Letters to the Editor / Brain Stimulation 8 (2015) 838e849
hypothesis of AD as a proteopathy with prion-like propagation is pivotal [8]. Physiological considerations provide evidence about the compatibility of both, the protein and the cholinergic hypotheses. Increased neuronal firing of the NBM provides a steady neocortical background activity that may modulate the influence of other afferents to the neocortex. Furthermore, cholinergic neurons may indirectly influence the Ab concentration in the cerebral cortex [9]. Particularly, the activation of the cholinergic muscarinic M1 receptor can effect a reduction of the neurotoxic Ab production and concentration in the cerebrospinal fluid [10]. Thus, stimulation of the NBM and its cholinergic output to the cortex could potentially slow down the development of neurotoxic Ab plaques. In summary our results and previous experimental research are supporting the attempt of DBS treatment in dementia with the aim to modulate cholinergic input and possibly via M1 receptor stimulation even the production of Ab. The study was supported by grants from the Marga and Walter Boll Foundation (Grant no. 210-07-09 (A)) and Medtronic Europe SARL.
Jens Kuhn*1 Katja Hardenacke1 Elena Shubina University of Cologne, Department of Psychiatry and Psychotherapy, Cologne, Germany Doris Lenartz Veerle Visser-Vandewalle University of Cologne, Department of Functional Neurosurgery and Stereotaxy, Cologne, Germany Karl Zilles Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Juelich, Germany Volker Sturm University Clinic of Würzburg, Department of Neurosurgery, Würzburg, Germany Hans-Joachim Freund Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Juelich, Germany * Corresponding author. Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany. Tel.: þ49 221 478 4005. E-mail address: [email protected] (J. Kuhn)
Received 26 February 2015 Available online 13 May 2015 http://dx.doi.org/10.1016/j.brs.2015.04.002
References [1] Hardenacke K, Shubina E, Buhrle CP, et al. Deep brain stimulation as a tool for improving cognitive functioning in Alzheimer’s dementia: a systematic review. Front Psychiatry 2013;4:159. [2] Hamani C, McAndrews MP, Cohn M, et al. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol 2008;63(1):119e23. [3] Freund HJ, Kuhn J, Lenartz D, et al. Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation. Arch Neurol 2009;66(6):781e5. 1
Shared first authorship.
839
[4] Laxton AW, Tang-Wai DF, McAndrews MP, et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann Neurol 2010; 68(4):521e34. [5] Kuhn J, Hardenacke K, Lenartz D, et al. Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer’s dementia. Mol Psychiatry 2014;20(3):353e60. [6] Gillette-Guyonnet S, Andrieu S, Nourhashemi F, et al. Long-term progression of Alzheimer’s disease in patients under antidementia drugs. Alzheimers Dement 2011;7(6):579e92. [7] Hardenacke K, Kuhn J, Lenartz D, et al. Stimulate or degenerate: deep brain stimulation of the nucleus basalis Meynert in Alzheimer dementia. World Neurosurg 2013;80(3e4). S27 e35e43. [8] Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 2013;501(7465):45e51. [9] Ovsepian SV, Herms J. Cholinergic neurons-keeping check on amyloid beta in the cerebral cortex. Front Cell Neurosci 2013;7:252. [10] Nitsch RM, Deng M, Tennis M, Schoenfeld D, Growdon JH. The selective muscarinic M1 agonist AF102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 2000;48(6):913e8.
