Repetitive Transcranial Magnetic Stimulation Induces Cognitive Recovery in Alzheimer's Disease via GABAergic Neuron Activation of the Cx3cl1-Cx3cr1 Axis

Abstract

This study aimed to investigate the impact of repetitive transcranial magnetic stimulation (rTMS) on cognitive recovery in Alzheimer's disease (AD) by exploring the role of GABAergic neuron activation and modulation of the Cx3cl1-Cx3cr1 signalling axis. The 5xFAD mouse model was utilised for scRNA-seq analysis to examine changes in gene expression post-rTMS. Microglial phagocytic activity, amyloid plaque burden, cell–cell communication, microglial morphology and neuroinflammation markers were assessed. Following rTMS, upregulation of Cx3cl1 in GABAergic neurons was observed, leading to enhanced microglial phagocytosis, reduced amyloid plaque burden, improved cell–cell communication, altered microglial morphology and decreased neuroinflammation markers. This study demonstrates that rTMS promotes Aβ clearance and cognitive recovery in AD by activating GABAergic neurons and enhancing Cx3cl1-Cx3cr1 signalling, providing a novel molecular target for non-invasive AD therapy. These findings support the transition from invasive to non-invasive AD treatments, improving patient adherence and therapeutic outcomes. Furthermore, the elucidation of cellular and molecular mechanisms facilitates drug development targeting the Cx3cl1-Cx3cr1 axis, offering new opportunities for AD intervention.

Keywords

Alzheimer's disease / cognitive function / Cx3cl1-Cx3cr1 axis / GABAergic neurons / microglia / rTMS

References

[1] W.-D. Bao, P. Pang, X.-T. Zhou, et al., “Loss of Ferroportin Induces Memory Impairment by Promoting Ferroptosis in Alzheimer's Disease,” Cell Death and Differentiation 28, no. 5 (2021): 1548–1562, https://doi.org/10.1038/s41418-020-00685-9.

[2] L. A. Manwell, M. Tadros, T. M. Ciccarelli, and R. Eikelboom, “Digital Dementia in the Internet Generation: Excessive Screen Time During Brain Development Will Increase the Risk of Alzheimer's Disease and Related Dementias in Adulthood,” Journal of Integrative Neuroscience 21, no. 1 (2022): 28, https://doi.org/10.31083/j.jin2101028.

[3] A. Ionescu-Tucker and C. W. Cotman, “Emerging Roles of Oxidative Stress in Brain Aging and Alzheimer's Disease,” Neurobiology of Aging 107 (2021): 86–95, https://doi.org/10.1016/j.neurobiolaging.2021.07.014.

[4] S. P. McKenna, M. Rouse, A. Heaney, and P. Hagell, “International Development of the Alzheimer's Patient Partners Life Impact Questionnaire (APPLIQue),” American Journal of Alzheimer's Disease and Other Dementias 35 (2020): 1533317520951690, https://doi.org/10.1177/1533317520951690.

[5] G. E. Smith, M. Chandler, J. A. Fields, J. Aakre, and D. E. C. Locke, “A Survey of Patient and Partner Outcome and Treatment Preferences in Mild Cognitive Impairment,” Journal of Alzheimer's Disease 63, no. 4 (2018): 1459–1468, https://doi.org/10.3233/JAD-171161.

[6] C. H. van Dyck, C. J. Swanson, P. Aisen, et al., “Lecanemab in Early Alzheimer's Disease,” New England Journal of Medicine 388, no. 1 (2023): 9–21, https://doi.org/10.1056/NEJMoa2212948.

[7] E. Passeri, K. Elkhoury, M. Morsink, et al., “Alzheimer's Disease: Treatment Strategies and Their Limitations,” International Journal of Molecular Sciences 23,22 (2022): 13954, https://doi.org/10.3390/ijms232213954.

