Brain Imaging of rTMS Treatment for Depression

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01829165
• Collaborator: The Dana Foundation (Other), National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 85
• Location: 1
• Arms: 2
• Duration (Months): 52.6
• Patients Per Site Per Month: 1.6

Study Details

Study Description

Brief Summary

The overarching goal of this research program is to elucidate causal and directional neural network- level abnormalities in depression, and how they are modulated by an individually-tailored, circuit-directed intervention. By using concurrent TMS and fMRI, the investigators can overcome a major limitation of neuroimaging - the inability to demonstrate causality. The investigators' findings will serve as a platform for future studies wherein TMS treatment can be directly guided by the investigators' ability to image and causally manipulate specific neural networks.

Aim 1: To examine causal interactions between two major brain networks in depression.

Aim 2: To examine the impact of antidepressant TMS on causal network abnormalities in depression.

Hypothesis 1: Depressed subjects will show blunted responses, compared to healthy controls, in two targeted and interacting networks, using concurrent transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI).

Hypothesis 2: Treatment of patients with high-frequency repetitive TMS (rTMS) will result in normalization of baseline network-level deficits, and be predicted by degree of baseline network abnormalities.

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

Detailed Description

This study has a single primary outcome measure and other measures are exploratory. Previous versions of this study record incorrectly listed some exploratory outcome measures as secondary.

Study Design

• Study Type: Interventional
• Actual Enrollment: 85 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: A Causal Neural Network-level Understanding of Depression and Its Treatment Through Concurrent TMS and fMRI
• Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Jan 20, 2017
• Actual Study Completion Date: Jan 20, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: rTMS Treatment rTMS will be delivered for 20 sessions over 4 weeks. Active 10 Hz rTMS will be delivered using neuro-navigation based on participants' own fMRI images. Daily treatment regiments will last 36.5 minutes and rTMS will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the rTMS sessions for adverse events and/or side effects.	Device: rTMS Treatment; MRI-compatible TMS stimulator; Other Names: Magstim Stimulator Magventure Stimulator
Sham Comparator: Sham Treatment rTMS will be delivered for 20 sessions over 4 weeks. Placebo 10Hz rTMS will be delivered through sham stimulation electrodes. The rTMS coil will be positioned using neuro-navigation based on participants' own fMRI images, mimicking active rTMS treatment. Daily treatment regiments will last 36.5minutes and sham rTMS will be delivered at 120% of the participant's motor threshold. Participants will be monitored during the rTMS sham sessions for adverse events and/or side effects. Upon completing the sham 20 sessions participants are unblinded and offered 20 further treatments of guaranteed open-label treatment. The open-label treatment would follow the active rTMS treatment protocol.	Device: Sham rTMS Treatment

Outcome Measures

Primary Outcome Measures

1. Clinician Administered HAM-D [Baseline; Day 10; Day 20]

   The Hamilton Depression Rating Scale (HAM-D) is a 24-item clinician-administered assessment utilized as a way of determining a patient's level of depression before, during, and after treatment. It takes approximately 15-20 minutes to complete the interview and score the results. Subscale scores are 0-2 (10 questions), 0-3 (2 questions), and 0-4 (12 questions). Subscales are totaled for an overall score (range 0 -76). For the overall score and all subscales, lower scores correspond to fewer symptoms, and higher scores correspond more symptoms.

Other Outcome Measures

1. fMRI/TMS Assessed Neural Network Connectivity [Up to 3 months.]

   From pre- to post-treatment, improvement will be based on enhanced functional connectivity.

2. Implicit Emotion Regulation [Up to 3 months]

   Implicit emotion regulation assessed through emotion conflict task performed during functional imaging. Performance based on reaction time and recruitment of emotion regulation regions during the task.

3. fMRI-assessed Resting Connectivity [Up to 3 months.]

