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A lack of effect from transcranial magnetic stimulation (TMS) on the vagus nerve stimulator (VNS)
Clinical Neurophysiology 116 (2005) 2501–2504 www.elsevier.com/locate/clinph
A lack of effect from transcranial magnetic stimulation (TMS) on the vagus nerve stimulator (VNS) Lara M. Schrader*, John M. Stern, Tony A. Fields, Marc R. Nuwer, Charles L. Wilson Department of Neurology, Geffen School of Medicine at UCLA, Reed Neurological Research Building, 710 Westwood Plaza, Room 1-194, Los Angeles, CA 90095, USA Accepted 24 June 2005
Abstract Objective: The effects of transcranial magnetic stimulation (TMS) on vagus nerve stimulation (VNS) are unknown. Understanding these effects is important before exposing individuals with an implanted VNS to TMS, as could occur in epilepsy or depression TMS research. To explore this issue, the TMS-induced current in VNS leads and whether TMS has an effect on the VNS pulse generator was assessed. Methods: Ex vivo measurement of current in VNS leads during single-pulse TMS and pulse generator function before, during, and after single-pulse TMS was assessed. Results: At the highest intensity and with the TMS coil held w5 mm from the VNS wires, a 200 nA, 1.0 ms current was induced by TMS. This translates to an induced charge density of 3.3 nC/cm2/phase. The function of the pulse generator was unaffected by single-pulse TMS, even when its case was directly stimulated by the coil. Conclusions: TMS-induced current in VNS electrodes was not only well outside of the range known to be injurious to peripheral nerve, but also below the activation threshold of nerve fibers. Significance: Using single-pulse TMS in individuals with VNS should not result in nerve stimulation or damage. Furthermore, single-pulse TMS does not affect the VNS pulse generator’s function. q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Safety; Vagus nerve stimulation; Transcranial magnetic stimulation; Stimulation; Epilepsy
1. Introduction Transcranial magnetic stimulation (TMS) utilizes rapidly changing magnetic fields to non-invasively induce electrical impulses in underlying brain tissue and has been a valuable tool in depression and epilepsy research. Single- and pairedpulse techniques have been used to understand cortical excitatory and inhibitory systems in both epilepsy and depression (Abarbanel et al., 1996; Dean et al., 2001; Di Lazzaro et al., 2004; Maeda et al., 2000; Tassinari et al., 2003). In addition, repetitive TMS has been investigated as a potential treatment for these disorders (Gershon et al., 2003; Tassinari et al., 2003). Thus, TMS is being used in
* Corresponding author. Tel.: C1 310 206 3093; fax: C1 310 267 1157. E-mail address: [email protected] (L.M. Schrader).
research studies and clinical trials of depression and epilepsy. Many individuals with depression and epilepsy have undergone vagus nerve stimulator (VNS) implantation. The VNS device has been FDA-approved for treating medically refractory epilepsy since 1997 and approved for treating treatment-resistant depression since July 15, 2005. The implanted VNS device consists of a pulse generator inserted in the subcutaneous tissue of the upper left chest that delivers intermittent electrical stimulation to the left cervical vagus nerve via a bifurcated helical electrode. Wires tunneled subcutaneously connect the pulse generator and the electrode. The safety of using TMS in individuals with implanted devices, such as the VNS, is unknown. The electrical effect of TMS-produced high intensity magnetic fields on implanted devices is unknown and may vary from device
1388-2457/$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2005.06.025
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to device. Thus, the presence of an implanted device is generally considered a relative contraindication (Keel et al., 2000). However, whether TMS is safe to use in individuals with implanted devices has never been systematically studied. Because the electrical effects of TMS on the VNS device are unknown, understanding these effects is important before exposing individuals with an implanted VNS to TMS, as could occur in epilepsy or depression research involving TMS. In this study, the ex vivo effects of singlepulse TMS on the VNS device were assessed in regard to any current induced in VNS leads during TMS, as well as any effect of TMS on the operation of the VNS pulse generator.
