KEYWORDS Summary Transcranial magnetic stimulation

(TMS) is a unique method for non-invasive brain

Brain mapping; imaging. The fundamental difference

between TMS and other available non-invasive brain imag-

Motor cortex; ing techniques is that when a

physiological response is evoked by stimulation of a cortical area,

Presurgical that specific cortical area is

causally related to the response. With other imaging methods, it

evaluation; is only possible to detect and map

a brain area that participates in a given task or reaction.

Stroke; TMS has been shown to be

clinically accurate and effective in mapping cortical motor areas and

Depression; applicable to the functional

assessment of motor tracts following stroke, for example. Many

TMS; hundreds of studies have been

published indicating that repetitive TMS (rTMS) may also have

Brain stimulation multiple therapeutic applications.

Techniques and protocols for individually targeting and dos-
ing rTMS urgently need to be
developed in order to ascertain the accuracy, repeatability and
reproducibility required of
TMS in clinical applications. We review the basic concepts behind
navigated TMS and evaluate
the currently accepted physical and physiological factors contribut-
ing to the accuracy and
reproducibility of navigated TMS. The advantages of navigated TMS over
functional MRI in motor
cortex mapping are briefly discussed. Illustrative cases utilizing nav-
igated TMS are shown in
presurgical mapping of the motor cortex, in therapy for depression,
and in the follow-up of
recovery from stroke.
© 2010 Elsevier Masson SAS.
All rights reserved.

Résumé La stimulation
magnétique transcrânienne (SMT) constitue une méthode unique
MOTS CLÉS d’imagerie cérébrale non invasive. La
différence fondamentale entre la SMT et les autres méth-

Cartographie odes d’imagerie non invasives réside

dans le fait que, lorsqu’une réponse physiologique est

cérébrale ; évoquée par la stimulation d’une

région donnée du cortex cérébral, cela signifie que cette
 Cortex moteur ; région spécifique est « causalement »
reliée à la réponse, les autres techniques d’imagerie ne

Évaluation permettant de cartographier que les

régions qui « participent » à une tâche ou une réaction. Par

préchirurgicale ; exemple, on a démontré l’efficacité et

l’utilité clinique de la SMT pour la cartographie des aires
corticales motrices et
l’évaluation des voies motrices après un accident vasculaire cérébral.

∗ Corresponding author.
E-mail address: jarmo.ruohonen@nexstim.com (J. Ruohonen).

0987-7053/$ – see front matter © 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.neucli.2010.01.006

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J. Ruohonen, J. Karhu

Plusieurs centaines d’études

publiées démontrent que la SMT répétitive (SMTr) présente
Accident vasculaire également de multiples applications
thérapeutiques potentielles. Il est urgent, si l’on veut
cérébral ; évaluer l’exactitude, la
répétabilité et la reproductibilité de la SMTr, que l’on dispose de
Dépression ; techniques et de protocoles de
ciblage et de dosage individuel de la SMTr. Dans cet article,
TMS ; nous examinons les concepts de
base sous-tendant la SMT assistée par navigation et évaluons
Stimulation cérébrale les facteurs physiques et physiologiques
considérés comme contribuant à la précision et à la
reproductibilité de la
technique. Nous discutons brièvement des avantages de la SMT assistée
par navigation par rapport à
l’IRM fonctionnelle en vue de la cartographie du cortex moteur.
Nous illustrons cela par des
exemples cliniques d’évaluation préchirurgicale du cortex moteur,
de traitement de la
dépression et du suivi de la récupération d’accidents vasculaires cérébraux.
© 2010 Elsevier Masson SAS.
Tous droits réservés.

Introduction
tumors, edema, bleeding and vascular alterations. Sulcal

patterns may also have a general scientific value when used

Transcranial magnetic stimulation evokes motor responses, collectively to
generate generic brain templates.

