Accelerated TMS to a Novel Brain Target in MDD and PTSD

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.

Study Overview

• Status: Completed
• Conditions: Post Traumatic Stress Disorder; Major Depressive Disorder
• Intervention / Treatment: Device: Transcranial Magnetic Stimulation (TMS); Behavioral: Task; Procedure: fMRI-guided TMS target

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 Type: Interventional
• Enrollment (Actual): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: First Round: fMRI-guided Target/Video, Second Round: 6cm Target/Task; First round: This site of stimulation will be created from participants' individualized resting connectivity data. We will identify a cortical target in the left prefrontal cortex (LPFC) that influences the subgenual anterior cingulate cortex (sgACC). Two daily sessions (~10min apart) of intermittent theta-burst stimulation will be administered to this fMRI-guided target for 10 consecutive weekdays. Between the two iTBS sessions, participants will watch a relaxing nature video. Second round: After 3 weeks, participants will undergo another set of two daily iTBS sessions for 10 consecutive weekdays to their 'standard' target (6cm anterior of their hand knob). Between the two iTBS sessions, participants will complete a working memory task.	Device: Transcranial Magnetic Stimulation (TMS); Transcranial Magnetic Stimulation (TMS) is a non-invasive form of brain stimulation. TMS can influence activity in various brain regions, and it allows researchers to test or modify brain circuit communication. In this study, we used administered theta burst TMS stimulation.; Behavioral: Task; Subject completes a working memory task (Letter Nback) between the two rounds of theta burst stimulation.; Procedure: fMRI-guided TMS target; Administration of TMS to individualized targeting from the participant's fMRI scans. Our preliminary data suggest this target region is particularly effective at influencing the sgACC.
Experimental: First Round: 6cm Target/Video, Second Round: fMRI-guided Target/Task; First round: This 'standard' target will be identified by measuring 6cm anterior of the hand knob. Two daily sessions (~10min apart) of intermittent theta-burst stimulation will be administered to this to this target for 10 consecutive weekdays. Between the two iTBS sessions, participants will watch a relaxing nature video. Second round: After 3 weeks, participants will undergo another set of two daily iTBS sessions for 10 consecutive weekdays to their fMRI-guided target (cortical target influencing sgACC). Between the two iTBS sessions, participants will complete a working memory task.	Device: Transcranial Magnetic Stimulation (TMS); Transcranial Magnetic Stimulation (TMS) is a non-invasive form of brain stimulation. TMS can influence activity in various brain regions, and it allows researchers to test or modify brain circuit communication. In this study, we used administered theta burst TMS stimulation.; Behavioral: Task; Subject completes a working memory task (Letter Nback) between the two rounds of theta burst stimulation.; Procedure: fMRI-guided TMS target; Administration of TMS to individualized targeting from the participant's fMRI scans. Our preliminary data suggest this target region is particularly effective at influencing the sgACC.
Experimental: First Round: fMRI-guided Target/Task, Second Round: 6cm Target/Video; First round: This site of stimulation will be created from participants' individualized resting connectivity data. We will identify a cortical target in the left prefrontal cortex (LPFC) that influences the subgenual anterior cingulate cortex (sgACC). Two daily sessions (~10min apart) of intermittent theta-burst stimulation will be administered to this fMRI-guided target for 10 consecutive weekdays. Between the two iTBS sessions, participants will complete a working memory task. Second round: After 3 weeks, participants will undergo another set of two daily iTBS sessions for 10 consecutive weekdays to their 'standard' target (6cm anterior of their hand knob). Between the two iTBS sessions, participants will watch a relaxing nature video.	Device: Transcranial Magnetic Stimulation (TMS); Transcranial Magnetic Stimulation (TMS) is a non-invasive form of brain stimulation. TMS can influence activity in various brain regions, and it allows researchers to test or modify brain circuit communication. In this study, we used administered theta burst TMS stimulation.; Behavioral: Task; Subject completes a working memory task (Letter Nback) between the two rounds of theta burst stimulation.; Procedure: fMRI-guided TMS target; Administration of TMS to individualized targeting from the participant's fMRI scans. Our preliminary data suggest this target region is particularly effective at influencing the sgACC.
