The role of noninvasive brain stimulation for behavioral and psychological symptoms of dementia: a systematic review and meta-analysis

  • Xin Wang
  • Zhiqi Mao
  • Xinguang YuEmail author
Review Article



This meta-analysis aimed at evaluating and comparing the efficacy of noninvasive brain stimulation (NIBS) techniques on the behavioral and psychological symptoms of dementia (BPSD).


An exhaustive literature retrieval was performed on PubMed, Embase, Cochrane Library, and Web of Science until October 2019. The primary outcome was the relative changes in BPSD severity scores immediately after NIBS and at the last follow-up visit. Subgroup analyses were conducted to compare the efficacy of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Changes in the severity scores after NIBS were also analyzed with restriction to patients with Alzheimer’s disease (AD).


Ten studies with 324 patients were included, out of which 7 studies involved patients with AD. The analysis results indicated that NIBS significantly improved the BPSD outcome immediately after stimulation (SMD, 0.31; 95% CI, 0.10–0.52; P = 0.005), but not at the last follow-up visit (0.15; − 0.11–0.41; 0.25). Our subgroup analyses suggested that the favorable effects of rTMS remained significant at the last follow-up visit (0.57; 0.18–0.96; 0.004). This discrepancy maybe caused by the continuously insignificant outcomes of tDCS on the whole data. The results for AD patients immediately after stimulation (0.37; 0.12–0.61; 0.003) and at the last follow-up visit (0.29; − 0.19–0.76; 0.24) were both largely similar to those in the whole patient group with dementia.


rTMS, rather than tDCS, was capable of persistently improving the BPSD at an early stage after treatment. More trials are warranted to confirm our results before the establishment of final conclusions.


Behavioral and psychological symptoms Dementia Transcranial direct current stimulation Transcranial magnetic stimulation Randomized controlled trial Meta-analysis 


Funding information

This study was supported by the National Natural Science Foundation of China (grant no. 8187052509) and National Clinical Research Center for Geriatric Diseases (grant no. NCRCG-PLAGH-2018006).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All studies in this review have been approved by the local ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.


