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doi:10.1016/j.br

Brain Stimulation (2009) 2, 2–13

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ORIGINAL RESEARCH

Consensus: New methodologies for brain stimulation

Ying-Zu Huang, MDa, Martin Sommer, MDb, Gary Thickbroom, PhDc,Masashi Hamada, MDd, Alvero Pascual-Leonne, MD, PhDe, Walter Paulus, MDb,Joseph Classen, MDf, Angel V. Peterchev, MDg, Abraham Zangen, MDh,Yoshikazu Ugawa, MD, PhDi

aDepartment of Neurology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taipei,TaiwanbDepartment of Clinical Neurophysiology, University of Goettingen, Goettingen, GermanycCentre for Neuromuscular and Neurological disorders, University of Western Australia, Adelaide, AustraliadDepartment of Neurology, Graduate School of Medicine, the University of Tokyo, Tokyo, JapaneBerenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard MedicalSchool, Boston, MassachesettsfDepartment Neurology, University of Wuerzburg, Wuerzburg, GermanygDivision of Brain Stimulation and Therapeutic Modulation, Department of Psychiatry, Columbia University, New YorkhDepartment of Neurobiology, Weizmann Institute of Science, Rehovot, IsraeliDepartment of Neurology, School of Medicine, Fukushima Medical University, Fukushima, Japan

We briefly summarized several new stimulation techniques. There are many new methods of humanbrain stimulation, including modification of already known methods and brand-new methods. In thisarticle, we focused on theta burst stimulation (TBS), repetitive monophasic pulse stimulation, paired-and quadri-pulse stimulation, transcranial alternating current stimulation (tACS), paired associativestimulation, controllable pulse shape TMS (cTMS), and deep-brain TMS. For every method, wesummarized the state of the art and discussed issues that remain to be addressed.� 2009 Elsevier Inc. All rights reserved.

Keywords transcranial magnetic stimulation; alternating current stimulation; monophasic and bi-phasic pulses; paired and quadri-pulse stimulation; theta burst stimulation

We briefly summarized several new stimulation tech-niques in this article. There are many new methods of human

nce: Dr Yoshikazu Ugawa, Department of Neurology,

icine, Fukushima Medical University, 1 Hikarigaoka,

1295, Japan.

ss: [email protected]

ne 14, 2008; revised September 10, 2008. Accepted for

ember 15, 2008.

-see front matter � 2009 Elsevier Inc. All rights reserved.

s.2008.09.007

brain stimulation, including modification of already knownmethods and brand-new methods. Here, we focuse on thetaburst stimulation (TBS), repetitive monophasic pulse stim-ulation, paired-pulse (PPS) and quadri-pulse stimulation(QPS), transcranial alternating current stimulation (tACS),paired associative stimulation, controllable pulse shapetranscranial magnetic stimulation (cTMS), and deep-brainTMS. For every method, we summarized the state of the artand discussed issues that remain to be addressed.

mailto:[email protected]

http://www.brainstimjrnl.com

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Figure 2 Twenty or 40 seconds of continuous theta burst stim-ulation (cTBS) suppresses the size of motor evoked potentials(MEPs) for 20 or 60 minutes, respectively. In contrast, 190 sec-onds of intermittent TBS (iTBS) enhances MEPs for around 20minutes.

New methodologies for brain stimulation 3

Theta burst stimulation (TBS)

The theta burst pattern of repetitive TMS (rTMS) wasdeveloped in 2004, based on the physiologic pattern ofneuronal firing found in the hippocampus of animal.1 Thebasic element of TBS contains a three-pulse burst at 50Hz given every 200 milliseconds (ie, 5 Hz). By usingthis basic pattern, two major TBS paradigms were devel-oped: continuous theta burst stimulation (cTBS) and inter-mittent theta burst stimulation (iTBS) (Figure 1). Thestimulus intensity required for TBS (80% of active motorthreshold) is lower than that for other rTMS protocols.Active motor threshold (AMT) is defined as the minimumintensity of single-pulse stimulation required to produce amotor evoked potential (MEP) of greater than 200 mV onmore than five of 10 trials from the contralateral first dor-sal interosseous muscle (FDI) while the subject is main-taining a voluntary contraction of about 20% ofmaximum in the FDI. With such low intensity, subjectsreceiving TBS seldom complain of any unpleasant sensa-tion that is seen in the other rTMS stimulation. In addi-tion, in comparison with other protocols, TBS canproduce plasticity-like effects with a much shorter condi-tioning time.

