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Electrical stimulation mapping in children
Seizure: European Journal of Epilepsy xxx (xxxx) xxx–xxx
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Review
Electrical stimulation mapping in children ⁎
Ann Hyslopa,b, , Michael Duchownya,b,c a b c
Nicklaus Children’s Hospital, 3100 SW 62nd Ave, Miami, FL, 33155, United States Florida International University Herbert Wortheim College of Medicine, 11200 SW 8th St, Miami, FL, 33199, United States University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, 33136, United States
A R T I C LE I N FO
A B S T R A C T
Keywords: Electrical stimulation mapping Pediatric epilepsy surgery Functional mapping sEEG Language mapping Motor mapping Intraoperative mapping
Electrical stimulation mapping is a longstanding practice that aids in identification and delineation of eloquent cortex. Initially used to expand our understanding of the typical human cortex, it now plays a significant role in mapping cortical function in individuals with atypical structural and functional tissue organization undergoing epilepsy surgery. This review discusses the unique challenges that arise in the functional testing of the immature cortex of a child and the parameters of stimulation that optimize accurate results in conventional open implantation and in stereo-electroencephalography. The prerequisite baseline evaluation and preparation recommended to increase the yield from pediatric stimulation mapping sessions is described, as are ideal approaches to the mapping of the sensory, motor, language, and visual cortices.
1. Introduction
2. Physics of electrical stimulation
Almost 150 years ago investigators began applying electrical stimulation to mammalian cerebral cortices, an endeavor that eventually gave rise to our understanding of the organization of the human cortex. While the consistency of general organization was striking, further investigations revealed fine variations in the localization of motor and sensory function between humans both in the presence and absence of intracerebral structural lesions. In a manuscript published in 1937, Penfield and Boldrey provide sketches of summated data from cortical stimulations mapping sensory and motor function performed in 126 anesthetized patients using electrical stimulation methodology similar to that used today [1]. In 1979, Woolsey et al. more thoroughly delineated the stimulus intensities required to create a functional response within the sensory and motor cortices [2]. Before the turn of the 21 st century, significant improvements in surgical and stimulation techniques and the introduction of chronic extraoperative electrode implantation led to standardized language mapping methods that confirmed the existence of wide variability of the language cortex in humans [3]. Electrical stimulation mapping is now safely and successfully performed in children [16], the results of which have, in conjunction with information from other modalities of cortical study, advanced our understanding of the impact of developmental stages and structural and functional lesions on the organization of the human cortex.
Electrical stimulation of the cortex causes a transient disruption of neuronal transmission in the tissue affected, exerting direct effects on axon bodies and nodes of Ranvier in the immediate vicinity and likely causing downstream dysfunction in networks affected by electrical field spread or propagation [4]. This type of stimulation has been used to determine whether or not removal of cortical tissue will result in a deficit of eloquent functions including motor, sensation, language, and vision. Direct electrical stimulation methods are chosen depending on the suspected function of the cortex in the region of interest. When applied at various durations and intensities during patient testing, stimulation of cortex harboring functional tissue produces either an elicitation or an inhibition of a response. Since most responses documented outside of the motor and sensory cortices are inhibitory [5] the paradigms used in, and the conditions of, clinical testing must be ageappropriate in order to produce interpretable and accurate results. For example, motor and sensory testing may only require brief periods of the patient maintaining a calm, awake state, while stimulation mapping of suspected expressive language regions necessitates cooperation in a repetitive object-naming task, and assessment of receptive language skills may demand engagement in lengthy question-and-answer exercises. Although it has been reported that identical stimulations may produce varying clinical responses [6], the results of a well-executed mapping session often yield a somatotopy that aids in safely determining margins of cortical resection.
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Corresponding author at: Nicklaus Children’s Hospital, 3100 SW 62nd Ave, Miami, FL, 33155, United States. E-mail addresses: [email protected] (A. Hyslop), [email protected] (M. Duchowny).
https://doi.org/10.1016/j.seizure.2019.07.023 Received 16 May 2019; Received in revised form 25 July 2019; Accepted 29 July 2019 1059-1311/ © 2019 Published by Elsevier Ltd on behalf of British Epilepsy Association.
Please cite this article as: Ann Hyslop and Michael Duchowny, Seizure: European Journal of Epilepsy, https://doi.org/10.1016/j.seizure.2019.07.023
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required for ictal capture. Functional mapping is ideally performed after capture of the target seizure type and should be preceded by the initiation of the child's home medications and, if warranted by assessment of risk for status epilepticus, by an intravenous bolus of an antiepileptic medication.
Typical electrical stimulation parameters are based on a combination of historical preferences and basic science research. Those used in grid and strip electrodes are different than those used in depth and stereotactically place electrodes due to the decreased surface area of the latter resulting in a higher charge density application to the cortex and increased risk of tissue damage [7]. In both, however, a rectangularpulse waveform is the method of electrical current delivery most optimal for the elicitation of action potentials [8]. Estimation of electrical field distribution within the irregular topography of an individual human brain [9] has shown that in bipolar stimulation, current density is highest immediately under the stimulation electrode and decreases significantly in the 0.5 cm penumbra. With unipolar stimulation, current density extends more deeply and generates a wider field, an advantage less favored in cortical functional mapping compared to the more focused current density created by bipolar stimulation. This is an important limitation as eloquent functions are organized discretely within small sections of tissue [10].
5. Accurate coregistration of informative modalities with volumetric brain MRI Prior to mapping, coregistration of three-dimensional brain MRI with relevant functional MRI (fMRI) BOLD signals or informative mapping results from transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) will optimize the time required for direct electrical stimulation. Some structural lesions, such as remote infarcts, tumors, tubers, cavernomas, and arteriovenous malformations, have been shown to cause destruction or derangement of anatomical landmarks and a displacement of cortical function [13,14], while early developmental lesions may not result in significant rearrangement of function [21]. In some pediatric cases, functional organization is not detected by fMRI due to lack of cooperation during testing or use of sedation and, even if present, is not well-demarcated due to the intrinsically poor spatial resolution of fMRI BOLD signals. Additionally, electrode shift from surgical and steroid effects can compromise the accuracy of the coregistration. Despite the technical constraints of coregistrations, referencing a coregistration of the three-dimensional MRI to available fMRI BOLD signals, regions of effective stimulation from TMS, or functional MEG clusters, enables initial stimulation to be performed in the regions suspected to have the greatest likelihood of producing a functional change. Margins of each eloquent region can then be mapped by stimulating along and adjacent to the involved gyrus. True positive responses, elicited early in a mapping session, also ensure that the technical setup is working properly and allows for faster determination of the lowest stimulation threshold required within the region to produce a functional change. Minimization of the time required for mapping is critical, especially in patients with limited attention spans and cooperation capabilities. Generally, areas of extreme hyperexcitability represented by very frequent interictal epileptogenic activity are avoided early in stimulation tests to avoid producing a seizure that would prematurely terminate the mapping session.
3. Typical parameters for extra-operative electrical stimulation mapping In order to optimize focal stimulation effects, short pulse durations are used to ensure activation of local rather than remote fibers [11], and range between 200–300 milliseconds. Train durations range from 0.5 to 10 seconds depending on the function being tested [12]. In children, current intensity is gradually increased from 1 mA to a maximum of 20 mA, a maximum stimulus intensity not often required in adults [13–15]. Utilizing a dual increment paradigm in which increases in pulse duration alternate with increases in stimulus intensity allows identification of optimal neurophysiologic thresholds with minimal risk of tissue injury [16]. This paradigm is particularly useful in children because higher intensities and longer stimulation times are often required to induce functional alteration compared to adults. This has long been attributed to the difference between developmentally immature and fully myelinated tissue and is affirmed by the finding that younger children typically have higher motor thresholds than older children and, unlike adults, the majority of children exhibit afterdischarges with stimulation [13,16,17]. Afterdischarges and seizures may induce functional alterations not related to focal stimulation, a feature that can complicate interpretation or lengthen the time required to obtain reliable mapping results. Interestingly, functional thresholds can be found at higher stimulation thresholds than those causing afterdischarges in children [13,18]; therefore, attempts have been made to minimize hyperexcitability without compromising functional mapping results. For example, the pulse rate of stimulation has historically been 50–60 Hz, but recently lower frequency stimulations of 5 and 10 Hz have been shown to generate less afterdischarges and are equally effective in mapping cortical function [19]. The administration of an antiepileptic medication prior to a functional mapping session has also been shown to reduce the occurrence of stimulation-induced seizures [20].