Transcranial Direct Current Stimulation Against Sudden Unexpected Death in Epilepsy: Press That Button Again, Please Dear Editor, We read with great interest a very comprehensive article titled “Transcranial Direct Current Stimulation in Epilepsy” by San-Juan and colleagues [1] published recently in Brain Stimulation. Given the dearth of published data about associations between transcranial direct current stimulation (tDCS) and epilepsy, we applaud Dr. San-Juan and his collaborators for pursuing this topic [1]. In this context, it is important to address a new perspective from their information. Epilepsy is a common, chronic, serious neurological disease affecting approximately 65 million people worldwide [2]. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in individuals with refractory epilepsy [2e7]. SUDEP is defined as a sudden, unexpected, witnessed or unwitnessed, nontraumatic and nondrowning death in patients with epilepsy, with or without evidence of a seizure and excluding documented status epilepticus, in which post mortem examination did not reveal a toxicological or anatomical cause of death [3]. SUDEP is responsible for 7.5%e17% of all deaths in people with epilepsy and has an incidence among adults between 1:500 and 1:1000 patient-years [2,4e7]. SUDEP risk factors include the presence of generalized toniceclonic seizures (GTCS), young age at epilepsy onset, longer duration of epilepsy, dementia, absence of cerebrovascular disease, asthma, male gender, symptomatic etiology of epilepsy, alcohol abuse and nocturnal seizures [4e7]. An exclusive mechanism is not established for SUDEP, but evidence suggests that the major problem is the autonomic system, i.e., respiratory and/or cardiovascular abnormalities during and after seizures [6,7]. Although it is well established that SUDEP mainly occurs in refractory epilepsy [7], our understanding of the best way to prevent it is still unsatisfactory. Some measures to minimize the risk of SUDEP include good seizure control, stress reduction, participation in physical activity and sports (with appropriate professional supervision), dietary management (omega-3 supplementation), night supervision, family members’ knowledge of cardiopulmonary resuscitation techniques and the basics of defibrillator use [7,8].
840
Letters to the Editor / Brain Stimulation 8 (2015) 838e849
The most important known and described risk factor for SUDEP is the occurrence and frequency of generalized toniceclonic seizures (GTCS), a seizure type that triggers the vast majority of witnessed SUDEP cases [9]. In this sense, one likely way to prevent SUDEP is to reduce the risk of GTCS with optimal medical management and patient education [9]. Obviously, this is a true, realistic and relevant proposal. In another sense, we must also consider that despite expanded pharmacological and surgical treatments for epilepsy, they are still limited in clinical efficacy. In this context, the desire to find alternative treatments for untreatable epilepsy has led epileptologists to look for alternatives such as tDCS. The review by San-Juan and co-workers [1], about the efficacy and safety of tDCS in epilepsy in humans and animals, clearly shows the current state of the art. They analyzed 9 articles with different methodologies (3 animals/6 humans) with 174 stimulated individuals; 109 animals and 65 humans [1]. In addition, in vivo and in vitro animal studies showed that direct current stimulation can successfully induce suppression of epileptiform activity without neurological injury and 4/6 (67%) clinical studies showed an very effective decrease in epileptic seizures and 5/6 (83%) reduction of inter-ictal epileptiform activity [1]. Furthermore, all patients evaluated tolerated tDCS well [1]. The authors concluded that, despite these data, further larger studies are needed to define the best stimulation protocols and long-term follow-up. tDCS trials have demonstrated preliminary safety and efficacy in animals and patients with epilepsy [1]. On the whole, how inspiring are these tDCS in epilepsy results to the phenomenon of SUDEP? First, tDCS has been the subject of great interest among researchers because of its ease of use, low cost, and benign side effect profile. This interest has generated several studies and randomized clinical trials, particularly in neuropsychiatry, including epilepsy [10]. Second, tDCS reduced seizure frequency and thus potentially reduced the need of hospitalization in people with some type of refractory epilepsies, and it should be considered as an option in countries with limited resources. Third and most promising, because the main risk factor for SUDEP is the high frequency of uncontrolled seizures and that tDCS was able to reduce substantially this frequency, it is possible that tDCS might be considered a line of defense against SUDEP. For instance, a tDCS-EEG system could be used to abort the occurrence of a GTCS by triggering the application of a DC stimulation prior to the seizure onset. Also, home-use tDCS devices could be used in high-risk patients to further decrease the occurrence of GTCS. Finally, we are sure that this is only a first step in a long journey. Obviously, further studies are needed to identify the specific and appropriate individuals for tDCS in epilepsy, and especially, carefully assess whether all this experimental and clinical effort will be able to prevent this tragic event, SUDEP, that should not be overlooked in epilepsy. This study has been supported by the following grants: FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo, JP 2012/20911-5); CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico); CEPID/FAPESP; FAPESP/ PRONEX, NARSAD (YI 13/20493) and FAPESP/CNPq/MCT (Instituto Nacional de Neurociência Translacional).