detectable using electromyography (EMG), and provides a Even with

easily recognizable individual anatomical land-

unique paradigm for human brain imaging. Physiological marks, our

ability to provide quantitative guidelines — for

responses can only be measured when there is function- example to

functional somatotopic representations — is

ing cortex with intact tracts through the sub-cortical layers limited.
One well-known landmark, the pli de passage fron-

distally to the corresponding muscles. Also, the functional topariétal

moyen (PPFM) [4], manifests as an elevation in

connectivity of the brain can be studied by recording the floor of

the sulcus at its midpoint and is currently thought

TMS-evoked changes in brain’s electric activity using elec- to localize the

somatotopic hand area, which can often be

troencephalography (EEG). Since TMS does not require clearly visualized

as ‘‘omega’’ or the ‘‘hand knob’’ [2,40,41]

active participation of the subject, the method does not on the

cortical surface. However, no quantitative guidelines

suffer from the confounding factors inherent in other func- exist for the
recognition of the PPFM relative to functional

tional brain imaging methods. Additionally, TMS can be

performed equally well on paralyzed, sedated or uncoop-
erative patients in the clinical setting. The capability to
non-invasively probe the cerebral cortex allows applications
ranging from straightforward diagnostic examinations of the
cortical and corticospinal pathways to studies where TMS is
used for the manipulation of complex brain network inter-
actions.

Why do we need individual navigation of TMS?

Clinical applications of TMS will place stringent require-

ments on the accuracy and repeatability of the specific TMS
method chosen. The size and shape of the head and brain,
the distance between the stimulating coil and responding
neuronal tissue as well as the location and orientation of
anatomical structures are all variables that will need to be
defined individually for each patient —asimple TMS method
using standard coil location with respect to external land-
marks of the skull would not be acceptable for preoperative
cortical mapping, for example. Anatomical measurements
of in vivo brain macroscopic anatomy have shown that the
anterior—posterior variation in the location of the central
sulcus with respect to the Talairach coordinate system is
±1.5—2 cm [36] and the variation is likely to be signifi- Figure 1
Anatomical structures are often smeared by brain
cantly larger with respect to external skull landmarks. These pathology;
tumors, oedema, bleeding and vascular alterations.
findings indicate that macroanatomic individuality in the The demands
for accuracy and repeatability require that the
cerebral surface cannot be adequately accounted for by any size and shape of
the head, the distance of the coil and its
proportional coordinates and certainly not by any morpho- location and
orientation with the tissue must be defined indi-
metric landmarks (e.g., [8]). Individual sulcal patterns need vidually. The
reconstructed 3D MR image illustrates lesions near
to be used for clinical purposes where anatomical structures the premotor
areas in the right hemisphere of a stroke patient
are often smeared by brain pathologies (Fig. 1), including (Courtesy of
Dr Kari Dunning, Drake Center, Cincinnati, US).

3
Navigated transcranial magnetic stimulation
9

Figure 2 Navigation for TMS: The individual MR images are aligned to the actual
head of the patient to allow for the visualization
of the E-field on the images. For this purpose, a sensor unit (1) locates the
tracker tools that are attached on the coil and the
reference frames on the forehead of the patient (2). Corresponding landmarks are
identified from the MRI’s and the actual head in
the registration phase (3). Thereby, the coil’s location and orientation are known
with respect to the MRI’s. Some of the navigation
software available can visualize the actual TMS E-field effects in the brain (4).

cortical representations in the central sulcus and, indeed, causes of

variability due to physical factors. Individual,
the variation in functional representations of other body anatomical
image-based navigation of TMS thus allows:
parts or the Broca’s motor speech area may exceed ±1.5 cm
with respect to Talairach coordinates [19].
In addition to spatially accurate information on cortical • definition of the
normal ranges of physiological responses

and clinical variability;

representations, information on the stimulation ‘‘dose’’ is
also needed for clinical applications. Clearly, the strength • definition of the
strength, or ‘‘dose’’, of stimulation in

terms that are applicable anywhere over the cortical man-

of the stimulating magnetic pulse, a simple measurement, tle;
cannot account for the observed large individual variation • definition of cortical
representations when individual
in responses. Currently, the generally accepted method to anatomy is
smeared and does not provide reliable land-
determine the strength of a stimulus is to relate it to
marks.
the motor threshold (MT), measured individually for each
patient, i.e., to the lowest stimulus intensity sufficient to

