Clinical Neurophysiology 125 (2014) 667–674
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Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Comparison of bipolar versus monopolar extraoperative electrical cortical stimulation mapping in patients with focal epilepsy Stjepana Kovac a,b, Catherine A. Scott c, Vesela Maglajlija c, Nathan Toms c, Roman Rodionov a, Anna Miserocchi a, Andrew W. McEvoy a, Beate Diehl a,c,⇑ a b c
Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK Department of Neurology, University of Muenster, Muenster, Germany Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
a r t i c l e
i n f o
Article history: Accepted 9 September 2013 Available online 14 October 2013 Keywords: Frontal lobe Electrical cortical stimulation Epilepsy surgery Afterdischarges
h i g h l i g h t s We compared bipolar and monopolar cortical stimulation (CS) for mapping of eloquent cortex in
patients undergoing subdural recording for presurgical evaluation of pharmacoresistant epilepsy. Bipolar CS required less stimulus current to elicit a clinical sign, but produced more afterdischarges
when compared to monopolar CS. Clinical signs identified are similar with in both CS procedures, although monopolar CS is less time
consuming.
a b s t r a c t Objective: Extraoperative cortical stimulation (CS) for mapping of eloquent cortex in patients prior to epilepsy surgery is not standardized across centres. Two different techniques are in use, referred to as bipolar and monopolar CS. We compared the ability of bipolar versus monopolar CS to identify eloquent cortex and their safety profile in patients undergoing subdural EEG recordings. Methods: Five patients undergoing intracranial EEG recordings and extraoperative CS. Systematic comparison of stimulus parameters, clinical signs and afterdischarges of bipolar versus monopolar CS. Results: Bipolar CS requires less stimulation current but is more time consuming and more likely to produce afterdischarges when compared to monopolar CS. None of the stimulations elicited seizures. The area defined as eloquent by either bipolar or monopolar CS reveals only minor discordances, involving mainly the outer row and edge of the electrode array producing clinical signs with monopolar CS only. Qualitatively, bi- and monopolar CS reproduced similar movements and types of muscle contractions. Conclusions: Bipolar and monopolar CS are safe procedures identifying similar cortical areas as eloquent, although monopolar cortical stimulation is less time consuming. Significance: Findings advocate the use of monopolar CS in a clinical setting. Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Electrocorticography and cortical stimulation mapping were first used in intraoperative settings and were described in detail by Penfield and colleagues (Penfield and Jasper, 1954). With the advent of subdural electrodes used to map the seizure onset zone prior to epilepsy surgery, extraoperative cortical stimulation mapping has emerged (Nair et al., 2008; Lesser et al., 2011). ⇑ Corresponding author at: Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. Tel.: +44 203 448 3287; fax: +44 207 713 7743. E-mail address: [email protected] (B. Diehl).
Extraoperative cortical stimulation mapping is performed outside the operating theatre, once the patient has been implanted with subdural electrodes. Therefore, it has less time constraints when compared to cortical stimulation performed intraoperatively. Despite extraoperative cortical stimulation mapping is being widely used in the presurgical workup of patients with pharmacoresistant seizures, it is not standardized across centres. In some centres adjacent pairs of electrodes are stimulated (bipolar stimulation) whereas in other centres one electrode, referenced to a distant electrode, overlying non-eloquent cortex is stimulated (monopolar stimulation). Bipolar stimulation requires that each electrode is stimulated twice to identify the function underlying each
1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.09.026
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electrode. Comparison of current flow during monopolar and bipolar stimulation using a 3-dimensional finite element model of the brain revealed that bipolar adjacent electrodes were found to be very efficient in producing localized current flow (Nathan et al., 1993). Monopolar cortical stimulation produced higher current densities when compared to bipolar stimulation with comparable stimulation current; however, monopolar stimulation also stimulated a larger amount of tissue when compared to bipolar stimulation. How this theoretical model translates into practice remains an open question. More importantly, how these parameters potentially affect the appearance and presence of clinical signs elicited by cortical stimulation remains to be determined. This has important implications for clinical practice and decision making in relation to which part of the cortex can be resected while minimising the risk of postoperative functional deficits. We therefore examined bipolar versus monopolar cortical stimulation in patients undergoing subdural recording for presurgical evaluation of pharmacoresistant epilepsy. Firstly, we aimed to determine whether there are differences in the number of electrodes eliciting clinical signs and therefore in the anatomical mapping result of eloquent cortex. Secondly, we asked whether these stimulation practices differed with regards to their safety profile and the propensity to generate afterdischarges which can evolve into stimulation induced seizures. Lastly, we investigated whether different modes of stimulation leading to movements are qualitatively different when the same electrode overlying eloquent cortex is stimulated with either bipolar or monopolar cortical stimulation. 2. Methods We studied 5 patients (3 female, 2 male) in whom presurgical work up included extraoperative cortical stimulation to map eloquent cortex prior to epilepsy surgery. Patients were included in the study if there was coverage of pre- and postcentral gyrus (for an example see Fig. 1A and B). Detailed patient characteristics are outlined in Supplementary Table S1) The study was approved by the local ethics committee and informed consent was obtained from the patients prior to the cortical stimulation procedure, as in our center stimulation procedure may be either bipolar or monopolar based on preference of the consultant in charge All patients had frontal lobe epilepsy (4 left, 1 right). 