[8] C. J. Swanson, Y. Zhang, S. Dhadda, et al., “A Randomized, Double-Blind, Phase 2b Proof-Of-Concept Clinical Trial in Early Alzheimer's Disease With Lecanemab, an Anti-Aβ Protofibril Antibody,” Alzheimer's Research & Therapy 13,1 (2021): 80, https://doi.org/10.1186/s13195-021-00813-8.

[9] A. Antal, B. Luber, A.-K. Brem, et al., “Non-Invasive Brain Stimulation and Neuroenhancement,” Clinical Neurophysiology Practice 7 (2022): 146–165, https://doi.org/10.1016/j.cnp.2022.05.002.

[10] H. Knotkova, C. Hamani, E. Sivanesan, et al., “Neuromodulation for Chronic Pain,” Lancet 397, no. 10289 (2021): 2111–2124, https://doi.org/10.1016/S0140-6736(21)00794-7.

[11] G. Lanza, F. Fisicaro, M. Cantone, et al., “Repetitive Transcranial Magnetic Stimulation in Primary Sleep Disorders,” Sleep Medicine Reviews 67 (2023): 101735, https://doi.org/10.1016/j.smrv.2022.101735.

[12] K. Richter, S. Kellner, and C. Licht, “rTMS in Mental Health Disorders,” Frontiers in Network Physiology 3 (2023): 943223, https://doi.org/10.3389/fnetp.2023.943223.

[13] J. Moretti, D. J. Terstege, E. Z. Poh, J. R. Epp, and J. Rodger, “Low Intensity Repetitive Transcranial Magnetic Stimulation Modulates Brain-Wide Functional Connectivity to Promote Anti-Correlated c-Fos Expression,” Scientific Reports 12, no. 1 (2022): 20571, https://doi.org/10.1038/s41598-022-24934-8.

[14] Y. Tu, J. Cao, S. Guler, et al., “Perturbing fMRI Brain Dynamics Using Transcranial Direct Current Stimulation,” NeuroImage 237 (2021): 118100, https://doi.org/10.1016/j.neuroimage.2021.118100.

[15] C. Pourzitaki, I. Dardalas, F. Poutoglidou, D. Kouvelas, and V. K. Kimiskidis, “The Combination of rTMS and Pharmacotherapy on In Vitro Models: A Mini-Review,” CNS & Neurological Disorders Drug Targets 19, no. 3 (2020): 220–226, https://doi.org/10.2174/1871527319666200518100716.

[16] T. S. Kaster, J. Downar, F. Vila-Rodriguez, et al., “Differential Symptom Cluster Responses to Repetitive Transcranial Magnetic Stimulation Treatment in Depression,” EClinicalMedicine 55 (2023): 101765, https://doi.org/10.1016/j.eclinm.2022.101765.

[17] A. H. Ansari, A. Pal, A. Ramamurthy, M. Kabat, S. Jain, and S. Kumar, “Fibromyalgia Pain and Depression: An Update on the Role of Repetitive Transcranial Magnetic Stimulation,” ACS Chemical Neuroscience 12, no. 2 (2021): 256–270, https://doi.org/10.1021/acschemneuro.0c00785.

[18] Z. Fengxia, Y. Qin, L. Xie, et al., “High-Frequency Repetitive Transcranial Magnetic Stimulation Combined With Cognitive Training Improves Cognitive Function and Cortical Metabolic Ratios in Alzheimer's Disease,” Journal of Neural Transmission 126, no. 8 (2019): 1081–1094, https://doi.org/10.1007/s00702-019-02022-y.

[19] C. Bagattini, M. Zanni, F. Barocco, et al., “Enhancing Cognitive Training Effects in Alzheimer's Disease: rTMS as an Add-On Treatment,” Brain Stimulation 13, no. 6 (2020): 1655–1664, https://doi.org/10.1016/j.brs.2020.09.010.

