- Email: [email protected]
Intra-stimulation discharges: An overlooked cortical electrographic entity triggered by direct electrical stimulation
Clinical Neurophysiology 126 (2015) 882–888
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Intra-stimulation discharges: An overlooked cortical electrographic entity triggered by direct electrical stimulation Ioannis Karakis a,⇑, Beth A. Leeman-Markowski a, Catherine L. Leveroni b, Ronan D. Kilbride b, Sydney S. Cash b, Emad N. Eskandar c, Mirela V. Simon b a b c
Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
a r t i c l e
i n f o
Article history: Accepted 14 August 2014 Available online 6 September 2014 Keywords: Functional brain mapping Electrical cortical stimulation After-discharges Intra-stimulation discharges
h i g h l i g h t s Intra-stimulation discharges (IDs) can occur during language mapping and before after-discharges
(ADs). High stimulus intensities, long stimulation durations, and presence of baseline epileptiform dis-
charges at the stimulation site increase the probability of triggering IDs, and consequently, ADs. Attention to IDs may improve the safety and precision of neurophysiologic mapping.
a b s t r a c t Objective: Intra-stimulation discharges (IDs) can occur during language mapping, are largely unrecognized, and may precede the occurrence of after-discharges (ADs) and seizures. This study aimed to identify predictors of ID occurrence and determine whether IDs increase the probability of triggered ADs. Methods: A total of 332 stimulation events performed during language mapping were analyzed in 3 patients who underwent intracranial EEG recordings during evaluations for epilepsy surgery. IDs were identified in 76 stimulation events. The relationships between IDs and the stimulus current intensity, stimulation duration, and proximity to regions of abnormal cortical excitability [characterized by the presence of baseline epileptiform discharges (BEDs)] were determined using regression analysis. Results: The presence of BEDs in close proximity to stimulation, an increase in stimulus intensity by 1 mA, and an increase in stimulation duration by 1 s independently increased the odds of triggering IDs by 7.40, 1.37, and 1.39 times, respectively. All IDs were triggered during stimulations in the temporal lobe. The occurrence of IDs increased the odds of triggering ADs 5-fold. Conclusions: Longer stimulations, higher currents, and the presence of BEDs at the stimulation site increase the probability of ID occurrence, which in turn increases the probability of triggering ADs. Significance: Attention to IDs may improve the safety and precision of neurophysiologic mapping. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Accurate identification of language areas is essential for safe and adequate resection of many supra-tentorial lesions. Visual recognition of anatomic regions highly associated with language ⇑ Corresponding author. Address: Emory University School of Medicine, Faculty Office Building at Grady Campus, 49 Jesse Hill Jr. Drive SE, Office 335, Atlanta, GA 30303, USA. Tel.: +1 404 616 4013; fax: +1 404 659 0849. E-mail address: [email protected] (I. Karakis).
function, such as the inferior frontal lobe or posterior superior temporal gyrus, is insufficient due to significant inter-individual variability of language representation (Mani et al., 2008; Ojemann et al., 1989), structural displacement from mass effect, and lesion-induced cortical re-organization (Lubrano et al., 2010). Despite the availability of sophisticated neuroimaging techniques such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and diffusion tensor imaging (DTI), mapping based on direct electrical cortical stimulation (Penfield, 1957; Penfield and Rasmussen, 1950) remains the gold
http://dx.doi.org/10.1016/j.clinph.2014.08.011 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
I. Karakis et al. / Clinical Neurophysiology 126 (2015) 882–888
883
standard procedure for identifying functional cortex. Its application has been shown to minimize post-operative neurological deficits, while allowing for optimal lesion resection (Duffau et al., 1999). Direct application of electrical currents, however, can unexpectedly increase cortical excitability beyond a certain threshold and thus trigger unwanted epileptiform discharges, known as afterdischarges (ADs). ADs occur after the cessation of stimulation and may propagate and organize into seizures. Seizures pose a significant safety risk to the patient, particularly when they occur intraoperatively or are associated with convulsions. ADs can also result in false localization of functional cortex and seizure foci, as the discharges may occasionally occur remotely from areas of baseline cortical irritability and/or spread beyond the stimulation site, resulting in clinical manifestations not representative of the stimulated cortex (Blume et al., 2004; Jasper, 1954). Therefore, Blume et al. (2004) advocated for the prompt identification of ADs by the use of concurrent electrocorticographic recordings (ECoG) during functional mapping requiring electrical stimulation. Contrary to ADs, intra-stimulation discharges (IDs) have drawn significantly less attention (Ishitobi et al., 2000). These authors found a strong correlation between language disruption and IDs triggered at a distance from the stimulating electrodes, occurring in areas well known to support language function. We have previously reported our experience with IDs (Simon et al., 2010). Although typically obscured by stimulation artifact, we found that IDs are commonly recorded on intra- or extra-operative ECoG recordings during functional mapping and seem to precede the occurrence of ADs. In agreement with Ishitobi et al., we cautioned regarding their potential implications for patient safety, as well as the risk for false localization of eloquent cortex. In this study, we describe this less recognized entity and identify factors that increase its probability of occurrence, as well as investigate the association between IDs and ADs. Finally, we propose potential areas for future research.
impairment or ADs. The stimulation was performed in epochs of 3–11 s duration (mean: 5.8 s). By using a notch filter, IDs could also be identified during the stimulation epochs. IDs and ADs were present in isolation, or in runs of epileptiform discharges, induced during and immediately after the stimulation respectively, and clearly distinguishable from the baseline epileptiform activity or any associated stimulus artifact. An area was considered safe for future resection if, when stimulated up to 12 mA, no language disruption was triggered. If language disruption was triggered by stimulation, the response was considered to be reliable if it was reproducible (i.e., the same language deficit was recorded upon repeated stimulations of the same region) and was obtained in the absence of ADs and/or IDs. Patient 1 was stimulated in the left temporal and frontal lobes, patient 2 in the left temporal, frontal and parietal lobes, and patient 3 in the left temporal lobe. All patients were on antiepileptic drugs at the time of stimulation. A summary of the patient characteristics, stimulation parameters, and mapping results are provided in Table 1.
