Repetitive transcranial magnetic stimulation or transcranial direct current stimulation?

Brain Stimulation (2009) 2, 241 5 www.brainstimjrnl.com Repetitive transcranial magnetic stimulation or transcranial direct current stimulation? Alberto Priori a, Mark Hallett b, John C. Rothwell c a Dipartimento di Scienze Neurologiche, Università degli Studi di Milano, Centro Clinico per le Neuronanotecnologie e la Neurostimolazione, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy b Human Motor Control Section, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland c Sobell Department, UCL Institute of Neurology, London, United Kingdom In recent years two techniques have become available to stimulate the human brain noninvasively through the scalp: repetitive transcranial magnetic stimulation (rtms) and transcranial direct current stimulation (tdcs). Prolonged application of either method (eg, several hundred TMS pulses [rtms] or several minutes of tdcs) leads to changes in excitability of the cortex that outlast the period of stimulation. Because of this, besides the implications for experimental neuroscientists, there is increasing interest in the potential for applying either method as a therapy in neurology, psychiatry, rehabilitation, and pain. Given that both techniques lead to the same final result, this article discusses in theory several issues that can help an investigator to decide whether rtms or tdcs would be more suitable for the scope of the planned work. Ó 2009 Elsevier Inc. Keywords rtms; tdcs; brain stimulation; neuromodulation In recent years two techniques have become available to stimulate the human brain painlessly and noninvasively through the intact scalp. Transcranial magnetic stimulation (TMS) uses a large, rapidly changing magnetic field to induce electrical stimulating currents in the brain that are similar to those that are produced by a conventional electric nerve stimulator. These short pulses initiate action potentials in axons of the cortex and subcortical white matter that then release neurotransmitters at their terminal JCR was funded by the Medical Research Council, UK. MH is supported by the Intramural Program of NINDS, NIH. Correspondence: Prof. Alberto Priori, Dipartimento di Scienze Neurologiche, Università di Milano, Ospedale Maggiore Policlinico di Milano, Via Francesco Sforza 35, 20122 Milano, Italy. E-mail address: alberto.priori@unimi.it Submitted January 7, 2009; revised February 17, 2009. Accepted for publication February 24, 2009. synapses. Stimulators can deliver either single pulses or repeated pulses (rtms) at frequencies of up to 50 Hz. Transcranial direct current stimulation (tdcs) involves delivering weak direct current (1-2mA) through a sponge electrode placed on the scalp for periods of 4-5 seconds to more than 20 minutes. A portion of the applied current enters the skull where it is thought to polarize cortical neurons. Theoretically, depending on the orientation of the cells with respect to the current, the membrane potentials may be hyperpolarized or depolarized by a few mv. It is important to note that tdcs does not induce action potentials in axons. However, polarization of neurons will tend to change their average level of discharge. Although brain polarization has been reintroduced only recently, it has a very long history and was used in the 19th and 20th centuries for the treatment of mental and neurologic disorders. 1 1935-861X/09/$ -see front matter Ó 2009 Elsevier Inc. doi:10.1016/j.brs.2009.02.004

242 A. Priori, M. Hallett, and J.C. Rothwell Prolonged application of either method (eg, several hundred TMS pulses [rtms] or several minutes of tdcs) leads to changes in excitability of the cortex that outlast the period of stimulation. There is evidence that some of these effects are due to changes in synaptic transmission, perhaps resembling long-term plasticity of synapses described in brain slice preparations. 2,3 Because of this, there is increasing interest in the potential for applying either method as a therapy in neurologic disease or after brain injury. But, given that both techniques lead to the same final result, can we consider one better than the other? To decide, unfortunately, there are not yet controlled systematic studies assessing the two techniques comparatively. We therefore will discuss several issues that might help an investigator to decide whether rtms or tdcs would be more suitable for the scope of planned work. Of course, both of these methods can be used in a variety of ways. rtms can have various patterns of pulses with various intensities, and both rtms and tdcs can have various anatomical placements. So these issues are addressed in general terms. Technology and cost There are a number of practical differences between TMS and tdcs. Although systems for TMS are heavy (several kilograms) and large, devices for tdcs are light (, 1 kg) and small (less than a shoe box). TMS devices require a power supplydoften with special featuresdwhereas systems for brain polarization are battery driven and can therefore be also easily portable. Portability is an