[20] X. Li, G. Qi, C. Yu, et al., “Cortical Plasticity Is Correlated With Cognitive Improvement in Alzheimer's Disease Patients After rTMS Treatment,” Brain Stimulation 14, no. 3 (2021): 503–510, https://doi.org/10.1016/j.brs.2021.01.012.

[21] G. Lanza, F. Fisicaro, R. Dubbioso, et al., “A Comprehensive Review of Transcranial Magnetic Stimulation in Secondary Dementia,” Frontiers in Aging Neuroscience 14 (2022): 995000, https://doi.org/10.3389/fnagi.2022.995000.

[22] S. M. Sears and S. J. Hewett, “Influence of Glutamate and GABA Transport on Brain Excitatory/Inhibitory Balance,” Experimental Biology and Medicine 246, no. 9 (2021): 1069–1083, https://doi.org/10.1177/1535370221989263.

[23] Y.-T. Cheng, J. Woo, E. Luna-Figueroa, E. Maleki, A. S. Harmanci, and B. Deneen, “Social Deprivation Induces Astrocytic TRPA1-GABA Suppression of Hippocampal Circuits,” Neuron 111, no. 8 (2023): 1301–1315, https://doi.org/10.1016/j.neuron.2023.01.015.

[24] C. Zhang, L. K. Vincelette, F. Reimann, and S. D. Liberles, “A Brainstem Circuit for Nausea Suppression,” Cell Reports 39, no. 11 (2022): 110953, https://doi.org/10.1016/j.celrep.2022.110953.

[25] A. Sędzikowska and L. Szablewski, “Insulin and Insulin Resistance in Alzheimer's Disease,” International Journal of Molecular Sciences 22, no. 18 (2021): 9987, https://doi.org/10.3390/ijms22189987.

[26] G. A. Czapski and J. B. Strosznajder, “Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer's Disease,” International Journal of Molecular Sciences 22, no. 21 (2021): 11677, https://doi.org/10.3390/ijms222111677.

[27] C. Mecca, I. Giambanco, R. Donato, and C. Arcuri, “Microglia and Aging: The Role of the TREM2-DAP12 and CX3CL1-CX3CR1 Axes,” International Journal of Molecular Sciences 19, no. 1 (2018): 318, https://doi.org/10.3390/ijms19010318.

[28] H. Park, B. Cho, H. Kim, et al., “Single-Cell RNA-Sequencing Identifies Disease-Associated Oligodendrocytes in Male APP NL-G-F and 5XFAD Mice,” Nature Communications 14, no. 1 (2023): 802, https://doi.org/10.1038/s41467-023-36519-8.

[29] H. Jäntti, V. Sitnikova, Y. Ishchenko, et al., “Microglial Amyloid Beta Clearance Is Driven by PIEZO1 Channels,” Journal of Neuroinflammation 19, no. 1 (2022): 147, https://doi.org/10.1186/s12974-022-02486-y.

[30] K. W. Jo, D. Lee, D. G. Cha, et al., “Gossypetin Ameliorates 5xFAD Spatial Learning and Memory Through Enhanced Phagocytosis Against Aβ,” Alzheimer's Research & Therapy 14, no. 1 (2022): 158, https://doi.org/10.1186/s13195-022-01096-3.

[31] Y. Lin, J. Jin, R. Lv, et al., “Repetitive Transcranial Magnetic Stimulation Increases the Brain's Drainage Efficiency in a Mouse Model of Alzheimer's Disease,” Acta Neuropathologica Communications 9, no. 1 (2021): 102, https://doi.org/10.1186/s40478-021-01198-3.

[32] F. Chu, R. Tan, X. Wang, et al., “Transcranial Magneto-Acoustic Stimulation Attenuates Synaptic Plasticity Impairment Through the Activation of Piezo1 in Alzheimer's Disease Mouse Model,” Research 6 (2023): 0130, https://doi.org/10.34133/research.0130.

