Neurophysiologie Clinique/Clinical Neurophysiology (2007) 37, 373382

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journal homepage: http://france.elsevier.com/direct/neucli

REVIEW/MISE AU POINT

Contribution of cortical and subcortical

electrostimulation in brain glioma surgery:
Methodological and functional considerations
Int
er
et des stimulations
electriques corticales et
sous-corticales dans la chirurgie des gliomes
c
er
ebraux : consid
erations m
ethodologiques et
fonctionnelles
H. Duffau
D
epartement de neurochirurgie, Inserm U678, h
opital Gui-de-Chauliac, CHU de Montpellier, 80, avenue Augustin-Fliche, 34295
Montpellier cedex 5, France
Received 5 September 2007; accepted 9 September 2007
Available online 11 October 2007

KEYWORDS
Brain mapping;
Connectivity;
Plasticity;
Intraoperative
electrical
stimulation;
Surgery;
Glioma

Summary The aim of brain glioma surgery is to maximize the quality of resection, while minimizing the risk of sequelae. Due to the frequent location of gliomas in eloquent areas and
because of major interindividual anatomofunctional variability, the cortical functional organization, effective connectivity and potential for plasticity must be studied for each patient
individually. Consequently, in addition to preoperative functional neuroimaging, intraoperative electrostimulation (IES) can be used, under general anesthesia for motor mapping or on
awake patient for language and cognitive mapping. This is an easy, accurate, reliable, and safe
technique of detection of both cortical and subcortical functionally essential structures. Thus,
IES enables: (i) to study the individual cortical functional organization before any resection;
(ii) to understand the pathophysiology of areas involved by gliomas; (iii) to map the subcortical structures along the resection, allowing a study of the anatomofunctional connectivity;
(iv) to analyze the mechanisms of on-line short-term plasticity, using repeated IES; (v) to tailor the resection according to individual cortico-subcortical functional boundaries, enabling to
optimize the benet:risk ratio of surgery. Moreover, IES can be combined with perioperative
functional neuroimaging, before and after surgery, to validate these noninvasive techniques
and to better understand the short-term and long-term plasticity mechanisms based on functional cortical reshaping and connectivity changes. Such individual knowledge allows planning

E-mail address: h-duffau@chu-montpellier.fr.

0987-7053/$ see front matter 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.neucli.2007.09.003

374

H. Duffau
multiple-stages surgery. In conclusion, IES enables to increase the impact of surgery on the
natural history of gliomas, to preserve the quality of life, and to better understand the dynamic
functional anatomy of the brain.
2007 Elsevier Masson SAS. All rights reserved.

MOTS CL
ES
Cartographie
c
er
ebrale ;
Connectivit
e;
Plasticit
e;
Stimulations
lectriques
e
perop
eratoires ;
Chirurgie ;
Gliome

R
esum
e Le but de la chirurgie des gliomes c
er
ebraux est de maximiser la qualit
e de la
r
esection, tout en minimisant le risque de s
equelles. En raison de la localisation fr
equente
loquentes , et du fait dune variabilit
des gliomes en aires e
e anatomofonctionnelle
interindividuelle majeure, lorganisation fonctionnelle corticale, la connectivit
e effective
tre e
tudi
et le potentiel de plasticit
e doivent e
es pour chaque patient individuellement.
Par cons
equent, en compl
ement de limagerie fonctionnelle pr
eop
eratoire, les stimulations
lectriques perop
tre utilis
e
eratoires peuvent e
ees, soit sous anesth
esie g
en
erale pour une carveill
tographie motrice, soit chez des patients e
es pour une cartographie langagi`
ere et cognitive.
` la fois des structures corIl sagit dune technique facile, pr
ecise, able et s
ure de d
etection a
ticales et sous-corticales fonctionnellement essentielles. Ainsi, les stimulations perop
eratoires
permettent : (i) d
etudier lorganisation corticale fonctionnelle individuelle avant la r
esection ;
(ii) de mieux comprendre la physiopathologie des aires inltr
ees par les gliomes ; (iii) de cartographier les structures sous-corticales tout au long de lex
er`
ese, permettant l
etude de la
` court
connectivit
e anatomofonctionnelle ; (iv) danalyser les m
ecanismes de plasticit
e aigu
ea
` laide de stimulations r
terme, a
ep
et
ees ; (v) dadapter la r
esection selon des limites fonctionnelles cortico-sous-corticales individuelles, permettant doptimiser le rapport b
en
ece/risque
tre coupl
` limagerie
de la chirurgie. De plus, les stimulations perop
eratoires peuvent e
ees a
` savoir avant et apr`
neurofonctionnelle p
eriop
eratoire, a
es chirurgie, an de valider ces tech` court et a
` long
niques non invasives et de mieux comprendre les m
ecanismes de plasticit
ea
terme sous-tendus par une redistribution fonctionnelle corticale et par une r
eorganisation de la
` l
connectivit
e. Une telle connaissance a
echelon individuel peut ainsi d
eboucher sur une planilectriques perop
cation de chirurgie en plusieurs temps. En r
esum
e, les stimulations e
eratoires
permettent doptimiser limpact de la chirurgie sur lhistoire naturelle des gliomes, tout en
pr
eservant la qualit
e de vie et en am
eliorant la compr
ehension de lanatomie fonctionnelle
dynamique du cerveau.
2007 Elsevier Masson SAS. All rights reserved.

Introduction
Maximal resection of brain glioma, when possible, currently
appears the rst treatment choice to inuence the natural history of this tumor [4,10,29,44,49,50,71]. Thus, the
double goal of surgery is to maximize the quality of resection, while minimizing the operative risk [31]. Nonetheless,
due to the frequent location of supratentorial gliomas near
or within the so-called eloquent areas [25] and due
to their inltrative feature (poorly demarcated), it was
for a long time considered that the chances to perform
an extensive glioma removal were low, whereas the risk
to induce postoperative sequelae was high. Indeed, many
surgical series reported a rate of permanent and severe
decit between 13 and 27.5% following removal of intraaxial tumors [6,8,68,75]. Consequently, the indications of
glioma resection are still controversial [78].
Therefore, to optimize the benet:risk ratio of surgery,
functional mapping methods were extensively used in the
last decade. Indeed, considerable interindividual anatomofunctional variability was demonstrated in healthy
volunteers [7,74]. Furthermore, this variability is higher in
cases of gliomas [20]. It is thus mandatory to study for
each patient: (i) the cortical functional organization; (ii)
the effective connectivity and (iii) the potentiality for brain
plasticity, in order to tailor the resection, according to not
only oncological, but also to cortico-subcortical functional
boundaries.

The aim of this article is to review how the method of

intraoperative electrical stimulation (IES) has enabled to
improve the results of glioma surgery, both concerning the
impact on the natural history of the tumor and the preservation of the quality of life. Some fundamental implications
of IES will also be considered.

