The neurolinguistic approach to awake surgery reviewed

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 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 b

a r t i c l e

i n f o

Article history: Received 6 May 2012 Received in revised form 6 August 2012 Accepted 7 September 2012 Available online 2 October 2012 Keywords: Awake craniotomy Direct electrical stimulation Language mapping Language testing Review

a b s t r a c t Objectives: Intraoperative direct electrical stimulation (DES) is increasingly used in patients operated on for tumours in critical language areas. Although a positive impact of DES on postoperative linguistic outcome is generally advocated, the literature is only scantily documented with information about the linguistic methods applied in awake surgery. This article critically reviews the neurolinguistic procedures currently used in awake studies. Methods: Based on an extensive review of the literature, an overview is given of the language mapping techniques applied in brain tumour surgery. Studies investigating linguistic testing and outcome in awake surgery were analysed. Information about the timing of the assessment(s), the linguistic tasks, the linguistic stimuli and the indication for awake surgery was also discussed. Results: Intraoperative DES remains the ‘gold standard’ for language mapping, but pre- and postoperative 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. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . History. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . State of the art . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Imaging techniques in awake surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Preoperative imaging techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Intraoperative imaging techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Postoperative imaging techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4. Correlations between imaging techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Language tasks in awake surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Preoperative language tasks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Intraoperative language tasks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Postoperative language tasks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author at: Department of Neurology, ZNA Middelheim Hospital, Lindendreef 1, B-2020 Antwerp, Belgium. Tel.: +32 032803136; fax: +32 032813748. E-mail addresses: [email protected], [email protected] (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

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Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Surgical treatment of supratentorial tumours (particularly gliomas) aims to maximise the quality of resection while minimising the risk of postoperative functional sequellae (including speech and language impairments) [1–7]. Low-grade gliomas, classified as WHO grade II tumours [8], are infiltrative tumours characterised by continuous and slow progression, migration, and anaplastic transformation [9–12]. Since gliomas are often located in critical language areas, the preservation and restoration of language function are of crucial importance [3,13]. Non-invasive language mapping methods, such as functional magnetic resonance imaging (fMRI), have been used to assess lateralisation and location of critical language areas for surgical preservation [14,15]. However, these imaging techniques do not seem to be highly reliable measures on which to base critical surgical decisions [16]. Direct electrical stimulation (DES) is currently applied as the standard intraoperative approach to language mapping to identify critical language areas and its pathways in the presence of a space-occupying lesion [2–5,13–15,17]. As DES requires conscious and cooperative patients, local anaesthesia (awake surgery) instead of general anaesthesia (classic surgery) is used. During DES, patients perform language tasks, such as picture naming tasks, verb-noun association tasks, comprehension tasks, repetition, reading, and writing tasks. Picture naming is commonly used as basic language paradigm [6,18], and the selection of additional language tasks differs widely across centres. Transient disturbances of speech and language function (speech arrest, anarthria, dysarthria, speech apraxia, phonological and semantic deficits, paraphasias, perseverations, anomia, comprehension disturbances, agraphia, alexia) occur if the cerebral tissue is electrically stimulated at the level of a functional language ‘epicentre’. Consequently, this stimulated area must be preserved during tumour resection [3]. Awake surgery with intraoperative DES is generally considered to have a positive impact on postoperative linguistic outcome [1–7,13,15,17,19,20]. Although transient language impairments are common in the immediate postoperative phase, the majority of patients seem to recover within three months, and permanent postoperative language deficits seem to be rare [1,3,7,13,15,20]. As a result, intraoperative DES is often regarded as the ‘gold standard’ to map linguistic functions in patients with tumoural lesions in the language dominant hemisphere [2–5,13–15,17]. However, no studies exist in which a standardised linguistic protocol is applied to identify the critical language zones, and no detailed, long-term linguistic data have been recorded. After ten years of linguistic experimenting with language mapping in an awake neurosurgical setting, a critical evaluation of the available data is warranted. The aim of this article is to review whether DES using language mapping is still the ‘gold standard’ to identify critical language areas in brain tumour surgery. 2. History The traditional approach to brain tumour surgery is resection of the mass lesion while preserving the main language centres of the brain: Broca’s and Wernicke’s area. In this approach, the brain is considered to be ‘static’ and to have a fixed functional neuroanatomical organisation that is similar in all patients [12].

