Journal of Neural Transmission

, Volume 120, Issue 5, pp 813–819 | Cite as

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

  • Jose M. Rabey
  • Evgenia Dobronevsky
  • Sergio Aichenbaum
  • Ofer Gonen
  • Revital Gendelman Marton
  • Michael Khaigrekht
Neurology and Preclinical Neurological Studies - Original Article

Abstract

Cortical excitability can be modulated using repetitive transcranial magnetic stimulation (rTMS). Previously, we showed that rTMS combined with cognitive training (rTMS-COG) has positive results in Alzheimer’s disease (AD). The goal of this randomized double-blind, controlled study was to examine the safety and efficacy of rTMS-COG in AD. Fifteen AD patients received 1-h daily rTMS-COG or sham treatment (seven treated, eight placebo), five sessions/week for 6 weeks, followed by biweekly sessions for 3 months. The primary outcome was improvement of the cognitive score. The secondary outcome included improvement in the Clinical Global Impression of Change (CGIC) and Neuropsychiatric Inventory (NPI). There was an improvement in the average ADAS-cog score of 3.76 points after 6 weeks in the treatment group compared to 0.47 in the placebo group and 3.52 points after 4.5 months of treatment, compared to worsening of 0.38 in the placebo (P = 0.04 and P = 0.05, respectively). There was also an improvement in the average CGIC score of 3.57 (after 6 weeks) and 3.67 points (after 4.5 months), compared to 4.25 and 4.29 in the placebo group (mild worsening) (P = 0.05 and P = 0.05, respectively). NPI improved non-significantly. In summary, the NeuroAD system offers a novel, safe and effective therapy for improving cognitive function in AD.

Keywords

rTMS Alzheimer’s disease Cognitive training ADAS-cog 

Notes

Acknowledgments

We thank Dr. Ariela Alter (Neuronix Ltd., Yokneam, Israel) for her contribution to the manuscript and Dr. Innesa Bekerman for performing the MRI anatomical determinations.

Conflict of interest

Neuronix Ltd, Yokneam, Israel financially supported this study through The Fund for Medical Research, Development of Infrastructure and Health Services––Assaf Harofeh Medical Center, Israel. The study sponsors supported the study by providing funds. The design, the collection, analysis and interpretation of the data, the writing of the report and the decision to submit the paper were the entire responsibility of the corresponding author and the co-authors. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Prof. Rabey (the corresponding author) is a consultant for Neuronix Ltd.