Fulvio A. Scorza Laboratory of Neuroscience, Department of Neurology and Neurosurgery, Paulista School of Medicine/Federal University of São Paulo (EPM/UNIFESP), São Paulo, Brazil André R. Brunoni* Center for Clinical and Epidemiological Research &Interdisciplinary Center for Applied Neuromodulation (CINA), University Hospital, University of São Paulo, São Paulo, Brazil
Service of Interdisciplinary Neuromodulation (SIN), Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine of University of São Paulo, São Paulo, Brazil author. Av. Prof. Lineu Prestes 2565, 3o andar, CEP 05508-000 São Paulo, SP, Brazil. Tel.: þ55 11 30919241. E-mail address: [email protected] (A.R. Brunoni)
* Corresponding
Received 5 April 2015 Available online 13 May 2015 http://dx.doi.org/10.1016/j.brs.2015.04.006
References [1] San-Juan D, Morales-Quezada L, Orozco Garduño AJ, et al. Transcranial direct current stimulation in epilepsy. Brain Stimul; 2015. http://dx.doi.org/10.1016/ j.brs.2015.01.001 (in press). [2] Moshé SL, Perucca E, Ryvlin P, Tomson T. Epilepsy: new advances. Lancet 2015 Mar 7;385(9971):884e98. [3] Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in epilepsy. Epilepsia 2012;53(2):227e33. [4] Hesdorffer DC, Tomson T. Sudden unexpected death in epilepsy: potential role of antiepileptic drugs. CNS Drugs 2013;27(2):113e9. [5] Hesdorffer DC, Tomson T, Benn E, et al. Commission on Epidemiology; Subcommission on Mortality. Combined analysis of risk factors for SUDEP. Epilepsia 2011;52(6):1150e9. [6] Surges R, Thijs RD, Tan HL, Sander JW. Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms. Nat Rev Neurol 2009;5(9): 492e504. [7] Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008; 7(11):1021e31. [8] Scorza FA, Arida RM, Terra VC, Cavalheiro EA. What can be done to reduce the risk of SUDEP? Epilepsy Behav 2010;18(3):137e8. [9] Ryvlin P, Nashef L, Tomson T. Prevention of sudden unexpected death in epilepsy: a realistic goal? Epilepsia 2013;(Suppl. 2):23e8. [10] Tortella G, Casati R, Aparicio LV, et al. Transcranial direct current stimulation in psychiatric disorders. World J Psychiatry 2015;5(1):88e102.
Subdural Continuous Theta Burst Stimulation of the Motor Cortex in Essential Tremor Continuous theta-burst stimulation (cTBS) using short bursts of low-intensity, high-frequency (50 Hz), pulses repeated every 200 ms is a repetitive transcranial magnetic stimulation (rTMS) protocol with inhibitory effects on human cortex [1]. Several studies suggested a role for the primary motor cortex (M1) within the central oscillatory network generating Essential Tremor (ET) [2]. Accordingly, recent studies have demonstrated that cTBS over M1 leads to a small and transient reduction of the tremor amplitude in ET patients [3,4]. In order to have a sustained clinical benefit, invasive motor cortex stimulation (MCS) with subdural electrodes connected to an implantable pulse generator (IPG) has been successfully tested in 6 ET patients [5]. In this preliminary experience, no specific parameters of stimulation were more effective than others, although frequencies >50 Hz were initially more effective whereas lower frequencies led to better tremor control in the long-term for some patients [5]. We have applied a cTBS protocol to the first ET patient with subdural MCS enrolled in the original study [5] using the implanted
hypothesis of AD as a proteopathy with prion-like propagation is pivotal [8]. Physiological considerations provide evidence about the compatibility of both, the protein and the cholinergic hypotheses. Increased neuronal firing of the NBM provides a steady neocortical background activity that may modulate the influence of other afferents to the neocortex. Furthermore, cholinergic neurons may indirectly influence the Ab concentration in the cerebral cortex [9]. Particularly, the activation of the cholinergic muscarinic M1 receptor can effect a reduction of the neurotoxic Ab production and concentration in the cerebrospinal fluid [10]. Thus, stimulation of the NBM and its cholinergic output to the cortex could potentially slow down the development of neurotoxic Ab plaques. In summary our results and previous experimental research are supporting the attempt of DBS treatment in dementia with the aim to modulate cholinergic input and possibly via M1 receptor stimulation even the production of Ab. The study was supported by grants from the Marga and Walter Boll Foundation (Grant no. 210-07-09 (A)) and Medtronic Europe SARL.