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This “localisationist’s view”, based on ‘post-mortem’ studies on language representation in the brain, relies on the view that specific language functions are invariably located in specific anatomical areas of the brain [21]. Fritsch en Hitzig (1870) experimented with electrocortical stimulation in animals and succeeded to elicit movements of the extremities of the animals [22]. The first evidence of brain mapping with DES in humans dates back to 1874. Bartholow stimulated the cerebral cortex of a 30-year-old woman through a skull defect resulting from osseous infiltration of an epithelioma. The electrical current caused movements in various parts of her body depending on which brain area was stimulated [22]. In the early 1930s, Penfield and co-workers used brain surgery to treat patients with intractable epilepsy. They hypothesised that if an aura could be provoked with electrical stimulation, it would be possible to locate the source of seizure activity and to resolve epilepsy by removing or destroying that tissue [22]. Subsequently, Penfield and Boldry (1937) introduced DES as a method to map the motor and sensory cortex in order to resect supratentorial tumours located in critical areas [13,19,22]. Penfield and Rasmussen (1950) started to map language and speech functions next to sensorimotor functions in awake brain surgery [13,22,23]. But it was the pioneer Ojemann (1979) who refined the technique. Ojemann showed that the areas identified to be crucially implicated in linguistic processing were not only located in the perisylvian language zone, but made up a larger cerebral network also involving subcortical white matter tracts. In addition, following refinement of the technique, evidence was found that language localisation is highly variable among individuals [13,22–25]. During the last 20 years non-invasive structural neuroimaging techniques (magnetic resonance imaging (MRI), computed tomography (CT)) and functional neuroimaging techniques (positron emission tomography (PET), functional MRI) became popular means to map the human brain and guide tumour surgery [23]. These techniques allowed researchers to study the whole brain, both in ‘healthy’ subjects and patients [4]. Functional mapping methods also demonstrated that there is a large interindividual variability in the neural organisation of linguistic functions. This observation supported a more ‘dynamic view’ on brain functions and ‘brain plasticity’, which is crucial in the process of functional recovery [12]. The first studies of preoperative functional mapping in tumour surgery used PET to map sensorimotor, language, and visual areas. During the past decades, fMRI has largely replaced PET [12]. However, fMRI has some major limitations with regard to the identification of functional language areas in patients with brain tumours. It cannot map subcortical language pathways [3,4,14] and cannot differentiate between ‘essential’ and ‘replaceable’ language areas [3,14]. The former limitation might be compensated by the use of diffusion tensor imaging (DTI), a non-invasive technique that enables to identify white matter tracts (subcortical language pathways). DTI however still needs to be validated and only provides anatomical information [12] (see Section 3.1.1). By contrast, on the basis of DES, ‘essential’ language regions (which should be preserved) and ‘modulatory’ areas (which may be compensated and resected without permanent functional loss) can be differentiated. Moreover, DES allows to map subcortical language areas as well. Although most studies [1–7,13,15,17,19,20] postulate that DES is an accurate, reliable, and safe technique

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to identify cortical and subcortical language areas, there are a number of limitations to this approach. Indeed, the technique cannot map the entire brain and it is rather demanding for both the awake patients and the staff. In addition, DES is time consuming 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. intraoperative 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 measures 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 cerebral 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 postoperative 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 ‘essential’ 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 identification – which ranges from 82 to 100% – the sensitivity of fMRI to identify linguistic functions is only 66% [3,13,18]. Since neurosurgical 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, language 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 specificity depends on the behavioural and control task paradigm. In comparison with fMRI the disadvantages of PET are a poor signalto-noise ratio, a mere moderate spatial resolution, and a poor

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temporal resolution. In addition, PET is more invasive and timeconsuming than fMRI. As with fMRI and any other observational technique, PET cannot separate functional ‘essential’ from ‘participating’ 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 fasciculus, 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 vulnerable 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 potential 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 preoperative motor mapping for tumours near the rolandic cortex. Shamov et al. [37] used rTMS combined with neuronavigation for preoperative 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 planning 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 coregistration 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 neuronavigation 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.

