Clinical Neurology and Neurosurgery 115 (2013) 127–145

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Clinical Neurology and Neurosurgery

journal homepage: www.elsevier.com/locate/clineuro

Review

The neurolinguistic approach to awake surgery reviewed

Elke De Witte a , Peter Mariën a,b,c,∗
a
Department of Clinical and Experimental Neurolinguistics, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium
b
Department of Neurology, ZNA Middelheim, Antwerp, Belgium
c
VLAC (Vlaams Academisch Centrum), Advanced Studies Institute of the Royal Flemish Academy of Belgium for Sciences and the Arts, Brussels, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Objectives: Intraoperative direct electrical stimulation (DES) is increasingly used in patients operated
Received 6 May 2012 on for tumours in critical language areas. Although a positive impact of DES on postoperative linguistic
Received in revised form 6 August 2012 outcome is generally advocated, the literature is only scantily documented with information about the
Accepted 7 September 2012
linguistic methods applied in awake surgery. This article critically reviews the neurolinguistic procedures
Available online 2 October 2012
currently used in awake studies.
Methods: Based on an extensive review of the literature, an overview is given of the language map-
Keywords:
ping techniques applied in brain tumour surgery. Studies investigating linguistic testing and outcome in
Awake craniotomy
Direct electrical stimulation
awake surgery were analysed. Information about the timing of the assessment(s), the linguistic tasks, the
Language mapping linguistic stimuli and the indication for awake surgery was also discussed.
Language testing Results: Intraoperative DES remains the ‘gold standard’ for language mapping, but pre- and postoperative
Review non-invasive mapping methods are important adjuncts. In the pre- and postoperative phase, standardised
linguistic test batteries are generally used to assess language function. In the intraoperative phase, only
naming and number counting are commonly applied. Most often no detailed information about the
linguistic stimuli is provided and no standardised protocols measuring different linguistic levels have
been described.
Conclusions: Awake surgery with DES is a useful tool for preserving linguistic functions in patients
undergoing surgery in critical brain regions. However, no studies exist that apply a well-balanced and
standardised linguistic protocol to reliably identify the critical language zones. The availability of a
standardised linguistic protocol might substantially increase intraoperative comfort and might improve
outcome and quality of life.
© 2012 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
2. History. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
3. State of the art . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
3.1. Imaging techniques in awake surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
3.1.1. Preoperative imaging techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
3.1.2. Intraoperative imaging techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
3.1.3. Postoperative imaging techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
3.1.4. Correlations between imaging techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
3.1.5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
3.2. Language tasks in awake surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
3.2.1. Preoperative language tasks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
3.2.2. Intraoperative language tasks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
3.2.3. Postoperative language tasks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
3.2.4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

∗ Corresponding author at: Department of Neurology, ZNA Middelheim Hospital, Lindendreef 1, B-2020 Antwerp, Belgium. Tel.: +32 032803136; fax: +32 032813748.
E-mail addresses: peter.marien5@telenet.be, peter.marien@zna.be (P. Mariën).

0303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.clineuro.2012.09.015
128 E. De Witte, P. Mariën / Clinical Neurology and Neurosurgery 115 (2013) 127–145

4. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

1. Introduction This “localisationist’s view”, based on ‘post-mortem’ studies on lan-

guage representation in the brain, relies on the view that specific
Surgical treatment of supratentorial tumours (particularly language functions are invariably located in specific anatomical
gliomas) aims to maximise the quality of resection while minimis- areas of the brain [21].
ing the risk of postoperative functional sequellae (including speech Fritsch en Hitzig (1870) experimented with electrocortical
and language impairments) [1–7]. Low-grade gliomas, classified as stimulation in animals and succeeded to elicit movements of
WHO grade II tumours [8], are infiltrative tumours characterised the extremities of the animals [22]. The first evidence of brain
by continuous and slow progression, migration, and anaplastic mapping with DES in humans dates back to 1874. Bartholow stim-
transformation [9–12]. Since gliomas are often located in criti- ulated the cerebral cortex of a 30-year-old woman through a skull
cal language areas, the preservation and restoration of language defect resulting from osseous infiltration of an epithelioma. The
function are of crucial importance [3,13]. Non-invasive language electrical current caused movements in various parts of her body
mapping methods, such as functional magnetic resonance imaging depending on which brain area was stimulated [22]. In the early
(fMRI), have been used to assess lateralisation and location of criti- 1930s, Penfield and co-workers used brain surgery to treat patients
cal language areas for surgical preservation [14,15]. However, these with intractable epilepsy. They hypothesised that if an aura could be
imaging techniques do not seem to be highly reliable measures provoked with electrical stimulation, it would be possible to locate
on which to base critical surgical decisions [16]. Direct electrical the source of seizure activity and to resolve epilepsy by removing
stimulation (DES) is currently applied as the standard intraoper- or destroying that tissue [22]. Subsequently, Penfield and Boldry
ative approach to language mapping to identify critical language (1937) introduced DES as a method to map the motor and sensory
areas and its pathways in the presence of a space-occupying lesion cortex in order to resect supratentorial tumours located in criti-
[2–5,13–15,17]. cal areas [13,19,22]. Penfield and Rasmussen (1950) started to map
As DES requires conscious and cooperative patients, local anaes- language and speech functions next to sensorimotor functions in
thesia (awake surgery) instead of general anaesthesia (classic awake brain surgery [13,22,23]. But it was the pioneer Ojemann
surgery) is used. During DES, patients perform language tasks, (1979) who refined the technique. Ojemann showed that the areas
such as picture naming tasks, verb-noun association tasks, com- identified to be crucially implicated in linguistic processing were
prehension tasks, repetition, reading, and writing tasks. Picture not only located in the perisylvian language zone, but made up
naming is commonly used as basic language paradigm [6,18], and a larger cerebral network also involving subcortical white matter
the selection of additional language tasks differs widely across tracts. In addition, following refinement of the technique, evidence
centres. Transient disturbances of speech and language function was found that language localisation is highly variable among indi-
(speech arrest, anarthria, dysarthria, speech apraxia, phonological viduals [13,22–25].
and semantic deficits, paraphasias, perseverations, anomia, com- During the last 20 years non-invasive structural neuroimaging
prehension disturbances, agraphia, alexia) occur if the cerebral techniques (magnetic resonance imaging (MRI), computed tomo-
tissue is electrically stimulated at the level of a functional language graphy (CT)) and functional neuroimaging techniques (positron
‘epicentre’. Consequently, this stimulated area must be preserved emission tomography (PET), functional MRI) became popular
during tumour resection [3]. means to map the human brain and guide tumour surgery [23].
Awake surgery with intraoperative DES is generally consid- These techniques allowed researchers to study the whole brain,
ered to have a positive impact on postoperative linguistic outcome both in ‘healthy’ subjects and patients [4]. Functional mapping
[1–7,13,15,17,19,20]. Although transient language impairments are methods also demonstrated that there is a large interindividual
common in the immediate postoperative phase, the majority of variability in the neural organisation of linguistic functions. This
patients seem to recover within three months, and permanent post- observation supported a more ‘dynamic view’ on brain functions
operative language deficits seem to be rare [1,3,7,13,15,20]. As a and ‘brain plasticity’, which is crucial in the process of functional
result, intraoperative DES is often regarded as the ‘gold standard’ recovery [12].
to map linguistic functions in patients with tumoural lesions in the The first studies of preoperative functional mapping in tumour
language dominant hemisphere [2–5,13–15,17]. surgery used PET to map sensorimotor, language, and visual areas.
However, no studies exist in which a standardised linguistic During the past decades, fMRI has largely replaced PET [12].
protocol is applied to identify the critical language zones, and no However, fMRI has some major limitations with regard to the
detailed, long-term linguistic data have been recorded. After ten identification of functional language areas in patients with brain
years of linguistic experimenting with language mapping in an tumours. It cannot map subcortical language pathways [3,4,14]
awake neurosurgical setting, a critical evaluation of the available and cannot differentiate between ‘essential’ and ‘replaceable’ lan-
data is warranted. The aim of this article is to review whether guage areas [3,14]. The former limitation might be compensated
DES using language mapping is still the ‘gold standard’ to identify by the use of diffusion tensor imaging (DTI), a non-invasive tech-
critical language areas in brain tumour surgery. nique that enables to identify white matter tracts (subcortical
language pathways). DTI however still needs to be validated and
2. History only provides anatomical information [12] (see Section 3.1.1). By
contrast, on the basis of DES, ‘essential’ language regions (which
The traditional approach to brain tumour surgery is resection should be preserved) and ‘modulatory’ areas (which may be com-
of the mass lesion while preserving the main language centres pensated and resected without permanent functional loss) can
of the brain: Broca’s and Wernicke’s area. In this approach, the be differentiated. Moreover, DES allows to map subcortical lan-
brain is considered to be ‘static’ and to have a fixed functional guage areas as well. Although most studies [1–7,13,15,17,19,20]
neuroanatomical organisation that is similar in all patients [12]. postulate that DES is an accurate, reliable, and safe technique
 E. De Witte, P. Mariën / Clinical Neurology and Neurosurgery 115 (2013) 127–145
to identify cortical and subcortical language areas, there are a
number of limitations to this approach. Indeed, the technique can-
not map the entire brain and it is rather demanding for both
the awake patients and the staff. In addition, DES is time con-
suming because of its intensive character that requires in-depth
preparations in both the pre- and intraoperative phase [12,24]
(see Section 3.1.2).
The combination of intraoperative DES and preoperative fMRI is
currently often used in the work-up of surgical removal of gliomas
in critical areas [12]. As neuroimaging techniques are continuously
improving (e.g. diffusion tensor imaging, transcranial magnetic
stimulation) and new techniques are being developed (e.g. intraop-
erative MRI) [26], the question arises whether DES is still the gold
standard for intraoperative language mapping, and fMRI the gold
standard for preoperative language mapping in the content of brain
tumour surgery?
3. State of the art
3.1. Imaging techniques in awake surgery
3.1.1. Preoperative imaging techniques
3.1.1.1. Structural magnetic resonance imaging (MRI). Structural
MRI is used in the presurgical phase to evaluate the morphology,
size and topography (e.g. location) of a brain tumour [26]. In order
to plan the resection rate, the borders of the tumour are identified
by means of preoperative MRI [5,27,28].
3.1.1.2. Functional magnetic resonance imaging (fMRI). fMRI meas-
ures blood oxygen level-dependent (BOLD) changes in the magnetic
resonance signal, which is related to neuronal activity. The changes
in blood flow and oxygenation are detected by fMRI during cere-
bral activation when performing a cognitive, linguistic or motor
task [29,30]. In awake settings, fMRI helps to determine the limits of
resection, to predict risk factors, to reduce time of surgery/mapping
and to decrease craniotomy size [3,23,26,31]. Moreover, fMRI is a
non-invasive procedure and can be easily repeated in the postop-
erative period to follow-up patients over time [29].
However, fMRI has a number of shortcomings. First, fMRI cannot
visualise subcortical activity in critical language areas [3,4,14,32].
Second, it is impossible to reliably distinguish between ‘essen-
tial’ areas and ‘modulatory’ areas [3,14]. Third, despite constant
improvements the accuracy to identify language areas is still not
optimal. In contrast to its sensitivity for sensorimotor identifica-
tion – which ranges from 82 to 100% – the sensitivity of fMRI to
identify linguistic functions is only 66% [3,13,18]. Since neurosur-
gical decision-making is conservative, 34% of false results is way
too high to solely rely on fMRI findings [26]. Fourth, motion-related
artifacts induced by heartbeat, breathing and most importantly by
head motion constitute a problem of reliability [26,32]. Fifth, lan-
guage maps may vary according to the language paradigm selected,
the neurological disease, the ability of the patient to perform a task
and the statistical analysis method chosen [29,32].
A final drawback for fMRI is the significance thresholds chosen
to generate language activation maps. Roux et al. [33] for instance
showed that variations in the threshold values disclose different
degrees in neural activity. Depending on the significance thresholds
used to analyse raw fMRI data, changes in the spatial extent and
number of activated cortical areas are found.
3.1.1.3. Positron emission tomography (PET). Using PET imaging, a
wide range of functions (e.g. language) can be studied. The speci-
ficity depends on the behavioural and control task paradigm. In
comparison with fMRI the disadvantages of PET are a poor signal-
to-noise ratio, a mere moderate spatial resolution, and a poor
129
temporal resolution. In addition, PET is more invasive and time-
consuming than fMRI. As with fMRI and any other observational
technique, PET cannot separate functional ‘essential’ from ‘partici-
pating’ areas. PET imaging is therefore mainly used in neurosurgical
planning to localise seizure foci [29].
3.1.1.4. Diffusion tensor imaging (DTI). Magnetic resonance DTI is
a non-invasive MR imaging method to study white matter tracts
by measuring the direction of diffusion of water molecules (water
diffusion in the brain tends to track along bundles of white matter
fibres). Because of the ability to map subcortical language pathways
(e.g. superior longitudinal fasciculus, inferior fronto-occipital fasci-
culus, uncinate fasciculus, and inferior longitudinal fasciculus), DTI
is increasingly becoming important in the preoperative planning
and guiding of awake surgery.
Furthermore, it can also be used to differentiate normal white
matter, oedematous brain tissue, and enhancing tumour margins.
DTI may also reveal whether fibres are displaced, disrupted, or
infiltrated by the tumour, which adds information to the selection
of surgical indications [9,12,23,26,29,30,34]. Until now DTI is not
routinely used in the neurosurgical setting as validation data are
still lacking. The technique has a poor signal-to-noise ratio, is vul-
nerable to artifacts from air spaces and has difficulties visualising
crossing tracts. In addition, the tracking of fibres in the vicinity of
or within a tumour is complicated due to associated phenomena
such as oedema, tissue compression, and degeneration [15,26,35].
Another restriction is that DTI provides little specific information
about the functional status of the white matter tracts. Young et al.
[26] indicated that fMRI may be more useful in the planning phase,
and DTI in the resection phase for guidance.
3.1.1.5. Transcranial magnetic stimulation (TMS). Single pulse TMS
can be used as an activation technique to map the motor cortex, and
repetitive TMS (rTMS) can be applied as an inhibition technique to
disrupt language processing and to assess language lateralisation
[29,36,37].
Disadvantages of TMS are its poor spatial resolution and a poten-
