Intraoperative electrical stimulation = in awake craniotomy: methodological aspects of current practice; = Neurosurgical FOCUS

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February 2010 = Volume 28, Number = 2

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Intraoperative electrical stimulation = in awake=20 craniotomy: methodological aspects of current = practice

Andrea Szel=C3=A9nyi, = M.D.,=20 Ph.D.¹, Lorenzo Bello,=20 M.D.², Hugues Duffau, M.D.,=20 Ph.D.³, Enrica Fava,=20 M.D., Ph.D.², Guenther C. Feigl,=20 M.D.⁴, Miroslav Galanda, M.D., = Ph.D.⁵, Georg Neuloh,=20 M.D.⁶, Francesco Signorelli,=20 M.D.⁷, and Francesco Sala,=20 M.D.⁸

¹Department of = Neurosurgery, Johann=20 Wolfgang Goethe University, Frankfurt am Main,=20 Germany; = ²Department of=20 Neurosurgery, University of Milan, Italy; ³Department of = Neurosurgery,=20 University of Montpellier, France;=20 ⁴Department of Neurosurgery, University of=20 T=C3=BCbingen, Germany;=20 ⁵Department of Neurosurgery, University = Hospital,=20 Bansk=C3=A1 Bystrica, Slovakia;=20 ⁶Department of Neurosurgery, University of = Bonn,=20 Germany; = ⁷Department of=20 Neurosurgery, University of Catanzaro; and ⁸Department of = Neurosurgery,=20 University of Verona, Italy

Abbreviations used in this = paper:=20 CUSA =3D Cavitron ultrasonic aspirator; DT =3D = diffusion tensor;=20 ECoG =3D electrocorticography; EMG =3D = electromyography; MEP =3D=20 motor evoked potential.

Address correspondence = to:=20 Andrea Szel=C3=A9nyi, M.D., Department of = Neurosurgery, Johann=20 Wolfgang Goethe University Hospital, Schleusenweg = 2-16,=20 D-60528 Frankfurt am Main, Germany. email: A.Szelenyi@em.uni-frankfurt.de.

DOI: 10.3171/2009.12.FOCUS09237

Figures = and Tables=20

Abstract	IntroductionElectrical = StimulationDocumentation of = Stimulat...Controversies in = Mapping...ConclusionsDisclosureAcknowledgmentsReferences

There is increasing evidence = that the=20 extent of tumor removal in low-grade glioma surgery is = related=20 to patient survival time. Thus, the goal of resecting = the=20 largest amount of tumor possible without leading to = permanent=20 neurological sequelae is a challenge for the = neurosurgeon.=20 Electrical stimulation of the brain to detect cortical = and=20 axonal areas involved in motor, language, and = cognitive=20 function and located within the tumor or along its = boundaries=20 has become an essential tool in combination with awake = craniotomy. Based on a literature review, discussions = within=20 the European Low-Grade Glioma Group, and illustrative = clinical=20 experience, the authors of this paper provide an = overview for=20 neurosurgeons, neurophysiologists, linguists, and=20 anesthesiologists as well as those new to the field = about the=20 stimulation techniques currently being used for = mapping=20 sensorimotor, language, and cognitive function in = awake=20 surgery for low-grade glioma. The paper is intended to = help=20 the understanding of these techniques and facilitate a = comparison of results between users.

KEYWORDS:awake craniotomy; = direct=20 cortical stimulation; low-grade glioma surgery; brain=20 mapping.

