Transcranial static magnetic field stimulation can modify disease progression in amyotrophic lateral sclerosis

Glutamate-mediated excitotoxicity is thought to play a pivotal role in the pathogenesis of amyotrophic lateral sclerosis (ALS) [[1]Eisen A. Braak H. Del Tredici K. Lemon R. Ludolph A.C. Kiernan M.C. Cortical influences drive amyotrophic lateral sclerosis.J Neurol Neurosurg Psychiatry. 2017; 88: 917-924https://doi.org/10.1136/jnnp-2017-315573Crossref PubMed Scopus (112) Google Scholar]. Current pharmacological treatments target glutamatergic neurotransmission, with limited efficacy. Cerebral cortex excitatory transmission can be targeted and modulated using non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS), with the purpose of antagonizing motor cortical hyper-excitability. RTMS was tested in several small studies [[2]Edmond E.C. Stagg C.J. Turner M.R. Therapeutic non-invasive brain stimulation in amyotrophic lateral sclerosis: rationale, methods and experience.J Neurol Neurosurg Psychiatry. 2019; 90: 1131-1138https://doi.org/10.1136/jnnp-2018-320213Crossref PubMed Scopus (4) Google Scholar], demonstrating a slight reduction of ALS progression related to duration and frequency of treatment. The main limitations of rTMS are that its after-effects are short-lived and that it can be performed only in specialized centers. Other techniques, such as transcranial direct current stimulation (tDCS), can be performed more easily, even under remote supervision at patient’s home [[3]Sivaramakrishnan A. Datta A. Bikson M. Madhavan S. Remotely supervised transcranial direct current stimulation: a feasibility study for amyotrophic lateral sclerosis.NeuroRehabilitation. 2019; 45: 369-378https://doi.org/10.3233/NRE-192851Crossref PubMed Scopus (13) Google Scholar]. Inhibitory tDCS was evaluated in ALS in two studies but the results are controversial [[4]Benussi A. Alberici A. Cotelli M.S. Dell’Era V. Cantoni V. Bonetta E. Manenti R. Filosto M. Morini R. Datta A. Thomas C. Padovani A. Borroni B. Cortico-spinal tDCS in ALS: a randomized, double-blind, sham-controlled trial.Brain Stimul. 2019; 12: 1332-1334https://doi.org/10.1016/j.brs.2019.06.011Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,[5]Di Lazzaro V. Ranieri F. Capone F. Musumeci G. Dileone M. Direct current motor cortex stimulation for amyotrophic lateral sclerosis: a proof of principle study.Brain Stimul. 2013; 6: 969-970https://doi.org/10.1016/j.brs.2013.06.005Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. Motor cortex stimulation can also be performed invasively using implanted electrodes, and it can be delivered chronically with obvious advantages. Epidural motor cortex stimulation (eMCS) produces physiologic effects that are comparable to those of rTMS [[6]Di Lazzaro V. Oliviero A. Pilato F. Saturno E. Dileone M. Meglio M. Cioni B. Papacci F. Tonali P.A. Rothwell J.C. Comparison of descending volleys evoked by transcranial and epidural motor cortex stimulation in a conscious patient with bulbar pain.Clin Neurophysiol. 2004; 115: 834-838https://doi.org/10.1016/j.clinph.2003.11.026Crossref PubMed Scopus (36) Google Scholar] and it has been evaluated in a single patient with rapidly progressive ALS: he was implanted in 2006 and he is surprisingly still alive after 14 years [[7]Di Lazzaro V. Pellegrino G. Capone F. Florio L. Dileone M. Cioni B. Ranieri F. Reduction of disease progression in a patient with amyotrophic lateral sclerosis after several years of epidural motor cortex stimulation.Brain Stimul. 2017; 10: 324-325https://doi.org/10.1016/j.brs.2016.11.012Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. The benefit of eMCS was recently confirmed in a murine model of ALS [[8]Kim H. Kim H.-I. Kim Y.-H. Kim S.-Y. Shin Y.-I. An animal study to examine the effects of the bilateral, epidural cortical stimulation on the progression of amyotrophic lateral sclerosis.J NeuroEng Rehabil. 2014; 11: 139https://doi.org/10.1186/1743-0003-11-139Crossref PubMed Scopus (3) Google Scholar]. Thus, the dose-effect observed in non-invasive studies and the pronounced effect of eMCS both in humans and in animals, suggest that chronic motor cortex stimulation might be effective in slowing ALS progression. Recently, a new technique of non-invasive transcranial static magnetic field stimulation (tSMS) [[9]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 (103) Google Scholar] has been shown to suppress motor cortex excitability of healthy subjects for 10–30 min [[9]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 (103) Google Scholar,[10]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 (39) Google Scholar]. Since tSMS does not require any electronic equipment, it is easily performed and suitable for daily chronic administration at patients’ site. In this open-label pilot study we evaluated the effects of chronic tSMS in two patients with rapidly progressive non-familial ALS, both taking Riluzole, treated under “compassionate use” authorization (Supplementary material). Moreover, in order to test more directly whether tSMS may reverse cortical hyper-excitability in ALS patients, we assessed the effects of a single tSMS session on cortical excitability. Disease severity was evaluated using the revised ALS Functional Rating Scale (ALSFRS-R). The first patient, a 50-year-old male, started to present right upper limb weakness in November 2015. At the first evaluation, in July 2017, 13 months before the beginning of stimulation, the ALSFRS-R score was 30. In the following months the patient developed progressive bulbar involvement with dysphagia and in July 2018, because of a respiratory crisis, tracheostomy was performed and ventilation during sleep was started. Because of severe dysphagia, percutaneous endoscopic gastrostomy was also performed at the same time, to ensure nutritional support. TSMS was started in August 2018: at that time, he was tracheotomized and required tube feeding, ALSFRS-R score was 13 (Fig. 1A). The second patient, a 54-year-old female, started to present lower limb weakness in December 2017. At the first evaluation, in October 2018, the ALSFRS-R score was 30. TSMS was started in May 2019: at that time ALSFRS-R score was 17 (Fig. 1A). In both patients, tSMS was performed daily without any interruption and it is