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Motor mapping with DES may be performed under general anaesthesia whereas for language (cognitive) mapping an asleep–awake–asleep procedure is generally used [28,40]. To eliminate 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 craniotomy). 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 generally 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 usually 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, repetition, 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 naming [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 stimulations (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 cortical 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 technique 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 cortical exposure allow aggressive resection of gliomas [47–49]. Duffau [50], however, postulated that decisions based on negative mapping 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 essential regions that should be preserved to avoid permanent language deficits. This is in contrast with other functional mapping techniques (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 noninvasive 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 impairments 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 postoperative 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 permanent 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 hospital expenses after postoperative intensive care unit. In a recent meta-analysis of the literature De Witt Hamer et al. [59] confirmed a generally favourable outcome of the awake patient group. The data of 8091 adult patients operated for supratentorial infiltrative 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 resections) and involved critical locations more frequently (99.9% versus 95.8%). In addition, awake surgery with DES allows more extensive resection since only the ‘critical/crucial’ language areas are preserved. The classical surgical approach uses a larger safety margin 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 language 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

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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. Yordanova 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 reshaping of the locoregional mechanism and/or the recruitment of remote areas (e.g. homologous areas in the contralateral hemisphere) [3,12,61]. Recent studies suggest that a second surgery should be performed when initially only partial 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 representations 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 subcortical 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 interactive cortico-subcortical networks rather than the sole product of individual centres. This connectionist view, the so-called ‘hodology’, 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 partial seizures, to the spreading of DES along the axon (acute false positives) and to brain plasticity (chronic false positives) [14]. Secondly, DES is time-consuming (lasts much longer than surgery under general anaesthesia) and only allows locoregional mapping (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, confusion 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]. Careful evaluation and selection of the patient, extensive planning, a detailed supply of information about the procedures and intensive 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 hospitalisation is consistently reported for awake surgery with DES, postsurgery sequellae requiring long-lasting, intensive and expensive rehabilitation strategies are avoided or kept to a minimum with a positive impact on Health Insurance costs (invalidity benefit). 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].

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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 postoperative 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 protection. 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 resolution 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 intraoperative tumour tissue, but only in high-grade (malignant) gliomas. Fluorescent 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 (5aminolevulinic acid) orally, dissolved in tap water. During the operation, 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 classification 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 language 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 plasticity to be studied as it can show possible new redistribution

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of functions following surgery that may be potentiated by specific 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 connectivity 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 language 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 functional 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 studied 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 function 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 mapping and subcortical DES in intraoperative mapping. Correlations between DTI and DES have been investigated and positive correlations 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 parameters 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 evaluate 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 intraoperative DES. Although the development and validation of preoperative 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 intraoperative DES. Since fMRI and DTI identify essential and involved cortical and subcortical language areas as well as their connecting 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 timeconsuming [13,24]. Utilisation of fMRI and DTI data (and even data from PET, iMRI) during neuronavigation, may facilitate intraoperative 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, longitudinal 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]. Comparing 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 preoperative language protocol [2,6,47,51,53,55,60,63,78,79,81,89–91]. and/or semantic verbal fluency tasks Phonological [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 spontaneous 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 psychological 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 assessment(s)

Tasks

Stimuli

Ilmberger et al. [6]

1–3 days before surgery

AAT-subtests: Token Test Repetition Written language Naming Comprehension

Phonemes, words and sentences Reading, writing Objects, colours, scenes NDI

fMRI language paradigm(s) NI

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 Test run of language testing

NDI

Patients with scores of at least 50% in all modules of the test battery → fMRI: word generation: produce words beginning with that letter presented (phonological fluency)

Lubrano et al. [63]

10 days before surgery

BDAE → short version: Oral and written comprehension, naming, oral fluency, reading, dictation, repetition, written transcription, (calculation, and object handling)

NDI

NI

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 DO80

NDI

NI

Robles et al. [82]

Unknown

BDAE

NDI

NI

Lurito et al. [73]

Unknown

NI

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 BDAE → 8 subtests: Comprehension Written comprehension Repetition Written language comprehension Writing

Picture naming

Semantic fluency task, covert sentence repetition task, and story listening task

Sentence dictation

BDAE

NDI

Mandonnet et al. [46]

Unknown

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)

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Spena et al. [15]

Commands and logic Reading Words, concrete phrases, abstract phrases Spelling test

Semantic verbal fluency, covert sentence repetition, and story listening 133

Table 1 (Continued) Timing of assessment(s)

Tasks

Stimuli

fMRI language paradigm(s)

Bizzi et al. [74]