Introduction	AbstractIntroduction = <<Electrical = StimulationDocumentation of = Stimulat...Controversies in = Mapping...ConclusionsDisclosureAcknowledgmentsReferences		<= IMG=20 height=3D9 hspace=3D5=20 = src=3D"http://thejns.org/templates/jsp/images/arrow_up.gif"=20 width=3D11 border=3D0>

The direct = intraoperative=20 application of electric current onto the human cortex = for=20 localizing and activating function dates back to the=20 1930s.^10,20,37 Its=20 definite impact on preserving function in the = resection of=20 low-grade gliomas has been reported.^{6=E2=80=938,13,18,36}=20 Nevertheless, methodological rigor and the meticulous=20 performance of mapping procedures are indispensable to = avoid=20 any false-positive or false-negative stimulation = results,=20 which could lead to inadequate tumor resection or = cause=20 permanent neurological deficits. If all the technical = rules=20 are not respected faithfully, inaccurate results will = create a=20 false sense of security, which could lead to undesired = surgical results and permanent neurological sequelae. = Based on=20 published material, personal experience, and = discussions with=20 members of the European Low-Grade Glioma Group who are = dedicated to the intraoperative stimulation procedure, = the=20 most important aspects of brain mapping during = surgeries in=20 awake patients are presented and reviewed.

The purpose of the mapping procedure = is to=20 reliably identify cortical areas and subcortical = pathways=20 involved in motor, sensory, language, and cognitive = function.=20 Although similar techniques are utilized, the = application of=20 mapping at different centers involves a diversity of=20 approaches.

Electrical = Stimulation	AbstractIntroductionElectrical Stimulation=20 <<ConclusionsDisclosureAcknowledgmentsReferences

The technical aspects of electrical stimulation = include the=20 stimulator device; the stimulation parameters = consisting of=20 the individual pulse type, pulse width, frequency of=20 stimulation, and applied intensity; and the = stimulation probe=20 being used to deliver the electric current.

Stimulator Device=20

For brain mapping purposes, = constant-current=20 stimulators are considered safer and more reliable = because=20 they deliver the preset current independently from the = impedance of the cortical or subcortical surface. = Conversely,=20 in constant-voltage stimulators, the delivered current = also=20 depends on the impedance. Hence, if impedance = decreases, the=20 amount of current delivered can dramatically increase = and=20 compromise the safety of the procedures. An extensive=20 discussion of the differences between constant-current = and=20 constant-voltage stimulators is beyond the scope of = this=20 review.

Stimulation Parameters=20

For brain mapping, a low frequency paradigm has = been=20 established, consisting of the application of short = pulse=20 trains with frequencies of 25=E2=80=9360 Hz. The most = commonly applied=20 frequencies are 50 Hz (Europe) or 60 Hz (North = America).

The individual pulse is rectangular and either = monophasic=20 or biphasic (Fig. 1). = As=20 described in the first experiments, cortical = stimulation is=20 more effective with anodal current; that is, a lower=20 stimulation intensity is needed to see a stimulation=20 effect.^21,23 Thus,=20 the first phase of the pulse should be anodal. If a = monophasic=20 pulse is used, it should be anodal (or positive); if a = biphasic pulse is used, it should be in an = anodal/cathodal=20 mode. The anodal phase duration can vary between 0.2 = and 0.5=20 msec. In applying a biphasic current, the duration of = the=20 pulse includes both the positive and negative phases.=20 Therefore, only half of the pulse duration is anodal = and=20 effective for stimulation=E2=80=94meaning that a = monophasic pulse of=20 0.5 msec delivers the same anodal current as a = biphasic pulse=20 of 1 msec. However, as the charge is dependent on = pulse=20 duration (charge [Asec] =3D pulse duration [sec] = =C3=97 intensity=20 [A]), the charge applied to the brain using a biphasic = pulse=20 is twice that applied using the same current but with = a=20 monophasic pulse. For safety considerations, the = maximum=20 stimulation intensity should not exceed 40=20 =CE=BCC/cm²/phase and is commonly limited = to 20=20 mA.¹ = For a=20 detailed physical background regarding monopolar = versus=20 bipolar stimulation techniques see the study by Kombos = and=20 S=C3=BCss.²⁸

View = larger=20 version (11K)

Fig. 1. = Schematic of=20 monophasic and biphasic pulse = forms.

