Effects of Transcranial Static Magnetic Field Stimulation (tSMS) in Progressive Multiple Sclerosis

NCT ID: NCT05811013

Last Updated: 2024-10-16

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-05-27
• Study Completion Date: 2026-05-27

Brief Summary

In multiple sclerosis (MS) brains, inflammation induces specific abnormalities of synaptic transmission, collectively called inflammatory synaptopathy. Such synaptopathy consists in unbalanced glutamatergic and GABAergic transmission and in remarkable changes in synaptic plasticity, causing excitotoxic neurodegeneration and impairing the clinical compensation of the ongoing brain damage, thereby exacerbating the clinical manifestation of the disease. In progressive MS (PMS), synaptopathy is characterized by pathological potentatiation of glutamate-mediated synaptic up-scaling (Centonze et al., 2008; Rossi et al., 2013) and loss of long-term synaptic potentiation [LTP (Weiss et al., 2014)], both caused by proinflammatory molecules (released by microglia, astroglia, and infiltrating T and B lymphocytes) (Malenka et al., 2004; Di Filippo et al., 2017; Stampanoni Bassi et al., 2019). The combination of increased up-scaling and decreased LTP has a significant impact on the clinical manifestations of PMS, often presenting with signs and symptoms indicating length-dependent degeneration of neurons of the corticospinal tract. Altered LTP expression impairs brain ability to compensate ongoing neuronal loss (Stampanoni Bassi et al., 2020), and pathological TNF-mediated up-scaling may directly promote excitotoxic damage and neurodegeneration (Rossi et al., 2014). In addition, up-scaling and LTP are mutually exclusive at a given synapse through a mechanism of synaptic occlusion (i.e., pre-existing up-scaling saturates and prevents subsequent LTP expression), further promoting neurodegeneration by preventing the pro-survival effect of LTP, the induction of which activates intracellular anti-apoptotic pathways (Bartlett & Wang, 2013). It follows that a neuromodulation approach that can chronically (over several months) dampen up-scaling expression in the primary motor cortex (M1) of PMS patients could be beneficial by preventing excitotoxic neurodegenerative damage triggered by up-scaling itself (Centonze et al. 2008, Rossi et al. 2014), and also by promoting LTP induction and LTP-dependent functional compensation of deficits, thereby reducing the speed of the neurodegeneration process through increased LTP-dependent neuronal survival and preservation of dendritic spines (Ksiazek-Winiarek et al., 2015). Our study aims to test whether transcranial static magnetic field stimulation (tSMS) could represent such a therapeutic approach, as recently proposed in patients with amyotrophic lateral sclerosis (ALS) (Di Lazzaro et al, 2021). Forty (40) ambulatory patients with PMS, presenting with the ascending myelopathy phenotype of the disease, will be recruited at the MS Center of the Unit of Neurology of the IRCCS Neuromed in Pozzilli (IS). In this randomized, sham-controlled, double-blind, within-subjects, cross-over study (allocation ratio 1:1), we will test the ability of repeated sessions of tSMS applied bilaterally over the M1 to safely reduce disability progression in patients with PMS. Patients will be randomly assigned to either real or sham tSMS. Each patient will participate in two experimental phases (real or sham stimulation). Each patient will self-administer tSMS over right and left M1, two session per day, 60 minutes each. The order will be randomly established and counterbalanced across participants. Both investigators and participants will be blinded to stimulation parameters. In the "real stimulation" phase, tSMS will be applied for 120 minutes each day, at home, for 12 consecutive months. In the "sham stimulation" phase, sham tSMS will be delivered with non-magnetic metal cylinders, with the same size, weight and appearance of the magnets. Clinical evaluations, including the Multiple Sclerosis Functional Composite measure (MSFC) will be performed before, during and after each experimental phase ("real" and "sham"). In addition, blood levels of neurofilaments, excitability and plasticity of M1, and MRI measures of cortical thickness will be measured before, during and after each stimulation phase.