  1. 1.
    Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, Ballard C, Banerjee S, Burns A, Cohen-Mansfield J, Cooper C, Fox N, Gitlin LN, Howard R, Kales HC, Larson EB, Ritchie K, Rockwood K, Sampson EL, Samus Q, Schneider LS, Selbaek G, Teri L, Mukadam N (2017) Dementia prevention, intervention, and care. Lancet 390(10113):2673–2734. CrossRefPubMedGoogle Scholar
  2. 2.
    Lyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JC (2000) Mental and behavioral disturbances in dementia: findings from the Cache County Study on memory in aging. Am J Psychiatry 157(5):708–714. CrossRefPubMedGoogle Scholar
  3. 3.
    Devshi R, Shaw S, Elliott-King J, Hogervorst E, Hiremath A, Velayudhan L, Kumar S, Baillon S, Bandelow S (2015) Prevalence of behavioural and psychological symptoms of dementia in individuals with learning disabilities. Diagnostics (Basel) 5(4):564–576. CrossRefGoogle Scholar
  4. 4.
    Vacas SM, Stella F, Loureiro JC, do Couto FS, Oliveira-Maia AJ, Forlenza OV (2018) Noninvasive brain stimulation for behavioural and psychological symptoms of dementia: a systematic review and meta-analysis. Int J Geriatr Psychiatry. CrossRefGoogle Scholar
  5. 5.
    Canevelli M, Adali N, Cantet C, Andrieu S, Bruno G, Cesari M, Vellas B (2013) Impact of behavioral subsyndromes on cognitive decline in Alzheimer’s disease: data from the ICTUS study. J Neurol 260(7):1859–1865. CrossRefPubMedGoogle Scholar
  6. 6.
    Rosenberg PB, Mielke MM, Appleby BS, Oh ES, Geda YE, Lyketsos CG (2013) The association of neuropsychiatric symptoms in MCI with incident dementia and Alzheimer disease. Am J Geriatr Psychiatry 21(7):685–695. CrossRefPubMedGoogle Scholar
  7. 7.
    Manso-Calderon R, Cacabelos-Perez P, Sevillano-Garcia MD, Herrero-Prieto ME, Gonzalez-Sarmiento R (2019) The impact of vascular burden on behavioural and psychological symptoms in older adults with dementia: the BEVASDE study. Neurol Sci 41:165–174. CrossRefPubMedGoogle Scholar
  8. 8.
    Jin B, Liu H (2019) Comparative efficacy and safety of therapy for the behavioral and psychological symptoms of dementia: a systemic review and Bayesian network meta-analysis. J Neurol 266(10):2363–2375. CrossRefPubMedGoogle Scholar
  9. 9.
    Livingston G, Johnston K, Katona C, Paton J, Lyketsos CG (2005) Systematic review of psychological approaches to the management of neuropsychiatric symptoms of dementia. Am J Psychiatry 162(11):1996–2021. CrossRefPubMedGoogle Scholar
  10. 10.
    Suemoto CK, Apolinario D, Nakamura-Palacios EM, Lopes L, Leite RE, Sales MC, Nitrini R, Brucki SM, Morillo LS, Magaldi RM, Fregni F (2014) Effects of a non-focal plasticity protocol on apathy in moderate Alzheimer’s disease: a randomized, double-blind, sham-controlled trial. Brain Stimul 7(2):308–313. CrossRefPubMedGoogle Scholar
  11. 11.
    Wu Y, Xu W, Liu X, Xu Q, Tang L, Wu S (2015) Adjunctive treatment with high frequency repetitive transcranial magnetic stimulation for the behavioral and psychological symptoms of patients with Alzheimer’s disease: a randomized, double-blind, sham-controlled study. Shanghai Arch Psychiatry 27(5):280–288. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ferrucci R, Mrakic-Sposta S, Gardini S, Ruggiero F, Vergari M, Mameli F, Arighi A, Spallazzi M, Barocco F, Michelini G, Pietroboni AM, Ghezzi L, Fumagalli GG, D’Urso G, Caffarra P, Scarpini E, Priori A, Marceglia S (2018) Behavioral and neurophysiological effects of transcranial direct current stimulation (tDCS) in fronto-temporal dementia. Front Behav Neurosci 12:235. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hsu WY, Ku Y, Zanto TP, Gazzaley A (2015) Effects of noninvasive brain stimulation on cognitive function in healthy aging and Alzheimer’s disease: a systematic review and meta-analysis. Neurobiol Aging 36(8):2348–2359. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ni Z, Chen R (2015) Transcranial magnetic stimulation to understand pathophysiology and as potential treatment for neurodegenerative diseases. Transl Neurodegener 4:22. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Valero-Cabre A, Amengual JL, Stengel C, Pascual-Leone A, Coubard OA (2017) Transcranial magnetic stimulation in basic and clinical neuroscience: a comprehensive review of fundamental principles and novel insights. Neurosci Biobehav Rev 83:381–404. CrossRefPubMedGoogle Scholar
