Home-based transcranial static magnetic field stimulation of the motor cortex for treating levodopa-induced dyskinesias in Parkinson's disease: A randomized controlled trial

Abstract

•tSMS is a portable, inhibitory, non-invasive brain stimulation technique.•Repeated sessions of home-based tSMS of the motor cortex are feasible and safe.•tSMS may provide subjective benefit for the treatment of levodopa-induced dyskinesias. Levodopa-induced dyskinesias are a common complication in patients with Parkinson's disease (PD) treated chronically with levodopa. Even though dyskinesias may be more tolerable than parkinsonism, they can be highly debilitating for some patients. The difficulty to achieve satisfactory pharmacological treatment of dyskinesias often motivates the escalation toward more advanced invasive treatments. However, even with invasive treatments dyskinesias may remain problematic.A promising approach is offered by non-invasive brain stimulation (NIBS). Several small, randomized studies (sample sizes ≤17 patients) suggest that presumably reducing the excitability of motor cortical areas with repetitive transcranial magnetic stimulation (rTMS) may be effective for reducing levodopa-induced dyskinesias [[1]Wu Y. Cao X. Zeng W. Zhai H. Zhang X. Yang X. et al.Transcranial magnetic stimulation alleviates levodopa-induced dyskinesia in Parkinson's disease and the related mechanisms: a mini-review.Front Neurol. 2021; 12https://doi.org/10.3389/fneur.2021.758345Crossref Scopus (1) Google Scholar]. However, rTMS is not portable, which limits its application to a center-based therapeutic model and possibly hindered the path toward larger, longer and more definitive clinical trials.We recently introduced transcranial static magnetic field stimulation (tSMS), which can reduce cortical excitability in both healthy subjects [[2]Oliviero A. Mordillo-Mateos L. Arias P. Panyavin I. Foffani G. Aguilar J. Transcranial static magnetic field stimulation of the human motor cortex.J Physiol. 2011; 589: 4949-4958https://doi.org/10.1113/jphysiol.2011.211953Crossref PubMed Scopus (99) Google Scholar,[3]Dileone M. Mordillo-Mateos L. Oliviero A. Foffani G. Long-lasting effects of transcranial static magnetic field stimulation on motor cortex excitability.Brain Stimul. 2018; 11: 676-688https://doi.org/10.1016/j.brs.2018.02.005Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar] and PD patients OFF medication [[4]Dileone M. Carrasco-López M.C. Segundo-Rodriguez J.C. Mordillo-Mateos L. López-Ariztegui N. Alonso-Frech F. et al.Dopamine-dependent changes of cortical excitability induced by transcranial static magnetic field stimulation in Parkinson's disease.Sci Rep. 2017; 7: 4329https://doi.org/10.1038/s41598-017-04254-yCrossref PubMed Scopus (14) Google Scholar]. Differently from rTMS, tSMS is portable, which makes it attractive for shifting the NIBS paradigm from a center-based to a home-based therapeutic model. We thus aimed to investigate the potential of tSMS as a novel non-invasive home-based treatment to manage levodopa-induced dyskinesias.1. MethodsWe conducted a randomized, sham-controlled, double-blind, parallel trial to test the ability of repeated sessions of tSMS to safely reduce levodopa-induced dyskinesias in PD (ClinicalTrials.gov: NCT02657681). Patients received 30-min sessions [[3]Dileone M. Mordillo-Mateos L. Oliviero A. Foffani G. Long-lasting effects of transcranial static magnetic field stimulation on motor cortex excitability.Brain Stimul. 2018; 11: 676-688https://doi.org/10.1016/j.brs.2018.02.005Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar] of either real or sham tSMS, one session per day, for 9 days over two weeks (Fig. 1A). Patients were allowed to receive the treatment in the hospital or self-deliver it at home. All but one preferred home treatment. The data were analyzed with Bayesian statistics (i.e. Bayes factor, BF). For detailed methods, see Online Supplementary Materials.2. ResultsA total of 50 patients were randomized, 25 were assigned to real tSMS, 25 to sham tSMS (Suppl. Table 1). Of them, 42 (21 real, 21 sham) were analyzed for the primary outcome (Fig. 1B). The objective part of the Unified Dyskinesia Rating Scale (UDysRS, primary outcome) displayed moderate evidence of improvement after treatment compared to baseline (p = 0.008, BFincl = 5.4), but there was also moderate evidence of absence of difference in the improvement between real and sham treatment (Fig. 1C and