Abstract
Transcranial magnetic stimulation (TMS) is a non-invasive method where an externally placed, rapidly changing magnetic field causes induction of weak electric currents that lead to changes in neuronal polarization and activity. TMS is a modality that has emerged as a unique tool in the study of functional neuroscience for several reasons. TMS can be used to selectively activate or inhibit specific cortical structures, leading to transient perturbations in their function. Systematic study of these perturbations has been employed to determine the function of specific cortical structures and to investigate structure-function relationships. These studies extend to the functional mapping of brain structures as well as brain networks. While TMS was first validated in studies of motor cortex function, it has been applied to the study of cognition and cognitive processing. “Virtual lesions” can be transiently induced in areas of eloquent cortex that allow for the evaluation of their function in cognition and behavior and can be used to evaluate the modes and hierarchy of control of these functions. When TMS is delivered in a repetitive fashion, long-term alterations of cortical function are induced which can be used to study functional brain plasticity, and the changes in brain plasticity in different cognitive states, including aging and diseases involving cognition. Furthermore, repetitive TMS strategies have been developed as possible modulators of cognitive function, with potential to serve as cognitive enhancers in both healthy and disease states. In this review, specific attention is given to the use of TMS in the evaluation of neurophysiologic changes in Alzheimer’s disease (AD), as well as the potential role of TMS as a cognitive enhancing therapy in AD.
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Merton PA, Morton HB. Stimulation of the cerebral cortex in the intact human subject. Nature. 1980;285(5762):227.
Barker AT, Jalinous R, Freeston IL. Non-invasive magnetic stimulation of human motor cortex. The Lancet. 1985:1106–7.
Zangen A, Roth Y, Voller B, Hallett M. Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-coil. Clin Neurophysiol. 2005;116(4):775–9. doi:10.1016/j.clinph.2004.11.008.
Epstein CM, Davey KR. Iron-core coils for transcranial magnetic stimulation. J Clin Neurophysiol. 2002;19(4):376–81.
Levkovitz Y, Roth Y, Harel EV, Braw Y, Sheer A, Zangen A. A randomized controlled feasibility and safety study of deep transcranial magnetic stimulation. Clin Neurophysiol. 2007;118(12):2730–44. doi:10.1016/j.clinph.2007.09.061.
Levkovitz Y, Rabany L, Harel EV, Zangen A. Deep transcranial magnetic stimulation add-on for treatment of negative symptoms and cognitive deficits of schizophrenia: a feasibility study. Int J Neuropsychopharmacol. 2011;14(7):991–6. doi:10.1017/s1461145711000642.
Levkovitz Y, Harel EV, Roth Y, Braw Y, Most D, Katz LN, et al. Deep transcranial magnetic stimulation over the prefrontal cortex: evaluation of antidepressant and cognitive effects in depressive patients. Brain Stimul. 2009;2(4):188–200. doi:10.1016/j.brs.2009.08.002.
Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the international workshop on the safety of repetitive transcranial magnetic stimulation, June 5–7, 1996. Electroencephalogr Clin Neurophysiol. 1998;108(1):1–16.
Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009;120(12):2008–39. doi:10.1016/j.clinph.2009.08.016.
Hallett M. Transcranial magnetic stimulation: a primer. Neuron. 2007;55(2):187–99. doi:10.1016/j.neuron.2007.06.026.
Ziemann U, Reis J, Schwenkreis P, Rosanova M, Strafella A, Badawy R, et al. TMS and drugs revisited 2014. Clinical Neurophysiol. 2014. doi:10.1016/j.clinph.2014.08.028.
Kobayashi M, Pascual-Leone A. Transcranial magnetic stimulation in neurology. Lancet Neurol. 2003;2(3):145–56. doi:10.1016/s1474-4422(03)00321-1.
Siebner HR, Hartwigsen G, Kassuba T, Rothwell JC. How does transcranial magnetic stimulation modify neuronal activity in the brain? Implications for studies of cognition. Cortex. 2009;45(9):1035–42. doi:10.1016/j.cortex.2009.02.007.
Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, et al. Corticocortical inhibition in human motor cortex. J Physiol. 1993;471:501–19.
Di Lazzaro V, Oliviero A, Meglio M, Cioni B, Tamburrini G, Tonali P, et al. Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex. Clin Neurophysiol. 2000;111(5):794–9.
