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doi:10.1016/j.br

Brain Stimulation (2009) 2, 241–5

www.brainstimjrnl.com

Repetitive transcranial magnetic stimulationor transcranial direct current stimulation?

Alberto Prioria, Mark Hallettb, John C. Rothwellc

aDipartimento di Scienze Neurologiche, Universita degli Studi di Milano, Centro Clinico per le Neuronanotecnologie e laNeurostimolazione, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, ItalybHuman Motor Control Section, National Institute of Neurological Disorders and Stroke, Bethesda, MarylandcSobell Department, UCL Institute of Neurology, London, United Kingdom

In recent years two techniques have become available to stimulate the human brain noninvasivelythrough the scalp: repetitive transcranial magnetic stimulation (rTMS) and transcranial direct currentstimulation (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 ofstimulation. Because of this, besides the implications for experimental neuroscientists, there isincreasing 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 intheory several issues that can help an investigator to decide whether rTMS or tDCS would be moresuitable for the scope of the planned work.� 2009 Elsevier Inc..

Keywords rTMS; tDCS; brain stimulation; neuromodulation

In recent years two techniques have become availableto stimulate the human brain painlessly and noninvasivelythrough the intact scalp. Transcranial magnetic stimula-tion (TMS) uses a large, rapidly changing magnetic fieldto induce electrical stimulating currents in the brain thatare similar to those that are produced by a conventionalelectric nerve stimulator. These short pulses initiate actionpotentials in axons of the cortex and subcortical whitematter that then release neurotransmitters at their terminal

ded by the Medical Research Council, UK.

rted by the Intramural Program of NINDS, NIH.

nce: Prof. Alberto Priori, Dipartimento di Scienze Neuro-

ita di Milano, Ospedale Maggiore Policlinico di Milano,

forza 35, 20122 Milano, Italy.

ss: alberto.priori@unimi.it

nuary 7, 2009; revised February 17, 2009. Accepted for

uary 24, 2009.

-see front matter � 2009 Elsevier Inc.

s.2009.02.004

synapses. Stimulators can deliver either single pulses orrepeated pulses (rTMS) at frequencies of up to 50 Hz.Transcranial direct current stimulation (tDCS) involvesdelivering weak direct current (1-2mA) through a spongeelectrode placed on the scalp for periods of 4-5 seconds tomore than 20 minutes. A portion of the applied currententers the skull where it is thought to polarize corticalneurons. Theoretically, depending on the orientation ofthe cells with respect to the current, the membranepotentials may be hyperpolarized or depolarized bya few mV. It is important to note that tDCS does notinduce action potentials in axons. However, polarizationof neurons will tend to change their average level ofdischarge. Although brain polarization has been reintro-duced only recently, it has a very long history and wasused in the 19th and 20th centuries for the treatment ofmental and neurologic disorders.1

242 A. Priori, M. Hallett, and J.C. Rothwell

Prolonged application of either method (eg, severalhundred TMS pulses [rTMS] or several minutes of tDCS)leads to changes in excitability of the cortex that outlast theperiod of stimulation. There is evidence that some of theseeffects are due to changes in synaptic transmission, perhapsresembling long-term plasticity of synapses described inbrain slice preparations.2,3 Because of this, there isincreasing interest in the potential for applying eithermethod as a therapy in neurologic disease or after braininjury. But, given that both techniques lead to the same finalresult, can we consider one better than the other? To decide,unfortunately, there are not yet controlled systematic studiesassessing the two techniques comparatively. We thereforewill discuss several issues that might help an investigatorto decide whether rTMS or tDCS would be more suitablefor the scope of planned work. Of course, both of thesemethods can be used in a variety of ways. rTMS can havevarious patterns of pulses with various intensities, andboth rTMS and tDCS can have various anatomicalplacements. So these issues are addressed in general terms.

Technology and cost

There are a number of practical differences between TMSand tDCS. Although systems for TMS are heavy (severalkilograms) and large, devices for tDCS are light (, 1 kg)and small (less than a shoe box). TMS devices requirea power supplydoften with special featuresdwhereassystems for brain polarization are battery driven and cantherefore be also easily portable. Portability is an importantcharacteristic, and would allow, for example, use of tDCSin the home. There is also a substantial difference in cost:whereas TMS or rTMS systems currently cost between20,000 to 100,000 dollars, tDCS devices are well below13,000 dollars (range: 400–10,000 dollars). With sucha large difference between the prices, tDCS is clearly themethod of choice where cash is a limitation, at least in ther-apeutic studies.