Methods of functional brain mapping:

advantages and limitations
Preoperative neurofunctional imaging
Advances in functional neuroimaging (FNI) have allowed performing a noninvasive cortical mapping of the whole brain
[76]. FNI gives an estimation of the location of the eloquent
areas in relation to the glioma and informs on hemispheric
language lateralization. These individual data enable both
better to select the surgical indications, depending on the
assessment of feasibility of tumor resection [36] and to plan
the best surgical approach and the limits of resection, in
order to avoid any damage of the functional cortex. This
helps decrease the surgical risk. Nevertheless, accumulating evidence indicates that the reliability of FNI is still not
optimal despite constant effort to improve it (sensitivity
ranging from 82100% for the identication of sensorimotor
sites, but only around 66% for the idencation of the language areas) [67]. Notably, bold response in the vicinity of
gliomas does not reect the neuronal signal as accurately as

Intraoperative electrostimulation in neurooncology

it does in healthy tissue, due to neurovascular decoupling
[2]. Moreover, FNI is not able to differentiate these areas
that are essential for the function, which should be surgically preserved, from those modulatory areas, which
can be functionally compensated and therefore, potentially
resected without permanent decit [20].
Intraoperatively, the integration of multimodal imaging
into frameless stereotactic surgery was extensively used
and referred to as functional neuronavigation [59]. However, there is a high risk of intraoperative brain shift, due
to surgical retraction, mass effect, gravity and extent of
resection or cerebrospinal uid leakage [65]. Several technical improvements were proposed to reduce the effects
of this shift, but their reliability has still to be optimized:
combination with intraoperative ultrasound, producing realtime imaging; use of mathematical models based on data
from ultrasonography or digital images that track cortical
displacement and intraoperative MRI [45].
The recent development of the diffusion tensor imaging (DTI) has also allowed identifying the main bundles and
their location in relation to the glioma. However, this new
method needs to be validated before it can be used routinely for surgical planning, especially because results of DTI
strongly depend on the biomathematical model that is used
for ber tracking [46]. Moreover, DTI enables the study of
the sole anatomy of the subcortical pathways, but not of
their function.
Consequently, despite its progress, FNI still has limitations, which makes it mandatory to use additional invasive
electrophysiological investigations for glioma surgery in eloquent structures.

Intraoperative electrophysiological investigations

Some methods rely on surface recordings. Thus, somatosensory evoked potentials were extensively used for tumor
resection within the central region [8,66]. Nonetheless,
their reliability is not optimal, since the accurate localization of the central sulcus has been reported only between
91 and 94% [8,66], with an overall sensitivity and negative
predictive value of 79 and 96%, respectively [79]. Moreover,
phase-reversal recording identies only the central sulcus
itself, but does not provide any direct information on the
precise organization of the retro- and precentral cortices.
As regards motor evoked potentials, even if this method has
been improved [58], only the monitored muscles can be controlled, that is, the technique does not allow detecting and
avoiding motor decits in nonmonitored muscles. Finally,
intraoperative evoked potentials cannot currently be used to
quickly and reliably map langague, memory, or other higher
functions.
Second, extraoperative electrophysiological recording
and stimulation were also perfomed through implanted subdural grids [48]. The patient may perform the tasks in his
room, that is, in optimal conditions: this point is particularly important for children [9]. Moreover, recent advances
in the interpretation of electrophysiological signals, such
as electrocorticographic spectral analysis evaluating the
event-related synchronization in specic frequency bands
[11], have allowed both a better understanding of the
organization of the functional cortex and a study of its con-

375
nectivity, especially via the recording of cortico-cortical
evoked potential [54]. However, extraoperative electrophysiological mapping usually used grids with 1 cm-spaced
electrodes, thus with a limited accuracy. In addition, two
surgical procedures are necessary, one to put grids and a
second one to resect the lesion. Furthermore, the prolonged
implantation of subdural grids may induce infection [61].
Finally, extraoperative mapping does not enable to map the
subcortical structures, while gliomas migrate along white
matter tracts [52].
Consequently, taking into account not only the advantages, but also the limits of these different mapping
techniques, the additional use of IES is still mandatory
[3,5,12,29,55,62,63,67,69,72,77].

Methodology of intraoperative electrostimulation

Principles of stimulation
The membrane potential (MP) of the neuron at rest varies
between 60 and 100 mV, because of an asymmetrical
distribution of charges, which is maintained by active mechanisms and ion diffusion through lipid layers: negative
charges predominate at the inner side of the membrane and
positive charges at the outer side. The principle of electrical stimulations is to increase membrane excitability, via
an initial phase of passive modication of the local MP in
front of the cathode (the negative stimulating electrode),
making the inner side of the membrane progressively less
negative, that is membrane depolarization. Conversely, the
membrane becomes hyperpolarized in front of the anode.
The intensity of this phenomenon depends both on stimulation parameters and membrane characteristics [43]. Indeed,
membrane excitability if higher at the initial segment of
the axon, and for larger and myelinated bers [64]. As soon
as the MP reaches the depolarization threshold, a second
phase starts with the opening of voltage-dependent ionic
canals, which allow entry of Na+ ions and inverts the MP
between +20 and +30 mV. A secondary output of K+ ions,
associated with an inhibition of the ux of entering Na+
ions, brings the MP back to its resting state. This corresponds
to the action potential, which corresponds to an all-ornothing phenomenon, that is, once generated, it has always
the same characteristics, irrespective of the stimulation
parameters.
Stimulation parameters: theoretical approach
An electrical stimulation is dened by its intensity (mA)
and its impulse duration (ms). The product of both parameters gives the charge represented in coulombs (C), or
in C/phase in case of a biphasic current with alternating
polarity. Charge density (or charge per unit of stimulated
surface area) is expressed in C/cm2 /phase. The product
[intensity resistance (or impedance, expressed in ohms)]
gives the voltage (V). The product (charge voltage) gives
the energy, expressed in Joules (J)/phase.
First and above all, these stimulations must be entirely
safe for the cerebral parenchyma. Indeed, these stimulations could induce a lesion by accumulation of negative
charge at the level of the cathode or through production of
metal ions at the level of the anode [1]. This risk has been
cancelled thanks to the use of biphasic impulses, since the

