This group will be under standard therapy (natalizumab) plus Transcranial Magnetic Stimulation (TMS) without any frequency (device doesn't running; it means, device turned off) but the same duration of sessions.

1 Hertz group (1 Hertz ) will be under standard therapy (natalizumab) plus Transcranial Magnetic Stimulation (TMS) running with a frequency of 1 Hertz.

5 Hertz group (5 Hertz ) will be under standard therapy (natalizumab) plus Transcranial Magnetic Stimulation (TMS) running with a frequency of 5 Hertz .

Multiple Sclerosis

By means of the magnetic stimulator we induce a cerebral electric current that is able to obtain a motor potential in the first dorsal interosseous bone of the left hand.
The intervention procedure consists of two steps: First step: Obtaining the Motor Evoked Threshold at Rest: Each patient, regardless of to the group to which they belong will have his/her threshold evoked motor calculated at rest, by stimulation of the right motor cortex, evoking electromyographic responses in the contralateral muscles. Second step: Administration of TMS: To calculate the motive threshold as the percentage of the same to which the treatment will have to be applied, a device equipped with a coil. The treatment will be administered for 5 consecutive days, with 3 weeks of rest, between each stimulation. To complete a treatment period of 14 months. The stimulation with TMS will be carried out every day in the same time slot for 5 consecutive days every 4 weeks, during a period of 14 months.

Transcranial Magnetic Stimulation (TMS)

Administration of Transcranial Magnetic Stimulation at 0 Hz (the patient will be only under drug standar therapy)

Placebos

Transcranial Magnetic Stimulation (TMS) in Multiple Sclerosis

Clinical and Neurochemical Effects of Transcranial Magnetic Stimulation (TMS) in Multiple Sclerosis

Expanded Disability Status Scale. Score from 0 (total absence of disability) to 10 (death due to multiple sclerosis).

Multiple Sclerosis Functional Composite. It consists of three tests: Timed 25-Foot Walk, 9-Hole Peg Test and Paced Auditory Serial Addition Task. Score measured as a function of time. The higher, the worse the patient's condition.

Brief Repeatable Battery of Neuropsychological Test. It consists of the selective reminding test, the 10/36 spatial recall test, the symbol digit modalities test, the paced auditory serial addition test and the word list generation test. A higher score means a better status in a person.

Fatigue Impact Scale. It is based on items derived from interviews with MS patients concerning how fatigue impacts their lives. This instrument provides an assessment of the effects of fatigue in terms of physical, cognitive, and psychosocial functioning. It consists of 21 items. A higher score means a worse status in a person.

Beck depression scale It is a 21-question multiple-choice self-report inventory, one of the most widely used psychometric tests for measuring the severity of depression. Score from 0 to 63 (0 is no depression and 30-63 interval means several depression).

Nuclear Magnetic Resonance with and without contrast

malondialdehyde (ng/mL) and 4-hydroxynonenal (ng/mL)

carbonyl reductase (nmol/mL) and carbonyl (nmol/mL)

Complete blood count (with formula and count of red, white and platelet series)

cholesterol (mg/dL) and triglycerides (mg/dL)

aspartate aminotransferase (AST) (IU/L) and alanine aminotransferase (AST) (IU/L)

To publish the protocol study and its results in Scientific Journals

Javier Caballero-Villarraso

Professor

Maimónides Biomedical Research Institute of Córdoba

Isaac Tunez-Fiñana

Eduardo Agüera-Morales

Phase I clinical trial, unicentric, controlled, randomised, single blind. Three arms.
The patients included will be assigned under the 1:1:1 randomization formula, constituting three groups for the present study: 30 patients treated with natalizumab + white (placebo) + 30 patients treated with natalizumab + TMS (1 Hertz) + 30 patients treated with natalizumab + TMS (5 Hertz).

Single-blind. Investigator who applies transcranial stimulation knows the kind of treatment (placebo, TMS 1 Hertz, TMS 5 Hertz). The patients don't know the frequency (measured Hertz) which TMS is running (0 Hertz= placebo, 1 Hertz, 5 Hertz) and the device and duration of sessions are the same.

Participants will be randomized to receive two teaspoons containing 840 mg GSH (420 mg/tsp) twice daily for 90 days after discharge from Emory University Hospital (EUH).

Participants will be randomized to receive a placebo product identical to liposomal glutathione (GSH) twice daily for 90 days after discharge from Emory University Hospital (EUH).