Sham stimulation

TMS coils produce a loud click when each stimulus isdelivered; in addition, because electric current is induced inthe scalp as well as the brain, there is usually some activationof local sensory nerves or muscle which is readily perceivedby subjects. Controlling for such effects involves eitherstimulating at some other inactive site on the scalp so thateffects can be ascribed to stimulation of a particular structure,or using a ‘‘sham’’ coil that gives no stimulation but producesthe same click sound. However, even if the click isindistinguishable from real TMS, lack of induced electriccurrent means that there is no accompanying scalp sensation.It is possible to control for this by including an externalelectrical stimulation under the sham coil that mimics the

sensation experienced during real stimulation.4 However, allthis 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 particularlytrue if low current intensity is used with large area stimu-lating electrodes (to reduce charge density) and lowimpedance (eg, with saline solution); in such conditionssubjects can be entirely unaware of the difference betweenreal and sham stimulation.6 A second point is thatalthough high-frequency and low-frequency rTMS areobviously different because of the rate of clicks producedby the coil, cathodal and anodal tDCS (that induce oppo-site excitability changes) cannot be discriminated bysubjects and their comparison could therefore be a furthercontrol condition.

Focality of stimulation

Although focality of stimulationdnamely, the spatialresolutiondis a critical issue in the choice of a stimulationtechnique for physiologic experiments, it is probably lessrelevant for current therapeutic applications. TMS coils canbe wound in a variety of different sizes and configurations,and although it is not possible without direct measurementsto be precise, they appear to be able to limit stimulation toan area of about 25 mm2. For example, mapping studies ofmotor cortex before surgery for brain tumors can reliablydistinguish excitable and nonexcitable areas with an accu-racy (compared with direct mapping of exposed cortex) of5 mm or so.

In contrast, tDCS has in the past usually been appliedthrough large electrodes about 2500 mm2 to maintain a lowcurrent density on the scalp (for safety reasons as well asminimal sensation). However, smaller electrodes havebeen used by some authors with some success, althoughthe information on these is limited. A second issue withtDCS is that two electrodes have to be used (and anodeand a cathode), and most authors place both of them onthe scalp, so that stimulation occurs in two sites ratherthan one. This issue is not insuperable because one of theelectrodes can be applied extracranially (eg, neck orshoulder). Nevertheless, wherever the electrodes are placed,current flows throughout the brain between the two sites sothat nerve polarization may occur over a wide area. Modelsare being developed that might give some insight into thedistribution of current flow and allow prediction of likelysites of stimulation.

For most therapeutic trials, focality of stimulation is notan issue: in many cases, large areas of cortex are targeted(eg, motor cortex in stroke; dorsolateral prefrontal cortex indepression). In this case, the large sites stimulated withtDCS are no problem. Indeed, tDCS has an advantage overTMS in that it is easy to cut the electrode sponges intodifferent shapes and areas, to tailor stimulation to anindividual brain. This is not possible with TMS unless

rTMS or tDCS? 243

laboratories possess a large number of very expensive coilsof different size and shape. In the context of therapy trials,it may also be no disadvantage to have two sites ofstimulation on the scalp. Thus, many models of the effectof focal brain lesions such as a stroke or a trauma postulatethat behavioral effects occur not only through dysfunctionat the damaged site, but also from overinhibition arisingfrom the contralateral healthy side of the brain.7 Under thisassumption therapy should not only aim to increase thedefective activation of the lesion area, but also to reducethe hyperactivity of the contralateral homologous brainregion. This approach, though theoretically feasible(having two devices working together) is difficult withrTMS. On the other hand, because there are oppositechanges of excitability below the two stimulating tDCSelectrodes, there is a possibility that tDCS could be usedto produce opposite effects on homologous brain areas ofthe two hemispheres by placing the anodal electrode (facil-itatory) over the affected hemisphere and the cathodal one(inhibitory) over the unaffected side. However, it shouldalso be borne in mind that changing the location of oneof the electrodes will also change the orientation of theelectric currents in the brain and could influence the effec-tiveness of stimulation under each of the electrodes. Lastly,though the effects of anodal and cathodal tDCS are knownfor the motor, somatosensory and visual cortex, no studieshave investigated differences in electrode placement per-taining to stimulation at other brain sites such as prefrontalcortex.

Neurophysiologic specificity

Specificity of stimulation refers to the ability to targetspecific neural populations and it is important in neuro-physiologic studies. Measures of motor cortical thresholdwith TMS appear to give information about axonalexcitability, which is greatly influenced by drugs thattarget Na1 channel function such as carbamazepine.8

Similarly, paired-pulse TMS studies of SICI and LICI arethought to give information about excitability of GABAaand GABAb synapses9; short afferent inhibition (SAI) isthought to have an important cholinergic influence.10

TMS has also been used to target specific I-wave inputsto corticospinal neurons of motor cortex.11 All of theseeffects help provide detailed knowledge of the operationof cortical areas. They are supplemented by one otheradvantage of TMS: the temporal accuracy of the stimulus.This allows for precise timings to be estimated to ms reso-lution, allowing measures, for example, of central motorconduction time and transcallosal conduction time. Inter-estingly, TMS methodologies that explore the intrinsiccortical circuitry provide important clues about themechanism of action of tDCS.

Although tDCS has not been yet used in this way, froma therapeutic viewpoint, there are no proposed therapies at

this time that are designed to take advantage of the specificityof TMS. Whether this would be advantageousdapart fromunderstanding how tDCS worksdis therefore unknown.