Time between fMRI and DES was within 3 weeks

NI

Verb generation (produce a verb silently in response to a noun)

Santini et al. [93]

Unknown

BADA: Phonemic discrimination Repetition Picture naming Auditory and visual word-to-picture matching Auditory and visual sentence-to-picture matching Writing to dictation Reading aloud Word Fluency:

NI Words Nouns and verbs Nouns and verbs

Unknown

Written, oral comprehension Denomination Language fluency Reading (Computation) Dictation Repetition Copying (Object handling)

NDI

NDI

Roux et al. [90]

Unknown

Written, oral comprehension 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

Verb generation (find verbs in relation to the objects presented) Naming (the patients were asked to name five objects shown by special MRI-design glasses)

Based on the patient’s written output (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

NI

Fluency in controlled word association, story listening, and covert sentence repetition tasks

Wu et al. [81]

Unknown

BNT MAE Visual Naming MAE Token Test

NI

Sarubbo et al. [89]

Unknown

Laiacona-Capitani Naming Test Token Test

NI

Duffau et al. [53] Duffau et al. [2]

Unknown

Verbal comprehension, spontaneous speech, naming, verbal fluency, narrative tasks, repetition

NDI

NI

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Letters F, A, S Roux et al. [33]

134

Study

Sanai et al. [47]

Unknown

Counting Naming Reading Repeating Writing

Counting 1–50 Object naming, slide show Reading single words Repeating complex sentences Writing words and sentences

NI

Bello et al. [51] Bello et al. [78]

Unknown

Spontaneous speech

Describe reason for admission to the hospital Letters F, P, L (1 min per letter)

Semantic fluency, story listening, and covert sentence repetition tasks

Phonological fluency

Categories, such cars, fruit, and animals (1 min)

Famous face naming

Famous and unknown faces, fame judgment + naming Nonliving, living categories, body parts, musical instruments Verb oral naming subtest Match word (1) to pictures (5) Match sentence (1) to pictures (2) Non-words, words, sentence, syntagm repetition

Object picture naming Action picture naming Word comprehension Sentence comprehension Transcoding tasks: repetition Token Test (Digit Span) Counting Talachi et al. [79]

Assessments were performed in 2 or 3 sessions over a period ranging from 1 to 5 days

Naming Phonological fluency

Visual objects Letters F, A, S

NI

Leclerq et al. [94]

Unknown

Bedside examination

NDI

NI

Pereira et al. [7]

Unknown

(Neuropsychological testing: WAIS III, Raven, MMPI)

NDI

NI

Vassal et al. [91]

Unknown

Phonological fluency Semantic fluency BDAE Naming DO80 Montreal Evaluation of Communication protocol

Letter P Animals

Verb generation (produce a semantically associated verb silently in response to an auditorily presented noun) → activation task Countdown task → control task

Phonological fluency Semantic fluency Naming

NDI NDI Famous faces, 50 items Nouns, 82 items Verbs, 50 items Naming by description,38 items 48 items Token Test 80 items Syllables, words, nonwords, sentences

Papagno et al. [92]

In the week before surgery

Pointing to picture Sentence comprehension Picture-to-sentence matching Repetition Bertani et al. [11] Quinones-Hinojosa et al. [75] Sacko et al. [57]

80 black and white pictures

Verb generation task (produce a semantically associated verb in respond to an object picture) Naming (objects)

Unknown Unknown

NI NI

NI NI

Unknown

NI

NI 135

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; WAIS III, Wechsler Adult Intelligence Scale III; MMPI, Minnesota Multiphasic Personality Inventory.

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Semantic fluency

136

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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], Teixidor 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 auditory 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 carefully 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 during 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 disturbances 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 normative 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) during 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 intraoperative 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 language 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 supramarginal gyri. Semantic or repetition tasks were used for tumours in the left mid-posterior temporal lobe. In Bello et al. [51,78], counting and object naming tasks were used to investigate frontal lesions, whereas object naming tasks and word and sentence comprehension tasks were used for temporal lesions. Mandonnet et al. [14] postulated that repetition tasks should be added to study the functional 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. Polczynska [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. Polczynska [95] developed three sets of ‘home made’ tasks that were used in patients with a multi-electrode subdural grid (extraoperative) and classified these tests as: (1) ‘grammar-focused tests’, (2) ‘non-dominant right-hemisphere tests’, and (3) ‘tests for subcortical stimulation’. The syntax tests (1) include making questions and negations of a presented stimulus sentence, producing inflections (e.g. I go → He. . .), production of regular and irregular plural forms (e.g. car–cars, sheep–sheep), and spontaneous speech production. The language tests composed to examine non-dominant right hemisphere function (2) contain tests investigating alternative 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 sentence. 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 stimulation (3) involve naming, articulation and language dynamics. Though these tests have not yet been applied during intraoperative 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 studies reveals that picture naming and/or counting are typically 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. However, 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 language 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 protocol [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 linguistic 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. Method