important characteristic, and would allow, for example, use of tdcs in the home. There is also a substantial difference in cost: whereas TMS or rtms systems currently cost between 20,000 to 100,000 dollars, tdcs devices are well below 13,000 dollars (range: 400 10,000 dollars). With such a large difference between the prices, tdcs is clearly the method of choice where cash is a limitation, at least in therapeutic studies. Sham stimulation TMS coils produce a loud click when each stimulus is delivered; in addition, because electric current is induced in the scalp as well as the brain, there is usually some activation of local sensory nerves or muscle which is readily perceived by subjects. Controlling for such effects involves either stimulating at some other inactive site on the scalp so that effects can be ascribed to stimulation of a particular structure, or using a sham coil that gives no stimulation but produces the same click sound. However, even if the click is indistinguishable from real TMS, lack of induced electric current means that there is no accompanying scalp sensation. It is possible to control for this by including an external electrical stimulation under the sham coil that mimics the sensation experienced during real stimulation. 4 However, all this is at the cost of increasing complexity and cost. In contrast, tdcs, especially at intensity below 1.5 ma, is generally not perceived by subjects. 5 This is particularly true if low current intensity is used with large area stimulating electrodes (to reduce charge density) and low impedance (eg, with saline solution); in such conditions subjects can be entirely unaware of the difference between real and sham stimulation. 6 A second point is that although high-frequency and low-frequency rtms are obviously different because of the rate of clicks produced by the coil, cathodal and anodal tdcs (that induce opposite excitability changes) cannot be discriminated by subjects and their comparison could therefore be a further control condition. Focality of stimulation Although focality of stimulationdnamely, the spatial resolutiondis a critical issue in the choice of a stimulation technique for physiologic experiments, it is probably less relevant for current therapeutic applications. TMS coils can be wound in a variety of different sizes and configurations, and although it is not possible without direct measurements to be precise, they appear to be able to limit stimulation to an area of about 25 mm 2. For example, mapping studies of motor cortex before surgery for brain tumors can reliably distinguish excitable and nonexcitable areas with an accuracy (compared with direct mapping of exposed cortex) of 5 mm or so. In contrast, tdcs has in the past usually been applied through large electrodes about 2500 mm 2 to maintain a low current density on the scalp (for safety reasons as well as minimal sensation). However, smaller electrodes have been used by some authors with some success, although the information on these is limited. A second issue with tdcs is that two electrodes have to be used (and anode and a cathode), and most authors place both of them on the scalp, so that stimulation occurs in two sites rather than one. This issue is not insuperable because one of the electrodes can be applied extracranially (eg, neck or shoulder). Nevertheless, wherever the electrodes are placed, current flows throughout the brain between the two sites so that nerve polarization may occur over a wide area. Models are being developed that might give some insight into the distribution of current flow and allow prediction of likely sites of stimulation. For most therapeutic trials, focality of stimulation is not an issue: in many cases, large areas of cortex are targeted (eg, motor cortex in stroke; dorsolateral prefrontal cortex in depression). In this case, the large sites stimulated with tdcs are no problem. Indeed, tdcs has an advantage over TMS in that it is easy to cut the electrode sponges into different shapes and areas, to tailor stimulation to an individual brain. This is not possible with TMS unless

rtms or tdcs? 243 laboratories possess a large number of very expensive coils of different size and shape. In the context of therapy trials, it may also be no disadvantage to have two sites of stimulation on the scalp. Thus, many models of the effect of focal brain lesions such as a stroke or a trauma postulate that behavioral effects occur not only through dysfunction at the damaged site, but also from overinhibition arising from the contralateral healthy side of the brain. 