Brain Stimulation xxx (2015) 1e3
Contents lists available at ScienceDirect
Brain Stimulation journal homepage: www.brainstimjrnl.com
Letter to the Editor
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 subdural electrodes (ScTBS) and the IPG (Activa PC, by Medtronic, MN, USA). The patient is a 75-year-old right-handed woman with a 50-year history of ET affecting mostly her upper limbs. Ten years ago, the patient underwent left subdural MCS with marked improvement in her contralateral upper limb tremor; four years later she received right subdural MCS, with beneficial tremor reduction of her left hand. Detailed clinical assessments up to 5 years after the first surgery have been described elsewhere (Patient 1) [5]. Recently, the patient started to complain worsening of upper limbs tremor (right > left) with an important impact on her activities of daily living. She also reported a sort of habituation of tremor to continuous MCS, partially relieved by turning off the stimulation for few days. At that time her chronic stimulation settings were as follows: left MCS, 4.0 V/60 ms/130 Hz, contacts 0þ and 1; right MCS, 4.5 V/60 ms/130 Hz, contacts 3þ and 2. In order to obtain a stronger inhibitory effect on M1, we trialed the patient with stimulation parameters matching the cTBS protocol. By using the cyclic mode embedded in the IPG, five 50-Hz pulses lasting 60 ms were delivered every 200 ms (4.0 V/60 ms/50 Hz, Cycling On/Off: 0.1/ 0.2 s). This new stimulation protocol induced a definite improvement in hand tremor, greater than the one used at baseline (Video 1). Although the patient reported an habituation to the baseline settings, they were clearly still quite effective as compared to off
1935-861X/Ó 2015 Published by Elsevier Inc.
stimulation (Video 1). A double-blind evaluation of tremor during 3 different conditions of stimulation was then performed over two different mornings: the first condition was stimulation off for 12 h; the second condition was 1 month of continuous ScTBS, and the third condition was the stimulation back to baseline parameters 30 min after the switch (Fig. 1). Bilateral ScTBS provided the most effective tremor control on both objective and subjective assessments. The patient is currently using ScTBS since three months with sustained benefit, no side effects and no evidence of habituation. Of note, she has not been turning the stimulation off for few days anymore. A limitation of the study is that baseline and ScTBS conditions were not matched and, thus, we cannot exclude the influence of an order effect. This preliminary experience suggests that the direct stimulation of the cortex with the cTBS paradigm can further enhance the ET improvement initially described with MCS [5]. The exact mechanisms of action remain speculative, though a plasticity effect has been hypothesized [3,4]. Interestingly, this “patterned” form of stimulation appears to be more efficient in producing long-term potentiation/depression effects in brain slice preparations compared to constant frequency stimulation [6]. It is additionally possible that, similarly to other forms of noninvasive brain stimulation techniques delivered at intensities below those needed for synaptic activation, like transcranial alternating current stimulation, ScTBS might induce subthreshold changes in the membrane potentials of affected neurons, thus altering their firing rate [7]. Further studies are needed to fully understand the clinical utility of invasive chronic ScTBS in ET patients. Supplementary video related to this article can be found at http://dx.doi.org/10.1016/j.brs.2015.05.003. Conflict of interest: None. Authors contributions: Marina Picillo organized and executed the study and drafted the manuscript. Elena Moro, Mark Edwards, Vincenzo Di Lazzaro, Andres M. Lozano revised the manuscript for intellectual content. Alfonso Fasano conceived and designed the study and drafted and revised the manuscript for intellectual content. Study funding: No targeted funding reported. Full financial disclosures: MP received salary from the University of Salerno, Italy and research grants from the Division of Neurology e University of Toronto and the Michael J. Fox Foundation. EM has received honoraria from Medtronicfor consulting service and lecturing. ME receives funding from NIHR, Parkinson’s UK and the Medical Research Council. VDL received personal fees from Medtronic during the conduct of the Crystal study. AML received speaker and/or consulting honoraria fromBoston Scientific, Medtronic, St. Jude, Schering, Elekta, InSightec; he is the co-founder ofFunctional Neuromodulation Ltd and deputy editor of Brain Stimulation Journal. AF received speaker and/or consulting honoraria from Abbvie, Boston Scientific, Chiesi pharmaceuticals, Medtronic, TEVA Canada, UCB pharma and research grants from NeurecaOnlus, AFaR, the Division of Neurology e University of Toronto and the Michael J. Fox Foundation. He is in the editorial board of BioMed Research International, Case Reports in Neurological Medicine and Plos One.