  16. 16.
    Gangitano M, Valero-Cabre A, Tormos JM, Mottaghy FM, Romero JR, Pascual-Leone A (2002) Modulation of input-output curves by low and high frequency repetitive transcranial magnetic stimulation of the motor cortex. Clin Neurophysiol 113(8):1249–1257. CrossRefPubMedGoogle Scholar
  17. 17.
    Ahmed MA, Darwish ES, Khedr EM, El Serogy YM, Ali AM (2012) Effects of low versus high frequencies of repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in Alzheimer’s dementia. J Neurol 259(1):83–92. CrossRefPubMedGoogle Scholar
  18. 18.
    Lee J, Choi BH, Oh E, Sohn EH, Lee AY (2016) Treatment of Alzheimer’s disease with repetitive transcranial magnetic stimulation combined with cognitive training: a prospective, randomized, double-blind, placebo-controlled study. J Clin Neurol 12(1):57–64. CrossRefPubMedGoogle Scholar
  19. 19.
    Zhang F, Qin Y, Xie L, Zheng C, Huang X, Zhang M (2019) High-frequency repetitive transcranial magnetic stimulation combined with cognitive training improves cognitive function and cortical metabolic ratios in Alzheimer’s disease. J Neural Transm 126(8):1081–1094. CrossRefPubMedGoogle Scholar
  20. 20.
    Kidgell DJ, Goodwill AM, Frazer AK, Daly RM (2013) Induction of cortical plasticity and improved motor performance following unilateral and bilateral transcranial direct current stimulation of the primary motor cortex. BMC Neurosci 14:64. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Fricke K, Seeber AA, Thirugnanasambandam N, Paulus W, Nitsche MA, Rothwell JC (2011) Time course of the induction of homeostatic plasticity generated by repeated transcranial direct current stimulation of the human motor cortex. J Neurophysiol 105(3):1141–1149. CrossRefPubMedGoogle Scholar
  22. 22.
    Lang N, Siebner HR, Ward NS, Lee L, Nitsche MA, Paulus W, Rothwell JC, Lemon RN, Frackowiak RS (2005) How does transcranial DC stimulation of the primary motor cortex alter regional neuronal activity in the human brain? Eur J Neurosci 22(2):495–504. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, Paulus W, Hummel F, Boggio PS, Fregni F, Pascual-Leone A (2008) Transcranial direct current stimulation: state of the art 2008. Brain Stimul 1(3):206–223. CrossRefPubMedGoogle Scholar
  24. 24.
    Bystad M, Gronli O, Rasmussen ID, Gundersen N, Nordvang L, Wang-Iversen H, Aslaksen PM (2016) Transcranial direct current stimulation as a memory enhancer in patients with Alzheimer’s disease: a randomized, placebo-controlled trial. Alzheimers Res Ther 8(1):13–17. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Im JJ, Jeong H, Bikson M, Woods AJ, Unal G, Oh JK, Na S, Park JS, Knotkova H, Song IU, Chung YA (2019) Effects of 6-month at-home transcranial direct current stimulation on cognition and cerebral glucose metabolism in Alzheimer’s disease. Brain Stimul. CrossRefGoogle Scholar
  26. 26.
    Khedr EM, Salama RH, Abdel Hameed M, Abo Elfetoh N, Seif P (2019) Therapeutic role of transcranial direct current stimulation in Alzheimer disease patients: double-blind, placebo-controlled clinical trial. Neurorehabil Neural Repair 33(5):384–394. CrossRefPubMedGoogle Scholar
  27. 27.
    Cai MJ, Guo ZW, Xing GQ, Peng HT, Zhou L, Chen HP, McClure MA, He L, Xiong LW, He B, Du F, Mu Q (2019) Transcranial direct current stimulation improves cognitive function in mild to moderate Alzheimer disease a meta-analysis. Alzheimer Dis Assoc Disord 33(2):170–178. CrossRefPubMedGoogle Scholar
  28. 28.