7 Under this assumption therapy should not only aim to increase the defective activation of the lesion area, but also to reduce the hyperactivity of the contralateral homologous brain region. This approach, though theoretically feasible (having two devices working together) is difficult with rtms. On the other hand, because there are opposite changes of excitability below the two stimulating tdcs electrodes, there is a possibility that tdcs could be used to produce opposite effects on homologous brain areas of the two hemispheres by placing the anodal electrode (facilitatory) over the affected hemisphere and the cathodal one (inhibitory) over the unaffected side. However, it should also be borne in mind that changing the location of one of the electrodes will also change the orientation of the electric currents in the brain and could influence the effectiveness of stimulation under each of the electrodes. Lastly, though the effects of anodal and cathodal tdcs are known for the motor, somatosensory and visual cortex, no studies have investigated differences in electrode placement pertaining to stimulation at other brain sites such as prefrontal cortex. Neurophysiologic specificity Specificity of stimulation refers to the ability to target specific neural populations and it is important in neurophysiologic studies. Measures of motor cortical threshold with TMS appear to give information about axonal excitability, which is greatly influenced by drugs that target Na1 channel function such as carbamazepine. 8 Similarly, paired-pulse TMS studies of SICI and LICI are thought to give information about excitability of GABAa and GABAb synapses 9 ; short afferent inhibition (SAI) is thought to have an important cholinergic influence. 10 TMS has also been used to target specific I-wave inputs to corticospinal neurons of motor cortex. 11 All of these effects help provide detailed knowledge of the operation of cortical areas. They are supplemented by one other advantage of TMS: the temporal accuracy of the stimulus. This allows for precise timings to be estimated to ms resolution, allowing measures, for example, of central motor conduction time and transcallosal conduction time. Interestingly, TMS methodologies that explore the intrinsic cortical circuitry provide important clues about the mechanism of action of tdcs. Although tdcs has not been yet used in this way, from a therapeutic viewpoint, there are no proposed therapies at this time that are designed to take advantage of the specificity of TMS. Whether this would be advantageousdapart from understanding how tdcs worksdis therefore unknown. Stimulus intensity A single TMS pulse to motor cortex or to the visual cortex causes muscle twitches on the opposite side of the body or phosphenes, respectively. Effectively these are a surrogate marker that the stimulus has activated neural tissue under the coil. Thus, although a clear relationship between stimulation intensity and clinical effects has not yet been demonstrated, it is relatively easy to grade stimulus intensity in terms of this active biologic marker. However, tdcs produces no similar effects on behavior so that there is no immediate phenomenologic indicator of the success or otherwise of the stimulus. Although tdcs strength in individual subjects could be quantified by using other neurophysiologic techniques such TMS, visual-evoked potentials (VEPs), somatosensory-evoked potentials (SEPs), or even EEG, at the present time tdcs intensities are still given simply in terms of the current flowing between the electrodes, with no overt indication of how much of this is likely to enter the brain and polarize neurons in each individual subject. Without such normalization, stimulus intensities across individuals in terms of biologic effectiveness is not possible. It may be that accurate modeling of scalp and skull will solve this problem, 12 but until that time it is not easy to equate the effectiveness of stimulation between individuals. Of course, even with rtms, there is no direct measure of effectiveness when outside the motor cortex (contralateral movement) or visual cortex (phosphenes). Methodologic approaches allowing EEG recordings during rtms and tdcs might in the future allow quantification of the effects induced by both techniques on non eloquent brain areas. Off versus online stimulation Online stimulation refers to stimulation delivered while the subject is executing a given motor or cognitive task; offline stimulation is when stimulation is delivered before a task, with the assumption that after effects (of rtms or several minutes tdcs) will interact with task performance. Because increasing cortical excitability can facilitate learning novel cognitive or motor strategies, online stimulation protocols may have a great impact in restorative neurology and rehabilitation. Although theoretically possible, the large bulk of TMS devices together with the problem of maintaining coil position on the head when subjects can move freely (eg, while walking) make TMS less than ideal for online use. Nevertheless, there are conditions in which TMS is the modality of choice. These involve timed stimulus paradigms such as those used to estimate the time course of cognitive