Continuous theta burst stimulation (cTBS)

This paradigm was designed to induce a long-term depres-sion (LTD)-like effect, and consists of a continuous train ofbursts without interruption. cTBS at an intensity of 80%AMT over the primary motor area produces significantinhibition of MEP size lasting for 20 or 60 minutesdepending on whether the stimulation is given for 20seconds (300 pulses) or 40 seconds (600 pulses) (Fig-ure 2).2-4 cTBS given at a lower intensity (ie, 60% AMT)produces no significant after-effect.2

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Figure 1 When bursts are given every 200 milliseconds contin-uously, continuous theta burst stimulation (cTBS), an long-termdisability (LTD)-like effect is induced. On the contrary, when 2-second trains of TBS are given with 8-second breaks in betweenintermittent theta burst stimulation (iTBS), an long-term potentia-tion (LTP)-like effect is induced.

Intermittent theta burst stimulation (iTBS)

The iTBS was developed to induce an long-term potenti-ation (LTP)-like effect. This protocol consists of a train of10 bursts (lasting 2 seconds) given every 10 seconds for atotal of 20 cycles. One hundred ninety seconds of iTBS at astimulus intensity of 80% AMT over the primary motorarea facilitates MEPs for about 20 minutes (Figure 2).2-4

Muscle activity and TBS

Huang et al5 have demonstrated that tonic contraction ofthe target muscle during cTBS or iTBS conditioning abol-ishes almost all of the after-effects of cTBS and iTBS. Sim-ilar contraction immediately after conditioning for 1 minuteenhances the effect of iTBS, and converts the suppressiveeffect of cTBS into a facilitation effect.5 Contraction at10 minutes after cTBS had no long-lasting effects.5 Thesedata imply that muscle activity during stimulation causesa serious problem with induction of any after-effect, andtherefore should be minimized or best avoided. Likewise,muscle activity should also be avoided for at least a fewminutes after the end of cTBS, if one is trying to inducean inhibitory effect. Nevertheless, if a facilitatory effect isdesired, such muscle contraction may be beneficial. It is im-portant that the stimulus intensity is referenced to the AMT.This implies that before TBS is applied, subjects are re-quired to contract the target muscle for about 3 to 5 min-utes, the time required to complete the assessment ofAMT. Gentner et al6 have recently suggested that this pre-activation might be crucial to produce the excitabilitydepressing effect of cTBS when it is applied over 20seconds. They found that cTBS (20 seconds) produced

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enhancement, instead of depression, of corticospinal excit-ability, unless it was conditioned by voluntary contractionof sufficient duration (5 minutes). A similar requirementfor isometric contraction was not noted for cTBS of twicethe duration (40 seconds).

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Issues that need to be addressed

TBS is a newly developed technique, and therefore thereare several technical parameters (eg, burst frequency,intervals between bursts, pause duration, stimulus intensity)that might be manipulated to enhance the effect of stim-ulation. At the current time, iTBS is less efficient thancTBS and the results of iTBS are usually weaker and lessconsistent compared with cTBS. Further improvement ofthe iTBS protocol is the focus of ongoing research. On theother hand, it is not uncommon to see a reduction in theamount of facilitation at around 7 and 9 minutes afteriTBS.2,3 It is not clear whether the dip is caused by a de-layed inhibition occurring at around this time or if iTBS in-duces two phases of facilitation with different mechanisms.Further study of this may help us to understand more aboutthe underlying mechanism of iTBS. Because the after-effect of other plasticity induction protocols on conscioushumans has never been studied minute by minute as hasbeen done with TBS, it is not clear whether this reductionis unique to iTBS. Another issue that deserves furtherstudies is the interaction between TBS and physiologicactivities.