Jens Kuhn*1 Katja Hardenacke1 Elena Shubina University of Cologne, Department of Psychiatry and Psychotherapy, Cologne, Germany Doris Lenartz Veerle Visser-Vandewalle University of Cologne, Department of Functional Neurosurgery and Stereotaxy, Cologne, Germany Karl Zilles Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Juelich, Germany Volker Sturm University Clinic of Würzburg, Department of Neurosurgery, Würzburg, Germany Hans-Joachim Freund Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, Juelich, Germany * Corresponding author. Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany. Tel.: þ49 221 478 4005. E-mail address: [email protected] (J. Kuhn)
Received 26 February 2015 Available online 13 May 2015 http://dx.doi.org/10.1016/j.brs.2015.04.002
References [1] Hardenacke K, Shubina E, Buhrle CP, et al. Deep brain stimulation as a tool for improving cognitive functioning in Alzheimer’s dementia: a systematic review. Front Psychiatry 2013;4:159. [2] Hamani C, McAndrews MP, Cohn M, et al. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol 2008;63(1):119e23. [3] Freund HJ, Kuhn J, Lenartz D, et al. Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation. Arch Neurol 2009;66(6):781e5. 1
Shared first authorship.
839
[4] Laxton AW, Tang-Wai DF, McAndrews MP, et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. Ann Neurol 2010; 68(4):521e34. [5] Kuhn J, Hardenacke K, Lenartz D, et al. Deep brain stimulation of the nucleus basalis of Meynert in Alzheimer’s dementia. Mol Psychiatry 2014;20(3):353e60. [6] Gillette-Guyonnet S, Andrieu S, Nourhashemi F, et al. Long-term progression of Alzheimer’s disease in patients under antidementia drugs. Alzheimers Dement 2011;7(6):579e92. [7] Hardenacke K, Kuhn J, Lenartz D, et al. Stimulate or degenerate: deep brain stimulation of the nucleus basalis Meynert in Alzheimer dementia. World Neurosurg 2013;80(3e4). S27 e35e43. [8] Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 2013;501(7465):45e51. [9] Ovsepian SV, Herms J. Cholinergic neurons-keeping check on amyloid beta in the cerebral cortex. Front Cell Neurosci 2013;7:252. [10] Nitsch RM, Deng M, Tennis M, Schoenfeld D, Growdon JH. The selective muscarinic M1 agonist AF102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 2000;48(6):913e8.
