the navigation of transcranial magnetic stimulation

Ž .Psychiatry Research: Neuroimaging Section 108 2001 123�131

The navigation of transcranial magnetic stimulation

Uwe Herwiga,�, Carlos Schonfeldt-Lecuonaa, Arthur P. Wunderlichb,¨Cyrill von Tiesenhausena, Axel Thielscher a, Henrik Walter a,

Manfred Spitzera

aDepartment of Psychiatry, Uni�ersity of Ulm, Leimgrubenweg 12, D-89070 Ulm, GermanybDepartment of Radiology, Uni�ersity of Ulm, Leimgrubenweg 12, D-89070 Ulm, Germany

Received 18 January 2001; received in revised form 21 August 2001; accepted 19 September 2001

Abstract

Ž .Transcranial magnetic stimulation TMS is a new method for investigating cortical information processing and forinvestigating therapeutic applications in psychiatry and neurology. A common problem of most studies in this fieldregards the localization of the magnetic coil with respect to the cortex. This article reviews the currently usedmethods and proposes a neuronavigational approach. The method of neuronavigated TMS is described and discussedin detail. It is used to guide the magnetic coil on an individual basis to a structurally or functionally predeterminedcortical area while monitoring the location of the coil in relation to the subject’s head in real time. Possibleapplications of TMS in combination with functional neuroimaging in clinical research within a cognitive neuroscienceframework are discussed. Future applications of TMS should take individual anatomy into account, and neuronaviga-tion provides the means to do so. � 2001 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Neuronavigation; Functional neuroimaging; Cognitive neuroscience; Psychiatric treatment

1. Introduction

Ž .Transcranial magnetic stimulation TMS is arelatively recent and promising method to investi-

� Corresponding author. Department of Psychiatry III, Uni-versity of Ulm, Leimgrubenweg 12, D-89070 Ulm, Germany.Tel.: �49-731-502-1499; fax: �49-731-502-6751.

ŽE-mail address: [email protected] U. Her-.wig .

Žgate cortical information processing Post et al.,1999; Pascual-Leone et al., 2000; Walsh and

.Cowey, 2000 . Furthermore, its therapeutic effi-cacy in psychiatric and neurological disorders is

Ž .being investigated George et al., 1999 . However,studies in this field face the general problem ofpositioning the magnetic coil above relevant corti-cal areas. Most study groups using TMS do nottake the individual anatomy into account, therebyrunning the risk of not reaching the intended

0925-4927�01�$ - see front matter � 2001 Elsevier Science Ireland Ltd. All rights reserved.Ž .PII: S 0 9 2 5 - 4 9 2 7 0 1 0 0 1 2 1 - 4

( )U. Herwig et al. � Psychiatry Research: Neuroimaging 108 2001 123�131124

area exactly. A solution to the problem of exactcoil positioning is offered by neuronavigationaldevices that enable the precise location of themagnetic coil.

TMS induces non-invasively the depolarizationof cortical neuronal assemblies. It has been used

Žto examine motor and sensory functions Barker.et al., 1985; Hess et al., 1987; Seyal et al., 1992 ,

Žvisual information processing Amassian et al.,. Ž1989 , speech functions Pascual-Leone et al.,. Ž1991 , memory and learning Grafman and

. ŽWassermann, 1999 , emotions George et al.,.1996; Pascual-Leone et al., 1996a and other do-

mains of brain function.Clinical applications of TMS in psychiatry and

neurology consist of the investigation of thera-Ž .peutic efficacy in depression George et al., 1999 ,

Ž .mania Grisaru et al., 1998 , obsessive�compul-Ž .sive disorder Greenberg et al., 1997 , posttrau-

Ž .matic stress disorder McCann et al., 1998 , audi-Ž .tory hallucinations Hoffman et al., 2000 , Parkin-

Ž .son’s disease Pascual-Leone et al., 1994 , writer’sŽ . Žcramp Siebner et al., 1999 , and epilepsy Tergau

.et al., 1999 .The use of TMS requires the knowledge of

where on the cortex the magnetic stimulation hasto be applied and to control where it is effectivelyapplied. In this article we focus on the problem oflocalizing the magnetic stimulation. Different po-sitioning methods are reviewed and the neuronav-igational approach is presented in detail.

