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Accelerated TMS to a Novel Brain Target in MDD and PTSD

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ClinicalTrials.gov Identifier: NCT03114891
Recruitment Status : Recruiting
First Posted : April 14, 2017
Last Update Posted : August 12, 2019
Sponsor:
Collaborator:
Cures Within Reach
Information provided by (Responsible Party):
University of Pennsylvania

Brief Summary:
This is a Clinical Trial designed to evaluate novel transcranial magnetic stimulation (TMS) methods for treating depression/PTSD. TMS is an FDA-approved procedure for treatment-resistant depression. The use of the stimulation in this current study is considered experimental. The purpose of this research study is to compare the effects of TMS at two different brain regions. This information will help the investigators to determine which treatment strategies provide the greatest clinical benefit to patients. Results of the study will provide brain and behavior measures for future work, which may be critical to developing effective disease markers and novel treatments for psychiatric conditions.

Condition or disease Intervention/treatment Phase
Post Traumatic Stress Disorder Major Depressive Disorder Procedure: Theta-burst stimulation Not Applicable

Detailed Description:

Non-invasive transcranial magnetic stimulation (TMS) is now FDA-approved for the treatment of major depressive disorder (MDD). However, there is growing evidence that the targeting strategy for delivering TMS treatment would yield superior clinical outcomes if it were more tailored to individual neuroanatomy. The current study take this idea one step further and suggest that functional MRI guided TMS might yield an even greater leap forward in promoting optimal clinical outcomes.

The sgACC has been well established as a brain area sensitive to negative mood inductions and implicated in neural abnormalities associated with affective and stress disorders. It is therefore one of the primary targets for deep brain stimulation (DBS) treatment of MDD using surgically implanted DBS devices. Recent posthoc imaging studies of patients who have undergone TMS treatment for depression suggest that treatment outcomes tended to be better when patients were by chance stimulated in an area of lateral prefrontal cortex that had high levels of functional connectivity with sgACC. Based on this finding and on interleaved TMS/fMRI probe data, the investigators contend that targeting delivery of TMS to the brain surface non-invasively as indicated by sgACC resting functional connectivity may be especially effective in downregulating sgACC and thereby producing superior clinical outcomes.

Researchers have used TMS/fMRI to better understand causal communication among circuits typically examined with resting fMRI alone. Recent work suggests that there are specific sites that, when stimulated, influence subcortical brain areas implicated in affective disorders such as the sgACC. Previously, TMS targets were based on brain atlases mapped onto individual brain surfaces. This proposal will utilize more individualized targeting from participants' own resting connectivity data to guide stimulation that we show is especially effective in influencing downstream brain areas of interest. The investigators will focus on a target region of the lateral prefrontal cortex (LPFC) that data suggest is particularly effective at influencing the sgACC. As an alternative brain target, we will also test the efficacy of the dorsolateral prefrontal cortex as a target given its precedence in the literature as an effective stimulation site for remediating depressive symptoms. The target will be chosen based on an atlas and will adjust the target coordinates based on the inverse of a nonlinear normalization of each participant's brain to standard brain space. Thus, individual anatomical differences will be taken account with this target though without guidance from individual functional imaging data.

To increase generalizability to other disorders and to patients with comorbid anxiety and depression (the typical clinical profile), the investigators will recruit patients who are diagnosed PTSD and have symptoms of depression or those who experience trauma-induced MDD. Participants will be scanned in an MRI to get anatomical and resting fMRI data to guide TMS, then participants will be invited to participate in two rounds of two week TMS treatment to each site (order counterbalanced) with one month between treatments. Participants will be monitored to assess PTSD symptoms, depressive symptoms,and quality of life before, acutely after, and one month following TMS treatments to evaluate the effectiveness of each site in mitigating symptoms or improving functioning.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: This is a randomized study. All subjects will receive active TMS, so there is no placebo or sham condition. However, the patients will be blinded as to whether or not their site of stimulation is based on the standard targeting method or our novel fMRI-guided targeting method. TMS is administered over to one of these two sites over a two week period, and then TMS will be administered to the other site over a subsequent two-week period. All subjects will receive TMS to both sites as a part of the study, but the order is randomized and counterbalanced.
Masking: Double (Participant, Care Provider)
Masking Description: The patients will be blinded as to whether or not their site of stimulation is based on the standard targeting method or our novel fMRI-guided targeting method. In addition, staff members administering TMS will not know if the site of stimulation was created based on the standard targeting method or novel fMRI method.
Primary Purpose: Treatment
Official Title: Accelerated TMS to a Novel Brain Target in MDD and PTSD
Actual Study Start Date : April 20, 2017
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : March 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: fMRI-guided target
This site of stimulation will be created from participants' individualized resting connectivity data to guide stimulation that we show is especially effective in influencing downstream brain areas of interest. We will focus on a target region of the lateral prefrontal cortex (LPFC) that our data suggest is particularly effective at influencing the sgACC. Theta-burst stimulation will be administered to this target.
Procedure: Theta-burst stimulation
A normal, FDA-approved clinical application of TMS involves long trains of repetitive TMS applied for approximately 40 minutes, 5 days/week, over 2-6 weeks, for a total of 10-30 TMS visits. The present study utilizes the same FDA-approved devices (Magventure Cool-Coil B65, MagVenture X100 Stimulator) to administer treatment. We will be modifying the FDA-approved protocol to stimulate in a well-replicated protocol, theta-burst stimulation (Huang et al., 2005), which will result in a greatly reduced number of total pulses delivered to the subject in any given TMS session.

