Multiple Sclerosis (MS) is the most frequent cause of non-traumatic disability in people under 55 years of age. Fatigue is the most frequent and disabling symptom in the disease, and for which there is no effective treatment. Among the proposed drugs, amantadine is the one that could be most useful, although up to now it has not been adequately demonstrated due to a lack of sufficiently powerful and methodologically appropriate clinical trials. Transcranial magnetic stimulation (TMS) has recently been proposed as a useful treatment for fatigue in MS in preliminary studies.

Multiple Sclerosis (MS) is the most frequent cause of non-traumatic disability in people under 55 years of age. Fatigue is the most frequent and disabling symptom in the disease, and for which there is no effective treatment. Among the proposed drugs, amantadine is the one that could be most useful, although up to now it has not been adequately demonstrated due to a lack of sufficiently powerful and methodologically appropriate clinical trials. Transcranial magnetic stimulation (TMS) has recently been proposed as a useful treatment for fatigue in MS in preliminary studies.

The main objective of the study is to evaluate the change in the severity of fatigue in MS patients undergoing treatment with amantadine, TMS and both in combination, compared to placebo. A randomized, placebo-controlled, crossover, double-blind clinical trial will be conducted. As secondary objectives, changes in cognition, depression and quality of life will be evaluated. For all this, the reference scales adequately validated for each of the objectives will be used.

Inclusion Criteria:

1. Expanded Disability Status Scale mark 1.5 - 4.5
2. Fatigue Severity Scale > 4
3. Beck Depression Inventory < 30
4. No relapse for, at least, three month prior to screening
5. Drug washout period = 4 weeks for any fatigue aimed drug
6. Patient capable to sign the informed consent

Exclusion Criteria:

1. Fatigue causing disease other than multiple sclerosis:

   1. sleep apnea
   2. other autoimmune disease that could be explain the fatigue.
   3. endocrine autoimmune disease if the blood test is not in range in the last 6 month.
   4. patient with diagnosis of chronic fatigue
   5. Patient with high blood pressure out of range or decompensated heart failure or New York Heart Association (NYHA) 3-4.

2. Secondary Epilepsy or neuropathic chronic pain which requires continuous treatment.

3. Contraindication for trial treatment:

   1. Some kind of magnetic metal.
   2. Epilepsy antecedents.
   3. Any drugs that could decrease the seizure threshold
   4. Amantadine sensitivity
   5. Cardiopathy disease, severe kidney failure, Angle-closure glaucoma

4. Breastfeeding, pregnancy, or pregnancy planning phase in the next year. Of childbearing potential and willing to use an acceptable method of contraception during the study period.

5. Patient with a terminal disease with no more than one year life expectancy.

6. Patient has been treated for a maligned disease in the past three years.

7. A scheduled surgery in the course of the trials.

8. Any condition that a member of research team consider could affect to participation/follow up patient.

9. Alcoholic o toxics condition in the last year.

10. Major mental disorders

11. Poor communication skills or poor cognitive condition.

12. Other trial participation in the previous 4 month.

13. Use a chronic drug that could interfere in the clinical outcome.

The data used will be deposited in a suitable repository that will be complied with the requirements of ISCIII and any other applicable national regulations. Due to the data collected retain their personal character and they can be traced back, they will be safeguarded maintaining their integrity and confidentiality. These data cannot be openly shared after the project's completion. The licenses and access permissions will be determined based on the following criteria before the project's completion: a) The guidelines or recommendations of ISCIII. b) The policies established by the data repository to which the data will be sent. c) Possible restrictions on data publication that may arise from applicable protection schemes for the project's results. In any case, the requirements set forth by ISCIII in the funding call received will be complied with, as well as those considered in other applicable regulations. The dataset used will be stored in a locked condition for a period of 5 years.