Historically, at times when only = uncoupled=20 stimulators were available, a biphasic pulse was seen = to be=20 less neurotoxic as the reversed pulse could minimize = those=20 effects.⁴⁰ With the=20 utilization of coupled stimulators and limited = application=20 times during surgical procedures, neurotoxic effects = have not=20 been described.^{2,22,31,40,41}

Stimulation Probe=20

The use of a bipolar probe with 2 tips separated by = 6=E2=80=9310 mm=20 has become standard (Fig. 2). = An=20 interelectrode distance > 10 mm seems to favor the=20 elicitation of large pyramidal tract neurons.²⁵=20 Alternatively, a monopolar probe with a frontal = reference=20 electrode can be used. The distribution of the = electric field=20 differs between monopolar and bipolar probes. Given = the same=20 stimulation intensities, a monopolar probe provides a=20 homogeneous radiant spreading electric field, which = leads to=20 lower current densities in the area surrounding the = reference=20 electrode but has the benefit of more spacious = stimulation=20 effects. With this probe the probability of = stimulating=20 nervous tissue at a more distant site increases. In = contrast,=20 stimulation with a bipolar probe creates an electric = field in=20 which the current density is more homogeneous and the = electric=20 field lines between both poles are close to parallel = (Fig.=20 3).^32,38 If=20 monopolar and bipolar electrodes have the same shape, = the=20 current density close to the stimulating electrodes is = the=20 same and the greatest.

View = larger=20 version (15K)

Fig. 2. = Schematic of=20 probes used for bipolar stimulation with = ball tips=20 (A) or straight tips (B) and = for=20 monopolar stimulations with a ball tip = (C)=20 or straight tip (D).

View = larger=20 version (16K)

Fig. 3. = Schematic of=20 electric field distribution in bipolar=20 (left) and monopolar (right) = stimulations.

Documentation of Stimulation's = Effect	AbstractIntroductionElectrical = StimulationDocumentation of Stimulat...=20 <<ConclusionsDisclosureAcknowledgmentsReferences

Observation of the Patient=20

The most simple and most complex task = for the=20 examiner is observing the patient's reaction to = stimulation.=20 Movement can be observed and categorized by its = complexity.=20 Clonic movement relates to stimulation of the primary = motor=20 area, whereas tonic movement is more related to = stimulation of=20 the premotor area (Area 6). Furthermore, the absence = of any=20 induced movement should be tested for negative motor = phenomena=20 (see Mapping of Motor Function).

Recording Electrodes=20

Small movements or movements at = distant sites=20 can go unrecognized. Simultaneous brain mapping and = monitoring=20 of muscle activity by continuous EMG recording (either = surface=20 electrodes or needle electrodes) can be = helpful.⁵⁰=20 Electromyography=E2=80=94complementary to = ECoG=E2=80=94also allows for early=20 detection of the spreading of muscle activation over a = limb as=20 a sign of seizure. These data can be stored and used = for=20 offline analysis and for the purpose of documentation. = To=20 record EMG activity, subdermal needle electrodes are = used and=20 are surprisingly well tolerated even during awake = procedures.=20 Alternatively, surface EMG electrodes placed in the=20 belly-tendon fashion can be used.

Mapping in Awake Patients=20

As stimulation-induced movements are = easy to=20 observe, it is typically recommended to start with the = mapping=20 of motor function. The presence of a speech therapist, = neuropsychologist, or neurologist is very important = for=20 observation and judgment, especially for language and=20 cognitive function. It is highly recommended to = introduce=20 members of the surgical team to the patient and to = explain the=20 intraoperative procedure as well as the testing to the = patient=20 at least a day prior to surgery. The patient might = feel=20 uncomfortable experiencing involuntary movement or the = inhibition of voluntary movement and language, which = could=20 lead to feelings of fear and angst and might be = accompanied by=20 an alteration of vital and vegetative signs such as = nausea,=20 hypertonia, and tachycardia. Moreover, patients might = conclude=20 from positive testing that the tumor has invaded = important=20 cortical structures and thus that the tumor surgery = might not=20 be successful. Some patients experience overwhelming = fear,=20 which could interfere with further testing and even = the whole=20 surgical procedure. In such patients, ECoG is helpful = for=20 ruling out nonconvulsive but focal temporal seizures. = The=20 patient's guidance is very important, and therefore = each step=20 of the testing and stimulation procedure should be = announced.=20 Patients should be carefully examined and asked about = any=20 sensation, feelings, or movements, especially the = contraction=20 of pharyngeal muscles, which might not be observed by = the=20 examiner.