Active Comparator: Standard brain target
As an alternative brain target, we will also test the efficacy of the dorsolateral prefrontal cortex as a target given its precedence as an FDA-approved stimulation site for remediating depressive symptoms. Theta-burst stimulation will be administered to this target.
Procedure: Theta-burst stimulation
A normal, FDA-approved clinical application of TMS involves long trains of repetitive TMS applied for approximately 40 minutes, 5 days/week, over 2-6 weeks, for a total of 10-30 TMS visits. The present study utilizes the same FDA-approved devices (Magventure Cool-Coil B65, MagVenture X100 Stimulator) to administer treatment. We will be modifying the FDA-approved protocol to stimulate in a well-replicated protocol, theta-burst stimulation (Huang et al., 2005), which will result in a greatly reduced number of total pulses delivered to the subject in any given TMS session.




Primary Outcome Measures :
  1. Change in depression and PTS symptoms from baseline to after TMS is performed at the standard brain target for 2 weeks [ Time Frame: Baseline-After two weeks of TMS performed at the standard brain target ]
    Clinical efficacy of TMS performed at standard brain target

  2. Change in depression and PTS symptoms from baseline to after TMS is performed at the fMRI-guided brain target for 2 weeks [ Time Frame: Baseline-After two weeks of TMS performed at the fMRI-guided brain target ]
    Clinical efficacy of TMS performed at fMRI-guided brain target


Secondary Outcome Measures :
  1. Correlation between resting-state connectivity and degree of clinical change [ Time Frame: Baseline through study completion, approximately 7 weeks ]
    Correlation between resting-state connectivity prior to TMS and the degree of clinical change in response to TMS treatment targeting this circuit



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 18-60 years old, male or female, any race
  2. Patients must currently meet sufficient DSM criteria for PTSD and have symptoms of depression; or meet criteria for trauma-induced MDD
  3. Capacity to give informed consent and follow study procedures
  4. English speaking

Exclusion Criteria:

  1. Outside age range
  2. Patient does not meet sufficient DSM criteria for PTSD or MDD
  3. Psychiatric medication use
  4. Significant handicaps (e.g. mental handicap) that would interfere with testing procedures
  5. MRI contraindications
  6. Additional TMS contraindications
  7. Medication use that substantially reduces seizure threshold to TMS (olanzapine, chlorpromazine, lithium)
  8. Opiate medication
  9. Known neurological disorders including multiple sclerosis, encephalopathy, seizure disorder, brain tumors
  10. Current alcohol or substance abuse disorder (moderate or severe)
  11. Current schizophrenia or other psychotic disorder, or current bipolar disorder
  12. Refusal to abstain from illicit drug use for the duration of the study
  13. Refusal to abstain from alcohol within 24 hours of the MRI scan
  14. Pregnancy
  15. Newly initiated psychotherapy (less than 6 weeks)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03114891


Contacts
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Contact: Almaris Figueroa-Gonzalez 215-746-6751 almaris.figueroa-gonzalez@pennmedicine.upenn.edu
Contact: Hannah Long 215-746-0295 hanlong@mail.med.upenn.edu

Locations
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United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Almaris Figueroa-Gonzalez    215-746-6751    almaris.figueroa-gonzalez@pennmedicine.upenn.edu   
Contact: Hannah Long    215-573-0085    hanlong@pennmedicine.upenn.edu   
Principal Investigator: Desmond J Oathes, PhD         
Sub-Investigator: Yvette I Sheline, M.D.         
Sponsors and Collaborators
University of Pennsylvania
Cures Within Reach
Investigators
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Principal Investigator: Desmond Oathes, Ph.D. University of Pennsylvania

Publications:
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Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03114891     History of Changes
Other Study ID Numbers: 826007
First Posted: April 14, 2017    Key Record Dates
Last Update Posted: August 12, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Pennsylvania:
post-traumatic stress
depression
Additional relevant MeSH terms:
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Disease
Depressive Disorder
Depressive Disorder, Major
Stress Disorders, Traumatic
Stress Disorders, Post-Traumatic
Pathologic Processes
Mood Disorders
Mental Disorders
Trauma and Stressor Related Disorders