Journal of Clinical Neuroscience 21 (2014) 263–267
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
The threshold of cortical electrical stimulation for mapping sensory and motor functional areas Zhang Guojun a,⇑, Ni Duanyu a, Paul Fu b, Cai Lixin a, Yu Tao a, Du Wei a, Qiao Liang a, Ren Zhiwei a a b
Beijing Institute of Functional Neurosurgery, Xuanwu Hospital of Capital Medical University, 45 Changchun Road, Xuanwu District, Beijing 100053, People’s Republic of China Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
a r t i c l e
i n f o
Article history: Received 29 September 2012 Accepted 1 April 2013
Keywords: Cortex functional mapping Cortical electrical stimulation Perirolandic epilepsy Sensor and motor cortex Stimulation threshold
a b s t r a c t This study aimed to investigate the threshold of cortical electrical stimulation (CES) for functional brain mapping during surgery for the treatment of rolandic epilepsy. A total of 21 patients with rolandic epilepsy who underwent surgical treatment at the Beijing Institute of Functional Neurosurgery between October 2006 and March 2008 were included in this study. Their clinical data were retrospectively collected and analyzed. The thresholds of CES for motor response, sensory response, and after discharge production along with other threshold-related factors were investigated. The thresholds (mean ± standard deviation) for motor response, sensory response, and after discharge production were 3.48 ± 0.87, 3.86 ± 1.31, and 4.84 ± 1.38 mA, respectively. The threshold for after discharge production was significantly higher than those of both the motor and sensory response (both p < 0.05). A negative linear correlation was found between the threshold of after discharge production and disease duration. Using the CES parameters at a stimulation frequency of 50 Hz and a pulse width of 0.2 ms, the threshold of sensory and motor responses were similar, and the threshold of after discharge production was higher than that of sensory and motor response. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Identification of functional cortical areas and the origin of epilepsy are prerequisites for the safe and effective removal of the seizure focus in rolandic epilepsy. Since cortical electrical stimulation (CES) has been applied in clinical practice, it has been widely accepted as the ‘‘gold standard’’ of functional brain mapping, due to the direct nature of the cortical stimulation and objective response.1,2 However, it has also been found that individuals can respond differently to electrical stimulation.3–5 Some patients may develop somatic sensory and motor responses with obvious after discharge (and possibly epilepsy) after even minor stimulation, while others may require much greater stimulation. This had led to the conclusion that there are differences in the threshold (the minimal stimulus intensity that develops a somatic response) for CES. Determination of the threshold is the basis of mapping functional areas using CES in clinical practice. It has been speculated that this disparity in minimal stimulus intensity is caused by individual differences in growth/development, lesion characteristics, disease duration, and variable cortical excitability between age groups.5–7 However, there has not been sufficient clinical data to prove any hypothesis. ⇑ Corresponding author. Tel.: +86 10 8319 8818/10 8319 8207. E-mail address: [email protected] (Z. Guojun). 0967-5868/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2013.04.015
The present study retrospectively analyzed data pertaining to the CES of 21 patients with refractory rolandic epilepsy. The CES used subdural electrodes to identify the seizure focus and to localize the functional areas in an attempt to determine the relationship between them. The purpose of the study was to investigate the response threshold of the motor and sensory cortex to electric stimulation in rolandic epilepsy patients, and to determine if a relationship exists between this threshold and factors such as disease duration, patient age, and pathological changes in epilepsy patients. Conclusions could then be used as a scientific basis for personalized CES functional mapping in clinical practice.
2. Materials and methods 2.1. Patients Patients were included in the study if they met the following criteria: (1) they had refractory epilepsy that required surgical treatment because of failed standard drug therapy; (2) their electroencephalogram (EEG) indicated that the seizure originated in or around the rolandic area, or the seizure focus was strongly suspected to be in the rolandic area; (3) brain MRI indicated that the seizure focus neighbored the rolandic area (subdural electrodes were implanted to localize functional areas and identify the relationship between functional areas and seizure focus); and (4) the
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brain cortex mapping data proved that the seizure originated in or around the rolandic area, and the seizure originated from the rolandic areas. CES was needed to identify the relationship between the functional areas and the seizure focus. Patients who failed to meet the above requirements were excluded, and those that met the following two criteria were also excluded: (1) young age or with mental or intellectual disorders who might have poor cooperation; and (2) hematoma or effusion following the implantation of intracranial electrodes, which could affect the result. According to the aforementioned inclusion and exclusion criteria, a total of 21 patients with rolandic epilepsy who underwent surgical treatment in the Beijing Institute of Functional Neurosurgery of Xuanwu Hospital between October 2006 and March 2008 were included in the present study. The study patients included 17 men and four women, aged 12–44 years, with a mean age of 20 years. The age at disease onset ranged from 0 to 25 years, with a mean of 9.8 years. The duration of disease ranged from 0 to 30 years, with a mean of 10.8 years. MRI revealed 10 patients with lesions and 11 patients without lesions. All patients underwent implantation of intracranial electrodes, pre-surgical CES functional mapping, and the surgical removal of the seizure focus. 2.2. Pre-surgical evaluation Standard pre-surgical evaluation included medical history, age at time of surgery, age at disease onset, clinical symptoms, physical examination of the nervous system, ictal and interictal EEG, neuroradiological examinations including MRI, a neuropsychological assessment, and other examinations if necessary (positron emission tomography, single photon emission computed tomography and magnetoencephalography). The approximate position of the seizure focus was determined by a comprehensive analysis of the pre-surgical assessment to best identify a position for the implantation of subdural electrodes.
