Advertisement

Journal of Neural Transmission

, Volume 123, Issue 12, pp 1449–1455 | Cite as

Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training is a safe and effective modality for the treatment of Alzheimer’s disease: clinical experience

  • Jose Martin Rabey
  • Evgenia Dobronevsky
Neurology and Preclinical Neurological Studies - Original Article

Abstract

Alzheimer’s disease (AD) is the most common type of dementia among the elderly. Common treatments available and non-pharmacological interventions have their limitations, and new therapeutic approaches are critically needed. Transcranial magnetic stimulation (TMS) is a non-invasive technique that generates an electric current-inducing modulation in cortical excitability. The previous clinical trials showed that combinations of rTMS and cognitive training (rTMS-COG), as provided by the NeuroAD medical device system, offer a novel, safe, and effective method improving mild-to-moderate AD patients. In this article, we present our experience with rTMS-COG treatment, in clinical settings, of 30 mild-to-moderate AD patients that received rTMS-COG commercial treatments in two clinics for 1-h daily sessions, 5 days per week, for 6 weeks (30 sessions). Five patients returned for a second treatment. ADAS-Cog and MMSE scores were measured pre- and post-treatments. The main analyses were conducted on patients who received 1 treatment (n = 30). Data received from the five returning patients were analyzed separately. The effect of rTMS-COG treatment was statistically significant regarding both ADAS-Cog (−2.4 point improvement, PV <0.001) and MMSE (+1.7 points improvement, PV <0.001) scores. About 80 % of patients gained some cognitive improvement following NeuroAD treatment, with more than 60 % improving by more than two points, for a minimum of 9 months. The Neuronix NeuroAD System was shown to be a safe and effective non-invasive modality for cognitive improvement of Alzheimer patients, with measurable outcomes lasting, in some of them, for up to 1 year, following completion of the 6-week daily intervention course (a carryover effect).

Keywords

rTMS Alzheimer’s disease Cognitive training Alzheimer’s Disease Assessment Scale-cognitive Dementia Mini–mental state examination 

Notes

Compliance with ethical standards

Study funding

Neuronix Ltd, Yokneam, Israel financially supported this study. 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-author. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Conflict of interest

Prof. Rabey (the corresponding author) and Evgenia Dobronevsky are both consultants for Neuronix Ltd.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study received the approval of the Assaf Harofeh Medical Center Ethical Committee.

Informed consent

Informed consent was obtained from all patients.