6. Extra-operative electrical stimulation mapping 6.1. Sensory and motor mapping Motor mapping in children is often a satisfying endeavor because face, arm, trunk, and leg movements are easily elicited and reliable. Identification of motor function in children is achievable in 75–82% of cases undergoing direct electrical stimulation in the expected motor cortex [18,22]. Thresholds for elicitation of motor response range between 2–10 mA in most patients, with a mean threshold of 5–6 mA [18]. Thresholds are higher in younger children and patients with neuronal migration disorders in perirolandic cortex [13]. Children with tumors, abscesses, AVMs, and cavernomas near motor areas may also require greater amperages [14]. Train durations as low as 0.5 s and frequencies between 5–50 Hz are often effective. Verbal children may report a sensation of movement or dysesthesia prior to visible motor responses representing activation of muscle fibers, but with small increases in current intensity, muscle contraction will positively identify primary motor cortex. Negative motor responses are characterized by the interruption or slowing of a volitional motor action and, therefore, require the child to sustain a repetitive or sustained movement such as finger tapping, arm elevation, or speech. These functions likely help regulate motor control through complex inhibitory processes [23]. A negative motor area can
4. Establishing baseline function Assessment of a child’s baseline functionality and ability to cooperate while awaiting ictal capture and in the testing of relevant functional domains is critical for planning chronic subdural implantation. A careful neurologic exam documenting gaze preferences, visual fields, focal weaknesses, handedness, sensory deficits, hearing, articulation, prosody, and expressive and receptive speech functions allows accurate detection of alterations from baseline during stimulation. In younger patients, lengthy periods of pretest observation can aid in identifying a behavioral deviation or aberrant movement elicited during stimulation. A child must also be able to tolerate the activity restrictions necessitated by electrode implantation for the time period, often 5–7 days, 2
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be found anterior to the motor cortex of the face within the inferior frontal gyrus [24], one resides in the supplementary motor area (SMA) [25] while another can be found in the dorsal premotor cortex [26]. Recent investigations show that negative motor areas can also be found within primary motor and sensory cortices [27] and that lower current intensities may elicit negative motor responses at the same sites that higher intensities trigger positive ones [26]. Avoiding these areas in resection is not necessary, as their removal does not result in a permanent neurologic deficit [26,28]. The sensory cortex can be mapped with direct electrical stimulation using parameters similar to motor mapping. Contralateral sensations of paresthesias or numbness may occur in the limbs and face although some facial and most oropharyngeal and lingual sensory changes may be bilateral. While it is atypical for evoked responses in primary sensory cortex to induce pain, such an occurrence during functional mapping may indicate activation of the adjacent parietal operculum, located in the superior bank of the Sylvian fissure, a second somatosensory area [29].
stimulating dural nerve fibers and anxiety from the mapping session should also be identified and alleviated to minimize the possibility of biasing stimulation-induced language assessment. With age, the boundaries of expressive language cortex become more defined and the sensitivity of electrical stimulation increases. Studies have shown such mapping is more likely to reveal the presence of language areas in children over the age of approximately 8–10 years of age [30,36]. It is unclear whether this finding can be attributed to the increase of language-dedicated cortical networks due to maturational processes or alterations in threshold or connectivity associated with pathological processes involving epileptogenic tissue. It is possible that the emergence of epileptogenicity and the degree to which, if any, disruption of language function occurs depends not only on maturation of cortical tissue, but also on the type of lesion giving rise to the epileptogenesis. Duchowny et al. showed that language function was in expected regions in 16 children with congenital disease within or adjacent to affected tissue but relocated contralaterally in three of six children with acquired cerebral injury [21].
6.2. Language mapping
6.3. Mapping other areas of interest
Expressive and receptive language function mapping can be performed successfully in many children. Mapping language with direct electrical stimulation has been performed in children as young as 2 years [21], but the rates of success rise with increasing age, particularly above 10 years [30], and higher intellect. In a series of 53 pediatric cases, Zea Vera et al. [18] successfully identified expressive language in 89% of children tested. Speech arrest due to aphasia indicates presence of expressive language function when electrical stimulation is performed in the expressive language cortex, most often localized to the posterior aspect of the inferior frontal gyrus in the dominant hemisphere, during tasks including reading, naming, counting, and recitation of well-known phrases [3,30,31]. Due to the presence of dysnomia in all aphasias, visual object naming is the most common language task used to map expressive speech [32]. After a brief period of preparatory practice, even young children can engage in picture or object naming, but the responses need to be reproducible and, therefore, multiple trials may be required for confirmation. This mandates examiner patience during testing and novel efforts to sustain or recapture the attention of the child. More than one testing session may be required to ensure that fatigue and the cumulative effects of stimulation are not responsible for observed language dysfunction. Stimulation train durations should be extended to 3–5 seconds to increase the likelihood of speech interruption and they must be delivered during the time interval of speech generation and production. Maximal stimulus intensities required to produce a response may be as high as 15 mA, but are found typically between 7–8 mA in children [18]. Receptive language cortex is often located in bilateral posterior superior temporal gyri in children and therefore should be tested whenever electrode implantation coverage spans this region in the dominant or non-dominant hemisphere. Stimulation of receptive language areas most often reveals dysfunction in tasks such as one-step direction instruction, reading comprehension questions, or picture selection [33,34]. Thresholds of receptive language dysfunction within the temporal lobes are typically higher than those required to elicit expressive speech dysfunction [35]. Careful observation during language mapping is warranted to avoid misinterpreting language competence. Speech arrest may be caused by activation of negative motor areas or the motor cortices of the face, tongue, or oropharynx while poor performance in receptive language tasks may occur from confusion due to alteration of awareness. Asking the child to explain what sensations they felt during the error and whether or not they understood the verbal instructions often sheds light on these occurrences, even in young children. Pain caused by
Direct electrical stimulation of primary visual association cortex in older children and adolescents can be successfully accomplished but is rarely performed due to the lack of functional visual reorganization; simply avoiding resection of the mesial occipital cortex and the optic radiations coursing through the temporal lobes ensures a low risk of visual field deficit. Visual association regions can also be mapped. For example, identification of the frontal eye fields (FEF) in the rostral bank of the precentral sulcus within the middle frontal gyrus is easily performed, but the authors’ personal experience in pediatric cortical resections as well as trials of cryogenic inactivation of the FEF in the macaque have shown that removal or deactivation of these regions does not result in visual deficits or significant limitations in eye movements [37]. Therefore, evocation of auras generated in this region by electrical stimulation may be helpful for seizure localization, but functional mapping in this region is of limited clinical use. Insular stimulation may result in sensorimotor or somatosensory responses depending on whether anterior or posterior aspects of the insula are targeted. Stimulation of the insula is therefore more likely to aid in aura localization than in functional mapping of discrete function to avoid a postoperative deficit [38]. 7. Intraoperative mapping Intraoperative mapping using direct cortical stimulation is efficacious in older children and adolescents. Strategies for intraoperative mapping of children are similar to those used extra-operatively, but careful planning is required to optimize its accuracy and minimize the child’s time under anesthesia. Intraoperative somatosensory evoked potentials (SSEPs), motor evoked potentials (MEPs), and expressive language mapping can be performed in the operating room in a select population of children. Monitoring of simultaneous EEG is critical for determining whether an interruption in language function or generation of motor activity can be accurately attributed to stimulation rather than underlying seizure activity. The most optimal anesthetic agents used for intraoperative mapping in children with epilepsy has not been established, but avoidance of pro-convulsant drugs is important. Drugs used for induction such as thiopental, methohexital, and etomidate can induce myoclonus that may interfere with accurate mapping [39]. Opiates can be used without risk of seizure induction and inhalants such as sevoflurane, isoflurane, and desflurane are safe for maintenance [40]. Commonly used anesthetics for awake mapping include propofol and dexmedetomidine [41–43]. SSEPs are usually performed in the anesthetized child to identify the central sulcus. This is especially helpful whenever surface anatomy is 3
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with lower excitability thresholds such as the hippocampus may be attempted at a 1 Hz frequency to decrease the likelihood of rapid seizure generalization [31,48]. The primary disadvantage of performing functional mapping via sEEG is the lack of spatial resolution when compared to conventional grid and strip electrode implantation. While sEEG placement allows for stimulation within a sulcus and regionalization of functional cortex, it does not allow for accurate delineation of the boundaries of eloquent cortex. In addition, the size of the bolts required to secure each depth to the skull prevent an optimal density of sEEG in any area of eloquence to allow for margin determination. Despite these disadvantages, complication rates of sEEG are lower than those in subdural implantations and surgical decision can be made after explantation, allowing more time for EEG analysis; therefore, in appropriately identified patients, the method may be more desirable [46,51].