[33] Y. Zhang, E. D. Bander, Y. Lee, C. Muoser, C. B. Schaffer, and N. Nishimura, “Microvessel Occlusions Alter Amyloid-Beta Plaque Morphology in a Mouse Model of Alzheimer's Disease,” Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism 40, no. 10 (2020): 2115–2131, https://doi.org/10.1177/0271678X19889092.

[34] M. Calvo-Rodriguez, S. S. Hou, A. C. Snyder, et al., “Increased Mitochondrial Calcium Levels Associated With Neuronal Death in a Mouse Model of Alzheimer's Disease,” Nature Communications 11, no. 1 (2020): 2146, https://doi.org/10.1038/s41467-020-16074-2.

[35] J. Shiu, L. Zhang, G. Lentsch, et al., “Multimodal Analyses of Vitiligo Skin Identify Tissue Characteristics of Stable Disease,” JCI Insight 7, no. 13 (2022): e154585, https://doi.org/10.1172/jci.insight.154585.

[36] Y. Huang, K. E. Happonen, P. G. Burrola, et al., “Microglia Use TAM Receptors to Detect and Engulf Amyloid β Plaques,” Nature Immunology 22, no. 5 (2021): 586–594, https://doi.org/10.1038/s41590-021-00913-5.

[37] J. V. Andersen, N. H. Skotte, S. K. Christensen, et al., “Hippocampal Disruptions of Synaptic and Astrocyte Metabolism Are Primary Events of Early Amyloid Pathology in the 5xFAD Mouse Model of Alzheimer's Disease,” Cell Death and Disease 12, no. 11 (2021): 954, https://doi.org/10.1038/s41419-021-04237-y.

[38] H. Oakley, S. L. Cole, S. Logan, et al., “Intraneuronal Beta-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice With Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation,” Journal of Neuroscience 26, no. 40 (2006): 10129–10140, https://doi.org/10.1523/JNEUROSCI.1202-06.2006.

[39] Q. Zhao, M. Maci, M. R. Miller, et al., “Sleep Restoration by Optogenetic Targeting of GABAergic Neurons Reprograms Microglia and Ameliorates Pathological Phenotypes in an Alzheimer's Disease Model,” Molecular Neurodegeneration 18, no. 1 (2023): 93, https://doi.org/10.1186/s13024-023-00682-9.

[40] K. Li, X. Wang, Y. Jiang, et al., “Early Intervention Attenuates Synaptic Plasticity Impairment and Neuroinflammation in 5xFAD Mice,” Journal of Psychiatric Research 136 (2021): 204–216, https://doi.org/10.1016/j.jpsychires.2021.02.007.

[41] D. Chen, Q. Lou, X.-J. Song, et al., “Microglia Govern the Extinction of Acute Stress-Induced Anxiety-Like Behaviors in Male Mice,” Nature Communications 15, no. 1 (2024): 449, https://doi.org/10.1038/s41467-024-44704-6.

[42] F.-W. Zhou, C. Hook, and A. C. Puche, “Frequency-Dependent Centrifugal Modulation of the Activity of Different Classes of Mitral and Tufted Cells in Olfactory Bulb,” Journal of Neurophysiology 129, no. 6 (2023): 1515–1533, https://doi.org/10.1152/jn.00390.2022.

[43] Q. Guan, W. Liu, K. Mu, et al., “Single-Cell RNA Sequencing of CSF Reveals Neuroprotective RAC1⁺ NK Cells in Parkinson's Disease,” Frontiers in Immunology 13 (2022): 992505, https://doi.org/10.3389/fimmu.2022.992505.

[44] W. Liu, H. Hu, Z. Shao, et al., “Characterizing the Tumor Microenvironment at the Single-Cell Level Reveals a Novel Immune Evasion Mechanism in Osteosarcoma,” Bone Research 11, no. 1 (2023): 4, https://doi.org/10.1038/s41413-022-00237-6.