2.1. Surgical implantation and localization of electrodes Electrodes were implanted in all patients and coverage was based on the hypothesis of the potential epileptogenic zone which was estimated on seizure semiology and the results of presurgical investigations. We obtained intraoperative photographs to monitor the position of the electrodes (Fig. 1A and B). After the implantation procedure postoperative CT images were obtained. Finally, preimplantation MRI was coregistered (rigid body coregistration) with postimplantation CT with the aim of creating electrode maps on 3D brain surface rendering to localize the implanted electrodes with relation to the brain structures. This coregistration and visualization of the 3-D reconstructions of electrodes coregistered with the preoperative MRI was performed using AmiraÒ software (http://www.vsg3d.com/amira/overview). This is a software for advanced 3D image processing and visualisation. The shortest distance between the center of the discordant electrode and central sulcus was measured (Supplementary Fig. S1). 2.2. Cortical stimulation procedure Cortical stimulation was performed using both bipolar and monopolar stimulation techniques to identify motor and language
areas of cortex underlying the electrode contacts. Previous reports have found that longer stimulus duration and shorter intertrial intervals when stimulating the same electrodes increase the likelihood of afterdischarges (ADs) (Lesser et al., 2008; Lee et al., 2010). The impact of the length of the total stimulation session has not been investigated, but it seems reasonable to assume that it might influence the occurrence of ADs as well. Therefore, monopolar and bipolar stimulations were performed in different sessions with each session lasting less than 80 min. However, in one patient, due to time constraints prior to electrode explantation and resection, monopolar cortical stimulation was performed immediately after bipolar cortical stimulation, with an increase of afterdischarges in the monopolar stimulation session. Therefore this patient was excluded in the analysis of afterdischarges. Additionally the order of bipolar and monopolar stimulation was inverted to avoid a systematic effect of the order (starting with mono- or either bipolar stimulation) on afterdischarges. The other four patients had a break between the sessions of at least 120 min. To avoid stimulation induced seizures, antiepileptic medication was reintroduced prior to cortical stimulation mapping. In both stimulation mode, 5 s trains of 50-Hz unipolar bi-phasic square wave pulses of a AC-current with a pulse with of 500 ls were delivered by a Nicolet™ cortical stimulator used with the C64-OR amplifiers with and Nicolet Cortical stimulator Control unit (ISO 13485, ISO 9001; Nicolet Biomedical, Madison, US). Current intensity was gradually increased from 1 mA in increments of 0.5 or 1 mA up to 7.5, 15 mA peak to peak of the biphasic stimulus, until the occurrence of a clinical sign or afterdischarges (AD) on EEG monitoring. Negative and positive motor symptoms were assessed and patients were asked to report sensations. We screened for language function by asking the patient to read aloud and name objects. If these screening tests were positive, more testing was performed according to our clinical protocol for language mapping. Intracranial EEG was recorded during electrical stimulation using a 128-channel EEG machine (Nicolet Biomedical, Madison, US). 2.3. Stimulation technique and analysis of stimulation responses Bipolar extraoperative stimulation is not a standardized method and the stimulation procedure varies substantially across centres and examiners. Possible approaches include: (1) Each pair of electrodes can be stimulated, moving across the grid by one electrode (example: pair 1: electrode G1 and 2; pair 2: electrode G2 and 3). (2) Alternatively, two electrodes, which are not far away from each other but still separated by one electrode contact, are stimulated, leading to lower spatial resolution of the stimulation response (pair 1: electrode G1 and 2; pair 2 electrode G3 and 4). In our centre, historically, bipolar mapping was performed by stimulating each adjacent electrode as in method 1, first stimulating each row of electrodes along the horizontal plane (Fig. 1C), and then in a vertical electrode row (Fig. 1D). The function ascribed to cortex underlying each electrode is then inferred from combining results of the stimulations involving that electrode. If two stimulations involving adjacent pairs with one electrode remaining the same, elicit the same clinical sign, then the sign can be attributed to the common electrode. Monopolar stimulation was performed with the active electrode systematically moving across the electrode array (Fig. 1E), whereas the reference electrode remained the same (Nair et al., 2008; Kombos and Süss, 2009; Lesser et al., 2011). In order to ensure that the elicited sign can be attributed to the active electrode, the reference electrode was tested prior to the monopolar stimulation to ensure that it is not overlying eloquent cortex. In this mode a fixed remote reference electrode is used. Hence, an electrode away from the central sulcus, at the opposite edge of the electrode array, was chosen for this purpose. This distant electrode, referenced to an
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Fig. 1. Intracranial electrode placement and bipolar and monopolar stimulation procedure. Intracranial EEG electrode placement (A and B): photographs show the intraoperatively exposed cortex (A) and intracranial EEG electrode array placement (B). Central sulcus is indicated by the dotted line, the inverted omega overlies the handknob, a landmark on the precentral gyrus. C and D illustrate a bipolar, whereas E shows a monopolar cortical stimulation procedure. The left side shows a schematic drawing of the hemisphere with an overlying electrode array. Electrodes highlighted in red produce clinical signs when stimulated. The electrodes on the right show a magnification of the area delineated. For bipolar cortical stimulation, adjacent electrodes were stimulated, both in horizontal (C) and then in vertical direction (D). Monopolar stimulation was performed by stimulating one electrode referenced to a distant electrode overlying non-eloquent cortex (highlighted in grey; E). I–IV indicate consecutive stimulation trials.
adjacent electrode, was tested prior to the stimulation procedure with the same stimulation protocol to ensure that no clinical response is elicited with maximum stimulation intensities. This also means that the current density changes with different pairs as the
distance between the target and fixed electrode may get less or more. Moving the fixed electrode to keep the distance similar is not very practical, since this would require to test each time whether the fixed electrode is overlying eloquent cortex.