2. Methods Transcranial magnetic stimulation was delivered in single pulses through the Magstim 220 using a 70 mm figure-of-eight coil (The Magstim Company Ltd, Whitland, Wales, UK). This stimulator provides biphasic stimulation with a rise time of approximately 80 ms and total pulse duration of 250 ms. At maximal output, the stimulator’s 70 mm figure-of-eight coil generates a 1.75 T field. VNS leads and cuff electrodes were embedded in a normal saline (0.09 M NaCl) gelatin matrix held in a Pyrex glass flask while connected to an operating VNS Model 102 pulse generator (Cyberonics, Inc., Houston, TX, USA). Oscilloscope measurements of TMS-induced current in the VNS electrodes were obtained using a Tektronix 2235 100 MHz oscilloscope (Tektronix, Inc., Beaverton, OR, USA) and a custom made amplifier with a gain setting of 5000 and bandpass filter settings of 0.1–5 kHz (Fig. 1). Maximal TMS intensities were used, and the center of the figure-of-eight coil was positioned next to the flask containing the gel matrix, approximately 5 mm from the electrodes. We also assessed whether TMS delivered in single pulses had a detectable effect on the pulse generator by oscilloscope measurement of the output of the VNS before, during and after stimulation by the TMS. For these assessments, maximal TMS intensities were used, and the center of the figure-of-eight coil was in direct contact with the lead wires or the case of the pulse generator.
Fig. 1. A schematic diagram illustrating the configuration of the testing setup, including the oscilloscope, amplifier, electrodes, and figure-of-eight TMS coil. The saline gelatin matrix containing the electrodes was inside in a Pyrex glass flask, and the electrode leads entering the flask were directly in contact with the crossing of the figure-of-eight. Testing of the effects of TMS on the VNS stimulator were also made with the case of the VNS stimulator in contact with the crossing of the figure-of-eight.
3.3 nC/cm2/phase based upon the 6 mm2 surface area of the VNS electrodes. The VNS pulse generator was turned on during the stimulation of VNS wires described in the preceding paragraph. The pulse generator continued to function normally during and after this single-pulse stimulation. This was assessed by interrogation of the pulse generator with the standard, Cyberonics-provided interrogation software. Specifically, the TMS did not result in any changes to the VNS stimulation parameters and the pulse generator magnet stimulation log did not include evidence that TMS produced spurious triggering of the VNS. The pulse generator was also unaffected even when its case was in direct contact with the center of the discharging TMS coil at 100% maximal stimulator output.
3. Results 4. Discussion The impedance across the TMS leads was 3000 Ohm at 1 kHz. At the highest TMS intensity (100% maximal stimulator output) and with the TMS coil held next to the glass flask containing the matrix-imbedded electrodes at a distance of approximately 5 mm, a 200 nA, 1.0 ms current was induced in the VNS wires by a single pulse of TMS. This is equivalent to an induced charge density of
In this experiment in which the TMS coil was held as close as possible to the VNS wires, the brief single pulses of 200 nA current induced in VNS wires by TMS were well within known safe stimulation intensities. Intensities used for VNS stimulation are much higher, ranging from 0.25 to 3.5 mA. However, the potential for stimulation-induced
L.M. Schrader et al. / Clinical Neurophysiology 116 (2005) 2501–2504
nerve damage is complex and depends on several factors in addition to intensity. Agnew et al. (1989) provided some insight into the underlying mechanism of electrical stimulation-induced injury. When peripheral nerves are damaged by electrical stimulation, injured nerve fibers are found uniformly throughout the diameter of the stimulated nerve. The large and medium-sized myelinated axons that are excited by stimulation are the ones that are damaged while the smaller myelinated and unmyelinated axons that are not excited by the stimulation are spared from injury (Agnew et al., 1989). A local anesthetic block of nerve action potentials prevents nerve injury from electrical stimulation, indicating that the stimulation-induced neuronal activity is responsible for