Conditions

Progressive Multiple Sclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Transcranial static magnetic field stimulation (tSMS)

Transcranial static magnetic field stimulation (tSMS) will be performed daily without any interruption during each session of 60 min. Each patient will be instructed to self-administer tSMS, two sessions per day (AM and PM, 6-10 hours apart), sequentially for 60 minutes each, for 6 +6 months.

Group Type: EXPERIMENTAL

Transcranial static magnetic field stimulation (tSMS)

Intervention Type: DEVICE

Patients will be randomly assigned to either real or sham tSMS. Real or sham tSMS will be performed daily without any interruption during each session of 60 min. Each patient will be instructed to self-administer tSMS, two sessions per day (AM and PM, 6-10 hours apart), sequentially for 60 minutes each, for 6 +6 months. Patients will choose whether to undergo stimulation at home or in the hospital on an outpatient setting. Real tSMS will be delivered with two cylindrical neodymium magnets (grade N45) of 45 mm diameter and 30 mm of thickness, with a weight of 360 g (MAG45r; Neurek SL, Toledo, Spain), applied with south polarity, each pointing toward the motor cortex. To discharge the weight of the helmet from the head during the sessions, patients will be instructed to rest the back of head and helmet on an inclined surface in a comfortable position. They will be also instructed to rest, minimizing movement, and not to watch audiovisuals during the stimulation sessions.

Sham tSMS

Sham Transcranial static magnetic field stimulation (tSMS) Sham tSMS will be delivered with non-magnetic metal cylinders, with the same size, weight and appearance of the magnets (MAG45s; Neurek SL, Toledo, Spain). Real and sham magnets will be held with an ergonomic helmet (MAGmv1.0; Neurek SL, Toledo, Spain).

Group Type: SHAM_COMPARATOR

Sham Transcranial static magnetic field stimulation (tSMS)

Intervention Type: DEVICE

Real or sham tSMS will be performed daily without any interruption during each session of 60 min. Each patient will be instructed to self-administer tSMS, two sessions per day (AM and PM, 6-10 hours apart), sequentially for 60 minutes each, for 6 +6 months. Sham tSMS will be delivered with non-magnetic metal cylinders, with the same size, weight and appearance of the magnets (MAG45s; Neurek SL, Toledo, Spain).

Interventions

Transcranial static magnetic field stimulation (tSMS)

Patients will be randomly assigned to either real or sham tSMS. Real or sham tSMS will be performed daily without any interruption during each session of 60 min. Each patient will be instructed to self-administer tSMS, two sessions per day (AM and PM, 6-10 hours apart), sequentially for 60 minutes each, for 6 +6 months. Patients will choose whether to undergo stimulation at home or in the hospital on an outpatient setting. Real tSMS will be delivered with two cylindrical neodymium magnets (grade N45) of 45 mm diameter and 30 mm of thickness, with a weight of 360 g (MAG45r; Neurek SL, Toledo, Spain), applied with south polarity, each pointing toward the motor cortex. To discharge the weight of the helmet from the head during the sessions, patients will be instructed to rest the back of head and helmet on an inclined surface in a comfortable position. They will be also instructed to rest, minimizing movement, and not to watch audiovisuals during the stimulation sessions.

Intervention Type: DEVICE

Sham Transcranial static magnetic field stimulation (tSMS)

Real or sham tSMS will be performed daily without any interruption during each session of 60 min. Each patient will be instructed to self-administer tSMS, two sessions per day (AM and PM, 6-10 hours apart), sequentially for 60 minutes each, for 6 +6 months. Sham tSMS will be delivered with non-magnetic metal cylinders, with the same size, weight and appearance of the magnets (MAG45s; Neurek SL, Toledo, Spain).