D; Suppl. Table 2). Changes in motor scores, as assessed by the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III scale, secondary outcome), were inconclusive (Suppl. Table 2). Conversely, the Patient's Global Rating of Change (P-GRC, secondary outcome) revealed moderate evidence of subjective improvement with real compared to sham treatment (p = 0.017, BF+0 = 6.6; Fig. 1E).No serious adverse events were reported. Anxiety occurred in two patients (one real, one sham), but was unlikely to be directly caused by the treatment. Transient mild dizziness and headache were reported by one patient, presumably attributed either to the static magnetic field or to the weight of the helmet. The latter was likely the cause of a mild periorbital hematoma transiently observed in one particularly fragile female patient.For detailed results, see Online Supplementary Materials.3. Discussion3.1 Objective evaluation of levodopa-induced dyskinesiasWe found non-significant difference in objective improvement (moderate evidence of absence) between patients who received real compared to patients who received sham treatment. One limitation and two experimental choices might have limited our ability to detect differences in objective improvement between groups. First, overall the patients that participated in the study displayed relatively mild dyskinesias. Our difficulty in recruiting patients with severe dyskinesias is in line with the epidemiologically decreasing prevalence and severity of levodopa-induced dyskinesias, at least in some countries [[5]Chaudhuri K.R. Jenner P. Antonini A. Should there be less emphasis on levodopa-induced dyskinesia in Parkinson's disease?.Mov Disord. 2019; 34: 816-819https://doi.org/10.1002/mds.27691Crossref PubMed Scopus (33) Google Scholar]. Second, we assessed dyskinesias after administration of 100% of the morning dose of levodopa, in order maintain real-life conditions and a stable pharmacological schedule. A higher levodopa dose might have decreased the variability of the assessment, at least in some patients. Third, since this was the first study with repeated sessions of tSMS, we conservatively delivered a relatively low number of sessions. With NIBS, it is not uncommon to observe an initial parallel improvement in patients receiving real or sham stimulation, with differences between groups becoming appreciable only after higher number of sessions and longer follow-ups [[6]Shirota Y. Ohtsu H. Hamada M. Enomoto H. Ugawa Y. Supplementary motor area stimulation for Parkinson disease.Neurology. 2013; 80: 1400-1405https://doi.org/10.1212/WNL.0b013e31828c2f66Crossref PubMed Scopus (107) Google Scholar]. Future studies should thus test longer home-based treatments, which are feasible with tSMS [[7]Di Lazzaro V. Musumeci G. Boscarino M. De Liso A. Motolese F. Di Pino G. et al.Transcranial static magnetic field stimulation can modify disease progression in amyotrophic lateral sclerosis.Brain Stimul. 2021; https://doi.org/10.1016/j.brs.2020.11.003Abstract Full Text Full Text PDF Scopus (4) Google Scholar].3.2 Objective evaluation of motor featuresA priori, we did not strongly expect tSMS to improve PD motor features, since excitatory rather than inhibitory NIBS protocols typically provide motor improvement when applied to the motor cortex. Yet, tSMS mechanisms unrelated to cortical excitability could have ameliorated motor features, and we wanted to ensure that possible improvements in dyskinesias did not come at the expense of motor impairment. This did not seem to be the case. An attractive alternative target would be the supplementary motor area (SMA), which can be reached with tSMS [[8]Pineda-Pardo J.A. Obeso I. Guida P. Dileone M. Strange B.A. Obeso J.A. et al.Static magnetic field stimulation of the supplementary motor area modulates resting-state activity and motor behavior.Commun 2019; PubMed Scopus (14) Google Scholar] and stimulation with inhibitory NIBS protocols may improve both dyskinesias [[1]Wu Y. Cao X. Zeng W. Zhai H. Zhang X. Yang X. et al.Transcranial magnetic stimulation alleviates levodopa-induced dyskinesia in Parkinson's disease and the related mechanisms: a mini-review.Front Neurol. 2021; 12https://doi.org/10.3389/fneur.2021.758345Crossref Scopus (1) Google Scholar] and motor [[6]Shirota Y. Ohtsu H. Hamada M. Enomoto H. Ugawa Y. Supplementary motor area stimulation for Parkinson disease.Neurology. 