Mapping of Motor Function=20

While performing direct cortical stimulation, the=20 stimulation intensity should be increased stepwise by = 1 mA=20 until a movement or EMG response is observed. This = stimulation=20 intensity should be used for further mapping of = sensorimotor,=20 language, and cognitive function. One to 2 msec = duration of=20 stimulation is sufficient to induce movement if the = primary=20 motor cortex is stimulated. Longer durations of = stimulus (2=E2=80=934=20 msec) are required to induce motor responses from = secondary=20 motor areas. Electromyography can be used to record = motor=20 phenomena, showing even low-amplitude muscle responses = and the=20 onset of clonic muscle activity (Fig. = 4).⁵⁰ Mapping=20 of motor function can be performed in both awake and=20 anesthetized patients. In awake patients, both muscle=20 activation and muscle inhibition should be = investigated,=20 following a protocol related to the site of surgery. = The=20 absence of movement might be explained by a=20 stimulation-induced inhibition of movement. In such = cases, the=20 testing of negative motor phenomena is helpful for = identifying=20 associative motor areas;³⁰ that is,=20 the patient is asked to perform a continuous = movement=E2=80=94for=20 example, alternating extension and flexion of the = wrist=E2=80=94which=20 is inhibited by the stimulation. Once a movement is = observed,=20 the whole of the exposed cortical area is = systematically=20 mapped every 5 mm² (according to the probe=20 spacing). The placement of sterile tags with numbers = or=20 letters on stimulationpositive spots is helpful for=20 visualizing the cortical areas involved in motor, = cognitive,=20 or language function.^14,37 A=20 meticulous drawing of the anatomy or a photograph and = notes=20 describing the evoked phenomena document the testing = as well=20 as help with further surgical planning and = intraoperative=20 reference.

View = larger=20 version (130K)

Fig. 4. = Awake surgery=20 ECoG (Traces 1=E2=80=934), surface = electroencephalography=20 (Traces 6=E2=80=939), and EMG traces = (remaining traces)=20 showing 60-Hz stimulations (6.5 mA) of the = premotor cortex. During stimulation for = language=20 testing, a speech arrest was induced, = followed by=20 clonic jerks in the right upper limb=20 muscles.

Mapping of Language and Cognitive=20 Function=20

For the mapping of language and cognitive function, = the=20 patient's compliance is very important, as is the = close=20 cooperation among members of the participating medical = team.=20 For stimulation-induced interference with speech, = language,=20 and cognition, the duration of the stimulus must be = longer=20 than that for motor mapping. The duration of = stimulation is=20 commonly set to 3=E2=80=934 seconds. To exclude = occasional=20 noncompliance or temporary impairment related to a=20 nonconvulsive seizure, every stimulation should start = after=20 presentation of the material has started and the = patient has=20 said an introductory sentence.²⁴ As=20 repetitive stimulation can trigger seizures (see = Side=20 Effects), one could use an alternating testing = mode; that=20 is, one in which the patient continuously performs = tasks, and=20 each task with stimulation is followed by a task with = sham=20 stimulation (Table = 1).

TABLE 1: = Practical=20 stimulation=20 = guide

During resection of the tumor, = continuous=20 assessment of function as well as the potential risk = of injury=20 is necessary to maximize the extent of resection and = prevent=20 iatrogenic injury. Continuous clinical assessment = during the=20 resection is alternated with cortical and subcortical = mapping=20 and specific testing of the function anatomically = closest to=20 the resection site. As subcortical pathways might be = involved=20 within the tumor and at risk during resection, = intermittent=20 subcortical stimulation and testing has been shown to = be=20 effective at successfully preventing iatrogenic = injury.^{5,13,15,16,26,29}

Motor Function=20

For continuous monitoring of motor function in = addition to=20 periodical cortical/subcortical mapping, intentional = movement=20 of the patient can be continuously assessed. However, = because=20 this process can be exhausting for the patient and = fatigue can=20 mimic paresis, the only way to truly continuously = assess the=20 functional integrity of the motor pathways is to = perform MEP=20 monitoring.

