velioglu et al., 2021 [71]; Wallace et al., 2007 [100]; Musacchio et al., 2017 [101]; Spieles-Engemann et al., 2011 [102]; Fischer et al., 2017 [103]; Rodrigues et al., 1998 [104]; Baldermann et al., 2018 [105]; Huang et al., 2019 [106]; Xia et al., 2017 [107]; Akwa et al., 2017 [108].