2013; 80: 1400-1405https://doi.org/10.1212/WNL.0b013e31828c2f66Crossref PubMed Scopus (107) Google found subjective improvement (moderate in patients who received real compared to patients who received sham also by the ability of patients to to some treatment they received Online Supplementary Even though we in some this unlikely to have the evidence of subjective the primary motor cortex is in brain for the of A. M. M. et of for PubMed Scopus (4) Google Scholar]. The observed between subjective and objective improvement thus that tSMS might have not the dyskinesias per but rather the subjective of patients dyskinesias of This is and the of tSMS A. Carrasco-López M.C. M. V. et study of transcranial static magnetic field stimulation of the human Stimul. Full Text Full Text PDF PubMed Scopus Google Scholar] to repeated sessions. The of the brain to static magnetic is also by of of the static magnetic or even are at least one order of than the field in tSMS at cortical suggest that repeated sessions of home-based tSMS of the motor cortex are and provide objective benefit (moderate evidence of absence) but subjective benefit (moderate for the treatment of levodopa-induced dyskinesias in evidence of objective studies should investigate longer tSMS treatments. Levodopa-induced dyskinesias are a common complication in patients with Parkinson's disease (PD) treated chronically with levodopa. Even though dyskinesias may be more tolerable than parkinsonism, they can be highly debilitating for some patients. The difficulty to achieve satisfactory pharmacological treatment of dyskinesias often motivates the escalation toward more advanced invasive treatments. However, even with invasive treatments dyskinesias may remain A promising approach is offered by non-invasive brain stimulation (NIBS). Several small, randomized studies (sample sizes ≤17 patients) suggest that presumably reducing the excitability of motor cortical areas with repetitive transcranial magnetic stimulation (rTMS) may be effective for reducing levodopa-induced dyskinesias [[1]Wu Y. Cao X. Zeng W. Zhai H. Zhang X. Yang X. et al.Transcranial magnetic stimulation alleviates levodopa-induced dyskinesia in Parkinson's disease and the related mechanisms: a mini-review.Front Neurol. 2021; 12https://doi.org/10.3389/fneur.2021.758345Crossref Scopus (1) Google Scholar]. However, rTMS is not portable, which limits its application to a center-based therapeutic model and possibly hindered the path toward larger, longer and more definitive clinical We recently introduced transcranial static magnetic field stimulation (tSMS), which can reduce cortical excitability in both healthy subjects [[2]Oliviero A. Mordillo-Mateos L. Arias P. Panyavin I. Foffani G. Aguilar J. Transcranial static magnetic field stimulation of the human motor cortex.J Physiol. 2011; 589: 4949-4958https://doi.org/10.1113/jphysiol.2011.211953Crossref PubMed Scopus (99) Google Scholar,[3]Dileone M. Mordillo-Mateos L. Oliviero A. Foffani G. Long-lasting effects of transcranial static magnetic field stimulation on motor cortex excitability.Brain Stimul. 2018; 11: 676-688https://doi.org/10.1016/j.brs.2018.02.005Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar] and PD patients OFF medication [[4]Dileone M. Carrasco-López M.C. Segundo-Rodriguez J.C. Mordillo-Mateos L. López-Ariztegui N. Alonso-Frech F. et al.Dopamine-dependent changes of cortical excitability induced by transcranial static magnetic field stimulation in Parkinson's disease.Sci Rep. 2017; 7: 4329https://doi.org/10.1038/s41598-017-04254-yCrossref PubMed Scopus (14) Google Scholar]. Differently from rTMS, tSMS is portable, which makes it attractive for shifting the NIBS paradigm from a center-based to a home-based therapeutic model. We thus aimed to investigate the potential of tSMS as a novel non-invasive home-based treatment to manage levodopa-induced dyskinesias. MethodsWe conducted a randomized, sham-controlled, double-blind, parallel trial to test the ability of repeated sessions of tSMS to safely reduce levodopa-induced dyskinesias in PD (ClinicalTrials.gov: NCT02657681). Patients received 30-min sessions [[3]Dileone M. Mordillo-Mateos L. Oliviero A. Foffani G. Long-lasting effects of transcranial static magnetic field stimulation on motor cortex excitability.Brain Stimul. 