tial risk to cause seizures [29]. The use of TMS in presurgical
mapping procedures is growing. Duffau [12] and Picht et al. [38,39]
postulated that TMS could be highly informative during preopera-
tive motor mapping for tumours near the rolandic cortex. Shamov
et al. [37] used rTMS combined with neuronavigation for preop-
erative mapping of the language area to treat opercular gliomas
of the dominant hemisphere. They found rTMS to be valuable for
preoperative localisation of the speech areas, for preoperative plan-
ning of the surgical approach and for intraoperative planning of the
direction of brain retraction and operative corridor.
3.1.1.6. Neuronavigation. Neuronavigation allows the coregistra-
tion and transfer of preoperative imaging data into the surgical
field, the physical space of the head of the patient. Anatomical data
from MRI or CT image sets are loaded into the anatomical neuronav-
igation system. Currently, functional neuronavigation, integrating
functional data from PET, fMRI is increasingly used. Since a brain
shift occurs due to surgical retraction, mass effect, gravity, extent
of resection, or cerebrospinal fluid leakage, significant inaccuracies
in image-guided systems occur during surgery [12]. Because of this
risk, sole reliance on the neuronavigation system to decide which
area to resect is insufficient [12,30]. Intraoperative MRI, fMRI, DTI
(iMRI, ifMRI, iDTI) may provide an efficient solution to cope with
this drawback (see Section 3.1.2) [9,26,28].
3.1.2. Intraoperative imaging techniques
3.1.2.1. Direct electrical stimulation (DES). Procedure: DES has
become the gold standard for intraoperative mapping of motor
and language areas in the preparation phase of tumour resection.
130 E. De Witte, P. Mariën / Clinical Neurology and Neurosurgery 115 (2013) 127–145
Motor mapping with DES may be performed under gen-
eral anaesthesia whereas for language (cognitive) mapping an
asleep–awake–asleep procedure is generally used [28,40]. To elim-
inate potential risks such as respiratory complications when the
patient is woken-up from sedation, an awake–awake protocol is
sometimes used during which the patient is not sedated [41–45]. As
there is no waken-up from anaesthesia in this approach, the patient
remains alert during the entire procedure [41–45]. However, this
procedure is psychologically very demanding for the patient as
it can cause potential distress and discomfort (e.g. during cran-
iotomy). For these reasons the awake–awake condition is rarely
applied [42].
Cortical mapping is used to identify the ‘essential’ language sites
and to define the boundaries of the resection [11,14,28]. DES is gen-
erally performed with a bipolar stimulator that produces biphasic
and rectangular pulses, each lasting 1 ms. Frequencies of 50 or 60 Hz
are used and the intensity is progressively increased from 1 to
10 mA with 0.5 mA each time. A stimulus duration of 1 or 2 s is usu-
ally applied to generate a motor response, but for language mapping
a more extensive duration of 3–4 s is required [5,11,27,46]. Patients
are asked to perform a variety of language tasks (naming, repeti-
tion, counting, verbal fluency. . .) (see Section 3.2.2) during cortical
stimulation. The stimulation starts just before the presentation of
the test item. In a picture naming task, for example, the cortex is
stimulated and then the picture is presented. The patient produces
a short introductive phrase ‘this is . . .’ before naming to ensure
that no seizures were generated that might explain distorted nam-
ing [6,10,27]. Linguistic disturbances are subsequently detailed
and categorised by a speech and language pathologist in speech
arrests, anomic disturbances, paraphasias (phonemic, semantic,
morphologic, visual), motor speech disturbances, perseverations,
etc.
To avoid seizures no site is stimulated twice in succession. It is
accepted that transient language deficits occurring during 3 stimu-
lations (with subsequent normalisation) is sufficient to ensure that
the stimulated site is essential for language processing [5,27,46].
The essential sites are marked on the cortex with sterile number
tags [5,27,46] or with a colour code on a ‘mapping grid’ (computer
screen) which is a projection of the cortex divided into squares of
1 cm2 [18]. Language critical sites are spared and a resection margin
of 1 cm is generally agreed to [18,47].
Subcortical areas are mapped during tumour resection by means
of similar electrical parameters and language tasks used at the cor-
tical level [5,27,46]. Functional subcortical pathways are identified
by repeated stimulations along the pathway [46].
Positive mapping, i.e. identification of at least one essential
region, is commonly accepted as the standard intraoperative tech-
nique to preserve essential functions [5,11]. On the other hand,
some studies suggest that craniotomies with negative mapping
(when no critical regions are found) in the setting of a limited corti-
cal exposure allow aggressive resection of gliomas [47–49]. Duffau
[50], however, postulated that decisions based on negative map-
ping are only acceptable for high-grade gliomas, since the aim of the
surgical intervention is to resect the enhanced part of the tumour.
As low-grade gliomas are poorly delineated, negative mapping is
not a reliable strategy on which to base decisions.
Advantages: One of the major advantages of DES is that no false
negative results occur if the method is rigorously applied. In other
words, DES has an optimal sensitivity and correctly identifies essen-
tial regions that should be preserved to avoid permanent language
deficits. This is in contrast with other functional mapping tech-
niques (fMRI, PET) which cannot distinguish between ‘essential’
and ‘modulatory’ language zones (see Section 3.1.1) [3,46]. Its high
sensitivity explains why DES is commonly considered the ‘gold
standard’ in brain mapping and why DES is used to validate non-
invasive functional methods such as fMRI, PET and DTI [14].
The ability to map subcortical pathways, and thus to detect
subcortical language pathways is another major advantage of
DES. The use of subcortical mapping is indeed increasingly
applied [3,9,11,35,51]. Studies [9,27,51–54] showed that the use
of subcortical mapping next to cortical mapping optimises the
benefit-to-risk ratio of surgery and offers the opportunity to study
language connectivity. In sum, DES allows to perform tumour
resection according to functional boundaries and minimises the
risk of permanent functional deficits.
A beneficial effect on postoperative outcome and quality of
life (QoL) is reported in several awake studies using DES (with
or without subcortical mapping). For example, Pereira et al. [7]
studied 79 patients with supratentorial brain tumours. They found
that DES with cortical and/or subcortical mapping is effective and
safe, showing clinical recovery in 40% of the cases (n = 32) and
neurological worsening in around 10% (n = 8). Duffau et al. [27]
described a series of 115 patients with grade II gliomas in the left
dominant hemisphere and reported persistent language impair-
ments in only 2% of the patients. In a study by Bello et al. [51],
88 gliomas were mapped at the cortical and subcortical level. Three
days after surgery, 66,9% of the patients (n = 59) showed postopera-
tive language deficits. Three months after tumour removal, 79.5%
(n = 70) of the patients had normal language, 18.6% (n = 16) had mild
language deficits and only 2.3% (n = 2) had a moderate or severe
language impairment. In conclusion, several awake studies have
shown that transient language deficits frequently occur, but per-
manent linguistic impairments are indeed very rare (well below
5%) [7,13,27,51,55].
Some studies [1,2,19,20,56–58] compared linguistic outcome of
awake surgery with the outcome of classic brain surgery. Though
reaching no statistical significance at 3 months postsurgery, Gupta
et al. [56] reported a better outcome of the classic approach.
No cortical mapping however was used in the awake group.
In the other studies [1,2,19,20,57,58] significantly better results
were reported in the awake group with DES. Peruzzi et al. [58]
found statistically significant beneficial effects in favour of the
awake group, that is a shorter hospital stay with reduced hospi-
tal expenses after postoperative intensive care unit. In a recent
meta-analysis of the literature De Witt Hamer et al. [59] con-
firmed a generally favourable outcome of the awake patient group.
The data of 8091 adult patients operated for supratentorial infil-
trative gliomas with or without DES were compared. The use of
DES resulted in fewer late severe neurological deficits (3.4% versus
8.2%), more extensive resection (75% versus 58% gross total resec-
tions) and involved critical locations more frequently (99.9% versus
95.8%).
In addition, awake surgery with DES allows more exten-
sive resection since only the ‘critical/crucial’ language areas are
preserved. The classical surgical approach uses a larger safety mar-
gin since the identification of functional areas is based on the
activations found in preoperative functional mapping disclosing
‘involved’ language areas as well [1]. Though extensive resection
is still controversial in neuro-oncology, current surgical results
support the view that a total or at least subtotal resection has a
beneficial effect on the natural history of the low-grade gliomas
and a positive impact on survival [3]. The “1 cm-safety rule” (1 cm
between the resection margin and the nearest language site) was
generally recommended as it would prevent postoperative lan-
guage deficits and their persistence [18,47]. Nowadays a growing
number of studies have provided evidence that no safety margin
around critical structures is required in case of low-grade glioma
resection since a more extensive resection is associated with a more
favourable life expectancy [1,10,34]. Moreover, Yordanova et al.
[60] suggest a supratotal resection – with a margin beyond MRI
abnormalities – when low-grade gliomas involve non-critical areas,
even in the left hemisphere. The following results were reported in
 E. De Witte, P. Mariën / Clinical Neurology and Neurosurgery 115 (2013) 127–145
a study by Duffau et al. [2]. A mortality rate of 20.6% was found
in cases of partial resection, whereas 8% mortality was found in
cases of subtotal resection and 0% in cases of total resection. Yor-
danova et al. [60] described transient neurological worsening in 60%
of cases, but three months after surgery no permanent deficits were
found. Although an extensive resection after DES typically causes
transient language worsening, most patients recover and return to a
normal socio-professional life without permanent language deficits
[1,3,7,13,15,20].
The phenomenon of temporary dysfunctions can be explained
by postoperative brain plasticity. The immediate postoperative
deficits noticed in most patients confirm that some structures
remain functional within the tumour mass or peri-tumoural
brain tissues. Secondary recovery might be due to reshap-
ing of the locoregional mechanism and/or the recruitment
of remote areas (e.g. homologous areas in the contralat-
eral hemisphere) [3,12,61]. Recent studies suggest that a
second surgery should be performed when initially only par-
tial resection was performed. Due to functional reshaping
total tumour removal is possible without permanent deficits
[3,4,10,12,23,29,50,62–64].
These findings indicate that there exist multiple cortical repre-
sentations or ‘functional redundancy’ (short-term plasticity) which
facilitate postoperative recovery (long-term plasticity) [12,61]. As
such, this might confirm that language is not only subserved by
Broca’s and Wernicke’s area (see Section 2), but processed within
multiple parallel networks.
DES studies have yielded new information about language
organisation in the (impaired) brain. Direct electrocortical and sub-
cortical stimulation allow a better understanding of the critical
regions (and their functional role) and connectivity. As a result
the neural basis of language is considered an end product of the
well-synchronised functioning of parallel, distributed, and interac-
tive cortico-subcortical networks rather than the sole product of
individual centres. This connectionist view, the so-called ‘hodol-
ogy’, also underlines the dynamic character of the brain that allows
functional compensation within a large distributed network (brain
plasticity) [3,4,14,50,65,66].
Disadvantages: DES also has some disadvantages and limitations
that need to be taken into account. Firstly, while the sensitivity
of DES is 100%, its specificity remains a matter of debate. False
positive results may be linked to the patient’s tiredness, to par-
tial seizures, to the spreading of DES along the axon (acute false
positives) and to brain plasticity (chronic false positives) [14]. Sec-
ondly, DES is time-consuming (lasts much longer than surgery
under general anaesthesia) and only allows locoregional map-
ping (cannot study reshaping in the contralateral brain) [3,12].
Thirdly, DES might also be demanding for the patients since
