The pathophysiology of Major Depression Disorder (MDD) is unclear, with several theories for its neurobiological mechanisms. One possible explanation is the presence of altered neuroplasticity, which can be studied by Transcranial Magnetic Stimulation (TMS). Using TMS to study these mechanisms is performed by applying electromagnetic stimuli to the motor cortex, to obtain measures of temporary cortical excitability modulation. It is known that depressed patients with higher cortical modulation are more responsive to a TMS treatment course. However, it is unknown if there are differences in cortical modulation between depressed patients and healthy subjects. Our goal is to answer this question and contribute towards clarification of the neuroplasticity mechanisms underlying MDD. Accordingly, the investigators will access cortical excitability modulation measures in both depressed patients and healthy volunteers and compare their results. The investigators will also re-assess these measures after 6 weeks of antidepressant treatment. Finally, the investigators will study the association between cortical excitability measures and cognitive processes using an innovative cognitive task.

Study objectives

The aim of this study is to evaluate differences in the modulation of cortical excitability by a repetitive Transcranial Magnetic Stimulation (rTMS) protocol between patients with Major Depressive Disorder (MDD) and healthy people. The investigators hypothesize that patients with MDD exhibit less modulation of cortical excitability when compared to healthy people.

In order to accomplish this goal the investigators will:

• Compare measures of cortical excitability between patients with MDD and healthy individuals;
• Compare the degree of modulation of cortical excitability in motor cortex after the application of rTMS, between healthy individuals and patients with MDD;
• Study the progression/evolution of these measures in the group of patients with MDD after 6 weeks of antidepressant treatment, while comparing patients that respond to treatment with patients with symptoms resistant to treatment;
• Analyze the relationship between cortical excitability measures and cortical excitability modulation. Study participants will perform a psychophysical task, on a computer game, in order to evaluate certain cognitive processes and understand if there are differences in performance between patients with depression and healthy subjects.

Data Collection

• Clinical assessment: Clinical interview will be performed with help of psychiatric, psychological and cognitive psychometric instruments (self-report questionnaires and structured interviews) to assess the participants' health.
• Behavioural assessment: Participants will perform a psychophysical task in the form of a computer game.
• Neurophysiological evaluation: protocol for assessing excitability and excitability modulation of the motor cortex by EMT and EMTr (ETBi).

Procedures

The participants recruited for the present project will be patients who are already being treated by health professionals at the Champalimaud Clinical Center, as well as healthy individuals, recruited from the nearby community. One cohort will include patients with active/symptomatic MDD and a second cohort will include patients with MDD in remission that are still in treatment. The third cohort will include a control group of healthy individuals. After they are referred to participate in this study, and if consent to participate is collected, they will be assessed to confirm their eligibility and group allocation will be performed. The study participants from all three observational groups will be submitted to (1) full clinical information assessment, (2) will be asked to perform a psychophysical task, i.e. a computer game. Finally, (3) the neurophysiological evaluation protocol will be applied. This neurophysiological evaluation protocol will be performed in two visits separated by at least 48h. This will make it possible to assess cortical excitability measures in both hemispheres independently and safely, allowing the acquisition of interhemispheric asymmetry measures. The order in which the cerebral hemispheres will be assessed will be randomized between participants. The first visit should take no longer than 120 minutes, and the second will last less than 45 minutes. Participants in the study will also be asked to come for a second study visit, to the Champalimaud Clinical Center, approximately 6 weeks after the first visit, the same study protocol will be repeated, in two consecutive sessions with the same procedures.Participants will not be rewarded monetarily; they will be supported for travel to the Clinical Center that may be necessary outside their individual clinical follow-up

Inclusion criteria (clinical groups):

1. Diagnosis of major depressive episode or disorder as provided in the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) (American Psychiatric Association. 2013).

Exclusion criteria (clinical groups):

1. Moderate to severe suicide risk;
2. Known personal history of bipolar disorder or psychotic disorder;
3. Alcohol or other substance abuse and/or dependence;
4. Developmental disorder;
5. Dementia;
6. Presence of uncontrolled active medical illness;
7. Known structural lesion of the central nervous system;
8. Electrical or metallic brain implants;
9. Cardiac implants;
10. Epilepsy;
11. Active use of medication known to cause seizures;
12. Pregnancy;
13. Breastfeeding.

For the healthy control group, participants will also be recruited at the Champalimaud Clinical Center, by advertisement in places of public circulation. The recruitment of this population will be done in order to generate a pairing with both clinical groups in terms of age and sex. The same exclusion criteria will be applied, as well as the presence of any history of neuropsychiatric disease. The total number of participants for this study will be approximately 90 volunteers. Exclusion criteria will be assessed through self-report and/or MINI.

Participants in this study will be adults, aged 18 to 65 years, that will be recruited either for the clinical groups or healthy subjects group. The clinical population will include individuals with MDE diagnosis, and will be divided into two clinical groups:

1. Patients in the acute phase of MDE, at the time they start a new antidepressant treatment (n≈30);
2. Patients with symptomatic improvement, on continuation or maintenance antidepressant treatment (n≈30).

All groups, including healthy subjects, will be paired by age and sex.

There is no plan to make individual participant data (IPD) available to other researchers.