Cortical Lesions in Patients With Multiple Sclerosis

NCT03653585 | Completed DMC

• 1 other identifier: CLiMS
• Study Type: observational
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

Multiple sclerosis (MS) is an autoimmune disease, leading to inflammation and degeneration of neurons in the entire central nervous system (CNS). Not only does MS attack CNS white matter, the wiring of the brain, but it also affects so called grey matter, involved in communication between brain cells. Some studies have shown that grey matter damage and lesions to the outermost layer of the brain, the cortex, might serve as a better diagnostic and prognostic tool for MS patients. The issue is that cortical lesions only to a limited extent can be visualized by conventional magnetic resonance imaging (MRI) at 3 tesla. The new generation of ultra-high field MR scanners with a field strength of 7 tesla, has a higher sensitivity towards detecting these cortical lesions. We therefore wish to use the improved sensitivity of ultra-high field MRI to improve detection of cortical lesions, and to elucidate the detrimental effects of single lesions to the cortex, thereby improving both diagnosis and prognosis of the disease. By implementing newly developed ultra-high-resolution MR-sequences the amount and extent of cortical lesions to the area of the brain responsible of the sensory and motor function of the hand (sensorimotor hand area - SM1-HAND) will be investigated in patients with relapsing remitting and secondary progressive MS. We will also assess how these lesions affect manual dexterity and sensory function and how cortical lesions affect communication within brain areas. It is hypothesized that the amount and size of cortical lesions is highly involved in brain communication and manual function, a major problem in MS, and that this project will shed new light on how the disease damages this important brain area.

Conditions

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Secondary Progressive

Keywords

Multiple Sclerosis; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Transcranial Magnetic Stimulation; Functional Neuroimaging; Cortical Lesion; Sensorimotor cortex; 7T; 7 Tesla

Outcome Measures

Primary Outcomes (2)

• Number of cortical lesions in the primary sensorimotor cortex (SM1)

  Quantified as cortical lesion number on a unihemispheric level in patients with relapsing remitting and secondary progressive multiple sclerosis (RRMS \& SPMS) The extent of damage to the SM1 is unknown, but based on clinical symptoms of motor function we expect that up to 40% of patients show focal cortical lesions in this area. Additionally we wish to explore the relationship between cortical lesions in SM1 and other MRI metrics (e.g. white matter lesion load of the cortico-spinal tract, cortical myelination, cortical thickness, metabolite levels of SM1-HAND and diffusion metrics of the cortico-spinal tract)

  Data collected on day 1 and 2

• Unimanual motor function

  A composite score computed as the mean of Z-scores from the health population (expected range +-4, lower being better motor performance) for unimanual performance in: 9-hole peg test (time in seconds, lower being better), Jebsen Taylor Hand Function Test (time in seconds, lower being better), Finger Tapping (mean times/10seconds from all 5 digits, higher being better). We hypothesize that unimanual motor function correlates negatively with the total cortical lesion load within the contralateral SM1-HAND area, independent of age, gender handedness, white matter lesion volume and axonal integrity of the cortico-spinal tract, central motor conduction time (CMCT) and cortical thickness of the primary sensorimotor cortex.

  Data acquired on day 1

Secondary Outcomes (8)

• Functional brain activation pattern as revealed by task related blood oxygenation level dependent (BOLD) signal changes.

  Data acquired on day 2

• Unimanual sensory acuity

  Data acquired on day 1

• Intra-cortical inhibition and facilitation (Exploratory outcome measure)

  Data acquisition on day 3

• Regional NAA concentration of the SM1

  Data acquired on day 2

• Cortical lesion subtype (Exploratory outcome measure)

  Data acquisition on day 1 and 2

Other Outcomes (10)

• MRI metrics (Exploratory outcome measure)

  Data is collected at a single time point during either the first, second and third day of the experiment

• Cognition

  Assessed on day 1

• Depression

  Assessed on day 1

Study Arms (3)

Lesion negative hemisphere in Healthy Controls (HC)

Data grouped as an un-lesioned primary sensorimotor cortical hemisphere in age and sex matched healthy voluntary participants

Lesion negative hemisphere in patients (PT-N)

Data grouped as an un-lesioned primary sensorimotor cortical hemisphere in MS patients

Lesion positive hemisphere in patients (PT-P)

Lesion positive hemisphere in patients: Data grouped as a lesioned primary sensorimotor cortical hemisphere in MS patients

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Up to 40 healthy control volunteers will be recruited from the general population via the departments webpage (www.drcmr.dk), publicly available advertising media 'http://www.forsoegsperson.dk/', links on social media portal: 'facebook' and advertisements in newsstands and communication-boards in public facilities like canteens, educational institutions, sports facilities and hospitals in the Copenhagen area. Recruitment of 80 patients will in addition be done through the ambulatory care at the Danish Multiple Sclerosis Centre (DMSC) at Rigshospitalet in Copenhagen, Denmark.