good compliance and cooperation from the patient are needed
when language mapping is executed. Feelings of anxiety, confu-
sion and stress may appear because DES is an invasive method.
Nevertheless, recent studies have suggested that most patients
tolerate the awake procedure well [7,22,42,49,53,57,67,68]. Care-
ful evaluation and selection of the patient, extensive planning, a
detailed supply of information about the procedures and inten-
sive training in the preoperative phase seem to be fundamental
for good tolerance during awake surgery [11,25,42,68]. Fourthly,
DES requires highly qualified multidisciplinary teams. However,
since a good postoperative outcome and reduced duration of hos-
pitalisation is consistently reported for awake surgery with DES,
postsurgery sequellae requiring long-lasting, intensive and expen-
sive rehabilitation strategies are avoided or kept to a minimum
with a positive impact on Health Insurance costs (invalidity ben-
efit). Consequently, the high demands and requirements for staff
and logistical support have to be critically studied in a substantial
cost-benefit analysis [11,13,24,58].
131
The final important disadvantage of DES seems to be the lack
of standardised linguistic protocol to reliably identify the critical
language zones. This issue will be discussed in Section 3.2.2.
3.1.2.2. iMRI, intraoperative ultrasound, fluorescence. MR imaging
has been recently introduced in the intraoperative phase to
identify residual tumour tissue during resection to overcome the
limitations of brain shift and to update preoperative information.
Thanks to the development of high-field iMRI, high-quality images
are produced and iMRI appears to improve the extent of resection
for gliomas without increasing the risk of permanent postoperative
deficits [26,30,69]. Parney et al. [70] combined DES with high-field
iMRI to facilitate safe and extensive tumour resection, which
resulted in a total tumour resection of 90% and a beneficial postop-
erative outcome with no new neurological deficits. However, the
combination of DES with iMRI is a complicated and expensive
procedure and therefore not frequently used. The patient has to
be wrapped in sterile drapes to keep the sterile field free from
contamination. This can cause claustrophobic reactions or may be
dangerous for sedated patients without definitive airway protec-
tion. In addition, the time of surgery is prolonged [69]. In the study
of Parney et al. [70] surgery time increased with approximately
40 min.
Although a high signal-to-noise quality and poor contrast res-
olution is frequently reported, intraoperative ultrasonography
may be an alternative for iMRI as it is inexpensive and easy
to use. The limitations of ultrasound are the image resolution
and the co-registration with preoperative MRI data. However, the
co-registration can nowadays be compensated with sonographic
integration into surgical navigation systems [30,71].
Fluorescent porphyrins can also be used to visualise intraopera-
tive tumour tissue, but only in high-grade (malignant) gliomas. Flu-
orescent porphyrins reflect tumour cell density and proliferation
and enable to distinguish cells of the brain parenchyma from those
of the tumour [71]. Preoperatively, the patients receive 5-ALA (5-
aminolevulinic acid) orally, dissolved in tap water. During the oper-
ation, when the tumour is reached, the degree of fluorescence is
usually evaluated. Tumour tissue is coloured intensively red while
normal brain tissue is non-fluorescent featuring a bluish colour
[71]. This method is easy to perform and less costly than iMRI [69].
3.1.2.3. ifMRI, iDTI. Intraoperative fMRI may be used to update
the neuronavigational system and to compensate for brain shift.
However, intraoperative fMRI is rarely performed since it is not
beneficial to intraoperative DES [26]. By contrast, intraoperative
DTI may be a valuable tool as brain shift is a critical issue for deep
white matter pathways. A limitation of iDTI is the specific position
of the head, necessary for brain surgery and so nonstandard for
DTI, which requires manual recalculations and prolongs surgical
time [26].
3.1.3. Postoperative imaging techniques
3.1.3.1. MRI and DTI. Repeat structural MRI is usually performed
immediately after tumour removal, 3 months postsurgery, and then
every 6 months during follow-up. MR imaging evaluates the extent
of glioma removal, which is often categorised according to the clas-
sification method of Berger and colleagues [72] (total = no residue,
subtotal = residue < 10 cm3 , partial = residue ≥ 10 cm3 ). MRI and DTI
enable to repeatedly analyse the anatomical location of the lan-
guage pathways (at the periphery of the cavity) in the postoperative
phase [5,27,28,52,53].
3.1.3.2. fMRI and TMS. Repeat fMRI may be performed after
surgery to evaluate linguistic outcome and to investigate neural
(re)organisation of linguistic functions. fMRI allows brain plas-
ticity to be studied as it can show possible new redistribution
132 E. De Witte, P. Mariën / Clinical Neurology and Neurosurgery 115 (2013) 127–145
of functions following surgery that may be potentiated by spe-
cific rehabilitation procedures. Postoperative fMRI is not routinely
conducted, but it can be very useful since second surgery may
be considered after partial resection if reorganisation is found on
fMRI [3,4,10,12,23,29,50,62–64]. Longitudinal functional imaging
studies after resection, linked to the results of intraoperative and
preoperative mapping enable a better understanding of brain con-
nectivity and brain plasticity [50]. Next to fMRI, TMS can be applied
in the postoperative phase to map linguistic functions or facilitate
aphasia recovery [37]. As already mentioned (see Section 3.1.1.5.),
rTMS can localise speech areas [37]. In addition TMS can also be
used for recovery purposes since it may modulate both the function
of the stimulated area and the effective connectivity. Consequently,
it may improve e.g. picture naming [64].
3.1.4. Correlations between imaging techniques
In some studies [15,33,73,74] the correlation between the
neurolinguistic findings of fMRI and DES is investigated. Poor
correlation was found for language mapping with fMRI (sensitivity
score of only 66% [15,33,73]). This result contrasts with higher
sensitivity scores (82–100%) for the detection of the sensorimotor
areas [15,26,29,30,62,75]. DES precisely locates the cortical areas
critically involved in speech and language processes. By contrast,
fMRI identifies many additional brain areas that are linked to
language processing, but not intrinsically involved [75,76]. Other
possible reasons for the poor correlation between fMRI and DES
may be the differences in pre- and intraoperative language tasks,
in correlation methods, and in study population characteristics
(tumour type, location, and craniotomy size) [15,23].
With regard to the linguistic paragdigms used, Petrovich et al.
[32] showed that the discordance between fMRI and DES could in
part be explained by the use of silent speech in fMRI (to avoid
motion artifacts) and vocalised speech in DES. It was found that
silent speech tasks under fMRI correctly predicted the sites of lan-
guage deficit with DES in the inferior and middle frontal gyrus but
failed to predict observed sites of speech arrest in the precentral
motor gyrus [26,32]. As a result, the use of at least one overt fMRI
speech task is recommended to support better concordance with
DES [26]. Similarly, in the study of Kim et al. [76], a much better
correlation was found when a battery of language tests with func-
tional redundancy (e.g. both passive and active tasks that overlap
functional areas) was built into the task design. In other words, the
correlation between fMRI and DES needs to be further studied with
appropriate language tasks, but the use of fMRI as a sole language
mapping technique appears to be insufficient.
The correlation between PET or TMS, and DES has not been stud-
ied in much detail, as their use in the presurgical planning is still
limited. Sobottka et al. [77] showed a relatively poor correlation
between PET imaging and DES when language function was tested.
Correlations have been found for TMS and DES when motor func-
tion is examined [29,37–39]. Correlations between TMS and DES
data for linguistic functions have not been extensively studied yet.
Because of the importance of subcortical language mapping
DTI has become an increasingly crucial tool in preoperative map-
ping and subcortical DES in intraoperative mapping. Correlations
between DTI and DES have been investigated and positive corre-
lations were reported [3,9,15,35,78]. However, DTI cannot replace
subcortical DES since the estimated distance between DTI and the
location of electric stimulation is influenced by the inaccuracies
of DTI, the invasiveness of the tumour, intraoperative brain shift
affecting navigation accuracy, and the various stimulation param-
eters and probe types used [35,62]. In the study by Bello et al. [78],
DTI fiber tracking (DTI-FT) and subcortical DES were used to eval-
uate the reliability of tracking from a functional point of view. The
data yielded a good concordance between DTI-FT data and those
obtained during subcortical mapping.
In conclusion, recent advances in preoperative mapping with
fMRI and DTI are very promising, but intraoperative DES is still
crucial in awake procedures.
3.1.5. Conclusion
Several anatomic and functional imaging techniques for tumour
surgery in critical language areas have been briefly discussed in
this overview. The strengths and weaknesses of each mapping
technique were set against those of the ‘gold standard’, that is intra-
operative DES. Although the development and validation of preop-
erative mapping techniques are expanding, the reliability of these
techniques in neurosurgical practice remains limited because of the
lack of standardisation [26]. Intraoperative DES is the most accurate
technique to identify critical language areas and their pathways, yet
pre- and postoperative mapping are important adjuncts to intra-
operative DES. Since fMRI and DTI identify essential and involved
cortical and subcortical language areas as well as their connect-
ing pathways, both techniques are relevant to assist in settling
the kind of surgical approach and the limits of resection [9,12].
Preoperative mapping is an ideal component of surgical planning
and may reduce surgery time, which is valuable since DES is time-
consuming [13,24]. Utilisation of fMRI and DTI data (and even data
from PET, iMRI) during neuronavigation, may facilitate intraopera-
tive guidance as well [9]. The integration of preoperative methods
and intraoperative DES in functional neuronavigation has extended
the indications for surgery of gliomas located in critical areas that
were previously considered ‘inoperable’ [3]. Furthermore, longi-
tudinal follow-up by repeat postoperative mapping with (f)MRI,
DTI or PET is important in studying the dynamic processes (brain
plasticity) involved in motor and cognitive rehabilitation [50]. Com-
paring the pre-, intra- and postoperative imaging data may predict
and show functional redistribution and reshaping [12,61].
3.2. Language tasks in awake surgery
3.2.1. Preoperative language tasks
In-depth linguistic assessments are performed preoperatively
to investigate speech and language functions. Due to a typically
slow growth of low-grade gliomas allowing neural reorganisation
(preoperative plasticity), no obvious linguistic deficits may be
noted. However, formal neuropsychological assessments may
disclose clinically relevant impairments [55,79–81]. Therefore,
extensive neuropsychological investigations in the preoperative
clinical work-up of brain tumours are advocated [55,79,80]. Type
and degree of aphasic, apraxic and dysarthric symptoms can be
identified and classified by a variety of standardised speech and
language test batteries. Most studies use the Boston Diagnostic
Aphasia Examination (BDAE) [85] or Aachener Aphasie Test (AAT)
[86] [6,15,17]. See sections ‘tasks’ and ‘stimuli’ in Table 1 for
more detailed information for each study. Naming tasks from the
AAT, BDAE, the Boston Naming Test (BNT) [87] or Dénomination
Orale 80 (DO80) [88] are usually included in the preopera-
tive language protocol [2,6,47,51,53,55,60,63,78,79,81,89–91].
Phonological and/or semantic verbal fluency tasks
[2,33,51,53,63,78,79,90–93], verb generation tasks [15,33,74],
repetition tasks [2,6,33,47,51,53,55,63,78,90,92,93] and sponta-
neous speech tasks [2,51,53,78] are also often administered in the
preoperative phase. Assessments take place within 5 days before
surgery (see section ‘timing of assessment(s)’ in Table 1).
If the preoperative cognitive and linguistic status (not too
severely impaired) allows awake surgery the patient is informed
in detail about the procedure. At the same time the patient’s psy-
chological ability to undergo an awake intervention is critically
evaluated.
Functional language representation may be investigated by a
number of linguistic tasks. fMRI is generally used to measure brain
Table 1
Language (cognitive) tasks in the preoperative phase of awake surgery.