Stimulus intensity

A single TMS pulse to motor cortex or to the visual cortexcauses muscle twitches on the opposite side of the body orphosphenes, respectively. Effectively these are a surrogatemarker that the stimulus has activated neural tissue underthe coil. Thus, although a clear relationship betweenstimulation intensity and clinical effects has not yet beendemonstrated, it is relatively easy to grade stimulusintensity in terms of this active biologic marker. However,tDCS produces no similar effects on behavior so that thereis no immediate phenomenologic indicator of the successor otherwise of the stimulus. Although tDCS strength inindividual subjects could be quantified by using otherneurophysiologic techniques such TMS, visual-evokedpotentials (VEPs), somatosensory-evoked potentials(SEPs), or even EEG, at the present time tDCS intensitiesare still given simply in terms of the current flowingbetween the electrodes, with no overt indication of howmuch of this is likely to enter the brain and polarizeneurons in each individual subject. Without such normal-ization, stimulus intensities across individuals in terms ofbiologic effectiveness is not possible. It may be thataccurate modeling of scalp and skull will solve thisproblem,12 but until that time it is not easy to equate theeffectiveness of stimulation between individuals. Ofcourse, even with rTMS, there is no direct measure ofeffectiveness when outside the motor cortex (contralateralmovement) or visual cortex (phosphenes). Methodologicapproaches allowing EEG recordings during rTMS andtDCS might in the future allow quantification of the effectsinduced by both techniques on non eloquent brain areas.

Off versus online stimulation

Online stimulation refers to stimulation delivered while thesubject is executing a given motor or cognitive task; offlinestimulation is when stimulation is delivered before a task,with the assumption that after effects (of rTMS or severalminutes tDCS) will interact with task performance. Becauseincreasing cortical excitability can facilitate learning novelcognitive or motor strategies, online stimulation protocolsmay have a great impact in restorative neurology andrehabilitation. Although theoretically possible, the largebulk of TMS devices together with the problem of maintain-ing 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 themodality of choice. These involve timed stimulus paradigmssuch 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 ata particular time during a cognitive task. If a task is disruptedat a particular time then it suggests that the brain area targetedis crucially involved in performance at that time.13

The advantage of tDCS is that electrodes are easilysecured to the scalp and can be worn while the subject is freeto move the head. This is clearly of some use in therapy asthe patient can be more comfortable while the stimulation isapplied. It is also useful in longer cognitive studies in whichtemporal information is not required. Another interestingpossibility is that of conducting noninvasive neuromodula-tion in more than one subject at a time.14 Although at firstsight curious, it could be an interesting application in exper-imental social neurosciences and even in clinical practicewhen there are several patients to be treated with a frequentpathologic factor such as stroke or depression. Althoughtheoretically possible, multisubject TMS would be muchmore expensive.

Safety

Both rTMS and tDCS are generally safe if used properly.Nonetheless, seizures are a well-recognized possibleserious adverse effect of rTMS, although present safetyguidelines have proved highly effective in minimizing thisas a problem. There is also a fairly extensive literature thathas demonstrated the safety of TMS in terms of effects onbrain anatomy and biochemistry.15 For tDCS, there are farfewer published studies of safety, and the main problem re-ported is transient skin reactions below the stimulatingelectrodes. Very rarely this reaction can be a small burnbelow the cathodal electrode of few millimeters in diameterthat heals spontaneously in several weeks16 [personalobservations]. Because tDCS for minutes does not increasethe markers of neuronal damage as neuron specific enolaseor brain N-acetyl-aspartate,17,18 it has been considered safefor the stimulated subjects.19-21 Whether tDCS is safe alsoat longer duration (hours) or higher intensities is, however,still unknown.

A safety issue that is rarely considered but that webelieve is important especially for techniques with poten-tial extensive use in the clinical practice is the safety forthe operators. Although the electrical field generated bytDCS is so weak that it cannot have a biologic relevance forthe operator, the magnetic field generated by rTMS caninduce small electromagnetic fields at a distance from thecoils. Whether these would have possible long-term effectsfor operators using TMS for several hours a day fora prolonged period are still unknown.

Conclusions and future directions

Although the reader will now be aware that there is nostrict recommendation about which of the two techniques

is better for specific uses, we believe that the high temporaland spatial resolution of rTMS is of advantage inexperiments that probe neurophysiologic effects on specificbrain circuits. In contrast, the simplicity and low cost oftDCS may be better suited for investigations that rely onmodulatory effects on nonselective populations of neurons,such as may be required in some types of clinicalstudies.22-24 However, it will be necessary to developsimple protocols to assess the strength (or ‘‘dose’’) oftDCS to overcome the interindividual variability inresponse.

At this time, noninvasive neuromodulation techniqueshold great promise as potential therapeutic tools that arecomplementary or alternative to drugs or surgery. BothrTMS and tDCS induce functional and neurochemicalchanges in the brain and may even affect inflammatoryresponse, immunity, and neuronal death. Future workwill be needed to optimize these effects to treatindividual patients with the most optimal stimulusparameters.

Acknowledgments

We wish to thank Dr Roberta Ferrucci for her kindassistance.

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