Treatment of Major Depression by rTMS on Dorsolateral Prefrontal Cortex: Study of Underlying Mechanisms

The study aims to evaluate the impact of repeated Transcranial Magnetic Stimulation (rTMS) on underlying neuronal mechanisms of adults suffering from major depression disorder (MDD). Short- and long-term effects are assessed by High-Resolution electroencephalography (HR-EEG) or Magnetic Resonance Imaging (MRI) records, experimental tasks and self-rated scales.

Depression is associated with functional and structural changes in the brain, notably in DLPFC (DorsoLateral PreFrontal Cortex). High-frequency rTMS (10 Hz) applied to the left DLPFC is associated with a response rate 3.75 times and remission 2.52 higher than placebo for the treatment of MDD with more reproducible results than those observed for the others rTMS stimulation modalities (low frequency, iTBS5). rTMS is validated as an indication for the treatment of MDD by all learned societies and regulatory authorities in a large number of countries, except in France. Limiting factors concern the lack of knowledge of the action mechanisms, due in particular to the absence of studies based on animal models, the focused application of TMS in rodents being a challenge that few teams have mastered. The rationale for the therapeutic use in the treatment of MDD is now based on some functional brain imaging data showing that rTMS induces a lasting change in brain activity at the site of stimulation (CPFDL) but also in remote interconnected areas such as the limbic region or the amygdala. The DEPSTIM clinical project is part of a translational project with a fundamental approach in rodents.

The main objective is to demonstrate that remission following rTMS of CPFDL occurs via the activation of CPFDL projections to these dysfunctional subcortical areas in MDD.

With a prospective, open design, this study aims to evaluate the impact of iTBS over the left DLPFC on neuronal mechanisms of adults suffering from MDD. Subjects will be submitted to 25 intermittent TBS (iTBS) stimulation sessions for five consecutive days (5 sessions of 9.5 minutes/day, 1,800 pulses per session, 90% of resting motor threshold, placed over the left DLPFC, as mentionned by Cole et al, 2018 (Stanford Neuromodulation Therapy: SNT)). Baseline measures will be compared to those obtained immediately after the end of sessions (Day 5 (D5): short-term effects with HR-EEG analysis), and 30 days (D30) later (long-term effects with MRI analysis).

Eligibility Criteria:
Inclusion Criteria:

* Diagnosis of MDD (Diagnostic and Statistical Manual of Mental Disorders V \[DSM-V\] and (Mini International Neuropsychiatric Interview \[MINI\] criteria, QIDS-C16≥18)
* Right-handed
* No response at a first antidepressant
* Under AD ≥ 6 weeks
* No contraindications for rTMS and MRI
* Absence of addictive comorbidities
* Absence of severe progressive neurologic and/or somatic pathologies (specially tumors, neurodegenerative diseases)
* Inpatients or outpatients of Adult Psychiatric Department
* Signed informed consent form
* Subjects affiliated to or beneficiary from a French social security regime

Exclusion Criteria:

* Subjects under 35 years old or over 65 years old
* Treated with over 4 AD for the current episode
* ECT or rTMS for current episode
* BZD or antiepileptic (except pregabalin up to 75 mg / d, zopiclone ≤7.5 mg / d)
* Left-handed
* Subject under measure of protection or guardianship of justice
* Presence of psychiatric comorbidities
* Subject beneficiary from a legal protection regime
* Subject unlikely to cooperate or low cooperation stated by investigator
* Subject not covered by social security
* Pregnant woman
* Subject being in the exclusion period of another study or provided for by the "National Volunteer File