stored by an oscilloscope. Upper part, waveform induced by aMagPro stimulator in the ‘‘monophasic’’ mode. Lower part, wave-form induced in the ‘‘biphasic’’ mode. B, Motor threshold with thetarget muscle at rest (RMT) in 12 healthy subjects, mean 6 stan-dard error (SE). Biphasic (bi) or monophac (mono) stimuli with ananterior (P-A) or posterior (A-P) initial current direction. Asterisksindicate significant post hoc differences between current direc-tions for a particular waveform. For all graphs the same DantecMagPro stimulator and the same MC-B70 coil were used. (Adap-ted from Sommer et al.11,18)

Influence of transcranial magnetic pulseshape and current direction

Because the very first days of TMS it was clear that theprecentral gyrus is sensitive to the direction of the appliedcurrent (Figure 3). Turning the round coil centered at thevertex resulted in a switch of the side of the excited cortexthat was much easier to excite and the motor thresholdmuch lower if the current in the brain flowed anteriorlyrather than posteriorly.7,8 With the advent of biphasic stim-ulators, the issue was lost, because for biphasic pulses thedifference between anterior and posterior current orienta-tion is much less pronounced than for monophasicpulses.9-11 Because biphasic pulses differed mainly in thesecond and third quarter cycles, it was therefore suggestedthat they contribute essentially to the net differences in theeffects of stimulation.12-14 Furthermore, epidural record-ings in vivo demonstrated a different dirct (D)- and indirect(I)-wave pattern for biphasic than for monophasic pulses,suggesting that either biphasic pulses stimulate inter-neurons at a different site than monophasic pulses, or thatthey activate a different subset of interneurons alltogether.15

The impact of pulse shape and direction on the effect ofrTMS is much less clear. For suprathreshold pulses, theMEP facilitation during fast rTMS16 is clearly modifiedby pulse shape and current orientation: Biphasic high-frequency stimuli of either direction induce a moderatefacilitation; this can be further enhanced by monophasicpulses directed anteriorly in the motor cortex. By contrast,monophasic pulses directed posteriorly induce an inhibi-tion, even seemingly paradoxically at high frequencies.17

For low frequencies the issue has not been studied in detail.For subthreshold rTMS, low frequency rTMS shows a

stronger MEP inhibition after monophasic posteriorlydirected than after biphasic pulses of any direction.18,19

For faster frequencies and for the current direction, theissue is still open.


For TBS, biphasic pulses directed posteriorly in themotor cortex appear most promising, although the differ-ence to other pulse types vanishes if the stimulus intensityis adjusted to the respective motor threshold.20

In the visual cortex, the phosphene threshold is lowerwith lateromedial than with the opposite current orienta-tion,21 and the scotoma induction is easier with monophasicthan with biphasic pulses.22 By contrast, the conditioningpulse of the transcallosally mediated interhemispheric inhi-bition effect is not sensitive to current direction.23

Conclusion and open questions

Current direction and pulse configuration differently influ-ence the effectiveness of single-pulse TMS and rTMS.However, a clear physiologic model or complete empiricaldata predicting the effect of all pulse shape parameters andtheir optimal values for a given application is not currentlyavailable. Understanding these relationships is importantfor both research and clinical uses of TMS. New TMSdevices that would allow more flexible control of the pulseparameters could help clarify this issue (a discussion ofcTMS follows).

