Neural Circuit Biomarkers of Transcranial Magnetic Stimulation Study

• ClinicalTrials.gov Identifier: NCT04663841
• Recruitment Status: Recruiting
• First Posted: December 11, 2020
• Last Update Posted: December 11, 2020
• Sponsor: Stanford University
• Collaborators: VA Palo Alto Health Care System; Florida State University; University of South Florida; Medical University of South Carolina; University of Minnesota; Minneapolis Veterans Affairs Medical Center; Brown University; Providence VA Medical Center; Dartmouth College; Dartmouth-Hitchcock Medical Center; White River Junction VA Medical Center
• Information provided by (Responsible Party): Leanne Williams, Stanford University

Study Description

Brief Summary:

The objective of this observational study is to test whether neuroimaging biomarkers of repetitive transcranial magnetic stimulation (TMS) can be prospectively replicated in a large ecologically valid sample. We focus on cognitive network connectivity as a predictive biomarker of the clinical effect of TMS, and as a response biomarker of change with TMS. We address this objective through a pragmatic approach in which we recruit patients undergoing routine clinical care and program evaluation in a Veterans Administration multi-site clinical TMS program.

Condition or disease	Intervention/treatment
Depression	Other: transcranial magnetic stimulation

Detailed Description:

Although repetitive transcranial magnetic stimulation (TMS) is becoming a gold standard treatment for pharmacoresistant depression, we lack neural target biomarkers for identifying who is most likely to respond to TMS and why. To address this gap in knowledge this observational study evaluates neural targets defined by activation and functional connectivity of the dorsolateral prefrontal cortex-anchored cognitive control circuit, regions of the default mode network and attention circuit, and interactions with the subgenual anterior cingulate.

The study evaluates whether these targets and interactions between them change in a dose-dependent manner, whether changes in these neural targets correspond to changes in cognitive behavioral performance, and whether baseline and early change in neural target and cognitive behavioral performance predict subsequent symptom severity, suicidality, and quality of life outcomes.

This study is designed as a pragmatic, mechanistic observational trial partnering with the National Clinical TMS Program of the Veteran's Health Administration.

All veterans will receive a clinical course of TMS as part of their routine care. Those who agree to enrollment in the observational study will be assessed at 'baseline' prior to commencement of their TMS treatment, 'first week' after initiation of TMS (targeting five sessions) and 'post-treatment' at the completion of TMS (targeting 30 sessions).

Veterans will be assessed using functional magnetic resonance imaging (fMRI), a cognitive behavioral performance battery, and established questionnaires.

To our knowledge, our study will be the first pragmatic, mechanistic observational trial to use fMRI imaging and cognitive-behavioral performance as biomarkers of TMS treatment response in pharmacoresistant MDD.

Study Design

• Study Type: Observational
• Estimated Enrollment: 100 participants
• Observational Model: Case-Only
• Time Perspective: Other
• Official Title: Mechanistic Circuit Markers of Transcranial Magnetic Stimulation Outcomes in Pharmacoresistant Depression
• Actual Study Start Date: November 2, 2020
• Estimated Primary Completion Date: December 31, 2025
• Estimated Study Completion Date: December 31, 2026

Groups and Cohorts

Intervention Details:

• Other: transcranial magnetic stimulation
  transcranial magnetic stimulation is delivered as part of routine care and is not managed by this observational study
  Other Name: TMS; repetitive transcranial magnetic stimulation

Outcome Measures

Primary Outcome Measures :