For this purpose, continuous direct cortical = stimulation of=20 the precentral gyrus can be performed with a modified=20 train-of-five technique. This technique, introduced = for=20 surgery in anesthetized patients, has been described = as=20 sensitive in detecting dysfunction of the motor cortex = and the=20 corticospinal tract.^{33=E2=80=9335,46=E2=80=9348}=20 A strip electrode containing 4=E2=80=938 electrodes = must be placed=20 over the precentral gyrus. In awake patients a single = stimulus=20 or a short train consisting of 2=E2=80=934 pulses = (individual pulse=20 width 0.3=E2=80=930.5 msec, anodal constant-current = stimulation;=20 interstimulus interval 4 msec, stimulation close to = motor=20 threshold) is usually sufficient to elicit muscle = MEPs. Motor=20 evoked potentials must be recorded either with needle=20 electrodes, preferably the same in use for continuous = EMG=20 assessment, or=E2=80=94if believed more convenient in = awake=20 patients=E2=80=94with surface EMG electrodes. The = method's advantage=20 lies in the independence of a patient's compliance and = the=20 ability to distinguish between lesions of the = supplementary=20 and those of the primary motor area.⁵¹=20 Moreover, MEPs are useful for preventing vascular = injury in=20 insular and/or deep temporal regions, where critical = arteries=20 are at risk during tumor resection.³⁴ Test=20 clamping can even be performed. The intraoperative use = of=20 direct cortical stimulation via a strip electrode to = elicit=20 MEPs can be performed repeatedly. As simultaneous = cortical and=20 subcortical stimulation can lead to false results, one = must=20 ensure that none of the methods is applied = simultaneously.

Note that the same stimulation = parameters=20 (short-train technique with interstimulus interval of = 4 msec)=20 used for continuous MEP monitoring from a strip = electrode can=20 be used for cortical (anodal stimulation) and = subcortical=20 (cathodal stimulation) mapping from a handheld = monopolar=20 probe. This option represents a valid alternative to = the=20 classic 60-Hz technique with the advantage of a lower = risk of=20 intraoperative seizures (see Side Effects).=20 Nevertheless, the widespread use of the short-train = technique=20 during awake surgery is just starting and has recently = been=20 reported as a possibility for language testing in = awake=20 patients.³

Cognitive and Language = Function=20

For cognitive and language tasks, = either=20 spontaneous speech or the continuous completion of=20 standardized tasks can be performed. It is beyond the = scope of=20 this paper to provide a detailed description and = philosophy of=20 the tests being utilized at different = centers.

Side Effects=20

Long-lasting side effects due to intraoperative = brain=20 stimulation have not been reported.²² Seizures=20 are the most common side effects and can be harmful to = the=20 patient, although there have been no reports of = serious injury=20 due to intraoperative seizures. Interestingly, = seizures are=20 easily terminated with the direct application of iced = Ringer=20 lactate onto the cortex.⁴⁴ Longer=20 stimulus durations can induce seizures and are related = to the=20 occurrence of afterdischarges at low stimulation = intensities.=20 Although preoperative epilepsy is expected to be = related to an=20 increased occurrence of intraoperative seizures, there = are no=20 data supporting this assumption.⁴⁵=20 Intraoperative seizures most frequently develop in = patients=20 with lesions involving the rolandic and prerolandic = areas.=20 Furthermore, they are more frequent with 50=E2=80=9360 = Hz of=20 stimulation than with the train-of-five = technique.⁴⁵ The=20 neurosurgeon should consider changing the stimulation = modality=20 in patients who are prone to have seizures during = mapping.

The resection procedure and = instruments, such as=20 the bipolar coagulation probe or the CUSA, can mimic=20 nonconvulsive seizure-related transient disturbance of = a=20 patient's performance. Reportedly, the use of the CUSA = can=20 interfere with motor and language mapping, inducing a=20 transient masking of active sites.⁹ = Therefore,=20 the simultaneous use of CUSA and bipolar coagulation = and=20 stimulation should be avoided.