Navigating electric field (E-field) in the cortex

activate a peripheral muscle when the stimulus is deliv-
ered to the presumed optimal cortical motor representation
area of the muscle. However, there are several theoretical Keeping the
above-mentioned important caveats in mind,

and practical caveats to this approach: the optimal location navigation

solves many of the critical measurement issues

of the stimulating coil is hard to define and repeat while

historically associated with TMS, with some valuable addi-

measuring MT and the MT’s of different muscles, even neigh- tional benefits.
Navigation combines data on anatomical

boring ones, may differ. Additionally, the real effect of the structures
with known delivery of stimulation, forming

stimulus reaching the cortex is completely unknown when the basis for
dose determination and targeting. The core

targeting area other than motor cortical areas. For exam- concept in
navigation is an accurate GPS-like navigator,

ple, the frontal cortical areas are known to atrophy faster where
structural brain maps acquired using MRI’s (Fig. 2) are

than the motor areas with age. As a consequence, natural used in place of
street maps. Metaphorically, just like each

aging may thus render stimulation of the frontal areas inef- country has
its own geography, each person has their own

fective if the stimulus intensity has been adjusted to a level individual

brain topography, with their own unique shapes,
slightly above the threshold for motor responses.
structures and cortical convolutions.

To summarize, methodological and technical factors

may severely obscure the detection and quantification Physics
of underlying physiological processes and confound clin-
ical interpretation. Many of the fundamental issues can A navigated
TMS examination, which utilizes on-line cal-
be resolved by using image-based navigation of stimula- culation and
targeting of stimulus-evoked electric field in
tion according to individual patient brain anatomy. Optimal the brain, E-
field, starts by linking the structural MRI’s,
localization and orientation of stimuli with respect to the preferably
high-resolution scans, to the actual head of the
targeted anatomical structure and maintaining the stim- patient in a
process called registration. Once registration is
uli location in repeated measurements eliminates the root successfully
completed, the stimulation coil can be guided

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J. Ruohonen, J. Karhu

Figure 3 Electric field in the tissue locally triggers action potentials. The
electric field is generated from the magnetic field of the
coil, but a multitude of variables will affect its shape and size before reaching
the neurons. Both fields are invisible, and intuitive
thinking of where stimulation takes place in the brain is likely to fail. Yet,
without knowing the fields, there is no simple way of
knowing where in the brain the coil stimulates. Navigation with electric field
calculators is required to reliably link the macroscopic
responses to the stimulated anatomical structures.

above the structures using optical tracking. The physiologi- trodes. Yet,
the spread of electric fields from the electrodes
cal response to a stimulus is recorded, normally as an EMG is very complex
because the electric current (and field) will
measurement, and temporally linked to the stimulus. At this follow the paths
of least impedance in the tissue, greatly
point, physiology and physics raise an important question: influenced by
macroscopic (e.g., sulci, cerebrospinal fluid)
how does one know the location of the neurons that gener- and microscopic
(e.g., cortical layers, preferred orientation
ated the action potentials that then led to an observed EMG of cells)
factors. In TMS, the interaction is relatively simple:
response? In other words, how can one relate the extracra- the magnetic field
from the coil is perfectly undisturbed by
nial coil location to the resulting intracranial physiological any
tissue variations. In each and every intracranial loca-
processes? How strong and widespread was the stimulation? tion, a magnetic field
will generate (induce) a stimulating
These questions were partly addressed in the early days of electric field.
Macroscopic (e.g., skull shape) and micro-
TMS (e.g., [28]) and the explanations have contributed to scopic (e.g.,
changes in resistivity along the path of the
the current navigation solutions (Fig. 3). E-
field) factors affect the electrical field also in TMS, but
TMS has many similarities to intraoperative stimulation the majority
of the electric field is generated by the undis-
following craniotomy using cortical electrodes. At a concep- turbed primary
magnetic field [30]. This is the main reason
tual level, TMS creates ‘‘virtual electrodes’’ in the brain and why TMS can
be modeled precisely, perhaps more so than
can thereby stimulate neurons. Indeed, the mechanisms of direct
intraoperative electrical stimulation.
action are the same for both methods: a potential differ- A
multitude of variables affect the shape, orientation and
ence (physicists will use the term electric field, E-field) acts size of the
electric field generated by a TMS pulse before it
a force in the tissue that tries to move electrical charges reaches the
targeted neurons. The fields cannot be seen and
(particles, ions, molecules). Because the neuronal cell mem- intuitive
thinking will normally fail to predict the location
brane is intrinsically sensitive to local changes in the electric of the
maximal field. Again, the literature is of help: the
potential along the path of the axon, wherever the elec- E-field can be
closely estimated when the following vari-
tric field is of adequate strength and suitable direction, it ables are
well known: the shape and size of the copper
will excite the neurons and trigger action potentials. It is windings
in the coil, the size and shape of the head, the
worth mentioning that while much of the literature uses electrical
characteristics of the stimulator, and the exact
the terms electrical current and electric field interchange- location and
orientation of the coil with respect to the head
ably, the electrical current is only a by-product resulting [29,30].
Note that the electrical conductivity of the tissue
from the electric field forcing the movement of electri- is not
listed here. In fact, the nearly spherical shape of the
cally charged ions in the tissue. An electric field can exist head
reduces the absolute value of electrical conductivity
without an electrical current, for instance where a cellu- to a
secondary role, at least when spherical head models are
lar membrane prevents a flow of ions and hence a current used that account
for the local variation in the head curva-
flowing. Therefore, it is not primarily the electric current ture.
Brain lesions do have an effect on E-fields, but even
that needs to be known in TMS, but rather the electric then the
prominent features of the E-field are determined
field.
primarily by the coil-to-head distance, coil orientation and
Above, we have described that an electric field is the local
skull shape.
required to excite neurons and that electrical and magnetic A 3D
navigation unit can be used to locate just the coil
stimulation are essentially equivalent techniques of neu- outside the
head, but, as can be inferred from the above
ronal stimulation. In the case of electrodes placed directly list, such
simplistic navigation will not provide information
in the brain, it is intuitive to assume, correctly, that the about
the intracranial location and spread of the stimulating
field is the strongest in the immediate vicinity of the elec- E-field.