Tasks

Stimuli

Indication

Ilmberger et al. [6] Lubrano et al. [63]

Cortical, subcortical DES Cortical, subcortical DES

Confrontation naming Naming

Picht et al. [17] Vassal et al. [91]

Cortical, subcortical DES Cortical, subcortical DES

Naming Naming: DO80

Pictures of objects Pictures of objects → line drawing (black and white) Pictures → line drawings Black and white pictures

Papagno et al. [92]

Cortical, subcortical DES

Naming

Quinones-Hinojosa et al. [75] Benzagmout et al. [10]

Cortical DES

Counting

Living and non-living objects, famous faces, verbs Number counting

Cortical, subcortical DES

Counting Naming: DO 80

1–10 over and over again Black and white pictures

Duffau et al. [34]

Cortical, subcortical DES

Yordanova et al. [60]

Cortical, subcortical DES

Robles et al. [82]

Cortical, subcortical DES

Counting Naming: DO 80 Counting Naming: DO 80 Counting Naming: DO 80

1–10 over and over again Black and white pictures 1–10 over and over again Black and white pictures 1–10 over and over again Black and white pictures

Lesions near or within language-related brain areas Brain tumours and cavernomas located within or invading the dominant inferior frontal cortex Left hemisphere tumours Right frontotemporal (close to the insula), right temporal gliomas Left temporal, frontal, parietal, right temporal and parietal LGGs and HGGs Lesions near precentral gyrus, central sulcus, postcentral gyrus, frontal operculum, angular gyrus LGGs in Broca’s area (involving the pars opercularis and pars triangularis of the left inferior frontal gyrus, BA 44, 45) LGGs located within the dominant hemisphere

Mandonnet et al. [46]

Cortical, subcortical DES

Scarone et al. [84]

Cortical, subcortical DES

Counting Naming DO80 Counting Naming DO80

Brennan et al. [83]

Cortical DES

Lurito et al. [73]

Cortical DES

1–10, over and over again Black and white pictures 1–10, over and over again Slides with black and white pictures Number counting Object naming paradigms NDI Object naming

De Benedictis et al. [1]

Cortical, subcortical DES

Duffau et al. [52]

Cortical, subcortical DES

Duffau et al. [27]

Cortical, subcortical DES

Leclerq et al. [94]

Cortical, subcortical DES

Sarubbo et al. [89]

Cortical, subcortical DES

Santini et al. [93]

Cortical, subcortical DES

Duffau et al. [53] Duffau et al. [2]

Cortical, subcortical DES

Sanai et al. [47]

Cortical DES

Counting Naming (BDAE) Counting Naming

LGGs in noneloquent areas in left dominant hemisphere Patients with cortico-subcortical LGGs, selection of patients with tumours involving dominant striatum (putamen, caudate) WHO grade II gliomas in left dominant hemisphere (in eloquent regions) LGGs located in language areas

Left frontal lesion, temporal lesion Gliomas in left perisylvian region Identification of Broca area Identification of Wernicke area LGGs in functional areas (already operated under general anaesthesia) Corticosubcortical LGGs in language regions in left dominant hemisphere Corticosubcortical WHO grade II gliomas located in eloquent areas in left dominant hemisphere LGGs or cortical dysplasia located in language areas

Counting Naming Counting Naming Counting Naming Counting Naming Counting Naming Counting Naming + additional tasks e.g. reading, comprehension tasks Counting, naming, reading

NDI Pictures NDI Pictures 1–10 (over and over again) Pictures NDI Pictures 0–10 Several naming tasks If impairment was observed in a specific BADA subtest, additional tasks were administered Pictures