Study Timing of Tasks Stimuli fMRI language paradigm(s)

assessment(s)

Ilmberger et al. [6] 1–3 days before AAT-subtests: NI

surgery Token Test
Repetition Phonemes, words and sentences
Written language Reading, writing
Naming Objects, colours, scenes
Comprehension NDI

Spena et al. [15] Unknown AAT NDI Listening to nouns → produce verb (verb
generation) (active condition)
Counting from 1 to 10 (rest condition)

Picht et al. [17] 1 day before surgery AAT NDI Patients with scores of at least 50% in all modules
of the test battery → fMRI: word generation:

E. De Witte, P. Mariën / Clinical Neurology and Neurosurgery 115 (2013) 127–145

Test run of language testing
produce words beginning with that letter
presented (phonological fluency)

Lubrano et al. [63] 10 days before BDAE → short version: NDI NI

surgery Oral and written
comprehension, naming, oral
fluency, reading,
dictation, repetition, written
transcription, (calculation, and
object handling)

Benzagmout et al. [10] Unknown BDAE → adapted version NDI Repetition tasks, story listening, verbal fluency

Duffau et al. [34] Unknown BDAE NDI NI

Yordanova et al. [60] Unknown BDAE NDI NI

DO80

Robles et al. [82] Unknown BDAE NDI NI

Lurito et al. [73] Unknown NI Listening to reading of a narrative text from a

popular novel (patients were instructed to
carefully listen to the text and be prepared to
answer questions regarding its content)

Brennan et al. [83] Unknown BDAE NDI Object naming, number counting
Three paradigms

De Benedictis et al. [1] Unknown BDAE NDI NI

Duffau et al. [52] Unknown BDAE NDI Semantic fluency, story listening and covert
sentence repetition tasks

Duffau et al. [27] Unknown BDAE NDI Semantic fluency, story listening and covert
sentence repetition

Teixidor et al. [55] Unknown DO80 Picture naming Semantic fluency task, covert sentence repetition
BDAE → 8 subtests: task, and story listening task
Comprehension Commands and logic
Written comprehension Reading
Repetition Words, concrete phrases, abstract phrases
Written language Spelling test
comprehension
Writing Sentence dictation

Mandonnet et al. [46] Unknown BDAE NDI Semantic verbal fluency, covert sentence
repetition, and story listening

133
Table 1 (Continued)

134
Study Timing of Tasks Stimuli fMRI language paradigm(s)
assessment(s)

Bizzi et al. [74] Time between fMRI NI Verb generation (produce a verb silently in
and DES was within response to a noun)
3 weeks

Santini et al. [93] Unknown BADA: NI

Phonemic discrimination
Repetition Words
Picture naming Nouns and verbs
Auditory and visual Nouns and verbs
word-to-picture matching
Auditory and visual
sentence-to-picture matching
Writing to dictation
Reading aloud

E. De Witte, P. Mariën / Clinical Neurology and Neurosurgery 115 (2013) 127–145

Word Fluency:

Letters F, A, S

Roux et al. [33] Unknown Written, oral comprehension NDI Verb generation (find verbs in relation to the
Denomination objects presented)
Language fluency
Reading Naming (the patients were asked to name five
(Computation) objects shown by special MRI-design glasses)
Dictation
Repetition Copying
(Object handling)

Roux et al. [90] Unknown Written, oral comprehension NDI NI

Naming
Language fluency
Reading
(Computation)
Dictation
Repetition
Written transcription
(Object handling)

Scarone et al. [84] Unknown BDAE
Mechanics of writing
Recall of written symbols
Dictated words
Written confrontation naming
Written formulation
Sentences to dictation
Fluency in controlled word association, story
Based on the patient’s written output listening, and covert sentence repetition tasks
(name, address. . .)
Serial writing (automised), Primer-level
dictation
10 words with increasing length and
complexity
Pictures from oral naming tasks
Cookie theft scene, to dictation
10 sentences graded in length and
grammatical complexity

Wu et al. [81] Unknown BNT NI

MAE Visual Naming
MAE Token Test

Sarubbo et al. [89] Unknown Laiacona-Capitani NI

Naming Test
Token Test

Duffau et al. [53] Unknown Verbal comprehension, NDI NI

Duffau et al. [2] spontaneous speech, naming,
verbal fluency, narrative tasks,
repetition
 Sanai et al. [47] Unknown Counting Counting 1–50 NI
Naming Object naming, slide show
Reading Reading single words
Repeating Repeating complex sentences
Writing Writing words and sentences

Bello et al. [51] Unknown Spontaneous speech Describe reason for admission to the Semantic fluency, story listening, and covert
Bello et al. [78] hospital sentence repetition tasks
Phonological fluency Letters F, P, L (1 min per letter)

Semantic fluency Categories, such cars, fruit, and animals

(1 min)

Famous face naming Famous and unknown faces, fame

judgment + naming
Object picture naming Nonliving, living categories, body parts,

E. De Witte, P. Mariën / Clinical Neurology and Neurosurgery 115 (2013) 127–145

musical instruments
Action picture naming Verb oral naming subtest
Word comprehension Match word (1) to pictures (5)
Sentence comprehension Match sentence (1) to pictures (2)
Transcoding tasks: repetition Non-words, words, sentence, syntagm
repetition
Token Test
(Digit Span)
Counting

Talachi et al. [79] Assessments were Naming Visual objects NI

performed in 2 or 3 Phonological fluency Letters F, A, S
sessions over a
period ranging from
1 to 5 days

Leclerq et al. [94] Unknown Bedside examination NDI NI

Pereira et al. [7] Unknown (Neuropsychological testing: NDI NI

WAIS III, Raven, MMPI)

Vassal et al. [91] Unknown Phonological fluency Letter P Verb generation (produce a semantically
Semantic fluency Animals associated verb silently in response to an
BDAE auditorily presented noun) → activation task
Naming DO80 80 black and white pictures Countdown task → control task
Montreal Evaluation of
Communication protocol

Papagno et al. [92] In the week before Phonological fluency NDI Verb generation task (produce a semantically
surgery Semantic fluency NDI associated verb in respond to an object picture)
Naming Famous faces, 50 items Naming (objects)
Nouns, 82 items
Verbs, 50 items
Naming by description,38 items
Pointing to picture 48 items
Sentence comprehension Token Test
Picture-to-sentence matching 80 items
Repetition Syllables, words, nonwords, sentences

Bertani et al. [11] Unknown NI NI

Quinones-Hinojosa et al. Unknown NI NI
[75]
Sacko et al. [57] Unknown NI NI

NI, no information (missing data); NDI, no detailed information; AAT, Aachener Aphasie Test; BDAE, Boston Diagnostic Aphasia Examination; DO80, Dénomination Orale (80 items); BNT, Boston Naming Test; BADA, Batteria per