pre-surgical evaluation. Digital imaging was used to photograph the implantation of the electrodes in surgery (Fig. 1b), and postimplantation imaging was used to confirm the placement (Fig. 1c). Dexamethasone (10 mg) was given to each patient immediately prior to surgery and was gradually tapered over 3 days to reduce post-operative discomfort. 2.4. EEG monitoring and CES functional mapping Generally, EEG (DaVinci Programmable Digital Signal Processors, Texas Instruments, TX, USA) monitoring was performed 1– 2 days after the implantation of subdural electrodes, and the ictal and interictal EEG were recorded to identify the seizure focus. Seizures were captured by EEG at least twice. CES mapping was conducted 3–4 days post-implantation to localize the sensory, motor, and language functional areas; however, the present study only focused on the assessment of sensory and motor functions. Electrical stimuli were presented using a Nicolet–Viking IV Constant Current Stimulator (Natus Medical, San Carlos, CA, USA), which generated a rectangular pulse at a rate of 5 Hz or 50 Hz.8 In the current study, CES functional mapping was performed using 50 Hz stimuli with a pulse duration of 0.2 ms. Current strengths of 1.0–8.0 mA were employed with a train duration of 3 s and an intertrain interval of 20 s. Stimuli at each electrode (using the adjacent electrode as reference) started at 1.0 mA and increased by 1.0 mA increments for each subsequent stimulation until a functional alteration was achieved, an after discharge was recorded, or 8 mA was reached. The stimulation threshold was defined as the intensity of the current that produced signs of contralateral limb or facial sensory or motor function. Each parameter for the effective stimulation threshold of sensory and motor function was summarized. A patient’s threshold response to electric stimulation was calculated by averaging the stimulation thresholds at different electrode sites. 2.5. Stimulation response
2.3. Implantation of subdural electrodes Implantation of subdural electrodes was carried out in all 21 patients. The electrode had an appearance similar to a grid or a strip made of stainless steel disks, with each disk containing a 5 mm diameter of exposed surface embedded in silastin at the center. A kerf was designed at the center of the seizure focus identified pre-surgery. Fig. 1a presents a typical rolandic kerf. The subdural electrodes were implanted in the most concentrated and evident site of discharge as indicated by electrocorticographic data and
A primary motor response was defined as a localized movement of the contralateral body in response to stimulation of the cortex while the patient was at rest. A simple isolated movement, such as contraction of the contralateral eyelid, cheek, tongue, hand, or foot are such examples. Movement of the arm was limited to a movement within an isolated joint, such as the wrist or elbow. Movement of the hand was often characterized by the simultaneous extension or flexion around several fingers at the joints.9 Primary sensory responses were defined as discrete sensory
Fig. 1. Perioperative photography showing (a) a rolandic skin flap, (b) axial view of the implantation of the electrodes at surgery, and (c) sagittal radiography showing the placement of the electrodes post-surgery.
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Fig. 2. Electroencephalogram of normal brain mapping pre-stimulation. Arrows indicate the rhythmic discharge post-stimulation.