atypical, and helps ensure accurate electrode coverage for motor and extraoperative sensory mapping. Stimulation of the median nerve and simultaneous recording from a strip of electrodes perpendicular to the presumed central sulcus allows identification of a phase reversal and verification of the location of the central sulcus. While MEPs are more often performed in tumoral surgeries when manipulation of the descending corticospinal tracts is required, they are also useful in pediatric epilepsy surgery cases to minimize or avoid motor deficits in children unsuitable for implantation for extraoperative mapping. Frequent interjection of cortical and/or tumoral resection by MEPs aids in safe resection of tissue immediately adjacent to primary motor cortex. Schucht et al. (2014) reports success in the use of highfrequency (200–300 Hz) stimulation in intraoperative motor mapping by administering four consecutive train-of-five stimulations, each with an interstimulus interval of 4 ms and pulse duration of 500 ms, at a 0.5Hz repetition rate via a monopolar probe. Using these parameters, cortex harboring motor responses (defined as at or above 30 μV in amplitude within the target muscle) at intensities as low as 1 mA were removed without permanent neurologic deficit. Cortical resection proceeded only with extreme caution where stimulus intensities of 3 mA elicited MEPs [44]. Intraoperative expressive language mapping is worthwhile in children able to cooperate fully in picture-naming tasks extra-operatively, and should be strongly considered to prevent chronic electrode implantation. Utilization of neuropsychologists or other staff can be helpful as the child must remain calm and engaged in the task for a reliable result.
9. Final resection planning after functional mapping When delineating surgical margins, epilepsy surgery teams often opt to leave a safety margin of 1 cm from identified eloquent areas. This was originally based on studies that identified persistent post-operative language deficits in patients who had undergone resections within 1 cm of a language area identified by electrical stimulation mapping [52]. After functional mapping data is superimposed on coregistered data and combined with electrocorticographic data, overlap between eloquent cortex and the epileptogenic zone can be determined with precision and the resection carefully planned. Should a resection be deemed incomplete due to proximity to eloquent tissue, documentation is imperative to avoid unnecessary future re-investigations.
8. StereoEEG
Declaration of Competing Interest
Functional mapping in children implanted with stereo-EEG (sEEG) has been more frequently performed with increasing use of this technique. As early as 1965, Bancaud and colleagues employed electrical stimulation using sEEG in a series of patients [45]. In this method, bipolar stimulation is applied between two consecutive contacts located on the same electrode, both of which should be contained within cortical tissue for best results. The use of clinical paradigms for expressive and receptive language mapping is identical to mapping with conventional subdural grids and strips. Not surprisingly, disruption of speech tasks is less likely to occur with this method, occurring in less than 50% of children in one series [46], due to the lack of spatial sampling offered by sEEG in conjunction with the variability of location and the complexity of functional networks involved in speech tasks. Elicitation of motor responses when electrodes are located in the pre-central gyrus is quite successful in children, occurring in 100% of the children in the same series [46]. Stereo-EEG allows placement of electrodes throughout both hemispheres and multiple lobes within the same patient enabling employment of electrical stimulation in eliciting afterdischarges or seizures which may provide information on an underlying epileptogenic network. Spontaneous ictal capture of typical seizures is preferred, but those triggered by electrical stimulation, if semiologically consistent with the target seizure type, can offer insight to the epileptogenic zone [31,47,48]. More recently, reports of cases in which electrical stimulation differentiates the epileptogenic zone from a region of propagation have emerged [31]. Electrical stimulation parameters for functional mapping in sEEG are different from those used in grid and strip implantation. Due to the smaller surface area of depth electrodes, the same stimulation intensity generates a current density and, therefore, a higher risk of damage to surrounding cortical tissue. Thus, Britton [49] has suggested using a max stimulation current of 8 mA and pulse duration of 200 ms to ensure no charge density above 30 μC per cm2 is generated, a limit that is not associated with tissue damage [50]. For functional mapping, the most commonly used frequency is 50 Hz; stimulation performed for the purpose of triggering a seizure, especially those performed in cortex
None. References [1] Penfield W, Boldrey E. Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain. Citeseer 1937;60:389–443. [2] Woolsey CN, Erickson TC, Gilson WE. Localization in somatic sensory and motor areas of human cerebral cortex as determined by direct recording of evoked potentials and electrical stimulation. J Neurosurg 1979;51:476–506. [3] 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. [4] Nowak LG, Bullier J. Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter. II. Evidence from selective inactivation of cell bodies and axon initial segments. Exp Brain Res 1998;118:489–500. [5] Ojemann GA. Electrical stimulation and the neurobiology of language. Behav Brain Sci 1983;6:221–30. Cambridge University Press. [6] Van Buren JM, Fedio P, Frederick GC. Mechanism and localization of speech in the parietotemporal cortex. Neurosurgery 1978;2:233–9. [7] 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. [8] Yeomans JS. “Temporal summation decay” in hypothalamic self-stimulation: Threshold changes at long intrapair intervals due to axonal subnormal periods. Behav Neurosci 1990;104:991. American Psychological Association. [9] 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. [10] Ojemann GA. The intrahemispheric organization of human language, derived with electrical stimulation techniques. Trends Neurosci 1983;6:184–9. [11] Grill Jr WM, Mortimer JT. The effect of stimulus pulse duration on selectivity of neural stimulation. IEEE Trans Biomed Eng 1996;43:161–6. [12] Lesser RP, Lüders H, Klem G, Dinner DS, Morris HH, Hahn JF, et al. Extraoperative cortical functional localization in patients with epilepsy. J Clin Neurophysiol 1987;4:27–53. [13] Chitoku S, Otsubo H, Harada Y, Jay V, Rutka JT, Weiss SK, et al. Extraoperative cortical stimulation of motor function in children. Pediatr Neurol 2001;24:344–50. [14] Signorelli F, Guyotat J, Mottolese C, Schneider F, D’Acunzi G, Isnard J. Intraoperative electrical stimulation mapping as an aid for surgery of intracranial lesions involving motor areas in children. Childs Nerv Syst 2004;20:420–6. [15] Resnick T. Cortical stimulation thresholds in children being evaluated for resective surgery. Epilepsia 1988;29:651–2. [16] Jayakar P, Alvarez LA, Duchowny MS, Resnick TJ. A safe and effective paradigm to