You may qualify if:

• Patients
• Expanded Disability Status Scale of \< 7.5
• Diagnosed with either relapsing-remitting or secondary progressive multiple sclerosis
• No clinical relapse within last three months
• Have the ability to comply with all requirements of the study protocol, as determined by the investigator
• Healthy controls
• Able bodied
• Have the ability to comply with all requirements of the study protocol, as determined by the investigator

You may not qualify if:

• Patients
• Pregnancy
• Pacemaker or other implanted electronic devices
• Claustrophobia
• Psychiatric disorder
• Administration of acute cortisol
• Changes in pharmacological treatment within the last 3 months
• Close relatives suffering from epilepsy (only relevant for TMS)
• Migraine (only relevant for TMS)
• Any contraindication to TMS or MRI
• Persons who do not wish to be informed about abnormal findings as part of the investigations
• Healthy controls
• Pregnancy
• Under medication at the time of the experiment (with the exception of contraceptive drugs)
• History of neurologic disease

Sponsors & Collaborators

• Danish Research Centre for Magnetic Resonance: lead
• Scleroseforeningen: collaborator
• Danish Multiple Sclerosis Center: collaborator

Study Sites (1)

Danish Research Centre for Magnetic Resonance

Hvidovre, 2650, Denmark

Location

Related Publications (8)

• Harrison DM, Roy S, Oh J, Izbudak I, Pham D, Courtney S, Caffo B, Jones CK, van Zijl P, Calabresi PA. Association of Cortical Lesion Burden on 7-T Magnetic Resonance Imaging With Cognition and Disability in Multiple Sclerosis. JAMA Neurol. 2015 Sep;72(9):1004-12. doi: 10.1001/jamaneurol.2015.1241.

  PMID: 26192316 BACKGROUND

• Nielsen AS, Kinkel RP, Madigan N, Tinelli E, Benner T, Mainero C. Contribution of cortical lesion subtypes at 7T MRI to physical and cognitive performance in MS. Neurology. 2013 Aug 13;81(7):641-9. doi: 10.1212/WNL.0b013e3182a08ce8. Epub 2013 Jul 17.

  PMID: 23864311 BACKGROUND

• Calabrese M, Poretto V, Favaretto A, Alessio S, Bernardi V, Romualdi C, Rinaldi F, Perini P, Gallo P. Cortical lesion load associates with progression of disability in multiple sclerosis. Brain. 2012 Oct;135(Pt 10):2952-61. doi: 10.1093/brain/aws246.

  PMID: 23065788 BACKGROUND

• de Graaf WL, Kilsdonk ID, Lopez-Soriano A, Zwanenburg JJ, Visser F, Polman CH, Castelijns JA, Geurts JJ, Pouwels PJ, Luijten PR, Barkhof F, Wattjes MP. Clinical application of multi-contrast 7-T MR imaging in multiple sclerosis: increased lesion detection compared to 3 T confined to grey matter. Eur Radiol. 2013 Feb;23(2):528-40. doi: 10.1007/s00330-012-2619-7. Epub 2012 Aug 17.

  PMID: 22898935 BACKGROUND

• Kilsdonk ID, Jonkman LE, Klaver R, van Veluw SJ, Zwanenburg JJ, Kuijer JP, Pouwels PJ, Twisk JW, Wattjes MP, Luijten PR, Barkhof F, Geurts JJ. Increased cortical grey matter lesion detection in multiple sclerosis with 7 T MRI: a post-mortem verification study. Brain. 2016 May;139(Pt 5):1472-81. doi: 10.1093/brain/aww037. Epub 2016 Mar 8.

  PMID: 26956422 BACKGROUND

• Raffin E, Pellegrino G, Di Lazzaro V, Thielscher A, Siebner HR. Bringing transcranial mapping into shape: Sulcus-aligned mapping captures motor somatotopy in human primary motor hand area. Neuroimage. 2015 Oct 15;120:164-75. doi: 10.1016/j.neuroimage.2015.07.024. Epub 2015 Jul 15.

  PMID: 26188259 BACKGROUND

• Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD. Corticocortical inhibition in human motor cortex. J Physiol. 1993 Nov;471:501-19. doi: 10.1113/jphysiol.1993.sp019912.

  PMID: 8120818 BACKGROUND

• Dubbioso R, Raffin E, Karabanov A, Thielscher A, Siebner HR. Centre-surround organization of fast sensorimotor integration in human motor hand area. Neuroimage. 2017 Sep;158:37-47. doi: 10.1016/j.neuroimage.2017.06.063. Epub 2017 Jun 29.

  PMID: 28669907 BACKGROUND

MeSH Terms

Conditions

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis, Chronic Progressive

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Hartwig R Siebner, Professor

  Danish Research Centre for Magnetic Resonance

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 22, 2018
• First Posted: August 31, 2018
• Study Start: September 4, 2018
• Primary Completion: September 3, 2020
• Study Completion: September 3, 2020
• Last Updated: April 8, 2021

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)