1.1. Localizing magnetic stimulation

The most commonly used figure-of-8 coils sti-mulate the cortex focally depending on the inten-sity over an area of up to 20 cm2 with twiceŽ . Ž . Ž200% the motor threshold MT Roth et al.,

. Ž1991 . Reducing the intensity most stimulations.are performed at approx. 100% MT reduces the

Ž .depolarized area Thickbroom et al., 1998 , con-verging to a nearly punctual stimulation effect atMT. This is obvious in practical use when a shiftof the coil over the motor cortex of a few millime-ters leads to marked differences of the evokedamplitudes or null amplitudes with stimulation atMT intensity. This underlines the importance ofprecise knowledge of coil location within a range

of a few mm to interfere with a certain corticalfunction. The conical shape of the induced elec-tric field under the midpoint of a figure-of-8 coil,calculated using a spherical head model, is illus-

Ž .trated in Fig. 1 Ilmoniemi et al., 1999 . It out-lines the steep decrease of the intensity of theelectric field with growing distance to the mid-point of the coil.

Experienced neurologists determine the stimu-lation site for measuring the latencies of pyrami-dal tract neurons quite easily. The position of thecoil over the skull is varied until the desiredeffect, in this case a motor response, is obtained.The optimal stimulation site is defined by thiseffect. In the neurological diagnostic routine, thisfunctionally oriented method is common andpracticable. This approach was further used inneuropsychological research with TMS for thelocalization of functional responses like speech

Ž .arrest Pascual-Leone et al., 1991 , as well as forthe detection of visual phenomena like

Žphosphenes over the occipital cortex Amassian.et al., 1998 . An overview of several positioning

methods is given in Table 1.In the first studies applying TMS as an antide-

pressive treatment to patients, the orientation ofthe coil in relation to certain anatomical markers

Ž .was used for positioning; Hoflich et al. 1993 and¨Ž .Kolbinger et al. 1995 stimulated over the vertex.

Several neuroscience research groups have de-termined the stimulation site using other ap-proaches such as the international EEG 10�20

Ž .system e.g. Seyal et al., 1992; Walsh et al., 1998 .The coil is placed above a certain 10�20 positionto depolarize neurons in the underlying cortex.While this method is oriented to the individualhead size, the individual cortex anatomy is notconsidered.

Coil positioning is difficult when targeting aregion that is not defined by objective parameters

Ž .such as the motor response. George et al. 1995Ž .and Pascual-Leone et al. 1996b aimed the sti-

mulation at the dorsolateral prefrontal cortexŽ .DLPFC when studying the antidepressive effect

Ž .of repetitive r TMS. In several neuroimagingstudies, the prefrontal cortex of depressed patients

Ž .showed hypometabolism Soares and Mann, 1997 ,mostly left-sided. The site for antidepressive sti-

( )U. Herwig et al. � Psychiatry Research: Neuroimaging 108 2001 123�131 125

Fig. 1. Distribution of the electric field in the head induced byŽ .a figure-8-shaped coil Dantec MC-B70 . The calculation was

made with a spherical head model. It shows the distribution ofthe electric field strength on a spherical approximation of the

Ž .cortex r�8 cm . The field strength is scaled to its maximumand coded as height.

mulation was defined as the region 5 cm anteriorof the region from which the most prominentmotor response of the M. abductor pollicis breviscan be recorded. This area was expected to beabove the DLPFC.

With these methods the coil position can berelated to certain cortical areas with an estimatedresolution in the range of centimeters. However,the individual differences of the cortical anatomyare not taken into account. Thus, it remains dif-ficult to compare results gained from differentsubjects in studies using this low resolution coilpositioning.

The individual anatomy of a subject is con-sidered by marking the stimulation sites with a

Žlocally attached MR contrast marker e.g. con-

Table 1Different methods to localize transcranial magnetic stimulation

Principle of Navigational method Advantage�disadvantage Authorlocalization

Functional Orientation to motor response, Verification by function, not Barker et al., 1985visual phenomenon, applicable if function is not Amassian et al., 1989

Ž .speech arrest monitorable e.g. memory Pascual-Leone et al., 1996b

Anatomical 10-20-system of EEG, Standardized, not oriented Amassian et al., 1989defined landmarks to individual Hoflich et al., 1993¨

function or cortex anatomy

Functional and anatomical 5 cm anterior to motor Not oriented to individual Pascual-Leone et al., 1996afeatures combined cortex in prefrontal cortex cortex anatomy, imprecise George et al., 1996

within cm Herwig et al., 2001

Digitizing devices like 3D-radio frequency Individual localization, resolution Wassermann et al., 1996‘Polhemus Isotrak’ localization and approximately 5 mm, not Bastings et al., 1998

coregistration with MRI applicable during stimulation

Marker in MRI scan, Marker fixed over stimulated Individual localization afterwards, Terao et al., 1998functional imaging area, combination not applicable during stimulation, Paus, 1999

with PET no monitoring

Stereotactical, mechanically 3D stereotaxy by Individual localization, Krings et al., 1997guided navigation joint sensors in potentially high precision, Kammer and Nusseck, 1998

mechanical arms monitoring, complexmechanical setup

Stereotactical, optically 3D-camera system, detection Individual localization, Ettinger et al., 1998tracked navigation of light-emitting diodes, resolution �2 mm Potts et al., 1998