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

• Ability to give written informed consent to the study
• Age range 18-65 years
• Diagnosis of primary of secondary progressive MS according to 2017 revised Macdonald's criteria (Thompson et al., 2017), presenting with signs of symptoms of progressive dysfunction of the corticospinal tract
• EDSS ≤ 6,5
• Ability to participate to the study protocol
• No or stable (at least six months) DMT or rehabilitative treatments before study entry, and willingness not to change these therapies (including cannabinoids, SSRI, baclofen) during the study.

Exclusion Criteria

• Relapsing-remitting MS or progressive MS presenting with signs of symptoms other than those typical of the ascending myelopathy phenotype (i.e. progressive cerebellar or cognitive involvement)
• Female with positive pregnancy test at baseline or having active pregnancy plans
• Comorbidities for which synaptic plasticity may be altered (i.e., Parkinson's disease, Alzheimer's disease, stroke)
• Contraindications to TMS
• History or presence of any unstable medical condition such as malignancy or infection
• Use of medications with increased risk of seizures (i.e. Fampridine, 4-Aminopyridine)
• Concomitant use of drugs that may alter synaptic transmission and plasticity (L-dopa, antiepileptics)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Neuromed IRCCS

OTHER

Sponsor Role: lead

Responsible Party

Diego Centonze

Head of Neurology Unit

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

IRCCS Neuromed

Pozzilli, Isernia, Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Diego Centonze, MD, PhD

Role: CONTACT

centonze@uniroma2.it

+39 0865 929170

Facility Contacts

Diego Centonze, MD, PhD

Role: primary

centonze@uniroma2.it

+39 0865 929170

References

Bartlett TE, Wang YT. The intersections of NMDAR-dependent synaptic plasticity and cell survival. Neuropharmacology. 2013 Nov;74:59-68. doi: 10.1016/j.neuropharm.2013.01.012. Epub 2013 Jan 25.

Reference Type: BACKGROUND

PMID: 23357336 (View on PubMed)

Bjornevik K, Munger KL, Cortese M, Barro C, Healy BC, Niebuhr DW, Scher AI, Kuhle J, Ascherio A. Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis. JAMA Neurol. 2020 Jan 1;77(1):58-64. doi: 10.1001/jamaneurol.2019.3238.

Reference Type: BACKGROUND

PMID: 31515562 (View on PubMed)

Bliss TV, Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol. 1973 Jul;232(2):331-56. doi: 10.1113/jphysiol.1973.sp010273.

Reference Type: BACKGROUND

PMID: 4727084 (View on PubMed)

Centonze D, Rossi S, Tortiglione A, Picconi B, Prosperetti C, De Chiara V, Bernardi G, Calabresi P. Synaptic plasticity during recovery from permanent occlusion of the middle cerebral artery. Neurobiol Dis. 2007 Jul;27(1):44-53. doi: 10.1016/j.nbd.2007.03.012. Epub 2007 Apr 5.

Reference Type: BACKGROUND

PMID: 17490888 (View on PubMed)

Di Filippo M, Mancini A, Bellingacci L, Gaetani L, Mazzocchetti P, Zelante T, La Barbera L, De Luca A, Tantucci M, Tozzi A, Durante V, Sciaccaluga M, Megaro A, Chiasserini D, Salvadori N, Lisetti V, Portaccio E, Costa C, Sarchielli P, Amato MP, Parnetti L, Viscomi MT, Romani L, Calabresi P. Interleukin-17 affects synaptic plasticity and cognition in an experimental model of multiple sclerosis. Cell Rep. 2021 Dec 7;37(10):110094. doi: 10.1016/j.celrep.2021.110094.

Reference Type: BACKGROUND

PMID: 34879272 (View on PubMed)

Di Lazzaro V, Profice P, Pilato F, Capone F, Ranieri F, Pasqualetti P, Colosimo C, Pravata E, Cianfoni A, Dileone M. Motor cortex plasticity predicts recovery in acute stroke. Cereb Cortex. 2010 Jul;20(7):1523-8. doi: 10.1093/cercor/bhp216. Epub 2009 Oct 5.