experiences in isolated regions of the contralateral body. A patient’s report of tingling in the corner of the lips after cortical stimulation is a typical example. The after discharge was defined as abnormal waves of slow, sharp, or rhythmic quality that exceed 10 s following CES.10 Fig. 2 shows normal brain mapping pre-stimulation, and the rhythmic discharge post-stimulation. 2.6. Surgical treatment, prognosis and follow-up All patients underwent removal of the seizure focus, and were followed-up for more than 24 months post-surgery. The post-operative outcome was graded into four classes according to Engel’s classification11: class I: free of disabling seizures; class II: rare disabling seizures (‘‘almost seizure free’’) or seizure-free intervals of 3–6 months; class III: worthwhile seizure reduction (more than 75%); and class IV: no worthwhile improvement with seizure reduction less than 75%. Post-surgical limb functional disorders were defined as including the two aspects of sensory and motor impairment. Motor disorder was characterized by weakness and inflexibility, while sensory disorder was characterized by hypoesthesia, continuous numbness and abnormal sensations. 2.7. Ethical consideration This study was approved by the Ethics Review Committee of the Beijing Institute of Functional Neurosurgery, Capital Medical University and the Ministry of Health, China. All measurements conducted in this study were in compliance with the current laws and regulations in China. 2.8. Statistical analysis All data were entered into Microsoft Excel (Microsoft, Redmond, WA, USA) and statistical analyses were performed using the Statistical Package for the Social Sciences version 11.5 (SPSS, Chicago, IL, USA). The measurement data, including the threshold of sensory and motor responses and after discharge production, are presented as mean ± standard deviation. Analysis of variance was performed to compare the differences among the thresholds of sensory, motor, and after discharge production along with the differences between sexes, left and right lobes, and the presence or absence of seizure focus. Correlation analyses were carried out to investigate the relationship between the threshold of the motor and sensory responses with the after discharge
production, age at disease onset, age at time of operation, and disease course. A p value 0.05). The correlation analysis indicated that among the possible factors affecting the threshold of motor, sensory, and after discharge production (including the age at disease onset, age at time of operation, and disease duration), a correlation was only found between disease duration and the threshold of after discharge production (r = –0.594, p = 0.020). The linear regression equation for this relationship was y = 5.97 1/10x (f = 0.020), and the regression curve is presented in Fig. 4. 4. Discussion CES mapping can be performed either during surgery or outside the operating room using subdural electrodes for seizure focus resection. The former method can be problematic due to the time limitations imposed by the use of narcotics in maintaining patient consciousness during surgery. The latter method uses subdural cortical electrodes for CES mapping before the removal of the seizure focus, which allows for a greater time and better cooperation from the patient as compared to the former method. This is becoming the more widely used mapping approach.1,12 Both CES mapping methods are jointly used within our institute to improve surgical. Considering that high stimulation intensity for CES may induce seizures and that low intensity stimulation may not activate functional reactions, minor differences in CES parameters are used among various centers to balance the reliability and safety of CES.13 However, the most widely used and accepted parameters are 50–60 Hz for rectangular pulse stimulation, 0.2–0.3 ms for pulse width, 2–5 s for the duration of each stimulation, 1–15 mA for stimulation intensity, and 10–20 s for stimulation interval.14–18 Given that CES mapping requires cooperation and concentration, very young patients and those with mental/intellectual
disorders were excluded from the current study because of their poor cooperation. Our experience with surgical removal of the seizure focus has shown that stimulation in the presence of a hematoma or effusion is unreliable. Therefore, those with hematoma or effusion following the implantation of intracranial electrodes were not included in the study. In the present study, CES with a stimulation frequency of 50 Hz, pulse width of 0.2 ms, and a stimulation intensity of less than 8 mA was able to activate the majority of functional reactions. Higher stimulation intensity was not helpful for functional cortex mapping, as reported by some previous studies.15 However, Chitoku and colleagues19 reported that some patients required up to 20 mA of stimulation intensity to activate motor function. This discrepancy is thought to be caused by several factors. Firstly, the selection of the study patients – the patients involved in the current study were 12–44 years old, with a mean age of 28 years. However, Chitoku et al.19 chose patients between 4 and 18 years of age. The increased threshold of response to electrical stimulation may be associated with the incomplete development of the cortex in younger children. Secondly, a different stimulation approach was used in the current study, with the neighboring electrode being used as a reference while employing cortical electrodes for point-to-point stimulation. Chitoku et al.19 performed an extraoperative CES using a ‘‘distance reference’’ technique, which may also have an effect on the stimulation parameters. Our findings showed that the threshold for after discharge production was higher than those of sensory and motor responses (both p < 0.05), which suggests that the level of stimulation was relatively safe for mapping sensory and motor functions. Our results indicate that with gradual increases in stimulus intensity, epilepsy or after discharge was not induced while achieving suprathreshold stimulation of the functional response. There was no significant difference found in the threshold of sensory and motor responses (p = 0.358), which suggests that the CES approach has a similar sensitivity in achieving sensory and motor functional mapping. Our results indicate that this method is suitable for sensory and motor functional mapping in rolandic
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lies in providing theoretical evidence for personalized treatment in CES functional mapping. For instance, in patients with a longer disease course, the stimulation intensity should be more gradually increased to avoid the production of epilepsy. In summary, CES functional mapping has been applied in clinical practice for about half a century and is considered the ‘‘gold standard’’ of cortical mapping. However, the stimulation parameters and approaches for CES are different among various centers and are being continually improved. In our study, we used a 50 Hz frequency and 0.2 ms pulse width rectangular pulse stimulation for mapping functional areas. The summarized threshold ranges of stimulation intensity in adults with rolandic epilepsy can provide a clinically standardized application of CES mapping. Use of CES for mapping functional areas is reliable and safe, and the performance of personalized CES mapping should be considered. Fig. 3. Column graph showing the mean thresholds (mAmp) of the motor (thr1) and sensory (thr2) responses, and after discharge (thr3) production. thr1 versus thr2, p > 0.05; thr1 or thr2 versus thr3, both p < 0.05.