2. Methods
We used multivariate logistic regression to evaluate the impact of stimulation intensity, duration, and proximity to regions of increased baseline cortical excitability on the probability of triggering IDs, adjusting for additional subject specific variability. The latter was represented as three category variables (P), each category representing the individual properties for each patient (i.e., P1 for patient 1, P2 for patient 2, and P3 for patient 3). The stimulation intensity and duration were introduced in the model as continuous variables. Presence of increased cortical excitability at the stimulation site was represented as a dichotomous variable (i.e., presence or absence of BEDs). The lobar location of the stimulation was not included in the logistic regression model, as all of the stimulations that triggered IDs were in the temporal lobe regions. The outcome was represented as a dichotomous variable (i.e., presence or absence of triggered IDs). Univariate logistic regression analysis was used to determine whether stimulations that triggered IDs had an increased probability of eliciting ADs when compared to stimulations that did not trigger IDs. Statistical analysis was performed in SAS, version 9.3 (North Carolina).
2.1. Subjects We evaluated 3 male patients with non-lesional refractory epilepsy, with a mean age of 27 years (range: 20–33), who were implanted with subdural electrodes as part of their phase II evaluations for epilepsy surgery. The subdural electrode arrays were composed of platinum–iridium electrodes of 2.3 mm exposed diameter, embedded in a plastic sheet with 1-cm center to center distance. Their location was determined by the clinical scenario and was confirmed with co-registration of pre-implantation MRI with post-implantation CT. Each patient underwent extraoperative language mapping in the Epilepsy Monitoring Unit (EMU). 2.2. Stimulation and recording The Penfield stimulation method was used; repetitive pulses, each of 1 ms width, at a frequency of 60 Hz, were applied to the cortex via two adjacent electrodes of the grid, connected to an XLTEK/NATUS stimulating device. Concomitant ECoG recordings were obtained from the remaining electrodes, using referential (referenced to the contralateral mastoid) and bipolar montages. The stimulus intensity was slowly increased, in 0.5 mA increments, from 1 mA up to 12 mA (mean: 4.9 mA). Stimulation of all areas of interest was performed. If stimulation of these regions did not produce any language disruption, the stimulus intensity was gradually ramped up in 0.5 mA increments until it resulted in language
2.3. Variables For each stimulation, the following variables were recorded: (1) subject (e.g., patient 1); (2) order (e.g., the fifth stimulation); (3) duration of stimulation (seconds); (4) intensity (mA); (5) location of stimulation (temporal, frontal or parietal); (6) presence or absence of triggered IDs and their duration (seconds); (7) field of IDs in relation to the stimulation site (at or beyond the ‘‘stimulation site,’’ defined as the area where the stimulation contacts and their immediately adjacent neighbors reside); (8) presence or absence of baseline interictal and ictal epileptiform activity (BEDs) at the stimulation site; (9) presence or absence of language disruption; (10) presence or absence of ADs; (11) the field of ADs in relation to the stimulation site. 2.4. Statistical analysis
3. Results A total of 332 stimulation events were performed and analyzed during language mapping. IDs were identified in 76 events (23% of all stimulation events), with an average duration of 4.3 s (range: 1–8 s). Sixty-four out of the 76 IDs (84.21%) had an electrical field beyond the stimulation site and 57 out of 76 (75%) were not followed by ADs. All IDs were exclusively triggered by the stimulation
884
I. Karakis et al. / Clinical Neurophysiology 126 (2015) 882–888
Table 1 Summary of patient, stimulation and outcome characteristics. Patient
Age
Stim location
Stim #
Stim intensity
Stim length
ADs #
IDs #
AEDs regimen
Successful mapping
1 2 3
20 33 27
T, F T, F, P T
80 37 215
5 (1–12) 3.9 (1–11) 5 (2–11)
7.3 (4–11) 5.1 (5–8) 5.3 (3–8)
8 5 24
5 5 66
Levetiracetam 750 mg bid Carbamazepine 400 qam/600 qpm Topiramate 200 mg qpm Levetiracetam 2000 mg bid, Lamotrigine 200 mg bid, Carbamazepine 600 mg bid
Yes Yes Yes
Stim location = location of stimulation. Stim # = number of stimulation events. Stim intensity = stimulus intensity applied. Stim length = length of the stimulation epoch. ADs # = number of after-discharges events. IDs # = number of inter-stimulation discharges events. T = temporal, F = frontal, P = parietal. AEDs = antiepileptic drugs.
of temporal lobe cortex and were recorded from temporal lobe locations. ADs were seen in approximately 11% of the stimulation events. They were more likely to occur close to the stimulation site (95% of the cases). Stimulation in close proximity to BEDs increased the odds of triggering IDs 7.40-fold, when compared to stimulation of cortical regions of normal excitability, after adjusting for the other variables (OR = 7.40, CI95 [2.83, 19.33], p < .0001). Each 1 mA increase in stimulus intensity increased the odds of triggering IDs 1.37 times, after adjusting for confounding variables (OR = 1.37, CI95 [1.18, 1.57], p < .0001). Each 1 s increase in stimulation duration independently increased the odds 1.39 times (OR = 1.39, CI95 [1.19, 1.62], p < .0001). The odds of triggering IDs were 25% lower in patient 2 versus patient 3 and 97% lower in patient 1 versus patient 3 (OR = 0.76, CI95 [0.26, 2.22], p = 0.02 and OR = 0.03, CI95 [0.01, 0.10], respectively). The occurrence of IDs increased the odds of triggering ADs 5-fold (OR = 5.02, CI95 [2.47, 10.2], p < .0001). A total of 25 stimulations triggered language disturbance, 11 of which triggered language dysfunction in the presence of ADs and/ or IDs. Four of these 11 stimulations triggered ADs without preceding IDs, three triggered ADs at the stimulating site and IDs with a field broader than the stimulating region, and four triggered IDs without ADs, again with an electrical field beyond the location of the stimulating electrodes. The results of our analysis are summarized in Tables 2 and 3. 4. Discussion Safe and accurate mapping of eloquent cortex via direct electrical stimulation relies on prompt identification and avoidance of triggered ADs. In this paper we describe IDs, an under-recognized cortical electrographic entity also triggered by electrical stimulation, which have potential clinical implications. Our results demonstrate that IDs: (1) are triggered by direct electrical cortical stimulation, even in the absence of the widely recognized ADs, but can be overlooked due to concomitant stimulus artifact (Fig. 1A and B); (2) are more likely to occur when stimulations are longer, performed at higher currents (Fig. 2A–C), and/or are in close proximity to baseline epileptiform discharges; (3) frequently precede the occurrence of ADs (Fig. 2B and C); (4) have an electrical field beyond the stimulation site, with a direction that is difficult to predict (Fig. 2C); and (5) can be associated with language disturbance in the absence of ADs, and thus may lead to false localization of language areas. 4.1. IDs–ADs relationship There is great variability in the threshold for ADs between individual patients and, even more, between individual cortical sites within the same patient (Blume et al., 2004; Lesser et al., 1984;
Table 2 Predictors of intrastimulation discharges during language mapping. Variable
Beta coeff
Stim length Stim intensity Baseline epileptiform discharges P1 P2
S.E.
p
OR
CI95
0.33 0.31 2.00
0.08 0.07 0.48
<.0001 <.0001 <.0001
1.39 1.37 7.4
[1.19, 1.62] [1.18, 1.57] [2.83, 19.33]
2.17 0.95
0.42 0.40
<.0001 0.02
0.03 0.76
[0.01, 0.10] [0.26, 2.22]
Stim length = length of the stimulation epoch. Stim intensity = stimulus intensity applied. P1 = patient 1 and P2 = patient 2.