376
second stimulus phase inverses the effects of the rst. Tissue
damage can also be caused, on the one hand, by excessive
heat, which is produced specically by hydrolysis that could
cause vacuolization and chromatolysis; and on the other
hand, by leaking of the intracellular current, which goes
from the anode to the cathode through the cytoplasm, with a
risk of lesion to the mitochondria and endoplasmic reticulum
or even by alteration in homeostasis, when the neurons are
activated in a manner that is too repetitive and synchronous
[80]. These risks are directly linked to charge density,
and studies based on animal experimentation allowed an
upper safety limit to be set at 55 microcoulombs/cm2 /phase
[40]. Stimulations may also generate seizures, whose frequency has been estimated between 5 and 20%. To prevent
this complication, it is recommended to perform simultaneous electrocorticographic recording and never exceed
the threshold for after-discharge occurrence. However, the nonmyelination of bers in young children may
sometimes necessitate to increase the intensity of stimulation beyond this threshold, in order to induce functional
response [42].
The second requirement for these stimulations is that
they set off a reproducible response when they are applied
to neural structures. The relationship between stimulation parameters and tissue response characteristics can be
summed up by the intensity/duration curve, in which the
current intensity is recorded as a function of impulse duration [42]. The rheobasis is thus dened as the minimal
intensity that is required to generate an action potential
for high impulse durations. The chronaxis is the impulse
duration that is required to induce a response when the
stimulus intensity is double the rheobasis. The chronaxis
corresponds to the point on the intensity/duration curve
where an action potential can be obtained with minimal
energy: this is the optimal stimulation point (best benet:risk ratio). The chronaxis depends on the characteristics
of the tissue being stimulated, particularly its impedance.
The infrequent studies that were made in this area [38] produced resistance values of 250  for gray matter, 500  for
white matter and 65  for cerebrospinal uid [57]. Moreover,
chronaxis is signicantly modied by the degree of cerebral
maturation, notably by myelination: chronaxis is considerably longer (0.43.5 ms) for nonmyelined nerve bers than
myelined axons (0.050.4 ms) [42]. Fiber diameter seems
also to be a factor, as axons of greater diameter are more
easily excitable [64]. Further, impedance can be modied
by anesthesia. Finally, any pathological process, whether
lesional (tumor) or nonlesional (epilepsy, postictal status),
can interfere directly with tissues excitability [43].
As regards the frequency of electrical impulses, myelinated axons produce a single response for each stimulus
delivered between 50 and 100 Hz [43]. Actually, the absolute refractory period of the neuronal membrane covers a
period of 0.6 to 2 ms, following the action potential. It is
followed by a second phase of transient hyperexcitability,
where the tissue can be stimulated by less intense currents
than for the preceding stimulus, which implies a greater risk
of seizure. Moreover, when neural structures are kept in a
state of subthreshold depolarization, there is an increase of
the MP threshold that must be reached in order to set off the
impulse: this phenomenon is known as accommodation.
Accommodation occurs only if the MP changes very pro-

H. Duffau
gressively, for example with sinusodal impulses. This is the
reason why rectangular impulses are recommended for stimulation.
Although two electrodes are always required to produce a
current, the stimulations are considered to be monopolar
if only one of the electrodes (in general, the cathode)
is active, that is, localized close to the target tissue,
whereas the reference electrode (in general, the anode)
is located at some distance. Even if the current density
is distributed in a relatively uniform manner around the
electrode, each tissue located in the currents pathway can
nevertheless be stimulated, most specically if its depolarization threshold is lower than that of the target. In order
to reduce this risk of a false positive, it is preferable to
use a bipolar stimulation. In this case, both the cathode
and the anode are active, that is, they are located close
to the target tissue [57]. In this way, only these structures
that are located between both electrodes are stimulated,
with a lesser risk of current diffusion and therefore, a
greater precision, as was demonstrated using the optical
imaging method [41]. However, because current distribution
is more complex with bipolar than monopolar stimulation, it
is more hardly modeled in order to choose optimal parameters for achieving the most reproducible responses [57]. This
is related to the overlapping of both effects of the cathode (depolarization of pericathodic tissues) and the anode
(hyperpolarization of perianodic tissues). Use of biphasic
impulses is recommended in order to compensate for this
limitation [43].

Stimulation parameters: practical approach [24]

In practice, a bipolar electrode with contacts spaced 5 mm
apart is applied on the cortex. It delivers a biphasic current (pulse frequency: 60 Hz; single-pulse phase duration:
1 ms; amplitude: 618 mA under general anesthesia, 26 mA
under local anesthesia). IES allows the mapping of motor
function (by inducing involuntary motor responses if the
stimulation is applied in front of a motor site, even under
general anesthesia), somatosensory function (by eliciting
dysesthesia, which is described by the patient himself intraoperatively), and in awake patients, cognitive functions such
as language (spontaneaous speech, picture naming, comprehension, reading, writing, bilinguism, etc.), calculation,
memory, or even visuospatial processing. Cognitive mapping
relies on the induction of transient disturbances when IES
is applied at the level of a functional epicenter [60].
Most importantly, a speech therapist must be present in
the operating room, in order to accurately interpret the
types of disorders that are induced by DES, for instance,
speech arrest, anarthria, speech apraxia, phonological disturbances, semantic paraphasia, perseveration, anomia,
dysculia, and so on. Thus, IES is able to identify in real-time
these cortical sites that are essential for the function (that
is, that must imperatively be preserved), before the beginning of the resection. This allows both selecting the best
surgical approach and dening the cortical limits of glioma
removal [29].
Moreover, IES can also identify and preserve these subcortical pathways that are crucial for sensorimotor, language
and other cognitive functions [21,27,73]. Indeed, IES allows
studying the anatomofunctional connectivity by directly

Intraoperative electrostimulation in neurooncology

stimulating the white matter tracts, very regularly throughout the resection. According to the same principle that
the one described at the cortical level, subcortical stimulation elicits functional response when entering into contact
with the essential eloquent bers. Thus, except for motor
mapping, it is important that the patient remains awake
throughout the entire duration of glioma removal, and not
exclusively for the initial stage of cortical simulation. This
is the reason why intraoperative cortico-subcortical stimulation is time-consuming, with a limitation of the number
of tasks that can be used during surgery, due to progressive
tiredness of the patient.
In summary, IES represents an accurate, reliable, and safe
technique of on-line detection of these cortical and subcortical structures that are functionally essential, at each
level and at each time of the resection. IES enables to
perform real-time anatomofunctional correlations in vivo.
Consequently, in all cases, a functional disturbance that
is reproducibly induced by the stimulation must lead to
interrupt the resection at this level, both for cortical and
subcortical structures. Tumor removal is thus performed
according to functional boundaries, in order to optimize the
quality of removal while minimizing the risk of postoperative
permanent decit [31].

