Aerobic Training Effects on Motor and Cognitive Performances in MS: an Exploratory Study With Structural and Functional MRI

NCT04097418 | Unknown

• 1 other identifier: Training aerobico-SM 2015
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

Aerobic training (AT) induces cardiovascular, metabolic and muscular changes and has been proposed as a promising rehabilitative approach in elderly adults and in neurological patients to improve both motor and cognitive performances. The Investigators wish to explore the role of AT in multiple sclerosis (MS) patients on physical and neuropsychological functions and its underlying anatomical and functional substrates, using advanced magnetic resonance imaging (MRI) methods. In this project, the Investigators wish to apply aerobic training in right-handed MS patients and healthy controls to assess:

1. 1.the effects of aerobic training compared to conventional motor training on motor and cardio-vascular parameters;
2. 2.the effect of aerobic training compared to conventional motor training on cognitive performance, depression and fatigue;
3. 3.the modifications of functional activations during a cognitive task and of functional connectivity in motor and cognitive networks during resting state following aerobic training and conventional motor training (functional plasticity);
4. 4.the regional variations of gray matter (GM) volumes and white matter (WM) architecture after aerobic training and conventional motor training (structural plasticity);
5. 5.the correlations between the changes detected with structural and functional MRI and clinical, motor and neuropsychological scales.

Conditions

Multiple Sclerosis

Keywords

Multiple Sclerosis; Aerobic Training; rehabilitation

Outcome Measures

Primary Outcomes (10)

• Longitudinal changes of brain GM volumes following aerobic training or conventional motor training

  Tensor-Based Morphometry will be applied on 3D T1-weighted sequence to evaluate regional GM volume changes that will be reported as t values, ranging from 0 (no statistically significant changes) to infinity (highly statistically significant changes).

  2 months

• Longitudinal changes of WM microstructural abnormalities following aerobic training or conventional motor training

  Tract-based Spatial Statistics will be applied on diffusion-tensor MRI sequence to evaluate longitudinal changes of fractional anisotropy (a dimensionless quantity ranging from 0 \[more severe damage\] to 1 \[less severe damage\]), mean diffusivity (expressed in \[(mm\^2)/s\]×10\^-3 and ranging from 0 \[less severe damage\] to infinity \[more severe damage\]), axial diffusivity (expressed in \[(mm\^2)/s\]×10\^-3 and ranging from 0 \[less severe damage\] to infinity \[more severe damage\]) and radial diffusivity (expressed in \[(mm\^2)/s\]×10\^-3 and ranging from 0 \[less severe damage\] to infinity \[more severe damage\]). Longitudinal WM microstructural changes will be reported as t values, ranging from 0 (no statistically significant changes) to infinity (highly statistically significant changes).

  2 months

• Resting State Functional Connectivity MRI changes following aerobic training or conventional motor training

  Group independent component analysis Of fMRI Toolbox (GIFT) software will be applied to evaluate the modifications of resting state functional connectivity. This will be reported as z-scores, ranging from minus infinity (reduced connectivity) to infinity (increased connectivity). Longitudinal changes in resting state functional connectivity will be obtained subtracting baseline z-score to z-score at follow-up. A positive score means increased connectivity, a negative score, a decreased connectivity.

  2 months

• Functional MRI changes following aerobic training or conventional motor training

  Statistical Parametric Mapping 12 will be applied to functional MRI sequence acquired during the Stroop task to evaluate the modifications of functional activations during this cognitive task. They will be reported as t values, ranging from 0 (no statistically significant changes) to infinity (highly statistically significant changes).

  2 months

• Effects of aerobic training compared to conventional motor training on global clinical disability

  Rating of Expanded Disability Status Scale (EDSS) score changes: EDSS is a scale ranging from 0 (no disability) to 10 (death due to multiple sclerosis). Longitudinal changes will be obtained subtracting baseline EDSS to EDSS at follow-up. A positive score means disability worsening, a negative score, an improvement in disability.