Paired-pulse I-wave TMS

Repetitive paired-pulse TMS interventions have beendescribed that target short-interval cortical inhibition(SICI) and intracortical facilitation (ICF), and these inter-ventions can modulate both of these effects.24-26 An excit-atory repetitive paired-pulse TMS intervention targetinginterneuronal networks involved in the generation ofhigh-frequency descending volleys known as I-waves hasalso been proposed.27 I-waves have a periodicity of w1.5milliseconds, and are thought to result from transsynapticactivation of corticospinal neurons via excitatory corticalinterneurones or via recurrent activation.28 Paired-pulseTMS at I-wave periodicity can lead to a facilitatory interac-tion between the second pulse and the I-waves generated bythe first,29-31which increases the amplitude of the MEPcompared with that of paired pulses at non-I-wave inter-vals. The rationale for designing a TMS interventionaround I-wave periodicity is that persistently activatingfacilitatory I-wave interactions might be a means forincreasing the efficacy of transsynaptic events involved intheir generation. It has been argued that this approachmight have an analog in spike-timing dependent modelsof synaptic plasticity.32

The intervention, originally given the acronym iTMS toindicate its association with I-waves, consists of paired-pulseTMS at an interpulse interval (IPI) of 1.5 milliseconds. Thepulses are of equal intensity and are adjusted so as to give aMEP of w0.5 to 1 mV when delivered as a pair.27,33-35

The original description of this technique used a 30-minute protocol, with paired TMS delivered every 5seconds, and reported a substantial increase in MEPamplitude, but a short-lived after-effect.27 More recently,a longer after-effect has been described with a shorter dura-tion of intervention and a lesser degree of MEP facilitation(15 minutes).33

Considerations other than the duration of the interven-tion are the intensity of stimulation, rate of presentation ofstimuli, and the choice of IPI. These parameters remain tobe systematically investigated. If I-wave networks are up-regulated through associative plasticity mechanisms, toostrong a stimulus intensity may saturate the system andlimit the effectiveness of the intervention. The low fre-quency of rate of stimulation (0.2 Hz) makes the interven-tion comfortable for the subject and allows for thepossibility of monitoring excitability changes during theintervention (MEP amplitude to the paired-pulse TMS) andof performing motor tasks in association with stimulation33;however, higher frequency rates may turn out to be moreeffective and time-efficient. The choice of IPI requiresfurther investigation and could, in principle, be adjustedto match each individual’s I-wave peaks, although errorsin the estimation of these peaks may limit the usefulnessof this embellishment to the protocol.

Quadripulse stimulation

Here, we introduce a new protocol of rTMS, which induceslong-lasting plastic changes in the human primary motorcortex. The impetus for developing the new rTMS protocol,QPS35 is similar to that of repetitive paired-pulse TMS.27

Because tetanic stimulation protocols are often used inanimal experiments to induce robust LTP and the number ofpulses per train in such tetanic stimulation protocol isknown to be a very potent factor to influence the level ofsynaptic plasticity in the hippocampus,36 Hamada et al35

presume that a greater enhancement of motor cortical excit-ability can be provoked by increasing the number of short-interval pulses per train. In QPS, one train consisted of fourmonophasic pulses at the same intensity separated by 1.5milliseconds, repeatedly given at 0.2 Hz, whereas it con-sisted of paired pulses of equal intensity separated by 1.5milliseconds, repeatedly given at 0.2 Hz in PPS. It wasfound that QPS induced long-lasting locally restricted facil-itation of motor cortical excitability for up to 75 minuteswithout affecting motor thresholds. This facilitation wasconsidered to be a cortical event because responses to brainstem stimulation were unchanged after QPS. Short-intervalICF was enhanced after QPS, whereas SICI was unaf-fected.37 These findings presumably indicate that QPSmainly enhances I-wave summations at the primary motorcortex and that a greater enhancement of motor corticalexcitability can be provoked by increasing the number ofpulses per train. QPS seems to be one of the promisingmethods for inducing plastic changes in the brain. It is

6 Y.-Z. Huang et al

unclear, however, if more repetitions and/or higher stimula-tion frequency would even be more effective.