Contribution of IES in surgery for glioma:

fundamental and clinical implications
New insights into the individual dynamic
anatomofunctional organization of the brain
Study of the cortical anatomofunctional organization
Brain mapping enables to study the individual functional
organization of the cortical areas. First, fMRI combined to
IES showed the existence of a somatotopy within the SMAproper with, from anterior to posterior, representation of
language (in the dominant hemisphere), face, upper limb,
and lower limb. Thus, it is possible to predict preoperatively
the severity and the pattern of the postoperative transient
decit to inform the patient and his family and to plan a
specic rehabilitation [35].
Similarly, IES demonstrated the involvement of the left
dominant insula in the complex planning of articulation,
explaining why patients may experience anarthria following
insular lesion [32]. In addition, IES supported the involvement of the dominant premotor area in language, by
inducing anomia in its dorsal part and anarthria in its ventral
part [22]. It also demonstrated the role of the left angular gyrus in calculation and enabled to distinguish these
areas involved in multiplication (below) from those involved
in subtraction (above) [16]. Using specic task based on
conceptual link, IES also showed the complexity of the functional organization of Wernickes area, with its participation
to, but also with possible dissociations between comprehension, naming and phonological processing [37].
The functional anatomy of the frontal eye elds (FEF),
which are implied in the regulation of both voluntary and
involuntary ocular saccades, was also studied. FEF stimulation elicited contraversive eye movements that were
recorded by electro-oculography. Moreover, stimulation of
an anterior subregion of FEF both elicited eye movement and

377
interfered with oculomotor behavior, supressing self-paced
saccades in awake patient [56].
Recently, a line bisection task was used in awake patients
with lesion involving the right parietotemporal junction,
with the aim to map the areas that are involved in spatial
awareness, essential for movement. A signicant rightward
deviation was observed during the stimulation of the anteroinferior part of the supramarginal gyrus and the caudal part
of the superior temporal gyrus. In other words, a transient and reproducible left neglect was induced by electrical
inactivation of cortical sites that are essential for the visuospatial integration. These eloquent areas were preserved
and the patients did not display any neglect postoperatively
[73].

Study of brain connectivity

The study of individual anatomofunctional connectivity
is also mandatory. Intraoperative subcortical stimulation
enables to identify functional white pathways [27]. In precentral lesions, after detection and preservation of the
primary motor cortical areas, it is possible to detect both
the corresponding descending motor pathways and their
somatotopy within the corona radiata. These so-identied
subcortical bers constituted the posterior and deep functional limits of the resection. The pyramidal pathways can
also be identied at the level of the posterior limb of
the internal capsule [21]. The thalamocortical somatosensory pathways and their somatotopy can also be detected
by subcortical stimulation, which induces dysesthesia in
awake patients. Similarly, subcortical visual pathways can
be mapped, with induction of a transient shadow in the
controlateral visual eld during stimulation of the optic radiation. If resection is stopped at this level, the patients may
keep only a residual quadrantanopsia without any consequence on the quality of life [26].
IES is also able to detect language pathways, such as the
arcuate fasciculus. Correlations were observed between the
anatomical data provided by DTI and the language symptoms
induced by stimulation of this pathway in different patients
presenting with lesions at various locations along the trajectory of the arcuate fasciculus, namely, within Brocas area,
insula, supramarginal gyrus and temporal lobe. In all cases,
phonemic paraphasias were reproducibly induced, supporting the role of this pathway in phonological processing, and
providing the limits of the resection [17]. Interestingly, subcortical stimulation combined to DTI recently demonstrated
the existence of a lateral part of the superior longitudinal fasciculus, directly connecting the supramarginal gyrus
and the Brocas area. This pathway looks involved in articulation, since its stimulation systematically induced speech
apraxia [23]. The existence of a parallel semantic ventral stream, corresponding to the inferior occipitofrontal
fasciculus, was demonstrated using the same method of
intraoperative anatomofunctional correlations, by eliciting
semantic paraphasias during stimulation of the white matter at the end of the removal of left temporal, insular, and
orbitofrontal lesions [30]. In addition, the subcallosal fasciculus medialis, connecting the supplementary motor area
and the cingulum to the head of the caudate nucleus, is
involved in the initiation of speech, since its stimulation
elicits a transcortical motor aphasia [17]. Finally, a descend-

378
ing pathway, which connects the anterior insula and ventral
premotor cortex to the primary sensorimotor area of the
mouth and eventually joins the pyramidal tract, allows the
nal speech production. Stimulation of these bers systematically induced anarthria [22].
Subcortical IES also allows mapping deep gray nuclei.
Indeed, stimulation of the head of the dominant caudate
generates perseverations, namely the repetition of the previous item while the next item is presented to the patient,
which supports an inhibitory role of the caudate in the control of cognition. Moreover, stimulation of the lateral part of
the dominant lentiform nucleus (at the end of the resection
of insular lesions) elicits anarthria, which demonstrates the
role of this structure in the planning of articulation [39].
The white matter tracts implied in spatial processing
can also be mapped in order to avoid postoperative left
neglect, using a task of line bisection in patients with lesion
located within the right parietotemporal junction. Indeed,
during stimulation of the superior fronto-occipital fasciculus, a signicant rightward deviation of more than 30% may
be observed [73]. Interestingly, a role of the superior longitudinal fasciculus was recently demonstrated in vestibular
function, by eliciting transient vertigo [70].

Study of brain plasticity

Another concept that should also be studied in order to help
understand interactions between host and tumors is that of
cerebral plasticity [33].
Preoperative plasticity. Most patients with slow-growing
lesion, such as low-grade glioma, have no decit, despite
the frequent invasion of eloquent structures. These tumors
have, indeed, induced progressive functional brain reshaping, as suggested by preoperative fMRI. Interestingly, the
patterns of reorganization may differ between patients. We
put three patterns into evidence. In the rst one, due to
the inltrative feature of low-grade glioma, function may
still persist within the tumor, which implies a very limited
chance to perform substantial resection without inducing
postoperative sequelae. In the second pattern, eloquent
areas may be redistributed around the tumor, thus with a
reasonable chance to perform a near-total resection despite
a likely immediate transient decit that eventually recovers
within some weeks to some months. In the third pattern, there is already a preoperative compensation by the
controlateral homologous area: consequently, the chance
to perform a real total resection with no decit is very
high [28].
Intraoperative acute plasticity. Acute functional reorganization was also observed intraoperatively, likely due to the
surgical act itself, which can generate a locoregional hyperexcitability. For instance, in cases of prerolandic lesions,
although stimulation of the precentral gyrus induced motor
responses over only a few cortical sites before resection,
we observed immediately following lesion removal an acute
unmasking of redundant motor sites that were located
within the same precentral gyrus, and whose stimulation
elicited the same movements as that of the previous adjacent sites [14]. In another example, an acute remapping was
also observed after resection of a precentral tumor, but with
unmasking of redundant motor sites that were located on
both sides of the central sulcus [13].

H. Duffau
Postoperative plasticity. The mechanisms of plasticity
induced by surgery within eloquent areas, was also studied
using postoperative fMRI once the patient had recovered,
often after a specic rehabilitation for some weeks. In
particular, following a transient postsurgical supplementarymotor-area syndrome, fMRI showed the occurrence of
activations of the controlateral supplementary motor and
premotor cortex, participating to recovery [47].