Controversies in = Mapping	AbstractIntroductionElectrical = StimulationDocumentation of = Stimulat...Controversies in Mapping...=20 <<ConclusionsDisclosureAcknowledgmentsReferences

Size of Craniotomy=20

A recent publication described a = tailored=20 craniotomy with sole exposure of the tumor region, = language=20 mapping of the exposed area, and guidance by positive = and=20 negative stimulation results,⁴² with=20 excellent effects. Note that this procedure has been=20 established by a team with vast experience in cortical = mapping=20 and thus should only be relied on if the cortical = stimulation=20 technique is well established within the mapping=20 team.

Electrocorticography Recording =

The simultaneous recording of ECoG is used to = determine=20 spontaneous or stimulation-induced epileptic = discharges,=20 so-called afterdischarges that can occur after = electrical=20 stimulation of the cortical areas to detect = nonconvulsive=20 seizures (Fig. 5). = As a rule,=20 current used for cortical mapping should not exceed = certain=20 thresholds to avoid the possibility of misleading=20 false-positive mapping results. Unfortunately, = afterdischarge=20 thresholds vary across the cortex.⁴⁹ For=20 certain cortical sites, mapping may be successful only = at=20 currents above the afterdischarge thresholds.³⁹=20 Therefore, although ECoG is recommended by most to = improve the=20 reliability of mapping and to prevent intraoperative = seizures,=20 it also has some limitations that should be remembered = during=20 mapping. Still other authors have reported vast = experience=20 with successful mapping in a large group of patients = without=20 the use of ECoG.¹⁷ To=20 compromise between the efficacy of mapping and the=20 afterdischarge thresholds, different stimulus = durations and/or=20 repetition rates may have to be used.

View = larger=20 version (146K)

Fig. 5. = Asleep=20 surgery ECoG (Traces 1=E2=80=936), surface = electroencephalography (Traces = 7=E2=80=9310), and EMG=20 traces (remaining traces) obtained during = 60-Hz=20 stimulations (6 mA) of the primary motor = cortex,=20 showing nonconvulsive seizure=20 activity.

Focality of Stimulation=20

From studies of transcranial magnetic=20 stimulation and direct cortical stimulation in tumor = surgery,=20 it is known that the excitation of cortical motor = areas other=20 than the primary motor cortex (M1) requires higher=20 intensities.²⁷=20 Nevertheless, in intraoperative practice, the most = practical=20 and sufficient way is to determine the motor threshold = and use=20 this stimulation intensity for further mapping.^11,14

Effectiveness of Monitoring and = Mapping=20

A recent meta-analysis has underlined = the=20 growing evidence of the positive relation among the = extent of=20 tumor removal, the tumor progression=E2=80=93free = interval, and the=20 5-year survival rate.⁴³ Despite=20 the lack of Class 1 evidence, the effect of = confounding=20 factors, such as tumor histology and the = intraoperative=20 utilization of neurophysiological methods, has not = been=20 investigated in the studies included in the = meta-analysis.=20 Subcortical mapping has been proven useful in several=20 studies;^{4,12,13,17,19,26} thus,=20 the deduction that it can help in maximizing the = extent of=20 tumor resection may be obvious.

Utilization of DT Imaging=20

As the extent of tumor removal seems = to be=20 important for a patient's overall survival, = preoperative=20 imaging for planning the resection becomes more and = more=20 important. Authors have analyzed relations between = subcortical=20 mapping and DT imaging.^5,29 A=20 positive correlation has been found between a = stimulation=20 intensity of 8=E2=80=9312 mA and a < 6-mm distance = between the=20 stimulation site and visualized tracts. Nevertheless, = the=20 estimated distance between DT imaging and the location = of=20 stimulation is influenced by the inaccuracies of DT = imaging,=20 the invasiveness of the tumor, intraoperative brain = shift=20 affecting navigation accuracy, and the various = stimulation=20 parameters and probe types used. Up to now, only = subcortical=20 stimulation allows for the in situ real-time = assessment of=20 subcortical tracks.

