Letters to the Editor / Brain Stimulation 7 (2014) 486e497
References
491
study protocol was approved by the Hospital Ethics Committee and was performed in accordance with international ethical regulations. All subjects received and signed informed consent to participate. During the trial, dose of anti-tremoric drugs was not changed. The study was double blind, crossover, and placebo-controlled. The tDCS was applied in ten consecutive sessions on working days. Active or sham-tDCS were administered in random order (Latin square design) with a three-month wash-out period. tDCS was administered with the patients at rest without concurrent cognitive or motor task. A battery driven stimulator (Neuroelectrics, Barcelona, Spain), delivered the tDCS through electrodes (saline soaked sponges, surface area 25 cm2). In order to increase the magnitude of the electrical field, we used two cathodal electrodes placed symmetrically over both cerebellar hemispheres (3 cm lateral to the inion). The inion was taken as a landmark of the boundary between the posterior cerebellum and the occipital cortex. We therefore stimulated the area caudal to the inion in order to stimulate the posterior cerebellum. Placement of active electrodes in our study was based on previous studies using rTMS or tDCS that demonstrated effective stimulation of the cerebellum [4,7]. Two anodal electrodes were positioned over both prefrontal areas (Fp1 and Fp2 EEG leads position). In the active-tDCS treatment group, cathodal tDCS (2 mA) was delivered for 20 min. This intensity of stimulation is below the threshold for tissue damage [8]. The stimulator has the possibility to perform sham-tDCS. The electrodes were identically placed as active-tDCS. The sham-tDCS induces a subjective sensation similar to that achieved with active-tDCS, but fails to induce a significant cortical stimulation. We compared results of tremor clinical rating scale (TCRS) [9], accelerometric recordings [10] and a self-reported disability scale (Bain et al.) between study days 1 (before first tDCS session), day 10 (5 min after last tDCS session) and day 40 (30 days after last tDCS session). Additionally, we used a subscale of the clinical rating scale (parts 1 þ 2) and accelerometric recordings to assess the time course of acute tDCS effects, evaluated at day 1 [before first tDCS session, during first tDCS session (10 min), þ5 min, and þ60 min after the first tDCS session]. Statistical analysis was evaluated using parametric tests. Results of TCRS part 4 were analyzed through the non-parametric Wilcoxon matched pairs test. Eight patients completed the study. Table 1 shows the data of the main variables. Clinical scores showed no significant changes (repeated-measures ANOVA) in motor task performance (TCRS parts 1 þ 2), daily living activities (TCRS part 3), or the patients’ subjective assessment (TCRS part 4) and global appraisal between baseline, day 10 and day 40. No significant differences were observed in the analysis of the patients’ subjective assessment, the accelerometry data, or the disability scale. The repeatedmeasures ANOVA also showed no significant acute tDCS effects in any outcome measure. The interaction between time and treatment was also non-significant.
[1] Kaltenbach JA, Zhang J, Zacharek MA. Neural correlates of tinnitus. In: Snow Jr JB, editor. Tinnitus: theory and management. 1st ed. Hamilton, ON: B.C. Decker, Inc; 2004. p. 141e61. [2] Burton H, Wineland A, Bhattacharya M, Nicklaus J, Garcia KS, Piccirillo JF. Altered networks in bothersome tinnitus: a functional connectivity study. BMC Neurosci 2012 Jan 4;13(1):3. [3] Wineland AM, Burton H, Piccirillo J. Functional connectivity networks in nonbothersome tinnitus. Otolaryngol Head Neck Surg 2012;147(5):900e6. [4] Martinez-Devesa P, Perera R, Theodoulou M, Waddell A. Cognitive behavioural therapy for tinnitus. Cochrane Database Syst Rev 2010;(9):CD005233 [Review] [101 refs][Update of Cochrane Database Syst Rev. 2007;(1):CD005233; PMID: 17253549]. [5] Piccirillo JF, Garcia KS, Nicklaus J, et al. Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus. Arch Otolaryngol Head Neck Surg 2011;137(3):221e8. [6] Piccirillo JF, Kallogjeri D, Nicklaus J, et al. Four-week low-frequency rTMS for tinnitus - a randomized clinical trial. JAMA Otolaryngol Head Neck Surg 2013; 139:388e95. [7] Kleinjung T, Eichhammer P, Landgrebe M, et al. Combined temporal and prefrontal transcranial magnetic stimulation for tinnitus treatment: a pilot study. Otolaryngol Head Neck Surg 2008;138(4):497e501. [8] Newman CW, Jacobson GP, Spitzer JB. Development of the tinnitus handicap inventory. Arch Otolaryngol Head Neck Surg 1996;122(2):143e8. [9] Pridmore S, Fernandes Filho JA, Nahas Z, Liberatos C, George MS. Motor threshold in transcranial magnetic stimulation: a comparison of a neurophysiological method and a visualization of movement method. J ECT 1998;14(1): 25e7. [10] Beam W, Borckardt JJ, Reeves ST, George MS. An efficient and accurate new method for locating the F3 position for prefrontal TMS applications. Brain Stimul 2009;2(1):50e4.
