Skip to main content

Advertisement

SpringerLink
Log in

High-frequency repetitive transcranial magnetic stimulation combined with cognitive training improves cognitive function and cortical metabolic ratios in Alzheimer’s disease

  • Neurology and Preclinical Neurological Studies - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Various studies report discordant results regarding the efficacy, parameters, and underlying mechanisms of repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (CT) on Alzheimer’s disease (AD). The objective of the study was to assess the effect of rTMS-CT on cognition, the activities of daily life, neuropsychiatric behavioral symptoms, and metabolite levels beneath the stimulated areas of the brain in patients with AD and to investigate the correlation of metabolic changes (measured with proton magnetic resonance spectroscopy [1H-MRS]) with clinical outcomes after treatment. Thirty consecutive patients with mild or moderate AD were enrolled and randomly divided into one of the two intervention groups: (1) real rTMS with CT (i.e., real group) and (2) sham rTMS with CT (i.e., sham group). 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex (DLPFC) and then to stimulate the left lateral temporal lobe (LTL) for 20 min each day for 4 weeks. Each patient underwent neuropsychological assessment at baseline (T0), immediately after treatment (T1), and 4 weeks after treatment (T2). The ratios of N-acetylaspartate/creatine (NAA/Cr), myoinositol/creatine (mI/Cr), and choline/creatine (Cho/Cr) in the stimulated cortex were measured using 1H-MRS at T0 and T1. Twenty-eight patients were treated with rTMS-CT for 4 weeks. Two patients in the sham group withdrew after being treated several times. Compared with the sham group, the cognitive function and behavior in the real rTMS group improved significantly at T1 and T2. In the real group, compared with the sham group, the NAA/Cr ratio in the left DLPFC was significantly elevated (p = 0.045); however, in the left LTL, it only showed a tendency toward increase (p = 0.162). The change in the NAA/Cr ratio in the left DLPFC was negatively correlated with the change in the cognitive scales of the Alzheimer’s Disease Assessment Scale (ADAS-cog). This study indicated a possible modest effect of rTMS-CT on preventing clinical and neuronal functional deterioration in the left DLPFC of patients with AD. The left DLPFC is a better candidate area than the left LTL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • 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 259:83–92. https://doi.org/10.1007/s00415-011-6128-4

    Article  PubMed  Google Scholar 

  • Alcala-Lozano R, Garza-Villarreal EA (2018) Overlap of large-scale brain networks may explain the similar cognitive improvement of single-site vs multi-site rTMS in Alzheimer’s disease. Brain Stimul 11:942–944. https://doi.org/10.1016/j.brs.2018.03.016

    Article  PubMed  Google Scholar 

  • Barbey AK, Koenigs M, Grafman J (2013) Dorsolateral prefrontal contributions to human working memory. Cortex 49:1195–1205

    Article  PubMed  Google Scholar 

  • Bentwich J et al (2011) Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer’s disease: a proof of concept study. J Neural Transm (Vienna) 118:463–471. https://doi.org/10.1007/s00702-010-0578-1

    Article  CAS  Google Scholar 

  • Boggio PS, Khoury LP, Martins DC, Martins OE, de Macedo EC, Fregni F (2009) Temporal cortex direct current stimulation enhances performance on a visual recognition memory task in Alzheimer disease. J Neurol Neurosurg Psychiatry 80:444–447. https://doi.org/10.1136/jnnp.2007.141853

    Article  CAS  PubMed  Google Scholar 

  • Boggio PS et al (2012) Prolonged visual memory enhancement after direct current stimulation in Alzheimer’s disease. Brain Stimul 5:223–230. https://doi.org/10.1016/j.brs.2011.06.006

    Article  PubMed  Google Scholar 

  • Brooks WM et al (2000) Metabolic and cognitive response to human traumatic brain injury: a quantitative proton magnetic resonance study. J Neurotrauma 17:629–640