epilepsy, which is different from the strategy proposed by Zangaladze et al.,20 where a 5–10 Hz low-frequency stimulation was used for motor function, followed by a 50–60 Hz stimulation to achieve sensory function. The present study indicated that there was no significant correlation between the threshold of motor and sensory responses to the age at operation (for patients more than 12 years old), age of disease onset, disease duration, and the presence of a seizure focus on MRI. This suggests that the approach used for mapping functional areas generally has a similar sensitivity among patients. Chitoku and colleagues19 investigated factors altering the threshold to provoke functional reactions in 20 children with epilepsy, and found an inverse relationship between the threshold of motor response and age, namely the younger the patient, the higher the threshold. This result was thought to be related to the immature development of the cortex and the resultant porr reaction to cortical stimulation. However, all patients involved in the current study were adults with a mature cortex. Therefore, no obvious difference of threshold for functional responses was found. In addition, the present study found a negative linear correlation between the threshold for after discharge production and the disease duration, namely the longer the disease course, the lower the threshold. It is thought that long-term recurring seizures cause increased excitability of the cortex. The clinical significance
Fig. 4. Graph showing the negative linear correlation found between the threshold of after discharge production (mA) and disease course (years). The linear regression equation is y = 5.97 1/10x (f = 0.020).
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References 1. Savoy L. History and future direction of human brain mapping and functional neuroimaging. Acta Psychol 2001;107:9–42. 2. Lachaux JP, Rudrauf D, Kahane P. Intracranial EEG and human brain mapping. J Physiol Paris 2003;97:613–28. 3. Pondal-Sordo M, Diosy D, Tellez-Zenteno JF, et al. Usefulness of intracranial EEG in the decision process for epilepsy surgery. Epilepsy Res 2007;74:176–82. 4. Jayakar P, Alvarez LA, Duchowny MS, et al. A safe and effective paradigm to functionally map the cortex in childhood. J Clin Neurophysiol 1992;9:288–93. 5. Wyllie E, Awad I. Invasive neurophysiologic techniques in the evaluation for epilepsy surgery in children. In: Lüders HO, editor. Epilepsy surgery. New York: Raven Press; 1991. p. 409–12. 6. Kuzniecky R, Andermann F, Tampieri D, et al. Bilateral central macrogyria: epilepsy, pseudobullbar palsy, and mental retardation – a recognizable neuronal migration disorder. Ann Neurol 1989;25:547–54. 7. Desbiens R, Berkovic SF, Dubeau F, et al. Life-threatening focal status epilepticus due to occult cortical dysplasia. Arch Neurol 1993;50:695–700. 8. Lesser RP, Lüders H, Klem G, et al. Cortical afterdischarge and functional responses thresholds: results of extraoperative testing. Epilepsia 1984;25: 615–21. 9. Uematsu S, Lesser R, Fisher RS, et al. Motor and sensory cortex in humans: topography studied with chronic subdural stimulation. Neurosurgery 1992;31: 59–72. 10. Blume WT, Jones DC, Pathak P. Properties of after discharges from cortical electrical stimulation in focal epilepsies. Clin Neurophysiol 2004;115:982–9. 11. Engel JJ, Van Ness PC, Rasmussen TB, et al. Outcome with respect to epileptic seizures. 2nd ed. In: Engel JJ, editor. Surgical treatment of the epilepsies. New York: Raven Press; 1993. p. 609–21. 12. Lachaux J, Rudrauf D, Kahane P. Intracranial EEG and human brain mapping. J Physiol Paris 2003;97:613–28. 13. Motamedi GK, Okunola O, Kalhorn CG, et al. After discharges during cortical stimulation at different frequencies and intensities. Epilepsy Res 2007;77: 65–9. 14. DuanYu N, GuoJun Z, Liang Q, et al. Surgery for perirolandic epilepsy: epileptogenic cortex resection guided by chronic intracranial electroencephalography and electric cortical stimulation mapping. Clin Neurol Neurosurg 2010;112:110–7. 15. Chauvel P, Landre E, Trottier S, et al. Electrical stimulation with intracerebral electrodes to evoke seizures. Adv Neurol 1993;63:115–21. 16. Schulz R, Lüders HO, Tuxhorn I, et al. Localization of epileptic auras induced on stimulation by subdural electrodes. Epilepsia 1997;38:1321–9. 17. Usui K, Ikeda A, Takayama M, et al. Processing of Japanese morphogram and syllabogram in the left basal temporal area: electrical cortical stimulation studies. Brain Res Cogn Brain Res 2005;24:274–83. 18. Hoshida T, Sakaki T. Functional brain mapping detected by cortical stimulation using chronically implanted subdural electrodes: basic knowledge of clinical nerve physiology for neurosurgeons. No Shinkei Geka 2003;31:811–8 discussion 8–9. 19. Chitoku S, Otsubo H, Harada Y, et al. Extraoperative cortical stimulation of motor function in children. Pediatr Neurol 2001;24:344–50. 20. Zangaladze A, Sharan A, Evans J, et al. The effectiveness of low-frequency stimulation for mapping cortical function. Epilepsia 2008;49:481–7.