2018; 11: 676-688https://doi.org/10.1016/j.brs.2018.02.005Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar] of either real or sham tSMS, one session per day, for 9 days over two weeks (Fig. 1A). Patients were allowed to receive the treatment in the hospital or self-deliver it at home. All but one preferred home treatment. The data were analyzed with Bayesian statistics (i.e. Bayes factor, BF). For detailed methods, see Online Supplementary We conducted a randomized, sham-controlled, double-blind, parallel trial to test the ability of repeated sessions of tSMS to safely reduce levodopa-induced dyskinesias in PD (ClinicalTrials.gov: NCT02657681). Patients received 30-min sessions [[3]Dileone M. Mordillo-Mateos L. Oliviero A. Foffani G. Long-lasting effects of transcranial static magnetic field stimulation on motor cortex excitability.Brain Stimul. 2018; 11: 676-688https://doi.org/10.1016/j.brs.2018.02.005Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar] of either real or sham tSMS, one session per day, for 9 days over two weeks (Fig. 1A). Patients were allowed to receive the treatment in the hospital or self-deliver it at home. All but one preferred home treatment. The data were analyzed with Bayesian statistics (i.e. Bayes factor, BF). For detailed methods, see Online Supplementary ResultsA total of 50 patients were randomized, 25 were assigned to real tSMS, 25 to sham tSMS (Suppl. Table 1). Of them, 42 (21 real, 21 sham) were analyzed for the primary outcome (Fig. 1B). The objective part of the Unified Dyskinesia Rating Scale (UDysRS, primary outcome) displayed moderate evidence of improvement after treatment compared to baseline (p = 0.008, BFincl = 5.4), but there was also moderate evidence of absence of difference in the improvement between real and sham treatment (Fig. 1C and D; Suppl. Table 2). Changes in motor scores, as assessed by the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III scale, secondary outcome), were inconclusive (Suppl. Table 2). Conversely, the Patient's Global Rating of Change (P-GRC, secondary outcome) revealed moderate evidence of subjective improvement with real compared to sham treatment (p = 0.017, BF+0 = 6.6; Fig. 1E).No serious adverse events were reported. Anxiety occurred in two patients (one real, one sham), but was unlikely to be directly caused by the treatment. Transient mild dizziness and headache were reported by one patient, presumably attributed either to the static magnetic field or to the weight of the helmet. The latter was likely the cause of a mild periorbital hematoma transiently observed in one particularly fragile female patient.For detailed results, see Online Supplementary A total of 50 patients were randomized, 25 were assigned to real tSMS, 25 to sham tSMS (Suppl. Table 1). Of them, 42 (21 real, 21 sham) were analyzed for the primary outcome (Fig. 1B). The objective part of the Unified Dyskinesia Rating Scale (UDysRS, primary outcome) displayed moderate evidence of improvement after treatment compared to baseline (p = 0.008, BFincl = 5.4), but there was also moderate evidence of absence of difference in the improvement between real and sham treatment (Fig. 1C and D; Suppl. Table 2). Changes in motor scores, as assessed by the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III scale, secondary outcome), were inconclusive (Suppl. Table 2). Conversely, the Patient's Global Rating of Change (P-GRC, secondary outcome) revealed moderate evidence of subjective improvement with real compared to sham treatment (p = 0.017, BF+0 = 6.6; Fig. serious adverse events were reported. Anxiety occurred in two patients (one real, one sham), but was unlikely to be directly caused by the treatment. Transient mild dizziness and headache were reported by one patient, presumably attributed either to the static magnetic field or to the weight of the helmet. The latter was likely the cause of a mild periorbital hematoma transiently observed in one particularly fragile female For detailed results, see Online Supplementary Discussion3.1 Objective evaluation of levodopa-induced dyskinesiasWe found non-significant difference in objective improvement (moderate evidence of absence) between patients who received real compared to patients who received sham treatment. One limitation and two experimental choices might have limited our ability to detect differences in objective improvement between groups. First, overall the patients that participated in the study displayed relatively mild dyskinesias. Our difficulty in recruiting patients with severe dyskinesias is in line with the epidemiologically decreasing prevalence and severity of levodopa-induced dyskinesias, at least in some countries [[5]Chaudhuri K.R. Jenner P. Antonini A. Should there be less emphasis on levodopa-induced dyskinesia in Parkinson's disease?.Mov Disord. 