Ž .coregistration with MRI unpublished data , monitoring Boroojerdi et al., 1999during stimulation


.taining tocopherol or nifedipine followed by aŽ .magnetic resonance scan. Terao et al. 1998 used

this method in order to correlate motor mappingwith TMS and fMRI. They found an overlap ofthe affected cortical areas. Localization was doneafterwards because the method does not allowthe selection of the stimulated site on a neu-roanatomical basis in advance.

The stimulation site can also be localized usingradio frequencies and digitized anatomical fea-

Ž TM . Žtures Polhemus Isotrak Bastings et al., 1998;.Wassermann et al., 1996 . This system registers

the relative positions of landmarks on the headand the position of the stimulation site, whichthen can be identified in the individual MRI.Before or after magnetic stimulation is applied,the stimulation position in relation to the brain islocated with the digitizer, for instance, on a griddrawn on a head cap, and visualized in the MRI.The accuracy of this method is within 5 mmŽ .Bastings et al., 1998 . However, because of thesusceptibility to the magnetic stimulus, this posi-tioning system cannot be used during the stimula-tion, which limits its application for TMS.

Another way to determine the desired stimula-tion site is by using mechanical arms with sensors

Ž .for joint movements. Krings et al. 1997 mountedthe magnetic coil to such an arm and monitoredthe position of the coil relative to the MRI of thebrain. The procedure allows to monitor the coilposition during the stimulation session. They per-formed TMS for presurgical planning and corre-lated the area of TMS evoked motor responseswith functional MRI data. They found a spatialcorrespondence between the cortical areas of aTMS-induced motor response and the corticalactivation in fMRI during the performance of atask involving the same muscles. A disadvantageis that the head has to be fixed strictly to rule outmovements during the stimulation.

Ž .Kammer and Nusseck 1998 solved this prob-lem by combining two mechanical arms in a com-mon reference system and attaching one arm tothe coil and the other one to the head. Therelative positions of coil and head in 3D spacewere calculated by correlation to a common coor-dinate system. This system allows the control ofthe coil position during the stimulation. Special

software enables the stimulated person to realignthe head relative to the desired coil position sothat in case of mislocation a quick correction ispossible.

The principle of visualizing the coil positionrelative to the brain during the stimulation in realtime by frameless stereotaxy was described by

Ž .Ettinger et al. 1998 . This system, based on opti-cal tracking, consists of three cameras monitoring

Ž .light-emitting diodes LEDs , which are attachedto the head and to the coil. Such neuronavigatio-nal systems have been used since the early 1990sin neurosurgery to locate and navigate surgicaltools stereotactically in relation to brain struc-

Žtures with a spatial resolution under 1 mm Wirtz.et al., 1998 .

Studies using neuronavigated TMS were per-formed to map the human motor cortex and the

Žvisual system Ettinger et al., 1998; Potts et al.,.1998 . The magnetic coil was positioned with neu-

ronavigation based on optical tracking to a cer-tain cortical area in order to identify TMS-induced changes in regional cerebral blood flowŽ . Ž .rCBF as revealed by PET Paus, 1999 . Boroo-

Ž .jerdi et al. 1999 used this form of navigationwith TMS to determine the center of gravity inmotor responses in the motor cortex in relation tofunctional MRI activations. The neuronavigatedTMS was presented briefly by these groups and isdescribed in more detail with a new technicalapproach in the following section.

2. Method: stereotactically neuronavigatedmagnetic stimulation

To address the problem of coil positioning, aneuronavigational system that is commonly used

Ž TMin neurosurgery Surgical Tool Navigator ,.Zeiss, Oberkochen, Germany; Fig. 2 was adapted

for TMS positioning. The method is based onframeless stereotaxy and avoids fixing the head ina stereotactic ring.

The position of the freely movable head ismonitored relative to the freely movable coil. Thestimulated brain area is visualized during thestimulation on a computer screen. Therefore, twocoordinate systems in 3D space are transferred to


TM Ž .Fig. 2. Surgical Tool Navigator Zeiss with workstation,3D camera system and subject with the magnetic coil.

a common reference system. These coordinateŽ .systems are a the brain coordinates in the MRI

Ž .scans; and b the head and coil coordinates mon-itored by a camera system.