5
Navigated transcranial magnetic stimulation
11

Physiology
bending/tapering of white matter structures. When a TMS-

induced E-field causes sufficient membrane depolarization,

It has been historically established that neurons are excited action
potentials are generated, leading to synaptic trans-
at lower thresholds when applied voltages induce currents mission and
excitatory or inhibitory postsynaptic potentials
oriented longitudinally along the axon rather than trans- (EPSPs or
IPSPs, respectively). With sufficiently strong TMS
versely across the axon [11,27,31]. Electrical stimulation has intensity, it
is possible to reach subcortical structures and
been found to be most effective when the applied current the cerebellum.
has the same orientation and timing as the normal flow of Finally,
the event-related potential (ERP) and magne-
post-synaptic current during depolarization: from dendrites,
toencephalography (MEG) literature have both repeatedly
through soma, and to the axon. In the application of TMS, addressed the
same issue of electric current location and
the threshold for excitation has been found to be similarly direction in
normal cortical network excitation. The over-
sensitive to orientation [3,22], with optimal responses when whelming
consensus is that virtually all measurable current
the induced current was oriented 45◦ medial to the antero- flows normal to
the cortical surface [9]. Taking into account
posterior plane. Although neither of these early TMS studies the converse
relationship between MEG and TMS [29,30],
used a navigation method to confirm the underlying surface the literature
provides further support for the hypothesis
anatomy, researchers interpreted this orientation as indi- that the
cortex is most sensitive to E-fields that are directed
cating that optimal stimulation of the primary motor cortex
perpendicularly to the cortical surface.
was achieved when the induced current was perpendicular The above
principles imply that navigated TMS is most
to the central sulcus, a finding that has been confirmed in effectively
applied by orienting the E-field longitudinally
later studies.
and orthodromically to the greatest possible number of
 With a flat TMS coil placed tangentially to the scalp, the neurons at
the site of interest. Since the human cortex
induced E-field is also tangential to the scalp. At the crown has a
generally uniform, columnar structure, the E-field
of the precentral gyrus the E-field is consequently in a plane should
therefore be targeted perpendicularly to the closest
horizontal to the radial alignment of the cortical columns. underlying
sulcus. However, the in vivo empirical evidence
Accordingly, Day et al. [11] hypothesized that TMS stim- supporting
this principle is still insufficient.
ulation must be exciting the tangentially oriented neural
elements at the gyral crown, such as horizontal interneu- Accuracy of navigation in
TMS
rons or horizontal collaterals of pyramidal track axons. This
hypothesis was based on the assumption that induced cur- The key
performance criterion for navigation is spatial accu-
rents are stronger in the proximity of the coil to a degree racy.
Published literature on navigation (as well as that of
that outweighs all other factors [11]. As sensitive as the E- non-
navigated TMS) currently lacks a discussion of accu-
field in the brain is to the distance between the coil and racy. The
determination of accuracy needs to be approached
the targeted area, this assumption clearly disagrees with from an
accepted definition: accuracy is the closeness of the
the orientation selectivity observed by Brasil-Neto et al. [3] predicted
and true locations. In TMS, accuracy is therefore
and Mills et al. [22]. Horizontal fibers extend uniformly in the