Application to cerebral glioma surgery

Surgical use of brain plasticity
It is particularly useful to study these pre-, intra-, and postoperative mechanisms of brain plasticity, using both FNI and
IES. Indeed, it is possible to rely on this brain dynamic potentiality to extend the indications and limits of resection of
glioma that are located in so-called eloquent areas, without inducing a denitive decit [20].
Thus, the SMA can be removed, despite the occurrence
of an immediate postsurgical transient SMA syndrome (with
akinesia and, sometimes, mutism), which resolved in some
weeks due to the recruitment of the controlateral homologous SMA [35]. Moreover, the resection of the insular lobe
could be performed without any permanent decit, even
in the dominant hemisphere, particularly due to the compensation by the frontal and temporal opercula, and deeply
by the left putamen [15]. Similarly, gliomas involving the
pars opercularis and pars triangularis of the left inferior
frontal gyrus, namely Brocas area, may be resected without producing aphasia, due to a perilesional reorganization
of language areas, especially in the ventral premotor cortex
behind the lesion and in the pars orbitaris of the inferior
frontal gyrus in front of the glioma [28]. In the same way,
the left dominant supramarginalis gyrus can be completely
resected without any aphasia (Fig.1ad). The removal of
the primary face sensorimotor area could also be performed without eliciting permanent postoperative central
facial palsy, but only within the non-dominant hemisphere
[51]. In these cases, the subcortical motor sites, which
represented the deep functional boundaries of the resection, corresponded to the pyramidal pathways of the upper
limb, running under the representation of the previously
removed face tracts [21]. As regards grey nuclei, compensation was also possible, particularly in gliomas involving
the right fronto-temporo-insular structures and the striatum, with a total resection without permanent palsy and
without movement disorders [18]. Recently, the claustrum
was also demonstrated to be compensated when resected
[34].
Finally, based on data provided by IES, the surgical use of
long-term functional reshaping induced by a rst surgical act
itself was also suggested [19]. Indeed, the above-described
intraoperative acute unmasking of redundancies during a
surgical resection might have a real functional role, that
is, these latent networks that are desinhibited during
tumor removal might be reinforced and then lead to a
durable remapping. Interestingly, this functional reorganization generated by the rst surgery could be useful to
consider a reoperation, with a possibility to extend tumor
removal without sequelae. For instance, in cases of precentral glioma, homologous areas generating the same motor

Intraoperative electrostimulation in neurooncology

379

Figure 1 (a): preoperative MRI showing a low-grade glioma involving the left inferior parietal gyrus (supramarginal gyrus). The
arrow shows the postcentral sulcus; (b): intraoperative views before resection of the tumor, which is delineated by letter tags.
Electrical cortical mapping shows a reshaping of the eloquent maps, with a recruitment of perilesional language sites, that is,
the rolandic operculum (tags 20 and 21), angular gyrus (tags 30 and 32), and posterior part of the superior temporal gyrus (tags
40 and 50). This language remapping induced by the slow-growing low-grade glioma has allowed the compensation of the entire
supramarginal gyrus. Therefore, a resection of this tumor can be considered despite its location in classical inoperable region. The
straight arrow shows the lateral part of the retrocentral sulcus. The curved arrow shows the end of the sylvian ssure. A = Anterior
and P = Posterior; (c): intraoperative views after tumor resection. Electrical subcortical mapping has enabled to study the individual
anatomofunctional language connectivity. Indeed, deeply and posteriorly, the posterosuperior loop of the arcuate fasciculus was
identied, by eliciting phonological paraphasia during each stimulation (tags 40, 47 and 49). More anteriorly, the lateral part of
the superior longitudinal fasciculus was detected by inducing speech apraxia (articulatory disturbances) (tag 45 and 46). It is worth
noting that in the depth, the resection was continued up to the contact of these language pathways, in order to optimize the
quality of resection while preserving the eloquent white matter tracts. The straight arrow shows the lateral part of the retrocentral
sulcus. A = anterior and P = posterior; (d): postsurgical control MRI, showing the glioma removal, performed according to individual
cortico-subcortical functional boundaries given by IES, in a patient with a normal neurological and neuropsychological status. The
resection was adapted to the cortical plasticity and language connectivity, with the goal to optimize the benet:ratio of surgery.
The arrow shows the retrocentral sulcus.

responses as previous sites, also localized within the precentral gyrus, were identied by stimulation in some patients,
after a tumor resection that had been left incomplete owing
to invasion of the primary hand motor area. Due to a recurrence some years later, a new surgery was performed, also
using IES. Stimulation showed a motor map reshaping, with
essential areas now corresponding to the sites that had
been unmasked during the rst procedure, thereby enabling
now to perform total glioma removal without decit [19].
These long-term plasticity phenomena that were induced
by surgical resection, and maybe also by glioma continued
growth, were also used to extend tumor removal in other
eloquent regions, during a second surgery when total resection was not possible initially. Notably, removal of primary
somatosensory areas and language sites could be performed
without permanent decit in re-operated patients [20].
In summary, IES has allowed to gain better knowledge
of dynamic anatomofunctional reorganization of the brain,
and its variability among patients, in order to integrate
this potential in the surgical indications and in multiplestage surgical planning. Both the extent of resection and
the number of surgical acts that are needed to perform this
resection should be adapted to the individual potentiality of
functional compensation.

Improvement of the functional and oncological results of

glioma surgery
Functional results. The integration in the surgical decision
and planning of the information provided by IES on individual functional mapping and connectivity, has enabled us
to extend the indications of surgery for gliomas located in
areas that had been until now considered as inoperable
[29]. Moreover, despite a frequent but transient immediate postoperative functional worsening (due to the attempt
to perform a maximal tumor removal according to corticosubcortical functional limits as dened by IES), more than
95% of patients recovered a normal neurological examination within a delay of three months following surgery;
moreover, some of these even described some improvement
in comparison with their preoperative status. There was also
a signicant decrease of seizures in 80% of patients who had
presented with preoperative chronic epilepsia.
This less-than-5% rate of sequels is very reproducible
among the teams using IES worldwide (for a review, see
[29]). Interestingly, in comparison, the rate of sequels
ranged from 13 to 27.5%, with a mean around 19%, in series
that did not use IES [6,8,68,75].
Neuro-oncological results. Since IES allows individual identication of the cortical and subcortical eloquent structures,

380
it seems logical to perform resection according to functional boundaries. Indeed, it was suggested to continue
the resection until the functional structures are detected
by IES, and not before, in order to optimize the quality of resection without increasing the risk of permanent
decit [29]. This surgical strategy enables a signicant
improvement of the quality of glioma removal despite a
higher number of surgeries within critical areas and a parallel decrease of the rate of sequels. Indeed, in a recent
study comparing low-grade gliomas that had been resected
without or with IES in the same institution, it was demonstrated on control MRIs that: (1) 62% of gliomas selected
for surgery were located within eloquent area in this series
with IES, instead of only 35% in that without IES; (2) only
37% of resections were subtotal (less than 10 cc of residue
according to the classication from Berger et al. [4]) and
6% were total (with no signal abnormality) in this series
without IES, whereas 50.8% of resections were subtotal
and 25.4% were total in that series with IES (P < 0.001)
[29].
Moreover, while extensive resection is still controversial
in neuro-oncology, especially concerning low-grade gliomas,
current surgical results support the positive impact of such
a maximal treatment strategy, that is, with a benet on
the natural history of the tumors, which seems to be directly
related to the quality of resection. Indeed, it was recently
shown in a consecutive series of low-grade gliomas operated
on according to functional boundaries using IES that the mortality rate was 20.6% in cases of partial resection, instead
of 8% in cases of subtotal resection and 0% in cases of total
resection (follow-up 48 months) (P = 0.02) [29].