2019; 34: 816-819https://doi.org/10.1002/mds.27691Crossref PubMed Scopus (33) Google Scholar]. Second, we assessed dyskinesias after administration of 100% of the morning dose of levodopa, in order maintain real-life conditions and a stable pharmacological schedule. A higher levodopa dose might have decreased the variability of the assessment, at least in some patients. Third, since this was the first study with repeated sessions of tSMS, we conservatively delivered a relatively low number of sessions. With NIBS, it is not uncommon to observe an initial parallel improvement in patients receiving real or sham stimulation, with differences between groups becoming appreciable only after higher number of sessions and longer follow-ups [[6]Shirota Y. Ohtsu H. Hamada M. Enomoto H. Ugawa Y. Supplementary motor area stimulation for Parkinson disease.Neurology. 2013; 80: 1400-1405https://doi.org/10.1212/WNL.0b013e31828c2f66Crossref PubMed Scopus (107) Google Scholar]. Future studies should thus test longer home-based treatments, which are feasible with tSMS [[7]Di Lazzaro V. Musumeci G. Boscarino M. De Liso A. Motolese F. Di Pino G. et al.Transcranial static magnetic field stimulation can modify disease progression in amyotrophic lateral sclerosis.Brain Stimul. 2021; https://doi.org/10.1016/j.brs.2020.11.003Abstract Full Text Full Text PDF Scopus (4) Google Scholar].3.2 Objective evaluation of motor featuresA priori, we did not strongly expect tSMS to improve PD motor features, since excitatory rather than inhibitory NIBS protocols typically provide motor improvement when applied to the motor cortex. Yet, tSMS mechanisms unrelated to cortical excitability could have ameliorated motor features, and we wanted to ensure that possible improvements in dyskinesias did not come at the expense of motor impairment. This did not seem to be the case. An attractive alternative target would be the supplementary motor area (SMA), which can be reached with tSMS [[8]Pineda-Pardo J.A. Obeso I. Guida P. Dileone M. Strange B.A. Obeso J.A. et al.Static magnetic field stimulation of the supplementary motor area modulates resting-state activity and motor behavior.Commun 2019; PubMed Scopus (14) Google Scholar] and stimulation with inhibitory NIBS protocols may improve both dyskinesias [[1]Wu Y. Cao X. Zeng W. Zhai H. Zhang X. Yang X. et al.Transcranial magnetic stimulation alleviates levodopa-induced dyskinesia in Parkinson's disease and the related mechanisms: a mini-review.Front Neurol. 2021; 12https://doi.org/10.3389/fneur.2021.758345Crossref Scopus (1) Google Scholar] and motor [[6]Shirota Y. Ohtsu H. Hamada M. Enomoto H. Ugawa Y. Supplementary motor area stimulation for Parkinson disease.Neurology. 2013; 80: 1400-1405https://doi.org/10.1212/WNL.0b013e31828c2f66Crossref PubMed Scopus (107) Google found subjective improvement (moderate in patients who received real compared to patients who received sham also by the ability of patients to to some treatment they received Online Supplementary Even though we in some this unlikely to have the evidence of subjective the primary motor cortex is in brain for the of A. M. M. et of for PubMed Scopus (4) Google Scholar]. The observed between subjective and objective improvement thus that tSMS might have not the dyskinesias per but rather the subjective of patients dyskinesias of This is and the of tSMS A. Carrasco-López M.C. M. V. et study of transcranial static magnetic field stimulation of the human Stimul. Full Text Full Text PDF PubMed Scopus Google Scholar] to repeated sessions. The of the brain to static magnetic is also by of of the static magnetic or even are at least one order of than the field in tSMS at cortical Objective evaluation of levodopa-induced dyskinesiasWe found non-significant difference in objective improvement (moderate evidence of absence) between patients who received real compared to patients who received sham treatment. One limitation and two experimental choices might have limited our ability to detect differences in objective improvement between groups. First, overall the patients that participated in the study displayed relatively mild dyskinesias. Our difficulty in recruiting patients with severe dyskinesias is in line with the epidemiologically decreasing prevalence and severity of levodopa-induced dyskinesias, at least in some countries [[5]Chaudhuri K.R. Jenner P. Antonini A. Should there be less emphasis on levodopa-induced dyskinesia in Parkinson's disease?.Mov Disord. 