Table 3 Association of intrastimulation discharges during with afterdischarges. Variable
Beta coeff
S.E.
p
OR
CI95
IDs
1.61
0.36
<.0001
5.02
[2.47, 10.2]
IDs = inter-stimulation discharges.
Pouratian et al., 2004). ADs occurred at lower stimulation thresholds and with higher probability in areas with abnormally increased cortical excitability (Lee et al., 2010; Wyler and Ward, 1981). Other investigators demonstrated that longer durations, higher intensities, and faster frequencies of the stimulation are linked with the occurrence of ADs (Zangaladze et al., 2008). While certain characteristics of ADs are universally accepted, the underlying mechanisms are not fully understood and remain a subject of debate. ADs were first described by Adrian (1936), who studied the spread of neuronal activity after cessation of cortical electrical stimulation in anesthetized patients. He hypothesized that successive stimulations will increase neuronal excitability, resulting in spontaneous discharges. Pinsky and Delisle Burns (1962) postulated that ADs are the result of a ‘‘differential repolarization’’ of the neurons. They suggested that cessation of repeated cortical stimulation produces cellular ‘‘exhaustion,’’ as one end of the cell repolarizes more slowly to resting membrane potential than the other, with differential recovery leading to a spontaneous discharge. Gerin (1960) described ADs as rhythmic fluctuations of the local field potentials (LFPs). Kalamangalam et al. (2014) also suggest that ADs are the result of the synchronization of LFPs, possibly due to inactivation of inhibitory interneurons, triggered by high frequency electrical stimulation (50 Hz). As a result, the adjacent LFPs are no longer separated by an inhibitory influence and can ‘‘couple’’ into an oscillatory rhythm around a common frequency; this rhythm will eventually result in a large amplitude potential identified on ECoG. The authors used a mathematical model to investigate how the ‘‘degree
I. Karakis et al. / Clinical Neurophysiology 126 (2015) 882–888
885
Fig. 1. Intra-stimulation discharges (IDs) triggered during extra-operative language mapping in patient 3. They were obscured by stimulus artifact (panel A) and revealed with a 60 Hz notch filter ‘‘on’’ (panel B). The recording was obtained from a 64 contact subdural grid electrode – GR1 through 64, placed over the left fronto-temporal regions; a 4 contact subdural strip electrode placed subtemporally-STMP 1 through 4; and two 4 contact hippocampal depth electrodes – AHP 1 through 4 and MHP 1 through 4 (panel C). Direct electrical cortical stimulation was performed via contacts 58 and 59. Notice the electrical field of the triggered IDs (arrows at the onset), with a direction of spread (in relationship to the stimulated area) difficult to predict: highest at adjacent contact GR50, less at GR60 and AHP 2 through 4, as well as at the most distal contact (contact 1) on the STMP strip.
886
I. Karakis et al. / Clinical Neurophysiology 126 (2015) 882–888
Fig. 2. Extra-operative language mapping in the same patient (#3). The stimulation was performed with contacts 45 and 46. Once again, notice the electrical field of the triggered IDs (underlined), which is hard to predict, present only at contacts 47 > 56 (panel A). A gradual increase in stimulus intensity from 3 mA (panel A) to 4 mA (panel B) and 5 mA (panel C) increases the amplitude and duration of the triggered IDs, which seem to precede the occurrence of ADs. The latter are triggered at the same location as IDs (single circle), but others are triggered at a distance, recorded at depth and subtemporal strip contacts (double circle).
I. Karakis et al. / Clinical Neurophysiology 126 (2015) 882–888
of coupling’’ (as a surrogate for the magnitude of stimulation) can modify the EEG power spectrum by condensation of the latter around certain frequencies. Based on their results, they concluded that subthreshold stimulation (represented in the model by weak coupling) results in ECoG changes, before well defined ADs can be visually identified. With an increase in the stimulation, this oscillatory coupling eventually becomes strong enough to translate into clear ADs on ECoG. Along these lines, we believe that IDs, recorded before the stimulation stops, may represent the first visible sign of such oscillatory coupling, not strong and not synchronized enough to trigger selfpropagating ADs beyond the stimulation epoch. In direct accord with the results of Kalamangalam et al., we found that both IDs and ADs seem to be part of a spectrum of ECoG patterns triggered by cortical electrical stimulation at increasing stimulus strengths. The similarities between IDs and ADs with respect to the stimulus threshold variability, their strong correlation with the current intensity and duration of the stimulation, and their propensity to occur in areas of abnormally increased cortical excitability support our hypothesis. This hypothesis is also supported by the close temporal relationship between the two, with the occurrence of IDs always preceding the occurrence of ADs (Fig. 2B and C). 4.2. Clinical significance of IDs It would be reasonable to hypothesize that the close relationship between IDs and ADs can also have direct clinical implications. ADs have an increased propensity to further organize and self-propagate, and consequently pose a threat to the patient’s safety and the validity of functional mapping (Pouratian et al., 2004). First, convulsive seizures triggered intra-operatively in awake patients could be difficult to manage; second, postictal confusion can hinder successful completion of language mapping; and third, functional disruption due to ictal events, may compromise the accuracy of mapping, leading to false localization of eloquent cortices (Simon, 2013). As ‘‘precursors’’ of ADs, IDs could help to identify those locations which, if stimulated for longer periods and/or at higher current intensities, have a higher risk for triggered ADs. Thus, IDs may present an opportunity to modify the stimulation paradigm in order to minimize the risk for occurrence of ADs. IDs were also found to be independently associated with triggered language deficits (Ishitobi et al., 2000). In our study, language disturbance was also detected in a total of seven stimulations which triggered IDs with broad electrical fields. More importantly, of these seven stimulations, four triggered exclusively IDs, without ADs. Language disturbance in the absence of both IDs and ADs was triggered in 14 cases, resulting in successful language mapping in all three subjects. An accurate interpretation of the triggered dysphasia was dependent upon recognition of ADs as well as IDs. Thus, we concur with previous investigators that ECoG during functional mapping is important and should be done every time direct electrical stimulation is applied to the brain (Blume et al., 2004; Lesser et al., 1984). Furthermore, we agree with other investigators regarding the need for an activated notch filter to investigate for the additional presence of IDs (Ishitobi et al., 2000). This method would still allow for the identification of stimulus artifact in the utilized contacts as a confirmation of effective delivery of the presumed electrical current (Pouratian et al., 2004), without obscuring the recording of adjacent contacts. 4.3. Limitations Several methodological aspects of this study may limit its impact. Its retrospective nature renders it susceptible to selection bias. This is further aggravated by the fact that subdural electrode