135
l’analisi dei deficit afasici; MAE, Multilingual Aphasia Examination; WAIS III, Wechsler Adult Intelligence Scale III; MMPI, Minnesota Multiphasic Personality Inventory.
136 E. De Witte, P. Mariën / Clinical Neurology and Neurosurgery 115 (2013) 127–145
activity while the patient performs linguistic tests. In Table 1 the
language paradigms that have been used in fMRI settings are listed.
Benzagmout et al. [10], Duffau et al. [27,52], Bello et al. [51,78], Teix-
idor et al. [55], Scarone et al. [84] and Mandonnet et al. [46] used
fluency tasks, repetition tasks, and story-listening tasks. A variety
of other fMRI language tasks have been used as well, including audi-
tory narrative tasks [73], object naming tasks [33,83,92], number
counting tasks [15,83] and verb generation tasks [15,33,74,91,92].
In the study of Shamov et al. [37], counting (from 1 to 50)
and object naming were preoperatively performed during rTMS to
localise speech representation in the frontal lobe. Shamov et al.
[37] postulate that rTMS is a valuable method for preoperative
localisation and planning.
Finally, in the preoperative phase a set of tasks/stimuli is care-
fully selected. This selected set of stimuli is practised in the
preoperative phase so that the patient feels comfortable in the
awake setting. The tasks the patient is unable to perform correctly
are left out of the set for intraoperative testing to ensure that the
errors in the awake setting are due to cortical stimulation and not
to a pre-existing deficit [46].
3.2.2. Intraoperative language tasks
The number and extent of language tasks that can be used dur-
ing surgery is limited because of the constraints imposed by the
awake surgery procedures. First of all, to avoid seizures the time of
an electrical stimulation is maximally 4 s. Consequently, stimulus
presentation and response cannot last longer than 4 s [46,51,78].
The time pressure is challenging especially for semantic tasks that
often include sentence comprehension tasks taking longer than 4 s.
Second, the fixed position of the patient on the operation table
makes it hard to perform certain language tasks, such as reading
a long text from a screen. Third, visual complexity has to be taken
into account, especially in cases of posteriorly localised tumours,
since the visual pathways may be under pressure during resection
[18]. Finally, patients get tired because the awake setting requires
intense and sustained attention during approximately 1–2 h [14].
Moreover, the wake-up phase from general anaesthesia can cause
disorientation and confusion [41–44]. As a result, linguistic distur-
bances may be due to secondary problems, which may lead to false
positive results [14]. Therefore, there is a need to develop a set of
sensitive language tests by means of which maximum information
can be obtained in minimum exposure time.
In general, the descriptions of the linguistic tests used during
DES lack sufficient detail. In addition, little is known about the
construction of these tests, their validity, the availability of nor-
mative data, etc. Table 2 presents an overview of the linguistic
tasks, stimuli and indications for DES. Five studies [6,17,63,91,92]
only report the use of picture naming tasks (object naming) dur-
ing cortical and subcortical stimulation in patients with lesions
near or within language-related brain areas. For naming tasks, both
experimental naming tasks and standardised naming tests such as
BNT [87], DO80 [88] and naming tasks from the BDAE [85] and
AAT [86] are used. Picture naming in combination with counting is
the most frequently used activation paradigm (n = 13) during intra-
operative mapping [1,10,27,34,46,52,60,73,82–84,89,94]. Brennan
et al. [83] compared object naming and counting during DES and
fMRI. They found that disruption of speech occurred in more brain
regions during object naming than during number counting. This
implies that more complex language tasks (involving phonology
and semantics) are more sensitive measures to localise lan-
guage than overlearned speech. Reading tasks [2,47,53,55,57,90],
spontaneous speech [7,15], comprehension tasks [7,11,51,78]
and verb generation tasks [11,33,74] have also been used
sporadically.
In a few studies [2,51,53,78] a more tailored selection of tasks
is described taking into account the location of the tumour. In
addition to a counting, naming and reading task, Duffau et al. [2,53]
included a calculation task for lesions in the left angular and supra-
marginal gyri. Semantic or repetition tasks were used for tumours
in the left mid-posterior temporal lobe. In Bello et al. [51,78], count-
ing and object naming tasks were used to investigate frontal lesions,
whereas object naming tasks and word and sentence comprehen-
sion tasks were used for temporal lesions. Mandonnet et al. [14]
postulated that repetition tasks should be added to study the func-
tional impact of lesions involving the posterior superior temporal
gyrus. In the study of Polczynska [95], detailed information is given
about a set of language tasks for intraoperative mapping. Polczyn-
ska [95] postulates that the language protocol – often restricted
to naming and counting tasks – should be expanded in order to
improve postsurgical preservation of language function. Polczyn-
ska [95] developed three sets of ‘home made’ tasks that were
used in patients with a multi-electrode subdural grid (extraopera-
tive) and classified these tests as: (1) ‘grammar-focused tests’, (2)
‘non-dominant right-hemisphere tests’, and (3) ‘tests for subcor-
tical stimulation’. The syntax tests (1) include making questions
and negations of a presented stimulus sentence, producing inflec-
tions (e.g. I go → He. . .), production of regular and irregular plural
forms (e.g. car–cars, sheep–sheep), and spontaneous speech pro-
duction. The language tests composed to examine non-dominant
right hemisphere function (2) contain tests investigating alterna-
tive meanings of words and broader semantic relationships (a),
and affective prosody (b). In a test of ‘metaphorical expressions’
(a) the patient, for example, needs to select one out of three
pictures that corresponds to the metaphorical meaning of the sen-
tence. To assess emotional prosody (b) a picture of a face showing
some emotional state is presented to the patient together with
an orally produced sentence expressed in a happy, bored, or sad
way. The patient has to decide if the sentence has been said in
a way that matches the picture. The tests for subcortical stim-
ulation (3) involve naming, articulation and language dynamics.
Though these tests have not yet been applied during intraopera-
tive DES, it is suggested they may be implemented in intraoperative
DES testing once standardisation of the test protocol has been
completed.
A review of the linguistic tasks in these awake stud-
ies reveals that picture naming and/or counting are typi-
cally used as basic and sometimes sole language paradigms
[1,10,27,34,43,49,56,70,79–81,86,89], and that the selection of
other language tasks varies greatly across different studies. How-
ever, the selection of the language paradigms to be used during
DES procedures is of crucial importance, because of its direct
effect on clinical outcome [96]. The sensitivity of various lan-
guage tasks still has to be systematically examined to maximise
efficiency during intraoperative language testing and to minimise
postoperative deficits [55,79]. More specific and more sensitive
‘home-made tasks’ have been implemented in the language proto-
col [2,7,11,78,95], but there is still no consensus about the rationale
and no norms exist for these tasks.
3.2.3. Postoperative language tasks
Although formal linguistic testing is important to evaluate lin-
guistic outcome, postoperative language investigations are not
routinely performed. In Table 3, the postoperative language tasks,
language stimuli and timing of the assessment(s) are described per
awake study. In most of these studies, immediately after surgery
or within 7 days, a short neurolinguistic evaluation is executed to
detect possible linguistic disturbances. After one week postsurgery,
speech and language functions are often examined by means of
standardised extensive test batteries such as the BDAE [85], AAT
[86] and naming tasks among which the BNT [87] and DO80 [88].
If necessary, speech and language rehabilitation is started. Repeat
assessments may be performed after 3 months, and then every 6
Table 2
Language (cognitive) tasks in the intraoperative phase of awake surgery.

Study Method Tasks Stimuli Indication

Ilmberger et al. [6] Cortical, subcortical DES Confrontation naming Pictures of objects Lesions near or within language-related brain areas
Lubrano et al. [63] Cortical, subcortical DES Naming Pictures of objects → line Brain tumours and cavernomas located within or
drawing (black and white) invading the dominant inferior frontal cortex
Picht et al. [17] Cortical, subcortical DES Naming Pictures → line drawings Left hemisphere tumours
Vassal et al. [91] Cortical, subcortical DES Naming: DO80 Black and white pictures Right frontotemporal (close to the insula), right
temporal gliomas
Papagno et al. [92] Cortical, subcortical DES Naming Living and non-living objects, Left temporal, frontal, parietal, right temporal and
famous faces, verbs parietal LGGs and HGGs
Quinones-Hinojosa Cortical DES Counting Number counting Lesions near precentral gyrus, central sulcus,
et al. [75] postcentral gyrus, frontal operculum, angular gyrus
Benzagmout et al. [10] Cortical, subcortical DES Counting 1–10 over and over again LGGs in Broca’s area (involving the pars opercularis
Naming: DO 80 Black and white pictures and pars triangularis of the left inferior frontal