Transcranial Direct Current Stimulation Against Sudden Unexpected Death in Epilepsy: Press That Button Again, Please Dear Editor, We read with great interest a very comprehensive article titled “Transcranial Direct Current Stimulation in Epilepsy” by San-Juan and colleagues [1] published recently in Brain Stimulation. Given the dearth of published data about associations between transcranial direct current stimulation (tDCS) and epilepsy, we applaud Dr. San-Juan and his collaborators for pursuing this topic [1]. In this context, it is important to address a new perspective from their information. Epilepsy is a common, chronic, serious neurological disease affecting approximately 65 million people worldwide [2]. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in individuals with refractory epilepsy [2e7]. SUDEP is defined as a sudden, unexpected, witnessed or unwitnessed, nontraumatic and nondrowning death in patients with epilepsy, with or without evidence of a seizure and excluding documented status epilepticus, in which post mortem examination did not reveal a toxicological or anatomical cause of death [3]. SUDEP is responsible for 7.5%e17% of all deaths in people with epilepsy and has an incidence among adults between 1:500 and 1:1000 patient-years [2,4e7]. SUDEP risk factors include the presence of generalized toniceclonic seizures (GTCS), young age at epilepsy onset, longer duration of epilepsy, dementia, absence of cerebrovascular disease, asthma, male gender, symptomatic etiology of epilepsy, alcohol abuse and nocturnal seizures [4e7]. An exclusive mechanism is not established for SUDEP, but evidence suggests that the major problem is the autonomic system, i.e., respiratory and/or cardiovascular abnormalities during and after seizures [6,7]. Although it is well established that SUDEP mainly occurs in refractory epilepsy [7], our understanding of the best way to prevent it is still unsatisfactory. Some measures to minimize the risk of SUDEP include good seizure control, stress reduction, participation in physical activity and sports (with appropriate professional supervision), dietary management (omega-3 supplementation), night supervision, family members’ knowledge of cardiopulmonary resuscitation techniques and the basics of defibrillator use [7,8].
840
Letters to the Editor / Brain Stimulation 8 (2015) 838e849
The most important known and described risk factor for SUDEP is the occurrence and frequency of generalized toniceclonic seizures (GTCS), a seizure type that triggers the vast majority of witnessed SUDEP cases [9]. In this sense, one likely way to prevent SUDEP is to reduce the risk of GTCS with optimal medical management and patient education [9]. Obviously, this is a true, realistic and relevant proposal. In another sense, we must also consider that despite expanded pharmacological and surgical treatments for epilepsy, they are still limited in clinical efficacy. In this context, the desire to find alternative treatments for untreatable epilepsy has led epileptologists to look for alternatives such as tDCS. The review by San-Juan and co-workers [1], about the efficacy and safety of tDCS in epilepsy in humans and animals, clearly shows the current state of the art. They analyzed 9 articles with different methodologies (3 animals/6 humans) with 174 stimulated individuals; 109 animals and 65 humans [1]. In addition, in vivo and in vitro animal studies showed that direct current stimulation can successfully induce suppression of epileptiform activity without neurological injury and 4/6 (67%) clinical studies showed an very effective decrease in epileptic seizures and 5/6 (83%) reduction of inter-ictal epileptiform activity [1]. Furthermore, all patients evaluated tolerated tDCS well [1]. The authors concluded that, despite these data, further larger studies are needed to define the best stimulation protocols and long-term follow-up. tDCS trials have demonstrated preliminary safety and efficacy in animals and patients with epilepsy [1]. On the whole, how inspiring are these tDCS in epilepsy results to the phenomenon of SUDEP? First, tDCS has been the subject of great interest among researchers because of its ease of use, low cost, and benign side effect profile. This interest has generated several studies and randomized clinical trials, particularly in neuropsychiatry, including epilepsy [10]. Second, tDCS reduced seizure frequency and thus potentially reduced the need of hospitalization in people with some type of refractory epilepsies, and it should be considered as an option in countries with limited resources. Third and most promising, because the main risk factor for SUDEP is the high frequency of uncontrolled seizures and that tDCS was able to reduce substantially this frequency, it is possible that tDCS might be considered a line of defense against SUDEP. For instance, a tDCS-EEG system could be used to abort the occurrence of a GTCS by triggering the application of a DC stimulation prior to the seizure onset. Also, home-use tDCS devices could be used in high-risk patients to further decrease the occurrence of GTCS. Finally, we are sure that this is only a first step in a long journey. Obviously, further studies are needed to identify the specific and appropriate individuals for tDCS in epilepsy, and especially, carefully assess whether all this experimental and clinical effort will be able to prevent this tragic event, SUDEP, that should not be overlooked in epilepsy. This study has been supported by the following grants: FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo, JP 2012/20911-5); CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico); CEPID/FAPESP; FAPESP/ PRONEX, NARSAD (YI 13/20493) and FAPESP/CNPq/MCT (Instituto Nacional de Neurociência Translacional).