distance (in millimeter), from the visualized ‘‘hotspot’’
all directions within a plane parallel to the cortical sur-
location to the location of the stimulated group of neurons.
face and this isotropism should translate into a lack of a The
hotspot, in turn, is defined as the location of the calcu-
preferred orientation for TMS, as the induced E-field should lated strongest
E-field that the navigator visualizes on the
excite an equivalent fraction of the fiber population in any individual
MRI of the cortex. By necessity, the accuracy of a
orientation.
navigation unit, as a system, is an aggregate sum of multiple
The observed sensitivity of TMS responses to the orien- factors. Below,
we divide the components of accuracy into
tation of the coil with respect to the central sulcus suggests four groups,
each group independently contributing to the
that the predominant activation mechanisms are related to visualized
location of the hotspot:
the trajectories of the pyramidal tract axons and the E-field
direction along the cortical columns. Increasing the total • Coil localization:
length of neuronal membrane exposed to an applied cur- ◦ 3D localization technique
to locate the coil and refer-
rent lowers the depolarization threshold and orthodromic ence
trackers (normally optical or electromagnetic),
current is more effective than antidromic current, which, ◦ Manufacturing
tolerances of the coil and trackers;
in turn, is more effective than transverse current [27,31]. • Movement of the
reference tracker during examinations:
Hence, aligning the E-field with a cortical column (along the movement
affects the detected coil position and thereby
long axis of the preponderance of neurons) exposes the max- the calculated
intracranial E-fields;
imum membrane length of the maximum number of neurons • E-field computation model:
to the exciting stimulus. When an optimally oriented E-field ◦ errors in the coil’s
output field, unknown and/or varying
is applied to cortex, the site of action-potential initiation is
coil characteristics: shape, size, details of the copper
in, or near, the soma [15,20,27]. More confirmation of the
windings,
role of somal initiation and axonal bends has been provided ◦ computational model
of the E-field (e.g., numerical
by modeling the effects of uniform E-fields [38]. It is likely
uncertainties, simplified tissue characteristics),
that several competing mechanisms of action are at work in ◦ fitting of the
computational model to the individual
TMS, as demonstrated in a modeling study by Silva et al. [35]. head;
Suprathreshold stimulation may result in the activation • Errors in alignment
of anatomical images to live situation:
of both transsynaptic pathways and the direct stimulation ◦ registration algorithm
that aligns the individual head
of axonal pathways deeper in the gray matter or in the MRI’s
and the live head,

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J. Ruohonen, J. Karhu

Table 1 Error sources contributing to accuracy.

Error source
Mean error in E-field hotspot (mm)

Coil localization
Optical tracking
1.6
Manufacturing tolerances

Movement of the head tracker during an examination

3.1

E-field computation model

The coil’s output and characteristics
3.8
Model of the intracranial E-field
Fitting of the model to individual head

Registration to anatomical MRI’s

MRI image imperfections
2.5
Registration algorithms

System accuracy

Root square sum of all errors sources #(1.6)2 + (3.1)2 + (3.8)2 + (2.5)2
5.7

The values are for Nexstim eXimia NBS system. Listed values are the effect of
each error or error group on the exact location of the
maximal E-field in the cerebral cortex.
 ◦ limited resolution of the MRI and distortions from the Navigated TMS and
functional MRI for motor cortex
true anatomy.
mapping