the injury (Agnew et al., 1990). A series of studies by Agnew and colleagues demonstrate that the degree of damage to peripheral nerves from electrical stimulation is dependent upon several factors (Agnew et al., 1989; Agnew and McCreery, 1990; McCreery et al., 1995). Smaller nerves are more likely to be injured than larger ones (Agnew and McCreery, 1990). In addition, stimulation parameters can influence whether injury occurs. In studies of the cat peroneal nerve, a nerve that is about same size as the human vagus nerve (Agnew and McCreery, 1990), continuous stimulation for 4 h at 50 Hz and 2.5 mA resulted in no nerve injury, but prolonging this 50 Hz 2.5 mA stimulation to 8–16 h did result in irreversible axonal injury. However, using the same stimulation parameters except reducing the frequency of from 50 to 20 Hz does not produce nerve damage (Agnew and McCreery, 1990; Agnew et al., 1989). Thus, duration of continuous stimulation is an important factor at high frequencies. At frequencies of 50–100 Hz, there is a positive correlation between the intensity of stimulation and the degree of injury. However, at 20 Hz there is no detectable correlation, indicating that lower frequencies of stimulation produce little or no damage even if the stimulation intensity is high (McCreery et al., 1995). Lastly, compared to continuous stimulation, intermittent duty cycles can reduce the degree and likelihood of nerve injury (Agnew et al., 1989). Since risk of injury from peripheral nerve stimulation appears to depend primarily on stimulation frequency, there is no risk to the peripheral nerve from a low amplitude current induced by single-pulse TMS. Thus, using singlepulse TMS in individuals with VNS should not result in nerve damage. Furthermore, single-pulse TMS does not affect the function of the VNS pulse generator, including any influence on the stimulation settings. In this experiment, we used the most extreme stimulation parameters to estimate the safety of single-pulse TMS. For this study, there was no distance between the TMS coil and the VNS leads/pulse generator. However, in actual TMS studies that involve cerebral cortex stimulation, the TMS coil would be at least 10 cm from any component of the VNS device. The magnitude of the TMS coil’s magnetic
2503
field decreases markedly with increasing distance from the coil. Thus, under usual protocols that involve stimulation of the cerebral cortex with TMS, any potential risk of interaction between TMS and VNS would be negligible. The effects of repetitive TMS were not studied. Although the results of these tests under artificial conditions were consistent with low risk, the safety of using TMS in individuals with VNS remains to be systematically studied in a population of patients. However, two studies have safely used TMS in individuals with epilepsy who had implanted VNS devices. In one study, single-pulse TMS was administered to the primary motor cortex of individuals with epilepsy during active VNS stimulation and 1 h after the device was turned off (Dean et al., 2001). No adverse events occurred (Labar, personal communication). In another study, single- and paired-pulse TMS was delivered to the primary motor cortex of individuals with epilepsy, again with the stimulator turned on and off (Di Lazzaro et al., 2004). There was no report of adverse event in any of the five patients tested. In summary, based on this ex vivo study and limited clinical experience described in previous publications (Dean et al., 2001; Di Lazzaro et al., 2004; Labar, personal communication), it appears that single-pulse TMS can be safely applied to individuals who have an implanted VNS device.
Acknowledgements For their generous support, the authors wish to thank the Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson-Lovelace Foundation, The Ahmanson Foundation, Tamkin Foundation, Jennifer Jones-Simon Foundation, Capital Group Companies Charitable Foundation, Robson Family, William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community Foundation, Northstar Fund, and the National Center for Research Resources grants RR12169, RR13642 and RR08655. The authors also thank Cyberonics, Inc. for providing the VNS device. This work was also supported in part by a grant from the American Academy of Neurology Foundation.
