Table I.
Neurobiological changes and neurobiological biomarkers associated with the potential disease-modifying and anti-AD effects of TMS.
| First author/s, year | Study subject | Neurobiological marker observed | TMS parameters | Results | TMS outcomes | (Refs.) |
|---|---|---|---|---|---|---|
| Choung et al, 2021 | Intracerebroventricular Aβ42-induced mouse model of AD | Dopamine, BDNF, DR4, Nestin and NeuN | 20 Hz HF-rTMS and 1 Hz LF-rTMS | DR4, BDNF, Nestin and NeuN increased in the Hr-AD group compared with that in the Lr-AD and Nr-AD groups. | Enhanced spatial working memory, improved neurocognitive progress, increased neurogenesis, and neurogenic, neuroprotective and neuroregenerative effects. | (32) |
| Chen et al, 2020 | APP/PS1 double-mutant transgenic mouse model of AD | BDNF, TrkB, synaptic plasticity-related proteins (PSD95 and SYN), p-AKT, LC3II, LC3I, ApoE and p62 | 5 Hz HF-rTMS | No differences in SYN, PSD95 and p-AKT. BDNF, BDNF-TrkB signaling and LC3II/LC3I ratio increased, and ApoE and p62 decreased. | Reduced the cognitive impairment of learning and memory, lessened the AD pathology progression and AD-like dysfunctions, enhanced the hippocampal autophagy level and enhanced the cognitive function. | (81) |
| Tan et al, 2013 | Aβ1-42-induced toxicity rat model of AD | Neurotrophins (NGF and BDNF) and NMDA-receptor levels (NR1, NR2A and NR2B) | 1 Hz LF-rTMS | BDNF, NGF, NR1, NR2A and NR2B increased. | Increased hippocampal neurotrophins and NMDA-receptor contents, enhanced hippocampal LTP, reversed memory deficits, and improved spatial memory retrieval ability. | (82) |
| Chen et al, 2019 | Aβ1-42-induced toxicity rat model of AD | BDNF, NGF, GSK-3β, p-GSK-3β, Tau, p-Tau, β-catenin and p-β-catenin, cleaved caspase-3, Bax, and Bcl-2 | 10 Hz HF-rTMS and 1 Hz LF-rTMS | BDNF, NGF, GSK-3β, Tau, Bcl-2, β-catenin increased. P-GSK-3β, p-Tau, cleaved caspase-3, Bax and p-β-catenin decreased. | Improved cognitive function, decreased neuron apoptosis, increased neuronal viability, promoted the survival of neurons and improved cognitive function. | (83) |
| Velioglu et al, 2021 | Patients with AD | BDNF, total antioxidant status, total thiol, native thiol, total oxidant status, oxidative stress index, oxidant enzyme activity and disulfide level | 20 Hz HF-rTMS | BDNF, total antioxidant status, total thiol and native thiol increased. Total oxidant status, oxidative stress index, oxidant enzyme activity and disulfide levels decreased. | Increased visual recognition memory functions, decreased oxidant status, increased anti-oxidant levels and improvement in familiarity-based cognition. | (36) |
| Zhang et al, 2019 | Patients with AD | Ratio of NAA/Cr, Cho/Cr and mI/Cr | 10 Hz rTMS | NAA/Cr increased. Cho/Cr and mI/Cr remained unchanged. | Prevented neuronal functional deterioration, improved cognitive function and ameliorated agitation and apathy. | (134) |
| Huang et al, 2017 | APP23/PS45 double-mutant transgenic mouse model of AD | APP, CTFs (C99 and C89) and BACE1 | 1 Hz LF-rTMS | APP, β-secretase-β-secretase-cleaved C-terminal fragments of amyloid precursor protein. (C99, C89), and BACE1 decreased. | Improved spatial learning and memory, rescued impaired hippocampal LTP, reduced AD-related neuropathology, inhibited β-secretase cleavage of APP proteins and reduced neuritic plaque formation. | (136) |
| Perez et al, 2021 | Primary human brain cultures | Aβ40 and Aβ42 levels | Repeated electromagnetic field stimulation (3 mT; 75 Hz) | Aβ40 and Aβ42 decreased. | Decreased Aβ toxicity. | (154) |
| Capelli et al, 2017 | Peripheral blood mononuclear cells from peripheral blood of patients with AD | miRNAs (miR-107, miR-335-5p and miR26b-5p) and BACE1 | 75 Hz low-frequency pulsed electromagnetic field | BACE1 and miRNAs decreased with increasing time of exposure. | Modulated the expression of miRNAs, stimulated epigenetic regulation, and regulated brain signaling and synaptic plasticity. | (70) |
Aβ40, amyloid β40 oligomer; Aβ1-42, 42-residue peptide of amyloid β; Aβ42, amyloid β42 oligomer; AD, Alzheimer's disease; ApoE, apolipoprotein E; APP, amyloid-β precursor protein; BACE1, β-site APP-cleaving enzyme 1; BDNF, brain-derived neurotrophic factor; Cho/Cr, choline/creatine; CTFs, C-terminal fragments; DR4, dopamine receptor 4; HF-rTMS, high-frequency repetitive transcranial magnetic stimulation; Hr-AD, high-frequency rTMS-treated subgroup; LF-rTMS, low-frequency rTMS; Lr-AD, low-frequency rTMS-treated subgroup; LTP, long-term potentiation; mI/Cr, myoinositol/creatine; miRNA/miR, microRNA; mT, Motor Threshold; NAA/Cr, N-acetylaspartate/creatine; NeuN, neuronal nuclear protein; NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; NMDAR, N-methyl-D-aspartate receptor; NR1, N-methyl-D-aspartate receptor subunit 1; NR2A, N-methyl-D-aspartate receptor subunit 2A; NR2B, N-methyl-D-aspartate receptor subunit 2B; Nr-AD, none rTMS-treated subgroup; p-, phosphorylated; PS1, presenilin-1; PS45, presenilin 45; PSD95, postsynaptic density protein 95; SYN, synaptophysin; TrkB, tropomyosin receptor kinase B.