Accelerated TMS to a Novel Brain Target in MDD and PTSD

Sponsor

University of Pennsylvania (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03114891

Collaborator

Cures Within Reach (Other)

Enrollment

Location

Arms

55.4

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

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	N/A

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.

Study Design

Study Type:

Interventional

Actual 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.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 :

Apr 20, 2017

Anticipated Primary Completion Date :

Dec 1, 2021

Anticipated Study Completion Date :

Dec 1, 2021

Arms and Interventions

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.

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

Outcome Measures

Primary Outcome Measures

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

Correlation between resting-state connectivity and degree of clinical change [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

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