Conclusions and perspectives

Brain glioma surgery may now benet from important technical developments in the eld of functional mapping, using
complementary noninvasive methods of FNI and invasive IES.
Such recent advances have enabled better to understand
the individual organization of the brain eloquent areas,
thereby integrating the notion of interindividual anatomofonctional variability in the surgical strategy. Furthermore,
intraoperative real-time subcortical stimulation, in association with cortical mapping, gives a unique opportunity
to study the so-called effective connectivity. Indeed, it
allows drawing on-line correlations between discrete and
transient virtual lesions, which can be performed at each
location of a distributed network (each cortical and subcortical sites being perfectly identied anatomically using
3D MRI), and their functional consequences, which should
be accurately analyzed by a speech therapist throughout
the surgical procedure. Combination of these intraoperative anatomofunctional data with those provided by DTI
(subcortical anatomical informations), MEG (chronological
data), fMRI and PET (perioperative functional data) could
enable one to elaborate individual and predictive models of
the functioning of neuronosynaptic circuits, that is, to open
a new door to connectionism [31]. Such correlations with
IES, which remains the golden standard regarding functional
brain mapping, could also help validate the noninvasive
methods of neuroimaging, particularly the new technique
of DTI [46].

H. Duffau
Moreover, such connectionist models [53] may lead to a
better knowledge of the dynamic potential of spatiotemporal reorganization of parallel and interactive networks,
namely the mechanisms of brain plasticity, which is thought
to play a major role for functional compensation in slowgrowing tumors and in their surgical resection. In this way,
the individual potentiality for plasticity could be better
understood using repeated intraoperative mappings combined to postsurgical FNI, thereby possibly guiding specic
postoperative rehabilitation programs in orders to optimize
the quality of functional recovery.
In addition to its fundamental implications, IES also
allows performing tumor resection according to functional
boundaries, thereby leading to the optimization of the benet:risk ratio of surgical removal in cerebral glioma. Such
optimization can be reached via (1) the extension of surgical indications, particularly in eloquent areas; (2) a better
quality of tumor resection with a greater neuro-oncological
impact and; (3) a minimization of the risk of postoperative
sequelae, with preservation of the quality of life.
The next step is to build a probabilistic atlas of postoperative residual low-grade glioma, after resection according to
cortical and subcortical functional boundaries determined
using IES [52]. The aim would be to predict, before the decision for surgery, whether the resection could be at least
subtotal (that is, leaving less than 10 cc of tumor), thus
with a real chance to have an impact on the natural history of the tumor. For that purpose, for each patient who
underwent surgery using IES, the postoperative imaging was
normalized in the Montreal Neurological Institute atlas, and
the residual glioma was segmented. We then computed a
probabilistic map of residues. The map enhanced the regions
where glioma cannot be resected, that is, within eloquent
structures, especially white matter pathways. The fusion
between the map and a preoperative image has allowed a
preoperative estimation of the expected extent of resection. Nonetheless, in order to increase its reliability, this
atlas currently needs to be validated in a higher number of
patients who will be operated on using IES. This is the reason
why this probabilistic map will be available on the web [52].

References
[1] Agnew WF, McCreery DB. Considerations for safety in the use
of extracranial stimulation for motor evoked potentials. Neurosurgery 1987;20:1437.
[2] Aubert A, Costalat R, Duffau H, Benali H. Modeling of pathophysiological coupling between brain electrical activation,
energy metabolism and hemodynamics: insights for the interpretation of intracerebral tumor imaging. Acta Biotheoretica
2002;50:28195.
[3] Bello L, Acerbi F, Giussani C, Baratta P, Taccone P, Songa V, et al.
Intraoperative language localization in multilingual patients
with gliomas. Neurosurgery 2006;59:11525.
[4] Berger MS, Deliganis AV, Dobbins J, Keles GE. The effect of
extent of resection on recurrence in patients with low grade
cerebral hemisphere gliomas. Cancer 1994;74:178491.
[5] Berger MS, Rostomily RC. Low grade gliomas: functional mapping resection strategies, extent of resection, and outcome.
J Neurooncol 1997;34:85101.
[6] Brell M, Ibanez J, Caral L, Ferrer E. Factors inuencing surgical complications of intra-axial brain tumors. Acta Neurochir
(Wien) 2000;142:73950.

Intraoperative electrostimulation in neurooncology

[7] Brett M, Johnsrude IS, Owen AM. The problem of functional localization in the human brain. Nat Rev Neurosci
2002;3:2439.
[8] Cedzich C, Taniguchi M, Sch
afer S, Schramm J. Somatosensory evoked potential phase-reversal and direct motor cortex
stimulation during surgery in and around the central region.
Technical application. Neurosurgery 1996;38:96271.
[9] Chitoku S, Otsubo H, Harada Y, Jay V, Rutka JT, Weiss SK, et al.
Extraoperative cortical stimulation of motor function in children. Pediatr Neurol 2001;24:34450.
[10] Claus EB, Horlacher A, Hsu L, Schwartz RB, Dello-Iacono D,
Talos F, et al. Survival rates in patients with low-grade glioma
after intraoperative magnetic resonance image guidance. Cancer 2005;103:122733.
[11] Crone NE. Functional mapping with ECoG spectral analysis. Adv
Neurol 2000;84:34351.
[12] Danks RA, Aglio LS, Gugino LD, Black PM. Craniotomy under
local anesthesia and monitored conscious sedation for the
resection of tumors involving eloquent cortex. J Neurooncol
2000;49:1319.
[13] Duffau H, Sichez JP, Lehericy S. Intraoperative unmasking of
brain redundant motor sites during resection of a precentral
angioma: evidence using direct cortical stimulation. Ann Neurol 2000;47:1325.
[14] Duffau H. Acute functional reorganisation of the human motor
cortex during resection of central lesions: a study using
intraoperative brain mapping. J Neurol Neurosurg Psychiatry
2001;70:50613.
[15] Duffau H, Bauchet L, Lehericy S, Capelle L. Functional compensation of the left dominant insula for language. Neuroreport
2001;12:215963.
[16] Duffau H, Denvil D, Lopes M, Gasparini F, Cohen L, Capelle L,
et al. Intraoperative mapping of the cortical areas involved
in multiplication and subtraction: an electrostimulation study
in a patient with a left parietal glioma. J Neurol Neurosurg
Psychiatry 2002;73:7338.
[17] Duffau H, Capelle L, Sichez N, Denvil D, Lopes M, Sichez JP,
et al. Intraoperative mapping of the subcortical language pathways using direct stimulations. An anatomofunctional study.
Brain 2002;125:199214.
[18] Duffau H, Denvil D, Capelle L. Absence of movement disorders
after surgical resection of glioma invading the right striatum.
J Neurosurg 2002;97:3639.
[19] Duffau H, Denvil D, Capelle L. Long-term reshaping of language, sensory, and motor maps after glioma resection: a new
parameter to integrate in the surgical strategy. J Neurol Neurosurg Psychiatry 2002;72:5116.
[20] Duffau H, Capelle L, Denvil D, Sichez N, Gatignol P, Lopes M,
et al. Functional recovery after surgical resection of low-grade
gliomas in eloquent brain: hypothesis of brain compensation.
J Neurol Neurosurg Psychiatry 2003;74:9017.
[21] Duffau H, Capelle L, Denvil D, Sichez N, Gatignol P,
Taillandier L, et al. Usefulness of intraoperative electrical subcortical mapping during surgery for low-grade gliomas located
within eloquent brain regions: functional results in a consecutive series of 103 patients. J Neurosurg 2003;98:76478.
[22] Duffau H, Capelle L, Denvil D, Gatignol P, Sichez N, Lopes M,
et al. The role of dominant premotor cortex in language:
a study using intraoperative functional mapping in awake
patients. Neuroimage 2003;20:190314.
[23] Duffau H, Gatignol P, Denvil D, Lopes M, Capelle L. The
articulatory loop: study of the subcortical connectivity by electrostimulation. Neuroreport 2003;14:20058.
[24] Duffau H. Peroperative functional mapping using direct
electrical stimulations. Methodological considerations. Neurochirurgie 2004;50:47483.
[25] Duffau L, Capelle L. Preferential brain locations of low-grade
gliomas. Cancer 2004;100:26226.