Reference Type: BACKGROUND

PMID: 19805417 (View on PubMed)

Di Lazzaro V, Musumeci G, Boscarino M, De Liso A, Motolese F, Di Pino G, Capone F, Ranieri F. Transcranial static magnetic field stimulation can modify disease progression in amyotrophic lateral sclerosis. Brain Stimul. 2021 Jan-Feb;14(1):51-54. doi: 10.1016/j.brs.2020.11.003. Epub 2020 Nov 10. No abstract available.

Reference Type: BACKGROUND

PMID: 33186779 (View on PubMed)

Disanto G, Barro C, Benkert P, Naegelin Y, Schadelin S, Giardiello A, Zecca C, Blennow K, Zetterberg H, Leppert D, Kappos L, Gobbi C, Kuhle J; Swiss Multiple Sclerosis Cohort Study Group. Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis. Ann Neurol. 2017 Jun;81(6):857-870. doi: 10.1002/ana.24954.

Reference Type: BACKGROUND

PMID: 28512753 (View on PubMed)

Kos D, Kerckhofs E, Carrea I, Verza R, Ramos M, Jansa J. Evaluation of the Modified Fatigue Impact Scale in four different European countries. Mult Scler. 2005 Feb;11(1):76-80. doi: 10.1191/1352458505ms1117oa.

Reference Type: BACKGROUND

PMID: 15732270 (View on PubMed)

Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989 Oct;46(10):1121-3. doi: 10.1001/archneur.1989.00520460115022.

Reference Type: BACKGROUND

PMID: 2803071 (View on PubMed)

Ksiazek-Winiarek DJ, Szpakowski P, Glabinski A. Neural Plasticity in Multiple Sclerosis: The Functional and Molecular Background. Neural Plast. 2015;2015:307175. doi: 10.1155/2015/307175. Epub 2015 Jul 2.

Reference Type: BACKGROUND

PMID: 26229689 (View on PubMed)

Lu Y, Christian K, Lu B. BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem. 2008 Mar;89(3):312-23. doi: 10.1016/j.nlm.2007.08.018. Epub 2007 Oct 17.

Reference Type: BACKGROUND

PMID: 17942328 (View on PubMed)

Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron. 2004 Sep 30;44(1):5-21. doi: 10.1016/j.neuron.2004.09.012.

Reference Type: BACKGROUND

PMID: 15450156 (View on PubMed)

Mori F, Kusayanagi H, Nicoletti CG, Weiss S, Marciani MG, Centonze D. Cortical plasticity predicts recovery from relapse in multiple sclerosis. Mult Scler. 2014 Apr;20(4):451-7. doi: 10.1177/1352458513512541. Epub 2013 Nov 21.

Reference Type: BACKGROUND

PMID: 24263385 (View on PubMed)

Mori F, Rossi S, Piccinin S, Motta C, Mango D, Kusayanagi H, Bergami A, Studer V, Nicoletti CG, Buttari F, Barbieri F, Mercuri NB, Martino G, Furlan R, Nistico R, Centonze D. Synaptic plasticity and PDGF signaling defects underlie clinical progression in multiple sclerosis. J Neurosci. 2013 Dec 4;33(49):19112-9. doi: 10.1523/JNEUROSCI.2536-13.2013.

Reference Type: BACKGROUND

PMID: 24305808 (View on PubMed)

Rossi S, Studer V, Moscatelli A, Motta C, Coghe G, Fenu G, Caillier S, Buttari F, Mori F, Barbieri F, Castelli M, De Chiara V, Monteleone F, Mancino R, Bernardi G, Baranzini SE, Marrosu MG, Oksenberg JR, Centonze D. Opposite roles of NMDA receptors in relapsing and primary progressive multiple sclerosis. PLoS One. 2013 Jun 28;8(6):e67357. doi: 10.1371/journal.pone.0067357. Print 2013.