1. Go-NoGo elicited neural circuit function [ Time Frame: Baseline ]
   Activation and connectivity assessed using functional magnetic resonance imaging during a GoNoGo task
2. Go-NoGo elicited neural circuit function [ Time Frame: Up to 2 weeks ]
   Activation and connectivity assessed using functional magnetic resonance imaging during a GoNoGo task
3. Go-NoGo elicited neural circuit function [ Time Frame: Up to 8 weeks ]
   Activation and connectivity assessed using functional magnetic resonance imaging during a GoNoGo task
4. N-Back elicited neural circuit function [ Time Frame: Baseline ]
   Activation and connectivity assessed using functional magnetic resonance imaging during an N-Back task
5. N-Back elicited neural circuit function [ Time Frame: Up to 2 weeks ]
   Activation and connectivity assessed using functional magnetic resonance imaging during an N-Back task
6. N-Back elicited neural circuit function [ Time Frame: Up to 8 weeks ]
   Activation and connectivity assessed using functional magnetic resonance imaging during an N-Back task
7. Resting state neural circuit function [ Time Frame: Baseline ]
   connectivity assessed using functional magnetic resonance imaging during a resting condition
8. Resting state neural circuit function [ Time Frame: Up to 2 weeks ]
   connectivity assessed using functional magnetic resonance imaging during a resting condition
9. Resting state neural circuit function [ Time Frame: Up to 8 weeks ]
   connectivity assessed using functional magnetic resonance imaging during a resting condition

Secondary Outcome Measures :

1. Symbol Digit Coding Test [ Time Frame: Baseline ]
   Cognitive-Behavioral Performance accuracy on the Symbol Digit Coding Test
2. Symbol Digit Coding Test [ Time Frame: Up to 2 weeks ]
   Cognitive-Behavioral Performance accuracy on the Symbol Digit Coding Test
3. Symbol Digit Coding Test [ Time Frame: Up to 8 weeks ]
   Cognitive-Behavioral Performance accuracy on the Symbol Digit Coding Test
4. Stroop Test [ Time Frame: Baseline ]
   Cognitive-Behavioral Performance accuracy and reaction time on the Stroop Test
5. Stroop Test [ Time Frame: Up to 2 weeks ]
   Cognitive-Behavioral Performance accuracy and reaction time on the Stroop Test
6. Stroop Test [ Time Frame: Up to 8 weeks ]
   Cognitive-Behavioral Performance accuracy and reaction time on the Stroop Test
7. Shifting Attention Test [ Time Frame: Baseline ]
   Cognitive-Behavioral Performance accuracy and reaction time on the Shifting Attention Test
8. Shifting Attention Test [ Time Frame: Up to 2 weeks ]
   Cognitive-Behavioral Performance accuracy and reaction time on the Shifting Attention Test
9. Shifting Attention Test [ Time Frame: Up to 8 weeks ]
   Cognitive-Behavioral Performance accuracy and reaction time on the Shifting Attention Test
10. Continuous Performance Test [ Time Frame: Baseline ]
    Cognitive-Behavioral Performance accuracy and reaction time on the Continuous Performance Test platform
11. Continuous Performance Test [ Time Frame: Up to 2 weeks ]
    Cognitive-Behavioral Performance accuracy and reaction time on the Continuous Performance Test platform
12. Continuous Performance Test [ Time Frame: Up to 8 weeks ]
    Cognitive-Behavioral Performance accuracy and reaction time on the Continuous Performance Test platform
13. Depressive Symptoms [ Time Frame: Baseline ]
    Clinical outcome assessed using the Quick Inventory of Depressive Symptoms (QIDS)- Self Report Form. The total score ranges from 0 to 27 with higher scores indicating greater severity.
14. Depressive Symptoms [ Time Frame: Up to 2 weeks ]
    Clinical outcome assessed using the Quick Inventory of Depressive Symptoms (QIDS)- Self Report Form. The total score ranges from 0 to 27 with higher scores indicating greater severity.
15. Depressive Symptoms [ Time Frame: Up to 8 weeks ]
    Clinical outcome assessed using the Quick Inventory of Depressive Symptoms (QIDS)- Self Report Form. The total score ranges from 0 to 27 with higher scores indicating greater severity.
16. Daily function related to quality of life [ Time Frame: Baseline ]
    Clinical outcome assessed using the Veterans' RAND 36-item Health Survey (VR-36). All questions are scored on a scale from 0 to 100, with 100 representing the highest level of functioning possible.
17. Daily function related to quality of life [ Time Frame: Up to 2 weeks ]
    Clinical outcome assessed using the Veterans' RAND 36-item Health Survey (VR-36). All questions are scored on a scale from 0 to 100, with 100 representing the highest level of functioning possible.
18. Daily function related to quality of life [ Time Frame: Up to 8 weeks ]
    Clinical outcome assessed using the Veterans' RAND 36-item Health Survey (VR-36). All questions are scored on a scale from 0 to 100, with 100 representing the highest level of functioning possible.
19. Suicidal ideation [ Time Frame: Baseline ]
    Columbia-Suicide Severity Rating Scale (C-SSRS). The total score ranges from 2 to 25, with a higher number indicating more intense ideation and greater risk.
20. Suicidal ideation [ Time Frame: Up to 2 weeks ]
    Columbia-Suicide Severity Rating Scale (C-SSRS). The total score ranges from 2 to 25, with a higher number indicating more intense ideation and greater risk.
21. Suicidal ideation [ Time Frame: Up to 8 weeks ]
    Columbia-Suicide Severity Rating Scale (C-SSRS). The total score ranges from 2 to 25, with a higher number indicating more intense ideation and greater risk.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Veterans with pharmacoresistant major depressive disorder (MDD) participating in the VA Clinical TMS Program. Given the complex nature of the veteran sample, the primary diagnosis of MDD may be comorbid with other disorders, including post-traumatic stress disorder (PTSD).