Several issues to be addressed in the future

This method is at the very early stage of development andmany issues should be resolved in the future. One point ofthis method is using monophsic pulses (discussed in the‘‘Influence of transcranial magnetic pulse shape and currentdirection’’ section). What occurs when the same protocolwith biphasic pulses is used? The following parametersshould be searched in the future: the interpulse interval,intertrain interval, pulse number of one train, and so on.After submission of this paper, it has been reported that bi-directional long term after-effects are induced by QPSswith different IPIs.37

Transcranial alternating current stimulation

The first systematic study to demonstrate interference withbrain rhythms as seen in the electroencephalogram (EEG)by noninvasive modulation of motor cortex using weaktACS through the intact human scalp used electrode sizesand positions similar to those in transcranial direct currentstimulation (tDCS) studies.38

MEPs revealed by TMS, EEG-power, and reaction timesmeasured in a motor implicit learning task were analyzed todetect changes of cortical excitability after 2 to 7 minutesof AC stimulation superimposed and without DC shiftusing 1, 10, 15, 30, and 45 Hz of stimulation frequencyover the primary motor cortex in 48 healthy subjects. Amarked decrease of MEP amplitude of up to 20%, andimproved implicit motor learning was observed after 10 HzAC stimulation only. If the anodal or cathodal DC stimu-lation was combined with 5, 10, and 15 Hz AC stimulation,the MEP amplitudes were increased after anodal 10 and 15Hz stimulation. No significant changes in any of theanalyzed frequency bands of EEG after sinusoidal AC orDC stimulation were found. Although transcranial applica-tion of weak AC current may appear to be a tool for clinicalresearch in diseases with altered EEG activity, the effects ofthis study were weak when compared with tDCS effects.This is probably because of the comparatively low ampli-tude of a maximum of 400 mA. Higher intensities led to aflickering sensation caused by retinal stimulation and wasthen not applied in this first study because of safetyconcerns about seizure induction. Just as with rTMS ortDCS in the past, future studies will have to explore thesafety limits of this new technique.

Paired associative stimulation

Paired associative stimulation (PAS) consists of low-frequency repetitive peripheral nerve stimulation combined

with near-synchronous TMS over the contralateral targetcortex. If 60 to 180 pairs are applied to the motor cortex,this protocol has been shown to induce amplitude changesof MEPs elicited in the resting target muscle. The relativetiming of the two stimulus modalities determines thedirection of amplitude changes. Shortening the intervalbetween the median nerve stimulation and TMS applied tothe optimal position for eliciting MEPs in the abductorpollicis brevis (APB) muscle from 25 milliseconds (PAS25)to 10 milliseconds (PAS10), changed the effect fromfacilitation to depression of APB MEP size, whereas longerintervals did not induce any lasting excitabilitychanges.39,40 This observation suggests that PAS-inducedplasticity in human motor cortex is governed by strict tem-poral rules. The dependence on the sequence of inducedevents resembles spike-timing dependent plasticity of asso-ciative LTP, a concept developed in animal studies. Toinduce reliable effects in the resting motor cortex, supra-threshold TMS-intensities are needed. When subjectsperform voluntary contractions during application of theprotocol, even subthreshold magnetic stimulation intensi-ties may be sufficient to produce similar effects.41 Shorterinterpair intervals may also enhance the efficacy of theprotocol.42

At present, it remains an open question as to whichdegree PAS-induced excitability changes are confined tothe cortical level39,40,43 or may be accompanied by changesat subcortical locations.44 Within the cortex, upper layersare implicated by a number of studies that use different ap-proaches41,45,46. PAS-induced excitability changes appearto be rather synapse specific. This is suggested by thefact that they were maximal in the muscle representationreceiving homotopical input by afferent stimulation andTMS47-50 that SICI remained unchanged afterPAS2541,49,51 and that PAS did not alter the degree to whichvibration of muscle bellies influenced the size of MEPs re-corded from the same or adjacent muscles.52