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Letter to the Editor / Brain Stimulation xxx (2015) 1e3
Figure 1. Clinical double-blind evaluation of the 3 different stimulation conditions. A) Clinical evaluations of both upper limbs with the Fahn-Tolosa-Marin Tremor Rating Scale; B) Postural tremor frequency for both hands; C) Postural tremor power for both hands; D) Spiral recordings for the right hand; E) Spiral recordings for the left hand; F) Significant reduction in the pressure on the paper for both hands (Kruscal Wallis test: P < 0.001). Tremor frequency and power were assessed by means a portable accelerometer (Axon MM-1 movement monitor, Axon Instruments, Inc.). The spirals were drawn on a digitizing tablet (Wacom Intuos 3 Model PTZ-930; Wacom Technology Corporation, Vancouver, WA), connected to a laptop and analyzed using an MS Windows-based software package (Neuroglyphics, developed by Camilo Toro, MD; available at: http://www.neuroglyphics. org). The digitized spirals included air points, x, y coordinates of the pen tip position within 6 mm of the tablet surface. The entire stream of position points during spiral execution was stored in binary format for off-line analysis [8].
Marina Picillo Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s Disease Toronto Western Hospital, Toronto, ON, Canada
Alfonso Fasano* Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, Toronto, ON, Canada Division of Neurology, University of Toronto, Toronto, ON, Canada
Division of Neurology, University of Toronto, Toronto, ON, Canada Centre for Neurodegenerative Diseases (CEMAND) Department of Medicine and Surgery, University of Salerno Salerno, Italy Elena Moro Service de Neurologie, CHU Grenoble, Joseph Fourier University INSERM U836, Grenoble, France Mark Edwards UCL Institute of Neurology, Queen Square, London, UK Vincenzo Di Lazzaro Institute of Neurology, Campus Bio Medico University, Rome, Italy Andres M. Lozano Division of Neurosurgery Toronto Western Hospital e UHN University of Toronto, Toronto, ON, Canada
* Corresponding author. Division of Neurology, University of Toronto, Movement Disorders Centre, Toronto Western Hospital , 399 Bathurst St, 7 Mc412, Toronto, ON, Canada M5T 2S8. Tel.: þ1 416 603 5800x5961; fax: þ1 416 603 5004. E-mail address: [email protected]
Received 2 May 2015 Available online xxx http://dx.doi.org/10.1016/j.brs.2015.05.003
References [1] Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron 2005;45:201e6. [2] Halliday DM, Conway BA, Farmer SF, Shahani U, Russell AJ, Rosenberg JR. Coherence between low-frequency activation of the motor cortex and tremor in patients with essential tremor. Lancet 2000;355:1149e53.
Letter to the Editor / Brain Stimulation xxx (2015) 1e3 [3] Chuang WL, Huang YZ, Lu CS, Chen RS. Reduced cortical plasticity and GABAergic modulation in essential tremor. Mov Disord 2014;29:501e7. [4] Hellriegel H, Schulz EM, Siebner HR, Deuschl G, Raethjen JH. Continuous thetaburst stimulation of the primary motor cortex in essential tremor. Clin Neurophysiol 2012;123:1010e5. [5] Moro E, Schwalb JM, Piboolnurak P, et al. Unilateral subdural motor cortex stimulation improves essential tremor but not Parkinson’s disease. Brain 2011;134: 2096e105.
3
[6] Larson J, Wong D, Lynch G. Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Res 1986;368(2):347e50. [7] Brittain J-S, Probert-Smith P, Aziz TZ, Brown P. Tremor suppression by rhythmic transcranial current stimulation. Curr Biol 2013;23(5):436e40. [8] Haubenberger D, Kalowitz D, Nahab FB, Toro C, Ippolito D, Luckenbaugh DA, et al. Validation of digital spiral analysis as outcome parameter for clinical trials in essential tremor. Mov Disord 2011;26(11):2073e80.