References

  1. Ahmed Z, Wieraszko A (2006) Modulation of learning and hippocampal, neuronal plasticity by repetitive transcranial magnetic stimulation (rTMS). Bioelectromagnetics 27:288–294PubMedCrossRefGoogle Scholar
  2. 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 259:83–92PubMedCrossRefGoogle Scholar
  3. Bellgowan PS, Buffalo EA, Bodurka J, Martin A (2009) Lateralized spatial and object memory encoding in entorhinal and perirhinal cortices. Learn Mem 16:433–438PubMedCrossRefGoogle Scholar
  4. Bentwich J, Dobronevsky E, Aichenbaum S, Shorer R, Peretz R, Khaigrekht M, Marton RG, Rabey JM (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 118:463–471PubMedCrossRefGoogle Scholar
  5. Birks J (2006) Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 1:CD005593. doi: 10.1002/14651858.CD005593
  6. Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39PubMedCrossRefGoogle Scholar
  7. Buck BH, Black SE, Behrmann M, Caldwell C, Bronskill MJ (1997) Spatial- and object-based attentional deficits in Alzheimer’s disease. Relationship to HMPAO-SPECT measures of parietal perfusion. Brain 120:1229–1244PubMedCrossRefGoogle Scholar
  8. Cotelli M, Manenti R, Cappa SF, Geroldi C, Zanetti O, Rossini PM, Miniussi C (2006) Effect of transcranial magnetic stimulation on action naming in patients with Alzheimer disease. Arch Neurol 63:1602–1604PubMedCrossRefGoogle Scholar
  9. 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 82:794–797PubMedCrossRefGoogle Scholar
  10. Courtney C, Farrell D, Gray R, Hills R, Lynch L, Sellwood E, Edwards S, Hardyman W, Raftery J, Crome P, Lendon C, Shaw H, Bentham P, AD2000 Collaborative Group (2004) Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 363:2105–2115PubMedCrossRefGoogle Scholar
  11. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J (1994) The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 44:2308–2314PubMedCrossRefGoogle Scholar
  12. Freitas C, Mondragón-Llorca H, Pascual-Leone A (2011) Noninvasive brain stimulation in Alzheimer’s disease: systematic review and perspectives for the future. Exp Gerontol 46:611–627PubMedGoogle Scholar
  13. Grafman J, Pascual-Leone A, Alway D, Nichelli P, Gomez-Tortosa E, Hallett M (1994) Induction of a recall deficit by rapid-rate transcranial magnetic stimulation. NeuroReport 5:1157–1160PubMedCrossRefGoogle Scholar
  14. Guy W (1976) Clinical global impressions. In: ECDEU Assessment Manual for Psychopharmacology, revised. National Institute of Mental Health, Rockville, pp 218–222Google Scholar
  15. Harpaz Y, Levkovitz Y, Lavidor M (2009) Lexical ambiguity resolution in Wernicke’s area and its right homologue. Cortex 45:1097–1103PubMedCrossRefGoogle Scholar
  16. Hoogendam JM, Ramakers GM, DiLazzaro V (2010) Physiology of repetitive transcranial magnetic stimulation of the human brain. Brain Stimul 3:95–118PubMedCrossRefGoogle Scholar
  17. Kimbrell TA, Little JT, Dunn RT, Frye MA, Greenberg BD, Wassermann EM, Repella JD, Danielson AL, Willis MW, Benson BE, Speer AM, Osuch E, George MS, Post RM (1999) Frequency dependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism. Biol Psychiatry 46:1603–1613PubMedCrossRefGoogle Scholar
  18. Lisanby SH, Luber B, Perera T, Sackeim HS (2000) Transcranial magnetic stimulation: applications in basic neuroscience and neuropsychopharmacology. Int J Neuropsychopharmacol 3:259–273PubMedCrossRefGoogle Scholar
  19. Mantovani A, Lisanby SH (2004) Applications of transcranial magnetic stimulation to therapy in psychiatry. Psychiatric Times 21:1–2Google Scholar
  20. Nardone R, Bergmann J, Christova M, Caleri F, Tezzon F, Ladurner G, Trinka E, Golaszewski S (2012) Effect of transcranial brain stimulation for the treatment of Alzheimer disease: a review. Int J Alzheimers Dis. Article ID 687909Google Scholar
  21. Pascual-Leone A, Tormos JM, Keenan J, Tarazona F, Cañete C, Catalá MD (1998) Study and modulation of human cortical excitability with transcranial magnetic stimulation. J Clin Neurophysiol 15:333–334PubMedCrossRefGoogle Scholar
  22. Perry EK, Perry RH, Blessed G, Tomlinson BE (1977) Necropsy evidence of central cholinergic deficits in senile dementia. Lancet 1:189PubMedCrossRefGoogle Scholar
  23. Rafii MS, Ellis RJ, Corey-Bloom J (2009) Dementing and degenerative disorders. In: Corey-Bloom J, David RB (eds) Clinical adult neurology. Demos Medical, New York, pp 395–417Google Scholar
  24. Reichman WE, Fiocco AJ, Rose NS (2010) Exercising the brain to avoid cognitive decline: examining the evidence. Aging Health 6:565–584CrossRefGoogle Scholar
  25. Rockwood K, Fay S, Gorman M, Carver D, Graham JE (2007) The clinical meaningfulness of ADAS-Cog changes in Alzheimer’s disease patients treated with donepezil in an open-label trial. BMC Neurology 30:7–26Google Scholar
  26. Rogalsky C, Matchin W, Hickok G (2008) Broca’s area, sentence comprehension, and working memory: an fMRI Study. Front Hum Neurosci 2:14PubMedCrossRefGoogle Scholar
  27. Rosen WG, Mohs RC, Davis KL (1984) A new rating scale for Alzheimer’s disease. Am J Psychiatry 141:1356–1364PubMedGoogle Scholar
  28. Rossi S, Hallett M, Rossini PM, Pascual-Leone A, Safety of TMS Consensus Group (2009) Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol 120:2008–2039PubMedCrossRefGoogle Scholar
  29. Siebner HR, Rothwell J (2003) Transcranial magnetic stimulation: new insights into representational cortical plasticity. Exp Brain Res 148:1–16PubMedCrossRefGoogle Scholar
  30. Sitzer DI, Twamley EW, Jeste DV (2006) Cognitive training in Alzheimer’s disease: a meta-analysis of the literature. Acta Psychiatr Scand 114:75–90PubMedCrossRefGoogle Scholar
  31. Spector A, Thorgrimsen L, Woods B, Royan L, Davies S, Butterworth M, Orrell M (2003) Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia: randomised controlled trial. Br J Psychiatry 183:248–254PubMedCrossRefGoogle Scholar
  32. Wagner T, Valero-Cabre A, Pascual-Leone A (2007) Noninvasisve human brain stimulation. Annu Rev Biomed Eng 9:527–565PubMedCrossRefGoogle Scholar
  33. Zheng XM (2000) Regional cerebral blood flow changes in drug-resistant depressed patients following treatment with transcranial magnetic stimulation: a statistical parametric mapping analysis. Psychiatry Res 100:75–80PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2012

Authors and Affiliations

  • Jose M. Rabey
    • 1
    • 2
  • Evgenia Dobronevsky
    • 1
    • 2
  • Sergio Aichenbaum
    • 1
    • 2
  • Ofer Gonen
    • 1
    • 2
  • Revital Gendelman Marton
    • 1
    • 2
  • Michael Khaigrekht
    • 2
    • 3
  1. 1.Department of NeurologyAssaf Harofeh Medical CenterZerifinIsrael
  2. 2.The Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Memory ClinicAssaf Harofeh Medical CenterZerifinIsrael

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