  2 months

• Effects of aerobic training compared to conventional motor training on clinical disability

  Rating of Multiple Sclerosis Functional Composite (MSFC) score changes: the MSFC a composite score ranging from minus infinity (worse performances) to infinity (better performances) obtained from the sum of the z-scores derived from 1) Paced Auditory Serial Addition Test (PASAT) to evaluate cognitive functions, 2) timed 25-foot walk test to evaluate walking speed, and 3) nine-hole peg test to evaluate arm and hand dexterity. Longitudinal changes will be obtained subtracting baseline MSFC to MSFC at follow-up. A positive score means disability improvement, a negative score, a worsening in disability.

  2 months

• Effects of aerobic training compared to conventional motor training on behavioural measures

  Rating of functional Independent measurement (FIM) scale changes: the FIM scale is an 18-item of physical, psychological and social functions, ranging from 18 (worse disability) to 126 (total autonomy) and obtained from the sum of 18 items, each of them ranging from 1 to 7. Longitudinal changes will be obtained subtracting baseline FIM to FIM at follow-up. A positive score means behavioural improvements, a negative score, a worsening in behavioural functions.

  2 months

• Effects of aerobic training compared to conventional motor training on spasticity

  Rating of Modified Ashworth Scale changes: the Modified Ashworth Scale is a 6-point scale, ranging from 0 to 4, where lower scores represent normal muscle tone and higher scores represent spasticity or increased resistance to passive movement. Longitudinal changes will be obtained subtracting baseline Modified Ashworth scale to Modified Ashworth scale at follow-up. A positive score means spasticity worsening, a negative score, an improvement in spasticity.

  2 months

• Effects of aerobic training compared to conventional motor training on walking ability

  Assessment of Six minutes walking test changes: this is a submaximal exercise test that entails measurement of distance walked over a span of 6 minutes. It is expressed in meters and ranges from 0 (worse performance) to infinity (better performance). Longitudinal changes will be obtained subtracting baseline distance to distance walked at follow-up. A positive score means walking improvement, a negative score, a worsening of walking ability.

  2 months

• Effects of aerobic training compared to conventional motor training on person's mobility

  Assessment of Time up-and-go test changes: this is test assessing both static and dynamic balance. It uses the time (expressed in seconds) that a person takes to rise from a chair, walk three meters, turn around, walk back to the chair, and sit down. It ranges from 0 (better performance) to infinity (worse performance). Longitudinal changes will be obtained subtracting baseline seconds to seconds needed at follow-up. A positive score means performance worsening, a negative score, an improvement in the performance.

  2 months

Secondary Outcomes (4)

• Effects of aerobic training compared to conventional motor training on cognitive functions

  2 months

• Effects of aerobic training compared to conventional motor training on fatigue

  2 months

• Effects of aerobic training compared to conventional motor training on depression

  2 months

• Effects of aerobic training compared to conventional motor training on quality of life

  2 months

Study Arms (4)

Aerobic training in healthy subjects

EXPERIMENTAL

For each healthy subject, the treatment will lasts 8 weeks. Each treatment will consists of 35 minutes of training, administered 3 times per week. Subjects of the experimental groups (both patients and healthy controls) will carry out an aerobic training of moderate intensity (fixed time and variable intensity) on a treadmill. The training will be set individually via direct method: during the first session, the subject will be trained at an intensity that gets the heart rate (HR) corresponding to 46-63% of VO2 peak measured during the exercise test; in subsequent sessions the intensity will increase to maintain the same HR, which will be always monitored. The intensity workout identified will be maintained for 30 minutes each session, preceded and followed by a few minutes of warm-up and cool-down.

Behavioral: Aerobic training compared to conventional motor training

Conventional motor training of healthy subjects

ACTIVE COMPARATOR

For each healthy subject, the treatment will lasts 8 weeks. Each treatment will consists of 35 minutes of training, administered 3 times per week. Control groups of both patients and healthy subjects will follow a conventional non-aerobic physiotherapy training, structured in: 15 minutes of passive mobilization of upper and lower limbs and spine, 5 minutes of stretching of the upper and the lower limbs and 10 minutes of balance training.