Transcranial Direct Current Stimulation of the Cerebellum in Essential Tremor: A Controlled Study Essential tremor (ET) is a common movement disorder in adults. Success of drug treatment for ET remains poor and is often unsatisfactory [1]. Increasing evidence suggests the cerebellum is involved in the pathophysiology of ET [1]. Two studies have shown an improvement in tremor amplitude during inhibitory repetitive transcranial magnetic stimulation (rTMS) applied on the cerebellum [2,3], and it has been reported that transcranial direct current stimulation (tDCS) can modulate the excitability of cerebellum in humans in a similar manner to rTMS [4]. tDCS has several advantages with respect to rTMS. It has a better safety profile, it is easier to implement, it is better tolerated by the patient, and it has higher cost effectiveness [5]. The aim of the present study was to evaluate the efficacy and safety of cerebellar tDCS in patients with ET in a randomized, controlled and crossover design. We investigated both acute and long-lasting effects of tDCS. Ten patients suffering moderate to severe ET [6] were included in the study (6 males, 4 females; mean age 71.4 years, range 60e78 years; mean tremor duration, 10.2 years, range 5e21). The
Table 1 Mean scores obtained in 8 patients at baseline (day 1, before the tDCS session), after 10 days of treatment (day 10, after tDCS), and 30 days after the last tDCS session (day 40). Variable
Potential score range
Active tDCS Day 1
TCRS Parts 1 and 2 Part 3 Part 4 Accelerometry (mV2) Disability
0e76 0e28 3 to 3 0e10,000 25e100
31.2 11.9 13.0 3.8 1180 1431 46.2 10.1
Sham tDCS Day 10 32.6 12.7 0.0 984 45.5
Day 40 16.4 2.7 0.2 958 11.1
32.1 13.1 0.0 944 45.5
Day 1 11.4 2.7 0.2 958 11.1
34.7 13.7 14.2 3.3 1401 1526 44.3 10.3
Day 10 33.2 13.7 0.0 1316 44.7
Day 40 15.1 2.8 0.2 1295 9.2
31.9 13.0 0.0 964 45.5
10.4 2.7 0.2 158 11.1
Data are given as mean standard deviation. Lower values indicate better functions for all items, except for Tremor Clinical Rating Scale (TCRS), part 4. Accelerometry indicates absolute power of the dominant frequency peak; disability, self-reported disability scale. No significant differences were observed between active-tDCS and sham-tDCS.