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
The threshold of cortical electrical stimulation for mapping sensory and motor functional areas Zhang Guojun a,⇑, Ni Duanyu a, Paul Fu b, Cai Lixin a, Yu Tao a, Du Wei a, Qiao Liang a, Ren Zhiwei a a b
Beijing Institute of Functional Neurosurgery, Xuanwu Hospital of Capital Medical University, 45 Changchun Road, Xuanwu District, Beijing 100053, People’s Republic of China Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
a r t i c l e
i n f o
Article history: Received 29 September 2012 Accepted 1 April 2013
Keywords: Cortex functional mapping Cortical electrical stimulation Perirolandic epilepsy Sensor and motor cortex Stimulation threshold
a b s t r a c t This study aimed to investigate the threshold of cortical electrical stimulation (CES) for functional brain mapping during surgery for the treatment of rolandic epilepsy. A total of 21 patients with rolandic epilepsy who underwent surgical treatment at the Beijing Institute of Functional Neurosurgery between October 2006 and March 2008 were included in this study. Their clinical data were retrospectively collected and analyzed. The thresholds of CES for motor response, sensory response, and after discharge production along with other threshold-related factors were investigated. The thresholds (mean ± standard deviation) for motor response, sensory response, and after discharge production were 3.48 ± 0.87, 3.86 ± 1.31, and 4.84 ± 1.38 mA, respectively. The threshold for after discharge production was significantly higher than those of both the motor and sensory response (both p < 0.05). A negative linear correlation was found between the threshold of after discharge production and disease duration. Using the CES parameters at a stimulation frequency of 50 Hz and a pulse width of 0.2 ms, the threshold of sensory and motor responses were similar, and the threshold of after discharge production was higher than that of sensory and motor response. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Identification of functional cortical areas and the origin of epilepsy are prerequisites for the safe and effective removal of the seizure focus in rolandic epilepsy. Since cortical electrical stimulation (CES) has been applied in clinical practice, it has been widely accepted as the ‘‘gold standard’’ of functional brain mapping, due to the direct nature of the cortical stimulation and objective response.1,2 However, it has also been found that individuals can respond differently to electrical stimulation.3–5 Some patients may develop somatic sensory and motor responses with obvious after discharge (and possibly epilepsy) after even minor stimulation, while others may require much greater stimulation. This had led to the conclusion that there are differences in the threshold (the minimal stimulus intensity that develops a somatic response) for CES. Determination of the threshold is the basis of mapping functional areas using CES in clinical practice. It has been speculated that this disparity in minimal stimulus intensity is caused by individual differences in growth/development, lesion characteristics, disease duration, and variable cortical excitability between age groups.5–7 However, there has not been sufficient clinical data to prove any hypothesis. ⇑ Corresponding author. Tel.: +86 10 8319 8818/10 8319 8207. E-mail address: [email protected] (Z. Guojun). 0967-5868/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2013.04.015
The present study retrospectively analyzed data pertaining to the CES of 21 patients with refractory rolandic epilepsy. The CES used subdural electrodes to identify the seizure focus and to localize the functional areas in an attempt to determine the relationship between them. The purpose of the study was to investigate the response threshold of the motor and sensory cortex to electric stimulation in rolandic epilepsy patients, and to determine if a relationship exists between this threshold and factors such as disease duration, patient age, and pathological changes in epilepsy patients. Conclusions could then be used as a scientific basis for personalized CES functional mapping in clinical practice.
2. Materials and methods 2.1. Patients Patients were included in the study if they met the following criteria: (1) they had refractory epilepsy that required surgical treatment because of failed standard drug therapy; (2) their electroencephalogram (EEG) indicated that the seizure originated in or around the rolandic area, or the seizure focus was strongly suspected to be in the rolandic area; (3) brain MRI indicated that the seizure focus neighbored the rolandic area (subdural electrodes were implanted to localize functional areas and identify the relationship between functional areas and seizure focus); and (4) the
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brain cortex mapping data proved that the seizure originated in or around the rolandic area, and the seizure originated from the rolandic areas. CES was needed to identify the relationship between the functional areas and the seizure focus. Patients who failed to meet the above requirements were excluded, and those that met the following two criteria were also excluded: (1) young age or with mental or intellectual disorders who might have poor cooperation; and (2) hematoma or effusion following the implantation of intracranial electrodes, which could affect the result. According to the aforementioned inclusion and exclusion criteria, a total of 21 patients with rolandic epilepsy who underwent surgical treatment in the Beijing Institute of Functional Neurosurgery of Xuanwu Hospital between October 2006 and March 2008 were included in the present study. The study patients included 17 men and four women, aged 12–44 years, with a mean age of 20 years. The age at disease onset ranged from 0 to 25 years, with a mean of 9.8 years. The duration of disease ranged from 0 to 30 years, with a mean of 10.8 years. MRI revealed 10 patients with lesions and 11 patients without lesions. All patients underwent implantation of intracranial electrodes, pre-surgical CES functional mapping, and the surgical removal of the seizure focus. 2.2. Pre-surgical evaluation Standard pre-surgical evaluation included medical history, age at time of surgery, age at disease onset, clinical symptoms, physical examination of the nervous system, ictal and interictal EEG, neuroradiological examinations including MRI, a neuropsychological assessment, and other examinations if necessary (positron emission tomography, single photon emission computed tomography and magnetoencephalography). The approximate position of the seizure focus was determined by a comprehensive analysis of the pre-surgical assessment to best identify a position for the implantation of subdural electrodes.