References Abarbanel JM, Lemberg T, Yaroslavski U, Grisaru N, Belmaker RH. Electrophysiological responses to transcranial magnetic stimulation in depression and schizophrenia. Biol Psychiatry 1996;40(2):148–50. Agnew WF, McCreery DB. Considerations for safety with chronically implanted nerve electrodes. Epilepsia 1990;31(Suppl. 2):S27–S32. Agnew WF, McCreery DB, Yuen TG, Bullara LA. Histologic and physiologic evaluation of electrically stimulated peripheral nerve: considerations for the selection of parameters. Ann Biomed Eng 1989; 17(1):39–60.
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L.M. Schrader et al. / Clinical Neurophysiology 116 (2005) 2501–2504
Agnew WF, McCreery DB, Yuen TG, Bullara LA. Local anaesthetic block protects against electrically-induced damage in peripheral nerve. J Biomed Eng 1990;12(4):301–8. Dean AC, Wu AT, Burgut FT, Labar DR. Motor cortex excitability in epilepsy patients treated with vagus nerve stimulation. Epilepsia 2001; 42(Suppl. 7):42. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Meglio M, Colicchio G, Barba D, Papacci F, Tonali PA. Effects of vagus nerve stimulation on cortical excitability in epileptic patients. Neurology 2004;62(12):2310–2. Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression. Am J Psychiatry 2003;160(5):835–45.
Keel JC, Smith MJ, Wassermann EM. A safety screening questionnaire for transcranial magnetic stimulation. Clin Neurophysiol 2000;112:720. Maeda F, Keenan JP, Pascual-Leone A. Interhemispheric asymmetry of motor cortical excitability in major depression as measured by transcranial magnetic stimulation. Br J Psychiatry 2000;177:169–73. McCreery DB, Agnew WF, Yuen TG, Bullara LA. Relationship between stimulus amplitude, stimulus frequency and neural damage during electrical stimulation of sciatic nerve of cat. Med Biol Eng Comput 1995;33(3 Spec No):426–9. Tassinari CA, Cincotta M, Zaccara G, Michelucci R. Transcranial magnetic stimulation and epilepsy. Clin Neurophysiol 2003;114(5): 777–98.
A lack of effect from transcranial magnetic stimulation (TMS) on the vagus nerve stimulator (VNS) Lara M. Schrader*, John M. Stern, Tony A. Fields, Marc R. Nuwer, Charles L. Wilson Department of Neurology, Geffen School of Medicine at UCLA, Reed Neurological Research Building, 710 Westwood Plaza, Room 1-194, Los Angeles, CA 90095, USA Accepted 24 June 2005
Abstract Objective: The effects of transcranial magnetic stimulation (TMS) on vagus nerve stimulation (VNS) are unknown. Understanding these effects is important before exposing individuals with an implanted VNS to TMS, as could occur in epilepsy or depression TMS research. To explore this issue, the TMS-induced current in VNS leads and whether TMS has an effect on the VNS pulse generator was assessed. Methods: Ex vivo measurement of current in VNS leads during single-pulse TMS and pulse generator function before, during, and after single-pulse TMS was assessed. Results: At the highest intensity and with the TMS coil held w5 mm from the VNS wires, a 200 nA, 1.0 ms current was induced by TMS. This translates to an induced charge density of 3.3 nC/cm2/phase. The function of the pulse generator was unaffected by single-pulse TMS, even when its case was directly stimulated by the coil. Conclusions: TMS-induced current in VNS electrodes was not only well outside of the range known to be injurious to peripheral nerve, but also below the activation threshold of nerve fibers. Significance: Using single-pulse TMS in individuals with VNS should not result in nerve stimulation or damage. Furthermore, single-pulse TMS does not affect the VNS pulse generator’s function. q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Safety; Vagus nerve stimulation; Transcranial magnetic stimulation; Stimulation; Epilepsy
1. Introduction Transcranial magnetic stimulation (TMS) utilizes rapidly changing magnetic fields to non-invasively induce electrical impulses in underlying brain tissue and has been a valuable tool in depression and epilepsy research. Single- and pairedpulse techniques have been used to understand cortical excitatory and inhibitory systems in both epilepsy and depression (Abarbanel et al., 1996; Dean et al., 2001; Di Lazzaro et al., 2004; Maeda et al., 2000; Tassinari et al., 2003). In addition, repetitive TMS has been investigated as a potential treatment for these disorders (Gershon et al., 2003; Tassinari et al., 2003). Thus, TMS is being used in
* Corresponding author. Tel.: C1 310 206 3093; fax: C1 310 267 1157. E-mail address: [email protected] (L.M. Schrader).