E. De Witte, P. Mariën / Clinical Neurology and Neurosurgery 115 (2013) 127–145

Duffau et al. [34] Cortical, subcortical DES Counting
Naming: DO 80
Yordanova et al. [60] Cortical, subcortical DES Counting
Naming: DO 80
Robles et al. [82] Cortical, subcortical DES Counting
Naming: DO 80
Mandonnet et al. [46] Cortical, subcortical DES Counting
Naming DO80
Scarone et al. [84] Cortical, subcortical DES Counting
Naming DO80
Brennan et al. [83] Cortical DES Counting
Naming (BDAE)
Lurito et al. [73] Cortical DES Counting
Naming
De Benedictis et al. [1] Cortical, subcortical DES Counting
Naming
Duffau et al. [52] Cortical, subcortical DES Counting
Naming
Duffau et al. [27] Cortical, subcortical DES Counting
Naming
Leclerq et al. [94] Cortical, subcortical DES Counting
Naming
Sarubbo et al. [89] Cortical, subcortical DES Counting
Naming
Santini et al. [93] Cortical, subcortical DES Counting
Naming
+ additional tasks
e.g. reading, comprehension
tasks
Duffau et al. [53] Cortical, subcortical DES Counting, naming, reading
Duffau et al. [2]
(+Calculation task)
+ Semantic, repetition task
Sanai et al. [47] Cortical DES Counting
Naming
Reading
gyrus, BA 44, 45)
1–10 over and over again LGGs located within the dominant hemisphere
Black and white pictures
1–10 over and over again LGGs in noneloquent areas in left dominant
Black and white pictures hemisphere
1–10 over and over again Patients with cortico-subcortical LGGs, selection of
Black and white pictures patients with tumours involving dominant
striatum (putamen, caudate)
1–10, over and over again WHO grade II gliomas in left dominant hemisphere
Black and white pictures (in eloquent regions)
1–10, over and over again LGGs located in language areas
Slides with black and white
pictures
Number counting Left frontal lesion, temporal lesion
Object naming paradigms
NDI Gliomas in left perisylvian region
Object naming Identification of Broca area
Identification of Wernicke area
NDI LGGs in functional areas (already operated under
Pictures general anaesthesia)
NDI Corticosubcortical LGGs in language regions in left
Pictures dominant hemisphere
1–10 (over and over again) Corticosubcortical WHO grade II gliomas located in
Pictures eloquent areas in left dominant hemisphere
NDI LGGs or cortical dysplasia located in language areas
Pictures
0–10 LGGs located in eloquent areas
Several naming tasks
If impairment was observed Gliomas in the left hemisphere
in a specific BADA subtest,
additional tasks were
administered
Pictures Corticosubcortical LGGs in eloquent brain areas
NDI Lesions in left angular and supramarginal gyri
ND Tumours in the left mid-posterior
temporal lobe
Counting 1–50 Dominant hemisphere gliomas in posterior inferior
Object naming frontal, anterior inferior parietal lobe, inferior to
Reading single words midportion of the motor cortex, or any portion of
the temporal lobe

137
 138
Table 2 (Continued)

Study Method Tasks Stimuli Indication

Teixidor et al. [55] Cortical, subcortical DES Counting NDI LGGs located in language areas
Picture naming
Reading
Sacko et al. [57] Cortical, subcortical DES Naming Pictures Lesions in eloquent areas
Reading Basic unrelated sentences

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Pereira et al. [7] Cortical, subcortical DES Naming objects NDI Lesions near eloquent cortex
Recalling objects
Spontaneous naming
Counting per minute
Comprehension of complex
commands
Spena et al. [15] Cortical, subcortical DES Naming Black and white pictures Eloquent area tumours
Spontaneous speech Spontaneous speech
Reading Reading from slides
Bello et al. [51] Cortical, subcortical DES Counting NDI Frontal lesion (Broca)
Bello et al. [78] Oral naming Pictures of objects, actions, Frontal lesion (oral naming essential sites)
famous people
Oral naming Pictures of objects, actions, Temporal lesion
famous people
Word and sentence Words and sentences Temporal lesion
comprehension
Bertani et al. [11] Cortical, subcortical DES Counting NDI LGGs in eloquent regions
Verbal naming Object naming and famous
faces naming
Verb generation NDI
Word- and sentence NDI
comprehension
Wu et al. [81] Asleep–awake–asleep Speech motor mapping Insular gliomas
NI
Bizzi et al. [74] Cortical DES Verb generation Produce a verb silently in Focal mass in or adjacent to at least one eloquent
response to an auditorily area of the language or motor systems
presented noun
Roux et al. [33] Cortical DES Naming Pictures of objects LGGs, HGGs, meningiomas in eloquent areas
Verb generation In response to objects
Roux et al. [90] Cortical DES Counting NDI Tumours or other lesions (such as cortical
Naming 30 pictures of various objects dysplasia) in eloquent regions
Reading aloud 30 different sentences
Talachi et al. [79] Awake mapping NI Gliomas

NI, no information (missing data); NDI, no detailed information; DO 80, Dénomination Orale (80 items); LGGs, low-grade gliomas; HGGs, high-grade gliomas; BADA, Batteria per l’analisi dei deficit afasici.
Table 3
Language (cognitive) tasks in the postoperative phase of awake surgery.

Study Timing of assessment(s) Tasks Stimuli

Ilmberger et al. [6] Within 21 days and 1-year after surgery AAT-subtests:
Token Test
Repetition Phonemes, words and sentences
Written language Reading, writing
Naming Objects, colours, scenes
Comprehension NDI
Spena et al. [15] 1 Week, 3 months, 6 months after surgery and AAT NDI
then yearly

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Picht et al. [17] 2 Weeks after surgery NI (probably same as preop phase)
Lubrano et al. [63] Immediately, 2 and 3, months postsurgery BDAE → short version: NDI
Patients with gliomas were systematically Oral and written comprehension, naming, oral
tested again at 6 months postsurgery fluency, reading, dictation, repetition, written
transcription, (calculation, and object
handling)
Benzagmout et al. [10] Immediately, 3 and 6 months after surgery BDAE (adapted version) NDI
Duffau et al. [34] Immediately, 3 months after surgery BDAE NDI
Yordanova et al. [60] 3, every 6 months thereafter BDAE NDI
DO 80
Robles et al. [82] Immediately, 3 months after surgery BDAE NDI
Lurito et al. [73] Unknown NI
Brennan et al. [83] Unknown BDAE: NDI
Naming
De Benedictis et al. [1] Immediately, 3 months, every 6 months after BDAE NDI
surgery
Duffau et al. [52] Immediately, 3 months after surgery NI (probably same as preop phase)
Duffau et al. [27] Immediately, 3 and 6 months BDAE NDI
Teixidor et al. [55] Immediately (within 7 days) and 3 months DO80 Picture naming
after surgery BDAE → 8 subtests:
Auditory comprehension Commands, logic and reasoning
Written comprehension Reading
Repetition Words, concrete phrases, abstract phrases
Written language comprehension: Spelling test
Writing Sentences to dictation
Mandonnet et al. [46] Immediately, 3 months postsurgery BDAE NDI
Bizzi et al. [74] Within 7 days and at 3 months postsurgery Verbal fluency NDI
denomination NDI
comprehension Simple objects and categories
Santini et al. [93] 3, 6 months postsurgery BADA: Words
Phonemic discrimination Nouns and verbs
Repetition Nouns and verbs
Picture naming
Auditory and visual word-to-picture matching
Auditory and visual sentence-to-picture
matching
Writing to dictation
Reading aloud
Word fluency Letters F, A, S

139
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Table 3 (Continued)

Study Timing of assessment(s) Tasks Stimuli

Roux et al. [33] Language and neuropsychological testing: Written, oral comprehension
4 to 8 weeks postsurgery Denomination
fMRI in 7 patients (of 14 patients): 1 to 2 Language fluency
months after surgery Reading
(Computation)
Dictation
Repetition
Copying
(Object handling)
Verb generation (during POSTOP fMRI) Find verbs in relation to the objects presented

E. De Witte, P. Mariën / Clinical Neurology and Neurosurgery 115 (2013) 127–145

Naming (during POSTOP fMRI) The patients were asked to name five objects
shown by special MRI-design glasses
Roux et al. [90] NI Written, oral comprehension NDI
Naming
Language fluency
Reading
(Computation)
Dictation
Repetition
Written transcription
(Object handling)
Scarone et al. [84] Within 48 h, 3 months postsurgery, then every Counting
6 months Object naming
Spontaneous speech

BDAE:
Mechanics of writing examination Based on the patient’s written output (name,
address . . .)
Recall of written symbols Serial writing (automised), Primer-level
dictation
Dictated words 10 words with increasing length and
complexity
Written confrontation naming Pictures from oral naming tasks
Written formulation Cookie theft (free narrative, to dictation)
Sentences to dictation 10 sentences graded in length and
grammatical complexity
Auditory comprehension
Wu et al. [81] Immediately, 3 months postsurgery BNT
MAE Visual Naming
MAE Token Test
Sarubbo et al. [89] Unknown Laiacona-Capitani Naming Test
Token Test
Duffau et al. [53] Immediately, 3 months, every 6 months Verbal comprehension, spontaneous speech, NDI
Duffau et al. [2] postsurgery naming, verbal fluency, narrative tasks,
repetition
Sanai et al. [47] Unknown Counting Counting 1–50
Naming Object naming (slide show)
Reading Reading single words
Repeating Repeating complex sentences
Writing Writing words and sentences
 Bello et al. [51] 3, 30 and 90 days after surgery Spontaneous speech Describe reason for admission to the
Bello et al. [78] hospital
Phonological fluency Letters F, P, L (1 min per letter)