Conclusions	AbstractIntroductionElectrical = StimulationDocumentation of = Stimulat...Controversies in = Mapping...Conclusions = <<DisclosureAcknowledgmentsReferences

The 50- or 60-Hz stimulation performed = with a=20 biphasic pulse and a bipolar stimulation probe is the = most=20 widely applied technique for mapping motor and = cognitive=20 function during awake surgery. The additional = application of=20 the MEP short-train technique broadens the stimulation = strategies being used, especially in patients who are = not=20 fully compliant or those suffering preexisting partial = neurological and developing partial deficits, which = can impair=20 intraoperative testing. The main advantage of this = technique=20 is the possibility of performing both mapping and = continuous=20 MEP monitoring while minimizing the risk of = intraoperative=20 seizures. The utilization of those short-train = stimulation=20 parameters for cognitive mapping is in its infancy. = The=20 relatively short duration of the stimulus has to be = timely=20 presented to interfere with the function being tested. = Close=20 clinical observation and guidance of the patient = combined with=20 recording of EMG activity allows for the best = documentation of=20 the mapping procedure.

Disclosure	AbstractIntroductionElectrical = StimulationDocumentation of = Stimulat...Controversies in = Mapping...ConclusionsDisclosure <<References

The authors report no conflict of interest = concerning the=20 materials or methods used in this study or the = findings=20 specified in this paper.

Conception and design: A = Szel=C3=A9nyi, H Duffau, E=20 Fava, G Feigl, G Neuloh, F Sala. Drafting the article: = A=20 Szel=C3=A9nyi, G Feigl, G Neuloh, F Sala. Critically = revising the=20 article: A Szel=C3=A9nyi, L Bello, H Duffau, E Fava, G = Feigl, M=20 Galanda, G Neuloh, F Signorelli, F Sala. Reviewed = final=20 version of manuscript and approved it for submission: = A=20 Szel=C3=A9nyi, L Bello, H Duffau, E Fava, G Feigl, M = Galanda, G=20 Neuloh, F Signorelli, F Sala.

Acknowledgments	AbstractIntroductionElectrical = StimulationDocumentation of = Stimulat...Controversies in = Mapping...ConclusionsDisclosureAcknowledgments = <<References

The authors are grateful to Adrian Praeger for his = help in=20 English editing.

European Low-Grade Glioma Network = Collaborators:=20 L. Capelle, M.D., Paris, France; H. Colle, M.D., = Ghent,=20 Belgium; G. Conesa, M.D., Barcelona, Spain; D. = Fontaine, M.D.,=20 Ph.D., Nice, France; N. Foroglou, M.D., Ph.D., = Thessaloniki,=20 Greece; V. Lubrano, M.D., Toulouse, France; E. = Mandonnet,=20 M.D., Montpellier, France; A. McEvoy, M.D., London, = United=20 Kingdom; S. Momjian, M.D., Gen=C3=A8ve, Switzerland; = J. Pallud,=20 M.D., Paris, France; I. Radovanovic, M.D., = Gen=C3=A8ve,=20 Switzerland; P. A. Robe, M.D., Liege, Belgium; E. = Robert,=20 Ghent, Belgium; S. G. Robles, M.D., Madrid, Spain; F. = E. Roux,=20 M.D., Ph.D., Toulouse, France; G. J. van Rutten, M.D., = Ph.D.,=20 Tilburg, The Netherlands; M. Sabel, M.D., Ph.D., = D=C3=BCsseldorf,=20 Germany; K. Schaller, M.D., Ph.D., Gen=C3=A8ve, = Switzerland; M.=20 Skrap, M.D., Udine, Italy; G. Spena, M.D., = Gen=C3=A8ve,=20 Switzerland.

References	AbstractIntroductionElectrical = StimulationDocumentation of = Stimulat...Controversies in = Mapping...ConclusionsDisclosureAcknowledgmentsReferences = <<

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