Total accuracy is obtained from the root sum of the Navigated

TMS enables active cartography of the functional
squares of the above uncertainties from all sources, quan- regions of the
brain in which a cortical region is stimulated
tified for use under true or simulated clinical, rather than and
responses are observed. MRI’s provide the structural
laboratory conditions. In the published literature, only the information
and navigated TMS provides the functional
accuracy of optical tracking is usually reported, rather than map.
total accuracy. Optical tracking error can be as good as
Functional MRI (fMRI) is widely available for functional
0.2 mm (RMS), but this is clearly misleading as this source brain mapping
and is occasionally used for motor cortex
of error represents a negligible component of total error. mapping,
although it is acknowledged to have great lim-
Precision, defined as the degree to which a previous loca- itations in
clinical work. Comparisons between navigated
tion can be repeated, is not the same as accuracy. In TMS TMS and fMRI
techniques on healthy volunteers are fea-
navigation, precision is significantly better than accuracy, sible (Fig.
4). In comparing and interpreting the results,
since many of the error sources direct to the same direction the fundamental
differences in the respective methodolo-
in repeat stimulations; these sources include uncertainties gies need to
be considered. Whereas TMS directly and
inherent in E-field calculation and MR-image distortions. causally
assesses the corticospinal pathways and the cor-
Table 1 lists the factors contributing to the accuracy of a tical
patches connected to them, fMRI reveals blood oxygen
navigated TMS system, the eXimia NBS System (Nexstim Oy, level dependency (BOLD)
signal changes, presumed to be
Helsinki, Finland). The authors were not able to find other due to
voluntary movements in response to operator com-
manufacturers’ equivalent specifications, but hopefully they mands. fMRI
therefore lacks information about causality.
are/become available to other users and researchers. The Since the
comparative literature is scarce, we are limited to
specified accuracy of the eXimia NBS System is 5.7 mm, that our own recent study
[23], where the primary representa-
is, in clinical use, the expected mean distance from the visu- tion areas of
50 muscles were mapped in 14 healthy subjects
alized hotspot to the true stimulated region of neurons is using both
methods. In this study, the distance from the
5.7 mm. It is likely that there are large variations in accuracy localization
found by navigated TMS (eXimia NBS System)
between various systems from different manufacturers. It is to the area of
activation found by fMRI was 3.7 ± 4.85 mm
important to note that the accuracy of a TMS navigation sys- (mean ± standard
deviation), with range 0—21.7 mm. The
tem without E-field-based navigation cannot be determined: distance reported
is the distance between the results of
if the predicted location of stimulation is not visualized, a the two
methods (agreement) and is not the distance to
given measure for the distance to the true location is mean- the ‘‘true
location’’ (accuracy). Agreement includes errors
ingless.
from both sources. If one assumes that the observations

are explained in both methods by normally distributed

Applications of navigated TMS
errors of the same magnitude, the study suggests that

the accuracy of navigated TMS and fMRI localization in

Below, the representative cases are discussed to illustrate healthy
subjects are both approximately 4—6 mm (mean
some of the applications for navigated TMS. error).

7
Navigated transcranial magnetic stimulation
13

Neurosurgery

Intraoperative direct cortical stimulation (DCS) is considered

the gold standard method for neurosurgical mapping. In the

literature, it is agreed that all non-invasive presurgical map-

ping methods should be compared to DCS. In their recent

abstracts, Picht et al. [25,26] and Forster et al. [13] have

independently compared E-field based navigated TMS to DCS

mapping; to date, the two groups have combined experience

from mapping approximately 50 brain tumor patients (per-

sonal communications, data to be published). Fig. 5 shows an

illustrative case, courtesy of Dr Thomas Picht. Both groups

observed a high degree of agreement between the results of

motor mapping with DCS and navigated TMS, where agree-

ment is defined as the distance between localizations of

the same cortical representation using both methods on the

same patients. The data indicate comparable accuracies for

both DCS and navigated TMS mapping. When mapping can-

didates for epilepsy surgery, Vitikainen et al. [39] have also

Figure 4 Thumb abduction fMRI (p < 0.05) shows a high degree found consistent
localization results using navigated TMS,
of overlap with NBS motor mapping results for APB muscle in DCS and
magnetoencephalography methods. Fujiki et al.
this normal subject. The colored region is the fMRI activation [16] reported
the use of navigated TMS in a patient with
whereas the smaller dots denote the location of the maximal meningioma,
concluding that preoperative TMS mapping
stimulation for each TMS pulse. The dot colors represent the has the potential
to explore anatomic shift, physiologic re-
MEP response size for each stimulus: gray: no response; pink: organization and
plastic changes to establish the degree of
weak response; red: strongest response. The dark-red arrow remaining
functionality in the motor cortex after long-term
at right angle with the central sulcus is the direction of the physical
compression and deviation in tumors. In Decem-
electric field for the TMS pulse that elicited the strongest MEP. ber 2009, the
food and drug administration (FDA) cleared
In patients, differences between fMRI and NBS can be greater the eXimia NBS
System for marketing and sale in the USA
because of altered functional anatomy or blood flow (courtesy for use in the
assessment of the primary motor cortex in
of Tuomas Neuvonen, Nexstim Ltd, Finland.). patients
prior to neurosurgery. Notably, the FDA clearance

was granted for use of navigated TMS as the sole method of

pre-surgical cortical mapping, not simply as an adjunct tool.