887
coverage and stimulation sites, albeit extensive, were mostly driven by clinical necessity. The relatively small number of events has limited our ability to detect additional associations, as increasing the number of predictors in the multivariate regression analysis would risk over-fitting the model. Moreover, our results suggested significant inter-individual variability in the odds of triggering IDs. In order to control for the impact of this variability on the probability of triggering IDs, and thus to accurately predict the independent effect of the other variables (i.e., stimulus intensity, duration of stimulation, and presence of baseline epileptiform discharges at the stimulation site), we introduced one single variable (P), to account for such idiosyncrasies among patients. The higher likelihood of triggering IDs in patient 3 may have been confounded by the fact that his stimulations were performed exclusively in temporal lobe regions. Since all IDs were triggered when stimulating the temporal lobe, and to comply with the requirements for building a logistic regression model, we could not introduce lobar location of stimulation as a covariate. In accordance with our results, prior studies have also suggested a propensity of temporal cortex to trigger such discharges (Ishitobi et al., 2000). Our data derives from only three patients, however, and thus any conclusive generalization of our results would be premature. Technical limitations inherent to extra-operative stimulation through subdural electrodes (e.g., electrode integrity, blood or CSF accumulation, orientation of electrodes in relation to the cortical columns) may also have altered the interpretation of cortical responsiveness to stimulation. Additionally, in the interest of time, stimulations often occurred with little time lapse, which may have modified the ID or AD thresholds. Given the step wise increase in the stimulus intensity, introducing the order of stimulation as an additional variable would have resulted in a high co-linearity between the stimulus intensity and the order of stimulation. Finally, we described IDs in a restricted sample: young adult epileptic patients during extra-operative cortical language mapping via the Penfield stimulation technique. Hence, generalization of our findings beyond our sample remains to be addressed. 4.4. Future directions Despite these limitations, the current pilot study provides valuable insight in an underexplored and potentially crucial phenomenon of functional mapping. Larger prospective studies are needed in order to: (1) investigate the prevalence of IDs in different patient groups (e.g., different pathology or normal brain, different stimulation techniques, intra-operative settings, older patients); (2) identify other factors that could increase the probability of the occurrence of IDs (i.e., certain frequency ranges of baseline background activity as recorded on ECoG); (3) better understand the spatial and temporal relationships between IDs and ADs; (4) determine whether ID occurrence is restricted to temporal cortex, and last but not least, (5) confirm and further investigate the potential clinical impact of IDs in functional mapping of the human brain. Acknowledgements Abstract presented at the 10th European Congress on Epileptology in London in 2012. Disclosures: None of the authors have any conflict of interest to disclose related to this project. No financial support was received for this work. References Adrian ED. The spread of activity in the cerebral cortex. J Physiol 1936;88:127–61. Blume WT, Jones DC, Pathak P. Properties of after-discharges from cortical electrical stimulation in focal epilepsies. Clin Neurophysiol 2004;115:982–9.
888
I. Karakis et al. / Clinical Neurophysiology 126 (2015) 882–888
Duffau H, Capelle L, Sichez J, Faillot T, Abdennour L, Law Koune JD, et al. Intraoperative direct electrical stimulations of the central nervous system: the Salpetriere experience with 60 patients. Acta Neurochir 1999;141:1157–67. Gerin P. Microelectrode investigations on the mechanisms of the electrically induced epileptiform seizure (‘afterdischarge’). Arc Ital Biol 1960;98:21–40. Ishitobi M, Nakasato N, Suzuki K, Nagamatsu K, Shamoto H, Yoshimoto T. Remote discharges in the posterior language area during basaltemporal stimulation. Neuroreport 2000;11:2997–3000. Jasper H. Epilepsy and the functional anatomy of the human brain. Boston, MA: Little Brown; 1954. Kalamangalam GP, Tandon N, Slater JD. Dynamic mechanisms underlying afterdischarge: a human subdural recording study. Clin Neurophysiol 2014;125:1324–38. 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, Luders H, Klem G, Dinner DS, Morris HH, Hahn J. Cortical afterdischarge and functional response thresholds: results of extraoperative testing. Epilepsia 1984;25:615–21. Lubrano V, Draper L, Roux FE. What makes surgical tumor resection feasible in Broca’s area? Insights into intraoperative brain mapping. Neurosurgery 2010;66:868–75 [discussion 875]. Mani J, Diehl B, Piao Z, Schuele SS, Lapresto E, Liu P, et al. Evidence for a basal temporal visual language center: cortical stimulation producing pure alexia. Neurology 2008;71:1621–7.
Ojemann G, Ojemann J, Lettich E, Berger M. Cortical language localization in left, dominant hemisphere. An electrical stimulation mapping investigation in 117 patients. J Neurosurg 1989;71:316–26. Penfield WJ, Rasmussen T. The cerebral cortex of man. New York: Macmillan; 1950. Penfield W. Speech and brain-mechanisms. Princeton: Princeton University Press; 1957. Pinsky C, Delisle Burns B. Production of epileptiform after-discharge in cat’s cerebral cortex. J Neurophysiol 1962;25:359–79. 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. Simon MV, Shields DC, Eskandar EN. Functional cortical mapping. In: Simon M, editor. Intraoperative neurophysiology: a comprehensive guide to monitoring and mapping. 1st ed. New York: Demos Medical Publishing; 2010. Simon MV. Intraoperative neurophysiologic sensorimotor mapping and monitoring in supratentorial surgery. J Clin Neurophysiol 2013;30:571–90. Wyler AR, Ward Jr AA. Neurons in human epileptic cortex. Response to direct cortical stimulation. J Neurosurg 1981;55:904–8. Zangaladze A, Sharan A, Evans J, Wyeth DH, Wyeth EG, Tracy JI, et al. The effectiveness of low-frequency stimulation for mapping cortical function. Epilepsia 2008;49:481–7.