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Seizure: European Journal of Epilepsy xxx (xxxx) xxx–xxx
A. Hyslop and M. Duchowny
[35] Wang SG, Eskandar EN, Kilbride R, Chiappa KH, Curry WT, Williams Z, et al. The variability of stimulus thresholds in electrophysiologic cortical language mapping. J Clin Neurophysiol 2011;28:210–6. [36] Ojemann SG, Berger MS, Lettich E, Ojemann GA. Localization of language function in children: results of electrical stimulation mapping. J Neurosurg 2003;98:465–70. [37] Peel TR, Hafed ZM, Dash S, Lomber SG, Corneil BD. A causal role for the cortical frontal eye fields in microsaccade deployment. PLoS Biol 2016;14:e1002531. [38] Ostrowsky K, Isnard J, Ryvlin P, Guénot M, Fischer C, Mauguière F. Functional mapping of the insular cortex: clinical implication in temporal lobe epilepsy. Epilepsia 2000;41:681–6. [39] Reddy RV, Moorthy SS, Dierdorf SF, Deitch Jr RD, Link L. Excitatory effects and electroencephalographic correlation of etomidate, thiopental, methohexital, and propofol. Anesth Analg 1993;77:1008–11. [40] Vakkuri AP, Seitsonen ER, Jäntti VH, Särkelä M, Korttila KT, Paloheimo MPJ, et al. A rapid increase in the inspired concentration of desflurane is not associated with epileptiform encephalogram. Anesth Analg 2005;101:396–400. table of contents. [41] Hosain S, Nagarajan L, Fraser R, Van Poznak A, Labar D. Effects of nitrous oxide (N2O) on interictal spikes during electrocorticography [Internet]. Electroencephalogr Clin Neurophysiol 1995:P18. https://doi.org/10.1016/00134694(95)97917-p. [42] Souter MJ, Rozet I, Ojemann JG, Souter KJ, Holmes MD, Lee L, et al. Dexmedetomidine sedation during awake craniotomy for seizure resection: effects on electrocorticography. J Neurosurg Anesthesiol 2007;19:38–44. [43] Soriano SG, Eldredge EA, Wang FK, Kull L, Madsen JR, Black PM, et al. The effect of propofol on intraoperative electrocorticography and cortical stimulation during awake craniotomies in children. Paediatr Anaesth 2000;10:29–34. [44] Schucht P, Seidel K, Murek M, Stieglitz LH, Urwyler N, Wiest R, et al. Low-threshold monopolar motor mapping for resection of lesions in motor eloquent areas in children and adolescents. J Neurosurg Pediatr 2014;13:572–8. [45] Bancaud J, Talairach J, Bonis A, Schaub C, Szikla G, Morel P, et al. La stéréoélectroencéphalographie dans l’épilepsie: Informations neurophysiopathologiques apportées par l’investigation fonctionnelle stéréotaxique. Paris: Masson; 1965. [46] Taussig D, Chipaux M, Lebas A, Fohlen M, Bulteau C, Ternier J, et al. Stereo-electroencephalography (SEEG) in 65 children: an effective and safe diagnostic method for pre-surgical diagnosis, independent of age. Epileptic Disord 2014;16:280–95. [47] Kahane P, Tassi L, Francione S, Hoffmann D, Lo Russo G, Munari C. Electroclinical manifestations elicited by intracerebral electric stimulation “shocks” in temporal lobe epilepsy. Neurophysiol Clin 1993;23:305–26. [48] Landré E, Chipaux M, Maillard L, Szurhaj W, Trébuchon A. Electrophysiological technical procedures. Neurophysiol Clin 2018;48:47–52. [49] Britton JW. Electrical stimulation mapping with stereo-EEG electrodes. J Clin Neurophysiol 2018;35:110–4. [50] Cogan SF, Ludwig KA, Welle CG, Takmakov P. Tissue damage thresholds during therapeutic electrical stimulation. J Neural Eng 2016;13:021001. [51] Mullin JP, Sexton D, Al-Omar S, Bingaman W, Gonzalez-Martinez J. Outcomes of subdural grid electrode monitoring in the stereoelectroencephalography era. World Neurosurg 2016;89:255–8. [52] Ojemann G, Mateer C. Human language cortex: localization of memory, syntax, and sequential motor-phoneme identification systems. Science 1979;205:1401–3.
functionally map the cortex in childhood. J Clin Neurophysiol 1992;9:288–93. [17] Aungaroon G, Zea Vera A, Horn PS, Byars AW, Greiner HM, Tenney JR, et al. Afterdischarges and seizures during pediatric extra-operative electrical cortical stimulation functional brain mapping: incidence, thresholds, and determinants. Clin Neurophysiol 2017;128:2078–86. [18] Zea Vera A, Aungaroon G, Horn PS, Byars AW, Greiner HM, Tenney JR, et al. Language and motor function thresholds during pediatric extra-operative electrical cortical stimulation brain mapping. Clin Neurophysiol 2017;128:2087–93. [19] 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. [20] Arya R, Aungaroon G, Zea Vera A, Horn PS, Byars AW, Greiner HM, et al. Fosphenytoin pre-medication for pediatric extra-operative electrical stimulation brain mapping. Epilepsy Res 2018;140:171–6. [21] Duchowny M, Jayakar P, Harvey AS, Resnick T, Alvarez L, Dean P, et al. Language cortex representation: effects of developmental versus acquired pathology. Ann Neurol 1996;40:31–8. [22] Taussig D, Dorfmüller G, Fohlen M, Jalin C, Bulteau C, Ferrand-Sorbets S, et al. Invasive explorations in children younger than 3 years. Seizure 2012;21:631–8. [23] Filevich E, Kühn S, Haggard P. Negative motor phenomena in cortical stimulation: implications for inhibitory control of human action. Cortex 2012;48:1251–61. [24] Lüders HO, Lesser RP, Dinner DS, Morris HH, Wyllie E, Godoy J, et al. A negative motor response elicited by electrical stimulation of the human frontal cortex. Adv Neurol 1992;57:149–57. [25] Lüders H, Lesser RP, Dinner DS, Morris HH, Wyllie E, Godoy J. Localization of cortical function: new information from extraoperative monitoring of patients with epilepsy. Epilepsia 1988;29(Suppl. 2):S56–65. [26] Mikuni N, Ohara S, Ikeda A, Hayashi N, Nishida N, Taki J, et al. Evidence for a wide distribution of negative motor areas in the perirolandic cortex. Clin Neurophysiol 2006;117:33–40. [27] Farrell DF, Burbank N, Lettich E, Ojemann GA. Individual variation in human motor-sensory (rolandic) cortex. J Clin Neurophysiol 2007;24:286–93. [28] Uematsu S, Lesser R, Fisher RS, Gordon B, Hara K, Krauss GL, et al. Motor and sensory cortex in humans: topography studied with chronic subdural stimulation. Neurosurgery 1992;31:59–71. discussion 71–2. [29] Mazzola L, Isnard J, Mauguière F. Somatosensory and pain responses to stimulation of the second somatosensory area (SII) in humans. A comparison with SI and insular responses. Cereb Cortex 2006;16:960–8. [30] Schevon CA, Carlson C, Zaroff CM, Weiner HJ, Doyle WK, Miles D, et al. Pediatric language mapping: sensitivity of neurostimulation and Wada testing in epilepsy surgery. Epilepsia 2007;48:539–45. [31] Trébuchon A, Chauvel P. Electrical stimulation for seizure induction and functional mapping in Stereoelectroencephalography. J Clin Neurophysiol 2016;33:511–21. [32] Ojemann GA. Individual variability in cortical localization of language. J Neurosurg 1979;50:164–9. [33] Hamberger MJ. Cortical language mapping in epilepsy: a critical review. Neuropsychol Rev 2007;17:477–89. [34] Hamberger MJ, Williams AC, Schevon CA. Extraoperative neurostimulation mapping: results from an international survey of epilepsy surgery programs. Epilepsia 2014;55:933–9.