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Schematic maps were drawn after each stimulation procedure and the electrodes that elicited clinical signs were marked separately for each stimulation mode. We analyzed the mismatch between the stimulation procedure by assessing the number of electrodes that were discordant with regards to the clinical sign when stimulating either in monopolar or bipolar mode, i.e. where a function was ascribed to the electrode in one stimulation mode and which was not unequivocally defined by the other stimulation mode. In addition, the exact locations of discordant electrode relative to the central sulcus were on the 3D cortical surface of the individual patients were determined using AmiraÒ software (Supplementary Fig. S1). 2.4. Afterdischarges and their properties ADs are by-products of cortical stimulation which can evolve into stimulation induced seizures. According to Blume and colleagues, ADs were scored when a repetitive EEG pattern >2 s resulted from direct cortical stimulation (Supplementary Fig. S2; Blume et al., 2004). Duration and number of electrodes involved in the ADs were examined to see whether these properties differed depending on stimulation technique. 2.5. Quality of motor responses depending on stimulation mode Qualitative assessment of the movements elicited by either bipolar or monopolar cortical stimulation was performed by comparing hand and wrist movements. These movements were chosen as hand function is represented on a relatively large cortical area within the precentral gyrus (Fig. 1A; Yousry et al., 1997). Hand and wrist movements are highly developed and different types of movements can be distinguished. Therefore differences between the stimulation types with regards to the hand/wrist movement elicited can be easily recognized. We performed visual qualitative video analysis of all hand or wrist movements elicited by stimulation of electrodes overlying the hand knob. We classified wrist and hand movements in both mono- and bipolar stimulation mode according to (1) the type of muscle contraction into clonic or tonic movements and (2) according to the type of movement performed. The type of movement was classified as finger or wrist flexion/extension, finger abduction and wrist ulnar adduction or radial abduction, respectively, or a combination of those. In each patient we evaluated whether all the hand movements elicited by bipolar cortical stimulation were also reproduced by monopolar stimulation. 2.6. Statistical analyses Statistical analyses were performed with SPSS 17.0 (SPSS, Chicago, IL, USA). All data are given as mean ± standard error and the significance level was set at p < 0.05. Significant differences between monopolar and bipolar stimulation were assessed by computing two sided t-tests. We used Chi square tests to compare the number of AD with each stimulation regimen. 3. Results 3.1. Stimulation characteristics and clinical signs elicited by stimulation The patients had 368 electrodes implanted in total. Of those, a total of 510 electrode-pair combinations were stimulated; 314 with bipolar and 196 with monopolar stimulation. This resulted in 1428 stimulation trials with bipolar and 995 stimulation trials with monopolar stimulation including the ‘‘titration’’ procedure, i.e. the stimulation with increasing current intensity. There was
no statistical difference between the percentages of electrodes pairs eliciting clinical signs when stimulated between bipolar when compared to monopolar stimulations (Chi square test; p > 0.05). Clinical signs were elicited with 59.6% of stimulations when stimulating in bipolar and 52.0% of stimulations when stimulating in monopolar configuration. However, the stimulation intensity to elicit a clinical sign differed between the groups. The mean stimulation intensity to elicit a clinical sign was lower in bipolar when compared to monopolar electrical cortical stimulation (3.3 ± 0.1 vs. 3.9 ± 0.2 mA; p = 0.006). A summary of the stimulation characteristics is given in Table 1. The mean duration of the whole stimulation procedure for each patient was 107.2 ± 11.9 min for bipolar and 74.8 ± 13.2 for monopolar stimulation (paired t-test p = 0.024). 3.2. Electrodes identified as eloquent by either bipolar or monopolar cortical stimulation Our next aim was to compare the distribution of electrodes generating clinical signs with either bipolar or monopolar stimulation. With bipolar stimulation a total of 91 electrodes were identified that elicited clinical signs when stimulated. Monopolar stimulation identified 98 electrodes overlying eloquent cortex (ns; p = 0.10). Analysis of the concordance of stimulation responses showed that 89 electrodes producing clinical signs when stimulated were identified both by bipolar and monopolar electrical cortical stimulation whereas 2 electrodes were identified exclusively by bipolar stimulation and 9 electrodes eliciting clinical signs were identified by monopolar cortical stimulation only (see Fig. 2). Of the 9 electrodes that revealed no clinical signs when stimulated in a bipolar manner 7 showed motor signs when stimulated in monopolar stimulation mode, one induced a speech arrest and the other one a sensory sign. In 5 out of those 9 electrodes this mismatch could be attributed to ADs when stimulating with bipolar stimulation. In 4 out of those electrode pairs, the mean stimulation current delivered was lower using bipolar stimulation compared to monopolar stimulation. Of the 2 electrodes that failed to elicit a clinical sign when monopolar stimulation was performed, but which showed a clinical sign on bipolar stimulation, one displayed motor signs and the other produced speech arrest when stimulated with bipolar cortical stimulation. ADs were observed in one of those monopolar stimulations; however in this trial ADs were also observed with bipolar stimulation and stimulus intensities of monopolar stimulations were higher when compared to bipolar stimulations in those electrodes. Of the electrodes that were not identified by bipolar cortical stimulation, but which yielded a clinical response when stimulated with monopolar cortical stimulation, 7 were lying on the outer electrode row of the electrode array. The other two electrodes that remained unidentified by bipolar stimulation mapping were in the centre of the electrode array. Of the two electrodes that did not elicit a clinical sign when stimulated in a monopolar stimulation mode but which were identified by bipolar cortical stimulation, one was in the centre of the electrode array whereas one was on the outer electrode row of a 2 8 row electrode grid. Measurement of the shortest electrodes distance to central sulcus (CS) of those electrodes that revealed a mismatch between the stimulation modes showed that 8 of those 11 electrodes were >1 cm away from CS. Only 3 were 1 cm away from central sulcus and therefore not overlying precentral gyrus. However, it needs to be emphasized that intraoperative cortical stimulation