research studies and clinical trials of depression and epilepsy. Many individuals with depression and epilepsy have undergone vagus nerve stimulator (VNS) implantation. The VNS device has been FDA-approved for treating medically refractory epilepsy since 1997 and approved for treating treatment-resistant depression since July 15, 2005. The implanted VNS device consists of a pulse generator inserted in the subcutaneous tissue of the upper left chest that delivers intermittent electrical stimulation to the left cervical vagus nerve via a bifurcated helical electrode. Wires tunneled subcutaneously connect the pulse generator and the electrode. The safety of using TMS in individuals with implanted devices, such as the VNS, is unknown. The electrical effect of TMS-produced high intensity magnetic fields on implanted devices is unknown and may vary from device
1388-2457/$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2005.06.025
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L.M. Schrader et al. / Clinical Neurophysiology 116 (2005) 2501–2504
to device. Thus, the presence of an implanted device is generally considered a relative contraindication (Keel et al., 2000). However, whether TMS is safe to use in individuals with implanted devices has never been systematically studied. Because the electrical effects of TMS on the VNS device are unknown, understanding these effects is important before exposing individuals with an implanted VNS to TMS, as could occur in epilepsy or depression research involving TMS. In this study, the ex vivo effects of singlepulse TMS on the VNS device were assessed in regard to any current induced in VNS leads during TMS, as well as any effect of TMS on the operation of the VNS pulse generator.
2. Methods Transcranial magnetic stimulation was delivered in single pulses through the Magstim 220 using a 70 mm figure-of-eight coil (The Magstim Company Ltd, Whitland, Wales, UK). This stimulator provides biphasic stimulation with a rise time of approximately 80 ms and total pulse duration of 250 ms. At maximal output, the stimulator’s 70 mm figure-of-eight coil generates a 1.75 T field. VNS leads and cuff electrodes were embedded in a normal saline (0.09 M NaCl) gelatin matrix held in a Pyrex glass flask while connected to an operating VNS Model 102 pulse generator (Cyberonics, Inc., Houston, TX, USA). Oscilloscope measurements of TMS-induced current in the VNS electrodes were obtained using a Tektronix 2235 100 MHz oscilloscope (Tektronix, Inc., Beaverton, OR, USA) and a custom made amplifier with a gain setting of 5000 and bandpass filter settings of 0.1–5 kHz (Fig. 1). Maximal TMS intensities were used, and the center of the figure-of-eight coil was positioned next to the flask containing the gel matrix, approximately 5 mm from the electrodes. We also assessed whether TMS delivered in single pulses had a detectable effect on the pulse generator by oscilloscope measurement of the output of the VNS before, during and after stimulation by the TMS. For these assessments, maximal TMS intensities were used, and the center of the figure-of-eight coil was in direct contact with the lead wires or the case of the pulse generator.
Fig. 1. A schematic diagram illustrating the configuration of the testing setup, including the oscilloscope, amplifier, electrodes, and figure-of-eight TMS coil. The saline gelatin matrix containing the electrodes was inside in a Pyrex glass flask, and the electrode leads entering the flask were directly in contact with the crossing of the figure-of-eight. Testing of the effects of TMS on the VNS stimulator were also made with the case of the VNS stimulator in contact with the crossing of the figure-of-eight.