Behavioral: Aerobic training compared to conventional motor training

Aerobic training in MS patients

EXPERIMENTAL

For each MS patient, the treatment will lasts 8 weeks. Each treatment will consists of 35 minutes of training, administered 3 times per week. Subjects of the experimental groups (both patients and healthy controls) will carry out an aerobic training of moderate intensity (fixed time and variable intensity) on a treadmill. The training will be set individually via direct method: during the first session, the subject will be trained at an intensity that gets the heart rate (HR) corresponding to 46-63% of VO2 peak measured during the exercise test; in subsequent sessions the intensity will increase to maintain the same HR, which will be always monitored. The intensity workout identified will be maintained for 30 minutes each session, preceded and followed by a few minutes of warm-up and cool-down.

Behavioral: Aerobic training compared to conventional motor training

Conventional motor training of MS patients

ACTIVE COMPARATOR

For each MS patient, the treatment will lasts 8 weeks. Each treatment will consists of 35 minutes of training, administered 3 times per week. Control groups of both patients and healthy subjects will follow a conventional non-aerobic physiotherapy training, structured in: 15 minutes of passive mobilization of upper and lower limbs and spine, 5 minutes of stretching of the upper and the lower limbs and 10 minutes of balance training.

Behavioral: Aerobic training compared to conventional motor training

Interventions

Aerobic training compared to conventional motor training BEHAVIORAL

Aerobic training: aerobic training by treadmill at moderate intensity. Each treatment will consists of 35 minutes of training, administered 3 times per week, for 8 weeks. Conventional motor training: 15 minutes of passive mobilization of upper and lower limbs and spine, 5 minutes of stretching of the upper and the lower limbs and 10 minutes of balance training, administered 3 times per week, for 8 weeks.

Also known as: Conventional motor training

Aerobic training in MS patients; Aerobic training in healthy subjects; Conventional motor training of MS patients; Conventional motor training of healthy subjects

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age between 18 and 65 years;
• Native italian language speaking;
• Right-handed;
• No particular motor skills;
• No additional neurologic, psychiatric, orthopaedic or rheumatologic diseases;
• Normal or corrected-to-normal vision;
• No contraindications to MRI;
• Ability to understand the purpose of the study and provide signed informed consent.
• Patients with a diagnosis of MS, regardless of sex, duration and course of the disease;
• EDSS score ranging from 0 to 6.0 (included);
• Stable treatment for MS from at least 1 month prior to study enrolment;
• Relapse- and steroid-free from at least 3 months before screening visit;
• An indication to perform a physiotherapy treatment by the treating physician.

You may not qualify if:

• Persons who perform regularly a structured training;
• Patients who performed a physiotherapy treatment for at least 3 months;
• Concomitant therapy with antidepressant, baclofen, psychoactive, and steroids drugs as well as symptomatic treatment for fatigue;
• History of alcohol or substance abuse;
• Pregnancy or breastfeeding.

Sponsors & Collaborators

• IRCCS San Raffaele: lead

Study Sites (1)

IRCCS San Raffaele

Milan, 20132, Italy

RECRUITING

Related Publications (9)

• Motl RW, Pilutti LA. The benefits of exercise training in multiple sclerosis. Nat Rev Neurol. 2012 Sep;8(9):487-97. doi: 10.1038/nrneurol.2012.136. Epub 2012 Jul 24.

  PMID: 22825702 BACKGROUND

• Prakash RS, Snook EM, Motl RW, Kramer AF. Aerobic fitness is associated with gray matter volume and white matter integrity in multiple sclerosis. Brain Res. 2010 Jun 23;1341:41-51. doi: 10.1016/j.brainres.2009.06.063. Epub 2009 Jun 25.

  PMID: 19560443 BACKGROUND

• Ashburner J. A fast diffeomorphic image registration algorithm. Neuroimage. 2007 Oct 15;38(1):95-113. doi: 10.1016/j.neuroimage.2007.07.007. Epub 2007 Jul 18.