pre-surgical evaluation. Digital imaging was used to photograph the implantation of the electrodes in surgery (Fig. 1b), and postimplantation imaging was used to confirm the placement (Fig. 1c). Dexamethasone (10 mg) was given to each patient immediately prior to surgery and was gradually tapered over 3 days to reduce post-operative discomfort. 2.4. EEG monitoring and CES functional mapping Generally, EEG (DaVinci Programmable Digital Signal Processors, Texas Instruments, TX, USA) monitoring was performed 1– 2 days after the implantation of subdural electrodes, and the ictal and interictal EEG were recorded to identify the seizure focus. Seizures were captured by EEG at least twice. CES mapping was conducted 3–4 days post-implantation to localize the sensory, motor, and language functional areas; however, the present study only focused on the assessment of sensory and motor functions. Electrical stimuli were presented using a Nicolet–Viking IV Constant Current Stimulator (Natus Medical, San Carlos, CA, USA), which generated a rectangular pulse at a rate of 5 Hz or 50 Hz.8 In the current study, CES functional mapping was performed using 50 Hz stimuli with a pulse duration of 0.2 ms. Current strengths of 1.0–8.0 mA were employed with a train duration of 3 s and an intertrain interval of 20 s. Stimuli at each electrode (using the adjacent electrode as reference) started at 1.0 mA and increased by 1.0 mA increments for each subsequent stimulation until a functional alteration was achieved, an after discharge was recorded, or 8 mA was reached. The stimulation threshold was defined as the intensity of the current that produced signs of contralateral limb or facial sensory or motor function. Each parameter for the effective stimulation threshold of sensory and motor function was summarized. A patient’s threshold response to electric stimulation was calculated by averaging the stimulation thresholds at different electrode sites. 2.5. Stimulation response
2.3. Implantation of subdural electrodes Implantation of subdural electrodes was carried out in all 21 patients. The electrode had an appearance similar to a grid or a strip made of stainless steel disks, with each disk containing a 5 mm diameter of exposed surface embedded in silastin at the center. A kerf was designed at the center of the seizure focus identified pre-surgery. Fig. 1a presents a typical rolandic kerf. The subdural electrodes were implanted in the most concentrated and evident site of discharge as indicated by electrocorticographic data and
A primary motor response was defined as a localized movement of the contralateral body in response to stimulation of the cortex while the patient was at rest. A simple isolated movement, such as contraction of the contralateral eyelid, cheek, tongue, hand, or foot are such examples. Movement of the arm was limited to a movement within an isolated joint, such as the wrist or elbow. Movement of the hand was often characterized by the simultaneous extension or flexion around several fingers at the joints.9 Primary sensory responses were defined as discrete sensory
Fig. 1. Perioperative photography showing (a) a rolandic skin flap, (b) axial view of the implantation of the electrodes at surgery, and (c) sagittal radiography showing the placement of the electrodes post-surgery.
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Fig. 2. Electroencephalogram of normal brain mapping pre-stimulation. Arrows indicate the rhythmic discharge post-stimulation.