492
Letters to the Editor / Brain Stimulation 7 (2014) 486e497
When asked which treatment they preferred all patients found both treatments similar. Two patients suffered skin erythema and chemosis in frontal anodal electrodes zone during active-tDCS, one patient after one session, and the other after 3 sessions. Both patients withdrew from the trial for this reason. This adverse effect resolved after 48 h. In this preliminary study in patients with ET, inhibitory tDCS of the cerebellum did not produce any acute or long lasting benefits using the described stimulation paradigm. Two studies have shown positive antitremoric effects using rTMS on the cerebellum [2,3]. In one of the studies, the clinical effect persisted for three weeks after rTMS sessions [3]. One possible explanation for the negative results of our study, is that the electrical field strength in tDCS, although applying bilateral stimulation, is too low to create neuromodulatory effects. Besides the small number of patients included due to the exploratory nature of the study, two further limitations of the study should be pointed out. The first of these is the intrinsic difficulty in assessing tremor in clinical trials, especially for accelerometric assessments which may have a great intra-subject variability. Nevertheless, this was minimized due to our crossover controlled design, and the use of a self-reported disability scale. Secondly, it is not clear whether it is possible to stimulate the human cerebellum through the intact scalp using tDCS. We collected no direct evidence to ensure that we had stimulated the cerebellum. Placement of the stimulating electrodes in accordance with previous studies [4] led us to suppose that cerebellar hemispheres were actively stimulated. We did not compare cerebellar stimulation with stimulation of other brain regions. However, the central pathways involved in the pathophysiology of tremor are incompletely known and cortical regions might be implicated. Thus, to preserve the singular stimulation of cerebellar areas we used the same stimulation location to make the sham stimulation. In conclusion, we failed to find an effect of tDCS of the cerebellum in ET in this small and preliminary study. Financial disclosures: All authors report no disclosures.
A. Gironell* S. Martínez-Horta S. Aguilar V. Torres J. Pagonabarraga B. Pascual-Sedano R. Ribosa-Nogué Movement Disorders Unit, Department of Neurology, Sant Pau Hospital, Autonomous University of Barcelona, Av. Sant Antoni Maria Claret, 167, 08025 Barcelona, Catalonia, Spain author. Tel.: þ34 935565986; fax: þ34 935565902. E-mail address: [email protected] (A. Gironell) * Corresponding
Received 28 January 2014 Available online 25 February 2014 http://dx.doi.org/10.1016/j.brs.2014.02.001
References [1] Louis ED. Essential tremor. Lancet Neurol 2005;4:100e10. [2] Gironell A, Kulisevsky J, Lorenzo J, et al. Transcranial magnetic stimulation of the cerebellum in essential tremor: a controlled study. Arch Neurol 2002;59: 413e7.
[3] Popa T, Russo M, Vidailhet M, et al. Cerebellar rTMS stimulation may induce prolonged clinical benefits in essential tremor, and subjacent changes in functional connectivity: an open label trial. Brain Stimul 2013;6:175e9. [4] Galea JM, Jayaram G, Ajagbe L, Celnik P. Modulation of cerebellar excitability by polarity-specific noninvasive direct current stimulation. J Neurosci 2009; 29:9115e22. [5] Brunoni AR, Nitsche MA, Bolognini N, et al. Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions. Brain Stimul 2012;5:175e95. [6] Deuschl G, Bain P, Brin M, et al. Consensus statement of the Movement Disorder Society on tremor. Mov Disord 1998;13(Suppl. 3):2e23. [7] Ugawa Y, Uesaka Y, Terao Y, Hanjima R, Kanazawa I. Magnetic stimulation over the cerebellum in humans. Ann Neurol 1995;37:703e13. [8] Boggio PS, Ferrucci R, Rigonatti SP, et al. Effects of transcranial direct current stimulation on working memory in patients with Parkinson’s disease. J Neurol Sci 2006;249:31e8. [9] Fahn S, Tolosa E, Marín C. Clinical rating scale for tremor. In: Jankovic J, Tolosa E, editors. Parkinson’s disease and movement disorders. BaltimoreMunich: Urban & Shwarzenberg; 1988. p. 225e34. [10] Gironell A, Kulisevsky J, Barbanoj M, et al. A double-blind placebo-controlled trial of gabapentin and propranolol in patients with essential tremor. Arch Neurol 1999;56:475e80.