Enhancement of cortical excitability induced by PASevolved rapidly (within 30 minutes), and was persistent(at least 30-60 minutes duration), yet reversible. Theduration of effects may be extended to more than 24 houswhen subjects are under the influence of L-DOPA whentreated with PAS.53 Neither of PAS25 or PAS10 led to asignificant change of cortical excitability if subjects werepremedicated with dextromethorphan, a blocker ofNMDA receptors.40,1 Because dextromethrophan blocksNMDA receptors, involvement of these receptors is impli-cated in PAS-induced plasticity. In addition, PAS10-induced depression of cortical excitability was blockedby premediation with nimodipine, an L-type voltage-gatedCa-channel blocker. The efficacy of PAS to induce plas-ticity may be modified by several modulating neurotrans-mitters, such as serotonin, dopamine, norepinephrine andacetylcholine.54 The role of dopamine is also implicatedin studies on Parkinsonian patients who show less-than-normal PAS-induced facilitation,55,56 which can be


restored by substitution of the dopaminergic deficit. Mod-ulation of cortical elements by acetylcholine may underliethe dramatic modulation of PAS-induced plasticity byattention.57

PAS-induced effects are variable between subjects.58 Al-though some of this variability might depend on circadianfactors,59 probably a substantial part arises from interindi-vidual genetic variations (unpublished data) or variationsin the activation history of the PAS-recipient cortex. Train-ing of ballistic60 or dynamic52 thumb abductions led to atemporary blockade of PAS-induced plasticity suggestingthat prior activity may profoundly influence the efficacyof the PAS-protocol. This finding may also indicate thatPAS-induced plasticity probes a functionally relevant corti-cal plasticity mechanism, one that is possibly related toacquisition of a motor skill and dexterity.61,62

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Some observations suggest that PAS may generate corticalexcitability changes with properties surprisingly similar tothose of LTP as revealed by invasive animal studies. Futurestudies should aim to prove or refute the hypothesis ofequivalence of mechanisms by studying PAS-protocols inanimals. In humans, methodologic studies should aim toaddress the source of variability between subjects andsessions. Likely, from these studies, it will be possible todevelop modifications that may lead to robust specific regionalexcitability changes that may be therapeutically useful.

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cTMS device features

Conventional TMS devices induce cosine electric fieldpulses with very limited control over the pulse parameters.In contrast, controllable pulse shape TMS (cTMS) devicesuse a different electronic circuit topology to generate near-rectangular pulses with parameters that are adjustable overa wide continuous range. Figure 4 shows the circuit

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Figure 4 Circuit topology of low-frequency, monophasic con-trollable pulse shape transcranial magnetic stimulation (cTMS)device generating near-rectangular electric field pulses withadjustable pulse width.

topology of a low-frequency, monophasic cTMS device.63

Unlike conventional TMS devices that use thyristors toswitch the coil current, this circuit deploys an insulated-gate bipolar transistor (IGBT) switch, Q, which allowsthe operator to control the pulse width (PW). Further, theenergy storage capacitor, C, is larger than that in conven-tional TMS devices, enabling a wide range of PW adjust-ment and near-rectangular electric field pulses. Figure 5shows pulse waveforms generated by the topology in Fig-ure 4, in comparison with those of a conventional mono-phasic TMS device. The cTMS magnetic field rise ismore linear, resulting in an approximately constant strengthof the initial electric field phase. This near-rectangularpulse produces faster neuronal membrane potential changethan the cosine pulse. Consequently, the energy necessaryto depolarize a neuron and the coil heating are significantlyreduced.63

The cTMS topology from Figure 4 can be enhanced touse an additional switch and energy storage capacitor torecycle the pulse energy and to allow independent controlof the amplitudes of the positive and negative electric fieldphases, in addition to PW control. This enhanced topologycan generate trains of both monophasic (Fig. 6, left panel)

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Figure 5 Waveform comparison of monophasic cosine transcra-nial magnetic stimulation (TMS) (dashed line) and controllablepulse shape transcranial magnetic stimulation (cTMS) (solidline, generated by topology in Fig. 1). (a) Magnetic field B; (b)induced electric field E; (c) neuronal membrane potential Vm formembrane time constant of 150 ms.