Corticosubcortical LGGs in eloquent brain areas

(+Calculation task) + Semantic, repetition task

NDI ND

Counting Naming Reading

Counting 1–50 Object naming Reading single words

Lesions in left angular and supramarginal gyri Tumours in the left mid-posterior temporal lobe Dominant hemisphere gliomas in posterior inferior frontal, anterior inferior parietal lobe, inferior to midportion of the motor cortex, or any portion of the temporal lobe

LGGs located in eloquent areas

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Study

Gliomas in the left hemisphere

137

138

Table 2 (Continued) Method

Tasks

Stimuli

Indication

Teixidor et al. [55]

Cortical, subcortical DES

NDI

LGGs located in language areas

Sacko et al. [57]

Cortical, subcortical DES Cortical, subcortical DES

Pictures Basic unrelated sentences NDI

Lesions in eloquent areas

Pereira et al. [7]

Spena et al. [15]

Cortical, subcortical DES

Cortical, subcortical DES

Black and white pictures Spontaneous speech Reading from slides NDI Pictures of objects, actions, famous people Pictures of objects, actions, famous people Words and sentences

Eloquent area tumours

Bello et al. [51] Bello et al. [78]

Counting Picture naming Reading Naming Reading Naming objects Recalling objects Spontaneous naming Counting per minute Comprehension of complex commands Naming Spontaneous speech Reading Counting Oral naming Oral naming

Bertani et al. [11]

Cortical, subcortical DES

Wu et al. [81]

Asleep–awake–asleep

Bizzi et al. [74]

Cortical DES

Roux et al. [33]

Cortical DES

Roux et al. [90]

Cortical DES

Talachi et al. [79]

Awake mapping

Word and sentence comprehension Counting Verbal naming Verb generation Word- and sentence comprehension Speech motor mapping NI Verb generation

Naming Verb generation Counting Naming Reading aloud NI

NDI Object naming and famous faces naming NDI NDI

Lesions near eloquent cortex

Frontal lesion (Broca) Frontal lesion (oral naming essential sites) Temporal lesion Temporal lesion LGGs in eloquent regions

Insular gliomas Produce a verb silently in response to an auditorily presented noun Pictures of objects In response to objects NDI 30 pictures of various objects 30 different sentences

Focal mass in or adjacent to at least one eloquent area of the language or motor systems LGGs, HGGs, meningiomas in eloquent areas Tumours or other lesions (such as cortical dysplasia) in eloquent regions 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.

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Study

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 Written language Naming Comprehension AAT

Phonemes, words and sentences Reading, writing Objects, colours, scenes NDI NDI

Spena et al. [15]

Benzagmout et al. [10] Duffau et al. [34] Yordanova et al. [60]

Immediately, 3 and 6 months after surgery Immediately, 3 months after surgery 3, every 6 months thereafter

Robles et al. [82] Lurito et al. [73] Brennan et al. [83]

Immediately, 3 months after surgery Unknown Unknown

De Benedictis et al. [1]

Immediately, 3 months, every 6 months after surgery Immediately, 3 months after surgery Immediately, 3 and 6 months Immediately (within 7 days) and 3 months after surgery

Duffau et al. [52] Duffau et al. [27] Teixidor et al. [55]

Mandonnet et al. [46] Bizzi et al. [74]

Immediately, 3 months postsurgery Within 7 days and at 3 months postsurgery

Santini et al. [93]

3, 6 months postsurgery

NI (probably same as preop phase) BDAE → short version: Oral and written comprehension, naming, oral fluency, reading, dictation, repetition, written transcription, (calculation, and object handling) BDAE (adapted version) BDAE BDAE DO 80 BDAE NI BDAE: Naming BDAE NI (probably same as preop phase) BDAE DO80 BDAE → 8 subtests: Auditory comprehension Written comprehension Repetition Written language comprehension: Writing BDAE Verbal fluency denomination comprehension BADA: Phonemic discrimination Repetition Picture naming Auditory and visual word-to-picture matching Auditory and visual sentence-to-picture matching Writing to dictation Reading aloud Word fluency

NDI

NDI NDI NDI NDI NDI NDI

NDI Picture naming Commands, logic and reasoning Reading Words, concrete phrases, abstract phrases Spelling test Sentences to dictation NDI NDI NDI Simple objects and categories Words Nouns and verbs Nouns and verbs

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Picht et al. [17] Lubrano et al. [63]

