Personalized rTMS for Resistant Depression

Study Overview
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Brief Summary
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The investigators hypothesize that personalizing the rTMS targets using functional MRI will increase its efficacy. The most dysfunctional regions or the most dysfunctional network will be stimulated homogeneously. Individualized rTMS will be compared to traditional rTMS procedure and to trans-cranial direct current stimulation (tDCS) in a randomized cross-over trial. In this pilot study the primary outcome measure will be the correction of the MRI anomalies. Symptoms reduction and the proportion of remitters will be secondary outcome measurements.

Official Title
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Validation of Personalized Antidepressant Treatment by Neuromodulation - Pilot Study

Conditions
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Depressive Disorder, Treatment-Resistant

Intervention / Treatment
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* Procedure: Functional magnetic resonance imaging used to individualize rTMS protocol
* Device: Individualized rTMS (transcranial magnetic stimulation)
* Device: Classical rTMS (transcranial magnetic stimulation)
* Device: Classical tDCS (transcranial direct current stimulation)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged from 18 to 65 Y Affiliated to the health insurance Having signed an informed consent Suffering from major depression according to the DSM5 Unresponsive or incomplete remission after at least one trial of antidepressant (> 6 weeks at efficient dose or side effects) Treatment stable for > 6 weeks Exclusion Criteria: Contraindication for MRI, rTMS or tDCS: non-removable ferromagnetic body, prosthesis, pacemaker, medication delivered by an implanted pump clip or vascular stent, heart valve or ventricular shunt, seizure disorders, skin pathology in the region of tDCS electrode placement. Pregnancy Severe and non-stabilized somatic pathology Patients deprived of liberty or hospitalized without their consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Individualized rTMS (transcranial magnetic stimulation)<br>The target region will be defined by comparing the rCBF scan of the patient to a control population (n = 38). rCBF will be measured using the QUIPS2 arterial spin labeling sequence on a Siemens 3T Verio. The therapeutic protocol will be design to correct the rCBF anomaly first by defining each point where to deliver the stimulation than the stimulation protocol for each point (180% of active motor threshold, 4-second 10 Hz train duration, with 26-second intertrain interval for a total of 3000 pulses). The whole target will be homogeneously stimulated. The active motor threshold will be assessed. The procedure will be repeated twice a day for 10 days over 2 weeks. | Procedure: Functional magnetic resonance imaging used to individualize rTMS protocol<br>* Procedure consisting in personalizing the rTMS targets and stimulation pattern based on functional magnetic resonance imaging<br>Device: Individualized rTMS (transcranial magnetic stimulation)<br> <br> |
| Active Comparator: Classical rTMS (transcranial magnetic stimulation)<br>rTMS will be performed as usual using a figure-eight coil: Defining the active motor threshold. For each session positioning the coil on F3, stimulating at 180% of active motor threshold (10 Hz, 4-second train duration, and 26-second intertrain interval) for 37.5 minutes (3000 pulses per session), twice a day for 10 days over 2 weeks. | Procedure: Functional magnetic resonance imaging used to individualize rTMS protocol<br>* Procedure consisting in personalizing the rTMS targets and stimulation pattern based on functional magnetic resonance imaging<br>Device: Classical rTMS (transcranial magnetic stimulation)<br> <br> |
| Active Comparator: Classical tDCS (transcranial direct current stimulation)<br>tDCS will be performed as usual: After controlling for skin healthiness, the anode and the cathode will be respectively placed over F3 and right shoulder. A commercial devices (MagStim), will deliver a constant current of 2 mA through 25 cm2 saline-soaked rubber sponges for 20 min per session. The procedure will be repeated twice a day for 10 days over 2 weeks. | Procedure: Functional magnetic resonance imaging used to individualize rTMS protocol<br>* Procedure consisting in personalizing the rTMS targets and stimulation pattern based on functional magnetic resonance imaging<br>Device: Classical tDCS (transcranial direct current stimulation)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of rCBF anomalies | The target region will be defined by comparing the rCBF scan of the patient to a control population. rCBF will be measured using the average of 2 ∙ 3 (=6) measures of rCBF using QUIPS2 arterial spin labeling sequence on a Siemens 3T Verio. rCBF change of the target region will be compared before & after therapeutic protocol between the different procedures (ANOVA). Functional connectivity map of the target region will be performed by extracting its average temporal course and looking at the region(s) which activity is correlated. Contrast map of each patient will be compared to the one of a control population submitted to the same analysis. Change in the number of above threshold voxels (F-test, p < 0.05 uncorrected, extension > 1 cm3) will be compared before & after therapeutic procedure (ANOVA). rCBF's change of the target region will be compared before & after therapeutic protocol between the different procedures (ANOVA). | Difference between before (assessed once between D-7 to -1) and after (assessed once between D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol) | 
| Change of the functional connectivity anomalies | The target region will be defined by comparing the rCBF scan of the patient to a control population. rCBF will be measured using the average of 2 ∙ 3 (=6) measures of rCBF using QUIPS2 arterial spin labeling sequence on a Siemens 3T Verio. rCBF change of the target region will be compared before & after therapeutic protocol between the different procedures (ANOVA). Functional connectivity map of the target region will be performed by extracting its average temporal course and looking at the region(s) which activity is correlated. Contrast map of each patient will be compared to the one of a control population submitted to the same analysis. Change in the number of above threshold voxels (F-test, p < 0.05 uncorrected, extension > 1 cm3) will be compared before & after therapeutic procedure (ANOVA). rCBF's change of the target region will be compared before & after therapeutic protocol between the different procedures (ANOVA). | Difference between before (assessed once between D-7 to -1) and after (assessed once between D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in symptoms evaluated by the clinician (QIDS16-C) | See http://www.ids-qids.org/ for documentation relative to these scales. Computation will be performed in terms of : percentage of symptom reduction Number responders (reduction of more than 50% of symptoms) & numbers of remitters (QIDS16-C ≤ 6). | Difference between before (assessed once between D-7 to -1) and after (assessed once between D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol). | 
| Change in symptoms evaluated by the patient (QIDS30-SR) | See http://www.ids-qids.org/ for documentation relative to these scales. Computation will be performed in terms of : percentage of symptom reduction Number responders (reduction of more than 50% of symptoms) & numbers of remitters (QIDS16-C ≤ 6). | Difference between before (assessed once between D-7 to -1) and after (assessed once between D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Individualized Medicine, Transcranial Magnetic Stimulation, Repetitive, Transcranial Direct Current Stimulation Monocentric, Compariative Cross-Over 3 Arms Study Randomized, Single-Blind Method, Functional Neuroimaging