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Intra-stimulation discharges: An overlooked cortical electrographic entity triggered by direct electrical stimulation Ioannis Karakis a,⇑, Beth A. Leeman-Markowski a, Catherine L. Leveroni b, Ronan D. Kilbride b, Sydney S. Cash b, Emad N. Eskandar c, Mirela V. Simon b a b c
Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
a r t i c l e
i n f o
Article history: Accepted 14 August 2014 Available online 6 September 2014 Keywords: Functional brain mapping Electrical cortical stimulation After-discharges Intra-stimulation discharges
h i g h l i g h t s Intra-stimulation discharges (IDs) can occur during language mapping and before after-discharges
(ADs). High stimulus intensities, long stimulation durations, and presence of baseline epileptiform dis-
charges at the stimulation site increase the probability of triggering IDs, and consequently, ADs. Attention to IDs may improve the safety and precision of neurophysiologic mapping.
a b s t r a c t Objective: Intra-stimulation discharges (IDs) can occur during language mapping, are largely unrecognized, and may precede the occurrence of after-discharges (ADs) and seizures. This study aimed to identify predictors of ID occurrence and determine whether IDs increase the probability of triggered ADs. Methods: A total of 332 stimulation events performed during language mapping were analyzed in 3 patients who underwent intracranial EEG recordings during evaluations for epilepsy surgery. IDs were identified in 76 stimulation events. The relationships between IDs and the stimulus current intensity, stimulation duration, and proximity to regions of abnormal cortical excitability [characterized by the presence of baseline epileptiform discharges (BEDs)] were determined using regression analysis. Results: The presence of BEDs in close proximity to stimulation, an increase in stimulus intensity by 1 mA, and an increase in stimulation duration by 1 s independently increased the odds of triggering IDs by 7.40, 1.37, and 1.39 times, respectively. All IDs were triggered during stimulations in the temporal lobe. The occurrence of IDs increased the odds of triggering ADs 5-fold. Conclusions: Longer stimulations, higher currents, and the presence of BEDs at the stimulation site increase the probability of ID occurrence, which in turn increases the probability of triggering ADs. Significance: Attention to IDs may improve the safety and precision of neurophysiologic mapping. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Accurate identification of language areas is essential for safe and adequate resection of many supra-tentorial lesions. Visual recognition of anatomic regions highly associated with language ⇑ Corresponding author. Address: Emory University School of Medicine, Faculty Office Building at Grady Campus, 49 Jesse Hill Jr. Drive SE, Office 335, Atlanta, GA 30303, USA. Tel.: +1 404 616 4013; fax: +1 404 659 0849. E-mail address: [email protected] (I. Karakis).
function, such as the inferior frontal lobe or posterior superior temporal gyrus, is insufficient due to significant inter-individual variability of language representation (Mani et al., 2008; Ojemann et al., 1989), structural displacement from mass effect, and lesion-induced cortical re-organization (Lubrano et al., 2010). Despite the availability of sophisticated neuroimaging techniques such as functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and diffusion tensor imaging (DTI), mapping based on direct electrical cortical stimulation (Penfield, 1957; Penfield and Rasmussen, 1950) remains the gold
http://dx.doi.org/10.1016/j.clinph.2014.08.011 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
I. Karakis et al. / Clinical Neurophysiology 126 (2015) 882–888
883
standard procedure for identifying functional cortex. Its application has been shown to minimize post-operative neurological deficits, while allowing for optimal lesion resection (Duffau et al., 1999). Direct application of electrical currents, however, can unexpectedly increase cortical excitability beyond a certain threshold and thus trigger unwanted epileptiform discharges, known as afterdischarges (ADs). ADs occur after the cessation of stimulation and may propagate and organize into seizures. Seizures pose a significant safety risk to the patient, particularly when they occur intraoperatively or are associated with convulsions. ADs can also result in false localization of functional cortex and seizure foci, as the discharges may occasionally occur remotely from areas of baseline cortical irritability and/or spread beyond the stimulation site, resulting in clinical manifestations not representative of the stimulated cortex (Blume et al., 2004; Jasper, 1954). Therefore, Blume et al. (2004) advocated for the prompt identification of ADs by the use of concurrent electrocorticographic recordings (ECoG) during functional mapping requiring electrical stimulation. Contrary to ADs, intra-stimulation discharges (IDs) have drawn significantly less attention (Ishitobi et al., 2000). These authors found a strong correlation between language disruption and IDs triggered at a distance from the stimulating electrodes, occurring in areas well known to support language function. We have previously reported our experience with IDs (Simon et al., 2010). Although typically obscured by stimulation artifact, we found that IDs are commonly recorded on intra- or extra-operative ECoG recordings during functional mapping and seem to precede the occurrence of ADs. In agreement with Ishitobi et al., we cautioned regarding their potential implications for patient safety, as well as the risk for false localization of eloquent cortex. In this study, we describe this less recognized entity and identify factors that increase its probability of occurrence, as well as investigate the association between IDs and ADs. Finally, we propose potential areas for future research.
impairment or ADs. The stimulation was performed in epochs of 3–11 s duration (mean: 5.8 s). By using a notch filter, IDs could also be identified during the stimulation epochs. IDs and ADs were present in isolation, or in runs of epileptiform discharges, induced during and immediately after the stimulation respectively, and clearly distinguishable from the baseline epileptiform activity or any associated stimulus artifact. An area was considered safe for future resection if, when stimulated up to 12 mA, no language disruption was triggered. If language disruption was triggered by stimulation, the response was considered to be reliable if it was reproducible (i.e., the same language deficit was recorded upon repeated stimulations of the same region) and was obtained in the absence of ADs and/or IDs. Patient 1 was stimulated in the left temporal and frontal lobes, patient 2 in the left temporal, frontal and parietal lobes, and patient 3 in the left temporal lobe. All patients were on antiepileptic drugs at the time of stimulation. A summary of the patient characteristics, stimulation parameters, and mapping results are provided in Table 1.
2. Methods
We used multivariate logistic regression to evaluate the impact of stimulation intensity, duration, and proximity to regions of increased baseline cortical excitability on the probability of triggering IDs, adjusting for additional subject specific variability. The latter was represented as three category variables (P), each category representing the individual properties for each patient (i.e., P1 for patient 1, P2 for patient 2, and P3 for patient 3). The stimulation intensity and duration were introduced in the model as continuous variables. Presence of increased cortical excitability at the stimulation site was represented as a dichotomous variable (i.e., presence or absence of BEDs). The lobar location of the stimulation was not included in the logistic regression model, as all of the stimulations that triggered IDs were in the temporal lobe regions. The outcome was represented as a dichotomous variable (i.e., presence or absence of triggered IDs). Univariate logistic regression analysis was used to determine whether stimulations that triggered IDs had an increased probability of eliciting ADs when compared to stimulations that did not trigger IDs. Statistical analysis was performed in SAS, version 9.3 (North Carolina).