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Seizure: European Journal of Epilepsy journal homepage: www.elsevier.com/locate/seizure
Review
Electrical stimulation mapping in children ⁎
Ann Hyslopa,b, , Michael Duchownya,b,c a b c
Nicklaus Children’s Hospital, 3100 SW 62nd Ave, Miami, FL, 33155, United States Florida International University Herbert Wortheim College of Medicine, 11200 SW 8th St, Miami, FL, 33199, United States University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL, 33136, United States
A R T I C LE I N FO
A B S T R A C T
Keywords: Electrical stimulation mapping Pediatric epilepsy surgery Functional mapping sEEG Language mapping Motor mapping Intraoperative mapping
Electrical stimulation mapping is a longstanding practice that aids in identification and delineation of eloquent cortex. Initially used to expand our understanding of the typical human cortex, it now plays a significant role in mapping cortical function in individuals with atypical structural and functional tissue organization undergoing epilepsy surgery. This review discusses the unique challenges that arise in the functional testing of the immature cortex of a child and the parameters of stimulation that optimize accurate results in conventional open implantation and in stereo-electroencephalography. The prerequisite baseline evaluation and preparation recommended to increase the yield from pediatric stimulation mapping sessions is described, as are ideal approaches to the mapping of the sensory, motor, language, and visual cortices.
1. Introduction
2. Physics of electrical stimulation
Almost 150 years ago investigators began applying electrical stimulation to mammalian cerebral cortices, an endeavor that eventually gave rise to our understanding of the organization of the human cortex. While the consistency of general organization was striking, further investigations revealed fine variations in the localization of motor and sensory function between humans both in the presence and absence of intracerebral structural lesions. In a manuscript published in 1937, Penfield and Boldrey provide sketches of summated data from cortical stimulations mapping sensory and motor function performed in 126 anesthetized patients using electrical stimulation methodology similar to that used today [1]. In 1979, Woolsey et al. more thoroughly delineated the stimulus intensities required to create a functional response within the sensory and motor cortices [2]. Before the turn of the 21 st century, significant improvements in surgical and stimulation techniques and the introduction of chronic extraoperative electrode implantation led to standardized language mapping methods that confirmed the existence of wide variability of the language cortex in humans [3]. Electrical stimulation mapping is now safely and successfully performed in children [16], the results of which have, in conjunction with information from other modalities of cortical study, advanced our understanding of the impact of developmental stages and structural and functional lesions on the organization of the human cortex.
Electrical stimulation of the cortex causes a transient disruption of neuronal transmission in the tissue affected, exerting direct effects on axon bodies and nodes of Ranvier in the immediate vicinity and likely causing downstream dysfunction in networks affected by electrical field spread or propagation [4]. This type of stimulation has been used to determine whether or not removal of cortical tissue will result in a deficit of eloquent functions including motor, sensation, language, and vision. Direct electrical stimulation methods are chosen depending on the suspected function of the cortex in the region of interest. When applied at various durations and intensities during patient testing, stimulation of cortex harboring functional tissue produces either an elicitation or an inhibition of a response. Since most responses documented outside of the motor and sensory cortices are inhibitory [5] the paradigms used in, and the conditions of, clinical testing must be ageappropriate in order to produce interpretable and accurate results. For example, motor and sensory testing may only require brief periods of the patient maintaining a calm, awake state, while stimulation mapping of suspected expressive language regions necessitates cooperation in a repetitive object-naming task, and assessment of receptive language skills may demand engagement in lengthy question-and-answer exercises. Although it has been reported that identical stimulations may produce varying clinical responses [6], the results of a well-executed mapping session often yield a somatotopy that aids in safely determining margins of cortical resection.
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Corresponding author at: Nicklaus Children’s Hospital, 3100 SW 62nd Ave, Miami, FL, 33155, United States. E-mail addresses: [email protected] (A. Hyslop), [email protected] (M. Duchowny).
https://doi.org/10.1016/j.seizure.2019.07.023 Received 16 May 2019; Received in revised form 25 July 2019; Accepted 29 July 2019 1059-1311/ © 2019 Published by Elsevier Ltd on behalf of British Epilepsy Association.
Please cite this article as: Ann Hyslop and Michael Duchowny, Seizure: European Journal of Epilepsy, https://doi.org/10.1016/j.seizure.2019.07.023
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required for ictal capture. Functional mapping is ideally performed after capture of the target seizure type and should be preceded by the initiation of the child's home medications and, if warranted by assessment of risk for status epilepticus, by an intravenous bolus of an antiepileptic medication.
Typical electrical stimulation parameters are based on a combination of historical preferences and basic science research. Those used in grid and strip electrodes are different than those used in depth and stereotactically place electrodes due to the decreased surface area of the latter resulting in a higher charge density application to the cortex and increased risk of tissue damage [7]. In both, however, a rectangularpulse waveform is the method of electrical current delivery most optimal for the elicitation of action potentials [8]. Estimation of electrical field distribution within the irregular topography of an individual human brain [9] has shown that in bipolar stimulation, current density is highest immediately under the stimulation electrode and decreases significantly in the 0.5 cm penumbra. With unipolar stimulation, current density extends more deeply and generates a wider field, an advantage less favored in cortical functional mapping compared to the more focused current density created by bipolar stimulation. This is an important limitation as eloquent functions are organized discretely within small sections of tissue [10].
5. Accurate coregistration of informative modalities with volumetric brain MRI Prior to mapping, coregistration of three-dimensional brain MRI with relevant functional MRI (fMRI) BOLD signals or informative mapping results from transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG) will optimize the time required for direct electrical stimulation. Some structural lesions, such as remote infarcts, tumors, tubers, cavernomas, and arteriovenous malformations, have been shown to cause destruction or derangement of anatomical landmarks and a displacement of cortical function [13,14], while early developmental lesions may not result in significant rearrangement of function [21]. In some pediatric cases, functional organization is not detected by fMRI due to lack of cooperation during testing or use of sedation and, even if present, is not well-demarcated due to the intrinsically poor spatial resolution of fMRI BOLD signals. Additionally, electrode shift from surgical and steroid effects can compromise the accuracy of the coregistration. Despite the technical constraints of coregistrations, referencing a coregistration of the three-dimensional MRI to available fMRI BOLD signals, regions of effective stimulation from TMS, or functional MEG clusters, enables initial stimulation to be performed in the regions suspected to have the greatest likelihood of producing a functional change. Margins of each eloquent region can then be mapped by stimulating along and adjacent to the involved gyrus. True positive responses, elicited early in a mapping session, also ensure that the technical setup is working properly and allows for faster determination of the lowest stimulation threshold required within the region to produce a functional change. Minimization of the time required for mapping is critical, especially in patients with limited attention spans and cooperation capabilities. Generally, areas of extreme hyperexcitability represented by very frequent interictal epileptogenic activity are avoided early in stimulation tests to avoid producing a seizure that would prematurely terminate the mapping session.
3. Typical parameters for extra-operative electrical stimulation mapping In order to optimize focal stimulation effects, short pulse durations are used to ensure activation of local rather than remote fibers [11], and range between 200–300 milliseconds. Train durations range from 0.5 to 10 seconds depending on the function being tested [12]. In children, current intensity is gradually increased from 1 mA to a maximum of 20 mA, a maximum stimulus intensity not often required in adults [13–15]. Utilizing a dual increment paradigm in which increases in pulse duration alternate with increases in stimulus intensity allows identification of optimal neurophysiologic thresholds with minimal risk of tissue injury [16]. This paradigm is particularly useful in children because higher intensities and longer stimulation times are often required to induce functional alteration compared to adults. This has long been attributed to the difference between developmentally immature and fully myelinated tissue and is affirmed by the finding that younger children typically have higher motor thresholds than older children and, unlike adults, the majority of children exhibit afterdischarges with stimulation [13,16,17]. Afterdischarges and seizures may induce functional alterations not related to focal stimulation, a feature that can complicate interpretation or lengthen the time required to obtain reliable mapping results. Interestingly, functional thresholds can be found at higher stimulation thresholds than those causing afterdischarges in children [13,18]; therefore, attempts have been made to minimize hyperexcitability without compromising functional mapping results. For example, the pulse rate of stimulation has historically been 50–60 Hz, but recently lower frequency stimulations of 5 and 10 Hz have been shown to generate less afterdischarges and are equally effective in mapping cortical function [19]. The administration of an antiepileptic medication prior to a functional mapping session has also been shown to reduce the occurrence of stimulation-induced seizures [20].