    Article  CAS  PubMed  Google Scholar 

  • Budson AE, Price BH (2005) Memory dysfunction. N Engl J Med 352:692

    Article  CAS  PubMed  Google Scholar 

  • Cacace AT, Hu J, Romero S, Xuan Y, Burkard RF, Tyler RS (2017) Glutamate is down-regulated and tinnitus loudness-levels decreased following rTMS over auditory cortex of the left hemisphere: a prospective randomized single-blinded sham-controlled cross-over stud. Hear Res. https://doi.org/10.1016/j.heares.2017.10.017

    Article  PubMed  Google Scholar 

  • Cotelli M, Manenti R, Cappa SF, Zanetti O, Miniussi C (2008) Transcranial magnetic stimulation improves naming in Alzheimer disease patients at different stages of cognitive decline. Eur J Neurol 15:1286–1292. https://doi.org/10.1111/j.1468-1331.2008.02202.x

    Article  CAS  PubMed  Google Scholar 

  • Cotelli M, Calabria M, Manenti R, Rosini S, Zanetti O, Cappa SF, Miniussi C (2011) Improved language performance in Alzheimer disease following brain stimulation. J Neurol Neurosurg Psychiatry 82:794–797. https://doi.org/10.1136/jnnp.2009.197848

    Article  PubMed  Google Scholar 

  • Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J (1994) The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 44:2308–2314

    Article  CAS  PubMed  Google Scholar 

  • Dlabacde Lange JJ, Liemburg EJ, Bais L, At PM, Es DLK, Knegtering H, Aleman A (2017) Effect of bilateral prefrontal rTMS on left prefrontal NAA and Glx levels in schizophrenia patients with predominant negative symptoms: an exploratory study. Brain Stimul 10:59–64

    Article  Google Scholar 

  • Dubois B et al (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS–ADRDA criteria. Lancet Neurol 6:734–746. https://doi.org/10.1016/s1474-4422(07)70178-3

    Article  PubMed  Google Scholar 

  • Ferrucci R et al (2008) Transcranial direct current stimulation improves recognition memory in Alzheimer disease. Neurology 71:493–498. https://doi.org/10.1212/01.wnl.0000317060.43722.a3

    Article  CAS  PubMed  Google Scholar 

  • Folstein MF, Folstein SE, Mchugh PR (1975) Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    Article  CAS  PubMed  Google Scholar 

  • Gauthier S, Loft H, Cummings J (2008) Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. Int J Geriatr Psychiatry 23:537–545. https://doi.org/10.1002/gps.1949

    Article  CAS  PubMed  Google Scholar 

  • Guse B, Falkai P, Wobrock T (2010) Cognitive effects of high-frequency repetitive transcranial magnetic stimulation: a systematic review. J Neural Transm 117:105–122. https://doi.org/10.1007/s00702-009-0333-7

    Article  PubMed  Google Scholar 

  • Henigsberg N et al (2011) 1-H MRS changes in dorsolateral prefrontal cortex after donepezil treatment in patients with mild to moderate Alzheimer’s disease. Coll Antropol 35(Suppl 1):159–162

    CAS  PubMed  Google Scholar 

  • 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 36:2348–2359. https://doi.org/10.1016/j.neurobiolaging.2015.04.016

    Article  PubMed  PubMed Central  Google Scholar 

  • Huang ML et al (2017) Relationships between dorsolateral prefrontal cortex metabolic change and cognitive impairment in first-episode neuroleptic-naive schizophrenia patients. Medicine 96:e7228

    Article  PubMed  PubMed Central  Google Scholar 

  • Hugg JW, Kuzniecky RI, Gilliam FG, Morawetz RB, Fraught RE, Hetherington HP (2010) Normalization of contralateral metabolic function following temporal lobectomy demonstrated by 1H magnetic resonance spectroscopic imaging. Ann Neurol 40:236–239

    Article  Google Scholar 

  • Kantarci K et al (2004) 1H MR spectroscopy in common dementias. Neurology 63:1393–1398

    Article  CAS  PubMed  Google Scholar 

  • Kantarci K et al (2007) Longitudinal 1H MRS changes in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 28:1330–1339