Malnutrition

Two teaspoons (containing 840 mg GSH, 420 mg/tsp) liposomal GSH (ReadiSorb®) will be taken orally twice daily for a total daily dose of 1680 mg GSH/day. Liposomal GSH will be refrigerated until use and mixed in ≈ 250 mL water or juice for oral intake. The study product will be consumed daily for 90 consecutive days after hospital discharge.

Liposomal Glutathione (GSH)

Two teaspoons of placebo product will be taken orally twice daily. The placebo will be refrigerated until use and mixed in ≈ 250 mL water or juice for oral intake. The placebo will be consumed daily for 90 consecutive days after hospital discharge.

Placebo

Emory University Hospital Clinical Research Center

Glutathione (GSH) Supplementation After Hospitalization

Bioavailable Glutathione Supplementation: During Hospitalization and Beyond

Plasma concentrations of GSH will be collected via blood draw.

GSH concentrations will be compared to glutathione disulfide. Concentrations will be collected and analyzed via blood draw.

GSH and GSSH will be collected via blood draw. Redox potential is a measure of the tendency of a chemical species to acquire electrons and thereby be reduced. The more positive the potential, the greater the affinity for electrons and tendency to be reduced

The DEXA scan will assess body composition by defining lean body mass, total fat mass, and visceral fat mass.

Waist circumference will be measured in centimeters. Change is defined as the difference in measurements from baseline to 90 days post discharge.

Hip circumference will be measured in centimeters. Change is defined as the difference in measurements from baseline to 90 days post discharge.

Body mass index (BMI) is a measure of body fat based on height and weight. A BMI below 18.5 = Underweight; 18.5 - 24.9 = Normal; 25.0 - 29.9 = Overweight; 30.0 and Above = Obese.

Body water is the water content that is contained in the tissues, the blood, the bones and elsewhere. The average TBW% ranges for a healthy adult are: Females - 45 to 60%, Males - 50 to 65%.

Intracellular water volume refers to water located within the cell. This will be measured by BIA, a method used for estimating body composition.

Extracellular water volume refers to water located outside of the cell. This will be measured by BIA, a method used for estimating body composition.

Phase angle is an indicator of cellular health and integrity. A low phase angle is consistent with an inability of cells to store energy and an indication of breakdown in the selective permeability of cellular membranes. A high phase angle is consistent with large quantities of intact cell membranes and body cell mass.

The Short Physical Performance Battery (SPPB) is a tool to assess lower extremity physical performance status.The scores range from 0 (worst performance) to 12 (best performance).

The Timed Up and Go Test assesses mobility. Participants are asked to walk to a line 9.8 feet away, turn around at the line, and walk back at a normal pace. An older adult who takes ≥12 seconds to complete the TUG is at high risk for falling.

Handgrip Dynamometers are instruments for measuring the maximum isometric strength of the hand and forearm muscles, used for testing handgrip strength. Hand muscle measurements are as follows:
Grade 5: full active range of motion & Normal muscle resistance Grade 4: full active range of motion & Reduced muscle resistance Grade 3: full active range of motion & No muscle resistance Grade 2: Reduced active range of motion & No muscle resistance Grade 1: No active range of motion & Palpable muscle contraction only Grade 0: No active range of motion & No palpable muscle contraction

The Life Space Assessment Questionnaire assesses how much the person gets out and about and the spatial extent of the person's typical life space, i.e., what is the usual range of places in which the person engages in activities within the designated time frame.

The Iowa Fatigue Scale assesses fatigue over the past month. General fatigue is a score between 30 and 39. Severe fatigue is a defined as a score between 40 - 55.

The Edmonton Frail Scale assesses and stratifies frailty. Scores range from 0-5 "not frail", 6-7 "vulnerable", 8-9 "mild frailty", 10-11 "moderate frailty", and 12-17 "severe frailty".

The Fatigue Symptom Inventory (FSI), is a 14-item self-report measure designed to assess the severity, frequency, and daily pattern of fatigue as well as its perceived interference with quality of life.

Plasma concentrations Cysteine (Cys) will be collected via blood draw.

Plasma concentrations CySS will be collected via blood draw.

Cys concentrations will be compared to CySS. Concentrations will be collected and analyzed via blood draw.

Cys and CySS will be collected via blood draw. Redox potential is a measure of the tendency of a chemical species to acquire electrons and thereby be reduced. The more positive the potential, the greater the affinity for electrons and tendency to be reduced

disulfide/fatigue

Transcranial Magnetic Stimulation (TMS) in Multiple Sclerosis

Glutathione (GSH) Supplementation After Hospitalization

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