Experimental: First Round: 6cm Target/Task, Second Round: fMRI-guided Target/Task; First round: This 'standard' target will be identified by measuring 6cm anterior of the hand knob. Two daily sessions (~10min apart) of intermittent theta-burst stimulation will be administered to this to this target for 10 consecutive weekdays. Between the two iTBS sessions, participants will complete a working memory task. Second round: After 3 weeks, participants will undergo another set of two daily iTBS sessions for 10 consecutive weekdays to their fMRI-guided target (cortical target influencing sgACC). Between the two iTBS sessions, participants will watch a relaxing nature video.	Device: Transcranial Magnetic Stimulation (TMS); Transcranial Magnetic Stimulation (TMS) is a non-invasive form of brain stimulation. TMS can influence activity in various brain regions, and it allows researchers to test or modify brain circuit communication. In this study, we used administered theta burst TMS stimulation.; Behavioral: Task; Subject completes a working memory task (Letter Nback) between the two rounds of theta burst stimulation.; Procedure: fMRI-guided TMS target; Administration of TMS to individualized targeting from the participant's fMRI scans. Our preliminary data suggest this target region is particularly effective at influencing the sgACC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in Depression Severity of TMS at fMRI-guided Brain Target vs Standard Brain Target	We used the Montgomery-Asberg Depression Rating Scale (MADRS) to measure depression severity after TMS at fMRI-guided brain target vs standard brain target. The MADRS is clinician-rated and consists of 10 items; each item is rated on a 0-6 scale, resulting in a maximum total score of 60 points. Higher MADRS score indicates more severe depression. For this outcome, we calculated the change (percent decrease) from the participant's baseline MADRS score to their MADRS score after the first round of TMS (to either fMRI-guided brain target or standard brain target). If the outcome is positive, there was a reduction in the MADRS total score, or a reduction in the presence of depressive symptoms after TMS. If the change is negative, there was an increase in the MADRS total score, or an increase in the presence of depressive symptoms after TMS. Higher positive values means better outcome (or more symptom reduction).	Before and after the first round of two weeks of TMS treatment (two daily iTBS sessions over 10 consecutive weekdays)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between resting-state connectivity and degree of clinical change	Correlation between resting-state connectivity prior to TMS and the degree of clinical change in response to TMS treatment targeting this circuit	Baseline through study completion, approximately 7 weeks

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Cures Within Reach
• Investigators: Principal Investigator: Desmond Oathes, Ph.D., University of Pennsylvania

Publications and helpful links

General Publications

• Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005 Jan 20;45(2):201-6. doi: 10.1016/j.neuron.2004.12.033.
• Chen AC, Oathes DJ, Chang C, Bradley T, Zhou ZW, Williams LM, Glover GH, Deisseroth K, Etkin A. Causal interactions between fronto-parietal central executive and default-mode networks in humans. Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):19944-9. doi: 10.1073/pnas.1311772110. Epub 2013 Nov 18.

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2017
• Primary Completion (Actual): December 1, 2021
• Study Completion (Actual): December 1, 2021

Study Registration Dates

• First Submitted: April 4, 2017
• First Submitted That Met QC Criteria: April 10, 2017
• First Posted (Actual): April 14, 2017

Study Record Updates

• Last Update Posted (Estimate): May 4, 2023
• Last Update Submitted That Met QC Criteria: April 13, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: depression; post-traumatic stress; ptsd; tms
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Mood Disorders; Trauma and Stressor Related Disorders; Depressive Disorder; Disease; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Depressive Disorder, Major
• Other Study ID Numbers: 826007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No