experiences in isolated regions of the contralateral body. A patient’s report of tingling in the corner of the lips after cortical stimulation is a typical example. The after discharge was defined as abnormal waves of slow, sharp, or rhythmic quality that exceed 10 s following CES.10 Fig. 2 shows normal brain mapping pre-stimulation, and the rhythmic discharge post-stimulation. 2.6. Surgical treatment, prognosis and follow-up All patients underwent removal of the seizure focus, and were followed-up for more than 24 months post-surgery. The post-operative outcome was graded into four classes according to Engel’s classification11: class I: free of disabling seizures; class II: rare disabling seizures (‘‘almost seizure free’’) or seizure-free intervals of 3–6 months; class III: worthwhile seizure reduction (more than 75%); and class IV: no worthwhile improvement with seizure reduction less than 75%. Post-surgical limb functional disorders were defined as including the two aspects of sensory and motor impairment. Motor disorder was characterized by weakness and inflexibility, while sensory disorder was characterized by hypoesthesia, continuous numbness and abnormal sensations. 2.7. Ethical consideration This study was approved by the Ethics Review Committee of the Beijing Institute of Functional Neurosurgery, Capital Medical University and the Ministry of Health, China. All measurements conducted in this study were in compliance with the current laws and regulations in China. 2.8. Statistical analysis All data were entered into Microsoft Excel (Microsoft, Redmond, WA, USA) and statistical analyses were performed using the Statistical Package for the Social Sciences version 11.5 (SPSS, Chicago, IL, USA). The measurement data, including the threshold of sensory and motor responses and after discharge production, are presented as mean ± standard deviation. Analysis of variance was performed to compare the differences among the thresholds of sensory, motor, and after discharge production along with the differences between sexes, left and right lobes, and the presence or absence of seizure focus. Correlation analyses were carried out to investigate the relationship between the threshold of the motor and sensory responses with the after discharge
production, age at disease onset, age at time of operation, and disease course. A p value 0.05). The correlation analysis indicated that among the possible factors affecting the threshold of motor, sensory, and after discharge production (including the age at disease onset, age at time of operation, and disease duration), a correlation was only found between disease duration and the threshold of after discharge production (r = –0.594, p = 0.020). The linear regression equation for this relationship was y = 5.97 1/10x (f = 0.020), and the regression curve is presented in Fig. 4. 4. Discussion CES mapping can be performed either during surgery or outside the operating room using subdural electrodes for seizure focus resection. The former method can be problematic due to the time limitations imposed by the use of narcotics in maintaining patient consciousness during surgery. The latter method uses subdural cortical electrodes for CES mapping before the removal of the seizure focus, which allows for a greater time and better cooperation from the patient as compared to the former method. This is becoming the more widely used mapping approach.1,12 Both CES mapping methods are jointly used within our institute to improve surgical. Considering that high stimulation intensity for CES may induce seizures and that low intensity stimulation may not activate functional reactions, minor differences in CES parameters are used among various centers to balance the reliability and safety of CES.13 However, the most widely used and accepted parameters are 50–60 Hz for rectangular pulse stimulation, 0.2–0.3 ms for pulse width, 2–5 s for the duration of each stimulation, 1–15 mA for stimulation intensity, and 10–20 s for stimulation interval.14–18 Given that CES mapping requires cooperation and concentration, very young patients and those with mental/intellectual
disorders were excluded from the current study because of their poor cooperation. Our experience with surgical removal of the seizure focus has shown that stimulation in the presence of a hematoma or effusion is unreliable. Therefore, those with hematoma or effusion following the implantation of intracranial electrodes were not included in the study. In the present study, CES with a stimulation frequency of 50 Hz, pulse width of 0.2 ms, and a stimulation intensity of less than 8 mA was able to activate the majority of functional reactions. Higher stimulation intensity was not helpful for functional cortex mapping, as reported by some previous studies.15 However, Chitoku and colleagues19 reported that some patients required up to 20 mA of stimulation intensity to activate motor function. This discrepancy is thought to be caused by several factors. Firstly, the selection of the study patients – the patients involved in the current study were 12–44 years old, with a mean age of 28 years. However, Chitoku et al.19 chose patients between 4 and 18 years of age. The increased threshold of response to electrical stimulation may be associated with the incomplete development of the cortex in younger children. Secondly, a different stimulation approach was used in the current study, with the neighboring electrode being used as a reference while employing cortical electrodes for point-to-point stimulation. Chitoku et al.19 performed an extraoperative CES using a ‘‘distance reference’’ technique, which may also have an effect on the stimulation parameters. Our findings showed that the threshold for after discharge production was higher than those of sensory and motor responses (both p < 0.05), which suggests that the level of stimulation was relatively safe for mapping sensory and motor functions. Our results indicate that with gradual increases in stimulus intensity, epilepsy or after discharge was not induced while achieving suprathreshold stimulation of the functional response. There was no significant difference found in the threshold of sensory and motor responses (p = 0.358), which suggests that the CES approach has a similar sensitivity in achieving sensory and motor functional mapping. Our results indicate that this method is suitable for sensory and motor functional mapping in rolandic
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lies in providing theoretical evidence for personalized treatment in CES functional mapping. For instance, in patients with a longer disease course, the stimulation intensity should be more gradually increased to avoid the production of epilepsy. In summary, CES functional mapping has been applied in clinical practice for about half a century and is considered the ‘‘gold standard’’ of cortical mapping. However, the stimulation parameters and approaches for CES are different among various centers and are being continually improved. In our study, we used a 50 Hz frequency and 0.2 ms pulse width rectangular pulse stimulation for mapping functional areas. The summarized threshold ranges of stimulation intensity in adults with rolandic epilepsy can provide a clinically standardized application of CES mapping. Use of CES for mapping functional areas is reliable and safe, and the performance of personalized CES mapping should be considered. Fig. 3. Column graph showing the mean thresholds (mAmp) of the motor (thr1) and sensory (thr2) responses, and after discharge (thr3) production. thr1 versus thr2, p > 0.05; thr1 or thr2 versus thr3, both p < 0.05.