244 A. Priori, M. Hallett, and J.C. Rothwell processing, in which a single TMS (or 2-3 pulses) is applied at a particular time during a cognitive task. If a task is disrupted at a particular time then it suggests that the brain area targeted is crucially involved in performance at that time. 13 The advantage of tdcs is that electrodes are easily secured to the scalp and can be worn while the subject is free to move the head. This is clearly of some use in therapy as the patient can be more comfortable while the stimulation is applied. It is also useful in longer cognitive studies in which temporal information is not required. Another interesting possibility is that of conducting noninvasive neuromodulation in more than one subject at a time. 14 Although at first sight curious, it could be an interesting application in experimental social neurosciences and even in clinical practice when there are several patients to be treated with a frequent pathologic factor such as stroke or depression. Although theoretically possible, multisubject TMS would be much more expensive. Safety Both rtms and tdcs are generally safe if used properly. Nonetheless, seizures are a well-recognized possible serious adverse effect of rtms, although present safety guidelines have proved highly effective in minimizing this as a problem. There is also a fairly extensive literature that has demonstrated the safety of TMS in terms of effects on brain anatomy and biochemistry. 15 For tdcs, there are far fewer published studies of safety, and the main problem reported is transient skin reactions below the stimulating electrodes. Very rarely this reaction can be a small burn below the cathodal electrode of few millimeters in diameter that heals spontaneously in several weeks 16 [personal observations]. Because tdcs for minutes does not increase the markers of neuronal damage as neuron specific enolase or brain N-acetyl-aspartate, 17,18 it has been considered safe for the stimulated subjects. 19-21 Whether tdcs is safe also at longer duration (hours) or higher intensities is, however, still unknown. A safety issue that is rarely considered but that we believe is important especially for techniques with potential extensive use in the clinical practice is the safety for the operators. Although the electrical field generated by tdcs is so weak that it cannot have a biologic relevance for the operator, the magnetic field generated by rtms can induce small electromagnetic fields at a distance from the coils. Whether these would have possible long-term effects for operators using TMS for several hours a day for a prolonged period are still unknown. Conclusions and future directions Although the reader will now be aware that there is no strict recommendation about which of the two techniques is better for specific uses, we believe that the high temporal and spatial resolution of rtms is of advantage in experiments that probe neurophysiologic effects on specific brain circuits. In contrast, the simplicity and low cost of tdcs may be better suited for investigations that rely on modulatory effects on nonselective populations of neurons, such as may be required in some types of clinical studies. 22-24 However, it will be necessary to develop simple protocols to assess the strength (or dose ) of tdcs to overcome the interindividual variability in response. At this time, noninvasive neuromodulation techniques hold great promise as potential therapeutic tools that are complementary or alternative to drugs or surgery. Both rtms and tdcs induce functional and neurochemical changes in the brain and may even affect inflammatory response, immunity, and neuronal death. Future work will be needed to optimize these effects to treat individual patients with the most optimal stimulus parameters. Acknowledgments We wish to thank Dr Roberta Ferrucci for her kind assistance. References 1. Aldini J. Essai théorique et experimental sur le galvanisme, avec une série d expériences faites devant des commissaires de l Institut nationale de France, et en divers amphithéâtres anatomiques de Londres. Paris: Fournier Fils; 1804. 2. Butefisch CM, Davis BC, Wise SP, et al. Mechanisms of use-dependent plasticity in the human motor cortex. Proc Natl Acad Sci U S A 2000;97(7):3661-3665. 3. Huang YZ, Chen RS, Rothwell JC, Wen HY. The after-effect of human theta burst stimulation is NMDA receptor dependent. Clin Neurophysiol 2007;118(5):1028-1032. 4. O Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry 2007;62(11):1208-1216. 5. Dundas JE, Thickbroom GW, Mastaglia FL. Perception of comfort during transcranial DC stimulation: effect of NaCl solution concentration applied to sponge electrodes. Clin Neurophysiol 2007;118(5): 1166-1170. 6. Gandiga PC, Hummel FC, Cohen LG. Transcranial DC stimulation (tdcs): a tool for double-blind sham-controlled clinical studies in brain stimulation. Clin Neurophysiol 2006;117(4):845-850. 7. Ward NS, Cohen LG. Mechanisms underlying recovery of motor function after stroke. Arch Neurol 2004;61(12):1844-1848. 8. Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W. Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol 1996;40(3):367-378. 9. Werhahn KJ, Kunesch E, Noachtar S, Benecke R, Classen J. Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans. J Physiol 1999;517(Pt 2):591-597. 10. Di Lazzaro V, Oliviero A, Tonali PA, et al. Noninvasive in vivo assessment of cholinergic cortical circuits in AD using transcranial magnetic stimulation. Neurology 2002;59(3):392-397.