[45] S. Ergin, N. Kherad, and M. Alagoz, “RNA Sequencing and Its Applications in Cancer and Rare Diseases,” Molecular Biology Reports 49, no. 3 (2022): 2325–2333, https://doi.org/10.1007/s11033-021-06963-0.

[46] Y.-J. Deng, E.-H. Ren, W.-H. Yuan, G.-Z. Zhang, Z.-L. Wu, and Q.-Q. Xie, “GRB10 and E2F3 as Diagnostic Markers of Osteoarthritis and Their Correlation With Immune Infiltration,” Diagnostics 10, no. 3 (2020): 171, https://doi.org/10.3390/diagnostics10030171.

[47] X. Zhan, S. Feng, X. Zhou, et al., “Immunotherapy Response and Microenvironment Provide Biomarkers of Immunotherapy Options for Patients With Lung Adenocarcinoma,” Frontiers in Genetics 13 (2022): 1047435, https://doi.org/10.3389/fgene.2022.1047435.

[48] A. Zahra, J. Jiang, Y. Chen, C. Long, and L. Yang, “Memantine Rescues Prenatal Citalopram Exposure-Induced Striatal and Social Abnormalities in Mice,” Experimental Neurology 307 (2018): 145–154, https://doi.org/10.1016/j.expneurol.2018.06.003.

[49] J. H. Lee, J. Y. Zhang, Z. Z. Wei, and S. P. Yu, “Impaired Social Behaviors and Minimized Oxytocin Signaling of the Adult Mice Deficient in the N-Methyl-d-Aspartate Receptor GluN3A Subunit,” Experimental Neurology 305 (2018): 1–12, https://doi.org/10.1016/j.expneurol.2018.02.015.

[50] X.-Y. Sun, L. J. Li, Q. X. Dong, et al., “Rutin Prevents Tau Pathology and Neuroinflammation in a Mouse Model of Alzheimer's Disease,” Journal of Neuroinflammation 18, no. 1 (2021): 131, https://doi.org/10.1186/s12974-021-02182-3.

[51] J.-P. Wei, W. Wen, Y. Dai, et al., “Drinking Water Temperature Affects Cognitive Function and Progression of Alzheimer's Disease in a Mouse Model,” Acta Pharmacologica Sinica 42, no. 1 (2021): 45–54, https://doi.org/10.1038/s41401-020-0407-5.

[52] L. Huang, J. Wang, G. Liang, et al., “Upregulated NMDAR-Mediated GABAergic Transmission Underlies Autistic-Like Deficits in Htr3a Knockout Mice,” Theranostics 11, no. 19 (2021): 9296–9310, https://doi.org/10.7150/thno.60531.

[53] M.-L. Chen, C.-G. Hong, T. Yue, et al., “Inhibition of miR-331-3p and miR-9-5p Ameliorates Alzheimer's Disease by Enhancing Autophagy,” Theranostics 11, no. 5 (2021): 2395–2409, https://doi.org/10.7150/thno.47408.

[54] S. Zou, C. Wang, Z. Cui, et al., “β-Elemene Induces Apoptosis of Human Rheumatoid Arthritis Fibroblast-Like Synoviocytes via Reactive Oxygen Species-Dependent Activation of p38 Mitogen-Activated Protein Kinase,” Pharmacological Reports: PR 68, no. 1 (2016): 7–11, https://doi.org/10.1016/j.pharep.2015.06.004.

[55] S. M. Ayuk, H. Abrahamse, and N. N. Houreld, “The Role of Photobiomodulation on Gene Expression of Cell Adhesion Molecules in Diabetic Wounded Fibroblasts In Vitro,” Journal of Photochemistry and Photobiology, B: Biology 161 (2016): 368–374, https://doi.org/10.1016/j.jphotobiol.2016.05.027.