Reference Type: BACKGROUND

PMID: 23840674 (View on PubMed)

Rossi S, Motta C, Studer V, Macchiarulo G, Volpe E, Barbieri F, Ruocco G, Buttari F, Finardi A, Mancino R, Weiss S, Battistini L, Martino G, Furlan R, Drulovic J, Centonze D. Interleukin-1beta causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53. Mol Neurodegener. 2014 Dec 12;9:56. doi: 10.1186/1750-1326-9-56.

Reference Type: BACKGROUND

PMID: 25495224 (View on PubMed)

Rossi S, Motta C, Studer V, Barbieri F, Buttari F, Bergami A, Sancesario G, Bernardini S, De Angelis G, Martino G, Furlan R, Centonze D. Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration. Mult Scler. 2014 Mar;20(3):304-12. doi: 10.1177/1352458513498128. Epub 2013 Jul 25.

Reference Type: BACKGROUND

PMID: 23886826 (View on PubMed)

Singer BH, Gamelli AE, Fuller CL, Temme SJ, Parent JM, Murphy GG. Compensatory network changes in the dentate gyrus restore long-term potentiation following ablation of neurogenesis in young-adult mice. Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5437-42. doi: 10.1073/pnas.1015425108. Epub 2011 Mar 14.

Reference Type: BACKGROUND

PMID: 21402918 (View on PubMed)

Stampanoni Bassi M, Iezzi E, Pavone L, Mandolesi G, Musella A, Gentile A, Gilio L, Centonze D, Buttari F. Modeling Resilience to Damage in Multiple Sclerosis: Plasticity Meets Connectivity. Int J Mol Sci. 2019 Dec 24;21(1):143. doi: 10.3390/ijms21010143.

Reference Type: BACKGROUND

PMID: 31878257 (View on PubMed)

Stampanoni Bassi M, Iezzi E, Mori F, Simonelli I, Gilio L, Buttari F, Sica F, De Paolis N, Mandolesi G, Musella A, De Vito F, Dolcetti E, Bruno A, Furlan R, Finardi A, Marfia GA, Centonze D, Rizzo FR. Interleukin-6 Disrupts Synaptic Plasticity and Impairs Tissue Damage Compensation in Multiple Sclerosis. Neurorehabil Neural Repair. 2019 Oct;33(10):825-835. doi: 10.1177/1545968319868713. Epub 2019 Aug 20.

Reference Type: BACKGROUND

PMID: 31431121 (View on PubMed)

Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintore M, Traboulsee AL, Trojano M, Uitdehaag BMJ, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-173. doi: 10.1016/S1474-4422(17)30470-2. Epub 2017 Dec 21.

Reference Type: BACKGROUND

PMID: 29275977 (View on PubMed)

Weiss S, Mori F, Rossi S, Centonze D. Disability in multiple sclerosis: when synaptic long-term potentiation fails. Neurosci Biobehav Rev. 2014 Jun;43:88-99. doi: 10.1016/j.neubiorev.2014.03.023. Epub 2014 Apr 12.

Reference Type: BACKGROUND

PMID: 24726576 (View on PubMed)

Yaka R, Biegon A, Grigoriadis N, Simeonidou C, Grigoriadis S, Alexandrovich AG, Matzner H, Schumann J, Trembovler V, Tsenter J, Shohami E. D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury. FASEB J. 2007 Jul;21(9):2033-41. doi: 10.1096/fj.06-7856com. Epub 2007 Mar 9.

Reference Type: BACKGROUND

PMID: 17351125 (View on PubMed)

Zepeda A, Aguilar-Arredondo A, Michel G, Ramos-Languren LE, Escobar ML, Arias C. Functional recovery of the dentate gyrus after a focal lesion is accompanied by structural reorganization in the adult rat. Brain Struct Funct. 2013 Mar;218(2):437-53. doi: 10.1007/s00429-012-0407-4. Epub 2012 Apr 6.

Reference Type: BACKGROUND

PMID: 22481229 (View on PubMed)

Other Identifiers

tSMS-MS

Identifier Type: -

Identifier Source: org_study_id