6. Extra-operative electrical stimulation mapping 6.1. Sensory and motor mapping Motor mapping in children is often a satisfying endeavor because face, arm, trunk, and leg movements are easily elicited and reliable. Identification of motor function in children is achievable in 75–82% of cases undergoing direct electrical stimulation in the expected motor cortex [18,22]. Thresholds for elicitation of motor response range between 2–10 mA in most patients, with a mean threshold of 5–6 mA [18]. Thresholds are higher in younger children and patients with neuronal migration disorders in perirolandic cortex [13]. Children with tumors, abscesses, AVMs, and cavernomas near motor areas may also require greater amperages [14]. Train durations as low as 0.5 s and frequencies between 5–50 Hz are often effective. Verbal children may report a sensation of movement or dysesthesia prior to visible motor responses representing activation of muscle fibers, but with small increases in current intensity, muscle contraction will positively identify primary motor cortex. Negative motor responses are characterized by the interruption or slowing of a volitional motor action and, therefore, require the child to sustain a repetitive or sustained movement such as finger tapping, arm elevation, or speech. These functions likely help regulate motor control through complex inhibitory processes [23]. A negative motor area can
4. Establishing baseline function Assessment of a child’s baseline functionality and ability to cooperate while awaiting ictal capture and in the testing of relevant functional domains is critical for planning chronic subdural implantation. A careful neurologic exam documenting gaze preferences, visual fields, focal weaknesses, handedness, sensory deficits, hearing, articulation, prosody, and expressive and receptive speech functions allows accurate detection of alterations from baseline during stimulation. In younger patients, lengthy periods of pretest observation can aid in identifying a behavioral deviation or aberrant movement elicited during stimulation. A child must also be able to tolerate the activity restrictions necessitated by electrode implantation for the time period, often 5–7 days, 2
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be found anterior to the motor cortex of the face within the inferior frontal gyrus [24], one resides in the supplementary motor area (SMA) [25] while another can be found in the dorsal premotor cortex [26]. Recent investigations show that negative motor areas can also be found within primary motor and sensory cortices [27] and that lower current intensities may elicit negative motor responses at the same sites that higher intensities trigger positive ones [26]. Avoiding these areas in resection is not necessary, as their removal does not result in a permanent neurologic deficit [26,28]. The sensory cortex can be mapped with direct electrical stimulation using parameters similar to motor mapping. Contralateral sensations of paresthesias or numbness may occur in the limbs and face although some facial and most oropharyngeal and lingual sensory changes may be bilateral. While it is atypical for evoked responses in primary sensory cortex to induce pain, such an occurrence during functional mapping may indicate activation of the adjacent parietal operculum, located in the superior bank of the Sylvian fissure, a second somatosensory area [29].
stimulating dural nerve fibers and anxiety from the mapping session should also be identified and alleviated to minimize the possibility of biasing stimulation-induced language assessment. With age, the boundaries of expressive language cortex become more defined and the sensitivity of electrical stimulation increases. Studies have shown such mapping is more likely to reveal the presence of language areas in children over the age of approximately 8–10 years of age [30,36]. It is unclear whether this finding can be attributed to the increase of language-dedicated cortical networks due to maturational processes or alterations in threshold or connectivity associated with pathological processes involving epileptogenic tissue. It is possible that the emergence of epileptogenicity and the degree to which, if any, disruption of language function occurs depends not only on maturation of cortical tissue, but also on the type of lesion giving rise to the epileptogenesis. Duchowny et al. showed that language function was in expected regions in 16 children with congenital disease within or adjacent to affected tissue but relocated contralaterally in three of six children with acquired cerebral injury [21].
6.2. Language mapping
6.3. Mapping other areas of interest
Expressive and receptive language function mapping can be performed successfully in many children. Mapping language with direct electrical stimulation has been performed in children as young as 2 years [21], but the rates of success rise with increasing age, particularly above 10 years [30], and higher intellect. In a series of 53 pediatric cases, Zea Vera et al. [18] successfully identified expressive language in 89% of children tested. Speech arrest due to aphasia indicates presence of expressive language function when electrical stimulation is performed in the expressive language cortex, most often localized to the posterior aspect of the inferior frontal gyrus in the dominant hemisphere, during tasks including reading, naming, counting, and recitation of well-known phrases [3,30,31]. Due to the presence of dysnomia in all aphasias, visual object naming is the most common language task used to map expressive speech [32]. After a brief period of preparatory practice, even young children can engage in picture or object naming, but the responses need to be reproducible and, therefore, multiple trials may be required for confirmation. This mandates examiner patience during testing and novel efforts to sustain or recapture the attention of the child. More than one testing session may be required to ensure that fatigue and the cumulative effects of stimulation are not responsible for observed language dysfunction. Stimulation train durations should be extended to 3–5 seconds to increase the likelihood of speech interruption and they must be delivered during the time interval of speech generation and production. Maximal stimulus intensities required to produce a response may be as high as 15 mA, but are found typically between 7–8 mA in children [18]. Receptive language cortex is often located in bilateral posterior superior temporal gyri in children and therefore should be tested whenever electrode implantation coverage spans this region in the dominant or non-dominant hemisphere. Stimulation of receptive language areas most often reveals dysfunction in tasks such as one-step direction instruction, reading comprehension questions, or picture selection [33,34]. Thresholds of receptive language dysfunction within the temporal lobes are typically higher than those required to elicit expressive speech dysfunction [35]. Careful observation during language mapping is warranted to avoid misinterpreting language competence. Speech arrest may be caused by activation of negative motor areas or the motor cortices of the face, tongue, or oropharynx while poor performance in receptive language tasks may occur from confusion due to alteration of awareness. Asking the child to explain what sensations they felt during the error and whether or not they understood the verbal instructions often sheds light on these occurrences, even in young children. Pain caused by
Direct electrical stimulation of primary visual association cortex in older children and adolescents can be successfully accomplished but is rarely performed due to the lack of functional visual reorganization; simply avoiding resection of the mesial occipital cortex and the optic radiations coursing through the temporal lobes ensures a low risk of visual field deficit. Visual association regions can also be mapped. For example, identification of the frontal eye fields (FEF) in the rostral bank of the precentral sulcus within the middle frontal gyrus is easily performed, but the authors’ personal experience in pediatric cortical resections as well as trials of cryogenic inactivation of the FEF in the macaque have shown that removal or deactivation of these regions does not result in visual deficits or significant limitations in eye movements [37]. Therefore, evocation of auras generated in this region by electrical stimulation may be helpful for seizure localization, but functional mapping in this region is of limited clinical use. Insular stimulation may result in sensorimotor or somatosensory responses depending on whether anterior or posterior aspects of the insula are targeted. Stimulation of the insula is therefore more likely to aid in aura localization than in functional mapping of discrete function to avoid a postoperative deficit [38]. 7. Intraoperative mapping Intraoperative mapping using direct cortical stimulation is efficacious in older children and adolescents. Strategies for intraoperative mapping of children are similar to those used extra-operatively, but careful planning is required to optimize its accuracy and minimize the child’s time under anesthesia. Intraoperative somatosensory evoked potentials (SSEPs), motor evoked potentials (MEPs), and expressive language mapping can be performed in the operating room in a select population of children. Monitoring of simultaneous EEG is critical for determining whether an interruption in language function or generation of motor activity can be accurately attributed to stimulation rather than underlying seizure activity. The most optimal anesthetic agents used for intraoperative mapping in children with epilepsy has not been established, but avoidance of pro-convulsant drugs is important. Drugs used for induction such as thiopental, methohexital, and etomidate can induce myoclonus that may interfere with accurate mapping [39]. Opiates can be used without risk of seizure induction and inhalants such as sevoflurane, isoflurane, and desflurane are safe for maintenance [40]. Commonly used anesthetics for awake mapping include propofol and dexmedetomidine [41–43]. SSEPs are usually performed in the anesthetized child to identify the central sulcus. This is especially helpful whenever surface anatomy is 3
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with lower excitability thresholds such as the hippocampus may be attempted at a 1 Hz frequency to decrease the likelihood of rapid seizure generalization [31,48]. The primary disadvantage of performing functional mapping via sEEG is the lack of spatial resolution when compared to conventional grid and strip electrode implantation. While sEEG placement allows for stimulation within a sulcus and regionalization of functional cortex, it does not allow for accurate delineation of the boundaries of eloquent cortex. In addition, the size of the bolts required to secure each depth to the skull prevent an optimal density of sEEG in any area of eloquence to allow for margin determination. Despite these disadvantages, complication rates of sEEG are lower than those in subdural implantations and surgical decision can be made after explantation, allowing more time for EEG analysis; therefore, in appropriately identified patients, the method may be more desirable [46,51].