Figure 5 Mapping results using intraoperative direct cortical stimulation (DCS)

(left) and navigated TMS (right) in a patient with a
metastatic brain tumor near the central fissure. Blue and red dots indicate cortical
sites with DCS motor responses (left) and orange
dots indicate navigated TMS motor responses (right). There is a good agreement
between the methods (courtesy of Thomas Picht,
Neurosurgery, Charité, Berlin).

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J. Ruohonen, J. Karhu

Figure 6 The importance of navigation in therapeutic uses is illustrated in this

case report by Lefaucheur et al. [21]. Non-
navigated rTMS used the standard procedure of placing the coil 5cm anterior to the
primary motor representation of the right
thumb. Navigated targeting of the DLPFC (BA 48) resulted in 3.3 cm more anterior
positioning and better therapeutic effect.

Reproduced from [21].

Therapy
quantifying the remaining capacity of the motor cortex and

the corticospinal tract to generate muscular activity [24]

Repetitive TMS (rTMS) has been shown to have a potential (Fig. 7). TMS
appears especially suitable for locating corti-
therapeutic effect in several psychiatric and neurological cal
structures that provide a viable pathway to the muscles.
illnesses as well as in stroke and pain. In October 2008, It is logical
to assume that navigation is indispensable in
the FDA approved rTMS in the USA for the treatment of these
applications. For instance, post-stroke neuronal plas-
major depressive disorder in adults who have failed at least ticity may be
linked to shifting of the primary representation
one antidepressant medication. This approval is likely to areas.
Moreover, given that 70% of the corticospinal (pyra-
increase also other therapeutic uses of rTMS. A frequent midal) tract
fibers arise from the supplementary motor area
challenge in the treatment of psychiatric diseases is to find (SMA), the
premotor cortex (PMC) and primary somatosen-
the optimal medication and dose for each individual patient. sory cortex
(S1) and only 30% from the primary motor cortex
Therefore, it is logical to also expect that rTMS therapies will (M1) [34],
compensatory mechanisms are likely to involve
face corresponding challenges. In case of rTMS, the chal- other cortical
areas. Using navigated TMS, Teitti et al. [37]
lenges are those of finding the optimal location and dose. have in fact
shown that non-primary motor areas (Brodmann
In fact, despite multiple successful investigations showing areas 6 and
8) have direct projections to lower motor neu-
positive effects of rTMS in depression, recent reports have rons. Navigated
TMS can therefore not only help locate the
indicated that non-responders may have received rTMS to origins of signal
pathways with ‘‘least resistance’’ to the
suboptimal locations (illustrative case in Fig. 6) [18,21]. muscles,
but also to quantify the strength and nature of
Navigation can help identify the optimal brain structures these and
other possibly complementary pathways.
for targeting rTMS [12,18,21], but solving this problem still
leaves the question of dose optimization. While specific
pulse train parameters have been extensively reviewed in Discussion
the literature, there is little knowledge of the intracranial
strength of applied stimulation and dose-response behavior. Clinical use of
TMS calls for the careful minimization of
It is to be expected that the induced electric field differs known
physical and non-physiological sources of variability.
greatly in patients with different head and brain shapes and Locating the
TMS coil only with respect to the head or the
of various ages. Further studies that employ E-field as the brain is
inadequate, it is critical to know the intracranial
basis for dosing rTMS therapy are anticipated. location
of the E-field and its orientation with respect to

the cortical structures. In order to define the ‘‘dose’’ of

Stroke
stimulation, we also need information on the strength of

the applied electric field at varying depths in the cortex and

MEP’s have predictive value in post-stroke motor recov- at varying
distances from the stimulating coil, as well as
ery [6]. Post-stroke motor recovery is related to recovered with respect
to the anatomical structure of the individual
neuronal capacity in the lesioned areas as well as compen- cortex. These
fundamental issues can all be solved by the
satory mechanisms. MEP’s may have an important role in appropriate
application of navigation techniques to TMS.