[56] Q. Wu and X. Yi, “Down-Regulation of Long Noncoding RNA MALAT1 Protects Hippocampal Neurons Against Excessive Autophagy and Apoptosis via the PI3K/Akt Signaling Pathway in Rats With Epilepsy,” Journal of Molecular Neuroscience: MN 65, no. 2 (2018): 234–245, https://doi.org/10.1007/s12031-018-1093-3.

[57] Q. Mao, X. L. Liang, C. L. Zhang, Y. H. Pang, and Y. X. Lu, “LncRNA KLF3-AS1 in Human Mesenchymal Stem Cell-Derived Exosomes Ameliorates Pyroptosis of Cardiomyocytes and Myocardial Infarction Through miR-138-5p/Sirt1 Axis,” Stem Cell Research & Therapy 10, no. 1 (2019): 393, https://doi.org/10.1186/s13287-019-1522-4.

[58] Q.-F. Zhang, J. Li, K. Jiang, et al., “CDK4/6 Inhibition Promotes Immune Infiltration in Ovarian Cancer and Synergizes With PD-1 Blockade in a B Cell-Dependent Manner,” Theranostics 10, no. 23 (2020): 10619–10633, https://doi.org/10.7150/thno.44871.

[59] N. Attal, F. Poindessous-Jazat, E. De Chauvigny, et al., “Repetitive Transcranial Magnetic Stimulation for Neuropathic Pain: A Randomized Multicentre Sham-Controlled Trial,” Brain: A Journal of Neurology 144, no. 11 (2021): 3328–3339, https://doi.org/10.1093/brain/awab208.

[60] M. D. Soler, H. Kumru, R. Pelayo, et al., “Effectiveness of Transcranial Direct Current Stimulation and Visual Illusion on Neuropathic Pain in Spinal Cord Injury,” Brain: A Journal of Neurology 133, no. 9 (2010): 2565–2577, https://doi.org/10.1093/brain/awq184.

[61] Z. Guo, L. Zhang, Z. Wu, Y. Chen, F. Wang, and G. Chen, “In Vivo Direct Reprogramming of Reactive Glial Cells Into Functional Neurons After Brain Injury and in an Alzheimer's Disease Model,” Cell Stem Cell 14, no. 2 (2014): 188–202, https://doi.org/10.1016/j.stem.2013.12.001.

[62] D. Bi, L. Wen, Z. Wu, and Y. Shen, “GABAergic Dysfunction in Excitatory and Inhibitory (E/I) Imbalance Drives the Pathogenesis of Alzheimer's Disease,” Alzheimer's & Dementia: The Journal of the Alzheimer's Association 16, no. 9 (2020): 1312–1329, https://doi.org/10.1002/alz.12088.

[63] G. Bivona, M. Iemmolo, and G. Ghersi, “CX3CL1 Pathway as a Molecular Target for Treatment Strategies in Alzheimer's Disease,” International Journal of Molecular Sciences 24, no. 9 (2023): 8230, https://doi.org/10.3390/ijms24098230.

[64] A. Nimmerjahn, F. Kirchhoff, and F. Helmchen, “Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma In Vivo,” Science 308, no. 5726 (2005): 1314–1318, https://doi.org/10.1126/science.1110647.

[65] B. Bassett, S. Subramaniyam, Y. Fan, et al., “Minocycline Alleviates Depression-Like Symptoms by Rescuing Decrease in Neurogenesis in Dorsal Hippocampus via Blocking Microglia Activation/Phagocytosis,” Brain, Behavior, and Immunity 91 (2021): 519–530, https://doi.org/10.1016/j.bbi.2020.11.009.

[66] J.-H. Baek, D. Whitfield, D. Howlett, et al., “Unfolded Protein Response Is Activated in Lewy Body Dementias,” Neuropathology and Applied Neurobiology 42, no. 4 (2016): 352–365, https://doi.org/10.1111/nan.12260.