epilepsy, which is different from the strategy proposed by Zangaladze et al.,20 where a 5–10 Hz low-frequency stimulation was used for motor function, followed by a 50–60 Hz stimulation to achieve sensory function. The present study indicated that there was no significant correlation between the threshold of motor and sensory responses to the age at operation (for patients more than 12 years old), age of disease onset, disease duration, and the presence of a seizure focus on MRI. This suggests that the approach used for mapping functional areas generally has a similar sensitivity among patients. Chitoku and colleagues19 investigated factors altering the threshold to provoke functional reactions in 20 children with epilepsy, and found an inverse relationship between the threshold of motor response and age, namely the younger the patient, the higher the threshold. This result was thought to be related to the immature development of the cortex and the resultant porr reaction to cortical stimulation. However, all patients involved in the current study were adults with a mature cortex. Therefore, no obvious difference of threshold for functional responses was found. In addition, the present study found a negative linear correlation between the threshold for after discharge production and the disease duration, namely the longer the disease course, the lower the threshold. It is thought that long-term recurring seizures cause increased excitability of the cortex. The clinical significance
Fig. 4. Graph showing the negative linear correlation found between the threshold of after discharge production (mA) and disease course (years). The linear regression equation is y = 5.97 1/10x (f = 0.020).
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References 1. Savoy L. History and future direction of human brain mapping and functional neuroimaging. Acta Psychol 2001;107:9–42. 2. Lachaux JP, Rudrauf D, Kahane P. Intracranial EEG and human brain mapping. J Physiol Paris 2003;97:613–28. 3. Pondal-Sordo M, Diosy D, Tellez-Zenteno JF, et al. Usefulness of intracranial EEG in the decision process for epilepsy surgery. Epilepsy Res 2007;74:176–82. 4. Jayakar P, Alvarez LA, Duchowny MS, et al. A safe and effective paradigm to functionally map the cortex in childhood. J Clin Neurophysiol 1992;9:288–93. 5. Wyllie E, Awad I. Invasive neurophysiologic techniques in the evaluation for epilepsy surgery in children. In: Lüders HO, editor. Epilepsy surgery. New York: Raven Press; 1991. p. 409–12. 6. Kuzniecky R, Andermann F, Tampieri D, et al. Bilateral central macrogyria: epilepsy, pseudobullbar palsy, and mental retardation – a recognizable neuronal migration disorder. Ann Neurol 1989;25:547–54. 7. Desbiens R, Berkovic SF, Dubeau F, et al. Life-threatening focal status epilepticus due to occult cortical dysplasia. Arch Neurol 1993;50:695–700. 8. Lesser RP, Lüders H, Klem G, et al. Cortical afterdischarge and functional responses thresholds: results of extraoperative testing. Epilepsia 1984;25: 615–21. 9. Uematsu S, Lesser R, Fisher RS, et al. Motor and sensory cortex in humans: topography studied with chronic subdural stimulation. Neurosurgery 1992;31: 59–72. 10. Blume WT, Jones DC, Pathak P. Properties of after discharges from cortical electrical stimulation in focal epilepsies. Clin Neurophysiol 2004;115:982–9. 11. Engel JJ, Van Ness PC, Rasmussen TB, et al. Outcome with respect to epileptic seizures. 2nd ed. In: Engel JJ, editor. Surgical treatment of the epilepsies. New York: Raven Press; 1993. p. 609–21. 12. Lachaux J, Rudrauf D, Kahane P. Intracranial EEG and human brain mapping. J Physiol Paris 2003;97:613–28. 13. Motamedi GK, Okunola O, Kalhorn CG, et al. After discharges during cortical stimulation at different frequencies and intensities. Epilepsy Res 2007;77: 65–9. 14. DuanYu N, GuoJun Z, Liang Q, et al. Surgery for perirolandic epilepsy: epileptogenic cortex resection guided by chronic intracranial electroencephalography and electric cortical stimulation mapping. Clin Neurol Neurosurg 2010;112:110–7. 15. Chauvel P, Landre E, Trottier S, et al. Electrical stimulation with intracerebral electrodes to evoke seizures. Adv Neurol 1993;63:115–21. 16. Schulz R, Lüders HO, Tuxhorn I, et al. Localization of epileptic auras induced on stimulation by subdural electrodes. Epilepsia 1997;38:1321–9. 17. Usui K, Ikeda A, Takayama M, et al. Processing of Japanese morphogram and syllabogram in the left basal temporal area: electrical cortical stimulation studies. Brain Res Cogn Brain Res 2005;24:274–83. 18. Hoshida T, Sakaki T. Functional brain mapping detected by cortical stimulation using chronically implanted subdural electrodes: basic knowledge of clinical nerve physiology for neurosurgeons. No Shinkei Geka 2003;31:811–8 discussion 8–9. 19. Chitoku S, Otsubo H, Harada Y, et al. Extraoperative cortical stimulation of motor function in children. Pediatr Neurol 2001;24:344–50. 20. Zangaladze A, Sharan A, Evans J, et al. The effectiveness of low-frequency stimulation for mapping cortical function. Epilepsia 2008;49:481–7.