Di Lazzaro V, Oliviero A, Profice P, Pennisi MA, Di Giovanni S, Zito G, et al. Muscarinic receptor blockade has differential effects on the excitability of intracortical circuits in the human motor cortex. Exp Brain Res. 2000;135(4):455–61.
Huerta PT, Volpe BT. Transcranial magnetic stimulation, synaptic plasticity and network oscillations. J Neuroeng Rehabil. 2009;6:7. doi:10.1186/1743-0003-6-7.
Silvanto J, Pascual-Leone A. State-dependency of transcranial magnetic stimulation. Brain Topogr. 2008;21(1):1–10. doi:10.1007/s10548-008-0067-0.
Silvanto J, Cattaneo Z, Battelli L, Pascual-Leone A. Baseline cortical excitability determines whether TMS disrupts or facilitates behavior. J Neurophysiol. 2008;99(5):2725–30. doi:10.1152/jn.01392.2007.
Pascual-Leone A, Bartres-Faz D, Keenan JP. Transcranial magnetic stimulation: studying the brain-behaviour relationship by induction of ‘virtual lesions’. Philos Trans R Soc Lond B Biol Sci. 1999;354(1387):1229–38.
Jeurissen D, Sack AT, Roebroeck A, Russ BE, Pascual-Leone A. TMS affects moral judgment, showing the role of DLPFC and TPJ in cognitive and emotional processing. Front Neurosci. 2014;8:18. doi:10.3389/fnins.2014.00018.
Devlin JT, Watkins KE. Stimulating language: insights from TMS. Brain. 2007;130(Pt 3):610–22. doi:10.1093/brain/awl331.
Meister IG, Boroojerdi B, Foltys H, Sparing R, Huber W, Topper R. Motor cortex hand area and speech: implications for the development of language. Neuropsychologia. 2003;41(4):401–6.
Watkins KE, Strafella AP, Paus T. Seeing and hearing speech excites the motor system involved in speech production. Neuropsychologia. 2003;41(8):989–94.
Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci U S A. 2005;102(27):9673–8. doi:10.1073/pnas.0504136102.
Hampson M, Hoffman RE. Transcranial magnetic stimulation and connectivity mapping: tools for studying the neural bases of brain disorders. Front Syst Neurosci. 2010;4. doi:10.3389/fnsys.2010.00040.
Civardi C, Cantello R, Asselman P, Rothwell JC. Transcranial magnetic stimulation can be used to test connections to primary motor areas from frontal and medial cortex in humans. NeuroImage. 2001;14(6):1444–53. doi:10.1006/nimg.2001.0918.
Ferbert A, Priori A, Rothwell JC, Day BL, Colebatch JG, Marsden CD. Interhemispheric inhibition of the human motor cortex. J Physiol. 1992;453:525–46.
Shafi MM, Westover MB, Fox MD, Pascual-Leone A. Exploration and modulation of brain network interactions with noninvasive brain stimulation in combination with neuroimaging. Eur J Neurosci. 2012;35(6):805–25. doi:10.1111/j.1460-9568.2012.08035.x.
Fox MD, Halko MA, Eldaief MC, Pascual-Leone A. Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS). NeuroImage. 2012;62(4):2232–43. doi:10.1016/j.neuroimage.2012.03.035.
Siebner HR, Bergmann TO, Bestmann S, Massimini M, Johansen-Berg H, Mochizuki H, et al. Consensus paper: combining transcranial stimulation with neuroimaging. Brain Stimul. 2009;2(2):58–80. doi:10.1016/j.brs.2008.11.002.
Ruff CC, Bestmann S, Blankenburg F, Bjoertomt O, Josephs O, Weiskopf N, et al. Distinct causal influences of parietal versus frontal areas on human visual cortex: evidence from concurrent TMS-fMRI. Cereb Cortex. 2008;18(4):817–27. doi:10.1093/cercor/bhm128.
van der Werf YD, Sanz-Arigita EJ, Menning S, van den Heuvel OA. Modulating spontaneous brain activity using repetitive transcranial magnetic stimulation. BMC Neurosci. 2010;11:145. doi:10.1186/1471-2202-11-145.
Eldaief MC, Halko MA, Buckner RL, Pascual-Leone A. Transcranial magnetic stimulation modulates the brain's intrinsic activity in a frequency-dependent manner. Proc Natl Acad Sci U S A. 2011;108(52):2122–34. doi:10.1073/pnas.1113103109.
Hebb DO. The organization of behavior: a neuropsychological theory. Lawrencw Erlbaum Associated, Inc., publishers; 1949.