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and biphasic (Fig. 6, right panel) magnetic pulses atfrequencies up to 200 Hz (depending on the pulse parame-ter selection).

cTMS Applications

Some examples of how cTMS technology could be used tostudy the effect of pulse shape parameters and optimizestimulation paradigms are listed below.

Strength-duration curve measurementThe PW adjustment feature of cTMS can be used toempirically derive the strength-duration response curvesof neuronal populations.63-65 The strength-duration curvedepends on the biophysical properties of the axonal mem-brane that can be altered by neurologic and psychiatric dis-eases, or by pharmacology. Thus, strength-duration curvemeasurement could give insight into the effect of diseasesand drugs on neuronal function.

rTMS optimizationThe ability of cTMS devices to generate high-frequencytrains of a wide range of pulse shapes could allowoptimization of the neuromodulatory effect of rTMS. Asdiscussed previously, there is some evidence that rTMSwith predominantly unipolar electric field pulses, likethose induced by conventional monophasic devices, mayhave a stronger and longer-lasting effect on neural excit-ability than the biphasic pulses generated by conventionalrTMS stimulators17-19,22,66,67 (discussed in the ‘‘Influenceof transcranial magnetic pulse shape and current direc-tion’’ section). Unlike existing monophasic machines,energy-recycling cTMS devices could generate long,high-frequency trains of predominantly unipolar pulses,

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enabling further study of the effectiveness of such stimu-lation paradigms.

Tolerability enhancementThe selection of pulse parameters may also affect scalpsensation relative to cortical stimulation.68 Thus, cTMScould be used to optimize the stimulus shape to improvethe tolerability of TMS.

Coil heating reductionThe reduction in coil heating associated with the use ofcTMS near-rectangular pulses63 could significantly benefithigh-frequency, high-power therapeutic applications suchas rTMS and magnetic seizure therapy (MST).

TMS of deep brain regions

Conventional rTMS methods are not able to activate deepbrain regions effectively because the induced electric fielddecreases rapidly as a function of the depth of the targetstructure.69-72 Direct stimulation of deeper regions is feasi-ble only at the expense of inducing high intensity in super-ficial cortical regions that might cause epileptic seizuresand other undesired effects.73-76

Generally, larger TMS coils have slower decay of theelectric field in depth, but they are also less focal. H-coilsare designed to achieve effective stimulation of deeperneuronal regions by inducing spatial summation of theinduced electric field and reducing the electric fieldattenuation as a function of distance, at the expense ofreduced focality. Figure 7 shows the decay rate of theelectric field induced by different coils, as a function ofdistance.

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Figure 8 shows the intensity required for inducing APBactivation with the standard figure-eight coil and with an H-coil, as a function of the coil distance from the ‘‘hot spot’’on the scalp.77

Figure 9 shows a three-dimensional distribution of theelectric field induced by a standard figure-eight coil andtwo H-coil versions when placed over the prefrontal cortex,using intensity of 120% of an average APB motor thresh-old. The H-coils can activate deeper brain areas and there-fore expand the potential feasibility of TMS for researchand treatment of various neurologic and psychiatricdisorders.

