fMRI-neuronavigated rTMS for the Treatment of Major Depression Associated With TBI

fMRI-neuronavigated Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depression Associated With Traumatic Brain Injury

This pilot study aims to investigate the efficacy of fMRI-targeted repetitive transcranial magnetic stimulation (rTMS) in treatment of major depression associated with traumatic brain injury (TBI). Half of patients will receive active treatment, while the other will receive a sham treatment with the option of receiving open-label active treatment afterwards.

Study Overview

• Status: Terminated
• Conditions: Traumatic Brain Injury; Major Depressive Disorder
• Intervention / Treatment: Procedure: Active; Procedure: Sham

Detailed Description

rTMS is an FDA-approved treatment for major depressive disorder, but its utility has not yet been investigated for major depression associated with traumatic brain injury.

This will be a prospective double-blind randomized sham-controlled crossover study. Patients in the treatment group will receive 20 sessions of high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) and low-frequency rTMS over the right DLPFC. The DLPFC will be identified as target by using individual subject-level resting state network estimation (Hacker et al, 2013). Patients in the control group will receive 20 sham treatments designed to be visibly indistinguishable from active treatment, and will subsequently have the option to be crossed over to receive active treatment with the aforementioned protocol. A subgroup of patients in each group will receive more detailed diffusion imaging (diffusion tensor and diffusion kurtosis imaging) and resting state fMRI scans before and after the treatment in order to assess for changes in white matter integrity and functional connectivity associated with the treatment.

• Study Type: Interventional
• Enrollment (Anticipated): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

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:

• Adults age 18 to 65
• History of traumatic brain injury (TBI) at least two weeks prior to study initiation
• Presence of an active major depressive episode as defined by DSM-5 criteria, including depression secondary to traumatic brain injury
• Baseline score of 10 or greater on Montgomery-Asberg Depression Rating Scale (MADRS)
• Failure of at least one prior antidepressant trial after the traumatic brain injury

Exclusion criteria

History of:

• Moderate or severe substance use disorder in the past six months as defined by DSM-5 criteria, with the exception of cannabis and nicotine use disorders.
• Dementia, as defined by treating neurologist
• Moderate or severe autism spectrum disorder
• Bipolar disorder
• Schizophrenia spectrum disorders

Current evidence of:

• Substance-induced mood disorder
• Active psychotic symptoms
• Depression secondary to a general medical illness, with the exception of TBI
• Dysphoria better explained by a baseline personality disorder than a major depressive episode
• Dysphoria better explained by a baseline anxiety disorder (including post-traumatic stress disorder) rather than a major depressive episode
• Active suicidal ideation

Contraindications to rTMS treatment:

• Seizure disorder
• Significantly elevated seizure risk, as determined by clinician assessment
• TBI associated with elevated seizure risk, including penetrating injury and/or cortical intraparenchymal hemorrhage
• Presence of metallic objects within the head
• Presence of an implanted neurostimulation device within the head

Contraindications to MRI

• Severe claustrophobia
• Severe pain/illness exacerbated by lying prone in the scanner
• Presence of non-MRI compatible metal foreign bodies or implants
• Weight in excess of 350 lbs
• Shoulder width in excess of maximum tolerable width for scanner

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active rTMS; Subjects will receive a full course of 20 rTMS treatments over 20 consecutive weekdays as described above.	Procedure: Active; Repetitive transcranial magnetic stimulation (rTMS) will be applied to the left dorsolateral prefrontal cortex (DLPFC) (4000 pulses, 10 Hz, 5-sec trains, 25-sec inter-train interval) followed by the right DLPFC (1000 pulses, 1 Hz frequency, single train). The DLPFC will be identified using individual subject-level resting-state network estimation (Hacker et al, 2013). Each treatment will be completed over the course of 1 hour, and each subject will receive a total of 20 treatments over the course of 20 consecutive weekdays.
Sham Comparator: Sham/crossover rTMS; Rather than receiving active treatment, subjects will receive sham treatment designed to be indistinguishable from active treatment to the patient. After completion of the sham course, patients will have the option to receive open-label active treatment at no cost.	Procedure: Sham; Treatment that looks and feels similar to active rTMS will be administered as a sham treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in depressive symptoms	This will be measured as the mean percentage change in baseline scores on Montgomery-Asberg Depression Rating Scale (MADRS) before treatment and immediately after the 4-week treatment period.	Difference between pre-treatment (baseline) and post-treatment (4 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in resting-state fMRI and DTI findings	MRI imaging will be conducted to assess resting-state functional connectivity using functional magnetic resonance imaging (fMRI). More detailed structural (DTI) and functional (fMRI) imaging will be measured in a subgroup of patients.	Difference between pre-treatment (baseline) and post-treatment (4 weeks)
Changes in NIH Toolbox Cognitive, Emotional, and Quality of Life batteries	The NIH Toolbox Cognitive battery will be used to determine change in cognitive symptoms with treatment. Emotional battery and TBI-QoL scales will be used to determine change in general neuropsychiatric symptom burden.	Difference between pre-treatment (baseline) and post-treatment (4 weeks)
Changes in temperament and character	Will administer the 140-question Temperament and Character Inventory (TCI-R140) before and after treatment.	Difference between pre-treatment (baseline) and post-treatment (4 weeks)
Response and remission rates in depressive symptoms	Percentage of subjects achieving response (>50% improvement in MADRS) and remission (final MADRS score <7) before treatment and immediately after the 4-week treatment period.	Difference between pre-treatment (baseline) and post-treatment (4 weeks)
Changes in headache scales	Mean percentage improvement in HIT-6 headache scores	Difference between pre-treatment (baseline) and post-treatment (4 weeks)
Changes in tinnitus score	Mean percentage improvement in tinnitus severity score and mini-Tinnitus Questionnaire scores	Difference between pre-treatment (baseline) and post-treatment (4 weeks)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Shan H Siddiqi, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Actual): August 1, 2017
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: February 25, 2016
• First Submitted That Met QC Criteria: November 29, 2016
• First Posted (Estimate): December 2, 2016

Study Record Updates

• Last Update Posted (Actual): March 29, 2018
• Last Update Submitted That Met QC Criteria: March 26, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: rTMS
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mood Disorders; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Depressive Disorder; Brain Injuries; Brain Injuries, Traumatic; Depressive Disorder, Major
• Other Study ID Numbers: 201603051

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified neuroimaging data will be submitted to FITBIR (Federal Interagency TBI Research)