still ongoing. Stimulation was self-administered at patients’ home, for 3 times every day at least 4 hours apart; in each session tSMS was applied sequentially for 20 minutes over each motor cortex. TSMS was delivered using a cylindrical Nickel-plated NdFeB magnet of 45 mm diameter with a nominal field strength of ∼69 Kg (MAG45r, Neurek, Toledo, Spain), held in place by an ergonomic helmet specifically designed to target the motor cortex (MAGmv1.0, Neurek) (Supplementary material). Disease monthly progression rate (MPR) was measured as the variation of the ALSFRS-R score over the period of observation. In each patient, we compared MPR before and during stimulation. We also compared disease progression with that of control patients’ groups with comparable functional impairment, obtained from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database (Fig. 1B; Supplementary material). Patients were evaluated at least 6 months before treatment and at multiple time points after tSMS beginning, up to 18 months in Patient 1 and up to 9 months in Patient 2. Both patients and caregivers did not report any difficulty in performing chronic tSMS. Both patients needed a headrest to sustain the helmet during the procedure. No side effects were reported. Acute effects of tSMS on primary motor cortex (M1) excitability were characterized by a reduction of about 20% of the mean motor evoked potential (MEP) amplitude immediately after a 20 min session of right M1 tSMS in Patient 1 (126 ± 21 (SD) μV at baseline vs 102 ± 15 μV (SD) after tSMS), comparable with the reduction observed in normal subjects [[9]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 (103) Google Scholar]. In Patient 2, due to pronounced involvement of upper and lower motor neuron, no MEPs could be recorded after stimulation of both motor cortices. Effects of chronic tSMS on disease progression are reported in Fig. 1. In Patient 1, survival probability at last observation (18 months) is estimated at 0.23, based on the survival function of the control population (Fig. 1B). After the beginning of stimulation, the overall functional status remained stable (MPR reduced to −0.06, in the lower 20th percentile of control population): it was mainly characterized by improvement of swallowing function (not requiring supplemental tube feeding or dietary consistency changes) and loss of functional lower limb movement; the patient continued to require ventilatory support during night only. The overall a priori probability, at the moment of starting tSMS, of surviving and of being in the observed clinical conditions at the last observation can thus be estimated at ∼0.05, i.e. 0.23 (survival probability) × 0.20 (probability of MPR ≤ −0.06) (Fig. 1B). In Patient 2, survival probability at last observation (9 months) is estimated at 0.43 (Fig. 1B). After the beginning of stimulation, MPR was reduced to 0.56 (lower 40th percentile of control population), due to slight deterioration of bulbar function and loss of residual lower limb movement. The overall a priori probability of surviving and of being in the observed clinical conditions at the last observation can be estimated at ∼0.17, i.e. 0.43 (survival probability) × 0.40 (probability of MPR ≤ 0.56) (Fig. 1B). In conclusion, we observed a dramatic and prolonged reduction in disease progression in two patients with rapidly progressive ALS treated chronically with tSMS. Patients reported no side effects and at-home self-administered stimulation was considered feasible both by patients and their caregivers. Considering that our patients had a rapidly progressive form of ALS, the fact that the first patient is still alive and stable, requiring ventilation only during sleep, and has also recovered speech and swallowing functions and that the second patient is also stable and still not tracheotomized suggests a pronounced change in disease course. Comparison with a large control population from the PRO-ACT database indicates that both patients had a low survival probability and a slower disease progression during tSMS than their respective control groups. Of note, we might have even overestimated survival in our 2-year period of analysis since many patients in the PRO-ACT database had a shorter follow-up. The study of motor cortex excitability before and after a single session of tSMS in Patient 1 shows for the first time that it is possible to reduce cortical excitability in ALS with an effect that is comparable to that observed in normal subjects. Our study has obvious limitations, because only two patients were treated and because we used a historical control group. Nevertheless, present results show that long-term self-administered tSMS is safe and feasible at home and suggest that it has therapeutic potential in ALS. Based on these preliminary observations we have now started a placebo-controlled trial evaluating tSMS as a disease-modifying treatment in ALS (Clinicaltrials.gov: NCT04393467). V.D., F.R., G.D., F.C. contributed to drafting the text and preparing the figures. V.D., G.D., F.C., F.R. contributed to the conception and design of the study. V.D., F.R., G.M., M.B., A.D., F.M. contributed to the acquisition and analysis of data. Nothing to report. Part of the data used in the preparation of this article were obtained from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database. As such, the following organizations and individuals within the PRO-ACT Consortium contributed to the design and implementation of the PRO-ACT Database and/or provided data, but did not participate in the analysis of the data or the writing of this report: Neurological Clinical Research Institute, MGH; Northeast ALS Consortium; Novartis; Prize4Life; Regeneron Pharmaceuticals, Inc.; Sanofi; Teva Pharmaceutical Industries, Ltd. We are grateful to the Prize4Life organization and the PRO-ACT Consortium members for making the PRO-ACT Database publicly available. The “Fondazione ‘Nicola Irti’ per le opere di carità e di cultura”, Rome, Italy, supported present study that is dedicated to the memory of Nicola Irti. We are extremely grateful to our patients Vincenzo and Nazarena who made this observation possible. The following is the Supplementary data to this article: Download .pdf (.11 MB) Help with pdf files Multimedia component 1