Various versions of the deep TMS H-coil have beenconstructed based on several design principles. The firstone is spatial summation of electric impulses. The inducedelectric field at a target deep brain region is obtained byoptimal summation of electric fields induced by severalcoils or coil elements with common direction placed atdifferent locations around the skull, which may be con-nected either in series or in parallel. The second principle isoptimal orientation of stimulating coil elements. Neuronalactivation occurs when the electric field magnitude reachesa certain threshold. This threshold depends on the orienta-tion of the induced field. Physiologic studies indicate thatoptimal activation occurs when the electric field is orientedparallel to the nerve fiber9,10,78 In the H-coils, because sev-eral coil elements are placed at different locations aroundthe scalp, it is especially important to guarantee optimalcoordinated orientation of the various elements. The thirdprinciple, which is critical for reducing the attenuationof the electric field with distance from the coil, is

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Figure 7 Decay of the electric with distance from various trans-cranial magnetic stimulation (TMS) coils. Phantom measurementsof the electric field induced at each distance is calculated relativeto the field induced 1 cm from the coil, in the ‘‘z‘‘ (superior-infe-rior) direction. Data are presented for the H1-coil, H2-coil, dou-ble-cone coil, and figure-eight coil.

minimization of nontangential components. It has beenshown that coil elements that are nontangential to the sur-face induce accumulation of surface charge, which leadsto a reduction of both the magnitude and the depth of pen-etration of the electric field.70-72 Hence, coil elements car-rying currents nontangential to the scalp have to beminimized and located far from the target deep brain re-gion. The fourth principle of H-coil design is remote place-ment of the return current paths. Coil elements carryingcurrents directed oppositely to the preferred direction (thereturn paths) should be located far from the deep brain tar-get. These elements may be located either adjacent to dis-tant head regions or far from the head, but limited indistance to avoid large nontangential elements as explainedpreviously.

The principle of summation can be used temporally aswell as spatially. Neuronal activation occurs when thetransmembrane potential at the target is depolarized to acritical level (threshold).80,81 This process depends onboth the magnitude and the duration of the induced elec-tric field,82-84 as demonstrated in the strength-durationcurve.64,85 The synchronized discharges of several stimu-lators, or a multichannels stimulator, can produce tempo-ral summation of electric impulses from different spatiallocations.86 In this setup, each channel or stimulator isdischarged via a different coil at a different locationaround the scalp. This setup may be used with anyTMS coil, but the H-coil design is preferable for

Figure 9 Maps of the electric field induced by three coils placed over the prefrontal cortex. The maps represent phantom brain measure-ments of the absolute electric field induced at each pixel. The red colors indicate field magnitude above the threshold for neuronal activa-tion, which was set to 100 V/m. The field maps are adjusted for stimulator output required to obtain 120% of the threshold (120 V/m), at adepth of 1.5 cm. (A) Field maps of a standard figure-eight coil. (B) Field maps of the H1L coil, which was designed to activate lateralprefrontal regions in the left hemisphere. (C) Field maps of the HAAD coil, which was designed to activate deep bilateral prefrontalregions.

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10 Y.-Z. Huang et al

activation of deep brain regions, allowing a combinationof both spatial and temporal summation. The time delaysbetween the various discharges can be controlled at thescale of microseconds. The use of multiple channels canimprove the heating rate and power consumption, aswell as the flexibility of controlling the spatial and tempo-ral field distribution.

Some H-coil designs with slow electric field decay ratehave been demonstrated to activate deep brain regions byusing mathematical simulations and phantom brain mea-surements.83,85,86 The safety of the H-coil used over theprefrontal cortex at low and high frequencies (up to 20Hz) and the initial characterization of cognitive effectsinduced by such stimulation have been reported.87,88

Future issues to be studied

Future studies are required to characterize the H-coil designefficacy for various clinical applications. A thorough

characterization of the neural response is required, toclarify its dependence on various parameters, includingthe shapes of the electric field pulses, the delay timesbetween pulses and relative current polarity. Preliminaryresults suggest that the value of the transmembrane poten-tial threshold for neural activation may depend on the timecourse of the induced electric field. If these findings areconfirmed, this may enable an increase in the focality ofactivation of deep brain regions. Another subject for futurestudies is the application of PPS or QPS with a multichan-nel system. Varying the relative amplitudes of the adjacentpulses may alter their effect on neural excitability.89 Thismay provide additional means of modulating facilitationand/or suppression in superficial and deep-brain regions.

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