2.1. Subjects We evaluated 3 male patients with non-lesional refractory epilepsy, with a mean age of 27 years (range: 20–33), who were implanted with subdural electrodes as part of their phase II evaluations for epilepsy surgery. The subdural electrode arrays were composed of platinum–iridium electrodes of 2.3 mm exposed diameter, embedded in a plastic sheet with 1-cm center to center distance. Their location was determined by the clinical scenario and was confirmed with co-registration of pre-implantation MRI with post-implantation CT. Each patient underwent extraoperative language mapping in the Epilepsy Monitoring Unit (EMU). 2.2. Stimulation and recording The Penfield stimulation method was used; repetitive pulses, each of 1 ms width, at a frequency of 60 Hz, were applied to the cortex via two adjacent electrodes of the grid, connected to an XLTEK/NATUS stimulating device. Concomitant ECoG recordings were obtained from the remaining electrodes, using referential (referenced to the contralateral mastoid) and bipolar montages. The stimulus intensity was slowly increased, in 0.5 mA increments, from 1 mA up to 12 mA (mean: 4.9 mA). Stimulation of all areas of interest was performed. If stimulation of these regions did not produce any language disruption, the stimulus intensity was gradually ramped up in 0.5 mA increments until it resulted in language
2.3. Variables For each stimulation, the following variables were recorded: (1) subject (e.g., patient 1); (2) order (e.g., the fifth stimulation); (3) duration of stimulation (seconds); (4) intensity (mA); (5) location of stimulation (temporal, frontal or parietal); (6) presence or absence of triggered IDs and their duration (seconds); (7) field of IDs in relation to the stimulation site (at or beyond the ‘‘stimulation site,’’ defined as the area where the stimulation contacts and their immediately adjacent neighbors reside); (8) presence or absence of baseline interictal and ictal epileptiform activity (BEDs) at the stimulation site; (9) presence or absence of language disruption; (10) presence or absence of ADs; (11) the field of ADs in relation to the stimulation site. 2.4. Statistical analysis
3. Results A total of 332 stimulation events were performed and analyzed during language mapping. IDs were identified in 76 events (23% of all stimulation events), with an average duration of 4.3 s (range: 1–8 s). Sixty-four out of the 76 IDs (84.21%) had an electrical field beyond the stimulation site and 57 out of 76 (75%) were not followed by ADs. All IDs were exclusively triggered by the stimulation
884
I. Karakis et al. / Clinical Neurophysiology 126 (2015) 882–888
Table 1 Summary of patient, stimulation and outcome characteristics. Patient
Age
Stim location
Stim #
Stim intensity
Stim length
ADs #
IDs #
AEDs regimen
Successful mapping
1 2 3
20 33 27
T, F T, F, P T
80 37 215
5 (1–12) 3.9 (1–11) 5 (2–11)
7.3 (4–11) 5.1 (5–8) 5.3 (3–8)
8 5 24
5 5 66
Levetiracetam 750 mg bid Carbamazepine 400 qam/600 qpm Topiramate 200 mg qpm Levetiracetam 2000 mg bid, Lamotrigine 200 mg bid, Carbamazepine 600 mg bid
Yes Yes Yes
Stim location = location of stimulation. Stim # = number of stimulation events. Stim intensity = stimulus intensity applied. Stim length = length of the stimulation epoch. ADs # = number of after-discharges events. IDs # = number of inter-stimulation discharges events. T = temporal, F = frontal, P = parietal. AEDs = antiepileptic drugs.
of temporal lobe cortex and were recorded from temporal lobe locations. ADs were seen in approximately 11% of the stimulation events. They were more likely to occur close to the stimulation site (95% of the cases). Stimulation in close proximity to BEDs increased the odds of triggering IDs 7.40-fold, when compared to stimulation of cortical regions of normal excitability, after adjusting for the other variables (OR = 7.40, CI95 [2.83, 19.33], p < .0001). Each 1 mA increase in stimulus intensity increased the odds of triggering IDs 1.37 times, after adjusting for confounding variables (OR = 1.37, CI95 [1.18, 1.57], p < .0001). Each 1 s increase in stimulation duration independently increased the odds 1.39 times (OR = 1.39, CI95 [1.19, 1.62], p < .0001). The odds of triggering IDs were 25% lower in patient 2 versus patient 3 and 97% lower in patient 1 versus patient 3 (OR = 0.76, CI95 [0.26, 2.22], p = 0.02 and OR = 0.03, CI95 [0.01, 0.10], respectively). The occurrence of IDs increased the odds of triggering ADs 5-fold (OR = 5.02, CI95 [2.47, 10.2], p < .0001). A total of 25 stimulations triggered language disturbance, 11 of which triggered language dysfunction in the presence of ADs and/ or IDs. Four of these 11 stimulations triggered ADs without preceding IDs, three triggered ADs at the stimulating site and IDs with a field broader than the stimulating region, and four triggered IDs without ADs, again with an electrical field beyond the location of the stimulating electrodes. The results of our analysis are summarized in Tables 2 and 3. 4. Discussion Safe and accurate mapping of eloquent cortex via direct electrical stimulation relies on prompt identification and avoidance of triggered ADs. In this paper we describe IDs, an under-recognized cortical electrographic entity also triggered by electrical stimulation, which have potential clinical implications. Our results demonstrate that IDs: (1) are triggered by direct electrical cortical stimulation, even in the absence of the widely recognized ADs, but can be overlooked due to concomitant stimulus artifact (Fig. 1A and B); (2) are more likely to occur when stimulations are longer, performed at higher currents (Fig. 2A–C), and/or are in close proximity to baseline epileptiform discharges; (3) frequently precede the occurrence of ADs (Fig. 2B and C); (4) have an electrical field beyond the stimulation site, with a direction that is difficult to predict (Fig. 2C); and (5) can be associated with language disturbance in the absence of ADs, and thus may lead to false localization of language areas. 4.1. IDs–ADs relationship There is great variability in the threshold for ADs between individual patients and, even more, between individual cortical sites within the same patient (Blume et al., 2004; Lesser et al., 1984;
Table 2 Predictors of intrastimulation discharges during language mapping. Variable
Beta coeff
Stim length Stim intensity Baseline epileptiform discharges P1 P2
S.E.
p
OR
CI95
0.33 0.31 2.00
0.08 0.07 0.48
<.0001 <.0001 <.0001
1.39 1.37 7.4
[1.19, 1.62] [1.18, 1.57] [2.83, 19.33]
2.17 0.95
0.42 0.40
<.0001 0.02
0.03 0.76
[0.01, 0.10] [0.26, 2.22]
Stim length = length of the stimulation epoch. Stim intensity = stimulus intensity applied. P1 = patient 1 and P2 = patient 2.