is substantially different from extraoperative cortical stimulation which was performed in our study. It also needs to be kept in mind that neither the above mentioned study nor our study can draw conclusions about the true extent of eloquent cortex. It was not within the scope of our study to define which technique is more useful in determining the extent of eloquent cortex. Such conclusions could be only drawn by extirpation of that part of the cortex, a technique which is ethically not feasible but would represent the gold standard to verify underlying function. The first pioneering reports on the function of the human motor cortex were in fact inferred from such surgical removal of eloquent cortex (Vilensky and Gilman, 2003). We found that few electrodes revealed discrepant results when interrogated using bipolar versus monopolar stimulation, with some electrodes only being identified as eloquent by one method. This discrepancy may be explained by the interpretation of the results of bipolar stimulation. This requires that each electrode is stimulated at least twice and the function is ascribed to one
electrode or the other comparing the stimulation results of adjacent electrodes. However, ascribing a function to one electrode is difficult if it is surrounded by electrodes eliciting clinical signs. It is therefore sometimes difficult to unequivocally determine the electrode responsible for the clinical sign elicited by only two stimulations. This in part may explain why some eloquent areas were determined by monopolar but not by bipolar stimulation. Another explanation of the mismatch is that ADs occurring in one stimulation mode may lead to discontinuing further stimulation with higher intensities. This may lead to failure of clinical signs being recognized due to low stimulation current. This was the case in 50% of our mismatch detected. The maximum stimulus intensity applied during cortical stimulation in our study is 7 mA (see Section 2.2). This raises the possibility that some of the mismatch detected between the stimulation modes may represent false negative results due to subthreshold stimulation and that higher stimulus intensities may have produced the sign in some instances of mismatch. However, mismatch occurring at electrode positions using stimulation intensities of 7 mA to obtain a clinical sign in one method but not the other was only seen in three mismatchelectrodes. Two elicited motor signs and were almost 2 cm anterior to central sulcus. This may suggest in fact a false positive response, as motor cortex typically can be identified with very low stimulus intensities (Kovac et al., 2011). One involved anterior language areas. This mismatch may have been caused by subthreshold stimulation. Therefore, overall ADs, and not subthreshold stimulations explained mainly the mismatch detected in our study. 4.2.1. Quality of the clinical signs elicited It is somewhat surprising that there were no significant differences in the quality of hand and wrist movements when comparing bipolar to monopolar cortical stimulation, given that the current flow modelled by Nathan and colleagues is different when comparing the two stimulation modes (Nathan et al.,
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1993). Recent reports have confirmed that single forearm muscles, such as the extensor indicis proprius, are distinctly represented within a small area of the primary motor cortex (Hadoush et al., 2011; Toxopeus et al., 2011), a finding which is supported by the fine-tuned movements that we observed when analyzing the quality of hand and wrist movements. We have previously shown that motor stimulation thresholds vary depending on the anatomic area stimulated; with stimulation of the hand knob requiring less stimulation current compared to precentral gyrus stimulation outside the hand knob (Kovac et al., 2011). This hierarchical organization principle is also maintained when looking at hand movements. Although not in the primary scope of their study, Boroojerdi and colleagues found that full activation of the abductor pollicis brevis, a functionally important hand muscle, was achieved at a stimulation intensity that did not activate other intrinsic hand muscles (Boroojerdi et al., 1999). The different threshold of activation of both intrinsic and forearm muscles might explain why we found similar stimulation patterns with both bipolar and monopolar cortical stimulation. The response elicited would therefore represent the movement pattern which has the lowest stimulation threshold in the surrounding cortex. Given that cortical stimulation is discontinued once a response occurs, it remains unclear whether other movements would be elicited by stimulating the same electrodes at higher stimulation intensity. 4.3. Safety issues In our study neither bipolar nor monopolar cortical stimulation induced a stimulation induced seizure. Moreover, previous studies have confirmed that there are no histopathological changes in the cortex underlying a reference electrode that is repetitively stimulated, receiving 250 stimulation trials during cortical stimulation mapping (Lesser et al., 1984; Gordon et al., 1990). 5. Limitations We systematically studied only a small number of patients. This is due to the fact that cortical stimulation mapping is time consuming and grid explanations and planned resections are scheduled in a timely fashion following mapping of eloquent cortex, hence time is of the essence. 6. Conclusion Bipolar and monopolar cortical stimulation are safe procedures that identify similar cortical areas as eloquent, although bipolar cortical stimulation may fail to identify clinical signs. This may be attributed to differences in current flow; a larger current distribution may occur during monopolar stimulation due to larger and variable inter-electrode distance (Gordon et al., 1990). Therefore it is advisable to stimulate the electrodes at the edge of an electrode array with monopolar cortical stimulation. Despite the fact that stimulation thresholds are slightly smaller in bipolar cortical stimulation when compared to monopolar stimulation; the likelihood of afterdischarges is higher with bipolar cortical stimulation. Monopolar stimulation requires significantly less time when compared to bipolar cortical stimulation and may therefore be more practical in a clinical setting. Acknowledgements This work was undertaken at UCLH/UCL who receives a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clinph.2013. 09.026. References Blume WT, Jones DC, Pathak P. Properties of after-discharges from cortical electrical stimulation in focal epilepsies. Clin Neurophysiol 2004;115:982–9. Boroojerdi B, Foltys H, Krings T, Spetzger U, Thron A, Töpper R. Localization of the motor hand area using transcranial magnetic stimulation and functional magnetic resonance imaging. Clin Neurophysiol 1999;110:699–704. Brodmann K. Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig, Germany: Barth; 1909. Buzsáki G, Anastassiou CA, Koch C. The origin of extracellular fields and currents – EEG, ECoG, LFP and spikes. Nat Rev Neurosci 2012;13:407–20. Von Economo C. The cytoarchitectonics of the human cerebral cortex. J Anat 1929;63:389. Gordon B, Lesser RP, Rance NE, Hart Jr J, Webber R, Uematsu S, et al. Parameters for direct cortical electrical stimulation in the human: histopathologic confirmation. Electroencephalogr Clin Neurophysiol 1990;75:371–7. Hadoush H, Sunagawa T, Nakanishi K, Endo K, Ochi M. Motor somatotopy of extensor indicis proprius and extensor pollicis longus. Neuroreport 2011;22:559–64. Kombos T, Suess O, Kern BC, Funk T, Hoell T, Kopetsch O, et al. Comparison between monopolar and bipolar electrical stimulation of the motor cortex. Acta Neurochir (Wien) 1999;141:1295–301. Kombos T, Süss O. Neurophysiological basis of direct cortical stimulation and applied neuroanatomy of the motor cortex: a review. Neurosurg Focus 2009;27:E3. Kovac S, Scott CA, Maglajlija V, Rodionov R, McEvoy AW, Diehl B. Extraoperative electrical cortical stimulation: characteristics of motor responses and correlation with precentral gyrus. J Clin Neurophysiol 2011;28:618–24. Lee HW, Webber WRS, Crone N, Miglioretti DL, Lesser RP. When is electrical cortical stimulation more likely to produce afterdischarges? Clin Neurophysiol 2010;121:14–20. Lesser RP, Crone NE, Webber WRS. Using subdural electrodes to assess the safety of resections. Epilepsy Behav 2011;20:223–9. Lesser RP, Lee HW, Webber WRS, Prince B, Crone NE, Miglioretti DL. Short-term variations in response distribution to cortical stimulation. Brain 2008;131:1528–39. Lesser RP, Lüders H, Klem G, Dinner DS, Morris HH, Hahn J. Cortical afterdischarge and functional response thresholds: results of extraoperative testing. Epilepsia 1984;25:615–21. Lothman EW, Williamson JM. Influence of electrical stimulus parameters on afterdischarge thresholds in the rat hippocampus. Epilepsy Res 1992;13:205–13. Nair DR, Burgess R, McIntyre CC, Lüders H. Chronic subdural electrodes in the management of epilepsy. Clin Neurophysiol 2008;119:11–28. Nathan SS, Sinha SR, Gordon B, Lesser RP, Thakor NV. Determination of current density distributions generated by electrical stimulation of the human cerebral cortex. Electroencephalogr Clin Neurophysiol 1993;86:183–92. Penfield W, Jasper HH. Epilepsy and the functional anatomy of human brain. Boston: Little, Brown; 1954. Penfield W, Boldrey E. Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain 1937:389–443. Pouratian N, Cannestra AF, Bookheimer SY, Martin NA, Toga AW. Variability of intraoperative electrocortical stimulation mapping parameters across and within individuals. J Neurosurg 2004;101:458–66. Szelényi A, Senft C, Jardan M, Forster MT, Franz K, Seifert V, et al. Intra-operative subcortical electrical stimulation: a comparison of two methods. Clin Neurophysiol 2011;122:1470–5. Taniguchi M, Cedzich C, Schramm J. Modification of cortical stimulation for motor evoked potentials under general anesthesia: technical description. Neurosurgery 1993;32:219–26. Toxopeus CM, De Jong BM, Valsan G, Conway BA, Leenders KL, Maurits NM. Direction of movement is encoded in the human primary motor cortex. PLoS One 2011;6:e27838. Toyoshima K, Sakai H. Exact cortical extent of the origin of the corticospinal tract (CST) and the quantitative contribution to the CST in different cytoarchitectonic areas. A study with horseradish peroxidase in the monkey. J Hirnforsch 1982;23:257–69. Vilensky JA, Gilman S. Using extirpations to understand the human motor cortex: Horsley, Foerster, and Bucy. Arch Neurol 2003;60:446–51. Yousry TA, Schmid UD, Alkadhi H, Schmidt D, Peraud A, Buettner A, et al. Localization of the motor hand area to a knob on the precentral gyrus. A new landmark. Brain 1997;120:141–57. Zilles K. Architecture of the human cerebral cortex. The Human Nervous System. 2nd ed. San Diego: Elsevier; 1990. pp. 997–1042.
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Comparison of bipolar versus monopolar extraoperative electrical cortical stimulation mapping in patients with focal epilepsy Stjepana Kovac a,b, Catherine A. Scott c, Vesela Maglajlija c, Nathan Toms c, Roman Rodionov a, Anna Miserocchi a, Andrew W. McEvoy a, Beate Diehl a,c,⇑ a b c
Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK Department of Neurology, University of Muenster, Muenster, Germany Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
a r t i c l e
i n f o
Article history: Accepted 9 September 2013 Available online 14 October 2013 Keywords: Frontal lobe Electrical cortical stimulation Epilepsy surgery Afterdischarges
h i g h l i g h t s We compared bipolar and monopolar cortical stimulation (CS) for mapping of eloquent cortex in
patients undergoing subdural recording for presurgical evaluation of pharmacoresistant epilepsy. Bipolar CS required less stimulus current to elicit a clinical sign, but produced more afterdischarges
when compared to monopolar CS. Clinical signs identified are similar with in both CS procedures, although monopolar CS is less time
consuming.
a b s t r a c t Objective: Extraoperative cortical stimulation (CS) for mapping of eloquent cortex in patients prior to epilepsy surgery is not standardized across centres. Two different techniques are in use, referred to as bipolar and monopolar CS. We compared the ability of bipolar versus monopolar CS to identify eloquent cortex and their safety profile in patients undergoing subdural EEG recordings. Methods: Five patients undergoing intracranial EEG recordings and extraoperative CS. Systematic comparison of stimulus parameters, clinical signs and afterdischarges of bipolar versus monopolar CS. Results: Bipolar CS requires less stimulation current but is more time consuming and more likely to produce afterdischarges when compared to monopolar CS. None of the stimulations elicited seizures. The area defined as eloquent by either bipolar or monopolar CS reveals only minor discordances, involving mainly the outer row and edge of the electrode array producing clinical signs with monopolar CS only. Qualitatively, bi- and monopolar CS reproduced similar movements and types of muscle contractions. Conclusions: Bipolar and monopolar CS are safe procedures identifying similar cortical areas as eloquent, although monopolar cortical stimulation is less time consuming. Significance: Findings advocate the use of monopolar CS in a clinical setting. Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Electrocorticography and cortical stimulation mapping were first used in intraoperative settings and were described in detail by Penfield and colleagues (Penfield and Jasper, 1954). With the advent of subdural electrodes used to map the seizure onset zone prior to epilepsy surgery, extraoperative cortical stimulation mapping has emerged (Nair et al., 2008; Lesser et al., 2011). ⇑ Corresponding author at: Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK. Tel.: +44 203 448 3287; fax: +44 207 713 7743. E-mail address: [email protected] (B. Diehl).