Criteria

Inclusion Criteria:

• Ages 18 years and older
• Meets Diagnostic and Statistical Manual edition 5 (DSM-5) criteria for Major Depressive Disorder (MDD) (as documented by the treating physician)
• Meet study criteria for pharmacoresistance in accordance with the Clinical transcranial magnetic stimulation (TMS) Program (i.e. failed at least one antidepressant in the current episode)
• Ability to obtain a motor threshold (MT) prior to the start of treatment
• Stable medical conditions and ability to maintain stability on current medication regimen for the duration of treatment
• Ability to participate in a daily treatment regimen
• Able to read, verbalize understanding, and voluntarily sign the Informed Consent Form prior to participating in any study-specific procedures or assessments

Exclusion Criteria:

• History of seizure disorder
• Structural or neurologic abnormalities present or in close proximity to the treatment site
• History of brain surgery
• Pacemaker or medical infusion device (unless magnetic resonance imaging compatible)
• History of traumatic brain injury within 60 days of the start of treatment
• Severe or uncontrolled alcohol or substance use disorders
• Active withdrawal from alcohol or substances
• Implanted device in the head
• Metal in the head
• Severe impediment to vision, hearing and/or hand movement, likely to interfere with ability to complete the assessments, or unable and/or unlikely to follow the study protocols
• Lifetime history of bipolar I disorder
• Inability to speak, read or understand English
• Plans to move out of the area during the study period
• Clinician and/or Investigator discretion for clinical safety or protocol adherence

Contacts and Locations

Contacts

Contact: Leanne Williams, PhD; 650-723-3579; leawillliams@stanford.edu

Contact: Laura Hack, MD, PhD; 650-655-9434; lhack@stanford.edu

Locations

United States, California

Stanford University Department of Psychiatry; Recruiting

Stanford, California, United States, 94305

Principal Investigator: Leanne M Williams, PhD

Sponsors and Collaborators

Stanford University

VA Palo Alto Health Care System

Florida State University

University of South Florida

Medical University of South Carolina

University of Minnesota

Minneapolis Veterans Affairs Medical Center

Brown University

Providence VA Medical Center

Dartmouth College

Dartmouth-Hitchcock Medical Center

White River Junction VA Medical Center

Investigators

• Principal Investigator: Leanne Williams, PhD; Stanford University

More Information

• Responsible Party: Leanne Williams, Professor, Stanford University
• ClinicalTrials.gov Identifier: NCT04663841
• Other Study ID Numbers: 52695
• First Posted: December 11, 2020
• Last Update Posted: December 11, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Leanne Williams, Stanford University:

treatment resistant depression

Additional relevant MeSH terms:

Depression; Depressive Disorder; Behavioral Symptoms; Mood Disorders; Mental Disorders