Table 3 Association of intrastimulation discharges during with afterdischarges. Variable
Beta coeff
S.E.
p
OR
CI95
IDs
1.61
0.36
<.0001
5.02
[2.47, 10.2]
IDs = inter-stimulation discharges.
Pouratian et al., 2004). ADs occurred at lower stimulation thresholds and with higher probability in areas with abnormally increased cortical excitability (Lee et al., 2010; Wyler and Ward, 1981). Other investigators demonstrated that longer durations, higher intensities, and faster frequencies of the stimulation are linked with the occurrence of ADs (Zangaladze et al., 2008). While certain characteristics of ADs are universally accepted, the underlying mechanisms are not fully understood and remain a subject of debate. ADs were first described by Adrian (1936), who studied the spread of neuronal activity after cessation of cortical electrical stimulation in anesthetized patients. He hypothesized that successive stimulations will increase neuronal excitability, resulting in spontaneous discharges. Pinsky and Delisle Burns (1962) postulated that ADs are the result of a ‘‘differential repolarization’’ of the neurons. They suggested that cessation of repeated cortical stimulation produces cellular ‘‘exhaustion,’’ as one end of the cell repolarizes more slowly to resting membrane potential than the other, with differential recovery leading to a spontaneous discharge. Gerin (1960) described ADs as rhythmic fluctuations of the local field potentials (LFPs). Kalamangalam et al. (2014) also suggest that ADs are the result of the synchronization of LFPs, possibly due to inactivation of inhibitory interneurons, triggered by high frequency electrical stimulation (50 Hz). As a result, the adjacent LFPs are no longer separated by an inhibitory influence and can ‘‘couple’’ into an oscillatory rhythm around a common frequency; this rhythm will eventually result in a large amplitude potential identified on ECoG. The authors used a mathematical model to investigate how the ‘‘degree
I. Karakis et al. / Clinical Neurophysiology 126 (2015) 882–888
885
Fig. 1. Intra-stimulation discharges (IDs) triggered during extra-operative language mapping in patient 3. They were obscured by stimulus artifact (panel A) and revealed with a 60 Hz notch filter ‘‘on’’ (panel B). The recording was obtained from a 64 contact subdural grid electrode – GR1 through 64, placed over the left fronto-temporal regions; a 4 contact subdural strip electrode placed subtemporally-STMP 1 through 4; and two 4 contact hippocampal depth electrodes – AHP 1 through 4 and MHP 1 through 4 (panel C). Direct electrical cortical stimulation was performed via contacts 58 and 59. Notice the electrical field of the triggered IDs (arrows at the onset), with a direction of spread (in relationship to the stimulated area) difficult to predict: highest at adjacent contact GR50, less at GR60 and AHP 2 through 4, as well as at the most distal contact (contact 1) on the STMP strip.
886
I. Karakis et al. / Clinical Neurophysiology 126 (2015) 882–888
Fig. 2. Extra-operative language mapping in the same patient (#3). The stimulation was performed with contacts 45 and 46. Once again, notice the electrical field of the triggered IDs (underlined), which is hard to predict, present only at contacts 47 > 56 (panel A). A gradual increase in stimulus intensity from 3 mA (panel A) to 4 mA (panel B) and 5 mA (panel C) increases the amplitude and duration of the triggered IDs, which seem to precede the occurrence of ADs. The latter are triggered at the same location as IDs (single circle), but others are triggered at a distance, recorded at depth and subtemporal strip contacts (double circle).
I. Karakis et al. / Clinical Neurophysiology 126 (2015) 882–888
of coupling’’ (as a surrogate for the magnitude of stimulation) can modify the EEG power spectrum by condensation of the latter around certain frequencies. Based on their results, they concluded that subthreshold stimulation (represented in the model by weak coupling) results in ECoG changes, before well defined ADs can be visually identified. With an increase in the stimulation, this oscillatory coupling eventually becomes strong enough to translate into clear ADs on ECoG. Along these lines, we believe that IDs, recorded before the stimulation stops, may represent the first visible sign of such oscillatory coupling, not strong and not synchronized enough to trigger selfpropagating ADs beyond the stimulation epoch. In direct accord with the results of Kalamangalam et al., we found that both IDs and ADs seem to be part of a spectrum of ECoG patterns triggered by cortical electrical stimulation at increasing stimulus strengths. The similarities between IDs and ADs with respect to the stimulus threshold variability, their strong correlation with the current intensity and duration of the stimulation, and their propensity to occur in areas of abnormally increased cortical excitability support our hypothesis. This hypothesis is also supported by the close temporal relationship between the two, with the occurrence of IDs always preceding the occurrence of ADs (Fig. 2B and C). 4.2. Clinical significance of IDs It would be reasonable to hypothesize that the close relationship between IDs and ADs can also have direct clinical implications. ADs have an increased propensity to further organize and self-propagate, and consequently pose a threat to the patient’s safety and the validity of functional mapping (Pouratian et al., 2004). First, convulsive seizures triggered intra-operatively in awake patients could be difficult to manage; second, postictal confusion can hinder successful completion of language mapping; and third, functional disruption due to ictal events, may compromise the accuracy of mapping, leading to false localization of eloquent cortices (Simon, 2013). As ‘‘precursors’’ of ADs, IDs could help to identify those locations which, if stimulated for longer periods and/or at higher current intensities, have a higher risk for triggered ADs. Thus, IDs may present an opportunity to modify the stimulation paradigm in order to minimize the risk for occurrence of ADs. IDs were also found to be independently associated with triggered language deficits (Ishitobi et al., 2000). In our study, language disturbance was also detected in a total of seven stimulations which triggered IDs with broad electrical fields. More importantly, of these seven stimulations, four triggered exclusively IDs, without ADs. Language disturbance in the absence of both IDs and ADs was triggered in 14 cases, resulting in successful language mapping in all three subjects. An accurate interpretation of the triggered dysphasia was dependent upon recognition of ADs as well as IDs. Thus, we concur with previous investigators that ECoG during functional mapping is important and should be done every time direct electrical stimulation is applied to the brain (Blume et al., 2004; Lesser et al., 1984). Furthermore, we agree with other investigators regarding the need for an activated notch filter to investigate for the additional presence of IDs (Ishitobi et al., 2000). This method would still allow for the identification of stimulus artifact in the utilized contacts as a confirmation of effective delivery of the presumed electrical current (Pouratian et al., 2004), without obscuring the recording of adjacent contacts. 4.3. Limitations Several methodological aspects of this study may limit its impact. Its retrospective nature renders it susceptible to selection bias. This is further aggravated by the fact that subdural electrode