Extraoperative cortical stimulation mapping is performed outside the operating theatre, once the patient has been implanted with subdural electrodes. Therefore, it has less time constraints when compared to cortical stimulation performed intraoperatively. Despite extraoperative cortical stimulation mapping is being widely used in the presurgical workup of patients with pharmacoresistant seizures, it is not standardized across centres. In some centres adjacent pairs of electrodes are stimulated (bipolar stimulation) whereas in other centres one electrode, referenced to a distant electrode, overlying non-eloquent cortex is stimulated (monopolar stimulation). Bipolar stimulation requires that each electrode is stimulated twice to identify the function underlying each
1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.09.026
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electrode. Comparison of current flow during monopolar and bipolar stimulation using a 3-dimensional finite element model of the brain revealed that bipolar adjacent electrodes were found to be very efficient in producing localized current flow (Nathan et al., 1993). Monopolar cortical stimulation produced higher current densities when compared to bipolar stimulation with comparable stimulation current; however, monopolar stimulation also stimulated a larger amount of tissue when compared to bipolar stimulation. How this theoretical model translates into practice remains an open question. More importantly, how these parameters potentially affect the appearance and presence of clinical signs elicited by cortical stimulation remains to be determined. This has important implications for clinical practice and decision making in relation to which part of the cortex can be resected while minimising the risk of postoperative functional deficits. We therefore examined bipolar versus monopolar cortical stimulation in patients undergoing subdural recording for presurgical evaluation of pharmacoresistant epilepsy. Firstly, we aimed to determine whether there are differences in the number of electrodes eliciting clinical signs and therefore in the anatomical mapping result of eloquent cortex. Secondly, we asked whether these stimulation practices differed with regards to their safety profile and the propensity to generate afterdischarges which can evolve into stimulation induced seizures. Lastly, we investigated whether different modes of stimulation leading to movements are qualitatively different when the same electrode overlying eloquent cortex is stimulated with either bipolar or monopolar cortical stimulation. 2. Methods We studied 5 patients (3 female, 2 male) in whom presurgical work up included extraoperative cortical stimulation to map eloquent cortex prior to epilepsy surgery. Patients were included in the study if there was coverage of pre- and postcentral gyrus (for an example see Fig. 1A and B). Detailed patient characteristics are outlined in Supplementary Table S1) The study was approved by the local ethics committee and informed consent was obtained from the patients prior to the cortical stimulation procedure, as in our center stimulation procedure may be either bipolar or monopolar based on preference of the consultant in charge All patients had frontal lobe epilepsy (4 left, 1 right). 2.1. Surgical implantation and localization of electrodes Electrodes were implanted in all patients and coverage was based on the hypothesis of the potential epileptogenic zone which was estimated on seizure semiology and the results of presurgical investigations. We obtained intraoperative photographs to monitor the position of the electrodes (Fig. 1A and B). After the implantation procedure postoperative CT images were obtained. Finally, preimplantation MRI was coregistered (rigid body coregistration) with postimplantation CT with the aim of creating electrode maps on 3D brain surface rendering to localize the implanted electrodes with relation to the brain structures. This coregistration and visualization of the 3-D reconstructions of electrodes coregistered with the preoperative MRI was performed using AmiraÒ software (http://www.vsg3d.com/amira/overview). This is a software for advanced 3D image processing and visualisation. The shortest distance between the center of the discordant electrode and central sulcus was measured (Supplementary Fig. S1). 2.2. Cortical stimulation procedure Cortical stimulation was performed using both bipolar and monopolar stimulation techniques to identify motor and language
areas of cortex underlying the electrode contacts. Previous reports have found that longer stimulus duration and shorter intertrial intervals when stimulating the same electrodes increase the likelihood of afterdischarges (ADs) (Lesser et al., 2008; Lee et al., 2010). The impact of the length of the total stimulation session has not been investigated, but it seems reasonable to assume that it might influence the occurrence of ADs as well. Therefore, monopolar and bipolar stimulations were performed in different sessions with each session lasting less than 80 min. However, in one patient, due to time constraints prior to electrode explantation and resection, monopolar cortical stimulation was performed immediately after bipolar cortical stimulation, with an increase of afterdischarges in the monopolar stimulation session. Therefore this patient was excluded in the analysis of afterdischarges. Additionally the order of bipolar and monopolar stimulation was inverted to avoid a systematic effect of the order (starting with mono- or either bipolar stimulation) on afterdischarges. The other four patients had a break between the sessions of at least 120 min. To avoid stimulation induced seizures, antiepileptic medication was reintroduced prior to cortical stimulation mapping. In both stimulation mode, 5 s trains of 50-Hz unipolar bi-phasic square wave pulses of a AC-current with a pulse with of 500 ls were delivered by a Nicolet™ cortical stimulator used with the C64-OR amplifiers with and Nicolet Cortical stimulator Control unit (ISO 13485, ISO 9001; Nicolet Biomedical, Madison, US). Current intensity was gradually increased from 1 mA in increments of 0.5 or 1 mA up to 7.5, 15 mA peak to peak of the biphasic stimulus, until the occurrence of a clinical sign or afterdischarges (AD) on EEG monitoring. Negative and positive motor symptoms were assessed and patients were asked to report sensations. We screened for language function by asking the patient to read aloud and name objects. If these screening tests were positive, more testing was performed according to our clinical protocol for language mapping. Intracranial EEG was recorded during electrical stimulation using a 128-channel EEG machine (Nicolet Biomedical, Madison, US). 2.3. Stimulation technique and analysis of stimulation responses Bipolar extraoperative stimulation is not a standardized method and the stimulation procedure varies substantially across centres and examiners. Possible approaches include: (1) Each pair of electrodes can be stimulated, moving across the grid by one electrode (example: pair 1: electrode G1 and 2; pair 2: electrode G2 and 3). (2) Alternatively, two electrodes, which are not far away from each other but still separated by one electrode contact, are stimulated, leading to lower spatial resolution of the stimulation response (pair 1: electrode G1 and 2; pair 2 electrode G3 and 4). In our centre, historically, bipolar mapping was performed by stimulating each adjacent electrode as in method 1, first stimulating each row of electrodes along the horizontal plane (Fig. 1C), and then in a vertical electrode row (Fig. 1D). The function ascribed to cortex underlying each electrode is then inferred from combining results of the stimulations involving that electrode. If two stimulations involving adjacent pairs with one electrode remaining the same, elicit the same clinical sign, then the sign can be attributed to the common electrode. Monopolar stimulation was performed with the active electrode systematically moving across the electrode array (Fig. 1E), whereas the reference electrode remained the same (Nair et al., 2008; Kombos and Süss, 2009; Lesser et al., 2011). In order to ensure that the elicited sign can be attributed to the active electrode, the reference electrode was tested prior to the monopolar stimulation to ensure that it is not overlying eloquent cortex. In this mode a fixed remote reference electrode is used. Hence, an electrode away from the central sulcus, at the opposite edge of the electrode array, was chosen for this purpose. This distant electrode, referenced to an
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Fig. 1. Intracranial electrode placement and bipolar and monopolar stimulation procedure. Intracranial EEG electrode placement (A and B): photographs show the intraoperatively exposed cortex (A) and intracranial EEG electrode array placement (B). Central sulcus is indicated by the dotted line, the inverted omega overlies the handknob, a landmark on the precentral gyrus. C and D illustrate a bipolar, whereas E shows a monopolar cortical stimulation procedure. The left side shows a schematic drawing of the hemisphere with an overlying electrode array. Electrodes highlighted in red produce clinical signs when stimulated. The electrodes on the right show a magnification of the area delineated. For bipolar cortical stimulation, adjacent electrodes were stimulated, both in horizontal (C) and then in vertical direction (D). Monopolar stimulation was performed by stimulating one electrode referenced to a distant electrode overlying non-eloquent cortex (highlighted in grey; E). I–IV indicate consecutive stimulation trials.