atypical, and helps ensure accurate electrode coverage for motor and extraoperative sensory mapping. Stimulation of the median nerve and simultaneous recording from a strip of electrodes perpendicular to the presumed central sulcus allows identification of a phase reversal and verification of the location of the central sulcus. While MEPs are more often performed in tumoral surgeries when manipulation of the descending corticospinal tracts is required, they are also useful in pediatric epilepsy surgery cases to minimize or avoid motor deficits in children unsuitable for implantation for extraoperative mapping. Frequent interjection of cortical and/or tumoral resection by MEPs aids in safe resection of tissue immediately adjacent to primary motor cortex. Schucht et al. (2014) reports success in the use of highfrequency (200–300 Hz) stimulation in intraoperative motor mapping by administering four consecutive train-of-five stimulations, each with an interstimulus interval of 4 ms and pulse duration of 500 ms, at a 0.5Hz repetition rate via a monopolar probe. Using these parameters, cortex harboring motor responses (defined as at or above 30 μV in amplitude within the target muscle) at intensities as low as 1 mA were removed without permanent neurologic deficit. Cortical resection proceeded only with extreme caution where stimulus intensities of 3 mA elicited MEPs [44]. Intraoperative expressive language mapping is worthwhile in children able to cooperate fully in picture-naming tasks extra-operatively, and should be strongly considered to prevent chronic electrode implantation. Utilization of neuropsychologists or other staff can be helpful as the child must remain calm and engaged in the task for a reliable result.
9. Final resection planning after functional mapping When delineating surgical margins, epilepsy surgery teams often opt to leave a safety margin of 1 cm from identified eloquent areas. This was originally based on studies that identified persistent post-operative language deficits in patients who had undergone resections within 1 cm of a language area identified by electrical stimulation mapping [52]. After functional mapping data is superimposed on coregistered data and combined with electrocorticographic data, overlap between eloquent cortex and the epileptogenic zone can be determined with precision and the resection carefully planned. Should a resection be deemed incomplete due to proximity to eloquent tissue, documentation is imperative to avoid unnecessary future re-investigations.
8. StereoEEG
Declaration of Competing Interest
Functional mapping in children implanted with stereo-EEG (sEEG) has been more frequently performed with increasing use of this technique. As early as 1965, Bancaud and colleagues employed electrical stimulation using sEEG in a series of patients [45]. In this method, bipolar stimulation is applied between two consecutive contacts located on the same electrode, both of which should be contained within cortical tissue for best results. The use of clinical paradigms for expressive and receptive language mapping is identical to mapping with conventional subdural grids and strips. Not surprisingly, disruption of speech tasks is less likely to occur with this method, occurring in less than 50% of children in one series [46], due to the lack of spatial sampling offered by sEEG in conjunction with the variability of location and the complexity of functional networks involved in speech tasks. Elicitation of motor responses when electrodes are located in the pre-central gyrus is quite successful in children, occurring in 100% of the children in the same series [46]. Stereo-EEG allows placement of electrodes throughout both hemispheres and multiple lobes within the same patient enabling employment of electrical stimulation in eliciting afterdischarges or seizures which may provide information on an underlying epileptogenic network. Spontaneous ictal capture of typical seizures is preferred, but those triggered by electrical stimulation, if semiologically consistent with the target seizure type, can offer insight to the epileptogenic zone [31,47,48]. More recently, reports of cases in which electrical stimulation differentiates the epileptogenic zone from a region of propagation have emerged [31]. Electrical stimulation parameters for functional mapping in sEEG are different from those used in grid and strip implantation. Due to the smaller surface area of depth electrodes, the same stimulation intensity generates a current density and, therefore, a higher risk of damage to surrounding cortical tissue. Thus, Britton [49] has suggested using a max stimulation current of 8 mA and pulse duration of 200 ms to ensure no charge density above 30 μC per cm2 is generated, a limit that is not associated with tissue damage [50]. For functional mapping, the most commonly used frequency is 50 Hz; stimulation performed for the purpose of triggering a seizure, especially those performed in cortex
None. References [1] Penfield W, Boldrey E. Somatic motor and sensory representation in the cerebral cortex of man as studied by electrical stimulation. Brain. Citeseer 1937;60:389–443. [2] Woolsey CN, Erickson TC, Gilson WE. Localization in somatic sensory and motor areas of human cerebral cortex as determined by direct recording of evoked potentials and electrical stimulation. J Neurosurg 1979;51:476–506. [3] 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. [4] Nowak LG, Bullier J. Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter. II. Evidence from selective inactivation of cell bodies and axon initial segments. Exp Brain Res 1998;118:489–500. [5] Ojemann GA. Electrical stimulation and the neurobiology of language. Behav Brain Sci 1983;6:221–30. Cambridge University Press. [6] Van Buren JM, Fedio P, Frederick GC. Mechanism and localization of speech in the parietotemporal cortex. Neurosurgery 1978;2:233–9. [7] 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. [8] Yeomans JS. “Temporal summation decay” in hypothalamic self-stimulation: Threshold changes at long intrapair intervals due to axonal subnormal periods. Behav Neurosci 1990;104:991. American Psychological Association. [9] 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. [10] Ojemann GA. The intrahemispheric organization of human language, derived with electrical stimulation techniques. Trends Neurosci 1983;6:184–9. [11] Grill Jr WM, Mortimer JT. The effect of stimulus pulse duration on selectivity of neural stimulation. IEEE Trans Biomed Eng 1996;43:161–6. [12] Lesser RP, Lüders H, Klem G, Dinner DS, Morris HH, Hahn JF, et al. Extraoperative cortical functional localization in patients with epilepsy. J Clin Neurophysiol 1987;4:27–53. [13] Chitoku S, Otsubo H, Harada Y, Jay V, Rutka JT, Weiss SK, et al. Extraoperative cortical stimulation of motor function in children. Pediatr Neurol 2001;24:344–50. [14] Signorelli F, Guyotat J, Mottolese C, Schneider F, D’Acunzi G, Isnard J. Intraoperative electrical stimulation mapping as an aid for surgery of intracranial lesions involving motor areas in children. Childs Nerv Syst 2004;20:420–6. [15] Resnick T. Cortical stimulation thresholds in children being evaluated for resective surgery. Epilepsia 1988;29:651–2. [16] Jayakar P, Alvarez LA, Duchowny MS, Resnick TJ. A safe and effective paradigm to