Contents lists available at ScienceDirect
Brain Stimulation journal homepage: www.brainstimjrnl.com
Letter to the Editor
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 subdural electrodes (ScTBS) and the IPG (Activa PC, by Medtronic, MN, USA). The patient is a 75-year-old right-handed woman with a 50-year history of ET affecting mostly her upper limbs. Ten years ago, the patient underwent left subdural MCS with marked improvement in her contralateral upper limb tremor; four years later she received right subdural MCS, with beneficial tremor reduction of her left hand. Detailed clinical assessments up to 5 years after the first surgery have been described elsewhere (Patient 1) [5]. Recently, the patient started to complain worsening of upper limbs tremor (right > left) with an important impact on her activities of daily living. She also reported a sort of habituation of tremor to continuous MCS, partially relieved by turning off the stimulation for few days. At that time her chronic stimulation settings were as follows: left MCS, 4.0 V/60 ms/130 Hz, contacts 0þ and 1; right MCS, 4.5 V/60 ms/130 Hz, contacts 3þ and 2. In order to obtain a stronger inhibitory effect on M1, we trialed the patient with stimulation parameters matching the cTBS protocol. By using the cyclic mode embedded in the IPG, five 50-Hz pulses lasting 60 ms were delivered every 200 ms (4.0 V/60 ms/50 Hz, Cycling On/Off: 0.1/ 0.2 s). This new stimulation protocol induced a definite improvement in hand tremor, greater than the one used at baseline (Video 1). Although the patient reported an habituation to the baseline settings, they were clearly still quite effective as compared to off
1935-861X/Ó 2015 Published by Elsevier Inc.
stimulation (Video 1). A double-blind evaluation of tremor during 3 different conditions of stimulation was then performed over two different mornings: the first condition was stimulation off for 12 h; the second condition was 1 month of continuous ScTBS, and the third condition was the stimulation back to baseline parameters 30 min after the switch (Fig. 1). Bilateral ScTBS provided the most effective tremor control on both objective and subjective assessments. The patient is currently using ScTBS since three months with sustained benefit, no side effects and no evidence of habituation. Of note, she has not been turning the stimulation off for few days anymore. A limitation of the study is that baseline and ScTBS conditions were not matched and, thus, we cannot exclude the influence of an order effect. This preliminary experience suggests that the direct stimulation of the cortex with the cTBS paradigm can further enhance the ET improvement initially described with MCS [5]. The exact mechanisms of action remain speculative, though a plasticity effect has been hypothesized [3,4]. Interestingly, this “patterned” form of stimulation appears to be more efficient in producing long-term potentiation/depression effects in brain slice preparations compared to constant frequency stimulation [6]. It is additionally possible that, similarly to other forms of noninvasive brain stimulation techniques delivered at intensities below those needed for synaptic activation, like transcranial alternating current stimulation, ScTBS might induce subthreshold changes in the membrane potentials of affected neurons, thus altering their firing rate [7]. Further studies are needed to fully understand the clinical utility of invasive chronic ScTBS in ET patients. Supplementary video related to this article can be found at http://dx.doi.org/10.1016/j.brs.2015.05.003. Conflict of interest: None. Authors contributions: Marina Picillo organized and executed the study and drafted the manuscript. Elena Moro, Mark Edwards, Vincenzo Di Lazzaro, Andres M. Lozano revised the manuscript for intellectual content. Alfonso Fasano conceived and designed the study and drafted and revised the manuscript for intellectual content. Study funding: No targeted funding reported. Full financial disclosures: MP received salary from the University of Salerno, Italy and research grants from the Division of Neurology e University of Toronto and the Michael J. Fox Foundation. EM has received honoraria from Medtronicfor consulting service and lecturing. ME receives funding from NIHR, Parkinson’s UK and the Medical Research Council. VDL received personal fees from Medtronic during the conduct of the Crystal study. AML received speaker and/or consulting honoraria fromBoston Scientific, Medtronic, St. Jude, Schering, Elekta, InSightec; he is the co-founder ofFunctional Neuromodulation Ltd and deputy editor of Brain Stimulation Journal. AF received speaker and/or consulting honoraria from Abbvie, Boston Scientific, Chiesi pharmaceuticals, Medtronic, TEVA Canada, UCB pharma and research grants from NeurecaOnlus, AFaR, the Division of Neurology e University of Toronto and the Michael J. Fox Foundation. He is in the editorial board of BioMed Research International, Case Reports in Neurological Medicine and Plos One.