Fitzgerald PB, Fountain S, Daskalakis ZJ. A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition. Clin Neurophysiol. 2006;117(12):2584–96. doi:10.1016/j.clinph.2006.06.712.
Larson J, Wong D, Lynch G. Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Res. 1986;368(2):347–50.
Freitas C, Farzan F, Pascual-Leone A. Assessing brain plasticity across the lifespan with transcranial magnetic stimulation: why, how, and what is the ultimate goal? Front Neurosci. 2013;7:42. doi:10.3389/fnins.2013.00042. A review of the possibility of TMS to monitor and access the physiological properties of brain plasticity.
Thut G, Veniero D, Romei V, Miniussi C, Schyns P, Gross J. Rhythmic TMS causes local entrainment of natural oscillatory signatures. Curr Biol. 2011;21(14):1176–85. doi:10.1016/j.cub.2011.05.049.
Miniussi C, Thut G. Combining TMS and EEG offers new prospects in cognitive neuroscience. Brain Topogr. 2010;22(4):249–56. doi:10.1007/s10548-009-0083-8.
Daskalakis ZJ, Farzan F, Barr MS, Maller JJ, Chen R, Fitzgerald PB. Long-interval cortical inhibition from the dorsolateral prefrontal cortex: a TMS-EEG study. Neuropsychopharmacology. 2008;33(12):2860–9. doi:10.1038/npp.2008.22.
Hoogendam JM, Ramakers GM, Di Lazzaro V. Physiology of repetitive transcranial magnetic stimulation of the human brain. Brain Stimul. 2010;3(2):95–118. doi:10.1016/j.brs.2009.10.005.
Pitcher JB, Ogston KM, Miles TS. Age and sex differences in human motor cortex input–output characteristics. J Physiol. 2003;546(Pt 2):605–13.
Kukull WA, Bowen JD. Dementia epidemiology. Med Clin North Am. 2002;86(3):573–90.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–59.
Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Ann Neurol. 1997;42(1):85–94. doi:10.1002/ana.410420114.
Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A. 2004;101(13):4637–42. doi:10.1073/pnas.0308627101.
Bradley KM, O'Sullivan VT, Soper ND, Nagy Z, King EM, Smith AD, et al. Cerebral perfusion SPET correlated with braak pathological stage in Alzheimer's disease. Brain. 2002;125(Pt 8):1772–81.
Cantone M, Di Pino G, Capone F, Piombo M, Chiarello D, Cheeran B, et al. The contribution of transcranial magnetic stimulation in the diagnosis and in the management of dementia. Clin Neurophysiol. 2014;125(8):1509–32. doi:10.1016/j.clinph.2014.04.010.
Ferreri F, Pauri F, Pasqualetti P, Fini R, Dal Forno G, Rossini PM. Motor cortex excitability in Alzheimer's disease: a transcranial magnetic stimulation study. Ann Neurol. 2003;53(1):102–8. doi:10.1002/ana.10416.
Perretti A, Grossi D, Fragassi N, Lanzillo B, Nolano M, Pisacreta A, et al. Evaluation of the motor cortex by magnetic stimulation in patients with Alzheimer disease. Journal of the Neurological Sciences. 1996;35(1):31–7. doi:10.1016/0022-510X(95)00244-V.
Freitas C, Mondragon-Llorca H, Pascual-Leone A. Noninvasive brain stimulation in Alzheimer's disease: systematic review and perspectives for the future. Exp Gerontol. 2011;46(8):611–27. doi:10.1016/j.exger.2011.04.001.
Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra C, et al. Neurophysiological predictors of long term response to AChE inhibitors in AD patients. J Neurol Neurosurg Psychiatry. 2005;76(8):1064–9. doi:10.1136/jnnp.2004.051334.
Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra C, et al. Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2004;75(4):555–9. doi:10.1136/jnnp.2003.018127.
Wegrzyn M, Teipel SJ, Oltmann I, Bauer A, Thome J, Grossmann A, et al. Structural and functional cortical disconnection in Alzheimer's disease: a combined study using diffusion tensor imaging and transcranial magnetic stimulation. Psychiatry Res. 2013;212(3):192–200. doi:10.1016/j.pscychresns.2012.04.008.
Inghilleri M, Conte A, Frasca V, Scaldaferri N, Gilio F, Santini M, et al. Altered response to rTMS in patients with Alzheimer's disease. Clin Neurophysiol. 2006;117(1):103–9. doi:10.1016/j.clinph.2005.09.016.
Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005;45(2):201–6. doi:10.1016/j.neuron.2004.12.033.
Koch G, Di Lorenzo F, Bonni S, Ponzo V, Caltagirone C, Martorana A. Impaired LTP- but not LTD-like cortical plasticity in Alzheimer's disease patients. J Alzheimers Disease. 2012;31(3):593–9. doi:10.3233/jad-2012-120532.
Niskanen E, Kononen M, Maatta S, Hallikainen M, Kivipelto M, Casarotto S, et al. New insights into Alzheimer's disease progression: a combined TMS and structural MRI study. PLoS One. 2011;6(10), e26113. doi:10.1371/journal.pone.0026113.
Nardone R, Bergmann J, Christova M, Caleri F, Tezzon F, Ladurner G, et al. Effect of transcranial brain stimulation for the treatment of Alzheimer disease: a review. Int J Alzheimers Dis. 2012;2012:687909. doi:10.1155/2012/687909.
Battaglia F, Wang HY, Ghilardi MF, Gashi E, Quartarone A, Friedman E, et al. Cortical plasticity in Alzheimer's disease in humans and rodents. Biol Psychiatry. 2007;62(12):1405–12. doi:10.1016/j.biopsych.2007.02.027.
Alberici A, Bonato C, Calabria M, Agosti C, Zanetti O, Miniussi C, et al. The contribution of TMS to frontotemporal dementia variants. Acta Neurol Scand. 2008;118(4):275–80. doi:10.1111/j.1600-0404.2008.01017.x.
Pennisi G, Ferri R, Lanza G, Cantone M, Pennisi M, Puglisi V, et al. Transcranial magnetic stimulation in Alzheimer's disease: a neurophysiological marker of cortical hyperexcitability. J Neural Transm. 2011;118(4):587–98. doi:10.1007/s00702-010-0554-9.
Cotelli M, Manenti R, Cappa SF, Zanetti O, Miniussi C. Transcranial magnetic stimulation improves naming in Alzheimer disease patients at different stages of cognitive decline. Eur J Neurol. 2008;15(12):1286–92. doi:10.1111/j.1468-1331.2008.02202.x.
Cotelli M, Manenti R, Cappa SF, Geroldi C, Zanetti O, Rossini PM, et al. Effect of transcranial magnetic stimulation on action naming in patients with Alzheimer disease. Arch Neurol. 2006;63(11):1602–4. doi:10.1001/archneur.63.11.1602.
Cotelli M, Calabria M, Manenti R, Rosini S, Zanetti O, Cappa SF, et al. Improved language performance in Alzheimer disease following brain stimulation. J Neurol Neurosurg Psychiatry. 2011;82(7):794–7. doi:10.1136/jnnp.2009.197848.
Ahmed MA, Darwish ES, Khedr EM, El Serogy YM, Ali AM. Effects of low versus high frequencies of repetitive transcranial magnetic stimulation on cognitive function and cortical excitability in Alzheimer's dementia. J Neurol. 2012;259(1):83–92. doi:10.1007/s00415-011-6128-4.
Rabey JM, Dobronevsky E, Aichenbaum S, Gonen O, Marton RG, Khaigrekht M. 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. 2013;120(5):813–9. doi:10.1007/s00702-012-0902-z.
Rossi S, Rossini PM. TMS in cognitive plasticity and the potential for rehabilitation. Trends Cogn Sci. 2004;8(6):273–9. doi:10.1016/j.tics.2004.04.012.
Ash E, Bregman N, Moore O, Korczyn A, Zangen A. Transcranial magnetic stimulation of deep brain regions in Alzheimer's disease. Alzheimer's & Dementia. 2014;10(4):450. doi:10.1016/j.jalz.2014.05.611.
Elder GJ, Taylor JP. Transcranial magnetic stimulation and transcranial direct current stimulation: treatments for cognitive and neuropsychiatric symptoms in the neurodegenerative dementias? Alzheimers Res Ther. 2014;6(9):74. doi:10.1186/s13195-014-0074-1.
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Naomi Nevler declares no conflict of interest. Elissa L. Ash has received a grant from Brightfocus Foundation, and travel and administrative support from Brainsway, Ltd.
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Nevler, N., Ash, E.L. TMS as a Tool for Examining Cognitive Processing. Curr Neurol Neurosci Rep 15, 52 (2015). https://doi.org/10.1007/s11910-015-0575-8
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DOI: https://doi.org/10.1007/s11910-015-0575-8