Fig. 3. Real time visualization during the stimulation in thethree axes and a 3D surface-rendered MR image of the head.The dotted line represents a line perpendicular through thecenter of the coil, where the peak of the magnetic field isestimated. The stimulation focus is above the left motorcortex.

MRI scans register the brain and the headsurface with their coordinates in one reference

Ž TMsystem. Special software STP4 , Zeiss-.Leibinger visualizes high resolution T1-weighted

ŽMR images isotrope voxels of 1�1�1 mm size,TM .1.5 T Magnetom Vision MR Scanner; Siemens

in all three axes together with a 3D reconstruc-Ž .tion of the head surface Fig. 3 .

The second registration system, the opticaltracker, is based on three cameras that aremounted aligned on a bar. They detect the posi-tions of several flashing infrared LEDs and calcu-late their spatial relationship. When at least threeLEDs are fixed to the head, the tracking systemcalculates the actual head position in space in allsix degrees of freedom. These are the translationsin the directions x, y, z and the rotation aroundthese axes. Three more LEDs are fixed to areference frame on the magnetic coil in order todetect its position by the same cameras in all sixdegrees of freedom. Accordingly, the head’s sur-face coordinates and the coil coordinates areregistered in a common reference system. Thehead surface coordinates, calculated by the opti-cal tracking system, and calculated as well in theMRI, serve as the interface for both referencesystems.

Both reference systems have to be coregisteredby a referencing procedure. Several anatomicallandmarks, fiducial markers, e.g. nose rims, na-sion, tragus, are defined on the surface of the 3Dreconstruction of the head. The same points areregistered on the subject’s head with an opticallytracked LED pointer. Both coordinate systemsare aligned to each other using a transformationmatrix that is generated by this referencing proce-dure. For a refinement of the matching proce-dure, a surface-matching algorithm can be used inaddition.

In the resulting common reference system, thecoil position is determined in relation to thecortex and visualized on the computer screen.The relative positions of the head and the coil areregistered in real time during the stimulation withan update rate of the actual position of 2�4 Hzdepending on the performance of the opticaltracking unit. The spatial resolution of thismethod is limited by the precision of the match-


ing procedure by approximately 1�3 mm and theMR voxel size by 1 mm3.

The peak of the electric field, calculated for theŽ .MC-B70 coil Dantec using a spherical head

model, is below the center of the figure-8-coilŽ .Fig. 1 . Therefore, we visualized a line perpen-dicular to the coil surface going through its cen-ter. The line can be lengthened virtually in thedirection of the brain, until the cortex is reached

Žafter 1�2 cm. The slices of all three axes coronal,.sagittal, transversal plane , defined by the end-

point of the line, are visualized on the computerŽ .screen Fig. 3 . Thus, the cortical region in the

peak of the magnetic field is indicated and can bestimulated.

During longer lasting stimulation sessions suchas the application of repetitive TMS in depres-sion, it is important to monitor and to correct thecoil position because of inevitable head move-ments if the head is not fixed. The preparation ofthe stimulation, including the referencing proce-dure, takes approximately 5�10 min.

It is an open question where the neuronaldepolarization effectively takes place in relationto the theoretically calculated peak of the electricfield. However, there is evidence that the depolar-ization occurs focally in the area of the peak ofthe induced electrical field, also depending upon

Žthe local cortical anatomy Amassian et al., 1998;.Ilmoniemi et al., 1999 .

The precision of the navigational method iswithin millimeters and can be easily controlled bypointing to defined anatomical landmarks. Theprecision depends on the resolution of the struc-

Žtural MRI, on the functional neuroimaging if.performed , on the precision of the referencing

procedure of the head in space and of the head inthe MRI, and on the properties of the electricfield and its effect on the cortex.

3. Applications of navigated magnetic stimulation

3.1. Combining functional neuroimaging andna�igated TMS

One application of this method in cognitiveneuroscience is the stimulation of functionally

specified cortical areas, for instance, as revealedby fMRI.

