Repetitive transcranial magnetic stimulation or transcranial direct current stimulation?

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  • Repetitive transcranial magnets

    th

    di diPolilogic

    c

    tion (TMS) uses a large, rapidly changing magnetic field

    electric nerve stimulator. These short pulses initiate action

    delivering weak direct current (1-2mA) through a sponge

    enters the skull where it is thought to polarize cortical

    of 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 of

    1

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

    logiche, Universita` 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 Febr

    1935-861X/09/$

    doi:10.1016/j.br

    Brain Stimulation (2009) 2, 2415potentials in axons of the cortex and subcortical whitematter that then release neurotransmitters at their terminal

    neurons. 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, polarization

    JCR was funded by the Medical Research Council, UK.

    MH is supported by the Intramural Program of NINDS, NIH.to induce electrical stimulating currents in the brain thatare similar to those that are produced by a conventional

    electrode placed on the scalp for periods of 4-5 seconds tomore than 20 minutes. A portion of the applied currentKeywords 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-

    synapses. Stimulators can deliver either single pulses orrepeated pulses (rTMS) at frequencies of up to 50 Hz.Transcranial direct current stimulation (tDCS) involvesIn 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..Sobell Department, UCL Institute of Neurology, London, United Kingdomor transcranial direct current

    Alberto Prioria, Mark Hallettb, John C. Ro

    aDipartimento di Scienze Neurologiche, Universita` degli StuNeurostimolazione, Fondazione IRCCS Ospedale MaggiorebHuman Motor Control Section, National Institute of Neurouary 24, 2009.

    -see front matter 2009 Elsevier Inc.s.2009.02.004ic stimulationtimulation?

    wellc

    Milano, Centro Clinico per le Neuronanotecnologie e laclinico, Mangiagalli e Regina Elena, Milano, Italyal Disorders and Stroke, Bethesda, Maryland

    www.brainstimjrnl.commental and neurologic disorders.

  • for the scope of planned work. Of course, both of these

    20,000 to 100,000 dollars, tDCS devices are well below

    the scalp, so that stimulation occurs in two sites rather

    242 A. Priori, M. Hallett, and J.C. Rothwell13,000 dollars (range: 40010,000 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 themethods 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 betweenProlonged 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 suitablethan 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 unlesssensation 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 on

  • for the motor, somatosensory and visual cortex, no studies

    or otherwise of the stimulus. Although tDCS strength in

    ing coil position on the head when subjects can move freely

    rTMS or tDCS? 243have 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 atlaboratories 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 known(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 cognitiveindividual 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-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 success

  • The advantage of tDCS is that electrodes are easily

    or brain N-acetyl-aspartate, it has been considered safe

    244 A. Priori, M. Hallett, and J.C. Rothwellfor the stimulated subjects.19-21 Whether tDCS is safe alsoat longer duration (hours) or high...

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