381
[26] Duffau H, Velut S, Mitchell MC, Gatignol P, Capelle L.
Intraoperative mapping of the subcortical visual pathways
using direct electrical stimulations. Acta Neurochir (Wien)
2004;146:2659.
[27] Duffau H. Intraoperative cortico-subcortical stimulations
in surgery of low-grade gliomas. Expert Rev Neurother
2005;5:47385.
[28] Duffau H. Lessons from brain mapping in surgery for low-grade
glioma: insights into associations between tumor and brain
plasticity. Lancet Neurol 2005;4:47686.
[29] Duffau H, Lopes M, Arthuis F, Bitar A, Sichez JP,
Van Effenterre R, et al. Contribution of intraoperative
electrical stimulations in surgery of low-grade gliomas: a
comparative study between two series without (198596) and
with (19962003) functional mapping in the same institution.
J Neurol Neurosurg Psychiatry 2005;76:84551.
[30] Duffau H, Gatignol P, Mandonnet E, Peruzzi P,
Tzourio-Mazoyer N, Capelle L. New insights into the
anatomofunctional connectivity of the semantic system: a
study using cortico-subcortical electrostimulations. Brain
2005;128:797810.
[31] Duffau H. New concepts in surgery of WHO grade II gliomas:
functional brain mapping, connectionism and plasticity. J Neurooncol 2006;79:77115.
[32] Duffau H, Taillandier L, Gatignol P, Capelle L. The insular lobe
and brain plasticity: Lessons from tumor surgery. Clin Neurol
Neurosurg 2006;108:5438.
[33] Duffau H. Brain plasticity: from pathophysiological mechanisms to therapeutic applications. J Clin Neurosci 2006;13:
88597.
[34] Duffau H, Mandonnet E, Gatignol P, Capelle L. Functional compensation of the claustrum: lessons from low-grade glioma
surgery. J Neurooncol 2007;81:3279.
[35] Fontaine D, Capelle L, Duffau H. Somatotopy of the supplementary motor area: evidence from correlation of the extent
of surgical resection with the clinical patterns of decit. Neurosurgery 2002;50:297303.
[36] Ganslandt O, Buchfelder M, Hastreiter P, Grummich P,
Fahlbusch R, Nimsky C. Magnetic source imaging supports clinical decision making in glioma patients. Clin Neurol Neurosurg
2004;107:20-6.
[37] Gatignol P, Capelle L, Le Bihan R, Duffau H. Double dissociation
between picture naming and comprehension: an electrostimulation study. Neuroreport 2004;15:1915.
[38] Geddes LA, Baker LE. The specic resistance of biological
material a compendium of data for the biomedical engineer
and physiologist. Med Biol Eng Comput 1967;5:27193.
[39] Gil Robles S, Gatignol P, Capelle L, Mitchell MC, Duffau H. The
role of dominant striatum in language: a study using intraoperative electrical stimulations. J Neurol Neurosurg Psychiatry
2005;76:9406.
[40] Gordon B, Lesser RP, Rance NE, Hart Jr J, Webber R, Uematsu S,
et al. Parameters for direct cortical electrical stimulation in
the human: histopathologic conrmation. Electroencephalogr
Clin Neurophysiol 1990;75:3717.
[41] Haglund MM, Ojemann GA, Bleasdel GG. Optical imaging of bipolar cortical stimulation. J Neurosurg 1993;78:
78593.
[42] Jayakar P, Alvarez LA, Duchowny MS, Resnick TJ. A safe and
effective paradigm to functionally map the cortex in childhood.
J Clin Neurophysiol 1992;9:28893.
[43] Jayakar P. Physiological principles of electrical stimulation. In:
Devinsky O, Beric A, Dogali M, editors. Electrical and magnetic
stimulation of the brain and spinal cord. New York: Raven Press
Ltd; 1993.
[44] Keles GE, Lamborn KR, Berger MS. Low-grade hemispheric
gliomas in adults: a critical review of extent of resection as
a factor inuencing outcome. J Neurosurg 2001;95:73545.