    Article  CAS  PubMed  Google Scholar 

  • Kumar S et al (2017) Extent of dorsolateral prefrontal cortex plasticity and its association with working memory in patients with Alzheimer disease. JAMA Psychiatry 74:1266

    Article  PubMed  PubMed Central  Google Scholar 

  • Kumfor F, Zhen A, Hodges JR, Piguet O, Irish M (2018) Apathy in Alzheimer’s disease and frontotemporal dementia: distinct clinical profiles and neural correlates. Cortex 103:350

    Article  PubMed  Google Scholar 

  • Kwak YT, Yang Y, Pyo SJ, Koo MS (2014) Clinical characteristics according to depression screening tools in patients with Alzheimer’s disease: view from self, caregiver-reported and drug-intervention pattern. Geriatr Gerontol Int 14:660–666. https://doi.org/10.1111/ggi.12154

    Article  PubMed  Google Scholar 

  • 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 12:57–64

    Article  PubMed  Google Scholar 

  • Lefaucheur JP et al (2014) Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol 125:2150–2206. https://doi.org/10.1016/j.clinph.2014.05.021

    Article  PubMed  Google Scholar 

  • Luborzewski A et al (2007) Metabolic alterations in the dorsolateral prefrontal cortex after treatment with high-frequency repetitive transcranial magnetic stimulation in patients with unipolar major depression. J Psychiatr Res 41:606–615

    Article  PubMed  Google Scholar 

  • Matias-Guiu JA, Ana C-M, Maria VS, Teresa R, Marta F-M, Teresa MR, Jorge M-G (2016) Addenbrooke’s cognitive examination III: diagnostic utility for mild cognitive impairment and dementia and correlation with standardized neuropsychological tests. Int Psychogeriatr 29:105–113

    Article  PubMed  Google Scholar 

  • Matíasguiu JA, Vallessalgado M, Rognoni T, Hamregil F, Morenoramos T, Matíasguiu J (2017) Comparative diagnostic accuracy of the ACE-III, MIS, MMSE, MoCA, and RUDAS for screening of Alzheimer disease. Dement Geriatr Cogn Disord 43:237

    Article  Google Scholar 

  • Mehta D, Jackson R, Paul G, Shi J, Sabbagh M (2017) Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010–2015. Expert Opin Investig Drugs 26:735–739. https://doi.org/10.1080/13543784.2017.1323868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michael N, Gosling M, Reutemann M, Kersting A, Heindel W, Arolt V, Pfleiderer B (2003) Metabolic changes after repetitive transcranial magnetic stimulation (rTMS) of the left prefrontal cortex: a sham-controlled proton magnetic resonance spectroscopy (1H MRS) study of healthy brain. Eur J Neurosci 17:2462–2468

    Article  PubMed  Google Scholar 

  • Modrego PJ, Pina MA, Fayed N, Díaz M (2006) Changes in metabolite ratios after treatment with rivastigmine in Alzheimer’s disease: a nonrandomised controlled trial with magnetic resonance spectroscopy Cns. Drugs 20:867–877

    CAS  Google Scholar 

  • Mohs RC, Marin D, Green CR, Davis KL (1997) The Alzheimer’s disease assessment scale: modifications that can enhance its use in future clinical trials. Birkhäuser, Boston

    Google Scholar 

  • Nardone R et al (2012) Effect of transcranial brain stimulation for the treatment of Alzheimer disease: a review. Int J Alzheimers Dis 2012:687909

    PubMed  Google Scholar 

  • Nguyen JP et al (2017) Repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer’s disease. Neurophysiol Clin 47:47–53. https://doi.org/10.1016/j.neucli.2017.01.001

    Article  PubMed  Google Scholar 

  • Noda Y et al (2015) Neurobiological mechanisms of repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex in depression: a systematic review. Psychol Med 45:3411–3432. https://doi.org/10.1017/S0033291715001609

