Stimulation of Parieto-hippocampal Connectivity in Patients With Major Depressive Disorder

Study Overview
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Brief Summary
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This study aims to investigate the effects of individualized repetitive transcranial magnetic stimulation (rTMS) of parieto-hippocampal functional connectivity in patients with major depressive disorder (MDD). Specifically, patients will be randomized to one of three groups and will receive 15 days of rTMS over three weeks. Each day they will receive one active session of rTMS over the dorsolateral parietal cortex (DLPFC) and depending on group assignment another session either A) active rTMS over DLPFC, B) active rTMS over left and right lateral parietal cortex (LPC), or C) sham rTMS over DLPFC or LPC. Stimulation targets in the LPC will be individualized for each patient based on their resting-state functional connectivity between the hippocampus and LPC. Clinical, neuropsychological and fMRI data will be acquired before and after the treatment course.

Official Title
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Stimulation of Parieto-hippocampal Connectivity in Patients With Major Depressive Disorder

Conditions
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Depression, Depressive Disorder, Depressive Episode, Depressive Disorder, Major

Intervention / Treatment
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* Device: active rTMS over DLPFC
* Device: Add-on active rTMS over DLPFC
* Device: Add-on active rTMS over LPC
* Device: Add-on sham rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: fulfilled criteria for unipolar major depressive disorder for at least four weeks did not respond to a minimum of one or did not tolerate a minimum of two antidepressants in the current episode Exclusion Criteria: metal in the brain or the skull cardiac pacemaker or intracardiac lines medication infusion devices heart or brain surgery pregnancy substance induced depression history of substance abuse psychotic episodes bipolar disorder anorexia posttraumatic stress disorder (current or within the last 12 months) claustrophobia any condition resulting in increased intracranial pressure traumatic brain injury history of epilepsy cerebral aneurysms dementia Morbus Parkinson Chorea Huntington multiple sclerosis stroke or transient ischemic attack (within the last 2 years) previous antidepressive treatment with rTMS, electroconvulsive therapy (within the last 3 months), vagus nerve stimulation or deep brain stimulation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: DLPFC-DLPFC<br>15 sessions of active rTMS over DLPFC + 15 sessions of active rTMS over DLPFC | Device: active rTMS over DLPFC<br>* 15 sessions of active rTMS over DLPFC<br>Device: Add-on active rTMS over DLPFC<br>* 15 additional sessions of active rTMS over DLPFC<br>|
| Experimental: DLPFC-LPC<br>15 sessions of active rTMS over DLPFC + 15 sessions of active rTMS over LPC | Device: active rTMS over DLPFC<br>* 15 sessions of active rTMS over DLPFC<br>Device: Add-on active rTMS over LPC<br>* 15 additional sessions of active rTMS over LPC<br>|
| Sham Comparator: DLPFC-SHAM<br>15 sessions of active rTMS over DLPFC + 15 sessions of sham rTMS over DLPFC or LPC | Device: active rTMS over DLPFC<br>* 15 sessions of active rTMS over DLPFC<br>Device: Add-on sham rTMS<br>* 15 additional sessions of sham rTMS over DLPFC or LPC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in depression severity as measured by the Hamilton Depression Rating Scale (HAMD-17) | Remission defined as HAMD-17 score (range: 0 to 52, lower scores represent better outcome) of less than or equal to 8 after the rTMS course. Response defined as a reduction of at least 50% from baseline in HAMD-17 score after treatment. | Four measurement time points with a seven-day interval starting on the first day of stimulation, and ending three days after the last day of stimulation | 
| Change in functional connectivity coefficients based on resting-state fMRI | Seed-to-voxel and ROI-to-ROI functional connectivity analysis of rs-fMRI data. | 3 days prior to first rTMS session and 3 days after last rTMS session | 
| Change in task-based fMRI activation during associative memory paradigm | Functional magnetic resonance imaging (fMRI) will be performed to measure blood-oxygen-level dependent signal encoding and retrieval with a focus on hippocampal regions. | 3 days prior to first rTMS session and 3 days after last rTMS session | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in depression severity as measured by the Beck's Depression Inventory (BDI-II) | Remission defined as BDI-II score (range: 0 to 63, lower scores represent better outcome) of less than or equal to 12 after the rTMS course. Response defined as a reduction of at least 50% from baseline in BDI-II score after treatment. | 3 days prior to first rTMS session and 3 days after last rTMS session, follow-up after 4, 8 and 12 weeks | 
| Change in visual memory as assessed by the Delayed Matching to Sample test (DMS) | Subjects will be assessed in the domain of visual memory by undergoing computorized neurological testing. Outcome varible is percentage of correct answers. | 3 days prior to first rTMS session and 3 days after last rTMS session | 
| Change in spatial planning as assessed by the One Touch Stockings of Cambridge (OTS) | Subjects will be assessed in the domain of spatial planning by undergoing computorized neurological testing. Outcome varible is the mean number of choices to correct answer. | 3 days prior to first rTMS session and 3 days after last rTMS session | 
| Change in visual sustained attention as assessed by the Rapid Visual Information Processing (RVP) | Subjects will be assessed in the domain of visual sustained attention by undergoing computorized neurological testing. Outcome varible is the target sensitivity A'. | 3 days prior to first rTMS session and 3 days after last rTMS session | 
| Change in working memory as assessed by the Spatial Working Memory (SWM) | Subjects will be assessed in the domain of working memory by undergoing computorized neurological testing. Outcome varible is the total number of errors. | 3 days prior to first rTMS session and 3 days after last rTMS session | 
| Change in task-based fMRI activation during social touch paradigm | Functional magnetic resonance imaging (fMRI) will be performed to measure blood-oxygen-level dependent signal while participants receive tactile stimulation. | 3 days prior to first rTMS session and 3 days after last rTMS session | 
| Change in task-based fMRI activation during emotional processing paradigm | Functional magnetic resonance imaging (fMRI) will be performed to measure blood-oxygen-level dependent signal while participants perform an emotional processing task. | 3 days prior to first rTMS session and 3 days after last rTMS session | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Repetitive Transcranial Magnetic Stimulation, Theta Burst Stimulation, rTMS, TBS, resting-state fMRI, functional connectivity