2
Letter to the Editor / Brain Stimulation xxx (2015) 1e3
Figure 1. Clinical double-blind evaluation of the 3 different stimulation conditions. A) Clinical evaluations of both upper limbs with the Fahn-Tolosa-Marin Tremor Rating Scale; B) Postural tremor frequency for both hands; C) Postural tremor power for both hands; D) Spiral recordings for the right hand; E) Spiral recordings for the left hand; F) Significant reduction in the pressure on the paper for both hands (Kruscal Wallis test: P < 0.001). Tremor frequency and power were assessed by means a portable accelerometer (Axon MM-1 movement monitor, Axon Instruments, Inc.). The spirals were drawn on a digitizing tablet (Wacom Intuos 3 Model PTZ-930; Wacom Technology Corporation, Vancouver, WA), connected to a laptop and analyzed using an MS Windows-based software package (Neuroglyphics, developed by Camilo Toro, MD; available at: http://www.neuroglyphics. org). The digitized spirals included air points, x, y coordinates of the pen tip position within 6 mm of the tablet surface. The entire stream of position points during spiral execution was stored in binary format for off-line analysis [8].
Marina Picillo Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s Disease Toronto Western Hospital, Toronto, ON, Canada
Alfonso Fasano* Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, Toronto, ON, Canada Division of Neurology, University of Toronto, Toronto, ON, Canada
Division of Neurology, University of Toronto, Toronto, ON, Canada Centre for Neurodegenerative Diseases (CEMAND) Department of Medicine and Surgery, University of Salerno Salerno, Italy Elena Moro Service de Neurologie, CHU Grenoble, Joseph Fourier University INSERM U836, Grenoble, France Mark Edwards UCL Institute of Neurology, Queen Square, London, UK Vincenzo Di Lazzaro Institute of Neurology, Campus Bio Medico University, Rome, Italy Andres M. Lozano Division of Neurosurgery Toronto Western Hospital e UHN University of Toronto, Toronto, ON, Canada
* Corresponding author. Division of Neurology, University of Toronto, Movement Disorders Centre, Toronto Western Hospital , 399 Bathurst St, 7 Mc412, Toronto, ON, Canada M5T 2S8. Tel.: þ1 416 603 5800x5961; fax: þ1 416 603 5004. E-mail address: [email protected]
Received 2 May 2015 Available online xxx http://dx.doi.org/10.1016/j.brs.2015.05.003
References [1] Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron 2005;45:201e6. [2] Halliday DM, Conway BA, Farmer SF, Shahani U, Russell AJ, Rosenberg JR. Coherence between low-frequency activation of the motor cortex and tremor in patients with essential tremor. Lancet 2000;355:1149e53.
Letter to the Editor / Brain Stimulation xxx (2015) 1e3 [3] Chuang WL, Huang YZ, Lu CS, Chen RS. Reduced cortical plasticity and GABAergic modulation in essential tremor. Mov Disord 2014;29:501e7. [4] Hellriegel H, Schulz EM, Siebner HR, Deuschl G, Raethjen JH. Continuous thetaburst stimulation of the primary motor cortex in essential tremor. Clin Neurophysiol 2012;123:1010e5. [5] Moro E, Schwalb JM, Piboolnurak P, et al. Unilateral subdural motor cortex stimulation improves essential tremor but not Parkinson’s disease. Brain 2011;134: 2096e105.
3
[6] Larson J, Wong D, Lynch G. Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Res 1986;368(2):347e50. [7] Brittain J-S, Probert-Smith P, Aziz TZ, Brown P. Tremor suppression by rhythmic transcranial current stimulation. Curr Biol 2013;23(5):436e40. [8] Haubenberger D, Kalowitz D, Nahab FB, Toro C, Ippolito D, Luckenbaugh DA, et al. Validation of digital spiral analysis as outcome parameter for clinical trials in essential tremor. Mov Disord 2011;26(11):2073e80.