    Lin Y, Jiang W-J, Shan P-Y, Lu M, Wang T, Li R-H, Zhang N, Ma L (2019) The role of repetitive transcranial magnetic stimulation (rTMS) in the treatment of cognitive impairment in patients with Alzheimer’s disease: a systematic review and meta-analysis. J Neurol Sci 398:184–191. CrossRefPubMedGoogle Scholar
  29. 29.
    Elder GJ, Colloby SJ, Firbank MJ, McKeith IG, Taylor JP (2019) Consecutive sessions of transcranial direct current stimulation do not remediate visual hallucinations in Lewy body dementia: a randomised controlled trial. Alzheimers Res Ther 11(1):9. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Shuster JJ (2011) Review: Cochrane handbook for systematic reviews for interventions, version 5.1.0, published 3/2011. Julian P.T. Higgins and Sally Green, Editors. Res Synth Methods 2 (2):126–130CrossRefGoogle Scholar
  31. 31.
    McInnes MDF, Moher D, Thombs BD, McGrath TA, Bossuyt PM, Clifford T, Cohen JF, Deeks JJ, Gatsonis C, Hooft L, Hunt HA, Hyde CJ, Korevaar DA, Leeflang MMG, Macaskill P, Reitsma JB, Rodin R, Rutjes AWS, Salameh JP, Stevens A, Takwoingi Y, Tonelli M, Weeks L, Whiting P, Willis BH (2018) Preferred reporting items for a systematic review and meta-analysis of diagnostic test accuracy studies: the PRISMA-DTA statement. JAMA 319(4):388–396. CrossRefPubMedGoogle Scholar
  32. 32.
    Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6(8):734–746. CrossRefPubMedGoogle Scholar
  33. 33.
    Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, Broe GA, Cummings J, Dickson DW, Gauthier S, Goldman J, Goetz C, Korczyn A, Lees A, Levy R, Litvan I, McKeith I, Olanow W, Poewe W, Quinn N, Sampaio C, Tolosa E, Dubois B (2007) Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 22(12):1689–1707; quiz 1837. CrossRefPubMedGoogle Scholar
  34. 34.
    (1994) Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J Neurol Neurosurg Psychiatry 57(4):416–418.
  35. 35.
    Moher D, Schulz KF, Altman D, Group C (2001) The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 285(15):1987–1991. CrossRefPubMedGoogle Scholar
  36. 36.
    Cotelli M, Manenti R, Brambilla M, Petesi M, Rosini S, Ferrari C, Zanetti O, Miniussi C (2014) Anodal tDCS during face-name associations memory training in Alzheimer’s patients. Front Aging Neurosci 6:38. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Cotelli M, Manenti R, Petesi M, Brambilla M, Cosseddu M, Zanetti O, Miniussi C, Padovani A, Borroni B (2014) Treatment of primary progressive aphasias by transcranial direct current stimulation combined with language training. J Alzheimers Dis 39(4):799–808. CrossRefPubMedGoogle Scholar
  38. 38.
    Koch G, Bonni S, Pellicciari MC, Casula EP, Mancini M, Esposito R, Ponzo V, Picazio S, Di Lorenzo F, Serra L, Motta C, Maiella M, Marra C, Cercignani M, Martorana A, Caltagirone C, Bozzali M (2018) Transcranial magnetic stimulation of the precuneus enhances memory and neural activity in prodromal Alzheimer’s disease. NeuroImage 169:302–311. CrossRefPubMedGoogle Scholar
  39. 39.
    Zhao J, Li Z, Cong Y, Zhang J, Tan M, Zhang H, Geng N, Li M, Yu W, Shan P (2017) Repetitive transcranial magnetic stimulation improves cognitive function of Alzheimer’s disease patients. Oncotarget 8(20):33864–33871. CrossRefPubMedGoogle Scholar
  40. 40.
    Habib R, Nyberg L, Tulving E (2003) Hemispheric asymmetries of memory: the HERA model revisited. Trends Cogn Sci 7(6):241–245CrossRefGoogle Scholar
  41. 41.
    Turriziani P, Smirni D, Zappala G, Mangano GR, Oliveri M, Cipolotti L (2012) Enhancing memory performance with rTMS in healthy subjects and individuals with mild cognitive impairment: the role of the right dorsolateral prefrontal cortex. Front Hum Neurosci 6:62. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Fondazione Società Italiana di Neurologia 2020

Authors and Affiliations

  1. 1.School of MedicineNankai UniversityTianjinChina
  2. 2.Department of NeurosurgeryChinese PLA General HospitalBeijingChina

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