Several studies demonstrated the spatial corre-spondence of TMS and functional neuroimaging

Žwithin a mm range Krings et al., 1997; Boroo-.jerdi et al., 1999; Bastings et al., 1998 . In a

previous study we found that navigated stimula-tion of individual motor cortical areas that areactive during a thumb movement task in fMRIled to a motor response of the M. abductor polli-

Žcis brevis in all eight subjects Herwig et al.,.2000 . Additionally, the spatial relation of the

cortical area that is active in a motor task in thefMRI and the area of magnetically evoked motor

Ž .potentials MEP was studied. The subjects wereŽ .stimulated with an intensity of 120% n�8 and

Ž . Ž .110% n�5 of the motor threshold MT , vary-ing the stimulation positions in 5-mm steps on a5�5 mm grid above the left motor cortex. Thestimulation coordinates were registered online. Aslight spatial offset of the centers of gravity fromfMRI and MEP, with the MEP centers beingconsistently anterior to the centers of fMRI acti-

Ž .vation in mean 7.5 mm , independent of theŽstimulation intensity was found Herwig et al.,

.unpublished observations . The cortical areasfrom which motor responses were obtained wereapproximately 6 cm2 for the 120% MT conditionand approximately 4 cm2 for the 110% MT condi-tion. The centers of gravity were basically thesame at both intensities. These findings underlinethe focal effect of the TMS.

The spatial difference of the MEP center ofgravity and the fMRI center of gravity is put into

Ž .perspective when regarding a the overlap of theŽ .MEP areas with the fMRI activity areas; and b

the fact that the fMRI activity also covered activ-ity of postcentral sensory areas and that the cal-culated center of gravity is therefore shifted dor-sally. However, the exact spatial relation shouldbe worked out further.

ŽIn conjunction with the earlier studies Kringset al., 1997; Boroojerdi et al., 1999; Bastings et al.,

.1998 , these findings support the practical use ofTMS navigation guided by fMRI findings. Severalauthors described applications of TMS in cogni-

Žtive studies Grafman and Wassermann, 1999;.Post et al., 1999; Pascual-Leone et al., 2000 and


also proposed the combination with functionalŽ .neuroimaging Walsh and Cowey, 2000 . Those

applications will gain significance if the stimula-tion is applied in an anatomically and functionallyprecise manner on an individual basis. Specificcortical areas in individual subjects can be identi-fied using fMRI during the performance of neu-ropsychological tasks such as, for instance, work-ing memory paradigms. The identified areas canbe further studied with TMS by navigating thecoil to the identified areas.

3.2. Neurona�igated TMS in clinical studies

One clinical application of the combination ofindividual fMRI responses and magnetic stimula-tion consists of the attempt to treat auditoryhallucinations. The intention is to modulate theactivity in brain areas that are active during audi-tory hallucinations. There is evidence that theseareas correspond to areas that are involved in

Žinner speech processes David, 1999; Dierks et al.,. Ž .1999 . Hoffman et al. 2000 stimulated 12 patients

with auditory hallucinations using low frequencyrTMS. They reported a therapeutic effect. Thegroup positioned the TMS according to the 10�20system over the temporoparietal cortex. The navi-gated stimulation of the individual brain regionsthat are involved in inner speech and the phono-logical loop is proposed to improve therapeuticeffects.

The importance of neuronavigation for target-ing intended brain areas is underlined by thefollowing finding: an antidepressive effect of TMShas been demonstrated by several studies. In al-most all these studies, the DLPFC was selected asthe target site for stimulation, using a standard-ized procedure: first the patient’s motor cortexwas identified, and then the coil was placed 5 cm

Ž .rostrally George et al., 1995 . In order to test thereliability of this procedure, neuronavigation wasused to relate the final coil position to the indi-vidual cortical anatomy. In only 7 of 22 subjectswas the Brodman Area 9 of the DLPFC targeted

Ž .correctly Herwig et al., 2001 . In the remainingsubjects the center of the coil was located moredorsally, as above the premotor cortex. This find-ing demonstrates that the currently practiced

method to locate the DLPFC in antidepressivetreatment is not reliable and should be replacedby navigating procedures that take individual ana-tomy into account. Therapeutic studies with TMSmay also use functional neuroimaging data, suchas hypometabolic prefrontal cortical areas in de-pression, to target the TMS. Further clinical stud-ies have to be conducted in order to evaluatewhether neuronavigated TMS can improve thetherapeutic efficacy of non-stereotactic stimula-tion. The fact that most studies are based onspecific hypotheses regarding functionally in-volved brain regions suggests that neuronavigatedTMS should be used.

4. Conclusion

Real time neuronavigation of transcranial mag-netic stimulation is a practical and comfortablemethod for stimulating individually selected corti-cal areas with high precision. Especially in combi-nation with functional neuroimaging, it enrichesthe spectrum of methods in cognitive neuro-science research and in investigations of psychi-atric and neurological TMS therapies. Positioningthe magnetic coil according to the individual brainanatomy, as with neuronavigation, should becomea standard.

Acknowledgements

Fa. Zeiss, Oberkochen, Germany.

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