Semantic fluency Categories, such as cars, fruit, and animals

(1 min)
Famous face naming Famous and unknown faces, fame

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judgment + naming
Object picture naming Nonliving, living categories, body parts,
musical instruments
Action picture naming Verb oral naming subtest
Word comprehension Match word (1) to pictures (5)
Sentence comprehension Match sentence (1) to pictures (2)

Transcoding tasks: Repetition Non-words, words, sentence, syntagm

repetition
Token Test
(Digit Span)
Counting
Talachi et al. [79] 2-3 months Naming Visual objects
Phonological fluency Letters F, A, S
Leclerq et al. [94] Unknown Counting NDI
Naming Pictures
Pereira et al. [7] Unknown Writing ability NDI
Speech questionnaire Grade system (from 0 to 5)
Vassal et al. [91] 1 day, 4 and 5 days, 3 months postsurgery DO80 Black and white pictures
Papagno et al. [92] 3-7 days, 3 months postsurgery Phonological fluency NDI
Semantic fluency NDI
Naming Famous faces (50 items),
nouns (82 items), verbs (50 items),
naming by description (38 items)
Pointing to picture 48 items
Sentence comprehension Token Test
Picture-to-sentence matching 80 items
Repetition Syllables, words, nonwords, sentences
Bertani et al. [11] Immediately, 3 months after surgery NI
Quinones-Hinojosa Unknown NI
et al. [75]
Sacko et al. [57] 3 months and 1 year after surgery NI

NI, no information (missing data); NDI, no detailed information; AAT, Aachener Aphasie Test; BDAE, Boston Diagnostic Aphasia Examination; DO80, Dénomination Orale (80 items); BNT, Boston Naming Test; BADA, Batteria per
l’analisi dei deficit afasici; MAE, Multilingual Aphasia Examination.

141
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months during follow-up. A longitudinal follow-up is relevant to
identify factors that may predict postoperative language outcome
[5–7,50,65,79,80,97]. Although postoperative fMRI may add to the
study of the dynamic processes subserving language reorganisation
only Roux et al. [33] performed fMRI studies in the postoperative
phase.
3.2.4. Conclusion
Although DES and the awake procedure are generally thor-
oughly described, the literature is only scantily documented with
information about the linguistic tasks applied in the pre-, intra-,
and postoperative phase of awake interventions. In addition, little
is known about the standardisation of the language paradigms used
in an awake setting.
In the pre- and postoperative phase, standardised linguistic
test batteries are usually applied to evaluate linguistic functions
[6,15,17,60]. However, extensive neuropsychological assessments
are often not performed [55,79,80]. No consensus exists with regard
to the linguistic tasks that may suit pre- and postoperative mapping
with fMRI, PET and TMS best.
In the intraoperative phase, extensive tests cannot be applied
to investigate language functions, and a tailored selection of tasks
is required [14,60]. The linguistic tasks currently used during DES
are restricted in number and often lack the sensitivity to examine
a variety of linguistic functions in sufficient detail (e.g. phonol-
ogy, semantics, grammar) [2,51,61,95]. The variability of linguistic
tasks used during DES makes it difficult to compare the linguistic
outcome reported in the follow-up studies.
In conclusion, the linguistic tasks used for intraoperative lan-
guage mapping with DES and pre- and postoperative fMRI, DTI
applications currently lack a solid scientific basis, and there are no
reliable guidelines for linguistic testing during awake interventions
[13].
4. Future directions
DES has high sensitivity and low specificity. According to Man-
donnet et al. [14], improvement of the specificity of DES should
follow from: (1) studies recording the distant effects of axonal
stimulation to investigate brain effective connectivity; (2) biomath-
ematical modelling to describe the neurophysiological mechanisms
involved at the level of single cells and long-range networks;
and (3) longitudinal studies with non-invasive imaging (e.g. fMRI)
to study neural reorganisation after surgical resection under
DES.
Advances in non-invasive mapping will improve surgical plan-
ning and functional follow-up. In this respect TMS, DTI and
tractography are promising techniques [12,26]. Further refinement
of neuronavigational systems, and assisting devices such as the
‘mapping grid’ will enable to delineate more accurately functionally
critical brain regions and tumour location. As a result, the quality of
tumour removal and the duration of life expectancy will increase
[26]. The extent of resection and preservation of a margin around
the critical regions is currently a matter of debate. Further studies
are needed that investigate functional outcome after total or even
supratotal resection [1,10,65].
In addition, more evidence from studies comparing cortico-
subcortical DES with pre- and postoperative mapping techniques
is needed to increase insights in the (re)organisation of criti-
cal areas. Current connectionist’s models have to be critically
evaluated with regard to treatment (e.g. second surgery)
[3,4,10,12,23,29,47,58,60,61].
Considerable progress needs to be made with regard to the lin-
guistic paradigms used in awake procedures. The linguistic test
battery should be expanded with more specific and sensitive tasks
taking into consideration the constraints of the awake proce-
dures. A formal protocol is needed that includes different tasks
(phonological, semantic, grammar tasks) controlled for linguistic
variables (e.g. frequency, familiarity, word length, phonological
and morphological form, . . .). Consequently, further research is
necessary to develop and standardise a linguistic protocol for
awake surgery. A standardised approach will improve the sci-
entific reliability of the neurosurgical procedure and will allow
a number of additional data analyses adding to current insights
in brain-behaviour relationships. Since intraoperative mapping
requires a personalised approach, a tailored selection per patient
based on the localisation of the tumour and the preoperative
level is of crucial importance. Therefore, a set of standardised
linguistic tests to choose from would be very useful for intraop-
erative linguistic mapping. In addition, cognitive tasks measuring
attention, memory, calculation, executive functioning, visual cog-
nition, etc. should be included in the intraoperative protocol
depending on the localisation of the tumour and the specific
needs of the patient [79,98]. For instance, Roux et al. [99] used
a line bisection task to map visuo-spatial functioning during
cortico-subcortical stimulation of the right hemisphere in 50 brain-
lesioned patients. In the study of Gras-Combe et al. [100], the optic
radiations were subcortically mapped in 14 patients who under-
went awake resection of a glioma involving visual pathways. A
modified picture-naming task with two pictures placed diagonally
on the screen (one in the quadrant to save, one in the opposite
quadrant) and a red cross at the centre of the screen was pre-
sented. While staring at the red cross, the patients had to name
both pictures. Examination of affective functions might be rele-
vant as well. Giussani et al. [101] assessed emotional functions
with a facial emotion recognition task in 18 patients with right
hemisphere lesions. The patients were asked to name the facial
expression that was illustrated on a photo while the cortex was
stimulated.
The more functions are tested, the more critical areas are identi-
fied which may interfere with a total tumour resection. Therefore,
an optimal balance has to be found between the extent of resection
and the preservation of functions strongly related to outcome and
quality of life of the patient [98].
Comparisons have been made between the outcome of awake
surgery and classic surgery [1,2,19,20,56,57,59] indicating that
awake surgery with DES should be implemented as the standard
approach for glioma surgery. Randomised controlled studies to
determine the impact of DES on survival rate are difficult to con-
duct for ethical reasons [18,50]. Comparison studies in which
awake patients are matched with non-awake patients according
to tumour location, WHO tumour grade, tumour volume, patient’s
age, sex, handedness, intelligence, educational level, etc. would be
ideal [81]. Comparative studies using standardised methods may
lead to scientifically reliable information about the most appro-
priate type of neurosurgical intervention and can show in which
conditions awake surgery with DES offers the most favourable
outcome.
Postoperative outcome of DES has been investigated in a number
of studies. Most of these studies [2,10,27,28,52,53,55,60,82,102]
had only a limited follow-up of 3 months to 1 year. However,
since tumours may recur, a more extended follow-up is needed.
Several studies [5–7,50,65,79,80,93,97,103] have emphasised the
importance of longitudinal neurolinguistic and quality of life
follow-up from the pre- to the postoperative phase until 2 years
postsurgery or even longer. It is expected that longitudinal studies
based on a large series of patients and detailed neurolinguistic
data will identify factors that may predict postoperative language
outcome and will enable objective evaluation of the qualitative
(linguistic outcome, quality of life) and quantitative outcome (real
life expectancy).
 E. De Witte, P. Mariën / Clinical Neurology and Neurosurgery 115 (2013) 127–145
5. Conclusion
Awake surgery with DES is a reliable and safe technique for
the surgical treatment of tumours in critical language areas. The
criteria of ‘operability’ have been modulated and it has become pos-
sible to maximise the resection while minimising the postoperative
linguistic deficits. Yet, additional use of advanced non-invasive
imaging techniques such as fMRI, DTI, TMS is required to plan, guide
and evaluate surgical outcome.
Further research concerning the specificity of DES, integration of
multimodal imaging data, longitudinal follow-up and brain plastic-
ity will improve the awake procedure. In addition, the development
and standardisation of a linguistic protocol for intraoperative map-
ping will offer unique opportunities to maximally reduce the risk
of permanent language impairments in the postoperative phase.
Acknowledgement
Elke De Witte is a PhD fellow of the Research Foundation-
Flanders (FWO).
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