2019; 34: 816-819https://doi.org/10.1002/mds.27691Crossref PubMed Scopus (33) Google Scholar]. Second, we assessed dyskinesias after administration of 100% of the morning dose of levodopa, in order maintain real-life conditions and a stable pharmacological schedule. A higher levodopa dose might have decreased the variability of the assessment, at least in some patients. Third, since this was the first study with repeated sessions of tSMS, we conservatively delivered a relatively low number of sessions. With NIBS, it is not uncommon to observe an initial parallel improvement in patients receiving real or sham stimulation, with differences between groups becoming appreciable only after higher number of sessions and longer follow-ups [[6]Shirota Y. Ohtsu H. Hamada M. Enomoto H. Ugawa Y. Supplementary motor area stimulation for Parkinson disease.Neurology. 2013; 80: 1400-1405https://doi.org/10.1212/WNL.0b013e31828c2f66Crossref PubMed Scopus (107) Google Scholar]. Future studies should thus test longer home-based treatments, which are feasible with tSMS [[7]Di Lazzaro V. Musumeci G. Boscarino M. De Liso A. Motolese F. Di Pino G. et al.Transcranial static magnetic field stimulation can modify disease progression in amyotrophic lateral sclerosis.Brain Stimul. 2021; https://doi.org/10.1016/j.brs.2020.11.003Abstract Full Text Full Text PDF Scopus (4) Google Scholar]. We found non-significant difference in objective improvement (moderate evidence of absence) between patients who received real compared to patients who received sham treatment. One limitation and two experimental choices might have limited our ability to detect differences in objective improvement between groups. First, overall the patients that participated in the study displayed relatively mild dyskinesias. Our difficulty in recruiting patients with severe dyskinesias is in line with the epidemiologically decreasing prevalence and severity of levodopa-induced dyskinesias, at least in some countries [[5]Chaudhuri K.R. Jenner P. Antonini A. Should there be less emphasis on levodopa-induced dyskinesia in Parkinson's disease?.Mov Disord. 2019; 34: 816-819https://doi.org/10.1002/mds.27691Crossref PubMed Scopus (33) Google Scholar]. Second, we assessed dyskinesias after administration of 100% of the morning dose of levodopa, in order maintain real-life conditions and a stable pharmacological schedule. A higher levodopa dose might have decreased the variability of the assessment, at least in some patients. Third, since this was the first study with repeated sessions of tSMS, we conservatively delivered a relatively low number of sessions. With NIBS, it is not uncommon to observe an initial parallel improvement in patients receiving real or sham stimulation, with differences between groups becoming appreciable only after higher number of sessions and longer follow-ups [[6]Shirota Y. Ohtsu H. Hamada M. Enomoto H. Ugawa Y. Supplementary motor area stimulation for Parkinson disease.Neurology. 2013; 80: 1400-1405https://doi.org/10.1212/WNL.0b013e31828c2f66Crossref PubMed Scopus (107) Google Scholar]. Future studies should thus test longer home-based treatments, which are feasible with tSMS [[7]Di Lazzaro V. Musumeci G. Boscarino M. De Liso A. Motolese F. Di Pino G. et al.Transcranial static magnetic field stimulation can modify disease progression in amyotrophic lateral sclerosis.Brain Stimul. 2021; https://doi.org/10.1016/j.brs.2020.11.003Abstract Full Text Full Text PDF Scopus (4) Google Scholar]. Objective evaluation of motor featuresA priori, we did not strongly expect tSMS to improve PD motor features, since excitatory rather than inhibitory NIBS protocols typically provide motor improvement when applied to the motor cortex. Yet, tSMS mechanisms unrelated to cortical excitability could have ameliorated motor features, and we wanted to ensure that possible improvements in dyskinesias did not come at the expense of motor impairment. This did not seem to be the case. An attractive alternative target would be the supplementary motor area (SMA), which can be reached with tSMS [[8]Pineda-Pardo J.A. Obeso I. Guida P. Dileone M. Strange B.A. Obeso J.A. et al.Static magnetic field stimulation of the supplementary motor area modulates resting-state activity and motor behavior.Commun 2019; PubMed Scopus (14) Google Scholar] and stimulation with inhibitory NIBS protocols may improve both dyskinesias [[1]Wu Y. Cao X. Zeng W. Zhai H. Zhang X. Yang X. et al.Transcranial magnetic stimulation alleviates levodopa-induced dyskinesia in Parkinson's disease and the related mechanisms: a mini-review.Front Neurol. 