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

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

Treatment of Major Depression by Magnetic Stimulation Repeated Transcranial on 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).

25 active iTBS sessions (5 sessions of 9.5 minutes/day, 1,800 pulses per session, 90% of resting motor threshold, placed over the left DLPFC)

Change from baseline connectivity with fMRI at D30 (prolonged effect) : Resting State Magnetic Resonance Imaging (MRI)

Resting State MRI will allow us to investigate the functional connectivity in the brain, by looking at resting state networks

Score achieved on the validated clinician questionnaire Quick Inventory of Depressive Symptomatology (QIDS-C16) evaluating the severity of depressive symptoms. The QIDS-C16 was derived from specified items in the IDS-C30, clinician-rated scale to assess the severity of a participant's depressive symptoms. Total scores range from 0-27, with a score of 0 indicating no depression and a score of 27 indicating the most severe depression. Negative change from baseline values indicate improvement in the severity of depression.

Score achieved on the validated self-reported (QIDS-SR16) evaluating the severity of depressive symptoms. QIDS-SR-16 is a standard questionnaire "The Quick Inventory of Depressive Symptomatology" (16-Item) (Self-Report). This covers questions on falling asleep, sleep during the night, waking up , sleeping too much, feeling sad ,appetite, weight, concentration , how they view themselves, thoughts of death and suicide, general interests, energy levels, feeling slowed down , feeling restless.

Score achieved on the validated Barratt Impulsiveness Scale (BIS-10) evaluating impulsivity. The French version of the BIS-10 is a self-rated 34 item questionnaire, composed by three subscales: motor-impulsivity, cognitive-impulsivity and non-planning-impulsivity. Each item is scored on a 0 to 4 points scale. Higher scores indicate higher levels of impulsivity.

In the BART participants blow up a series of virtual balloons. With each pump: (a) they earn 5 cents that accumulate in a temporary reserve, but (b) the likelihood of the balloon exploding increases. When this occurs participants lose the money in their temporary reserve. At any time, participants can choose to transfer their earnings to a permanent savings bank (and move to the next balloon). Thus, participants weigh the likelihood of the negative outcome (i.e., the balloon exploding and losing money) with the potential gains (i.e., 5 cents per pump). In the low ambiguity version of the task, the likelihood of the balloon exploding is known. In the high ambiguity version, the likelihood of the balloon exploding is unknown. The average adjusted pump score = average number of pumps on trials in which the balloons did not explode.

Score achieved on the validated MCQ scale (Monetary Choice Questionnaire), assessing delay discounting. Participants will be asked to make a series of hypothetical choices between small, sooner (impulsive) vs. larger, later (self controlled) hypothetical monetary outcomes

Based on the Five-Factor Model, personality traits will be assessed by the French Big Five Inventory questionnaire (BFI-Fr). The BFI-Fr contains 45 self-descriptive statements that assess the 5 personality traits: neuroticism (which refers to a propensity to experience negative emotions, distress, and anxiety), extraversion (a propensity to be energetic, sociable, and experience positive emotions); openness to experience (the tendency to be curious, imaginative, and to entertain new ideas, values, and experiences); conscientiousness (reflecting self-disciplined, planful, and organized); and agreeableness (which refers to cooperativeness and altruism). Each item was rated on a 5-point Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree). All items will be recoded in the direction of the trait label, and the mean will be taken across items for each personality trait.

Score achieved on the validated EEfRT (Effort Expenditure for Rewards Task as an Objective Measure of Motivation and Anhedonia) experimental task. A measure of effort-based decision-making in humans, the Effort Expenditure for Reward Task (EEfRT), will be used. The EEfRT requires participants to choose between a low-effort, low reward task vs a high-effort, high reward task. Willingness to exert effort, or reward motivation, is measured by taking the average number of hard task choices from the first 50 trials.

Score achieved on the validated CyberBall experimental task: a ball tossing playing game in which the experimentor can control the number of throws received by the participants. The task is into 2 parts : first, inclusion condition (Participating in wich they will receive 33% of the throw : 10 in a total of 30) and second, exclusion condition (Participating in wich they will receive 2 time the ball in the 10 first throw then none of them in the last 20 throw).

b-value is a key technique parameter for DTI, which will decide the quality of DTI image. DTI is a sensitive probe of cellular structure that works by measuring the diffusion of water molecules. The measured quantity is the diffusion coefficient, a proportionality constant that relates diffusive flux to a concentration gradient and has units of mm2/s.

Scores achieved on the validated Fagerström scale. The Fagerström test consists of six questions. A score of 0 - 10 is obtained depending on the answers given. A score of 0 - 2 = zero addiction, 3 - 4 = slight addiction, 5 - 6 = moderate addiction, 7 ou 8 heavy addiction and 9 - 10 = very heavy addiction.

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