   From pre- to post-treatment of patients with high-frequency repetitive TMS (rTMS) improvement shall be measured by normalization of baseline network-level deficits.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Men and women, ages 18 to 50

• Depression assessed through phone screen

• Must comprehend English well to ensure adequate comprehension of the fMRI and TMS instructions, and of clinical scales

• Has failed >1 previous adequate antidepressant medication trials

• Right-handed

• No current or history of neurological disorders

• No seizure disorder or risk of seizures

Exclusion Criteria:

• Any contraindication to being scanned in the 3T scanners at the Lucas Center or CNI such as having a pacemaker or implanted device that has not been cleared for scanning at the Lucas Center or CNI

• Any unstable medical condition, any significant CNS neurological condition such as stroke, seizure, tumor, hemorrhage, multiple sclerosis, etc

• Current rTMS treatment or prior treatment failure with rTMS

• Current electroconvulsive therapy (ECT) or prior treatment failure with ECT

• Currently pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University	Palo Alto	California	United States	94304

Sponsors and Collaborators

• Stanford University
• The Dana Foundation
• National Institute of Mental Health (NIMH)

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 17, 2018

More Information

Publications

None provided.

• Responsible Party: Amit Etkin, Principal Investigator, Stanford University
• ClinicalTrials.gov Identifier: NCT01829165
• Other Study ID Numbers: 21206; P30MH089888-01
• First Posted: Apr 11, 2013
• Last Update Posted: Apr 10, 2018
• Last Verified: Mar 1, 2018

• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major

Study Results

Participant Flow

Pre-assignment Detail	85 participants were enrolled and 33 were randomized.

Arm/Group Title	rTMS Treatment	Sham Treatment
Arm/Group Description	Rapid transcranial magnetic stimulation (rTMS) was to be delivered for 20 sessions over 4 weeks. Active 10 Hz rTMS was delivered using neuro-navigation based on participants' own functional magnetic resonance imaging (fMRI) images. Daily treatment regiments were to last 36.5 minutes and rTMS was delivered at 120% of the participant's motor threshold. Participants were monitored during the rTMS sessions for adverse events and/or side effects. rTMS Treatment: MRI-compatible TMS stimulator	Sham rTMS was to be delivered for 20 sessions over 4 weeks. Placebo 10Hz rTMS was delivered through sham stimulation electrodes. The rTMS coil was positioned using neuro-navigation based on participants' own fMRI images, mimicking active rTMS treatment. Daily treatment regiments were to 36.5minutes and sham rTMS was delivered at 120% of the participant's motor threshold. Participants were monitored during the rTMS sham sessions for adverse events and/or side effects. Upon completing the sham 20 sessions participants are unblinded and offered 20 further treatments of guaranteed open-label treatment. The open-label treatment would follow the active rTMS treatment protocol. rTMS Treatment: MRI-compatible TMS stimulator
Period Title: Overall Study
STARTED	20	13
COMPLETED	18	13
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	rTMS Treatment	Sham Treatment	Total
Arm/Group Description	rTMS was to be delivered for 20 sessions over 4 weeks. Active 10 Hz rTMS was delivered using neuro-navigation based on participants' own fMRI images. Daily treatment regiments were to last 36.5 minutes and rTMS was delivered at 120% of the participant's motor threshold. Participants were monitored during the rTMS sessions for adverse events and/or side effects. rTMS Treatment: MRI-compatible TMS stimulator	Sham rTMS was to be delivered for 20 sessions over 4 weeks. Placebo 10Hz rTMS was delivered through sham stimulation electrodes. The rTMS coil was positioned using neuro-navigation based on participants' own fMRI images, mimicking active rTMS treatment. Daily treatment regiments were to 36.5minutes and sham rTMS was delivered at 120% of the participant's motor threshold. Participants were monitored during the rTMS sham sessions for adverse events and/or side effects. Upon completing the sham 20 sessions participants are unblinded and offered 20 further treatments of guaranteed open-label treatment. The open-label treatment would follow the active rTMS treatment protocol. rTMS Treatment: MRI-compatible TMS stimulator	Total of all reporting groups
Overall Participants	20	13	33
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	20 100%	13 100%	33 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.2 (11.2)	35.0 (6.5)	36.2 (8.9)
Sex: Female, Male (Count of Participants)
Female	11 55%	9 69.2%	20 60.6%
Male	9 45%	4 30.8%	13 39.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	5 25%	3 23.1%	8 24.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 5%	0 0%	1 3%
White	14 70%	9 69.2%	23 69.7%
More than one race	0 0%	1 7.7%	1 3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Hamilton Depression Rating Scale (HAM-D 24) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	27.0 (8.0)	26.2 (5.9)	26.9 (7.1)