[67] J. M. Morganti, K. R. Nash, B. A. Grimmig, et al., “The Soluble Isoform of CX3CL1 Is Necessary for Neuroprotection in a Mouse Model of Parkinson's Disease,” Journal of Neuroscience 32, no. 42 (2012): 14592–14601, https://doi.org/10.1523/JNEUROSCI.0539-12.2012.

[68] P. Chakraborty, S. Saha, G. Deco, A. Banerjee, and D. Roy, “Structural-and-Dynamical Similarity Predicts Compensatory Brain Areas Driving the Post-Lesion Functional Recovery Mechanism,” Cerebral Cortex Communications 4, no. 3 (2023): tgad012, https://doi.org/10.1093/texcom/tgad012.

[69] L. Luo, M. Liu, Y. Fan, et al., “Intermittent Theta-Burst Stimulation Improves Motor Function by Inhibiting Neuronal Pyroptosis and Regulating Microglial Polarization via TLR4/NFκB/NLRP3 Signaling Pathway in Cerebral Ischemic Mice,” Journal of Neuroinflammation 19, no. 1 (2022): 141, https://doi.org/10.1186/s12974-022-02501-2.

[70] H. R. Siebner, K. Funke, A. S. Aberra, et al., “Transcranial Magnetic Stimulation of the Brain: What Is Stimulated?—A Consensus and Critical Position Paper,” Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology 140 (2022): 59–97, https://doi.org/10.1016/j.clinph.2022.04.022.

[71] G. Darmani, T. O. Bergmann, K. Butts Pauly, et al., “Non-Invasive Transcranial Ultrasound Stimulation for Neuromodulation,” Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology 135 (2022): 51–73, https://doi.org/10.1016/j.clinph.2021.12.010.

[72] Y. Xing, Y. Zhang, C. Li, et al., “Repetitive Transcranial Magnetic Stimulation of the Brain After Ischemic Stroke: Mechanisms From Animal Models,” Cellular and Molecular Neurobiology 43, no. 4 (2023): 1487–1497, https://doi.org/10.1007/s10571-022-01264-x.

[73] J. Bok, J. Ha, B. J. Ahn, and Y. Jang, “Disease-Modifying Effects of Non-Invasive Electroceuticals on β-Amyloid Plaques and Tau Tangles for Alzheimer's Disease,” International Journal of Molecular Sciences 24, no. 1 (2022): 679, https://doi.org/10.3390/ijms24010679.

[74] I. Stevanovic, B. Mancic, T. Ilic, et al., “Theta Burst Stimulation Influence the Expression of BDNF in the Spinal Cord on the Experimental Autoimmune Encephalomyelitis,” Folia Neuropathologica 57, no. 2 (2019): 129–145, https://doi.org/10.5114/fn.2019.86294.

[75] C. Z. W. Lee and F. Ginhoux, “Biology of Resident Tissue Macrophages,” Development 149, no. 8 (2022): dev200270, https://doi.org/10.1242/dev.200270.

[76] C. Bouter, C. Irwin, T. N. Franke, N. Beindorff, and Y. Bouter, “Quantitative Brain Positron Emission Tomography in Female 5XFAD Alzheimer Mice: Pathological Features and Sex-Specific Alterations,” Frontiers in Medicine 8 (2021): 745064, https://doi.org/10.3389/fmed.2021.745064.

[77] V. G. Nicoletti, F. Fisicaro, E. Aguglia, et al., “Challenging the Pleiotropic Effects of Repetitive Transcranial Magnetic Stimulation in Geriatric Depression: A Multimodal Case Series Study,” Biomedicine 11,3 (2023): 958, https://doi.org/10.3390/biomedicines11030958.

[78] P. Wei, L. Li, G. Lanza, M. Cantone, and P. Gu, “Editorial: Application of Noninvasive Neuromodulation in Cognitive Rehabilitation,” Frontiers in Neurology 14 (2023): 1333474, https://doi.org/10.3389/fneur.2023.1333474.

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