382
[45] Keles GE. Intracranial neuronavigation with intraoperative magnetic resonance imaging. Curr Opin Neurol
2004;17:497500.
[46] Kinoshita M, Yamada K, Hashimoto N, Kato A, Izumoto S, Baba T,
et al. Fiber-tracking does not accurately estimate size of ber
bundle in pathological condition: initial neurosurgical experience using neuronavigation and subcortical white matter
stimulation. Neuroimage 2005;25:4249.
[47] Krainik A, Duffau H, Capelle L, Cornu P, Boch AL, Mangin JF,
et al. Role of the healthy hemisphere in recovery after
resection of the supplementary motor area. Neurology
2004;62:132332.
[48] Kral T, Kurthen M, Schramm J, Urbach H, Meyer B. Stimulation mapping via implanted grid electrodes prior to
surgery for gliomas in highly eloquent cortex. Neurosurgery
2006;58:3643.
[49] Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W,
DeMonte F, et al. A multivariate analysis of 416 patients with
glioblastoma multiforme: prognosis, extent of resection, and
survival. J Neurosurg 2001;95:1908.
[50] Laws ER, Parney IF, Huang W, Anderson F, Morris AM, Asher A,
et al. Survival following surgery and prognostic factors
for recently diagnosed malignant glioma: data from
the Glioma Outcomes Project. J Neurosurg 2003;99:
46773.
[51] LeRoux PD, Berger MS, Haglund MM, Pilcher WH, Ojemann GA.
Resection of intrinsic tumors from nondominant face motor cortex using stimulation mapping: report of two cases. Surg Neurol
1991;36:448.
[52] Mandonnet E, Jbabdi S, Taillandier L, Galanaud D, Benali H,
Capelle L, et al. Preoperative estimation of residual volume for
WHO grade II glioma resected with intraoperative functional
mapping. Neuro Oncol 2007;9:639.
[53] Marrelec G, Krainik A, Duffau H, Pelegrini-Issac M, Lehericy S,
Doyon J, et al. Partial correlation for functional brain
interactivity investigation in functional MRI. Neuroimage
2006;32:22837.
[54] Matsumoto R, Nair DR, LaPresto E, Najm I, Bingaman W,
Shibasaki H, et al. Functional connectivity in the human language system: a cortico-cortical evoked potential study. Brain
2004;127:231630.
[55] Meyer FB, Bates LM, Goerss BS, Friedman JA, Windschitl WL,
Duffy JR, et al. Awake craniotomy for aggressive resection
of primary gliomas located in eloquent brain. Mayo Clin Proc
2001;76:67787.
[56] Milea D, Lobel E, Leh
ericy S, Duffau H, Rivaud-Pechoux S,
Berthoz A, et al. Intraoperative frontal eye eld stimulation
elicits ocular deviation and saccade suppression. Neuroreport
2002;13:135964.
[57] Nathan SS, Lesser RP, Gordon B, Thakor NV. Electrical stimulation of the human cerebral cortex. Theoretical approach. In:
Devinsky O, Beric A, Dogali M, editors. Electrical and magnetic
stimulation of the brain and spinal Cord. New York: Raven Press,
Ltd; 1993.
[58] Neuloh G, Schramm J. Motor evoked potential monitoring for
the surgery of brain tumors and vascular malformations. Adv
Tech Stand Neurosurg 2004;29:171228.
[59] Nimsky C, Ganslandt O, Fahlbusch R. Functional neuronavigation and intraoperative MRI. Adv Tech Stand Neurosurg
2004;29:22963.
[60] Ojemann G, Ojemann G, Lettich E, Berger M. Cortical language localization in left, dominant hemisphere. An electrical
stimulation mapping investigation in 117 patients. J Neurosurg
1989;71:31626.
[61] Onal C, Otsubo H, Araki T, Chitoku S, Ochi A, Weiss S, et al.
Complications of invasive subdural grid monitoring in children
with epilepsy. J Neurosurg 2003;98:101726.

H. Duffau
[62] Peraud A, Ilmberger J, Reulen HJ. Surgical resection of gliomas
WHO grade II and III located in the opercular region. Acta Neurochir (Wien) 2004;146:917.
[63] Picht T, Kombos T, Gramm HJ, Brock M, Suess O. Multimodal protocol for awake craniotomy in language cortex tumor
surgery. Acta Neurochir (Wien) 2006;148:12738.
[64] Ranck JB. Extracellular stimulation. In: Patterson MM,
Kesner RP, editors. Electrical stimulation research methods.
New York: Academic Press; 1981. p. 236.
[65] Reinges MH, Nguyen HH, Krings T, Hutter BO, Rohde V, Gilsbach JM. Course of brain shift during microsurgical resection
of supratentorial cerebral lesions: limits of conventional neuronavigation. Acta Neurochir (Wien) 2004;146:36977.
[66] Romst
ock J, Fahlbusch R, Ganslandt O, Nimsky C,
Strauss C. Localisation of the sensorimotor cortex during
surgery for brain tumors: feasibility and waveform patterns
of somatosensory evoked potentials. J Neurol Neurosurg
Psychiatry 2002;72:2219.
[67] Roux FE, Boulanouar K, Lotterie JA, Mejdoubi M, LeSage JP,
Berry I. Language functional magnetic resonance imaging
in preoperative assessment of language areas: correlation with direct cortical stimulation. Neurosurgery 2003;52:
133545.
[68] Sawaya R, Hammoud M, Schoppa D, Hess KR, Wu SZ, Shi WM,
et al. Neurological outcomes in a modern series of 400 craniotomies for treatment of parenchymal tumors. Neurosurgery
1998;42:104456.
[69] Signorelli F, Guyotat J, Isnard J, Schneider F, Mohammedi R,
Bret P. The value of cortical stimulations applied to the
surgery of malignant gliomas in language areas. Neurol Sci
2001;22:310.
[70] Spena G, Gatignol P, Capelle L, Duffau H. Superior longitudinalis fasciculus subserves vestibular network in humans.
Neuroreport 2006;17:14036.
[71] Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F,
Reulen HJ, et al. Fluorescence-guided surgery with 5aminolevulinic acid for resection of malignant glioma: a
randomised controlled multicentre phase III trial. Lancet Oncol
2006;7:392401.
[72] Taylor MD, Bernstein M. Awake craniotomy with brain mapping
as a routine surgical approach to treating patients with supratentorial intraaxial tumors: a prospective trial of 200 cases. J
Neurosurg 1999;90:3541.
[73] Thiebaut de Schotten M, Urbanski M, Duffau H, Volle E, Levy R,
Dubois B, et al. Direct evidence for a parietal-frontal
pathway subserving spatial awareness in humans. Science
2005;309:22268.
[74] Tzourio-Mazoyer N, Josse G, Crivello F, Mazoyer B. Interindividual variability in the hemispheric organization for speech.
Neuroimage 2004;21:42235.
[75] Vives KP, Piepmeier JM. Complications and expected outcome
of glioma surgery. J Neurooncol 1999;42:289302.
[76] Vlieger EJ, Majoie CB, Leenstra S, den Heeten GJ. Functional
magnetic resonance imaging for neurosurgical planning in neurooncology. Eur Radiol 2004;14:114353.
[77] Whittle IR, Borthwick S, Haq N. Brain dysfunction following
awake craniotomy, brain mapping and resection of glioma.
Br J Neurosurg 2003;17:1307.
[78] Whittle IR. The dilemma of low grade glioma. J Neurol Neurosurg Psychiatry 2004;75:316.
[79] Wiedemayer H, Sandalcioglu IE, Armbruster W, Regel J, Schaefer H, Stolke D. False negative ndings in intraoperative SEP
monitoring: analysis of 658 consecutive neurosurgical cases
and review of published reports. J Neurol Neurosurg Psychiatry
2004;75:2806.
[80] Yeomans JS. Principles of brain stimulation. New York: Oxford
University Press; 1990.