Deep TMS for Comorbid Depression and Cognitive Impairment in Older Adults

Study Overview
=================
Brief Summary
-----------------
In this study, the investigators will be examining the effects of the deep repetitive transcranial magnetic stimulation (rTMS) using the H1 coil in patients over the age of 60 diagnosed with mild to early-moderate Alzheimer's disease (AD) or mild cognitive impairment (MCI) and comorbid Major Depressive Disorder (MDD) who have been unable to tolerate or failed to respond to antidepressant medications. The coil was designed to stimulate deeper regions of the left dorsolateral prefrontal cortex (DLPFC). Based on prior research, the investigators propose that active stimulation with the H1 coil for 4 weeks may result in significant remission rates and will be tolerable and safe.

Detailed Description
-----------------
This study is an open-label trial to evaluate the safety and efficacy of H1-coil dTMS in treating depression in MCI and mild AD patients over 60 years of age who have not tolerated or failed to respond to antidepressant medications. 28 patients will be assigned to receive 4 consecutive weeks of daily active dTMS treatment. The long-term effects of treatment on emotional cognitive measures will be assessed at a 4-week follow-up visit (8 weeks from baseline). Symptom change and remission criteria will be assessed using the Montogmery-Asberg Depression Rating Scale (MADRS). Cognition will be assessed using a validated neuropsychological battery. We will also offer patients to receive 4 weeks of treatment using theta-burst TMS, which is a milder version of TMS.

Official Title
-----------------
Treatment of Comorbid Depression and Cognitive Impairment in Older Adults With Neurocognitive Disorders Using Deep Transcranial Magnetic Stimulation (dTMS)

Conditions
-----------------
Major Depressive Disorder, Alzheimer Disease, Mild Cognitive Impairment

Intervention / Treatment
-----------------
* Device: Brainsway H1-Coil Deep TMS System


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: meet DSM 5 criteria for Major or Mild Neurocognitive Disorder due to Alzheimer's disease with Clinical Dementia Rating Scale (CDR) score of at least 0.5 have been diagnosed with DSM5 Major Depressive Disorder, with the current episode longer than 4 weeks but less than 5 years did not respond to or did not tolerate antidepressant treatment are willing to provide informed consent are able to follow the treatment schedule are stable on medications for 2 months and are not expected to change medication during the entire study period (if they are taking medications) have a satisfactory safety screening questionnaire for TMS have an informant/study partner who is able to complete study questionnaires regarding the participant Exclusion Criteria: have a metal plate in their head, except in the mouth (such as an ear implant, implanted brain stimulators, aneurysm clips) have known increased pressure or a history of increased pressure in their brain, which may increase their risk for having seizures have a cardiac pacemaker have an implanted medication pump have a central venous line have a significant heart disease or history of stroke Modified Hachinski Score (MHIS) > 3 (to exclude those with significant vascular component to memory loss) have a history of any psychotic disorder, bipolar disorder, eating disorder, obsessive compulsive disorder, post-traumatic stress disorder, or dementia other than AD have a history of substance abuse in the last 6 months have a history of stroke or other brain lesions have a personal history of epilepsy have a family history of epilepsy are a pregnant or breast-feeding woman are taking psychotropic medications including antidepressant medications, antipsychotics or mood stabilizing medications due to increased risk of seizure are taking memantine have a history of abnormal MRI of the brain have significant hearing loss requiring use of hearing aids have untreated hypo- or hyper-thyroidism

Ages Eligible for Study
-----------------
Minimum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active H1 Coil deep rTMS active treatment<br> | Device: Brainsway H1-Coil Deep TMS System<br>* Deep Transcranial Magnetic Stimulation (dTMS) is a new form of TMS which allows direct stimulation of deeper neuronal pathways than the standard TMS. The H-coil is a novel dTMS coil designed to allow deeper brain stimulation without a significant increase of electric fields induced in superficial cortical regions. dTMS will be administered daily for 4 consecutive weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline on the Montgomery-Asberg Depression Rating Scale (MADRS) | Therapeutic efficacy will be evaluated with the MADRS, a 10-item checklist. An effect size (Cohen's d) of 0.5 will be considered a minimally important effect size. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission Rates Compared Within Treatment Group | Remission defined as MADRS < 10. | 4 weeks | 
| Response Rates Compared Within Treatment Group | Response rate refers to the percentage of patients who responded to dTMS treatment and response is defined as a ≥50% reduction in MADRS score from baseline. | 4 weeks | 
| Change From Baseline on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) | This 16-item questionnaire is designed to help assess the degree of enjoyment and satisfaction experienced during the past week. Administration time is approximately 5 minutes. | 4 weeks | 
| Change From Baseline on the Neuropsychological Battery | Cognitive scores from the neuropsychological battery at baseline will be compared to 4 weeks post-intervention Cognitive domains tested include executive function, memory, language, attention, and intelligence. | 4 weeks | 
| Change in Functional Connectivity between PFC and Limbic Regions | Subjects will have magnetic resonance imaging (MRI) scans of the brain. The change in functional connectivity between PFC and limbic regions, and within the default mode network, at rest is measured using resting state fMRI. | 4 weeks | 
| Change in Perfusion within Prefrontal Cortex (PFC) and Posterior Cingulate Cortex (PCC) | Measured using Arterial Spin Labeling (ASL) fMRI scan. | 4 weeks | 
| Change in frontal theta power within the Anterior Cingulate Cortex (ACC) | Measured with electroencephalography (EEG) and/or magnetoencephalography (MEG). | 4 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
dTMS, depression, magnetic, iTBS