e-PAT Neuromod Evaluation of Personalized rTMS for Resistant Depression

Validation of Individualized rTMS Protocol Using Non Invasive Functional Brain Imaging and Robotic Coil Placement in Resistant Depression: Comparison With Classical rTMS and tDCS

Although repetitive trans-cranial magnetic stimulation (rTMS) is an effective therapy for resistant depression, it still fail to remit up to 70% of these patients. We hypothesize that personalizing the procedure using functional MRI to better select dysfunctional regions and robotic coil placement to stimulate these regions homogeneously, will increase its efficacy. Individualized rTMS will be compared to traditional rTMS procedure and to trans-cranial direct current stimulation (tDCS).

In this small proof of principle study our primary outcome measure will be the correction of the MRI anomalies. Symptoms reduction and the proportion of remitters will be secondary outcome measurements.

Study Overview

• Status: Withdrawn
• Conditions: Depressive Disorder; Treatment-Resistant
• Intervention / Treatment: Procedure: Functional magnetic resonance imaging used to individualize rTMS protocol using robotic coil positioning

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Individualized rTMS protocol; The target region will be defined by comparing the rCBF scan of the patient to a control population (n = 80). 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 programmed protocol will be delivered while a figure of eight coil will be positioned by a robotic device (Axilum Robotics). The procedure will be repeated twice a day for 10 days over 2 weeks.	Procedure: Functional magnetic resonance imaging used to individualize rTMS protocol using robotic coil positioning
Active Comparator: High frequency rTMS as usual; rTMS will be performed as usual using a figure-eight coil: Defining the active motor threshold. For each session positioning the coil 5 cm ahead of the abductor pollicis brevis muscle, 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. Coil and stimulator will remain the same between individualized and "as usual" proceedures.	Procedure: Functional magnetic resonance imaging used to individualize rTMS protocol using robotic coil positioning
Active Comparator: Trans-cranial direct current stimulation (tDCS); tDCS will be performed as usual: After controlling for skin healthiness, the anode and the cathode will be respectively placed over F3 and F4. 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 using robotic coil positioning

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction of the target regional cerebral blood flow (rCBF) anomaly	The target region will be defined by comparing the rCBF scan of the patient to a control population (n = 80). rCBF will be measured using the QUIPS2 arterial spin labeling sequence on a Siemens 3T Verio. We will compare the average rCBF of the target region before and after the therapeutic protocol between the different procedures (ANOVA).	difference between before (D-7 to -1) and after (D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol)
Reduction of the functional connectivity anomalies	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 (smoothed by a 8 mm Gaussian kernel). The contrast map of each patient will be compared to the one of a control population submitted to the same analysis. We will compare the number of above threshold voxels (F-test, p < 0.05 uncorrected, extension > 1 cm3) before and after the therapeutic procedure (ANOVA). We will compare the average rCBF of the target region before and after the therapeutic protocol between the different procedures (ANOVA).	difference between before (D-7 to -1) and after (D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 (D-7 to -1) and after (D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol)
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 (D-7 to -1) and after (D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response time and accuracy at the attentional network test	Switch or mixed states (MAThyS); NAA/Choline and Lactate of the target (NMR spectroscopy)	Difference between before (D-7 to -1) and after (D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol)
Quality of life ("Echelle synoptique des 3 temps")	Switch or mixed states (MAThyS); NAA/Choline and Lactate of the target (NMR spectroscopy)	difference between before (D-7 to -1) and after (D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol)
Global Assessment of Functioning	Switch or mixed states (MAThyS); NAA/Choline and Lactate of the target (NMR spectroscopy)	Difference between before (D-7 to -1) and after (D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol)
Activity measured by an actimeter	Switch or mixed states (MAThyS); NAA/Choline and Lactate of the target (NMR spectroscopy)	Difference between before (D-7 to -1) and after (D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol)
Acceptance of each therapeutic procedure	Feeling comfortable with the environment (visual analog scale), this will be evaluated at each stimulation	We will directly compare each therapeutic protocol by averaging this value from D1 to D12.

Collaborators and Investigators

• Sponsor: University Hospital, Strasbourg, France
• Investigators: Principal Investigator: Jack FOUCHER, MD, Service de Psychiatrie 1, Hôpitaux Universitaires de Strasbourg

Study record dates

Study Major Dates

• Primary Completion (Anticipated): May 1, 2020
• Study Completion (Anticipated): May 1, 2020

Study Registration Dates

• First Submitted: April 1, 2015
• First Submitted That Met QC Criteria: April 6, 2015
• First Posted (Estimate): April 7, 2015

Study Record Updates

• Last Update Posted (Estimate): January 5, 2016
• Last Update Submitted That Met QC Criteria: January 4, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Functional Neuroimaging; Transcranial Magnetic Stimulation, Repetitive; Individualized Medicine; Robotic Proceedure; Transcranial Direct Current Stimulation Monocentric; Compariative Cross-Over 3 Arms Study Randomized, Single-Blind Method
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder
• Other Study ID Numbers: 5055