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Seizure: European Journal of Epilepsy xxx (xxxx) xxx–xxx
A. Hyslop and M. Duchowny
[35] Wang SG, Eskandar EN, Kilbride R, Chiappa KH, Curry WT, Williams Z, et al. The variability of stimulus thresholds in electrophysiologic cortical language mapping. J Clin Neurophysiol 2011;28:210–6. [36] Ojemann SG, Berger MS, Lettich E, Ojemann GA. Localization of language function in children: results of electrical stimulation mapping. J Neurosurg 2003;98:465–70. [37] Peel TR, Hafed ZM, Dash S, Lomber SG, Corneil BD. A causal role for the cortical frontal eye fields in microsaccade deployment. PLoS Biol 2016;14:e1002531. [38] Ostrowsky K, Isnard J, Ryvlin P, Guénot M, Fischer C, Mauguière F. Functional mapping of the insular cortex: clinical implication in temporal lobe epilepsy. Epilepsia 2000;41:681–6. [39] Reddy RV, Moorthy SS, Dierdorf SF, Deitch Jr RD, Link L. Excitatory effects and electroencephalographic correlation of etomidate, thiopental, methohexital, and propofol. Anesth Analg 1993;77:1008–11. [40] Vakkuri AP, Seitsonen ER, Jäntti VH, Särkelä M, Korttila KT, Paloheimo MPJ, et al. A rapid increase in the inspired concentration of desflurane is not associated with epileptiform encephalogram. Anesth Analg 2005;101:396–400. table of contents. [41] Hosain S, Nagarajan L, Fraser R, Van Poznak A, Labar D. Effects of nitrous oxide (N2O) on interictal spikes during electrocorticography [Internet]. Electroencephalogr Clin Neurophysiol 1995:P18. https://doi.org/10.1016/00134694(95)97917-p. [42] Souter MJ, Rozet I, Ojemann JG, Souter KJ, Holmes MD, Lee L, et al. Dexmedetomidine sedation during awake craniotomy for seizure resection: effects on electrocorticography. J Neurosurg Anesthesiol 2007;19:38–44. [43] Soriano SG, Eldredge EA, Wang FK, Kull L, Madsen JR, Black PM, et al. The effect of propofol on intraoperative electrocorticography and cortical stimulation during awake craniotomies in children. Paediatr Anaesth 2000;10:29–34. [44] Schucht P, Seidel K, Murek M, Stieglitz LH, Urwyler N, Wiest R, et al. Low-threshold monopolar motor mapping for resection of lesions in motor eloquent areas in children and adolescents. J Neurosurg Pediatr 2014;13:572–8. [45] Bancaud J, Talairach J, Bonis A, Schaub C, Szikla G, Morel P, et al. La stéréoélectroencéphalographie dans l’épilepsie: Informations neurophysiopathologiques apportées par l’investigation fonctionnelle stéréotaxique. Paris: Masson; 1965. [46] Taussig D, Chipaux M, Lebas A, Fohlen M, Bulteau C, Ternier J, et al. Stereo-electroencephalography (SEEG) in 65 children: an effective and safe diagnostic method for pre-surgical diagnosis, independent of age. Epileptic Disord 2014;16:280–95. [47] Kahane P, Tassi L, Francione S, Hoffmann D, Lo Russo G, Munari C. Electroclinical manifestations elicited by intracerebral electric stimulation “shocks” in temporal lobe epilepsy. Neurophysiol Clin 1993;23:305–26. [48] Landré E, Chipaux M, Maillard L, Szurhaj W, Trébuchon A. Electrophysiological technical procedures. Neurophysiol Clin 2018;48:47–52. [49] Britton JW. Electrical stimulation mapping with stereo-EEG electrodes. J Clin Neurophysiol 2018;35:110–4. [50] Cogan SF, Ludwig KA, Welle CG, Takmakov P. Tissue damage thresholds during therapeutic electrical stimulation. J Neural Eng 2016;13:021001. [51] Mullin JP, Sexton D, Al-Omar S, Bingaman W, Gonzalez-Martinez J. Outcomes of subdural grid electrode monitoring in the stereoelectroencephalography era. World Neurosurg 2016;89:255–8. [52] Ojemann G, Mateer C. Human language cortex: localization of memory, syntax, and sequential motor-phoneme identification systems. Science 1979;205:1401–3.
functionally map the cortex in childhood. J Clin Neurophysiol 1992;9:288–93. [17] Aungaroon G, Zea Vera A, Horn PS, Byars AW, Greiner HM, Tenney JR, et al. Afterdischarges and seizures during pediatric extra-operative electrical cortical stimulation functional brain mapping: incidence, thresholds, and determinants. Clin Neurophysiol 2017;128:2078–86. [18] Zea Vera A, Aungaroon G, Horn PS, Byars AW, Greiner HM, Tenney JR, et al. Language and motor function thresholds during pediatric extra-operative electrical cortical stimulation brain mapping. Clin Neurophysiol 2017;128:2087–93. [19] 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. [20] Arya R, Aungaroon G, Zea Vera A, Horn PS, Byars AW, Greiner HM, et al. Fosphenytoin pre-medication for pediatric extra-operative electrical stimulation brain mapping. Epilepsy Res 2018;140:171–6. [21] Duchowny M, Jayakar P, Harvey AS, Resnick T, Alvarez L, Dean P, et al. Language cortex representation: effects of developmental versus acquired pathology. Ann Neurol 1996;40:31–8. [22] Taussig D, Dorfmüller G, Fohlen M, Jalin C, Bulteau C, Ferrand-Sorbets S, et al. Invasive explorations in children younger than 3 years. Seizure 2012;21:631–8. [23] Filevich E, Kühn S, Haggard P. Negative motor phenomena in cortical stimulation: implications for inhibitory control of human action. Cortex 2012;48:1251–61. [24] Lüders HO, Lesser RP, Dinner DS, Morris HH, Wyllie E, Godoy J, et al. A negative motor response elicited by electrical stimulation of the human frontal cortex. Adv Neurol 1992;57:149–57. [25] Lüders H, Lesser RP, Dinner DS, Morris HH, Wyllie E, Godoy J. Localization of cortical function: new information from extraoperative monitoring of patients with epilepsy. Epilepsia 1988;29(Suppl. 2):S56–65. [26] Mikuni N, Ohara S, Ikeda A, Hayashi N, Nishida N, Taki J, et al. Evidence for a wide distribution of negative motor areas in the perirolandic cortex. Clin Neurophysiol 2006;117:33–40. [27] Farrell DF, Burbank N, Lettich E, Ojemann GA. Individual variation in human motor-sensory (rolandic) cortex. J Clin Neurophysiol 2007;24:286–93. [28] Uematsu S, Lesser R, Fisher RS, Gordon B, Hara K, Krauss GL, et al. Motor and sensory cortex in humans: topography studied with chronic subdural stimulation. Neurosurgery 1992;31:59–71. discussion 71–2. [29] Mazzola L, Isnard J, Mauguière F. Somatosensory and pain responses to stimulation of the second somatosensory area (SII) in humans. A comparison with SI and insular responses. Cereb Cortex 2006;16:960–8. [30] Schevon CA, Carlson C, Zaroff CM, Weiner HJ, Doyle WK, Miles D, et al. Pediatric language mapping: sensitivity of neurostimulation and Wada testing in epilepsy surgery. Epilepsia 2007;48:539–45. [31] Trébuchon A, Chauvel P. Electrical stimulation for seizure induction and functional mapping in Stereoelectroencephalography. J Clin Neurophysiol 2016;33:511–21. [32] Ojemann GA. Individual variability in cortical localization of language. J Neurosurg 1979;50:164–9. [33] Hamberger MJ. Cortical language mapping in epilepsy: a critical review. Neuropsychol Rev 2007;17:477–89. [34] Hamberger MJ, Williams AC, Schevon CA. Extraoperative neurostimulation mapping: results from an international survey of epilepsy surgery programs. Epilepsia 2014;55:933–9.
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