3.3 nC/cm2/phase based upon the 6 mm2 surface area of the VNS electrodes. The VNS pulse generator was turned on during the stimulation of VNS wires described in the preceding paragraph. The pulse generator continued to function normally during and after this single-pulse stimulation. This was assessed by interrogation of the pulse generator with the standard, Cyberonics-provided interrogation software. Specifically, the TMS did not result in any changes to the VNS stimulation parameters and the pulse generator magnet stimulation log did not include evidence that TMS produced spurious triggering of the VNS. The pulse generator was also unaffected even when its case was in direct contact with the center of the discharging TMS coil at 100% maximal stimulator output.
3. Results 4. Discussion The impedance across the TMS leads was 3000 Ohm at 1 kHz. At the highest TMS intensity (100% maximal stimulator output) and with the TMS coil held next to the glass flask containing the matrix-imbedded electrodes at a distance of approximately 5 mm, a 200 nA, 1.0 ms current was induced in the VNS wires by a single pulse of TMS. This is equivalent to an induced charge density of
In this experiment in which the TMS coil was held as close as possible to the VNS wires, the brief single pulses of 200 nA current induced in VNS wires by TMS were well within known safe stimulation intensities. Intensities used for VNS stimulation are much higher, ranging from 0.25 to 3.5 mA. However, the potential for stimulation-induced
L.M. Schrader et al. / Clinical Neurophysiology 116 (2005) 2501–2504
nerve damage is complex and depends on several factors in addition to intensity. Agnew et al. (1989) provided some insight into the underlying mechanism of electrical stimulation-induced injury. When peripheral nerves are damaged by electrical stimulation, injured nerve fibers are found uniformly throughout the diameter of the stimulated nerve. The large and medium-sized myelinated axons that are excited by stimulation are the ones that are damaged while the smaller myelinated and unmyelinated axons that are not excited by the stimulation are spared from injury (Agnew et al., 1989). A local anesthetic block of nerve action potentials prevents nerve injury from electrical stimulation, indicating that the stimulation-induced neuronal activity is responsible for the injury (Agnew et al., 1990). A series of studies by Agnew and colleagues demonstrate that the degree of damage to peripheral nerves from electrical stimulation is dependent upon several factors (Agnew et al., 1989; Agnew and McCreery, 1990; McCreery et al., 1995). Smaller nerves are more likely to be injured than larger ones (Agnew and McCreery, 1990). In addition, stimulation parameters can influence whether injury occurs. In studies of the cat peroneal nerve, a nerve that is about same size as the human vagus nerve (Agnew and McCreery, 1990), continuous stimulation for 4 h at 50 Hz and 2.5 mA resulted in no nerve injury, but prolonging this 50 Hz 2.5 mA stimulation to 8–16 h did result in irreversible axonal injury. However, using the same stimulation parameters except reducing the frequency of from 50 to 20 Hz does not produce nerve damage (Agnew and McCreery, 1990; Agnew et al., 1989). Thus, duration of continuous stimulation is an important factor at high frequencies. At frequencies of 50–100 Hz, there is a positive correlation between the intensity of stimulation and the degree of injury. However, at 20 Hz there is no detectable correlation, indicating that lower frequencies of stimulation produce little or no damage even if the stimulation intensity is high (McCreery et al., 1995). Lastly, compared to continuous stimulation, intermittent duty cycles can reduce the degree and likelihood of nerve injury (Agnew et al., 1989). Since risk of injury from peripheral nerve stimulation appears to depend primarily on stimulation frequency, there is no risk to the peripheral nerve from a low amplitude current induced by single-pulse TMS. Thus, using singlepulse TMS in individuals with VNS should not result in nerve damage. Furthermore, single-pulse TMS does not affect the function of the VNS pulse generator, including any influence on the stimulation settings. In this experiment, we used the most extreme stimulation parameters to estimate the safety of single-pulse TMS. For this study, there was no distance between the TMS coil and the VNS leads/pulse generator. However, in actual TMS studies that involve cerebral cortex stimulation, the TMS coil would be at least 10 cm from any component of the VNS device. The magnitude of the TMS coil’s magnetic
2503
field decreases markedly with increasing distance from the coil. Thus, under usual protocols that involve stimulation of the cerebral cortex with TMS, any potential risk of interaction between TMS and VNS would be negligible. The effects of repetitive TMS were not studied. Although the results of these tests under artificial conditions were consistent with low risk, the safety of using TMS in individuals with VNS remains to be systematically studied in a population of patients. However, two studies have safely used TMS in individuals with epilepsy who had implanted VNS devices. In one study, single-pulse TMS was administered to the primary motor cortex of individuals with epilepsy during active VNS stimulation and 1 h after the device was turned off (Dean et al., 2001). No adverse events occurred (Labar, personal communication). In another study, single- and paired-pulse TMS was delivered to the primary motor cortex of individuals with epilepsy, again with the stimulator turned on and off (Di Lazzaro et al., 2004). There was no report of adverse event in any of the five patients tested. In summary, based on this ex vivo study and limited clinical experience described in previous publications (Dean et al., 2001; Di Lazzaro et al., 2004; Labar, personal communication), it appears that single-pulse TMS can be safely applied to individuals who have an implanted VNS device.