    Article  CAS  PubMed  Google Scholar 

  • Padala PR et al (2018) Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: A double-blind, randomized, sham-controlled, cross-over pilot study. Psychiatry Res 261:312–318. https://doi.org/10.1016/j.psychres.2017.12.063

    Article  PubMed  PubMed Central  Google Scholar 

  • Rabey JM, Dobronevsky E (2016) Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training is a safe and effective modality for the treatment of Alzheimer’s disease: clinical experience. J Neural Transm 123:1–7

    Article  Google Scholar 

  • Rabey JM, Dobronevsky E, Aichenbaum S, Gonen O, Marton RG, Khaigrekht M (2013) Repetitive transcranial magnetic stimulation combined with cognitive training is a safe and effective modality for the treatment of Alzheimer’s disease: a randomized, double-blind study. J Neural Transm (Vienna) 120:813–819. https://doi.org/10.1007/s00702-012-0902-z

    Article  Google Scholar 

  • Rosenberg PB, Nowrangi MA, Lyketsos CG (2015) Neuropsychiatric symptoms in Alzheimer’s disease: what might be associated brain circuits? Mol Aspects Med 43–44:25–37. https://doi.org/10.1016/j.mam.2015.05.005

    Article  PubMed  Google Scholar 

  • Rossi S, Hallett M, Rossini PM, Pascual-Leone A (2011) Screening questionnaire before TMS: an update. Clin Neurophysiol 122:1686

    Article  PubMed  Google Scholar 

  • Rossini PM et al (2015) Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N Committee. Clin Neurophysiol 126:1071–1107. https://doi.org/10.1016/j.clinph.2015.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 1:1. https://doi.org/10.1002/gps.5003

    Article  Google Scholar 

  • Wang BR, Ou Z, Gu XH, Wei CS, Xu J, Shi JQ (2017) Validation of the Chinese version of Addenbrooke's cognitive examination III for diagnosing dementia. Int J Geriatr Psychiatr 32:e173–e179. https://doi.org/10.1002/gps.4680

    Article  Google Scholar 

  • 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 27:280–288. https://doi.org/10.11919/j.issn.1002-0829.215107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang M (1995) Epidemiological investigation tool for dementia and its application. Shanghai Psychiatr 1995(A01):1–62 (in Chinese)

    Google Scholar 

Download references

Acknowledgements

The authors thank Professor Ping Yin (Department of Epidemiology and Biostatistics, School of Public Health Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China) for his statistical analysis advice. We also thank Fengfei Ding and Xiaofan Zhang (Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China) for their advice in this research.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Beijing, China; Grant numbers 81873890, 81271406, 81702231).

Author information

Authors and Affiliations

  1. Department of Rehabilitation, Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Fengxia Zhang, Lingfeng Xie, Caixia Zheng & Xiaolin Huang

  2. Department of Radiology, Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Yuanyuan Qin

  3. Department of Neurology, Medicine Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Min Zhang

Authors
  1. Fengxia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuanyuan Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lingfeng Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Caixia Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaolin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Min Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Xiaolin Huang or Min Zhang.

Ethics declarations

Conflict of interest

The authors in the present study disclose no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

702_2019_2022_MOESM1_ESM.tif

Figure 1 Supplement 1. The images show the spectroscopic volume of interest in the left dorsolateral prefrontal cortex (a) and the left temporal lobe (b) (TIFF 9662 kb)

702_2019_2022_MOESM2_ESM.tif

Figure 1 Supplement 2. A representative image shows the spectrum of the left dorsolateral prefrontal cortex (DLPFC) and left temporal lobe (TL) before and immediately after treatment in the real repetitive transcranial magnetic stimulation–cognitive training (rTMS-CT) group (TIFF 10066 kb)

Supplementary material 3 (DOCX 22 kb)

Supplementary material 4 (DOCX 17 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, F., Qin, Y., Xie, L. et al. 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, 1081–1094 (2019). https://doi.org/10.1007/s00702-019-02022-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-019-02022-y

Keywords

Search

Navigation