Deep Transcranial Magnetic Stimulation in a Woman With Chronic Tinnitus: Clinical and fMRI Findings. Seeking Relief From a Symptom and Finding Vivid Memories by Serendipity Tinnitus is an auditory sensation that is not due to an external acoustic stimulus, occurring in approximately 10e15% of the adult population [1]. Although the pathophysiology of tinnitus is still barely understood, it has been assumed that chronic symptoms are due to an altered pattern of neuronal activity. Functional neuroimaging studies have suggested altered neuronal activity in both auditory and non-auditory pathways [2]. There is no current treatment for tinnitus that has shown efficacy unequivocally. Several studies evaluated the effect of rTMS on tinnitus using both high (>1 Hz) and low (
References
491
study protocol was approved by the Hospital Ethics Committee and was performed in accordance with international ethical regulations. All subjects received and signed informed consent to participate. During the trial, dose of anti-tremoric drugs was not changed. The study was double blind, crossover, and placebo-controlled. The tDCS was applied in ten consecutive sessions on working days. Active or sham-tDCS were administered in random order (Latin square design) with a three-month wash-out period. tDCS was administered with the patients at rest without concurrent cognitive or motor task. A battery driven stimulator (Neuroelectrics, Barcelona, Spain), delivered the tDCS through electrodes (saline soaked sponges, surface area 25 cm2). In order to increase the magnitude of the electrical field, we used two cathodal electrodes placed symmetrically over both cerebellar hemispheres (3 cm lateral to the inion). The inion was taken as a landmark of the boundary between the posterior cerebellum and the occipital cortex. We therefore stimulated the area caudal to the inion in order to stimulate the posterior cerebellum. Placement of active electrodes in our study was based on previous studies using rTMS or tDCS that demonstrated effective stimulation of the cerebellum [4,7]. Two anodal electrodes were positioned over both prefrontal areas (Fp1 and Fp2 EEG leads position). In the active-tDCS treatment group, cathodal tDCS (2 mA) was delivered for 20 min. This intensity of stimulation is below the threshold for tissue damage [8]. The stimulator has the possibility to perform sham-tDCS. The electrodes were identically placed as active-tDCS. The sham-tDCS induces a subjective sensation similar to that achieved with active-tDCS, but fails to induce a significant cortical stimulation. We compared results of tremor clinical rating scale (TCRS) [9], accelerometric recordings [10] and a self-reported disability scale (Bain et al.) between study days 1 (before first tDCS session), day 10 (5 min after last tDCS session) and day 40 (30 days after last tDCS session). Additionally, we used a subscale of the clinical rating scale (parts 1 þ 2) and accelerometric recordings to assess the time course of acute tDCS effects, evaluated at day 1 [before first tDCS session, during first tDCS session (10 min), þ5 min, and þ60 min after the first tDCS session]. Statistical analysis was evaluated using parametric tests. Results of TCRS part 4 were analyzed through the non-parametric Wilcoxon matched pairs test. Eight patients completed the study. Table 1 shows the data of the main variables. Clinical scores showed no significant changes (repeated-measures ANOVA) in motor task performance (TCRS parts 1 þ 2), daily living activities (TCRS part 3), or the patients’ subjective assessment (TCRS part 4) and global appraisal between baseline, day 10 and day 40. No significant differences were observed in the analysis of the patients’ subjective assessment, the accelerometry data, or the disability scale. The repeatedmeasures ANOVA also showed no significant acute tDCS effects in any outcome measure. The interaction between time and treatment was also non-significant.
[1] Kaltenbach JA, Zhang J, Zacharek MA. Neural correlates of tinnitus. In: Snow Jr JB, editor. Tinnitus: theory and management. 1st ed. Hamilton, ON: B.C. Decker, Inc; 2004. p. 141e61. [2] Burton H, Wineland A, Bhattacharya M, Nicklaus J, Garcia KS, Piccirillo JF. Altered networks in bothersome tinnitus: a functional connectivity study. BMC Neurosci 2012 Jan 4;13(1):3. [3] Wineland AM, Burton H, Piccirillo J. Functional connectivity networks in nonbothersome tinnitus. Otolaryngol Head Neck Surg 2012;147(5):900e6. [4] Martinez-Devesa P, Perera R, Theodoulou M, Waddell A. Cognitive behavioural therapy for tinnitus. Cochrane Database Syst Rev 2010;(9):CD005233 [Review] [101 refs][Update of Cochrane Database Syst Rev. 2007;(1):CD005233; PMID: 17253549]. [5] Piccirillo JF, Garcia KS, Nicklaus J, et al. Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus. Arch Otolaryngol Head Neck Surg 2011;137(3):221e8. [6] Piccirillo JF, Kallogjeri D, Nicklaus J, et al. Four-week low-frequency rTMS for tinnitus - a randomized clinical trial. JAMA Otolaryngol Head Neck Surg 2013; 139:388e95. [7] Kleinjung T, Eichhammer P, Landgrebe M, et al. Combined temporal and prefrontal transcranial magnetic stimulation for tinnitus treatment: a pilot study. Otolaryngol Head Neck Surg 2008;138(4):497e501. [8] Newman CW, Jacobson GP, Spitzer JB. Development of the tinnitus handicap inventory. Arch Otolaryngol Head Neck Surg 1996;122(2):143e8. [9] Pridmore S, Fernandes Filho JA, Nahas Z, Liberatos C, George MS. Motor threshold in transcranial magnetic stimulation: a comparison of a neurophysiological method and a visualization of movement method. J ECT 1998;14(1): 25e7. [10] Beam W, Borckardt JJ, Reeves ST, George MS. An efficient and accurate new method for locating the F3 position for prefrontal TMS applications. Brain Stimul 2009;2(1):50e4.