887
coverage and stimulation sites, albeit extensive, were mostly driven by clinical necessity. The relatively small number of events has limited our ability to detect additional associations, as increasing the number of predictors in the multivariate regression analysis would risk over-fitting the model. Moreover, our results suggested significant inter-individual variability in the odds of triggering IDs. In order to control for the impact of this variability on the probability of triggering IDs, and thus to accurately predict the independent effect of the other variables (i.e., stimulus intensity, duration of stimulation, and presence of baseline epileptiform discharges at the stimulation site), we introduced one single variable (P), to account for such idiosyncrasies among patients. The higher likelihood of triggering IDs in patient 3 may have been confounded by the fact that his stimulations were performed exclusively in temporal lobe regions. Since all IDs were triggered when stimulating the temporal lobe, and to comply with the requirements for building a logistic regression model, we could not introduce lobar location of stimulation as a covariate. In accordance with our results, prior studies have also suggested a propensity of temporal cortex to trigger such discharges (Ishitobi et al., 2000). Our data derives from only three patients, however, and thus any conclusive generalization of our results would be premature. Technical limitations inherent to extra-operative stimulation through subdural electrodes (e.g., electrode integrity, blood or CSF accumulation, orientation of electrodes in relation to the cortical columns) may also have altered the interpretation of cortical responsiveness to stimulation. Additionally, in the interest of time, stimulations often occurred with little time lapse, which may have modified the ID or AD thresholds. Given the step wise increase in the stimulus intensity, introducing the order of stimulation as an additional variable would have resulted in a high co-linearity between the stimulus intensity and the order of stimulation. Finally, we described IDs in a restricted sample: young adult epileptic patients during extra-operative cortical language mapping via the Penfield stimulation technique. Hence, generalization of our findings beyond our sample remains to be addressed. 4.4. Future directions Despite these limitations, the current pilot study provides valuable insight in an underexplored and potentially crucial phenomenon of functional mapping. Larger prospective studies are needed in order to: (1) investigate the prevalence of IDs in different patient groups (e.g., different pathology or normal brain, different stimulation techniques, intra-operative settings, older patients); (2) identify other factors that could increase the probability of the occurrence of IDs (i.e., certain frequency ranges of baseline background activity as recorded on ECoG); (3) better understand the spatial and temporal relationships between IDs and ADs; (4) determine whether ID occurrence is restricted to temporal cortex, and last but not least, (5) confirm and further investigate the potential clinical impact of IDs in functional mapping of the human brain. Acknowledgements Abstract presented at the 10th European Congress on Epileptology in London in 2012. Disclosures: None of the authors have any conflict of interest to disclose related to this project. No financial support was received for this work. References Adrian ED. The spread of activity in the cerebral cortex. J Physiol 1936;88:127–61. Blume WT, Jones DC, Pathak P. Properties of after-discharges from cortical electrical stimulation in focal epilepsies. Clin Neurophysiol 2004;115:982–9.
888
I. Karakis et al. / Clinical Neurophysiology 126 (2015) 882–888
Duffau H, Capelle L, Sichez J, Faillot T, Abdennour L, Law Koune JD, et al. Intraoperative direct electrical stimulations of the central nervous system: the Salpetriere experience with 60 patients. Acta Neurochir 1999;141:1157–67. Gerin P. Microelectrode investigations on the mechanisms of the electrically induced epileptiform seizure (‘afterdischarge’). Arc Ital Biol 1960;98:21–40. Ishitobi M, Nakasato N, Suzuki K, Nagamatsu K, Shamoto H, Yoshimoto T. Remote discharges in the posterior language area during basaltemporal stimulation. Neuroreport 2000;11:2997–3000. Jasper H. Epilepsy and the functional anatomy of the human brain. Boston, MA: Little Brown; 1954. Kalamangalam GP, Tandon N, Slater JD. Dynamic mechanisms underlying afterdischarge: a human subdural recording study. Clin Neurophysiol 2014;125:1324–38. 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, Luders H, Klem G, Dinner DS, Morris HH, Hahn J. Cortical afterdischarge and functional response thresholds: results of extraoperative testing. Epilepsia 1984;25:615–21. Lubrano V, Draper L, Roux FE. What makes surgical tumor resection feasible in Broca’s area? Insights into intraoperative brain mapping. Neurosurgery 2010;66:868–75 [discussion 875]. Mani J, Diehl B, Piao Z, Schuele SS, Lapresto E, Liu P, et al. Evidence for a basal temporal visual language center: cortical stimulation producing pure alexia. Neurology 2008;71:1621–7.
Ojemann G, Ojemann J, Lettich E, Berger M. Cortical language localization in left, dominant hemisphere. An electrical stimulation mapping investigation in 117 patients. J Neurosurg 1989;71:316–26. Penfield WJ, Rasmussen T. The cerebral cortex of man. New York: Macmillan; 1950. Penfield W. Speech and brain-mechanisms. Princeton: Princeton University Press; 1957. Pinsky C, Delisle Burns B. Production of epileptiform after-discharge in cat’s cerebral cortex. J Neurophysiol 1962;25:359–79. 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. Simon MV, Shields DC, Eskandar EN. Functional cortical mapping. In: Simon M, editor. Intraoperative neurophysiology: a comprehensive guide to monitoring and mapping. 1st ed. New York: Demos Medical Publishing; 2010. Simon MV. Intraoperative neurophysiologic sensorimotor mapping and monitoring in supratentorial surgery. J Clin Neurophysiol 2013;30:571–90. Wyler AR, Ward Jr AA. Neurons in human epileptic cortex. Response to direct cortical stimulation. J Neurosurg 1981;55:904–8. Zangaladze A, Sharan A, Evans J, Wyeth DH, Wyeth EG, Tracy JI, et al. The effectiveness of low-frequency stimulation for mapping cortical function. Epilepsia 2008;49:481–7.