Fulvio A. Scorza Laboratory of Neuroscience, Department of Neurology and Neurosurgery, Paulista School of Medicine/Federal University of São Paulo (EPM/UNIFESP), São Paulo, Brazil André R. Brunoni* Center for Clinical and Epidemiological Research &Interdisciplinary Center for Applied Neuromodulation (CINA), University Hospital, University of São Paulo, São Paulo, Brazil
Service of Interdisciplinary Neuromodulation (SIN), Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry, Faculty of Medicine of University of São Paulo, São Paulo, Brazil author. Av. Prof. Lineu Prestes 2565, 3o andar, CEP 05508-000 São Paulo, SP, Brazil. Tel.: þ55 11 30919241. E-mail address: [email protected] (A.R. Brunoni)
* Corresponding
Received 5 April 2015 Available online 13 May 2015 http://dx.doi.org/10.1016/j.brs.2015.04.006
References [1] San-Juan D, Morales-Quezada L, Orozco Garduño AJ, et al. Transcranial direct current stimulation in epilepsy. Brain Stimul; 2015. http://dx.doi.org/10.1016/ j.brs.2015.01.001 (in press). [2] Moshé SL, Perucca E, Ryvlin P, Tomson T. Epilepsy: new advances. Lancet 2015 Mar 7;385(9971):884e98. [3] Nashef L, So EL, Ryvlin P, Tomson T. Unifying the definitions of sudden unexpected death in epilepsy. Epilepsia 2012;53(2):227e33. [4] Hesdorffer DC, Tomson T. Sudden unexpected death in epilepsy: potential role of antiepileptic drugs. CNS Drugs 2013;27(2):113e9. [5] Hesdorffer DC, Tomson T, Benn E, et al. Commission on Epidemiology; Subcommission on Mortality. Combined analysis of risk factors for SUDEP. Epilepsia 2011;52(6):1150e9. [6] Surges R, Thijs RD, Tan HL, Sander JW. Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms. Nat Rev Neurol 2009;5(9): 492e504. [7] Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008; 7(11):1021e31. [8] Scorza FA, Arida RM, Terra VC, Cavalheiro EA. What can be done to reduce the risk of SUDEP? Epilepsy Behav 2010;18(3):137e8. [9] Ryvlin P, Nashef L, Tomson T. Prevention of sudden unexpected death in epilepsy: a realistic goal? Epilepsia 2013;(Suppl. 2):23e8. [10] Tortella G, Casati R, Aparicio LV, et al. Transcranial direct current stimulation in psychiatric disorders. World J Psychiatry 2015;5(1):88e102.
Subdural Continuous Theta Burst Stimulation of the Motor Cortex in Essential Tremor Continuous theta-burst stimulation (cTBS) using short bursts of low-intensity, high-frequency (50 Hz), pulses repeated every 200 ms is a repetitive transcranial magnetic stimulation (rTMS) protocol with inhibitory effects on human cortex [1]. Several studies suggested a role for the primary motor cortex (M1) within the central oscillatory network generating Essential Tremor (ET) [2]. Accordingly, recent studies have demonstrated that cTBS over M1 leads to a small and transient reduction of the tremor amplitude in ET patients [3,4]. In order to have a sustained clinical benefit, invasive motor cortex stimulation (MCS) with subdural electrodes connected to an implantable pulse generator (IPG) has been successfully tested in 6 ET patients [5]. In this preliminary experience, no specific parameters of stimulation were more effective than others, although frequencies >50 Hz were initially more effective whereas lower frequencies led to better tremor control in the long-term for some patients [5]. We have applied a cTBS protocol to the first ET patient with subdural MCS enrolled in the original study [5] using the implanted