  PMID: 17761438 BACKGROUND

• Leow AD, Klunder AD, Jack CR Jr, Toga AW, Dale AM, Bernstein MA, Britson PJ, Gunter JL, Ward CP, Whitwell JL, Borowski BJ, Fleisher AS, Fox NC, Harvey D, Kornak J, Schuff N, Studholme C, Alexander GE, Weiner MW, Thompson PM; ADNI Preparatory Phase Study. Longitudinal stability of MRI for mapping brain change using tensor-based morphometry. Neuroimage. 2006 Jun;31(2):627-40. doi: 10.1016/j.neuroimage.2005.12.013. Epub 2006 Feb 15.

  PMID: 16480900 BACKGROUND

• Smith SM, Jenkinson M, Johansen-Berg H, Rueckert D, Nichols TE, Mackay CE, Watkins KE, Ciccarelli O, Cader MZ, Matthews PM, Behrens TE. Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. Neuroimage. 2006 Jul 15;31(4):1487-505. doi: 10.1016/j.neuroimage.2006.02.024. Epub 2006 Apr 19.

  PMID: 16624579 BACKGROUND

• Calhoun VD, Adali T, Pearlson GD, Pekar JJ. A method for making group inferences from functional MRI data using independent component analysis. Hum Brain Mapp. 2001 Nov;14(3):140-51. doi: 10.1002/hbm.1048.

  PMID: 11559959 BACKGROUND

• Nichols TE, Holmes AP. Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp. 2002 Jan;15(1):1-25. doi: 10.1002/hbm.1058.

  PMID: 11747097 BACKGROUND

• Hayasaka S, Peiffer AM, Hugenschmidt CE, Laurienti PJ. Power and sample size calculation for neuroimaging studies by non-central random field theory. Neuroimage. 2007 Sep 1;37(3):721-30. doi: 10.1016/j.neuroimage.2007.06.009. Epub 2007 Jun 18.

  PMID: 17658273 BACKGROUND

• Friston KJ, Holmes AP, Price CJ, Buchel C, Worsley KJ. Multisubject fMRI studies and conjunction analyses. Neuroimage. 1999 Oct;10(4):385-96. doi: 10.1006/nimg.1999.0484.

  PMID: 10493897 BACKGROUND

MeSH Terms

Conditions

Multiple Sclerosis

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Massimo Filippi, MD

  IRCCS San Raffaele

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Massimo Filippi, MD

CONTACT

00390226433054; filippi.massimo@hsr.it

Maria Assunta Rocca, MD

CONTACT

00390226433019; rocca.mara@hsr.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The computerized randomization software will generate personal codes to allocate every patient to a treatment arm. These codes will be placed in opaque envelopes and delivered to the patient by an operator external to the study.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Neurology

Model Details: This study is a monocentric, non-pharmacological, longitudinal, randomized, blind, controlled study. Subjects The Investigators will study 40 MS patients and 40 HC. Subjects will then be randomized through a sequence generated by the computer to determine their assignment to the conventional motor rehabilitation therapy group (control group) or to the aerobic training (experimental group). The computerized randomization software will generate personal codes to allocate every patient to a treatment arm. Participants will be split into 4 groups of 20 subjects per group: 1. Group of aerobic training of healthy subjects: aerobic training by treadmill at moderate intensity; 2. Group of conventional motor training of healthy subjects: training of passive mobility, stretching and balance; 3. Group of aerobic training of MS patients: aerobic training by treadmill at moderate intensity; 4. Treatment group control of MS patients: training of passive mobility, stretching and balance.

Study Record Dates

• First Submitted: September 17, 2019
• First Posted: September 20, 2019
• Study Start: June 13, 2015
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: September 28, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: The dataset including all the data obtained from this study will be available 6 months after the publication of the results.
• Access Criteria: The dataset including all the data obtained from this study will be available from the Principal Investigator upon reasonable request.

Locations

IT (1)