Article Text

Original research
Cognitive effects and acceptability of non-invasive brain stimulation on Alzheimer’s disease and mild cognitive impairment: a component network meta-analysis
  1. Che-Sheng Chu1,2,3,
  2. Cheng-Ta Li4,5,6,7,
  3. Andre R. Brunoni8,
  4. Fu-Chi Yang9,
  5. Ping-Tao Tseng10,
  6. Yu-Kang Tu11,
  7. Brendon Stubbs12,13,14,
  8. André F. Carvalho15,16,
  9. Trevor Thompson17,
  10. Tarek k. Rajji15,18,
  11. Ta-Chuan Yeh19,
  12. Chia-Kuang Tsai9,
  13. Tien-Yu Chen9,20,
  14. Dian-Jeng Li2,21,
  15. Chih-Wei Hsu22,
  16. Yi-Cheng Wu23,
  17. Chia-Ling Yu24,
  18. Chih-Sung Liang25,26
  1. 1 Department of Psychiatry and Center for Geriatric and Gerontology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
  2. 2 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
  3. 3 Non-invasive Neuromodulation Consortium for Mental Disorders, Society of Psychophysiology, Taipei, Taiwan
  4. 4 Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
  5. 5 Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei, Taiwan
  6. 6 Division of Psychiatry, Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
  7. 7 nstitute of Cognitive Neuroscience, National Central University, Jhongli, Taiwan
  8. 8 Service of Interdisciplinary Neuromodulation (SIN), Laboratory of Neurosciences (LIM-27), and National Institute of Biomarkers in Neuropsychiatry (INBioN), Department of Internal Medicine and Department of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil
  9. 9 Department of Neurology, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan
  10. 10 WinShine Clinics in Specialty of Psychiatry, Kaohsiung, Taiwan
  11. 11 Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
  12. 12 Department of Physiotherapy, South London and Maudsley NHS Foundation Trust, London, UK
  13. 13 Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, De Crespigny Park, London, UK
  14. 14 Positive Ageing Research Institute (PARI), Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, UK
  15. 15 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
  16. 16 Centre for Addiction & Mental Health (CAMH), Toronto, Ontario, Canda
  17. 17 School of Human Sciences, University of Greenwich, London, UK
  18. 18 Adult Neurodevelopment and Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
  19. 19 Department of Psychiatry, Tri-Service General Hospital, Schoool of Medicine, National Defense Medical Center, Taipei, Taiwan
  20. 20 Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
  21. 21 Department of Addiction Science, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan
  22. 22 Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
  23. 23 Department of Sports Medicine, Landseed International Hospital, Taoyuan, Taiwan
  24. 24 Department of Pharmacy, Chang Gung Memorial Hospital, Linkou, Taiwan
  25. 25 Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, Taipei, Taiwan
  26. 26 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
  1. Correspondence to Dr Chih-Sung Liang, Department of Psychiatry, No.60, Xinmin Road, Beitou District, Taipei 11243, Taiwan; lcsyfw{at}


Objectives To compare cognitive effects and acceptability of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) in patients with Alzheimer’s disease (AD) or mild cognitive impairment (MCI), and to determine whether cognitive training (CT) during rTMS or tDCS provides additional benefits.

Methods Electronic search of PubMed, Medline, Embase, the Cochrane Library and PsycINFO up to 5 March 2020. We enrolled double-blind, randomised controlled trials (RCTs). The primary outcomes were acceptability and pre–post treatment changes in general cognition measured by Mini-Mental State Examination, and the secondary outcomes were memory function, verbal fluency, working memory and executive function. Durability of cognitive benefits (1, 2 and ≥3 months) after brain stimulation was examined.

Results We included 27 RCTs (n=1070), and the treatment components included high-frequency rTMS (HFrTMS) and low-frequency rTMS, anodal tDCS (atDCS) and cathodal tDCS (ctDCS), CT, sham CT and sham brain stimulation. Risk of bias of evidence in each domain was low (range: 0%–11.1%). HFrTMS (1.08, 9, 0.35–1.80) and atDCS (0.56, 0.03–1.09) had short-term positive effects on general cognition. CT might be associated with negative effects on general cognition (−0.79, –2.06 to 0.48) during rTMS or tDCS. At 1-month follow-up, HFrTMS (1.65, 0.77–2.54) and ctDCS (2.57, 0.20–4.95) exhibited larger therapeutic responses. Separate analysis of populations with pure AD and MCI revealed positive effects only in individuals with AD. rTMS and tDCS were well tolerated.

Conclusions HFrTMS is more effective than atDCS for improving global cognition, and patients with AD may have better responses to rTMS and tDCS than MCI.

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  • C-SC and C-TL contributed equally.

  • Contributors C-SC and ARB contributed equally as first authors, independently screened the studies, and extracted the relevant information from the manuscripts and drafted the current manuscript. Y-KT and TT, the specialists of statistics, took the responsibility of supervising the whole statistical process and technical support. T-CY and C-KT evaluated the risk of bias. F-CY, P-TT, BS, AFC, TkR, T-YC, D-JL, C-WH, Y-CW and C-LY contributed in concept formation, study design, methodology support and manuscript revision. C-SL and C-TL, the corresponding authors, took the responsibility of data deposit, collection of all information from the other authors and submitting the current manuscript.

  • Funding This study was sponsored by grants from Taipei Veterans General Hospital (V108D44-003-MY3-1) and Kaohsiung Veterans General Hospital (VGHKS 109-070), and the Ministry of Science and Technology (MOST 106-2314-B-075-034 -MY3; 108-2321-B-075-004-MY2). In addition, this work was supported by the Brain Research Center (108BRC-B502), National Yang-Ming University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request from corresponding author (C-SL).

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.