Outcome Measures

1. Primary Outcome

Title	Clinician Administered HAM-D
Description	The Hamilton Depression Rating Scale (HAM-D) is a 24-item clinician-administered assessment utilized as a way of determining a patient's level of depression before, during, and after treatment. It takes approximately 15-20 minutes to complete the interview and score the results. Subscale scores are 0-2 (10 questions), 0-3 (2 questions), and 0-4 (12 questions). Subscales are totaled for an overall score (range 0 -76). For the overall score and all subscales, lower scores correspond to fewer symptoms, and higher scores correspond more symptoms.
Time Frame	Baseline; Day 10; Day 20

Outcome Measure Data

Analysis Population Description

Randomized and treated

Arm/Group Title	rTMS Treatment	Sham Treatment
Arm/Group Description	rTMS was to be delivered for 20 sessions over 4 weeks. Active 10 Hz rTMS was delivered using neuro-navigation based on participants' own fMRI images. Daily treatment regiments were to last 36.5 minutes and rTMS was delivered at 120% of the participant's motor threshold. Participants were monitored during the rTMS sessions for adverse events and/or side effects. rTMS Treatment: MRI-compatible TMS stimulator	Sham rTMS was to be delivered for 20 sessions over 4 weeks. Placebo 10Hz rTMS was delivered through sham stimulation electrodes. The rTMS coil was positioned using neuro-navigation based on participants' own fMRI images, mimicking active rTMS treatment. Daily treatment regiments were to 36.5minutes and sham rTMS was delivered at 120% of the participant's motor threshold. Participants were monitored during the rTMS sham sessions for adverse events and/or side effects. Upon completing the sham 20 sessions participants are unblinded and offered 20 further treatments of guaranteed open-label treatment. The open-label treatment would follow the active rTMS treatment protocol. rTMS Treatment: MRI-compatible TMS stimulator
Measure Participants	20	13
Baseline	27.0 (8.0)	26.2 (5.9)
Day 10	22.0 (9.3)	22.7 (6.9)
Day 20	17.9 (9.9)	17.6 (9.8)

2. Other Pre-specified Outcome

Title	fMRI/TMS Assessed Neural Network Connectivity
Description	From pre- to post-treatment, improvement will be based on enhanced functional connectivity.
Time Frame	Up to 3 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Other Pre-specified Outcome

Title	Implicit Emotion Regulation
Description	Implicit emotion regulation assessed through emotion conflict task performed during functional imaging. Performance based on reaction time and recruitment of emotion regulation regions during the task.
Time Frame	Up to 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	fMRI-assessed Resting Connectivity
Description	From pre- to post-treatment of patients with high-frequency repetitive TMS (rTMS) improvement shall be measured by normalization of baseline network-level deficits.
Time Frame	Up to 3 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 9 months
Adverse Event Reporting Description	Randomized and treated population
Arm/Group Title	rTMS Treatment		Sham Treatment
Arm/Group Description	rTMS was to be delivered for 20 sessions over 4 weeks. Active 10 Hz rTMS was delivered using neuro-navigation based on participants' own fMRI images. Daily treatment regiments were to last 36.5 minutes and rTMS was delivered at 120% of the participant's motor threshold. Participants were monitored during the rTMS sessions for adverse events and/or side effects. rTMS Treatment: MRI-compatible TMS stimulator		Sham rTMS was to be delivered for 20 sessions over 4 weeks. Placebo 10Hz rTMS was delivered through sham stimulation electrodes. The rTMS coil was positioned using neuro-navigation based on participants' own fMRI images, mimicking active rTMS treatment. Daily treatment regiments were to 36.5minutes and sham rTMS was delivered at 120% of the participant's motor threshold. Participants were monitored during the rTMS sham sessions for adverse events and/or side effects. Upon completing the sham 20 sessions participants are unblinded and offered 20 further treatments of guaranteed open-label treatment. The open-label treatment would follow the active rTMS treatment protocol. rTMS Treatment: MRI-compatible TMS stimulator
All Cause Mortality
	rTMS Treatment		Sham Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/13 (0%)
Serious Adverse Events
	rTMS Treatment		Sham Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	rTMS Treatment		Sham Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		1/13 (7.7%)
General disorders
Abdominal Cramping Pain	0/20 (0%)		1/13 (7.7%)
Nervous system disorders
Startled by rTMS device	1/20 (5%)		0/13 (0%)
Vascular disorders
Hypotension	0/20 (0%)		1/13 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.