adjacent electrode, was tested prior to the stimulation procedure with the same stimulation protocol to ensure that no clinical response is elicited with maximum stimulation intensities. This also means that the current density changes with different pairs as the
distance between the target and fixed electrode may get less or more. Moving the fixed electrode to keep the distance similar is not very practical, since this would require to test each time whether the fixed electrode is overlying eloquent cortex.
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Schematic maps were drawn after each stimulation procedure and the electrodes that elicited clinical signs were marked separately for each stimulation mode. We analyzed the mismatch between the stimulation procedure by assessing the number of electrodes that were discordant with regards to the clinical sign when stimulating either in monopolar or bipolar mode, i.e. where a function was ascribed to the electrode in one stimulation mode and which was not unequivocally defined by the other stimulation mode. In addition, the exact locations of discordant electrode relative to the central sulcus were on the 3D cortical surface of the individual patients were determined using AmiraÒ software (Supplementary Fig. S1). 2.4. Afterdischarges and their properties ADs are by-products of cortical stimulation which can evolve into stimulation induced seizures. According to Blume and colleagues, ADs were scored when a repetitive EEG pattern >2 s resulted from direct cortical stimulation (Supplementary Fig. S2; Blume et al., 2004). Duration and number of electrodes involved in the ADs were examined to see whether these properties differed depending on stimulation technique. 2.5. Quality of motor responses depending on stimulation mode Qualitative assessment of the movements elicited by either bipolar or monopolar cortical stimulation was performed by comparing hand and wrist movements. These movements were chosen as hand function is represented on a relatively large cortical area within the precentral gyrus (Fig. 1A; Yousry et al., 1997). Hand and wrist movements are highly developed and different types of movements can be distinguished. Therefore differences between the stimulation types with regards to the hand/wrist movement elicited can be easily recognized. We performed visual qualitative video analysis of all hand or wrist movements elicited by stimulation of electrodes overlying the hand knob. We classified wrist and hand movements in both mono- and bipolar stimulation mode according to (1) the type of muscle contraction into clonic or tonic movements and (2) according to the type of movement performed. The type of movement was classified as finger or wrist flexion/extension, finger abduction and wrist ulnar adduction or radial abduction, respectively, or a combination of those. In each patient we evaluated whether all the hand movements elicited by bipolar cortical stimulation were also reproduced by monopolar stimulation. 2.6. Statistical analyses Statistical analyses were performed with SPSS 17.0 (SPSS, Chicago, IL, USA). All data are given as mean ± standard error and the significance level was set at p < 0.05. Significant differences between monopolar and bipolar stimulation were assessed by computing two sided t-tests. We used Chi square tests to compare the number of AD with each stimulation regimen. 3. Results 3.1. Stimulation characteristics and clinical signs elicited by stimulation The patients had 368 electrodes implanted in total. Of those, a total of 510 electrode-pair combinations were stimulated; 314 with bipolar and 196 with monopolar stimulation. This resulted in 1428 stimulation trials with bipolar and 995 stimulation trials with monopolar stimulation including the ‘‘titration’’ procedure, i.e. the stimulation with increasing current intensity. There was
no statistical difference between the percentages of electrodes pairs eliciting clinical signs when stimulated between bipolar when compared to monopolar stimulations (Chi square test; p > 0.05). Clinical signs were elicited with 59.6% of stimulations when stimulating in bipolar and 52.0% of stimulations when stimulating in monopolar configuration. However, the stimulation intensity to elicit a clinical sign differed between the groups. The mean stimulation intensity to elicit a clinical sign was lower in bipolar when compared to monopolar electrical cortical stimulation (3.3 ± 0.1 vs. 3.9 ± 0.2 mA; p = 0.006). A summary of the stimulation characteristics is given in Table 1. The mean duration of the whole stimulation procedure for each patient was 107.2 ± 11.9 min for bipolar and 74.8 ± 13.2 for monopolar stimulation (paired t-test p = 0.024). 3.2. Electrodes identified as eloquent by either bipolar or monopolar cortical stimulation Our next aim was to compare the distribution of electrodes generating clinical signs with either bipolar or monopolar stimulation. With bipolar stimulation a total of 91 electrodes were identified that elicited clinical signs when stimulated. Monopolar stimulation identified 98 electrodes overlying eloquent cortex (ns; p = 0.10). Analysis of the concordance of stimulation responses showed that 89 electrodes producing clinical signs when stimulated were identified both by bipolar and monopolar electrical cortical stimulation whereas 2 electrodes were identified exclusively by bipolar stimulation and 9 electrodes eliciting clinical signs were identified by monopolar cortical stimulation only (see Fig. 2). Of the 9 electrodes that revealed no clinical signs when stimulated in a bipolar manner 7 showed motor signs when stimulated in monopolar stimulation mode, one induced a speech arrest and the other one a sensory sign. In 5 out of those 9 electrodes this mismatch could be attributed to ADs when stimulating with bipolar stimulation. In 4 out of those electrode pairs, the mean stimulation current delivered was lower using bipolar stimulation compared to monopolar stimulation. Of the 2 electrodes that failed to elicit a clinical sign when monopolar stimulation was performed, but which showed a clinical sign on bipolar stimulation, one displayed motor signs and the other produced speech arrest when stimulated with bipolar cortical stimulation. ADs were observed in one of those monopolar stimulations; however in this trial ADs were also observed with bipolar stimulation and stimulus intensities of monopolar stimulations were higher when compared to bipolar stimulations in those electrodes. Of the electrodes that were not identified by bipolar cortical stimulation, but which yielded a clinical response when stimulated with monopolar cortical stimulation, 7 were lying on the outer electrode row of the electrode array. The other two electrodes that remained unidentified by bipolar stimulation mapping were in the centre of the electrode array. Of the two electrodes that did not elicit a clinical sign when stimulated in a monopolar stimulation mode but which were identified by bipolar cortical stimulation, one