Transcranial Direct Current Stimulation of the Cerebellum in Essential Tremor: A Controlled Study Essential tremor (ET) is a common movement disorder in adults. Success of drug treatment for ET remains poor and is often unsatisfactory [1]. Increasing evidence suggests the cerebellum is involved in the pathophysiology of ET [1]. Two studies have shown an improvement in tremor amplitude during inhibitory repetitive transcranial magnetic stimulation (rTMS) applied on the cerebellum [2,3], and it has been reported that transcranial direct current stimulation (tDCS) can modulate the excitability of cerebellum in humans in a similar manner to rTMS [4]. tDCS has several advantages with respect to rTMS. It has a better safety profile, it is easier to implement, it is better tolerated by the patient, and it has higher cost effectiveness [5]. The aim of the present study was to evaluate the efficacy and safety of cerebellar tDCS in patients with ET in a randomized, controlled and crossover design. We investigated both acute and long-lasting effects of tDCS. Ten patients suffering moderate to severe ET [6] were included in the study (6 males, 4 females; mean age 71.4 years, range 60e78 years; mean tremor duration, 10.2 years, range 5e21). The
Table 1 Mean scores obtained in 8 patients at baseline (day 1, before the tDCS session), after 10 days of treatment (day 10, after tDCS), and 30 days after the last tDCS session (day 40). Variable
Potential score range
Active tDCS Day 1
TCRS Parts 1 and 2 Part 3 Part 4 Accelerometry (mV2) Disability
0e76 0e28 3 to 3 0e10,000 25e100
31.2 11.9 13.0 3.8 1180 1431 46.2 10.1
Sham tDCS Day 10 32.6 12.7 0.0 984 45.5
Day 40 16.4 2.7 0.2 958 11.1
32.1 13.1 0.0 944 45.5
Day 1 11.4 2.7 0.2 958 11.1
34.7 13.7 14.2 3.3 1401 1526 44.3 10.3
Day 10 33.2 13.7 0.0 1316 44.7
Day 40 15.1 2.8 0.2 1295 9.2
31.9 13.0 0.0 964 45.5
10.4 2.7 0.2 158 11.1
Data are given as mean standard deviation. Lower values indicate better functions for all items, except for Tremor Clinical Rating Scale (TCRS), part 4. Accelerometry indicates absolute power of the dominant frequency peak; disability, self-reported disability scale. No significant differences were observed between active-tDCS and sham-tDCS.