rtms or tdcs? 245 11. Hanajima R, Furubayashi T, Iwata NK, et al. Further evidence to support different mechanisms underlying intracortical inhibition of the motor cortex. Exp Brain Res 2003;151(4):427-434. 12. Miranda PC, Lomarev M, Hallett M. Modeling the current distribution during transcranial direct current stimulation. Clin Neurophysiol 2006; 117(7):1623-1629. 13. Walsh V, Cowey A. Transcranial magnetic stimulation and cognitive neuroscience. Nat Rev Neurosci 2000;1(1):73-79. 14. Knoch D, Nitsche MA, Fischbacher U, Eisenegger C, Pascual-Leone A, Fehr E. Studying the neurobiology of social interaction with transcranial direct current stimulationdthe example of punishing unfairness. Cereb Cortex 2008;18(9):1987-1990. 15. Liebetanz D, Fauser S, Michaelis T, et al. Safety aspects of chronic low-frequency transcranial magnetic stimulation based on localized proton magnetic resonance spectroscopy and histology of the rat brain. J Psychiatr Res 2003;37(4):277-286. 16. Palm U, Keeser D, Schiller C, Fintescu Z, Reisinger E, Padberg F. Skin lesions after treatment with transcranial direct current stimulation (tdcs). Brain Stimulation 2008;1(4):386-387. 17. Cogiamanian F, Vergari M, Pulecchi F, Marceglia S, Priori A. Effect of spinal transcutaneous direct current stimulation on somatosensory evoked potentials in humans. Clin Neurophysiol 2008;119(11): 2636-2640. 18. Rango M, Cogiamanian F, Marceglia S, et al. Myoinositol content in the human brain is modified by transcranial direct current stimulation in a matter of minutes: a 1H-MRS study. Magn Reson Med 2008; 60(4):782-789. 19. Nitsche MA, Liebetanz D, Antal A, Lang N, Tergau F, Paulus W. Modulation of cortical excitability by weak direct current stimulationdtechnical, safety and functional aspects. Suppl Clin Neurophysiol 2003;56:255-276. 20. Nitsche MA, Liebetanz D, Lang N, Antal A, Tergau F, Paulus W. Safety criteria for transcranial direct current stimulation (tdcs) in humans. Clin Neurophysiol 2003;114(11):2220-2222. author reply 2 3. 21. Poreisz C, Boros K, Antal A, Paulus W. Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients. Brain Res Bull 2007;72(4-6):208-214. 22. Arul-Anandam AP, Loo C. Transcranial direct current stimulation: a new tool for the treatment of depression? [published online ahead of print February 6, 2009]. J Affect Disord doi:10.1016/j.jad.2009. 01.016. 23. Schlaug G, Renga V, Nair D. Transcranial direct current stimulation in stroke recovery. Arch Neurol 2008;65(12):1571-1576. 24. Ferrucci R. Transcranial direct current stimulation in severe, drug-resistant major depression. J Affect Disord doi:1016/j.jad.2009. 02.015.