1 Week, 3 months, 6 months after surgery and then yearly 2 Weeks after surgery Immediately, 2 and 3, months postsurgery Patients with gliomas were systematically tested again at 6 months postsurgery

Letters F, A, S

139

140

Table 3 (Continued) Timing of assessment(s)

Tasks

Roux et al. [33]

Language and neuropsychological testing: 4 to 8 weeks postsurgery fMRI in 7 patients (of 14 patients): 1 to 2 months after surgery

Written, oral comprehension Denomination Language fluency Reading (Computation) Dictation Repetition Copying (Object handling) Verb generation (during POSTOP fMRI) Naming (during POSTOP fMRI)

Roux et al. [90]

NI

Scarone et al. [84]

Within 48 h, 3 months postsurgery, then every 6 months

Written, oral comprehension Naming Language fluency Reading (Computation) Dictation Repetition Written transcription (Object handling) Counting Object naming Spontaneous speech BDAE: Mechanics of writing examination Recall of written symbols Dictated words Written confrontation naming Written formulation Sentences to dictation

Wu et al. [81]

Immediately, 3 months postsurgery

Sarubbo et al. [89]

Unknown

Duffau et al. [53] Duffau et al. [2]

Immediately, 3 months, every 6 months postsurgery

Sanai et al. [47]

Unknown

Auditory comprehension BNT MAE Visual Naming MAE Token Test Laiacona-Capitani Naming Test Token Test Verbal comprehension, spontaneous speech, naming, verbal fluency, narrative tasks, repetition Counting Naming Reading Repeating Writing

Stimuli

Find verbs in relation to the objects presented The patients were asked to name five objects shown by special MRI-design glasses NDI

Based on the patient’s written output (name, address . . .) Serial writing (automised), Primer-level dictation 10 words with increasing length and complexity Pictures from oral naming tasks Cookie theft (free narrative, to dictation) 10 sentences graded in length and grammatical complexity

NDI

Counting 1–50 Object naming (slide show) Reading single words Repeating complex sentences Writing words and sentences

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Study

Bello et al. [51] Bello et al. [78]

3, 30 and 90 days after surgery

Spontaneous speech Phonological fluency Semantic fluency

Object picture naming Action picture naming Word comprehension Sentence comprehension Transcoding tasks: Repetition

Talachi et al. [79]

2-3 months

Leclerq et al. [94]

Unknown

Pereira et al. [7]

Unknown

Vassal et al. [91] Papagno et al. [92]

1 day, 4 and 5 days, 3 months postsurgery 3-7 days, 3 months postsurgery

Bertani et al. [11] Quinones-Hinojosa et al. [75] Sacko et al. [57]

Token Test (Digit Span) Counting Naming Phonological fluency Counting Naming Writing ability Speech questionnaire DO80 Phonological fluency Semantic fluency Naming

Immediately, 3 months after surgery Unknown

Pointing to picture Sentence comprehension Picture-to-sentence matching Repetition NI NI

3 months and 1 year after surgery

NI

Categories, such as cars, fruit, and animals (1 min) Famous and unknown faces, fame judgment + naming Nonliving, living categories, body parts, musical instruments Verb oral naming subtest Match word (1) to pictures (5) Match sentence (1) to pictures (2) Non-words, words, sentence, syntagm repetition

Visual objects Letters F, A, S NDI Pictures NDI Grade system (from 0 to 5) Black and white pictures NDI NDI Famous faces (50 items), nouns (82 items), verbs (50 items), naming by description (38 items) 48 items Token Test 80 items Syllables, words, nonwords, sentences

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Famous face naming

Describe reason for admission to the hospital Letters F, P, L (1 min per letter)

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 thoroughly 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. phonology, 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 language 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 Mandonnet 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) biomathematical 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 planning 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 corticosubcortical DES with pre- and postoperative mapping techniques is needed to increase insights in the (re)organisation of critical 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 linguistic 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 procedures. 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 scientific 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 intraoperative linguistic mapping. In addition, cognitive tasks measuring attention, memory, calculation, executive functioning, visual cognition, 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 brainlesioned patients. In the study of Gras-Combe et al. [100], the optic radiations were subcortically mapped in 14 patients who underwent 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 presented. While staring at the red cross, the patients had to name both pictures. Examination of affective functions might be relevant 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 identified 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 conduct 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 appropriate 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).

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