2021; 12https://doi.org/10.3389/fneur.2021.758345Crossref Scopus (1) Google Scholar] and motor [[6]Shirota Y. Ohtsu H. Hamada M. Enomoto H. Ugawa Y. Supplementary motor area stimulation for Parkinson disease.Neurology. 2013; 80: 1400-1405https://doi.org/10.1212/WNL.0b013e31828c2f66Crossref PubMed Scopus (107) Google Scholar]. A priori, we did not strongly expect tSMS to improve PD motor features, since excitatory rather than inhibitory NIBS protocols typically provide motor improvement when applied to the motor cortex. Yet, tSMS mechanisms unrelated to cortical excitability could have ameliorated motor features, and we wanted to ensure that possible improvements in dyskinesias did not come at the expense of motor impairment. This did not seem to be the case. An attractive alternative target would be the supplementary motor area (SMA), which can be reached with tSMS [[8]Pineda-Pardo J.A. Obeso I. Guida P. Dileone M. Strange B.A. Obeso J.A. et al.Static magnetic field stimulation of the supplementary motor area modulates resting-state activity and motor behavior.Commun 2019; PubMed Scopus (14) Google Scholar] and stimulation with inhibitory NIBS protocols may improve both dyskinesias [[1]Wu Y. Cao X. Zeng W. Zhai H. Zhang X. Yang X. et al.Transcranial magnetic stimulation alleviates levodopa-induced dyskinesia in Parkinson's disease and the related mechanisms: a mini-review.Front Neurol. 2021; 12https://doi.org/10.3389/fneur.2021.758345Crossref Scopus (1) Google Scholar] and motor [[6]Shirota Y. Ohtsu H. Hamada M. Enomoto H. Ugawa Y. Supplementary motor area stimulation for Parkinson disease.Neurology. 2013; 80: 1400-1405https://doi.org/10.1212/WNL.0b013e31828c2f66Crossref PubMed Scopus (107) Google Scholar]. found subjective improvement (moderate in patients who received real compared to patients who received sham also by the ability of patients to to some treatment they received Online Supplementary Even though we in some this unlikely to have the evidence of subjective the primary motor cortex is in brain for the of A. M. M. et of for PubMed Scopus (4) Google Scholar]. The observed between subjective and objective improvement thus that tSMS might have not the dyskinesias per but rather the subjective of patients dyskinesias of This is and We found subjective improvement (moderate in patients who received real compared to patients who received sham also by the ability of patients to to some treatment they received Online Supplementary Even though we in some this unlikely to have the evidence of subjective the primary motor cortex is in brain for the of A. M. M. et of for PubMed Scopus (4) Google Scholar]. The observed between subjective and objective improvement thus that tSMS might have not the dyskinesias per but rather the subjective of patients dyskinesias of This is and the of tSMS A. Carrasco-López M.C. M. V. et study of transcranial static magnetic field stimulation of the human Stimul. Full Text Full Text PDF PubMed Scopus Google Scholar] to repeated sessions. The of the brain to static magnetic is also by of of the static magnetic or even are at least one order of than the field in tSMS at cortical Our the of tSMS A. Carrasco-López M.C. M. V. et study of transcranial static magnetic field stimulation of the human Stimul. Full Text Full Text PDF PubMed Scopus Google Scholar] to repeated sessions. The of the brain to static magnetic is also by of of the static magnetic or even are at least one order of than the field in tSMS at cortical suggest that repeated sessions of home-based tSMS of the motor cortex are and provide objective benefit (moderate evidence of absence) but subjective benefit (moderate for the treatment of levodopa-induced dyskinesias in evidence of objective studies should investigate longer tSMS treatments. The suggest that repeated sessions of home-based tSMS of the motor cortex are and provide objective benefit (moderate evidence of absence) but subjective benefit (moderate for the treatment of levodopa-induced dyskinesias in evidence of objective studies should investigate longer tSMS treatments.

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