Interleaved TMS-fMRI in Ultra-treatment Resistant Depression

Sponsor

Sunnybrook Health Sciences Centre (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05813093

Collaborator

(none)

Enrollment

Arm

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This is a study that will recruit patients from the neurosurgery clinic and the regular TMS clinic. It's a smaller study designed to collect brain imaging pre-treatment and then use image guided TMS to treat patient with a one week "accelerated" rTMS protocol using the research TMS machine that is housed in Dr. Sean Nestor's lab. The idea is to examine whether severe treatment resistant depression has a different brain signature than less severe/TRD and whether we can get a therapeutic response from patients that would otherwise undergo neurosurgery or will ultimately undergo neurosurgery.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Device: rTMS	N/A

Detailed Description

The objective of this study is to assess plasticity in both whole brain connectivity and a mood/affective circuit involving the dorsolateral prefrontal cortex (DLPFC) in individuals undergoing repetitive transcranial magnetic stimulation (rTMS) for treatment of ultra-treatment resistant depression. Our second aim is to explore how these markers predict response to rTMS. The DLPFC is a brain region known to support mood regulation and has functional brain activity that is altered in depression. Past evidence from healthy controls suggests that rTMS increases coupling of the DLPFC network with another functional brain network involved in reward. Using sophisticated neuroimaging techniques that concurrently capture functional MRI while patients are being stimulated with rTMS, we will identify patterns of brain activity associated with depressed mood and measure the coupling of the DLPFC mood circuit with a reward network prior to an acute course of rTMS. Following baseline imaging, all patients will then undergo an accelerated rTMS protocol over the course of five days, using the pre-treatment imaging to localize the brain region (circuit) targeted by the TMS coil. We will also use questionnaires to assess mood and function before, during and after rTMS treatment. Two comparison groups will be included in this study: 1) patients with depression who have ultra-treatment resistant depression and have been referred for consideration of neurosurgical neuromodulation for depression, and 2) persons with milder treatment resistant depression who are referred to the Harquail Centre for rTMS treatment of depression. This research will help us better understand the mechanisms of how rTMS modulates brain activity, improve TMS targeting in depression, and identify pre-treatment imaging/EEG markers that predict response to rTMS with potentially far-reaching clinical implications.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

58 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

We propose a pilot study using state-of-the-art concurrent fMRI and EEG acquisition to identify circuits involved with mood, and to subsequently use concurrent interleaved iTBS-fMRI and neuronavigation to examine/dynamically probe, for the first time, how iTBS of the left DLPFC mediates target engagement/functional connectivity between the DLPFC-sgACC circuit and reward system in TRD versus UTRD across varying stimulation amplitude (i.e. doses). Our secondary objective is to identify subtypes of UTRD/TRD patients from pre-treatment iTBS-fMRI and concurrent EEG-fMRI connectivity patterns who demonstrate clinical improvement in depressive symptoms with a previously validated accelerated iTBS treatment protocol over 5 consecutive days [6].We propose a pilot study using state-of-the-art concurrent fMRI and EEG acquisition to identify circuits involved with mood, and to subsequently use concurrent interleaved iTBS-fMRI and neuronavigation to examine/dynamically probe, for the first time, how iTBS of the left DLPFC mediates target engagement/functional connectivity between the DLPFC-sgACC circuit and reward system in TRD versus UTRD across varying stimulation amplitude (i.e. doses). Our secondary objective is to identify subtypes of UTRD/TRD patients from pre-treatment iTBS-fMRI and concurrent EEG-fMRI connectivity patterns who demonstrate clinical improvement in depressive symptoms with a previously validated accelerated iTBS treatment protocol over 5 consecutive days [6].

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Interleaved TMS-fMRI to Evaluate Intermittent Theta-burst and Dorsolateral Prefrontal Circuit Engagement in Ultra-treatment Resistant Depression

Anticipated Study Start Date :

Jul 7, 2023

Anticipated Primary Completion Date :

Jul 7, 2025

Anticipated Study Completion Date :

Jul 7, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Accelerated iTBS treatment accelerated iTBS treatment protocol over 5 consecutive days	Device: rTMS Accelerated iTBS treatment

Arm

Intervention/Treatment

Experimental: Accelerated iTBS treatment

accelerated iTBS treatment protocol over 5 consecutive days

Device: rTMS

Accelerated iTBS treatment

Outcome Measures

Primary Outcome Measures

Imaging [3 years]
fMRI circuits involved with mood

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Age 20-65
Have a diagnosis of MDD or persistent depressive disorder and meet criteria for a major depressive episode (moderate-severe) according to the DSM 5.0 with a 17-item Hamilton Rating Scale Score in Depression (HRSD-17) of >=18
UTRD subjects will also have a duration of depressive symptoms >=5 years, treatment resistance to antidepressants will be defined by Maudsley-staging, failing >6 antidepressants (level 4) and >1 adjunctive antidepressants of adequate dose/duration, failed at >=1 psychotherapy, and no response to >=1 trial of esketamine, IV ketamine, ECT or rTMS
Milder TRD participants will have failed at least 1 antidepressant medication of adequate dose/duration and never had neuromodulation treatment

Exclusion criteria:

Contraindications to MRI
Medical/psychiatric co-morbidities that prevent participation in the study or where depression is not the primary psychiatric symptom of concern
History of psychosis, pregnancy, substance dependence within the last 6 months
Active neurological disorder
History of seizure disorder
Cognitive impairment
Unable to provide informed consent on their own
Pregnant

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Sunnybrook Health Sciences Centre

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Dr. Sean Michael Nestor, Clinician Investigator, Sunnybrook Health Sciences Centre

ClinicalTrials.gov Identifier:

NCT05813093

Other Study ID Numbers:

5408

First Posted:

Apr 14, 2023

Last Update Posted:

Apr 19, 2023

Last Verified:

Apr 1, 2023

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Additional relevant MeSH terms:

Depressive Disorder

Depressive Disorder, Major

Depressive Disorder, Treatment-Resistant

Study Results

No Results Posted as of Apr 19, 2023