References

  1. 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 259:83–92CrossRefPubMedGoogle Scholar
  2. Alzheimer’s Association (2013) 2013 Alzheimer’s disease facts and figures. Alzheimers Dement 9:208–245CrossRefGoogle Scholar
  3. Bellgowan PS, Buffalo EA, Bodurka J, Martin A (2009) Lateralized spatial and object memory encoding in entorhinal and perirhinal cortices. Learn Mem 16:433–438CrossRefPubMedPubMedCentralGoogle 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 118:463–471CrossRefPubMedGoogle Scholar
  5. Birks J (2006) Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 1:CD005593Google Scholar
  6. Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39CrossRefPubMedGoogle Scholar
  7. Brem AK, Schilberg L, Freitas C, Atkinson N, Seligson E, Pascual-Leone A (2013) Effect of cognitive training and rTMS in Alzheimer’s Disease. Alzheimers Dement Suppl 9:S664CrossRefGoogle Scholar
  8. 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 120:1229–1244CrossRefPubMedGoogle 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 82:794–797CrossRefPubMedGoogle Scholar
  10. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra C, Daniele A, Ghirlanda S, Gainotti G, Tonali PA (2004a) Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 75:555–559CrossRefPubMedGoogle Scholar
  11. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Mazzone P, Insola A, Tonali PA, Rothwell JC (2004b) The physiological basis of transcranial motor cortex stimulation in conscious humans. Clin Neurophysiol 115:255–266CrossRefPubMedGoogle Scholar
  12. Fargo KN, Aisen P, Albert M, Au R, Corrada MM, DeKosky S, Drachman D, Fillit H, Gitlin L, Haas M, Herrup K, Kawas C, Khachaturian AS, Khachaturian ZS, Klunk W, Knopman D, Kukull WA, Lamb B, Logsdon RG, Maruff P, Mesulam M, Mobley W, Mohs R, Morgan D, Nixon RA, Paul S, Petersen R, Plassman B, Potter W, Reiman E, Reisberg B, Sano M, Schindler R, Schneider LS, Snyder PJ, Sperling RA,Yaffe K, Bain LJ, Thies WH, Carrillo MC (2014) 2014 Report on the milestones for the US national plan to address Alzheimer's disease. Alzheimer’s Dement 10(5):S430–S452Google Scholar
  13. 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 12:189–198CrossRefPubMedGoogle Scholar
  14. Gilligan AM, Malone DC, Warholak TL, Armstrong EP (2013a) Predictors of hospitalization and institutionalization in Medicaid patient populations with Alzheimer’s Disease. Adv Alzheimer’s Dis 2:74–82CrossRefGoogle Scholar
  15. Gilligan AM, Malone DC, Warholak TL, Armstrong EP (2013b) Health disparities in cost of care in patients with Alzheimer’s disease: an analysis across 4 state medicaid populations. Am J Alzheimer’s Dis Other Demen 28(1):84–92CrossRefGoogle Scholar
  16. 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 5:1157–1160CrossRefPubMedGoogle Scholar
  17. Grayson VK, Velkoff VA, US Census Bureau (2010) The next four decades: the older population in the United States: 2010 to 2050. In: Current population reports. US Census Bureau, US Department of Commerce, Economics and Statistics Administration, Washington DC, pp 25–1138Google Scholar
  18. Guse B, Falkai P, Wobrock T (2010) Cognitive effects of high-frequency repetitive transcranial magnetic stimulation: a systematic review. J Neural Transm (Vienna) 117:105–122CrossRefGoogle Scholar
  19. Harpaz Y, Levkovits Y, Lavidor M (2009) Lexical ambiguity resolution in Wernicke’s area and its right homologue. Cortex 45:1097–1103CrossRefPubMedGoogle Scholar
  20. Hebert LE, Weuve J, Scherr PA, Evans DA (2013) Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 80:1778–1783CrossRefPubMedPubMedCentralGoogle Scholar
  21. Hoogendam JM, Ramakers GM, DiLazzaro V (2010) Physiology of repetitive transcranial magnetic stimulation of the human brain. Brain Stimul 3:95–118CrossRefPubMedGoogle Scholar
  22. Hoyert DL, Xu J (2012) Deaths: preliminary data for 2011. Natl Vital Stat Rep 61(6):1–51PubMedGoogle Scholar
  23. Ito K, Ahadieh S, Corrigan B, French J, Fullerton T, Tensfeldt T, Alzheimer’s Disease Working Group (2010) Disease progression meta-analysis model in Alzheimer’s disease. Alzheimers Dement 6:39–53CrossRefPubMedGoogle Scholar
  24. Kammer T, Beck S, Thielsher A, Laubis-Herrmann U, Topka H (2001) Motor thresholds in humans: a transcranial magnetic stimulation study comparing different pulse waveforms, current directions and stimulators types. Clin Neurophysiol 112:250–258CrossRefPubMedGoogle Scholar
  25. Lee J, Choi BH, Oh E, Sohn EH, Lee AY (2015) 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 12:57–64CrossRefPubMedPubMedCentralGoogle Scholar
  26. Lefaucheur JP, André-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH et al (2014) Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol 125:2150–2206CrossRefPubMedGoogle Scholar
  27. Mohs RC, Knopman D, Petersen RC, Ferris SH, Ernesto C, Grundman M, Sano M, Bieliauskas L, Geldmacher D, Clark C, Thal LJ (1997) Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer’s Disease Assessment Scale that broaden its scope. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 11:S13–S21CrossRefPubMedGoogle Scholar
  28. NIH National Institute on Aging (2015) Alzheimer’s disease medications fact sheet. Retrieved May 2014, from NIH; National Institute on Aging: http://www.nia.nih.gov/sites/default/files/ad_meds_fact_sheet-2014_update-final_2-12-14.pdf. Accessed 23 May 2014
  29. Olazarán J, Reisberg B, Clare L, Cruz I, Peña-Casanova J, Del Ser T, Woods B, Beck C, Auer S, Lai C, Spector A, Fazio S, Bond J, Kivipelto M, Brodaty H, Rojo JM, Collins H, Teri L, Mittelman M, Orrell M, Feldman HH, Muñiz R (2010) Nonpharmacological therapies in Alzheimer’s disease: a systematic review of efficacy. Dement Geriatr Cogn Dis 30:161–178CrossRefGoogle Scholar
  30. 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 120:813–819CrossRefPubMedGoogle Scholar
  31. Reichman WE, Fiocco AJ, Rose NS (2010) Exercising the brain to avoid cognitive decline: examining the evidence. Aging Health 6:565–584CrossRefGoogle Scholar
  32. Rogalsky C, Matchin W, Hickok G (2008) Broca’s area, sentence comprehension, and working memory: an fMRI Study. Front Hum Neurosci 2:14CrossRefPubMedPubMedCentralGoogle Scholar
  33. 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 120:2008–2039CrossRefPubMedPubMedCentralGoogle Scholar
  34. Schrag A, Schott JM (2012) What is the clinically relevant change on the ADAS-Cog? J Neurol Neurosurg Psychiatry 83:171–173CrossRefPubMedGoogle Scholar
  35. Siebner HR, Rothwell J (2003) Transcranial magnetic stimulation: new insights into representational cortical plasticity. Exp Brain Res 148:1–16CrossRefPubMedGoogle Scholar
  36. Sitzer DI, Twamley EW, Jeste DV (2006) Cognitive training in Alzheimer’s disease: a meta-analysis of the literature. Acta Psychiatr Scand 114:75–90CrossRefPubMedGoogle Scholar
  37. Xie J, Brayne C, Matthews FE, Medical Research Council Cognitive Function and Ageing Study collaborators (2008) Survival times in people with dementia: analysis from population based cohort study with 14 year follow-up. BMJ 336:258–262CrossRefPubMedPubMedCentralGoogle Scholar
  38. 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 100:75–80CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  1. 1.Department of NeurologyAssaf Harofeh Medical CenterZerifinIsrael
  2. 2.Sackler Faculty of MedicineTel-Aviv UniversityTel-AvivIsrael

Personalised recommendations