Acknowledgements For their generous support, the authors wish to thank the Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson-Lovelace Foundation, The Ahmanson Foundation, Tamkin Foundation, Jennifer Jones-Simon Foundation, Capital Group Companies Charitable Foundation, Robson Family, William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community Foundation, Northstar Fund, and the National Center for Research Resources grants RR12169, RR13642 and RR08655. The authors also thank Cyberonics, Inc. for providing the VNS device. This work was also supported in part by a grant from the American Academy of Neurology Foundation.
References Abarbanel JM, Lemberg T, Yaroslavski U, Grisaru N, Belmaker RH. Electrophysiological responses to transcranial magnetic stimulation in depression and schizophrenia. Biol Psychiatry 1996;40(2):148–50. Agnew WF, McCreery DB. Considerations for safety with chronically implanted nerve electrodes. Epilepsia 1990;31(Suppl. 2):S27–S32. Agnew WF, McCreery DB, Yuen TG, Bullara LA. Histologic and physiologic evaluation of electrically stimulated peripheral nerve: considerations for the selection of parameters. Ann Biomed Eng 1989; 17(1):39–60.
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L.M. Schrader et al. / Clinical Neurophysiology 116 (2005) 2501–2504
Agnew WF, McCreery DB, Yuen TG, Bullara LA. Local anaesthetic block protects against electrically-induced damage in peripheral nerve. J Biomed Eng 1990;12(4):301–8. Dean AC, Wu AT, Burgut FT, Labar DR. Motor cortex excitability in epilepsy patients treated with vagus nerve stimulation. Epilepsia 2001; 42(Suppl. 7):42. Di Lazzaro V, Oliviero A, Pilato F, Saturno E, Dileone M, Meglio M, Colicchio G, Barba D, Papacci F, Tonali PA. Effects of vagus nerve stimulation on cortical excitability in epileptic patients. Neurology 2004;62(12):2310–2. Gershon AA, Dannon PN, Grunhaus L. Transcranial magnetic stimulation in the treatment of depression. Am J Psychiatry 2003;160(5):835–45.
Keel JC, Smith MJ, Wassermann EM. A safety screening questionnaire for transcranial magnetic stimulation. Clin Neurophysiol 2000;112:720. Maeda F, Keenan JP, Pascual-Leone A. Interhemispheric asymmetry of motor cortical excitability in major depression as measured by transcranial magnetic stimulation. Br J Psychiatry 2000;177:169–73. McCreery DB, Agnew WF, Yuen TG, Bullara LA. Relationship between stimulus amplitude, stimulus frequency and neural damage during electrical stimulation of sciatic nerve of cat. Med Biol Eng Comput 1995;33(3 Spec No):426–9. Tassinari CA, Cincotta M, Zaccara G, Michelucci R. Transcranial magnetic stimulation and epilepsy. Clin Neurophysiol 2003;114(5): 777–98.