492
Letters to the Editor / Brain Stimulation 7 (2014) 486e497
When asked which treatment they preferred all patients found both treatments similar. Two patients suffered skin erythema and chemosis in frontal anodal electrodes zone during active-tDCS, one patient after one session, and the other after 3 sessions. Both patients withdrew from the trial for this reason. This adverse effect resolved after 48 h. In this preliminary study in patients with ET, inhibitory tDCS of the cerebellum did not produce any acute or long lasting benefits using the described stimulation paradigm. Two studies have shown positive antitremoric effects using rTMS on the cerebellum [2,3]. In one of the studies, the clinical effect persisted for three weeks after rTMS sessions [3]. One possible explanation for the negative results of our study, is that the electrical field strength in tDCS, although applying bilateral stimulation, is too low to create neuromodulatory effects. Besides the small number of patients included due to the exploratory nature of the study, two further limitations of the study should be pointed out. The first of these is the intrinsic difficulty in assessing tremor in clinical trials, especially for accelerometric assessments which may have a great intra-subject variability. Nevertheless, this was minimized due to our crossover controlled design, and the use of a self-reported disability scale. Secondly, it is not clear whether it is possible to stimulate the human cerebellum through the intact scalp using tDCS. We collected no direct evidence to ensure that we had stimulated the cerebellum. Placement of the stimulating electrodes in accordance with previous studies [4] led us to suppose that cerebellar hemispheres were actively stimulated. We did not compare cerebellar stimulation with stimulation of other brain regions. However, the central pathways involved in the pathophysiology of tremor are incompletely known and cortical regions might be implicated. Thus, to preserve the singular stimulation of cerebellar areas we used the same stimulation location to make the sham stimulation. In conclusion, we failed to find an effect of tDCS of the cerebellum in ET in this small and preliminary study. Financial disclosures: All authors report no disclosures.
A. Gironell* S. Martínez-Horta S. Aguilar V. Torres J. Pagonabarraga B. Pascual-Sedano R. Ribosa-Nogué Movement Disorders Unit, Department of Neurology, Sant Pau Hospital, Autonomous University of Barcelona, Av. Sant Antoni Maria Claret, 167, 08025 Barcelona, Catalonia, Spain author. Tel.: þ34 935565986; fax: þ34 935565902. E-mail address: [email protected] (A. Gironell) * Corresponding
Received 28 January 2014 Available online 25 February 2014 http://dx.doi.org/10.1016/j.brs.2014.02.001
References [1] Louis ED. Essential tremor. Lancet Neurol 2005;4:100e10. [2] Gironell A, Kulisevsky J, Lorenzo J, et al. Transcranial magnetic stimulation of the cerebellum in essential tremor: a controlled study. Arch Neurol 2002;59: 413e7.
[3] Popa T, Russo M, Vidailhet M, et al. Cerebellar rTMS stimulation may induce prolonged clinical benefits in essential tremor, and subjacent changes in functional connectivity: an open label trial. Brain Stimul 2013;6:175e9. [4] Galea JM, Jayaram G, Ajagbe L, Celnik P. Modulation of cerebellar excitability by polarity-specific noninvasive direct current stimulation. J Neurosci 2009; 29:9115e22. [5] Brunoni AR, Nitsche MA, Bolognini N, et al. Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions. Brain Stimul 2012;5:175e95. [6] Deuschl G, Bain P, Brin M, et al. Consensus statement of the Movement Disorder Society on tremor. Mov Disord 1998;13(Suppl. 3):2e23. [7] Ugawa Y, Uesaka Y, Terao Y, Hanjima R, Kanazawa I. Magnetic stimulation over the cerebellum in humans. Ann Neurol 1995;37:703e13. [8] Boggio PS, Ferrucci R, Rigonatti SP, et al. Effects of transcranial direct current stimulation on working memory in patients with Parkinson’s disease. J Neurol Sci 2006;249:31e8. [9] Fahn S, Tolosa E, Marín C. Clinical rating scale for tremor. In: Jankovic J, Tolosa E, editors. Parkinson’s disease and movement disorders. BaltimoreMunich: Urban & Shwarzenberg; 1988. p. 225e34. [10] Gironell A, Kulisevsky J, Barbanoj M, et al. A double-blind placebo-controlled trial of gabapentin and propranolol in patients with essential tremor. Arch Neurol 1999;56:475e80.
Deep Transcranial Magnetic Stimulation in a Woman With Chronic Tinnitus: Clinical and fMRI Findings. Seeking Relief From a Symptom and Finding Vivid Memories by Serendipity Tinnitus is an auditory sensation that is not due to an external acoustic stimulus, occurring in approximately 10e15% of the adult population [1]. Although the pathophysiology of tinnitus is still barely understood, it has been assumed that chronic symptoms are due to an altered pattern of neuronal activity. Functional neuroimaging studies have suggested altered neuronal activity in both auditory and non-auditory pathways [2]. There is no current treatment for tinnitus that has shown efficacy unequivocally. Several studies evaluated the effect of rTMS on tinnitus using both high (>1 Hz) and low (