9
Navigated transcranial magnetic stimulation
15
Figure 7 A 74-year-old, physically active patient experienced sudden weakness and a
partial paresis of the left leg and arm.
Acute subcortical stroke affected the left-side corticospinal tracts. When cortex
was stimulated at the known leg representation
area using the navigated brain stimulation, muscle responses could be registered at
the acute stage. This enabled the intensive
rehabilitation of leg functions and follow-up of the development of muscle
responses by exact targeting to the original stimulation
site. The recovery process could be evaluated objectively and in a clinically
useful fashion (courtesy of Prof. Sivenius, Brain research
and rehabilitation center Neuron, Finland).

Stimulating the optimal site

Stability, repetition

The largest source of variability in TMS measurements is Unintended

movement of the coil during measurement is
likely to be inaccurate coil positioning, in other words another
large source of variability in non-navigated TMS.
misplacing the coil such that a different cortical area is Minor
movements in the position or angulation of a coil will
stimulated to the one intended by the operator. The identi- change the
stimulus location as well as the strength of the
fication of a TMS target site on the cortex has traditionally field applied
in the cortex [10]. Coil movement may, for
been based on the measuring the distances in centimeters example, hide
clinically relevant changes in cortical plas-
from external landmarks (e.g., [7]). As discussed above, ticity or
excitability. The use of external fixation devices
this simple approach inaccurately relates stimulation loci for stable
coil positioning in non-navigated TMS has been
with intracranial anatomies and cannot take into account suggested, but
such a method also requires fixation of the
individual differences in brain size, anatomy, or cortical head,
which is difficult procedure and uncomfortable for
morphology. Indeed, it has recently been shown that the the patient.
Coil movement is particularly problematic when
golden standard for therapeutic frontal lobe stimulation determining
MT, since movement may cause an increased,
in depression, placing the coil 5cm anterior to the corti- erroneous
MT to be measured, as well as causing the entire
cal representation of the thumb, may lead to stimulation procedure to
be prolonged. The high precision of current
of a wide variety of cortical areas — leading to a wide
commercially available navigation devices enables the focus
range of clinical outcomes [18]. The introduction of nav- of the
stimulating field to be maintained within an area
igation methods has shown that even minor changes in several
millimetres across, improving the repeatability of
coil location and orientation significantly affect at least the
MEP’s [32] elicited. Similar precision can be achieved
MEP’s [33], TMS-evoked EEG [5] and blocking of sensations repeatedly in
longitudinal studies, which require return to
[17].
the same stimulus location in follow-up examinations. The

10
16
J. Ruohonen, J. Karhu

inherent capability of navigation to correct for transient epilepsy

or chronic pain implants. Other clinical applications
changes in the coil/head relationship in real-time is likely include
objective post-stroke quantification of motor tract
to greatly facilitate clinical trials with navigated TMS.
integrity and assessment of motor recovery from stroke.

Therapeutic applications of rTMS are expected to benefit

Dose
greatly from the knowledge and documentation of the E-

field dose administered during treatment.

TMS has its strongest effect on neurons where the induced
electric field is strongest. The E-field can, therefore, be Conflict of interest
statement
considered the stimulation dose. When the stimulating time-
varying magnetic field pulse enters the brain, there is a J.R. is
employed fully and J.K. partially by Nexstim Ltd., a
complex interaction between the field and the head and the manufacturer of
navigated brain stimulation systems.
brain anatomies that sum up to determine the stimulating
electric field in the brain. Factors such as the individual skull Acknowledgements
shape and scalp-cortex distances determine the spread and
direction of the E-field in the brain. Additionally, there are

We thank Dr Tomas Picht, Charite Mitte, Berlin, Germany,

complex interactions between the electric field and neu-

Dr Jean-Pascal Lefaucheur, hôpital Henri Mondor, Creteil,

ronal tissues.

France, Dr Kari Dunning, Drake Center, Cincinnati, US, and

When taking into account the direction of the electric

Tuomas Neuvonen and Henri Hannula, Nexstim Ltd. for data

field with respect to the underlying anatomy, it has been

and images used in this report and Sean Donovan for English
observed that a TMS-induced electric field is most effec-

editing.
tive when the field is perpendicular to the cortex and
directed into it, i.e., from the dendrites toward the soma

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