Combining TMS and EEG, this study investigates a personalized therapeutic non-invasive brain stimulation protocol in patients with major depression, whereby the timing of the TMS pulses is synchronized with the instantaneous phase of ongoing brain oscillations in order to modulate the inter-hemispheric left and right dorso-lateral prefrontal cortical brain network.

Major depressive disorder is a severe psychiatric illness with a lifetime prevalence of about 8-16%. Many patients fail to achieve complete remission of symptoms under antidepressant medication, with about 10% of patients being chronically resistant to several psychopharmacological treatments. Development of alternative non-pharmacological treatments is therefore essential to improve patient care.

Repetitive transcranial magnetic stimulation (rTMS) offers therapeutic potential in this context. Current protocols apply high-frequency rTMS over left dorsolateral prefrontal cortex (DLPFC) to reverse the increased alpha-band oscillatory activity and cortical hypo-excitability in patients with depression. However, translation of rTMS therapy into routine clinical practice has been limited due to low efficacy and high inter-individual variability.

This study aims to optimize rTMS stimulation protocols for MDD by deterministically coupling the timing of TMS to the ongoing oscillatory neural activity in the underlying cortex as measured in real-time with high-density surface EEG. It is hypothesized that alpha phase-locked rTMS of the left DLPFC reverses increased alpha-band oscillatory activity and cortical hypo-excitability more efficiently than current open-loop rTMS protocols used in the treatment of MDD.

Subject inclusion criteria

1. Subjects are between 18 to 65 years old
2. Subjects meet the Diagnostic and Statistical Manual of Mental Disorders (DSM)-4 criteria for current major depressive disorder (MDD), confirmed with the Structured Clinical Interview for DSM-4.
3. On the 21-item Hamilton Rating Scale for Depression (HRSD) subjects need to score 8 points or more.
4. Subject is in good physical and mental health. Subject understands the study procedures and agrees to participate in the study by giving written informed consent.
5. Subject is willing to comply with the study restrictions.

Subject exclusion criteria

1. Subject is under the age of legal consent.
2. Subject suffers of bipolar disorder.
3. Previous failure of nine or more electroconvulsive therapy treatments.
4. A current major depressive episode longer than 5 years.
5. A history of substance abuse or dependence within the past 2 years.
6. Subject suffers of antisocial or borderline personality disorder, active suicidal ideation with plan and/or intent.
7. Subject suffers of current symptoms of psychosis.
8. Subject has a history of seizure disorder.
9. Subject has a history of severe head injury with loss of consciousness.
10. Subject had a prior brain surgery, or any other major psychiatric or medical comorbidity.
11. Subjects with intake of pro-convulsive medication, e.g. imipramine, amitriptyline, doxepin, nortriptyline, maprotiline, chlorpromazine, clozapine, foscarnet, ganciclovir, ritonavir, amphetamines, cocaine, ecstasy, phencyclidine (PCP, angel's dust), ketamine, gamma-hydroxybutyrate (GHB), alcohol, theophylline, in accord with present consensus guidelines on safety, ethical considerations, and application of TMS in clinical practice and research (Rossi et al. 2009).
12. Subjects are allowed to continue their antidepressant medication, but must be on that medication for at least 2 months and on a stable dose for at least 4 weeks (6 weeks in the case of fluoxetine). Drug doses have to be kept constant during the study.
13. Patients with need of regular anxiolytic (e.g. benzodiazepine) treatment above 1 mg lorazepam/d.
14. Subjects are allowed to continue psychotherapy, but must be treated a minimum of 12 weeks prior to inclusion in the study, and type and frequency of psychotherapy must not be changed during the study period.
15. Subject has a cardiac pacemaker, implanted medication pump, intracardiac line, or acute, unstable cardiac disease.
16. Subject has an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head (excluding the mouth) that cannot be safely removed.
17. Subject has participated in another study within 2 weeks prior to the first study visit.
18. Subject has contra-indications to MRI scans or does not agree that (1) the scans are obtained for research purposes only and will not be evaluated by a qualified neuroradiologist; if an abnormality is present, this may well not be noticed by the doctors, scientists and other staff involved in the study and handling the MRI data; and that (2) if any of the staff involved in the study do suspect a relevant abnormality to be present in any of the scans, they will reveal this to the subject so that a further diagnostic workup can be conducted outside of the study.
19. Subject is pregnant or trying to get pregnant.
20. Women of childbearing age should avoid.
21. Contraindications to an MRI