was in the centre of the electrode array whereas one was on the outer electrode row of a 2 8 row electrode grid. Measurement of the shortest electrodes distance to central sulcus (CS) of those electrodes that revealed a mismatch between the stimulation modes showed that 8 of those 11 electrodes were >1 cm away from CS. Only 3 were 1 cm away from central sulcus and therefore not overlying precentral gyrus. However, it needs to be emphasized that intraoperative cortical stimulation is substantially different from extraoperative cortical stimulation which was performed in our study. It also needs to be kept in mind that neither the above mentioned study nor our study can draw conclusions about the true extent of eloquent cortex. It was not within the scope of our study to define which technique is more useful in determining the extent of eloquent cortex. Such conclusions could be only drawn by extirpation of that part of the cortex, a technique which is ethically not feasible but would represent the gold standard to verify underlying function. The first pioneering reports on the function of the human motor cortex were in fact inferred from such surgical removal of eloquent cortex (Vilensky and Gilman, 2003). We found that few electrodes revealed discrepant results when interrogated using bipolar versus monopolar stimulation, with some electrodes only being identified as eloquent by one method. This discrepancy may be explained by the interpretation of the results of bipolar stimulation. This requires that each electrode is stimulated at least twice and the function is ascribed to one
electrode or the other comparing the stimulation results of adjacent electrodes. However, ascribing a function to one electrode is difficult if it is surrounded by electrodes eliciting clinical signs. It is therefore sometimes difficult to unequivocally determine the electrode responsible for the clinical sign elicited by only two stimulations. This in part may explain why some eloquent areas were determined by monopolar but not by bipolar stimulation. Another explanation of the mismatch is that ADs occurring in one stimulation mode may lead to discontinuing further stimulation with higher intensities. This may lead to failure of clinical signs being recognized due to low stimulation current. This was the case in 50% of our mismatch detected. The maximum stimulus intensity applied during cortical stimulation in our study is 7 mA (see Section 2.2). This raises the possibility that some of the mismatch detected between the stimulation modes may represent false negative results due to subthreshold stimulation and that higher stimulus intensities may have produced the sign in some instances of mismatch. However, mismatch occurring at electrode positions using stimulation intensities of 7 mA to obtain a clinical sign in one method but not the other was only seen in three mismatchelectrodes. Two elicited motor signs and were almost 2 cm anterior to central sulcus. This may suggest in fact a false positive response, as motor cortex typically can be identified with very low stimulus intensities (Kovac et al., 2011). One involved anterior language areas. This mismatch may have been caused by subthreshold stimulation. Therefore, overall ADs, and not subthreshold stimulations explained mainly the mismatch detected in our study. 4.2.1. Quality of the clinical signs elicited It is somewhat surprising that there were no significant differences in the quality of hand and wrist movements when comparing bipolar to monopolar cortical stimulation, given that the current flow modelled by Nathan and colleagues is different when comparing the two stimulation modes (Nathan et al.,
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1993). Recent reports have confirmed that single forearm muscles, such as the extensor indicis proprius, are distinctly represented within a small area of the primary motor cortex (Hadoush et al., 2011; Toxopeus et al., 2011), a finding which is supported by the fine-tuned movements that we observed when analyzing the quality of hand and wrist movements. We have previously shown that motor stimulation thresholds vary depending on the anatomic area stimulated; with stimulation of the hand knob requiring less stimulation current compared to precentral gyrus stimulation outside the hand knob (Kovac et al., 2011). This hierarchical organization principle is also maintained when looking at hand movements. Although not in the primary scope of their study, Boroojerdi and colleagues found that full activation of the abductor pollicis brevis, a functionally important hand muscle, was achieved at a stimulation intensity that did not activate other intrinsic hand muscles (Boroojerdi et al., 1999). The different threshold of activation of both intrinsic and forearm muscles might explain why we found similar stimulation patterns with both bipolar and monopolar cortical stimulation. The response elicited would therefore represent the movement pattern which has the lowest stimulation threshold in the surrounding cortex. Given that cortical stimulation is discontinued once a response occurs, it remains unclear whether other movements would be elicited by stimulating the same electrodes at higher stimulation intensity. 4.3. Safety issues In our study neither bipolar nor monopolar cortical stimulation induced a stimulation induced seizure. Moreover, previous studies have confirmed that there are no histopathological changes in the cortex underlying a reference electrode that is repetitively stimulated, receiving 250 stimulation trials during cortical stimulation mapping (Lesser et al., 1984; Gordon et al., 1990). 5. Limitations We systematically studied only a small number of patients. This is due to the fact that cortical stimulation mapping is time consuming and grid explanations and planned resections are scheduled in a timely fashion following mapping of eloquent cortex, hence time is of the essence. 6. Conclusion Bipolar and monopolar cortical stimulation are safe procedures that identify similar cortical areas as eloquent, although bipolar cortical stimulation may fail to identify clinical signs. This may be attributed to differences in current flow; a larger current distribution may occur during monopolar stimulation due to larger and variable inter-electrode distance (Gordon et al., 1990). Therefore it is advisable to stimulate the electrodes at the edge of an electrode array with monopolar cortical stimulation. Despite the fact that stimulation thresholds are slightly smaller in bipolar cortical stimulation when compared to monopolar stimulation; the likelihood of afterdischarges is higher with bipolar cortical stimulation. Monopolar stimulation requires significantly less time when compared to bipolar cortical stimulation and may therefore be more practical in a clinical setting. Acknowledgements This work was undertaken at UCLH/UCL who receives a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme.
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